Beruflich Dokumente
Kultur Dokumente
CHEMISTRY
VOLUME TWO
STEREOCHEMISTRY
L.
FINAR
LONGMANS
/.
CITY OF LEEDS
TRAINING COLLEGE
LIBRARY.
Acc
31 JUM
'Class......
1865
f4l
&
1964
L.
FINAR
I.
1958
VI
L.
FINAR
compounds
1955
Vll
L.
FINAR
CONTENTS
LIST OF
CHAPTER
I.
....
AND CHEMICAL
....
JOURNAL ABBREVIATIONS
PHYSICAL PROPERTIES
CONSTITUTION
Van
PAGE
*xii
17.
graphy,
ance,
II.
17.
17.
17.
Absorption spectra,
Neutron
13.
crystallo-
OPTICAL ISOMERISM
20
symmetry,
III.
....
NUCLEOPHILIC SUBSTITUTION AT A
60.
60
ism, 73.
IV.
GEOMETRICAL ISOMERISM
Nature of geometrical isomerism,
....
87
V.
87.
STEREOCHEMISTRY OF DIPHENYL
COMPOUNDS
Configuration of the diphenyl molecule, 126. Optical activity of
the diphenyl compounds, 127. Absolute configurations of diphenyls, 130. Other examples of restricted rotation, 130. Molecular overcrowding, 133.
Racemisation of diphenyl compounds,
135.
Evidence for the obstacle theory, 138. Stereochemistry
OF THE AlXENES, 139. STEREOCHEMISTRY OF THE SPIRANS, 140.
ix
126
CONTENTS
PAGB
CHAPTER
VI.
143
VII.
CARBOHYDRATES
176
VIII.
Polysaccharides,
TERPENES
242
IX.
CAROTENOIDS
321
X.
Vitamin A, 330.
Xantho-
339
Benz-
XL STEROIDS
358
XII.
Nomenclature, 421.
Imidazoles, 428.
XIII.
.449
XIV.
ALKALOIDS
Introduction, 484.
484
General methods
PhenylethylClassification, 488.
group, 495. Pyridine group, 497.
Quinoline group, 520. isoQuinogroup, 537. Biosynthesis of alka-
CONTENTS
XV.
XI
ANTHOCYANINS
545
Introduction, 645. General nature of anthocyanins, 545. Structure of the anthocyanidins, 546. Flavones, 557. moFlavones,
565.
Biosynthesis of flavonoids, 566. Depsides, 566.
XVI.
.569
Introduction,
569.
Uric acid, 569. Purine derivatives, 576.
Xanthine bases, 580. Biosynthesis of purines, 586. Nucleic
Acids, 587.
XVII.
VITAMINS
598
Vitamin
Introduction, 598.
619.
XVIII.
Vitamin
complex, 598.
Vitamin
group
group, 623.
CHEMOTHERAPY
627
Introduction, 627.
Arsenical drugs, 631.
Sulphonamides, 627.
Antimalarials, 630.
Antibiotics: The Penicillins, 632. Streptomycin, 637. Aureomycin and Terramycin, 638. Patulin, 639.
Chloramphenicol, 640.
XIX.
643
AUTHOR INDEX
667
SUBJECT INDEX
674
LIST OF
Abbreviations
Ann. Reports (Chem. Soc.)
Ber.
JOURNAL ABBREVIATIONS
Journals
Annual Reports of the Progress of Chemistry (The
Chemical Society, London).
Berichte der deutschen chemischen Gesellschaft (name
now changed to Chemische Berichte).
Chem. Reviews
Chemical Reviews.
Experientia
Experientia.
Amer. Chem.
J. Chem. Educ.
J.
Industrial
Soc.
J.C.S.
J.
J.
Pharm. Pharmacol.
Roy. Inst. Chem.
Nature
Nature.
Science
Science.
Tetrahedron
Tetrahedron.
Xll
CHAPTER
(ii)
(iii)
(iv)
Qualitative analysis.
Quantitative analysis, which leads to the empirical formula.
Determination of the molecular weight, which leads to the molecular
formula.
If the molecule is relatively simple, the various possible structures
are written down (based on the valency of carbon being four, that
of hydrogen one, oxygen two, etc.). Then the reactions of the
compound are studied, and the structure which best fits the facts
is chosen.
In those cases where the molecules are not relatively
simple, the compounds are examined by specific tests to ascertain
the nature of the various groups present (see, e.g., alkaloids, 4.
XIV). The compounds are also degraded and the smaller fragments examined. By this means it is possible to suggest a tentative structure.
(v)
ORGANIC CHEMISTRY
[CH.
in nature.
They
are relatively
forces),
"
London
known
as
effect,
4]
i.e., by the spatial or steric factor; e.g., w-pentanol is completely associated, whereas totf.-pentanol is only partially associated. Intermolecular hydrogen bonding is also responsible for the formation of various
molecular compounds, and also affects solubility if the compound can form
hydrogen bonds with the solvent.
Intramolecular hydrogen bonding gives rise to chelation, i.e., ring formation, and this normally occurs only with the formation of 5-, 6-, or 7-membered rings. Chelation has been used to explain the volatility of orthocompounds such as o-halogenophenols and o-nitrophenols (as compared with
the corresponding m- and ^-derivatives). Chelation has also been used to
account for various or^o-substituted benzoic acids being stronger acids than
the corresponding m- and ^-derivatives (see Vol. I, Ch. XXVIII).
When chelation occurs, the ring formed must be planar or almost planar.
the molecules,
CHjCO
CH 3 Ca
,H
In
II,
method
4. Melting point.
In most solids the atoms or molecules are in a state
of vibration about their fixed mean positions.
These vibrations are due
to the thermal energy and their amplitudes are small compared
with interatomic distances. As the temperature of the solid is raised, the amplitude
of vibration increases and a point is reached when the crystalline
structure
suddenly becomes unstable; this is the melting point.
In many homologous series the melting points of the M-members rise
continuously, tending towards a maximum value. On the other hand, some
homologous series show an alternation or oscillation of melting points
" the saw-tooth rule ", e.g., in the fatty acid series
the melting point of an
"even " acid is higher than that of the " odd " acid immediately below and
above
it.
It has been shown by X-ray analysis that this alternation of
melting points depends on the packing of the crystals. The shape of the
molecule is closely related to the melting point; the more symmetrical the
molecule, the higher is the melting point. Thus with isomers, branching of
the chain (which increases symmetry) usually raises the melting point; also
*ras-isomers usually have a higher melting point than the cis-, the former
haying greater symmetry than the latter (see 5. IV). In the benzene
series, of the three disubstituted derivatives, the ^-compound
usually has
the highest melting point.
Apart from the usual van der Waals forces which affect melting points
ORGANIC CHEMISTRY
[CH.
hydrogen bonding may also play a part, e.g., the melting point of an alcohol
is higher than that of its corresponding alkane.
This may be attributed to
hydrogen bonding, which is possible in the former but not in the latter.
Various empirical formulae have been developed from which it is possible
to calculate melting points; these formulae, however, only relate members
of an homologous series.
The method of mixed melting points has long been used to identify a
compound, and is based on the principle that two different compounds
mutually lower the melting point of each component in the mixture. This
method, however, is unreliable when the two compounds form a solid
solution.
is
increased.
In an homologous
the w-members,
e.g.,
series,
Kopp
arise
e.g.,
alkanes
8]
and alkyl halides are miscible; the cohesion forces of both of these groups
of compounds are largely due to dispersion forces.
In some cases solubility may be due, at least partly, to the formation of
a compound between the solute and the solvent, e.g., ether dissolves in
concentrated sulphuric acid with the formation of an oxonium salt,
(CHJ,OH}+HS04 -
shape and
sponding as-isomer.
Equations have been developed relating viscosity to the shape and size
of large molecules (macromolecules) in solution, and so viscosity measurements have offered a means of determining the shape of, e.g., proteins, and
the molecular weight of, e.g., polysaccharides.
8.
litres
The
of a liquid in milli-
density
11-0
5-5
12-2
7-8
H
O (0=0)
0(0H)
22-8
27-8
37-5
CI
Br
I
should be noted that Kopp found that the atomic volume of oxygen
(and sulphur) depended on its state of combination. Kopp also showed
that the molecular volume of a compound can be calculated from the sum
of the atomic volumes, e.g., acetone, CH 3 'COCH 3
It
3C
6H
O(CO)
= 33-0
= 33-0
= 12-2
78-2
[cole.)
,
molecular volume
(obs.)
V
;
= 58
= 0-749
58
tt-^tk
= 77-4
0-749
ORGANIC CHEMISTRY
[CH.
Further work has shown that the molecular volume is not strictly addibut also partly constitutive (as recognised by Kopp who, however,
tended to overlook this feature). If purely additive, then isomers with
similar structures will have the same molecular volume. This has been
found to be the case for, e.g., isomeric esters, but when the isomers belong
to different homologous series, the agreement may be poor.
Later tables have been compiled for atomic volumes with structural corrections.
Even so, the relation breaks down in the case of highly polar
liquids where the attractive forces between the molecules are so great that
the additive (and structural) properties of the atomic volumes are completely masked.
tive,
9.
Parachor.
= C(* - d y
a
where y is the surface tension, dt and dg the densities of the liquid and
vapour respectively, and C is a constant which is independent of the
temperature.
Macleod's equation can be rewritten as:
r*
dl
c*
dg
by the molecular
should also be valid. Sugden called the constant P for a given compound
the parachor of that compound. Provided the temperature is not too high,
dg will be negligible compared with di, and so we have
The parachor is largely an additive property, but it is also partly constiThe following table of atomic and structural parachors is that
given by Mumford and Phillips (1929).
tutive.
9-2
15-4
Single
bond
Co-ordinate bond
20
Double bond
19
17-5
Triple
38
CI
55
69
90
50
bond
3-Membered
Br
I
ring 12-5
-4
6
0-8
^-benzoquinone.
4567-
e.g.,
11]
9-2
+4
[6
+4
X
15-4
15-4
+2
x 20
+4
19
+ 0-8]
+ 2X20 + 3X19 + 2X
0-8]
I.
II
-[P] log
1)
The authors have found that the observed refrachor of any compound is
composed of two constants, one dependent on the nature of the atoms,
and the other on structural factors, e.g., type of bond, size of ring, etc.,
i.e., the refrachor is partly additive and partly constitutive.
Joshi and
Tuli have used the refrachor to determine the percentage of tautomers in
equilibrium mixtures, e.g., they found that ethyl acetoacetate contains
7-7 per cent, enol, and penta-2 4-dione 72-4 per cent. enol.
:
11. Refractive
index.
and Lorenz
Lorentz
(1880)
simultaneously
showed that
wa
where
is
cular weight,
2-413
CI
1092
Br
O(OH)
1-522
2-189
1-639
O(CO)
O(ethers)
5-933
8-803
13-757
1-686
2-328
Molecular refractivities have been used to determine the structure of compounds, e.g., terpenes (see 25. VIII). They have also been used to detect the
presence of tautomers and to calculate the amount of each form present. Let
us consider ethyl acetoacetate as an example; this behaves as the keto form
CH 3COCH 2-C0 2C2 B and as the enol form CH sC(OH)=CH'C0 2C2 5
ORGANIC CHEMISTRY
The
[CH.
CH 3 CO-CH
6
10
2
(CO)
(ether)
-C0 2 C 2 H6
=
=
=
=
14-478
10-92
4-378
1-639
31-415
CH3 -C(OH)=:CH-C0 C H5
6 C
= 14-478
10 H
= 10-92
2
=
=
(ether) =
Double bond =
(OH)
(CO)
1-522
2-189
1-639
1-686
32-434
this has
has been found that the amount of the rotation depends, for a given
number of factors:
The amount of the rotation is
thickness of the layer traversed.
directly proportional to the length of the active substance traversed (Biot,
substance, on a
(i)
The
1835).
12]
[I
where
This
nrs
is
or
H! =
ccx
I
;
is
is
fal X
L Ja
100
between structure and optical activity is discussed later
(see 2, 3. II).
The property of optical activity has been used in the study
of the configuration of molecules and. mechanisms of various reactions, and
also to decide between alternative structures for a given compound.
The
use of optical rotations in the determination of structure depends largely
on the application of two rules.
(i) Rule of Optical Superposition (van't Hoff, 1894)
When a compound
contains two or more asymmetric centres, the total rotatory power of the
molecules is the algebraic sum of the contributions of each asymmetric
centre.
This rule is based on the assumption that the contribution of each
asymmetric centre is independent of the other asymmetric centres present.
It has been found, however, that the contribution of a given asymmetric
The
relation
centre is affected by neighbouring centres and also by the presence of chainbranching and unsaturation. Hence the rule, although useful, must be
treated with reserve (see also 6. VII).
A more satisfactory rule is the Rule of Shift (Freudenberg, 1933): If two
asymmetric molecules A and B are changed in the same way to give A'
and B', then the differences in molecular rotation (A'
A) and (B'
B)
are of the same sign (see, e.g., 4b. XI).
ORGANIC CHEMISTRY
10
[CH.
number
of troughs.
Plain curves.
more
These show no
maximum or minimum,
i.e.,
curves,
and may be
$
300 ny<
700 m//
300 m/<
700mft
(a)
(*)
Fig. 1.1.
mum
13]
11
(see Index).
and
bond moment
results.
Hybridisation of orbitals produces asymmetric atomic orbitals; consequently the centres of gravity of the hybridised orbitals are no longer at
the parent nuclei. Only if the orbitals are pure s, p or d, are the centres of
gravity at the parent nuclei. Thus hybridised orbitals produce a bond
(iii)
moment.
(iv) Lone-pair electrons (e.g., on the oxygen atom in water) are not
" pure " s electrons; they are " impure " because of hybridisation with
p
electrons.
If lone-pair electrons were not hybridised, their centre of gravity
would be at the nucleus; hybridisation, however, displaces the centre of
gravity from the nucleus and so the asymmetric orbital produced gives rise
to a bond moment which may be so large as to outweigh the contributions
of the other factors to the dipole moment.
The following points are useful in organic chemistry:
(i) In the bond
Z, where Z is any atom other than hydrogen or carbon,
is
Z, where Z
atom
is
i.e.,
(Coulson, 1942).
ORGANIC CHEMISTRY
12
[CH. I
(iii) When a molecule contains two or more polar bonds, the resultant
dipole moment of the molecule is obtained by the vectorial addition of the
constituent bond dipole moments.
symmetrical molecule will thus be
non-polar, although it may contain polar bonds, e.g., CC1 4 has a zero dipole
moment although each C CI bond is strongly polar.
Since dipole moments are vector quantities, the sum of two equal and
opposite group moments will be zero only if the two vectors are collinear or
parallel.
When the group moment is directed along the axis of the bond
formed by the " key " atom of the group and the carbon atom to which it
is joined, then that group is said to have a linear moment.
Such groups
On the other hand, groups which have
are H, halogen, Me, CN,
2 etc.
This problem of linear
non-linear moments are OH, OR, C0 2 H,
a etc.
or non-linear group moments has a very important bearing on the use of
dipole data in, e.g., elucidating configurations of geometrical isomers (see
5. IV), orientation in benzene derivatives (see Vol. I).
When any molecule (polar or non-polar) is placed in an electric field, the
electrons are displaced from their normal positions (towards the positive
pole of the external field). The positive nuclei are also displaced (towards
the negative pole of the external field), but their displacement is much less
than that of the electrons because of their relatively large masses. These
displacements give rise to an induced dipole, and this exists only while the
external electric field is present. The value of the induced dipole depends
on the strength of the external field and on the polarisability of the molecule,
i.e., the ease with which the charged centres are displaced by the external
If P is the total dipole moment, P^ the permanent dipole moment,
field.
and Pa the induced dipole moment, then
N0
NH
= P + Pa
decreases as the temperature rises, but Pa is independent of the temperaThe value of P in solution depends on the nature of the solvent and
on the concentration.
By means of dipole moment measurements, it has been possible to get a
great deal of information about molecules, e.g.,
(i) Configurations of molecules have been ascertained, e.g., water has a
dipole moment and hence the molecule cannot be linear.
In a similar way
it has been shown that ammonia and phosphorus trichloride are not flat
molecules.
(ii) Orientations in benzene derivatives have been examined by dipole
moments (see Vol. I). At the same time, this method has shown that the
"Pf,
ture.
have
(vi) The existence of dipole moments gives rise to association, the formation of molecular complexes, etc.
inducing
it,
k, is
given by
15]
The magnetic
induction, B, is given
by
B=H
Since
The quantity
+ 4ttI
= H(l + 4n K
*H,
13
-f-
Paramagnetic:
in this group
[i is
and k
is
there-
fore positive.
(ii) Diamagnetic: in this group
fi is less than unity and k is therefore
negative.
All compounds are either paramagnetic or diamagnetic.
Paramagnetic
substances possess a permanent magnetic moment and consequently orient
themselves along the external magnetic field. Diamagnetic substances do
not possess a permanent magnetic moment, and tend to orient themselves
at right angles to the external magnetic field.
Electrons, because of their spin, possess magnetic dipoles. When electrons
are paired {i.e., their spins are anti-parallel), then the magnetic field is
cancelled out. Most organic compounds are diamagnetic, since their elec" Odd electron molecules ", however, are paramagnetic
trons are paired.
&
15. Absorption spectra. When light (this term will be used for electromagnetic waves; of any wavelength) is absorbed by a molecule, the molecule
undergoes transition from a state of lower to a state of higher energy. If
the molecule is monatomic, the energy absorbed can only be used to raise
the energy levels of electrons. If, however, the molecule consists of more
than one atom, the light absorbed may bring about changes in electronic,
....
Ultraviolet
Visible
Near infra-red
Far infra-red
Wavelength (A)
2000-4000
4000-7500
7500-15 x 10 4
15 x 10 4 -100 x 10 4
The
/i,
(Angstrom)
10~ 8 cm.
10-'
mm.
m =
fi
10 A.
10*
v
-1
v (cm.
)
(cm.- 1 )
10 4
A (cm.)
10 8
A (A)
(/i)
10-"
or
log 10
^=
el
ORGANIC CHEMISTRY
14
[CH. I
=i
io-rf
This equation is Beer's law (1852), and is obeyed by most solutions provided they are dilute. In more concentrated solutions there may be divergencies from Beer's law, and these may be caused by association, changes
in solvation, etc.
If the extinction coefficient is plotted against the wavelength of the light
used, the absorption curve of the compound is obtained, and this is characteristic for a pure compound (under identical conditions).
In a molecule which has some definite conatoms vibrate with frequencies which depend on
the masses of the atoms and on the restoring forces brought into play when
the molecule is distorted from its equilibrium configuration. The energy
for these vibrations is absorbed from the incident light, and thereby gives
A given bond has a characteristic absorption
rise to a vibrational spectrum.
band, but the frequency depends, to some extent, on the nature of the
other atoms joined to the two atoms under consideration. It is thus possible
to ascertain the nature of bonds (and therefore groups) in unknown compounds by comparing their infra-red spectra with tables of infra-red absorption spectra. At the same time it is also possible to verify tentative
structures (obtained from chemical evidence) by comparison with spectra
of similar compounds of known structure.
The study of infra-red spectra leads to information on many types of
15b. Infra-red spectra.
problems,
(i)
e.g.,
15c]
15
metrical isomers, and recently Kuhn (1950) has shown that the spectra of
the stereoisomers methyl a- and ^-glycosides are different. It also appears
that enantiomorphs in the solid phase often exhibit different absorption
spectra. Infra-red spectroscopy has also been a very valuable method in
conformational studies (see 11. IV).
(ii) The three isomeric disubstituted benzenes have characteristic absorption bands, and this offers a means of determining their orientation.
(hi) Infra-red spectroscopy has given a great deal of information about
the problem of free rotation about a single bond; e.g., since the intensity of
absorption is proportional to the concentration, it has been possible to
ascertain the presence and amounts of different conformations in a mixture
(the intensities vary with the temperature when two or more conformations
are present).
(iv) Tautomeric mixtures have been examined and the amounts of the
tautomers obtained. In many cases the existence of tautomerism can be
ascertained by infra-red spectroscopy (cf. iii).
(v) Infra-red spectroscopy appears to be the best means of ascertaining
the presence of hydrogen bonding (both in association and chelation). In
" ordinary " experiments it is not possible to distinguish between intraand intermolecuiar hydrogen bonding. These two modes of bonding can,
however, be differentiated by obtaining a series of spectra at different
dilutions.
As the dilution increases, the absorption due to intermolecuiar
hydrogen bonding decreases, whereas the intramolecular hydrogen-bonding
absorption is unaffected.
(vi) It is possible to evaluate dipole moments from infra-red spectra.
(vii) When a bond between two atoms is stretched, a restoring force immediately operates. If the distortion is small, the restoring force may be
assumed to be directly proportional to the distortion, i.e.,
f
where k is the
oc
or
H
C
C
C
0-30
0-77
(double) 0-67
0-60
(triple)
(single)
N
N
O
O
0-70
(double) 0-61
0-55
(triple)
0-66
(single)
(double) 0-57
(single)
CI 0-99
Br 1-14
I
1-33
104
ORGANIC CHEMISTRY
16
[CH.
change from higher to lower frequency is known as the Raman effect (Raman
shift)
It is independent of the frequency of the light used, but is characteristic for a given bond.
Raman spectra have been used to obtain information on structure, e.g.,
the Raman spectrum of formaldehyde in aqueous solution shows the absence
of the oxo group, and so it is inferred that formaldehyde is hydrated:
CH 2 (OH) 2 Raman spectra have also been used to ascertain the existence
of keto-enol tautomerisrft and different conformations, to provide evidence
for resonance, to differentiate between geometrical isomers, to show the
presence of association, and to give information on force constants of bonds.
.
cell,
M=
n
Many long-chain polymers
(iii) Determination of the shapes of molecules.
These fibres are composed of bundles
exist as fibres, e.g., cellulose, keratin.
of tiny crystals with one axis parallel, or nearly parallel, to the fibre axis.
When X-rays fall on the fibre in a direction perpendicular to its length,
then the pattern obtained is similar to that from a single crystal rotated
about a principal axis. It is thus possible to obtain the unit cell dimensions
of such fibres (see, e.g., rubber, 33. VIII).
The intensities of the diffracted beams depend on the positions of the
atoms in the unit cell. A knowledge of these relative intensities leads to
the following applications:
(i)
19a]
17
difficult, if
By means
momentum:
the wavelength is
Because of their small diffractnot impossible, to locate.
by
ORGANIC CHEMISTRY
18
[CH. I
NMR
association, etc.
and for distinguishing
is
between various
READING REFERENCES
Partington, An Advanced Treatise on Physical Chemistry, Longmans, Green. Vol. I-V
(19491964).
Ferguson, Electronic Structures of Organic Molecules, Prentice-Hall (1952).
Ketelaar, Chemical Constitution, Elsevier (1953).
Gilman, Advanced Organic Chemistry, Wiley (1943, 2nd ed.). (i) Vol. II. Ch. 23. Con(n) Vol. Ill (19a)
stitution and Physical Properties of Organic Compounds,
Chemistry.
Ch. 2. Applications of Infra-red and Ultra-violet Spectra to Organic
Wells, Structural Inorganic Chemistry, Oxford Press (1950, 2nd ed.).
Syrkin and Dyatkina, Structure of Molecules and the Chemical Bond, Butterworth (1950
translated and revised by Partridge and Jordan).
Weissberger (Ed.), Technique of Organic Chemistry, Interscience Publishers. Vol. 1
Physical Methods of Organic Chemistry.
(1949, 2nd ed.).
I (1950);
Berl (Ed.), Physical Methods in Chemical Analysis, Academic Press. Vol.
Waters, Physical Aspects of Organic Chemistry, Routledge and Kegan Paul (1950,
4th ed.).
5th ed.).
Reilly and Rae, Physico-Chemical Methods, Methuen (Vol. I and II; 1954,
Stuart, Die Struklur des Freien Molekiils, Springer-Verlag (1952).
Mizushima, Structure of Molecules and Internal Rotation, Academic Press (1954).
Ch. III.
Ingold, Structure and Mechanism in Organic Chemistry, Bell and Sons (1953).
Physical Properties of Molecules.
Advances in Organic Chemistry, Interscience (1960). Klyne, Optical Rotatory Dispersion and the Study of Organic Structures, Vol. I, p. 239.
Smith, Electric Dipole Moments, Butterworth (1955).
Herzberg, Infrared and Raman Spectra, Van Nostrand (1945).
Whiffen, Rotation Spectra, Quart. Reviews (Chem. Soc), 1950, 4, 131.
Bellamy, The Infrared Spectra of Complex Molecules, Methuen (1958, 2nd ed.).
Cross, Introduction to Practical Infrared Spectroscopy, Butterworth (1959).
Mason, Molecular Electronic Absorption Spectra, Quart. Reviews (Chem. Soc), 19bl,
15, 287.
Raman
Rose,
Newman
(Vol. I, 1950;
19
).
38, 438.
CHAPTER
II
OPTICAL ISOMERISM
Stereoisomerism. Stereochemistry is the " chemistry of space ",
stereochemistry deals with the spatial arrangements of atoms and groups
Stereoisomerism is exhibited by isomers having the same
in a molecule.
structure but differing in their spatial arrangement, i.e., having different
Different configurations are possible because carbon forms
configurations.
mainly covalent bonds and these have direction in space. The covalent
bond is formed by the overlapping of atomic orbitals, the bond energy
being greater the greater the overlap of the component orbitals. To get
the maximum overlap of orbitals, the orbitals should be in the same plane.
Thus non-spherical orbitals tend to form bonds in the direction of the greatest
concentration of the orbital, and this consequently produces a directional
bond (see also Vol. I, Ch. II).
There are two types of stereoisomerism, optical isomerism and geometrical isomerism (ofs-trans isomerism). It is not easy to define
them, but their meanings will become clear as the study of stereochemistry
progresses.
Even so, it is highly desirable to have some idea about their
meanings at this stage, and so the following summaries are given.
Optical isomerism is characterised by compounds having the same
structure but different configurations, and because of their molecular asymmetry these compounds rotate the plane of polarisation of plane-polarised
Optical isomers have similar physical and chemical properties the
light.
most marked difference between them is their action on plane-polarised
Optical isomers may rotate the plane of polarisation by
light (see 12. I).
equal and opposite amounts these optical isomers are enantiomorphs (see
On the other hand, some optical isomers may rotate the plane of
|).
polarisation by different amounts; these are diastereoisomers (see 7b).
Finally, some optical isomers may possess no rotation at all; these are
diastereoisomers of the meso-type (see 7d).
Geometrical isomerism is characterised by compounds having the same
structure but different configurations, and because of their molecular symmetry these compounds do not rotate the plane of polarisation of planeGeometrical isomers differ in all their physical and in many
polarised light.
of their chemical properties. They can also exhibit optical isomerism if
the structure of the molecule, apart from giving rise to geometrical isomerIn general, geometrical isomerism involves moleism, is also asymmetric.
cules which can assume different stable configurations, the ability to do
so being due, e.g., to the presence of a double bond, a ring structure, or
1.
i.e.,
IV and
V).
and dissymmetry).
given molecule which has at least one element of symmetry (6) when
"classical" configuration (i.e., the Fischer projection formula; 5) is
20
A
its
OPTICAL ISOMERISM
3]
21
optical activity.
Optical activity due to molecular structure. There are many compounds which are optically active in the solid, fused, gaseous or dissolved
state, e.g., glucose, tartaric acid, etc.
In this case the optical activity is
entirely due to the asymmetry of the molecular structure (see, however, 11).
The original molecule and its non-superimposable mirror image are known
as enantiomorphs (this name is taken from crystallography) or optical antipodes. They are also often referred to as optical isomers, but there is a
tendency to reserve this term to denote all isomers which have the same
structural formula but different configurations (see 1).
i.e.,
reaction with other optically active compounds are usually different [see
10(vii)].
They may also be different physiologically, e.g., (-f-)-histidine is
sweet, ( )-tasteless; ( )-nicotine is more poisbnous than (+)-.
3. The tetrahedral carbon atom.
In 1874, van't Hoff and Le Bel,
independently, gave the solution to the problem of optical isomerism in
organic compounds, van't Hoff proposed the theory that if the four valencies
of the carbon atom are arranged tetrahedrally (not necessarily regular) with
the carbon atom at the centre, then all the cases of isomerism known are
accounted for. Le Bel's theory is substantially the same as van't Hoff 's, but
differs in that whereas van't Hoff believed that the valency distribution was
definitely tetrahedral and fixed as such, Le Bel believed that the valency directions were not rigidly fixed, and did not specify the tetrahedral arrangement.
ORGANIC CHEMISTRY
22
[CH. II
but thought that whatever the spatial arrangement, the molecule Cdbde
would be asymmetric. Later work has shown that van't Hoff's theory is
more in keeping with the facts (see below). Both van't Hoff's and Le Bel's
theories were based on the assumption that the four hydrogen atoms in
methane are equivalent; this assumption has been shown to be correct by
means of chemical and physico-chemical methods. Before the tetrahedral
was proposed, it was believed that the four carbon valencies were planar,
with the carbon atom at the centre of a square (Kekule, 1858).
Pasteur (1848) stated that all substances fell into two groups, those which
were superimposable on their mirror images, and those which were not.
In substances such as quartz, Optical activity is due to the dissymmetry
of the crystal structure, but in compounds like sucrose the optical activity
is due to molecular dissymmetry.
Since it is impossible to have molecular
dissymmetry if the molecule is fiat, Pasteur's work is based on the idea
that molecules are three-dimensional and arranged dissymmetrically. A
further interesting point in this connection is that Pasteur quoted an
irregular tetrahedron as one example of a dissymmetric structure. Also,
Patemo (1869) had proposed tetrahedral models for the structure of the isomeric compounds C S 4C1 2 (at that time it was thought that there were
three isomers with this formula; one ethylidene chloride and two ethylene
chlorides).
CX
CX
kFig. 2.1.
(i) If the molecule is planar, then two forms are possible (Fig. 1).
This
planar configuration can be either square or rectangular; in each case there
are two forms only.
Fig. 2.2.
(ii) If the molecule is pyramidal, then two forms are possible (Fig. 2).
There are only two forms, whether the base is square or rectangular.
(iii) If the molecule is tetrahedral, then only one form is possible (Fig. 3
the carbon atom is at the centre of the tetrahedron).
3a]
OPTICAL ISOMERISM
23
Fig. 2.3.
Compounds of
(i)
If
the molecule
is
a*-
T'A
!
Fig. 2.4.
If
the molecule
is
ei~
i
Fig. 2.5.
(iii) If the molecule is tetrahedral, there are
two forms possible, one related
to the other as object and mirror image, which are not
superimposable,
i.e., the tetrahedral configuration gives
rise to one pair of enantiomorphs
(Fig. 6).
Fig. 2.6.
In practice, compounds of the type Cabde give rise to only one pair
of enantiomorphs; this agrees with the tetrahedral configuration.
ORGANIC CHEMISTRY
24
[CH. II
molecule may contain two or more asymmetric carbon atoms and still
not be optically active (see, e.g., 7d).
A most interesting case of an optically active compound containing one
asymmetric carbon atom is the resolution of s-butylmercuric bromide,
EtMeCH'HgBr (Hughes, Ingold et al., 1958). This appears to be the first
example of the resolution of a simple organometaUic compound where the
asymmetry depends only on the carbon atom attached to the metal.
Isotopic asymmetry. In the optically active compound Cabde, the
groups a, b, d and e (which may or may not contain carbon) are all different,
but two or more may be structural isomers, e.g., propylz'sopropylmethanol
The substitution of hydrogen by deuterium has also
is optically active.
been investigated in recent years to ascertain whether these two atoms are
sufficiently different to give rise to optical isomerism.
The earlier work
gave conflicting results, e.g., Clemo et al. (1936) claimed to have obtained a
small rotation for a-pentadeuterophenylbenzylamine, C 6 5 *CH(C 6 H5)'NH 2
but this was disproved by Adams et al. (1938). Erlenmeyer et al. (1936)
failed to resolve C 6 5 -CH(C 6 D 5 )-C0 2 H, and Ives et al. (1948) also failed
to resolve a number of deutero-compounds, one of which was
CH 3
,0H8
CHD
CHD
H2
CH 2
\)H
CH 3
CH 3
e.g.,
optically active
(Ill; Streitwieser, 1955)
CHD
CH2
CH2
CH2
CH
Some other
CH3
^CH
CH
CH3
II
CH 3 -CHDOH
III
IV
are,
point of interest here is that almost all optically active deuterium compounds have been prepared from optically active precursors. Exceptions
are (V) and (VI), which have been resolved by Pocker (1961).
C 6H 5 -CHOH-C 6D s
C 6 H 6 -CDOH-C 6D 5
VI
3a]
OPTICAL ISOMERISM
25
C02 H
OH
HO
CH-,
CH
D-lactic acid
3
L-lactic acid
propionic acid
Fig. 2.7.
two groups
and e (see
(+)-wopropylmalonamic
Fig. 2.8.
CONH 2
CONH
H C GH(CH
3 )2
C02 H
C02 H
MVH-C-CH(CH
3 )2
S^ H C CH(CH
C0 2 CH3
C0 2 CH 3
C0 2 H
C0 2 H
3 )!j
(+)-acid
CONHNH
CON,
CONH 2
(-)-acid
Ch. III).
enant iomorph into the other is in agreement with
iu
the
tetrahedral theory. At the same time, this series of
reactions shows
that optical isomers have identical structures, and
so the difference must
be due to the spatial arrangement.
iS Cl an ge fr
x x
i
J
,
?
m one
26
ORGANIC CHEMISTRY
[CH. II
case are the four bond lengths equal. In all other cases the bond lengths
will be different, the actual values depending on the nature of the atoms
joined to the carbon atom (see 15b. I).
4.
(i)
Mathematical
\
\
\
c
*\\
L/-C43J
/~^--'''
Fig. 2.9.
3
i.e., there are four sp
bonds (see Vol. I, Ch. II).
calculations show that the four carbon valencies in
the molecule Ca 4 are equivalent and directed towards the four corners of
a regular tetrahedron. Furthermore, quantum-mechanical calculations require the carbon bond angles to be close to the tetrahedral value, since
change from this value is associated with loss in bond strength and consequently decrease in stability. According to Coulson et al. (1949), calculation has shown that the smallest valency angle that one can reasonably
expect to find is 104. It is this value which is found in the cyc/opropane
and cyc/obutane rings, these molecules being relatively unstable because of
the " bent " bonds (Coulson; see Baeyer Strain Theory, Vol. I, Ch. XIX).
(ii) The principle of free rotation about a single bond.
Originally,
it was believed that internal rotation about a single bond was completely
free.
When the thermodynamic properties were first calculated for ethane
on the assumption that there was complete free rotation about the carboncarbon single bond, the results obtained were in poor agreement with those
obtained experimentally. This led Pitzer et al. (1936) to suggest that there
2s
and 2p
orbitals,
Quantum mechanical
H
c
60
Angle of Rotation
fR
*x
H-^O^H
H
^v/H
II
stags ered
(tra ns)
(a)
(
eel ipsed
is)
( c)
Fig. 2.10.
restricted rotation about the single bond, and calculations on this basis
gave thermodynamic properties in good agreement with the experimental
ones. The potential energy curve obtained for ethane, in which one methyl
group is imagined to rotate about the C C bond as axis with the other
group at rest, is shown in Fig. 10 (a). Had there been complete free rotaFig. 10 (b) is
tion, the graph would have been a horizontal straight line.
the Newman (1952) projection formula, the carbon atom nearer to the eye
was
OPTICAI, ISOMERISM
4]
27
being designated by equally spaced radii and the carbon atom further from
the eye by a circle with three equally spaced radial extensions. Fig. 10 (b)
represents the trans- or staggered form in which the hydrogen atoms (on
the two carbon atoms) are as far apart as possible. Fig. 10 (c) represents
the cis- or eclipsed form in which the hydrogen atoms are as close together
as possible. It can be seen from the graph that the eclipsed form has a
higher potential energy than the staggered, and the actual difference has
been found to be (by calculation) about 2-85 kg.cal./mole. The value of
60
120
180
Angle of Rotation
CI
^O^H
CI
CI
CI
Cl^-J^/H
H \^-4-v/Cl
H^O^H
h-^O^h
staggered
gauche or skew
(trattsoid)
fully eclipsed
eclipsed
(cisoid)
Fig. 2.11
this potential
energy barrier
by chemical methods.
Now
is
(i).
stem
let
ORGANIC CHEMISTRY
28
[CH. II
3-6kg.cal.
2-9kg.cal.
t
E
60
--V/
120
180
0-8kg.cal.
300 360
240
Angle of Rotation
Fig. 2.11
(ii).
Me
Me
tt^^/Me
Me^-^H
2'
4a]
OPTICAL ISOMERISM
originally introduced
29
by W. N. Haworth,
1929).
In its widest sense, conformation has been used to describe different spatial arrangements of a
molecule which are not superimposable. This means, in effect, that the
terms conformation and configuration are equivalent. There is, however,
an
important difference in meaning between these terms. The definition of
configuration, in the classical sense (1), does not include the
problem of
the internal forces acting on the molecule. The term conformation,
however, is the spatial arrangement of the molecule when all the
internal' forces
acting on the molecule are taken into account. In this more
restricted
sense, the term conformation is used to designate different
spatial arrange-
however,
of internal rotation is
CH
CH
ORGANIC CHEMISTRY
30
[CH. II
When
by
the molecule can take up a less favoured conformation, e.g., during the course
of reaction with other molecules (see 11. IV).
Because of the different environments a reactive centre may have in
different conformations, conformation will therefore affect the course and
rate of reactions involving this centre (see 11. IV).
Many methods are now used to investigate the conformation of molecules, e.g., thermodynamic calculations, dipole moments, electron and X-ray
and
diffraction, infra-red and Raman spectra, rotatory dispersion,
NMR
chemical methods.
and
system.
diagrams of the mechanical models instead of the
Fischer, working on the configurations of the sugars (see 1. VII), obtained
the plane formulae I and II for the enantiomorphs of saccharic acid, and
C0 2H
C0 2H
H COH
HO C
HOC
HCOH
HCOH
HOC
HOC
CHO
HCOH
HCOH
C0 2H
C0 2H
II
HOC
HCOH
HCOH
CH 2OH
III
arbitrarily chose I for dextrorotatory saccharic acid, and called it dsaccharic acid. He then, from this, deduced formula III for rf-glucose.
Furthermore, Fischer thought it was more important to indicate stereo-
OPTICAL ISOMERISM
31
chemical relationships than merely to indicate the actual direction
of rotation.
He therefore proposed that the prefixes d and / should refer to
stereochemical relationships and not to the direction of rotation of
the compound. For this scheme to be self-consistent (among
the sugars)
it is necessary to choose one sugar as standard
and then refer all the others
to it. Fischer apparently intended to use the scheme
whereby the compounds derived from a given aldehyde sugar should be designated
according
to the direction of rotation of the parent aldose.
Natural mannose is dextrorotatory. Hence natural mannose
will be
rf-mannose, and all derivatives of rf-mannose, e.g., mannonic
acid, mannitol
mannose phenylhydrazone, etc., will thus belong to the ^-series. Natural
glucose is dextrorotatory. Hence natural glucose will be
rf-glucose and all
its derivatives will belong to the rf-series.
Furthermore, Fischer (1890)
converted natural mannose into natural glucose as follows:
>.
i-mannolactone
> rf-glucose
(see 1. VII).
ORGANIC CHEMISTRY
32
[CH.
II
of the four groups joined to the central carbon atom must be placed as
shown in Fig. 12 (a), i.e., the accepted convention for drawing d(+)glyceraldehyde places the hydrogen atom at the left and the hydroxyl
group at the right, with the aldehyde group at the top corner. Now
imagine the tetrahedron to rotate about the horizontal line joining H and
OH
CHO
CHO
CHO
CHO
OH HO-
CH 2 OH
(d)
being above the plane of the paper, and those joined to broken vertical lines
being below the plane of the paper. The conventional plane-diagram is
obtained by drawing the full horizontal and broken vertical lines of Fig. 12 (b)
as full lines, placing the groups as they appear in Fig. 12 (b), and taking the
asymmetric carbon atom to be at the point where the lines cross. Although
Fig. 12 (c) is a plane-diagram, it is most important to remember that horizontal lines represent groups above the plane, and vertical lines groups
below the plane of the paper. Many authors prefer to draw Fig. 12 (c)
[and Fig. 12 (d)] with a broken vertical line. Fig. 12 {d) represents the
plane-diagram formula of l( )-glyceraldehyde here the hydrogen atom is
Thus any compound that can
to the right and the hydroxyl group to the left.
be prepared from, or converted into, D(+)-glyceraldehyde will belong to
the D-series. Similarly, any compound that can be prepared from, or converted into, l( )-glyceraldehyde will belong to the L-series. When representing relative configurational relationship of molecules containing more
than one asymmetric carbon atom, the asymmetric carbon atom of glyceraldehyde is always drawn at the bottom, the rest of the molecule being built
;
up from
this unit.
D-senes
L-senes
Fischer
CC
OPTICAL ISOMERISM
5]
33
wrote the configuration of natural dextrorotatory tartaric acid as IV. If
we use the convention of writing the glyceraldehyde unit at the bottom,
C0 2 H
COjjH
HC OH
HO C
HO O
HC OH
C02 H
IV
then IV
C02 H
V
V
CHO
H-O-OH
CN
HcN
CN
H-C*- OH
>-
H -_ C _ 0H
|
CH2 OH
HO-C -H
+
H_c
I
D(+) -glyceraldehyde
CH OH
CH 2 OH
C02 H
C02 H
H Cr-OH
(0 hydrolysis
(ii)
HO
I
"*"
oxidation
0H
HC! OH
H C. OH
f
C02H
G02 H
mesotartaric
acid
(-)-tartaric
acid
into tevorotatory tartaric acid via the Kiliani reaction
(see Vol. I)
Thus
(-)-tartanc acid is D(-)-tartaric acid (V). On the other hand,
(+)-tartaric
.^te.conyjrtei into D(-)-glyceric acid, and so (+)-tartaric acid is
D(+)-tartaric acid (IV). In this reduction of (+)-tartaric acid to
(+)-malic
C02H
H OH
HO-C-H
2
O02 H
(+)-KO'serine
>|
CH2
C0 2H
CONH2
(+)-p-malamic
acid
C0 2 H
CH2 -NH2
H OH
(+)-maIic
acid
COaH
2
H OH
CH2
IV
H-C OH
COiH.
CHO
5-
H -C-OH
I
CH 2 OH
D(-) -glyceric
acid
H-G OH
I
-*
CH 2 OH
D(+) -glyceraldehyde
ORGANIC CHEMISTRY
34
[CH. II
acid (by hydriodic acid), it has been assumed that it is C x which has been
reduced, i.e., in this case the configuration of C 2 has been correlated with
glyceraldehyde and not that of Cj as in the previous set of reactions. Had,
however, C 2 been reduced, then the final result would have been (+)-tartaric
acid still through the intermediate, {-\-)-malic acid (two exchanges of groups
give the same malic acid as before). Since (+)-malic acid has been correlated
C0 2H
COJE
H OH
-IH
HO-Cty
x
~>
CH 2
CH 2OH
">
HOC!
HOCH
C0 2H
Co 2H
CC
C0 2H
IV
d( )-glyceric
(-f)-malic
-me
acid
acid
with (-f)-glyceraldehyde
since the configurations assigned to them are actually the absolute configurations.
The methods used for correlating configurations are:
(i) Chemical reactions without displacement at the asymmetric centre
(iii)
(iv)
synthesis, 7. III).
(v)
(vii)
Enzyme
studies.
The
method
of correlation.
(i)
CHO
-h
HO-
C02 H
_ H J! hoae*. ho-
CH 2 OH
l(
-glyceraldehyde
CH 2 OH
l(+) -glyceric acid
C02 H
_
CH 2 NH 2
l( )-soserine
^ H0
C0 2 H
-H
CH2 Br
L-
6c]
OPTICAL ISOMERISM
35
002 H
Na/Hg
>
'
HO
CH -H
I
f-
L(+)-lactic acid
It can be seen from this example that change
in the sign of rotation does
not necessarily indicate a change in configuration.
()
Me
Me
(i)
HO-
co2"h
EtOH/HCl
HO-
(u)Na/ EtOH
-j
Me
HBr
HO-
CH2 OH
-J
CH2 Br
D-
Me
(i)
KCN
(ii)
hydrolysis
HO-
-H
OH2 -002 H
r>{ )--hydroxybatyric acid
(iii)
Me
H-
-OH
CH2 C02 H
Me
(i)
(ii)
EtOH/HCl
Na/EtOH
*"
Me
HT
OH
CH2 CH2 OH
*-(+)--hydroxybutyric acid
H-
-OH
CH2 CH2l
Me
OH
CH 2 *CH3
L(+)-butan-2-ol
(iv)
Another example
is
C
51 *1011
,f as ymmetric configurations.
Cahn, Ingold and
u ? ' (1956) have produced
Frelog
a scheme for the specification of absolute configurations.
Let us consider the procedure for a molecule containing
mE!^
one
asymmetric carbon atom.
(i) The four groups are first
ordered according to the sequence rule.
According to this rule, the groups are arranged in decreasing
atomic number
pt the atoms by which they are bound to the
asymmetric carbon atom
11 two or more of these atoms have the same atomic
number, then the
relative priority of the groups is determined by
a similar comparison of
the atomic numbers of the next atoms in the groups (i.e.,
the atoms joined
to the atom joined to the asymmetric carbon atom).
If this fails then the
next atoms of the groups are considered. Thus one works
outwards from
the asymmetric carbon atom until a selection can be made
for the sequence
^
of the groups.
(ii) Next is determined whether the
sequence describes a right- or lefthanded pattern on the molecular model as viewed according to
the conversion rule. When the four groups in the molecule Cubed
have been
ORGANIC CHEMISTRY
36
[CH. II
The asymmetry
(iii) Absolute configuration labels are then assigned.
leading under the sequence and conversion rules to a right- and left-handed
b
/ >
-Cr-~
c
(I)
Fig. 2.13.
pattern
indicated
is
by
rectus, right:
S;
sinister,
left).
CI
-C02 H
Br-
H
(II)
Now
let
III (this is
rule, (II) is
-OH
CHO
CHO
CHO
H-
CH 2 OH-
-OH
HO
-CH 2OH
IV
III
a-
CH2 OH
VI
and
OH
CH 2 OH
OH
OH
C02 H
H- r- OH
CHOH-C0 2H
C02 H
-OH
HH
HOC02 H
CH0H-C0 2 H
HO-
C02 H
(2 interchanges)
(2 interchanges)
CO-H
C0 2 H
HO- -y-CHOHC0 2 H
-H
-CHOHCO.H
HO-
OPTICAL ISOMERISM
6]
37
When
H-
CHO
-OH
HOH-
H-
(R)
-H
(S)
-OH
-OH
(R)
(.R)
CH2 OH
D(+)-glucose
Elements of symmetry.
The test of superimposing a formula (tetramirror image definitely indicates whether the molecule is
symmetrical or not it is asymmetric if the two forms are not superimposable.
The most satisfactory way in which superimposability may be ascertained
is to build up models of the molecule and its mirror image.
Usually this is
not convenient, and so, in practice, one determines whether the molecule
possesses (i) a plane of symmetry, (ii) a centre of symmetry or (iii) an alternating axis of symmetry. If the molecule contains at least one of these
elements of symmetry, the molecule is symmetrical; if none of these elements
of symmetry is present, the molecule is asymmetric.
It should be remembered that it is the Fischer projection formula
that
is normally used for inspection.
As pointed out in 2, it is necessary, when
dealing with conformations, to ascertain whether at least one of them has
one or more elements of symmetry. If such a conformation can be drawn,
then the compound is not optically active.
(i) A plane of symmetry divides a molecule in such
a way that points
(atoms or groups of atoms) on the one side of the plane form mirror images
of those on the other side. This test may be applied to both solid (tetrahedral) and plane-diagram formulae, e.g., the plane-formula of the mesoform of Cabd'Cabd possesses a plane of symmetry; the other two,
(+) and
( ), do not
6.
hedral)
on
its
a-
-d
d-
-a
a-
d-
-a
a~
-d
a-
(+)-form
(-)-form
plane of
symmetry
b
meso form
38
ORGANIC CHEMISTRY
[CH. II
to three-dimensional formulae, particularly those of ring systems, e.g., 2 4dimethylcycfobutane-1 : 3-dicarboxylic acid (Fig. 14). The form shown possesses a centre of symmetry which is the centre of the ring.
This form is
therefore optically inactive.
Another example we shall consider here is that of dimethyldiketopiperazine; this molecule can exist in two geometrical isomeric forms, cis and
:
H3
-02 H
H_Z/
\~7
/
\
\
:o2h
CH3
Fig. 2.14.
trans (see also 11. IV). The cw-isomer has no elements of symmetry and
can therefore exist in two enantiomorphous forms; both are known. The
fraws-isomer has a centre of symmetry and is therefore optically inactive.
CH3
NH|
CH3
CO
N
|
NH
<?H
?H3
NHI
NHl
,CO
XX>
<N NH CO>
ccy
CH3
trans
cts
H SC A
H
CH3/ CH 3 H3C
(a)
2;+
I1
/i
h/i
(0
z~
I1
*/
Z +//z4
1i
r+ /
2
A
I1
Fig. 2.15.
H // H
3
id)
OPTICAL ISOMERISM
6]
39
AB
(+)CH(CH3 )-C a 8 and (_)_CH(CH3 )-C2 B) represented by Z+ and irrespectively, the resulting molecule (Fig. 15c) now has no planes
of symmetry. Nevertheless, this molecule is not optically active since
it does
possess a four-fold alternating axis of symmetry [reflection of Id)
(which
is produced by rotation of (c) through 90 about the
vertical axis) in the
plane of the ring gives (c); it should be remembered that the reflection
of
a (+)-form is the ( )-form].
H
^CH 3
<JH,"1
\+hT
-vH^CH
^H
CH 3^
*S
CH^
CHf
v\
II
3:4:3':
4'-tetramethylspiro-(l
l')-dipyrrolidinium ^-toluenesulphonate, I
symmetry, but
To show the
McCasland
thritol ester,
16. VIII):
(-)-ROCH2 COOCH,
(+)-RO- CH2 COO- Cft/
^CHa-OCOCHijOR (-)
^CRVO- CO
City OR
(+)
ORGANIC CHEMISTRY
40
[CH. II
The number
7a.
Compounds
With
the molecule Cabde only two optical isomers are possible, and these are
related as object and mirror image, i.e., there is one pair of enantiomorphs,
e.g., d- and L-lactic acid.
If we examine an equimolecular mixture of dextrorotatory and laevorotatory lactic acids, we shall find that the mixture is
optically inactive. This is to be expected, since enantiomorphs have equal
but opposite rotatory power. Such a mixture (of equimolecular amounts)
is said to be optically inactive by external compensation, and is known
as a racemic modification (see also 9). A compound which is optically
inactive by external compensation is known as the racemic compound
and is designated as r-, ()- or dl-, e.g., r-tartaric acid, (ij-limonene,
DL-lactic acid.
and
CO z H
bromopropionic acid.
CQ 2 H
C0 2 H
atoms.
II
III
IV
Fig. 2.17.
and an equimolecular mixture of them forms a racemic modification; simiand IV. Thus there are six forms in all for a compound of
the type Cabd-Cabe: two pairs of enantiomorphs and two racemic modificalarly for III
tions.
and
7b]
OPTICAL ISOMERISM
41
-d
d-
-a
a-
-d
d-
-a
a-
-e
e-
-a
e-
-a
a-
-e
VI
VII
VIII
Li
or
DL
Conversion of molecule Ca b-Cabe into Cabd-Cabe. Let us
z
consider the
brommation of /?-methylvaleric acid to give a-bromo-0-methylvaleric
acid.
CH 3 -CH 2-CH(CH3).CHBr-C0 2H
C02 H
H-
H-
-Br
CH,
C02 H
COjjH
3-
-H
H-
D4 -CHj
Br-
-CH,
C 2 H5
C2H5
C2H5
IX
XI
ORGANIC CHEMISTRY
42
[CH.
II
both cases, the positions of the bromine atoms with respect to the methyl
group are the same. Similarly, the amount of XIV from XII will be the
same as that of XI from IX. Thus bromination of ()-/?-methylvaleric
in
C02 H
Br-
CHr
L,
C02 H
-H
H-
-H
CHo-
Lx
COj-H
-H
H-
-H
CH,-
-Br
Lx
C 2 H5
C 2 H5
C 2 HS
XIV
XII
four bromo
XIII
-H
r> 3
1.3
DL
DL
DL
compounds which
7d.
Compounds
of the type
Cabd^CaVj^Cabd.
In compounds of
this type the two terminal asymmetric carbon atoms are similar, and the
number of optically active forms possible depends on whether x is odd or
even.
EVEN SERIES
(i)
e.g.,
D
D
I
tartaric acid.
L
L
II
III
D
IV
In molecules I and II, the upper and lower halves reinforce each other;
hence I, as a whole, has the dextro- and II, the lsevo-configuration, i.e., I and
On the other hand, in III
II are optically active, and enantiomorphous.
the two halves are in opposition, and so the molecule, as a whole, will not
show optical activity. It is also obvious that III and IV are identical,
Molecule III
i.e., there is only one optically inactive form of Cabd'Cabd.
Molecule III
is said to be optically inactive by internal compensation.
7d]
OPTICAL ISOMERISM
known
as the meso-form,
and
43
a diastereoisomer of the pair of enantiomorphs I and II. The meso-iorm is also known as the inactive form and is
represented as the t'-form; the meso-torm cannot be resolved (see also
Thus there are four forms possible for the molecule Cabd'Cabd: one
10).
pair of enantiomorphs, one racemic modification and one tneso- (*-) form.
These forms for tartaric acid are:
is
C02 H
COjH
HO-
is
-H
C0 2 H
-OH
H-
H-
-OH
plane of
H-
-OH
HO-
-H
H-
COs H
CQjH
symmetry
jj
COgH
L-
meso~(i-)
DLInspection of these formula; shows that the d- and l- forms do not possess
any elements of symmetry; the meso-form, however, possesses a plane of
symmetry.
(6)
Cabd'Cab'Cab-Cabd,
e.g.,
saccharic acid,
C0 2H-CHOH-CHOH-CHOH-CHOH-CO aH.
The rotatory powers of the two terminal asymmetric carbon atoms are
the same, and so are those of the middle two (the rotatory powers
of the
latter are almost certainly different from those of the
former; equality
fortuitous).
The possible optical isomers are as follows (V-XIV)
would be
Li
D,
Li
La
*>a
d2
La
l
VII
IX
VIII
DL
XI XII
DL
DL
"1
La
D2
La
Li
Li
XIII
XIV
meso-iorms
Molecules
and VI are optically active (enantiomorphous) and are not
"internally compensated"; VII and VIII are optically active (enantiomorphous) and are not " internally compensated "; IX and
are optically
active (enantiomorphous) but are " internally compensated at the
ends ";
XI and XII are optically active (enantiomorphous) but are " internally
compensated in the middle "; XIII and XIV are meso-iorms and are optically inactive by (complete) internal compensation.
Thus there are eight
optically active forms (four pairs of enantiomorphs), and two meso-forms.
In general, in the series of the type Cabd'{Cab) n - 2 -Cabd, if n is the number
of asymmetric carbon atoms and is even, then there will be 2 n ~ 1 optically
active forms,
and
2~
weso-forms.
(H)
(a)
Cabd-Cab-Cabd,
ODD SERIES
ORGANIC CHEMISTRY
44
[CH. II
Cabd
Cab
-^t>"-
..I'.jj.'
plane of
symmetry
Cabd
XV XVI
DL
XVII
XVIII
meso
meso
is
said to be pseudo-asymmetric,
and
if
acids, all of
HO
-H
C0 2 H
CO ?H
C02H
H-
CO,H
-OH
H-
-OH
H-
H-
-OH HO-
-H
H-
-OH
HO-
H-
-OH
-H
H-
-OH
H-
C02H
D
HO-
C02H
-H
-OH
C02 H
C02H
meso
meso
-OH
Ends with
opposite configurations
"d'
D,
meso
Ends with
the
meso
same configurations
DL
DL
83
OPTICAL ISOMERISM
46
of
optically active
synthesis, 7. III).
Racemisation.
The process of converting an optically active compound into the racemic modification is known as racemisation. The
{+)and ( )-forms of most compounds are capable of racemisation
under the
influence of heat, light, or chemical reagents. Which agent
is used depends
on the nature of the compound, and at the same time the ease of
racemisation also depends on the nature of the compound, e.g.,
{a) Some compounds racemise so easily that they
cannot be isolated in
(iii)
(b)
number of compounds racemise spontaneously when isolated in
optically active forms.
(c) The majority of compounds racemise
with various degrees of ease
under the influence of different reagents.
(d)A relatively small number of compounds cannot be racemised at all
ORGANIC CHEMISTRY
46
[CH.
II
enol-form can produce equally well the keto-form III in which the configuration of the asymmetric carbon atom is opposite to that in I. Thus racemisation, according to this scheme, occurs via the enol-form, e.g., ( )-lactic acid
00=0
I
^==
C=C OH
,i
I
is
C 0=0
I
==^r
,11
II
racemised in
III
this
change
may
be formu-
lated:
0H O
CH 3,
COf
C^s
*J CH C C'
^=*
of
3
X 0-
0-
o-
HO,
.0
<
>
/
CH X
C=C
\X0-
(-)
H+
.0
i-c/
CH.
AhV
(+)
a great deal of evidence to support this tautomeric mechanism.
When the hydrogen atom joined to the asymmetric carbon atom is replaced
by some group that prevents tautomerism (enolisation) then racemisation
comis also prevented (at least under the same conditions as the original
pound), e.g., mandelic acid, C 6H 5 -CHOH-C0 2H, is readily racemised by
wanning with aqueous sodium hydroxide. On the other hand, atrolactic
acid, C 6 H 6 'C(CH 3 )(OH)'C0 2 H, is not racemised under the same conditions;
in this case keto-enol tautomerism is no longer possible.
Racemisation of compounds capable of exhibiting keto-enol tautomerism is catalysed by acids and bases. Since keto-enol tautomerism is also
catalysed by acids and bases, then if racemisation proceeds via enolisation,
the rates of racemisation and enolisation should be the same. This relationship has been established by means of kinetic studies, e.g., Bartlett et al.
(1935) found that the rate of acid-catalysed iodination of 2-butyl phenyl
ketone was the same as that of racemisation in acid solution. This is in
keeping with both reactions involving the rate-controlling formation of the
enol (see Vol. I, Ch. X)
There
is
OH
slow
fast
fast
9low
(+)
I,
fast
* Ph-CO-CHMeEt
(-)
Ph-CO-CIMeEt
On the other hand, on the basis that the rate-determining step in basecatalysed enolisation and racemisation is the formation of the enolate ion,
then the two processes will also occur at the same rate.
OH
O-
fast
OPTICAL ISOMERISM
8]
47
Hsii et al. (1936) found that the rates of bromination and racemisation (in
the presence of acetate ions) of 2-o-carboxybenzyl-l-indanone were identical.
CO,H
Further support for this mechanism is the work of Ingold et al. (1938)
that the rate of racemisation of (+)-2-butyl phenyl ketone in
dioxan-deuterium oxide solution in the presence of NaOD is the same as
the rate of deuterium exchange. This is in keeping with the formation
of the enolate ion (or carbanion), which is common to both reactions.
who showed
PhC=CMeEt
(+)-Pll-CO'CHMeEt +
OIT^sHOD
Ph-CO-CDMeEt
PhCOCMeEt
(-)-Ph-CO-CHMeEt
+
OD~
'
2H
R-G-OH
^= R-6=0
I
H
R-C-OH
+o
H
^:
(+)-
B-
1933).
C 6H B -CHC1-CHS
(+)"
The carbonium
^CH
6
-CH-CH 3
Cl~
^CH
6
-CHC1-CH3
(-)-
planar (the positively charged carbon atom is probably in a state of trigonal hybridisation) and consequently symmetrical;
recombination with the chlorine ion can occur equally well to form the
(+)- and ( )-forms, i.e., racemisation occurs. The basis of this mechanism
is that alkyl halides in liquid sulphur dioxide exhibit an electrical conductivity, which has been taken as indicating ionisation.
Hughes, Ingold
ion
is
ORGANIC CHEMISTRY
48
[CH. II
-^ C
C 6 H 5 -CH-CH 3
+ Cl~
H -CH = CH + H+
5
C 6H 5 -CHC1-CH3
^CH
6
-CH
= CH + HC1 ^ C H
2
-CHC1-CH 3
(-)-
(+)-
1948).
et al.,
R CH + 2H S0 R C+ + HSO,- + SO + 2H
R C+ + R CH > R CH + R C+, etc.
3
CH S
CH 3
C 2H 6 CH
-
H, + C 2H 5
C+ H
4
(+)-
CH a
C 2H 6
C+ H
4
+ C 2H 5CH 4H 9
()-
The racemisation
compounds
is
described
compounds, 4. V; nitrogen compounds, 2a. VI; phosphorus compounds, 3b. VI; arsenic compounds, 4a. VI).
later (see diphenyl
Properties of the racemic modification. The racemic modificaexist in three different forms in the solid state.
This is also known as a () -conglomerate,
(i) Racemic mixture.
and is a mechanical mixture of two types of crystals, the (+)- and ( )9.
tion
may
forms; there are two phases present. The physical properties of the racemic
mixture are mainly the same as those of its constituent enantiomorphs.
The most important difference is the m.p. (see 9a).
This consists of a pair of enantiomorphs in
(ii) Racemic compound.
combination as a molecular compound; only one solid phase is present.
The physical properties of a racemic compound are different from those
of the constituent enantiomorphs, but in solution racemic compounds dissociate into the (+)- and ( )-forms.
This is also known as a. pseu do -racemic
(iii) Racemic solid solution.
compound, and is a solid solution (one phase system) formed by a pair of
enantiomorphs crystallising together due to their being isomorphous. The
OPTICAL ISOMERISM
9a]
49
properties of the racemic solid solution are mainly the same as those of its
constituent enantiomorphs ; the m.p.s may differ (see 9a).
9a.
tion.
Methods for determining the nature of a racemic modificaOne simple method of examination is to estimate the amounts of
tartaric acids.
D-Tartaric acid
Melting point
Water
of crystallisation
Density
Solubility in
H,0
(at 20)
Racemic
L-Tartaric acid
Tartaric acid
170
170
206
None
None
1-7598
lH sO
1-7598
1-697
20-6 g./lOO ml.
There are, however, two main methods for determining the nature of a
racemic modification: a study of the freezing-point curves and a study of
the solubility curves (Roozeboom, 1899; Andriani, 1900).
Freezing-point curves. These are obtained by measuring the melting
points of mixtures containing different amounts of the racemic modification
and its corresponding enantiomorphs. Various types of curves are possible
according to the nature of the racemic modification. In Fig. 18 (a) the
ioo7o(+)
sol
()
ioo%<-)
100%(+) 50%
(*)
100%(-)
100%(+)
50%
100%(-)
(0
Fig. 2.18.
melting points of all mixtures are higher than that of the racemic modification alone.
In this case the racemic modification is a racemic mixture (a
eutectic mixture is formed at the point of 50 per cent, composition of each
enantiomorph), and so addition of either enantiomorph to a racemic mixture
raises the melting point of the latter; ()-pinene is an example of this type.
In Fig. 18 (6) and (c) the melting points of the mixtures are lower than the
melting point of the racemic modification which, therefore, is a racemic
compound. The melting point of the racemic compound may be above
that of each enantiomorph (Fig. 18 b) or below (Fig. 18 c) in either case
the melting point is lowered when the racemic compound is mixed with an
enantiomorph; an example of Fig. 18 (b) is methyl tartrate, and one of
Fig. 18 (c) is mandelic acid.
When the racemic modification is a racemic solid solution, three types
of curves are possible (Fig. 19). In Fig. 19 (a) the freezing-point curve is
a horizontal straight line, all possible compositions having the same melting
point, e.g., (+)- and ( )-camphor.
In Fig. 19 (b) the freezing-point curve
shows a maximum, e.g., (+)- and ( )-carvoxime; and in Fig. 19 (c) the
freezing-point curve shows a minimum, e.g., (+)- and ( )-w>opentyl (isoamyl) carbamate.
;
ORGANIC CHEMISTRY
50
[CH. II
ioo%(+)
100%B
100%(+)
ioo%(->
100%(+)
100%(-)
(c)
(b)
()
Fig. 2.19.
means
eC-f
II
C0 2 H
H-
oh;
C0 2 H
HS-
-J
CH2 -C02 H
III
IV
C0 2 H
I Me
CH2 C02 H
acid (IV) had opposite configurations. He then showed (1942) that ( )mercaptosuccinic acid formed a quasi-racemic compound with (+)-methylsuccinic acid (V). Therefore (IV) and (V) have opposite configurations and
consequently (-f-)-malic acid and (+)-methylsuccinic acid have the same
configuration (see also 10(vi) and 23e. VIII).
Mislow et al. (1956) have applied the m.p. curves in a somewhat different
manner. They worked with 3-mercapto-octanedioic acid (VI) and 3-methyloctanedioic acid (VII). These authors found that compounds ( )-VI and
(+)-VII gave solid solutions for all mixtures (unsymmetrical 19 a), whereas
(-f-)-VI
OPTICAL ISOMERISM
10]
18
a).
01
These results indicate that ( )-VI and (+)-VII are of the same
CH2-C02H
CH2 -C02H
HCMe
H CSH
(CH 2) 4-C0 2H
(CH2 4-C0 2H
( )-form
(+)-form
VI
VII
of opposite con-
figurations.
ORGANIC CHEMISTRY
52
[CH. II
resolution of glutamic acid by inoculation has been perfected for inHarada et al. (1962) have
dustrial use (Ogawa et al., 1957; Oeda, 1961).
also resolved the copper complex of DL-aspartic acid by inoculation.
Certain bacteria and
(Pasteur, 1858).
(iii) Biochemical separation
moulds, when they grow in a dilute solution of a racemic modification,
destroy one enantiomorph more rapidly than the other, e.g., Penicillium
glaucum (a mould), when grown in a solution of ammonium racemate,
attacks the D-form and leaves the L-.
This biochemical method of separation has some disadvantages:
(a) Dilute solutions must be used, and so the amounts obtained will be
The
small.
(b) One form is always destroyed and the other form is not always
obtained in 50 per cent, yield since some of this may also be destroyed.
(c) It is necessary to find a micro-organism which will attack only one of
the enantiomorphs.
This method,
(iv) Conversion into diastereoisomers (Pasteur, 1858).
which is the best of all the methods of resolution, consists in converting
the enantiomorphs of a racemic modification into diastereoisomers (7b);
the racemic modification is treated with an optically active substance and
the diastereoisomers thereby produced are separated by fractional crystallisation.
Thus racemic acids may be separated by optically active bases,
and
Lacid)
+ 2Dba >
se
may
(D a ciflDbase)
(L ac idDbase)
Many optically active acids have been used, e.g., tartaric acid,
(6) Bases.
camphor-/3-sulphonic acid and particularly a-bromocamphor-Tr-sulphonic
acid (see 23a. VIII).
These are converted into the acid ester derivative using
(c) Alcohols.
either succinic or phthalic anhydride (Pickard and Kenyon, 1912). The
acid ester, consisting of equimolecular amounts of the (+)- and ( )-forms,
may now
by
ROCH
In these equations
-COC1
is
the
( )-menthyl
OPTICAL ISOMERISM
10]
N-( )-menthyl-^-sulphamylbenzoyl
chloride,
I,
53
(Mills et al.,
1950).
C10H19 NHSO2-^^^~COCl
I
These have been resolved by means of optiSugars have been resolved with (+)-Mopentanethiol (cf. 1. VII). Nerdel et al. (1952) have
resolved oxo compounds with D-tartramide acid hydrazide,
(d)
e.g.,
( )-menthylhydrazine.
NH a-CO-CHOH-CHOH-CO-NH-NH a
''
NHCOR'
NH-COR'
papain
R-CH-C02 H+ C 6 H5 -NH*
*"r-CH-CO-NH-C6 H5 +
DL-acid
NHCOR'
R-CHC02 H
D-acid
L-acid
phenomenon
is
exhibited
by compounds that
i.e.,
the
(+)-c^(-)-c
There are two types of asymmetric transformation, first order and second
order. These were originally defined by Kuhn (1932), but were later redefined by Jamison and Turner (1942).
Suppose we have an optically stable (+)-base (one equivalent) dissolved
in some solvent, and this is then treated with one equivalent of an optically
unstable ()-acid. At the moment of mixing, the solution will contain
equal amounts of [(+)-Base'(+)-Acid] and [(-f-)-Base'(- )-Acid] ; but since
the acid is optically unstable, the two diastereoisomers will be present in
unequal amounts when equilibrium is attained.
[(+)-Base-(+)-Acid]
^ [(+)-Base-(-)-Acid]
the solvent.
ORGANIC CHEMISTRY
54
[CH. II
CHjj-COsjH
NO,
O00 H
0H-CO 2 H
II
COH
2-acetomethylamido-4'
5-dimethylphenylsulphone, III.
CH3
CO-CH3
r"^3>cH3
m
pound was
acid,
10]
OPTICAL ISOMERISM
55
is
provided that their structures are not too dissimilar from that of the reference compound. Thus silica gel prepared in the presence of quinine adsorbs
quinine more readily than its stereoisomer quinidine; cinchonidine (configurationally related to quinine) is adsorbed more readily than its stereoisomer cinchonine (configurationally related to quinidine).
(vii) Kinetic method of resolution.
Marckwald and McKenzie (1899)
found that ( )-menthol reacts more slowly with ( )-mandelic acid than
with the (+)-acid. Hence, if insufficient ( )-menthol is used to completely
esterify ()-mandelic acid, the resulting mixture of diastereoisomers will
contain more ( )-menthyl (-f-)-mandelate than ( )-menthyl ( )-mandelate.
Consequently there will be more ( )-mandelic acid than (-f-)-mandelic acid in the unchanged acid, i.e., a partial resolution of ()-mandelic
acid has been effected (see also 5b. VI).
(viii) Ferreira (1953) has partially resolved ()-narcotine and ()-laudanosine (1-2-5 per cent, resolution) without the use of optically active
reagents. He dissolved the racemic alkaloid in hydrochloric acid and then
slowly added pyridine; the alkaloid was precipitated, and it was found to
be optically active. The explanation offered for this partial resolution is
as follows (Ferreira). When a crystalline racemic substance is precipitated
from solution, a crystallisation nucleus is first developed. Since this nucleus
contains a relatively small number of molecules, there is more than an even
chance that it will contain an excess of one enantiomorph or other. If it
be assumed that the forces acting on the growth of crystals are the same
kind as those responsible for adsorption [cf. (vi)], the nucleus will grow
preferentially, collecting one enantiomorph rather than the other.
Crystallisation, when carried out in the usual manner, results in the formation of
crystals containing more or less equivalent numbers of both enantiomorphs.
Channel complex formation has also been used to resolve racemic modifications (see Vol. I).
This also offers a means of carrying out a resolution
without asymmetric reagents, e.g., Schlenk (1952) added ()-2-chloro-octane
to a solution of urea and obtained, on fractional crystallisation, the two urea
inclusion complexes urea/(+)-2-chloro-octane and urea/( )-2-chloro-octane.
Baker et al. (1952) have prepared tri-o-thymotide, and found that it formed
clathrates with ethanol, -hexane, etc.
Powell et al. (1952) have shown that
tri-o-thymotide crystallises as a racemate, but that resolution takes place
when it forms clathrates with w-hexane, benzene or chloroform. By means
of seeding and slow growth of a single crystal, it is possible to obtain the
56
ORGANIC CHEMISTRY
[CH.
II
Me,CH
CHMe2
CHMe
tri-o-thymotide
11. The cause of optical activity. Two important points that arise
from the property of optical activity are: What types of structure give
(a)
(b)
(c)
Fig. 2.20.
a beam of plane-polarised light through a series of prisms composed alternately of dextro- and lsevorotatory quartz (Fig. 21). Two separate beams
emerged, each circularly polarised in opposite senses; this is an agreement
with Fresnel's explanation. Fresnel suggested that when plane-polarised
light passed through an optically active crystalline substance, the plane of
polarisation was rotated because of the retardation of one of the circular
components. Stated in another way, Fresnel's theory requires that the
refractive indices for dextro- and laevocircularly polarised light should be
It has been shown mathematically
different for optically active substances.
that only a very small difference between these refractive indices gives rise
OPTICAL ISOMERISM
11]
57
to fairly large rotations, and that if the refractive index for the laevocircularly
polarised light is greater than that for the dextro component, the substance
will be dextrorotatory.
The difficulty of Fresnel's theory is that it does
not explain why the two circular components should travel with different
velocities.
It is interesting to note, however, that Fresnel (1824) suggested
that the optical activity of quartz is due to the structure being built up
in right- and left-handed spirals (cf. 2).
Fig. 2.21.
Now
Fig. 2.22.
through molecule I makes an angle 8 with the plane of symmetry, and that the resultant rotation is +a. Then if the direction of
the light through molecule II also makes an angle 8 with the plane of
a.
symmetry, the resultant rotation will be
Thus the total rotation produced by molecules I and II is zero. In a solution of compound Ca 2 bd,
there will be an infinite number of molecules in random orientation. Statistically one can expect to find that whatever the angle 8 is for molecule I,
there will always be molecule II also being traversed by light entering at
angle 8. Thus, although each individual molecule rotates the plane
of polarisation by an amount depending on the value of 8, the statistical sum of the contributions of the individual molecules will be zero.
When a molecule is not superimposable on its mirror image, then if only
one enantiomorph is present in the solution, the rotation produced by each
individual molecule will (presumably) depend on the angle of incidence (with
respect to any face), but there will be no compensating molecules (i.e.,
mirror image molecules) present. Hence, in this case, there will be a net
light passing
ORGANIC CHEMISTRY
58
[CH.
II
rotation that is not zero, the actual value being the statistical sum of the
individual contributions (which are all in the same direction). Thus, if we
consider the behaviour of a compound in a solution (or as a pure liquid)
as a whole, then the observed experimental results are always in accord
with the statement that if the molecular structure of the compound
Any
is asymmetric, that compound will be optically active (2).
compound composed of molecules possessing a plane but not a centre of
symmetry is, considered as a whole, optically inactive, the net zero rotation
being the result of " external compensation " (cf. 7a). This point is of
great interest in connection with flexible molecules (4). Let us consider
wesotartaric acid, a compound that is optically inactive by internal compensation (7b). X-ray studies (Stern et al., 1950) have shown that the
staggered form of the molecule is the favoured one (Fig. 23 a). This has
a centre of symmetry, and so molecules in this configuration are individually
CQ 2 H
C0 2 H
OH
C0 2 H
-OH
HO
-OH
CO z H
HO
CO z H
C0 2 H
w
Fig. 2.23.
On the other hand, wesotartaric acid is usually represented by the plane-diagram formula in Fig. 23 (b). This corresponds to
the eclipsed form, and has a plane of symmetry. In this conformation the
individual molecules are optically active except when the direction of the
light is perpendicular (or parallel) to the plane of symmetry; the net rotation
is zero by " external compensation ".
It is possible, however, for the molecule to assume, at least theoretically, many conformations which have no
elements of symmetry, e.g., Fig. 23 (c). All molecules in this conformation
will contribute in the same direction to the net rotation.
If the total number
of molecules present were in this conformation, then mesotartaric acid would
have some definite rotation. On the theory of probability, however, for
every molecule taking up the conformation in Fig. 23 (c), there will also be
present its mirror image molecule, thereby giving a net zero rotation due
to " external compensation ". As we have seen, raesotartaric acid is optically inactive (as shown experimentally), and by common usage the inactivity is said to be due to internal compensation (7b).
optically inactive.
READING REFERENCES
Gilman, Advanced Organic Chemistry, Wiley (1943, 2nd
ed.).
Vol.
I.
Ch.
4.
Stereo-
isomerism.
290
et seq.
Vol.
IV
Optical Activity.
OPTICAL ISOMERISM
Mann and
59
Barker and Marsh, Optical Activity and Enantiomorphism of Molecular and Crystal
Structure, J.C.S., 1913, 103, 837.
Jones and Eyring, A Model for Optical Rotation, /. Chem. Educ., 1961, 38, 601.
Hargreaves, Optical Rotatory Dispersion: Its Nature and Origin, Nature, 1962, 195,
560.
Vol. 3 (1948).
Ch.
1.
Barton and Cookson, The Principles of Conformational Analysis, Quart. Reviews (Chem.
Soc), 1956, 10, 44.
Newman
Wiley
(1956).
Ch.
I.
Conforma-
tional Analysis.
Newman,
Chem. Educ,
CHAPTER
III
CARBON ATOM
1. The most extensively studied type of heterolytic substitution in
saturated compounds is the nucleophilic type, i.e., the SN 1 and S N 2 mechan-
isms.
One-stage process.
When two
labelled
Sn2
(Ingold, 1933).
The main difference between the two mechanisms is the kinetic order of the
reaction. Sn2 reactions would be expected to be second order (first order with
respect to each reactant), whereas SnI reactions would be expected to be first
These orders are only true under certain circumstances. In a biorder.
molecular reaction, if both reactants are present in small and controllable conIf, however, one of the
centrations, the reaction will be of the second order.
reactants is in constant excess (e.g., one reactant is the solvent), then the mechanism is still bimolecular but the reaction is now of the first order. Unimolecular
mechanisms often lead to first-order kinetics but may, under certain circumSince, however, it is possible
stances, follow a complicated kinetic expression.
to derive such an equation theoretically, it may be still decided whether the
mechanism is SnI by ascertaining whether the data fit this kinetic expression.
Another important difference between the Sn2 and the Sn 1 mechanism is that
in the former the configuration of the molecule is always inverted, whereas in
the latter there may be inversion and/or retention, the amount of each depending
on various factors (see later).
S N2
Y-
= transition
+ R-X-^Y-"R-X-^Y-R + XT.S.
slow
SN 1
<*
^~
fast
RX-^>R---X-^!>R+ + XT.S.
R+
+ Y--^>RY
A
fundamental
particular interest is the evidence for the SnI mechanism.
part of this mechanism is the postulate of carbonium ions as transient intermediates; but there appears to be no direct physical evidence for the presence
Symons et al. (1959) have shown that monoarylof aliphatic carbonium ions.
Of
6o
61
NUCLEOPHILIC SUBSTITUTION
2a]
carbonium ions axe stable in dilute solutions of sulphuric acid. They have also
found that the spectroscopic examination of solutions of 2-butanol and tsobutene
in sulphuric acid shows a single measurable ultraviolet band in both solutions.
This band appears slowly according to the first-order rate law for *-butanol, but
very rapidly for the olefin; the solutions are stable (and reproducible). The
authors conclude that there are trimethylcarbonium ions, CMe 3 +, in solution,
and that it is probable that this ion is planar. Symons et al. (1961) have also
obtained evidence, from ultraviolet studies, for the existence of the allyl carbonium ion in sulphuric acid; they examined solutions of allyl alcohol, chloride,
bromide, etc., in sulphuric acid.
On the other hand, triarylcarbonium ions have been obtained as salts, e.g.,
triphenylmethyl perchlorate, Ph sC+C10 4 - , and fluoroborate, Ph s C+BF 1 _
(Dauben jun. et al., 1960).
2. Any factor that affects the energy of activation (E) of a given type
Attempts have been
of reaction will affect the rate and/or the mechanism.
made to calculate
in terms of bond strengths, the steric factor, heats of
solutions of ions, etc., but apparently the results are conflicting. The
following discussion is therefore largely qualitative, and because of this, one
cannot be sure which are the predominant factors in deciding the energy of
activation.
shall discuss, for the hydrolysis of alkyl halides, the influence of the following factors The nature of
(polar and steric effects)
the nature of
and Y; and the nature of the solvent.
We
Me-^CH2 -^-X
Me^>V
OS-
^;cH-*>-:
Me'
Me
RX
RX
x 10 5
MeBr
EtBr
2140
170
t-PrBr
f-BuBr
4-7
0-24
1010
ORGANIC CHEMISTRY
62
[CH. Ill
by the S N 2 mechanism,
*'-PrBr
by
both
that the hydroxide ion does not enter into the rate-determining step of
the hydrolysis (1). This has been proved as follows. The hydrolysis of
<-BuBr was carried out in an alkaline solution containing less than the
equivalent amount of hydroxide ion (compared with the alkyl bromide).
Thus, although the solution was originally alkaline, as the hydrolysis proceeds, the solution becomes neutral and finally acid; nevertheless, the rate
constant of the hydrolysis remained unchanged.
As pointed out above, there are reactions which occur under intermediate
conditions, i.e., at the border-line between the extreme S^l and Sn2
mechanisms. Some authors believe that in this border-line region there
is only one mechanism operating, e.g., Prevost (1958) has postulated, on
theoretical grounds, the existence of a more universal " mesomechanism ".
is, however, much experimental work in favour of concurrent Si*l
and SN 2 mechanisms operating. Gold (1956) has described evidence for
this view, and more recently Swart et al. (1961) have shown that the exchange reaction between diphenylmethyl chloride and radiochlorine (as
LiCl*) in dimethylformamide occurs by a simultaneous Sn1-Sn2 mechanism.
The actual position where the mechanism changes over from Sn2 to SnI
There
graded series, e.g., in the one already described, is not fixed but depends
on other factors such as the concentration and nature of the nucleophilic
reagent, and on the nature of the solvent (see below).
Experimental work has shown that higher -alkyl groups behave similarly
to ethyl. For a given set of conditions, the kinetic order is the same, but
the rates tend to decrease as the number of carbon atoms increases, e.g.,
Hughes, Ingold et al. (1946, 1948) showed that the reactions between primary
alkyl bromides and ethoxide ion in dry ethanol are all S N 2, and their relative
rates (at 55) are Me, 17-6; Et, 1-00; -Pr, 0-31; -Bu, 0-23; w-pentyl, 0-21.
Similar results were obtained for secondary alkyl groups. In these cases
the mechanisms were both S N 2 and SN 1, but the rates for one or other
order were reasonably close, e.g., for the second-order reactions of secondary
bromides with ethoxide ion in dry ethanol at 25, Hughes, Ingold et al.
(1936- ) found that the relative rates were: *-Pr, 1-00; 2--Bu, 1-29;
2-w-pentyl, 1-16; 3--pentyl, 0-93. These authors also showed that higher
tertiary alkyl groups behaved similarly to t-Bu, all showing a strong tendency
to react by the S^l mechanism.
When hydrogen atoms in methyl chloride are replaced by phenyl groups,
the mechanism of the hydrolysis may be changed (from S N 2). The presence
of a phenyl group produces a carbonium ion which can be stabilised by
in a
<3-cH
2C
,^cr +
^3-6h
~ <^3=
:
e.g.,
CH2 *-^
(
stability of the
63
NUCLEOPHILIC SUBSTITUTION
2b]
>
>
>
Me^
a^>WJ
y-GH^Cl
fa
is
/N*<
V-CH -K>1
2
is
electron-attracting
(through resonance):
I
a+l
-c1
illustrate these
compounds:
COi
s-
Br-t-CH2---a
t26-
Br-w-CH
co2
Sn2
SnI
C0
t 35 -
Br-**-C -t-Me
col
SnI
2b. The nature of R. (b) Steric effects. In the transition state for
the Sjf2 mechanism, there are five atoms or groups bonded or partly bonded
to the reaction carbon atom (see 4). Thus the larger the bulk of these
groups, the greater will be the compression energy (i.e., greater steric strain)
in the transition state and consequently the reaction will be stericaUy
hindered. The problem is different for the S N 1 mechanism.
Here, the
transition state does not contain more than four groups attached to the
reaction carbon atom and hence one would expect that steric hindrance
should be less important. On the other hand, if the molecule undergoing
64
"
ORGANIC CHEMISTRY
[CH. Ill
the SN 1 mechanism contains particularly large groups, then the first step
of ionisation may relieve the steric strain (4a. II) and so assist the formation
of the carbonium ion, i.e., the reaction may be sterically accelerated.
Let us now examine some examples involving steric effects.
(i) The following series of alkyl halides, MeX, EtX, '-PrX
and tf-BuX,
may be made to undergo the SN2 mechanism under suitable conditions
the transition state contains three o-bonds (sp 2 hybridisation) in
(cf. 2a)
one plane and two partial bonds which are collinear and perpendicular to
this plane.
Thus we have:
;
-i
-i
T--C--X
_t
Y--C--X
f*
.,
.t
Y--C--X
Y--C--X
-1
"4.
Me
Y C -X
4
At
Y C
-i
their transi-
Me
Kj/H
H\l/H
Me\ I^Me
-x
-i
Y CX
-i
sight one
position close to the plane of the transition state (i.e., the plane containing
the three <r-bonds), and so would not offer any appreciable steric hindrance.
In practice, however, w-propyl halides are less reactive than the corresponding ethyl halides (cf. 2a). The reason for this relatively large decreased
reactivity is not certain. Magat et al. (1950) have offered the following
explanation. The smaller the number of conformations available in the
activated as compared with the initial state produces a decrease in the
frequency factor (A in the Arrhenius equation k
A<?- E / BT ).
In w-propyl
halides (2
and 1 Me) there is only one conformation for the transition
state whereas for ethyl halides (3 H) there are three equivalent conformations.
Thus the frequency factor for w-propyl halides is 1/3 that for the
ethyl halides, and so the reaction rate (k) of the former will be 1/3 that of
the latter (on the assumption that
of both reactions is the same).
In wobutyl halides the methyl groups will produce a large steric effect
since at least one methyl group will be fairly close to
or Y. It has been
shown experimentally that wobutyl halides are less reactive than -propyl
halides.
Finally, in weopentyl halides, the presence of three methyl groups
produces a very large steric effect. In the " normal " transition state,
the entering and displaced groups are collinear. This is readily possible
with all the halides except possibly wobutyl halides but it is not possible
with weopentyl halides because of the presence of the three methyl groups
(in the 2-butyl group).
Thus in the transition state involving the weopentyl
radical, the
bonds are believed not to be collinear but " bent
away " from the J-butyl group. Such a " bent " transition state has a large
compression energy and so is far more difficult to form than a " normal
Y C X
NUCLEOPHILIC SUBSTITUTION
2c]
transition state.
e.g.,
Hughes
et al.
65
::
0-04
10~ s
These very slow SN 2 reactions of eopentyl halides occur with the neopentyl
radical remaining intact. By changing the solvent conditions so that the
mechanism becomes SN 1, the products are no longer weopentyl derivatives
but rearranged products formed by a 1,2-shift (see 23d. VIII).
(ii) A very interesting example of steric hindrance is the case of 1-chloroapocamphane (I). Bartlett et al. (1938) found that this compound does
not react with reagents that normally react with alkyl halides, e.g., it is
unaffected when refluxed with aqueous ethanolic potassium hydroxide or
ci
IV
III
pounds) is not certain, but it has been suggested that the extra bonds in
the larger bridge in (IV) help to relieve the strain in the formation of the
carbonium ion which tries to assume a planar configuration.
(iji) Brown et al. (1949) showed that the solvolysis of tertiary halides
is
subject to steric acceleration. {Solvolysis is the nucleophilic reaction in
which the solvent is the nucleophilic reagent.)
R3C-^X -^- R 3 C +
It
X"
tetrahedral
planar; trigonal
(large strain)
(small strain)
The nature
ORGANIC CHEMISTRY
66
>
[CH. Ill
>
RI
RBr RC1. It has been suggested that a contributing factor to
this order is steric strain, since the volume order of these halogen atoms is
I
Br
CI.
Another contributing factor is the increase in energy of
activation in the order RC1
RBr RI, since the bond to be broken
increases in strength in this order; the bond energies are: C CI, 77 kg.cal.
C Br, 65 kg.cal.; C I, 57 kg.cal. These energy differences also explain
the order of reactivity RI
RBr RC1 in SN2 reactions.
>
>
>
>
>
>
OH-
OPh-
74,300
1340
Anion
2nd-order rate const,
lst-order rate const,
x 10 5
x 10 6
HCO,-
Br-
ci-
7-38
7-85
7-32
can be seen from these results that the strong nucleophiles OH- and
react rapidly by the Sn2 mechanism and the other, and weaker,
nucleophiles react at about the same slow speed by the S N 1 mechanism.
Although many kinetic investigations of displacement reactions with
alkyl halides have been carried out, relatively little information is available for determining nucleophilicity. One set of data that may be cited
is that obtained from the reaction between methyl iodide and various bases
in benzene at 25 (Hinshelwood el al., 1935):
It
OPh~
Relative rate
Pyridine
Me,N
Et sN
Quinoline
1730
144
0-26
F-;
RS~
> RO~.
This order
is
NUCLEOPHILIC SUBSTITUTION
2e]
67
The
Experimentally,
it
Dissociation
intimate
ion-pair
N.B.
external
lon-pair
dissociated
ions
of ion-pair
is
ORGANIC CHEMISTRY
68
[CH. Ill
We
Increasing the polarity of the solvent will greatly increase the reaction rate,
and since the transition state has a larger charge than the initial reactant
molecule, the former is more solvated than the latter (rule ii). Thus the
transition state is more stabilised than the reactant molecule. Thus solvation lowers the energy of activation and so the reaction is assisted.
The rates of SN2 reactions are also affected by the polarity of the solvent.
HO^R-41
^V HO R X
-^HO-R +
X~
solvent with high dipole moment will solvate both the reactant ion and
the transition state, but more so the former than the latter, since in the
1/2), is more
latter the charge, although unchanged in magnitude (d
dispersed than in the former (rule iv). Thus solvation tends to stabilise
the reactants more than the transition state, i.e., the activation energy is
increased and so the reaction is retarded.
Now let us consider the Menschutkin reaction:
A
R3 N+
R-Lx
s+
s-
> R 3 N R X
>-
R4 N + X
transition state is greater than that on the reactant molecules ; hence the former is more solvated than the latter. Thus the energy
of activation is lowered and the rate of reaction thereby increased. Also,
the greater the polarity of the solvent, the greater should be the solvation.
The foregoing predictions have been observed experimentally.
In the following S N 2 reaction, charges decrease in the transition state,
HO"'RNR 3
**
NR ~HOR +
HO-~R
R3N
and hence increasing the polarity of the solvent will retard the reaction;
and retardation will be greater than that in the SN2 hydrolysis of alkyl
halides (see above; only the hydroxide ion is charged in this case).
The polarity of the solvent not only affects rates of reactions, but may
also change the mechanism of a reaction, e.g., Olivier (1934) showed that
the alkaline hydrolysis of benzyl chloride in 50 per cent, aqueous acetone
proceeds by both the Su2 and S^l mechanisms. In water as solvent, the
mechanism was changed to mainly SN 1. The dipole moment of water is
greater than that of aqueous acetone, and consequently the ionisation of
benzyl chloride
is facilitated.
NUCLEOPHILIC SUBSTITUTION
3]
69
+1
groups,
effects of the
for i-BuBr.
These results were explained by the
but it also follows that the greater the ionising power of the solvent, the less
will be the +1 effect of an
group necessary to change the mechanism
Sjj2 to S^l.
RY -^ RX %- RZ
In the Sn2 mechanism there is only one reaction step, and so the overall rate
and product ratio will be determined by that stage. In the S^l mechanism,
however, the rate is determined by the rate of ionisation of RX, and the
product ratio is thus determined by the competition of the fast second steps.
It therefore follows that for solvent changes, in the Sn2 mechanism the
rate and product ratio will proceed in a parallel fashion, whereas in the
S N 1 mechanism the rate and product ratio will be independent of each
other.
A simple example that illustrates this problem is the solvolysis of
benzhydryl chloride (diphenylmethyl chloride). Hammett et al. (1937,
1938) showed that the solvolysis of benzhydryl chloride in initially neutral
aqueous ethanol gave benzhydryl ethyl ether and benzhydrol. Hughes,
Ingold et al. (1938) showed that if ethanol is first used as solvent and then
water is progressively added, the overall rate increases, but there is very
little increase in benzhydrol formation the main effect is an increased rate
of formation of benzhydryl ethyl ether.
Thus the rate of the reaction and
the ratio of the products are determined independently; this is consistent
with the S N 1 mechanism but not with the Sjj2.
It can be seen from this example that kinetic solvent effects may be used
to differentiate between Su2 and S^l mechanisms.
;
3.
By a series of replace-
(Optical inversion).
ment reactions, Walden (1893, 1895) transformed an optically active compound into its enantiomorph. In some cases the product is 100 per cent,
optically pure, i.e., the inversion is quantitative; in other cases the product
a mixture of the (+)- and ( )-forms in unequal amounts, i.e., inversion
and retention (racemisation) have taken place.
The phenomenon was first discovered by Walden with the following
reactions
is
CHOH-CO.H
CHCl-CO aH
pci.
>
I
CH2 -C0 2H
koh
"AgOH"
CH a -C02H
CHOH-C0 2H
j
^CHg-CCyi
(+)-chlorosuccinic
acid
(+)-malic acid
acid
I
II
III
( )-malic
The Walden
( )-form
ORGANIC CHEMISTRY
70
[CH. Ill
mechanism
J-OH H-^OR'
R-CO)-L(M*
H-^5
,(
>-
RCOOR'
H2
Kenyon assumed that in all reactions of this type the R' O bond remained
and consequently no inversion of the alcohol is possible. The follow-
intact
C0 2Et
Me
f/
>
OH
iv
(+);
C0 8Et
Me
TsC1
\r
N
OTs
(+)-;
J AcO"K+
Ac.O
C0 8Et
Me
Me
W/\OAc
(-) -; vi
OAc
C
CO aEt
(+)-; vii
(VI) have the same relative configurations even though the sign of rotation
has changed. Similarly, (IV) and (V) have the same relative configurations.
Reaction of (V) with potassium acetate, however, produces (VII), the
enantiomorph of (VI). Therefore inversion must have occurred in the
formation of (VII); (V) and (VI) are produced without inversion since in
these cases the C O bond in (IV) is never broken. It should be noted
here that if inversion is going to take place at all, the complete group attached
to the asymmetric carbon atom must be removed (in a displacement reaction) (cf. Fischer's work on (+)-*sopropylmalonamic acid, 3a. II).
The
converse, however, is not true, i.e., removal of a complete group does not
7l
NUCLEOPHILIC SUBSTITUTION
4]
of potassium acetate,
configuration:
Me
Me
C0 2Et
CI
OTs
C02Et
and
Mechanism
amount
HO
R-^X
>
HO RX
*-
HO R
(1)
Hughes et al. (1935) studied (a) the interchange reaction of (+)-2-iodooctane with radioactive iodine (as Nal*) in acetone solution, and (b) the
racemisation of (+) -2-iodo-octane by ordinary sodium iodide under the same
conditions. These reactions were shown to take place by the Su2 mechanism, and the rate of racemisation was shown to be twice the rate of
radioactive exchange, i.e., every iodideiodide* displacement is always
accompanied by inversion. (Suppose there are n molecules of optically
active iodo-octane. When w/2 molecules have exchange with I* and in
doing so have been inverted, racemisation is now complete although the
exchange has taken place with only half of the total number of molecules.)
Thus this experiment leads to the assumption that inversion always occurs
in the Sjf2 mechanism. This is fully supported by other experimental
work, e.g., Hughes et al. (1936, 1938) studied the reaction of optically active
oc-bromoethylbenzene and a-bromopropionic acid with radioactive bromide
ions, and again found that the rates of exchange (of bromide ions) and
inversion were the same.
Thus the Walden inversion affords a means of studying the mechanism
of substitution reactions.
If complete inversion occurs, the mechanism is
S N2, or conversely, if the mechanism is known to be S N 2 (by, e.g., kinetic
data), complete inversion will result. This is the stereokinetic rule for Sjj2
reactions, and its use thus offers a means of correlating configurations.
The essential problem that now arises is the consideration of the forces
that determine the direction of attack, since the S N2 mechanism might
conceivably have taken place with retention as follows:
,x
RX
+ OH"
*-
8-
RC'
\>H-
**
ROH
X"
(2)
72
ORGANIC CHEMISTRY
[CH.
HI
CX bond causes
RX from the
R\
CX > HO CX
HO~ +
,.
,.
*-
HO C^
KR
R
Hughes and Ingold
+ X"
AcO
(1937),
*\>CNMe
Hy
AcO O.
^H
Me
Me
1.
2.
3.
4.
+ Me.N
3
is
Reagent
Substrate
negative
negative
neutral
neutral
neutral
positive
neutral
positive
The
stereokinetic rule for Sn2 reactions is well established for only reactions
of type 1.
Hughes, Ingold et al. (1960) have also shown that the rule
applies to type 2, e.g., the reaction between a sulphonium iodide and sodium
azide (cf. Snyder's work):
CHMePh-SMe2+
+ N,-
- CHMePh-N
+ Me S
2
These authors have also demonstrated that type 4 proceeds by the Sn2
mechanism, e.g., with a sulphonium nitrate:
Me3N
Now
let
Me3NMe+
Me^S
R-^X
When
+ MeSMe +
>-
R---X
> R+ +X"
-^V ROH
X"
the reaction proceeds by this mechanism, then jnversion and retention (racemisation) will occur, the amount of each depending on various
factors.
The carbonium ion is flat (trigonal hybridisation), and hence
attack by the nucleophilic reagent can take place equally well on either side,
i.e., equal amounts of the (+)- and ( )-forms will be produced; this is
racemisation. One can expect complete racemisation only if the carbonium
ion has a sufficiently long life; this is favoured by low reactivity of the
carbonium ion and low concentration of the nucleophilic reagent. However,
during the actual ionisation step, the retiring group will " protect " the
carbonium ion from attack on that side, i.e., there is a shielding effect, and
this encourages an end-on attack on the other side, thereby leading to
NUCLEOPHILIC SUBSTITUTION
5]
inversion.
73
An example
above)
18
EtMeCHOH
HCIO
+ H+
EtMeCHOH 2 +
fast
^+
slow
EtMeCHOH 2 + =^
H 0* + EtMeCH OH
2
i=
(3)
v
'
0+
EtMeCH OH a
(4)
=*H 0* EtMeCH OH
=<
fast
H 0*CHMeEt + H 2
HO*CHMeEt + H+
(5)
fast
H 20* CHMeEt
OH
H
results
..
(6)
8+
slow
6+
H 0* + EtMeCHOH 2 +
H 2Q* EtMeCH OH
H 20* CHMeEt + H 2
,
fnai
2
>,
R O
S=0
>~
R O S=0
HC1
CI
CI
R-O- S=0
-***-+
CI -R- OSO
(ii)
S N 1.
R-0-S=0
Cf +
**>.
-J
CIR + S02
R-^ S=0
CI
+
-i!*^R + o"S=0
-^^
RC1 + S02
ORGANIC CHEMISTRY
74
possibly be:
0 8=0
(iii)
SNt.
[CH. III
-&|L>- S0 2 + Cf
*,
*-
RC1
is
effectively
a four-
centre type).
R-^-0^
S=0
s=o
-> RCl
+ S02
In practice, the a-chloroethylbenzene obtained has almost complete retention of configuration, and consequently the mechanism must be Sn*.
point of interest here is that it is apparently difficult to postulate the nature
of the transition state in this mechanism.
When a-phenylethanol and thionyl chloride react in the presence of
pyridine, the a-chloroethylbenzene obtained now has the inverted configuraThe explanation offered is that the SN2
tion (Hughes, Ingold et al., 1937).
mechanism
R0S0C1
is
now being a
C 5H 6N -*
CI-
+ ROSONC H
5
pyridine complex:
Participation of neighbouring groups in nucleophilic substituSo far, we have discussed polar effects (inductive and resonance)
and steric effects on the rates and mechanisms of reactions. In recent
years it has been found that another factor may also operate in various
This factor is known as neighbouring group participation. Here
reactions.
we have a group attached to the carbon atom adjacent to the carbon atom
where nucleophilic substitution occurs and, during the course of the reaction,
6.
tions.
becomes bonded or partially bonded to the reaction centre. Thus the rate
and/or the stereochemistry of a reaction may be affected by this factor.
When a reaction is accelerated by neighbouring group participation, that
reaction is said to be anchimerically assisted (Winstein et al., 1953). For
anchimeric assistance to occur, the neighbouring group, which behaves as a
nucleophilic reagent, must be suitably placed stereochemically with respect
to the group that is ejected. This is the ^raws-configuration, and in this
conditions for intramolecular displacement are best.
is also of great importance in the 1,2-shifts
(see Vol. I; see also 2h. VI).
configuration the
al.
(1937)
NUCLEOPHILIC SUBSTITUTION
6a]
75
When the ester was subjected to methanolysis, i.e., methanol was the
solvent (no methoxide ion now present), the product was again L-methoxy
ester (100 per cent, inversion).
The reaction was now first order [i.e., pseudo
first order), but still Sn2, the nucleophilic reagent being the solvent molecules of methanol.
When the sodium salt of D-a-bromopropionic acid was
hydrolysed in dilute sodium hydroxide solution, the mechanism was shown
and the product was now D-a-hydroxypropionate anion (100 per
In concentrated sodium hydroxide solution, however, the
mechanism was S^2 (due to the high concentration of the hydroxide ion),
and the product was L-oc-hydroxypropionate anion (100 per cent, inversion).
Hughes and Ingold have proposed the following explanation for the
retention experiment. The first step is ionisation to a carbonium ion in
which the negatively charged oxygen atom forms a " weak electrostatic
bond " with the positively charged carbon atom on the side remote from
that where the bromide ion is expelled. Thus this remote side is " protected " from attack by the hydroxide ion, which is consequently forced
to attack from the same side as that of the expelled bromide ion, thereby
to be SnI,
cent, retention).
/Me
7>
Ox
r/
stow
XBr
t,
^^ \h
>
Br-
/Me
+/
+O
oh-
Nx>/ \h
protection
Me
Ox
XXX
XOI
OH
\H
retention
COi
-^ H
Nh2
H
Me
-^6^I
*2
C02 H
OH
Me
Me
d(-) -alanine
ORGANIC CHEMISTRY
76
[CH. Ill
Me
Me
.CHNj
N2
(^
.+
CH2
participa-
shown:
tion occurring as
CH
CH
/\}
f
*-CH2
CH COH.
CH2
N CH C^O-^H
?
/CO
cHa
site,
originally
were
first
OH/Me
0H 2..Me
TT
H.
-H 2
H+
inversion
at
H-Y
Br
,.c 2
Ci
ii--
H'
-Me
,-Me
+
>Br
~-Me
Br
( )-forma
H-.
-^>
B,
YMe
f
H''
H-.
B VMe
Y
.c 2
HX Br^Me
"Me
Br
(+)-form
(--)-form
Br
S N2
C Ci
2
Br
^-
C (V- + H
2
+OH 2
Br
Br
SnI
-H s
Cj
2
Br+OH,
*2
^i\
I
>
Br-
^2
*^i
Br Br
Br
^2
^1
Br
occurred only at
have been a
Cv
classical
NUCLEOPHILIC SUBSTITUTION
6c]
3-bromobutan-2-ol
meso-form.
(I)
(II)
and
(III)
OH 2
OH
.Me
Me
^
inversion
at
-'C2-.
PH
Me
Ci
.-Me
H-.
-H 2 o
Vie'
77
Me
^>Br
."< H
Br
Br
I
Br
Br
H\T/-Me
H-..
Br^
Me'
..-Me
^H
Me";
"H
Br
Br
II
III
evidence that all the halogen atoms can form cyclic ions and
offer anchimeric assistance, e.g., Winstein et al. (1948, 1951) studied the
acetolysis of cis- and ft-s-2-halogeno-cycZohexyl brosylates (i.e., />-bromobenzenesulphonates; this group is often written as OBs):
There
is
-X
-OBs"
trans
X
AcOH
OAc
X
:OBs~
BsO.
as
In the absence of neighbouring group participation, the rates would be
expected to be about the same. If participation occurs, then this is readfly
possible in the trans-isomer (la 2a) by attack of
at the rear of the ejected
OBs- ion, but this is not so for the cw-isomer (le 2a; see 11. IV). The
rate ratios observed were:
trans /cis:
Thus
X=
I,
2-7
10 6 /1;
X = Br,
800/1;
X = CI,
3-8/1.
oh:
H2
-cr
ORGANIC CHEMISTRY
78
[CH. Ill
Bergvist (1948) showed that this reaction proceeds more than 100 times as
fast as that when the cts-compound is used.
Here again, the trans-iorm
permits ready attack at the rear of the chloride ion whereas the cw-isomer
does not (cf. 6b). The fact that the cw-form does react may be explained
by assuming that the reaction proceeds via the trans-torm, i.e., the former
is first converted into the latter.
This requires energy of activation and
consequently the reaction for the a's-form is slowed down (cf. 6d).
Another example of neighbouring hydroxyl participation is the conversion
of sugars into epoxy-sugars (see 9. VII).
6d. Neighbouring acetoxyl group. Winstein et al. (1942, 1943)
showed that a neighbouring acetoxyl group leads to the formation of an
acetoxonium ion. foms-2-Acetoxycyc/ohexyl brosylate (I) forms trans-1,2diacetoxycyc/ohexane (II) when treated with silver acetate, and the same
product (II) is obtained when the starting material is trans-2-acetoxycyclohexyl bromide (III). The authors believe that the course of the reaction,
based on the stereochemical evidence, proceeds through the same acetoxonium ion (IV). This mechanism is supported by the fact that in each
case, when the reaction was carried out in the presence of a small amount
of water, the product was now the monoacetate of c*'s-cycMiexane-l,2-diol(V)
some diacetate
of this a's-diol
was
also obtained.
Me
,0
A.c
AcO"
-BsO"
<$
OAc
-OBs
(II)
(I)
Me
HO^JU-0
/
o
OAc
HO.
>Br
(v)
(in)
Further support
(V)
EtO
79
NUCLEOPHILIC SUBSTITUTION
7]
fact that
when the
(Winstein
et al.,
solvolysis of
(I) is
is
obtained
1943).
ASYMMETRIC SYNTHESIS
Partial asymmetric synthesis may
7. Partial asymmetric synthesis.
be defined as a method for preparing optically active compounds from
symmetrical compounds by the intermediate use of optically active compounds, but without the necessity of resolution (Marckwald, 1904). In
ordinary laboratory syntheses, a symmetrical compound always produces
the racemic modification (7a. II).
The first asymmetric synthesis was carried out by Marckwald (1904),
who prepared an active ( )-valeric acid (laevorotatory to the extent of
about 10 per cent, of the pure compound) by heating the half-brucine salt
of ethylmethylmalonic acid at 170.
I
and
V and VI
and IV.
are enantio-
morphs, and since the mixture is optically active, they must be present in
unequal amounts. Marckwald believed this was due to the different rates
of decomposition of diastereoisomers I and II, but according to Eisenlohr
and Meier (1938), the half-brucine salts I and II are not present in equal
amounts in the solid form (as thought by Marckwald). These authors suggested that as the less soluble diastereoisomer crystallised out (during
CH3\
/C0 H
2
w brudne
.
CgH^ ^C02 H
C02 H[B-brucine]
CH,
^C02 H
<\Kf
G02 H
CH3
NX> H [(-)-brucine]
G2 Bf
II
, y
CjsHf'
^H
CH3 ^
^H
C 2 H.f
^C0
CI
hc.
2 H[(-)-brucine]
IV
III
/C0 H
2
Hf ^H
V
CH.
C2 Hf^
^0O H
2
VI
evaporation of the solution), some of the more soluble diastereoisomer spontaneously changed into the less soluble diastereoisomer to restore the
equilibrium between the two; thus the final result was a mixture of the
half-brucine salt containing a larger proportion of the less soluble diastereoisomer. If this be the explanation, then we are dealing with an example
of asymmetric transformation and not of asymmetric synthesis (see 10. II).
Further work, however, has shown that Marckwald had indeed carried out
an asymmetric synthesis. Kenyon and Ross (1951) decarboxylated optically
active ethyl hydrogen ethylmethylmalonate, VII, and obtained an optically
inactive product, ethyl (^J-a-methylbutyrate, VIII.
CHS
/C0 H
2
C2 H 5-^ ^C02 C2 H5
VII
active
co2 +
C 2 Hr
^C0
VIII
inactive
C2 H5
80
ORGANIC CHEMISTRY
[CH. Ill
salt of VII,
and
still
CH^
>-
C2 H,<
^H
.0 ^
\C0
+ COo +
C 2 H5
cinchonidine
VIII
inactive
C02 H[(-)-brucine]
CHj.
^C0 H
C2 Hf^
\
/"*"
T
1
C02 H
CH3
C
C 2Hf^
CH3. e
^0-C0 HT(-)-brucine]
2
2H5
la
'
^C0
2 H[(-)-brucine]
II
CH3
C2 H 5
/ C0 H
2
\C0
VH
C2 H5
> >
/
C0 H(cinchonidine)/
CH3
C2 Hf
ch3
C 2 H5
^C-C0 C H
Vila
^C0
C 2 H5
^CQjHCB-brucine]
*\QT
C2Hs
^COaHCH-brucine]
CHj^G
CH,.
*~
^C 0O H [(-)-brucine]
2
C2Hf
la
On
if
Ross did, in
fact,
the carbanion la
NUCLEOPHILIC SUBSTITUTION
7]
McKenzie
by reduction
81
C 6 H 5 -COC0 2 H
(-)-C10H 19OH
CeHs-CHOH-COjAoHi,
+ H ^%
H -CHOH-C0 H + (-)-C H 19OH
-+ C 6H 6 -COC0 2C10H 19
-^ C
10
() -rotation
Similarly, the pyruvates of ( )-menthol, ( )-pentyl alcohol and ( )-borneol
gave an optically active lactic acid (slightly laevorotatory) on reduction.
McKenzie
/OMgl
C 6 Hs-CO-CO2 C10HM +
CH3-MgI
>-
CeHs-C^-COjAoHjg
CH3
^*-
OH
C 6 H5
C^C0 H
2
^CH
(-)-C10
19
OIi
(-)-rotation
Turner
0=0
OH/
CsH^
OHs^
Zn+ CHaBr-COadoHj,
C6 H5
^.OZnBr
>
^CHa-COgCioHjg
\ c ^,OH
\CH -C0 H
CHj^
(+) -rotation
Reid
tory alcohol.
WWTOM
>
(CH3 3C.CHOH.C 6H 13
( )-rotation
)
(CH 3) 3OCOCH 3
'^-ch.^.ch^.ch.m.c^
ORGANIC CHEMISTRY
82
[CH. Ill
CH3 -COCa2H s
^^
(+)-camphor
>
CH B3 -CHOH-Cz2H s5
(+)-rotation
It has already been pointed out that a molecule containing one asymmetric carbon atom gives rise to a pair of diastereoisomers in unequal
amounts when a second asymmetric carbon atom is introduced into the
molecule (7b. II). In general, if a new asymmetric centre is introduced
into a molecule which is already asymmetric, the asymmetric part of the
molecule influences the configuration formed from the symmetrical part of
the molecule, the two diastereoisomers being formed in unequal amounts,
e.g., the Kiliani reaction (see also Vol. I).
CN
CN
CHO
hcn
*-
H C OH
I
HO C
CHOH
CHOH
CHOH
I
'
et al.
(1953)
steric course of
^% C H -CR(OH)CO H
6
Prelog et al. found that the configuration of the asymmetric carbon atom
in the stereoisomer that predominated in this reaction could be correlated
with that of the carbinol carbon of the alcohol. The basis of this correlation
was the assumption that the Grignard reagent attacks the carbon atom (of
the ketone group) preferentially from the less hindered side. This necessitates a consideration of the possible conformations of the ester molecule.
The authors considered that the most stable conformation of the ester was
the one in which the two carbonyl groups are planar and trans to each
other, with the smallest group lying in this plane and the other two groups
skew. Furthermore, with the groups on the carbinol atom of the alcohol
arranged in the staggered conformation with respect to the rest of the
will be the conformations of the esters with the
molecule, then IX and
a respectively (thick lines
enantiomorphous alcohol residues IX a and
represent groups in front of the plane, broken lines groups behind, and
ordinary lines groups in the plane). Thus, with L behind, methylmagnesium halide attacks preferentially from the front (IX); and with L in
The a-hydroxyacid obtained from
front, the attack is from behind (X).
IX is IX b, and that from is b. IX b and b are enantiomorphs and
hence the configuration of the new asymmetric centre is related to that of
the adjacent asymmetric centre in the original molecule. Thus for the
same keto-acid and the same Grignard reagent, and using different optically
active alcohols belonging to the same configurational series, the product
should contain excess of a-hydroxyacids with the same sign of rotation.
This has been shown to be so in practice, e.g., ( )-menthol and ( )-borneol
83
NUCLEOPHILIC SUBSTITUTION
7]
M
HO
-c -OH
i
I
i
L
IX a
Xa
O
-M
II
Ph
N^N)'
Ph.
.,0^
II
MeMgX
.OH
-L
O'
MeMgX
IX
Ph.
,Cb
.Me
Plu
A,
||
/0^-m
^O'
OH
Me
C02 H
C02 H
HO
Me
Ph
IX b
Ph
Xb
be seen from the following equation starting with the pyruvic ester XI in
which the configuration of the alcohol is IX a, the product would be
b.
:
XL
Me.
-XT
NK
-M
ll\
Me^
,L
II
>-
.OH
^CTPh
PhMgBr
XI
C09 H
i
Xb
||
CL
Au
JOg-M
ORGANIC CHEMISTRY
84
[CH. Ill
results
R'MgX
H-
..R'
IT
^R
M^C C^-OH
or,
using the
Newman
projection formulae:
:A
HO
R'MgX^
R
L
An example
Xy^
Me
Me
Me
^H
HOv.
MeMgBr
?NPh
H^
Me
XII
/H
Mes
i?
OH
IK
^Ph
X][II
According to the above rule, XII should predominate; this has been found
to be so in practice.
Cram's rule does not give the correct stereochemical prediction when one
of the groups (e.g., hydroxyl) attached to the carbon atom alpha to the
carbonyl group is capable of chelating with a metal atom in the reagent,
unless this chelating group is " medium " in effective bulk.
The influence of enzymes on the steric course of reactions has also been
investigated, e.g., Rosenthaler (1908) found that emulsin converted benzaldehyde and hydrogen cyanide into dextrorotatory mandelonitrile which was
almost optically pure. It has been found that in most enzymic reactions
the product is almost 100 per cent, of one or other enantiomorph. Enzymes
are proteins and optically active (see also 12. XIII), but since they are so
" one-sided " in their action, it appears likely that the mechanism of the
reactions in which they are involved differs from that of partial asymmetric
85
NUCLEOPHILIC SUBSTITUTION
8]
syntheses where enzymes are not vised. It has been suggested that enzymes
are the cause of the formation of optically active compounds in plants.
Although this is largely true, the real problem is: How were the optically
Ferreira's work [10(viii). II], howactive enzymes themselves produced?
ever, shows that optically active compounds may possibly be produced in
living matter by activation of a racemic modification. This theory appears
to be superior to that of the formation of optically active compounds by
the action of naturally polarised light (see following section).
products.
Davis and Heggie (1935) found that the addition of bromine to 2 4 6a beam of right-circularly polarised light gave a dextro:
trinitrostilbene in
rotatory product.
N02
N0^2V-CH=CH-h^>
N0 2
NOy^^-CHBr-CHBr-^^
N02
N0
(+) -rotation
al.,
1945).
86
ORGANIC CHEMISTRY
[CH. Ill
READING REFERENCES
Hinshelwood, The Kinetics of Chemical Change, Oxford Press (1940, 4th ed.).
Moelwyn-Hughes, The Kinetics of Reactions in Solutions, Oxford Press (1947, 2nd ed.).
Glasstone, Laidler and Eyring, The Theory of Rate Processes, McGraw-Hill (1941).
Frost and Pearson, Kinetics and Mechanism, Wiley (1961, 2nd ed.).
Friess and Weissberger (Ed.), Technique of Organic Chemistry, Interscience Publishers.
Vol. 8 (1953). Investigation of Rates and Mechanisms of Reactions.
Ingold, Structure and Mechanism in Organic Chemistry, Bell and Sons (1953).
Hine, Physical Organic Chemistry, McGraw-Hill (1962, 2nd ed.).
Gould, Mechanism and Structure in Organic Chemistry, Holt and Co. (1959).
Streitwieser, Solvolytic Displacement Reactions at Saturated Carbon Atoms, Chem.
Reviews, 1956, 56, 571.
Bethell and Gold, The Structure of
Carbonium
12, 173.
CHAPTER IV
GEOMETRICAL ISOMERISM
Maleic and fumaric acids both
1. Nature of geometrical isomerism.
have the same molecular formula C4H 4 4 but differ in most of their physical
and in many of their chemical properties, and neither is optically active.
It was originally thought that these two acids were structural isomers;
this is the reason for different names being assigned to each form (and to
many other geometrical isomers). It was subsequently shown, however,
that maleic and fumaric acids were not structural isomers, e.g., both (i) are
catalytically reduced to succinic acid; (ii) add one molecule of hydrogen
bromide to form bromosuccinic acid; (iii) add one molecule of water to form
malic acid; (iv) are oxidised by alkaline potassium permanganate to tartaric
acid (the stereochemical relationships in reactions (ii), (iii) and (iv) have been
ignored; they are discussed later in 5a). Thus both acids have the same
,
we assume
C0 2 H
C0 2 H
H *-
^CQ2 H
H0 2 C
Fig. 4.1.
an arrangement would be rigid, i.e., free rotation about the double bond is
not to be expected. Furthermore, according to the above arrangement, the
two hydrogen atoms and the two carboxyl groups are all in one plane, i.e.,
the molecule is flat. Since a flat molecule is superimposable on its mirror
image, maleic and fumaric acids are therefore not optically active (2. II).
As we shall see later, modern theory also postulates a planar structure for
these two acids, but the reasons are very much different from those proposed
by van't Hoff as described above (see also 3a. V).
The type of isomerism exhibited by maleic and fumaric acids is known as
geometrical isomerism or cis-trans isomerism. One isomer is known
as the cts-compound, and the other as the trans, the as-compound being
the one which (usually) has identical or similar atoms or groups, on the
same side (see also 4). Thus molecule I is c*s-butenedioic acid, and II is
87
ORGANIC CHEMISTRY
88
[CH. IV
frans-butenedioic acid.
(i)
(ii)
(iii)
We
CH 2=CH 2
40 kg.cal./mole;
C 6H 5 -CH=CH-C 6 H 5
42-8 kg.cal./mole;
CH 3 -CH=CH-CH 3 18 kg.cal./mole;
C0 2 H-CH=CH-C0 2H, 15-8 kg.cal./mole.
,
Let us consider the case of maleic and fumaric acids in more detail. It
can be seen from the diagram (Fig. 2 b) that there are two favoured positions,
with the trans-iorm more stable than the cis, the energy difference between
the two being 6-7 kg.cal./mole. The conversion of the trans to the cis
requires 15-8 kg.cal. energy, but the reverse change requires about 10 kg.cal.
(see also 6 for a further discussion of cis-trans isomerisation).
90
180
270'
360'
90"
Angle
Angle of Rotation
180
270
360
of Rotation
(6)
(a)
Fig. 4.2.
In the foregoing
3. Modern theory of the nature of double bonds.
account of geometrical isomerism, the distribution of the carbon valencies
was assumed to be tetrahedral (as postulated by van't Hoff). According
to modern theory, the four valency bonds of a carbon atom are distributed
tetrahedrally only in saturated compounds. In such compounds the carbon
3 bonds being referred
is in a state of tetrahedral hybridisation, the four sp
compounds,
however, the two
In
olefinic
Ch.
II).
(see
Vol.
I,
to as ff-bonds
carbon atoms exhibit the trigonal mode of hybridisation. In this condition
there are three coplanar valencies (three c-bonds produced from sp 2 hybrid-
89
GEOMETRICAL ISOMERISM
4]
and the fourth bond (?r-bond) at right angles to the trigonal hybrids
7r-Bonds, which appear to be weaker than cr-bonds, tend to overlap
as much as possible in order to make the bond as strong as possible. Maxi-
isation),
(Fig. 3).
mum
overlap is achieved when the molecule is planar, since in this configuration the two p orbitals are parallel.
Distortion of the molecule from
the planar configuration decreases the overlap of the ^-electrons, thereby
weakening the zr-bond; and this distortion can only be effected by supplying
energy to the molecule. It is therefore this tendency to produce
overlap of the ^-electrons in the 7r-bond that gives rise to resistance
maximum
Fig. 4.3.
For simplicity we
shall
still
represent
a " double " bond by the conventional method, e.g., C=C, but it should
always be borne in mind that one of these bonds is a a-bond (sp 2 bond),
and the other is a rc-bond perpendicular to the <r-bond. It is these ^-electrons
{mobile electrons) which undergo the electromeric and resonance effects.
They are held less firmly than the a-electrons and are more exposed to
external influences; it is these 7t-electrons which are responsible for the high
reactivity of unsaturated compounds.
In compounds containing a triple bond, e.g., acetylene, the two carbon
atoms are in a state of digonal hybridisation there are two c-bonds (sp bonds)
and two w-bonds (one p y and one pz orbital), both perpendicular to the
a-bonds which are collinear (see Vol. I, Ch. II).
The above treatment of the double (and triple) bond is in terms of sp 2
(and sp) hybridisation and jr-bonds. It is still possible, however, to use sp 3
hybridisation to describe carbon-carbon multiple bonds this treatment gives
rise to " banana-shaped " orbitals, i.e., " bent " bonds (Fig. 4
see also
;
Vol. I):
H\
y\ / H
) c\ ) C C
^^ (/ H
H\
)c
Fig. 4.4
is
no
free rotation
Nomenclature
of geometrical isomers. When geometrical isodue to the presence of one double bond in a molecule, it is easy to
name the geometrical isomers if two groups are identical, e.g., in molecules
I and II, I is the a's-isomer, and II the trans; similarly III is cis, and IV is
trans.
When, however, all four groups are different, nomenclature is more
difficult.
In this case it has been suggested that the prefixes cis and trans
should indicate the disposition of the first two groups named, e.g., the two
stereoisomers of l-bromo-l-chloro-2-iodoethylene, V and VI; V is cis-14.
merism
is
bromo-2-iodo-l-chloroethylene
or
fraws-l-chloro-2-iodo-l-bromo-ethylene
90
ORGANIC CHEMISTRY
[CH. IV
VI
is cis-l-chloro-2-iodo-l-bromoethylene or tfrs-l-bromo-2-iodo-l-chloroethylene. On the other hand, since this method of nomenclature usually
deviates from the rule of naming groups in alphabetical order, it has been
NK
NK
II
II
J>
a.
Nj^
^C"
II
^%
II
b^^a
^N
II
III
IV
cis
trans
cis
trans
/(
*
suggested that the groups corresponding to the prefix cis or trans should be
italicised, thus V may be named cw-l-6rowo-l-chloro-2-i'o^oethylene and VI
2ras-l-&rowo-l-chloro-2-M>rfoethylene. This method, it must be admitted,
would offer difficulties when the names are spoken.
Br^
^Cl
JBv
CI
VI
Some pairs of geometrical isomers have trivial names, e.g., maleic and
fumaric acids, angelic and tiglic acids, etc. (c/. 1). Sometimes the prefix
tso has been used to designate the less stable isomer, e.g., crotonic acid
(foms-isomer) and isocrotonic acid (cis-isomer; the cis-isomer is usually the
The use of iso in this connection is undesirable
less stable of the two ; see 2)
since it already has a specific meaning in the nomenclature of alkanes. The
prefix alio has also been used to designate the less stable isomer (cis), e.g.,
aWocinnamic acid.
When geometrical isomers contain two or more double bonds, nomenIn this case the compound is considered
clature may be difficult, e.g., VII.
.
XC=C
CH
X CH(CH3)
X
H
vn
as a derivative of the longest chain which contains the maximum number
of double bonds, the prefixes cis and trans being placed before the numbers
indicating the positions of the double bonds to describe the relative positions
of the carbon atoms in the main chain; thus VII is 3-isopropylhexa-cis-
cis-4-diene.
If
e.g.,
CHa=CHCH=CH6,
four geo-
^a
II
II
II
B<
II
II
II
b' ^H
^b
II
C^
b' V H
e.g.,
2",
CHa=CH CH=CHa,
:
isomers
is
91
GEOMETRICAL ISOMERISM
6]
is
2"- 1
odd (Kuhn
2P~ l where p
,
et al.,
n/2 when n
is
p =
even, and
^ when n
1928).
There
[see, e.g.,
(xi)].
Of the two acids maleic and fumaric, only the former readily forms a
cyclic anhydride when heated; the latter does not form an anhydride of its
own, but when strongly heated, gives maleic anhydride. Thus I is maleic
acid, and II is fumaric acid.
(a)
Hx
^COisH
c
<+
II
H^ ^C0 H
H^ ^C0 H
c
II
H0 2 C^ ^H
fumaric acid
maleic acid
H \'/ C <?
/> + H,0
II
H/^ CO
Cyclisation reactions must be performed carefully, since one isomer may
be converted into the other during the cyclising process, and so lead to unreliable results.
In the above reaction, somewhat vigorous conditions have
been used; hence there is the possibility that intercon version of the stereoisomers has occurred. Since maleic acid cyclises readily, and fumaric acid
only after prolonged heating, the former is most probably the cw-isomer,
and the latter the trans which forms maleic anhydride via the formation of
maleic acid (see also 6). The correctness of the conclusion for the configurations of the two acids may be tested by hydrolysing maleic anhydride
in the cold; only maleic acid is obtained.
Under these mild conditions it
is most unlikely that interconversion occurs, and so we may accept I as the
configuration of maleic acid.
(6) Citraconic acid forms a cyclic anhydride readily, whereas the geometrical isomer, mesaconic acid, gives the same anhydride but much less
readily. Thus these two acids are:
^C0 H
CHj..
C
II
II
H^ ^CO H
g
citraconic acid
H0 C^ ^H
2
mesaconic acid
ORGANIC CHEMISTRY
92
[CH. IV
acid.
II
^H
H0 2 CT
II
TJO,H
H-
coumaric acid
coumarinic acid
coumarin
(d) Two forms of hexahydroterephthalic acid are known, one of which
forms a cyclic anhydride, and the other does not. Thus the former is the
ct's-isomer, and the latter the trans (see also 9, 11).
H0
HOgC
C02 H
as -acid
trans -a,cid
H^
,C0 2 H
/CC13
II
H0 2
.0.
^H
HO 0^ ^H
2
fumaric acid
H^ ^C0 H
2
IV
III
|[H]
|[H]
H \^/ CH 3
^H
H0 CT
2
V
crotonic acid
H^
,CH 3
^C0 2 H
VI
zsocrotonic acid
93
GEOMETRICAL ISOMERISM
5]
CH
H,C
HC
C0 2 H
C02 H
trans- form
CK-form
-co 2
H,C
H,C
CH,
Method
one form
may
COaH C0 2 H
cii- form
optically inactive
C02H
trans-form.
resolvable
ORGANIC CHEMISTRY
94
[CH. IV
between the dipole moments of the cis- and trans-isomers may be too small
to assign configuration with any confidence, e.g., the dipole moment of
diethyl maleate is 2-54 D and that of diethyl fumarate is 2-38 D.
(vi) X-ray analysis method.
This method of determining the configuration of geometrical isomers is probably the best where it is readily
applicable (see also 16. I).
(vii) Ultraviolet, visible, infra-red,
Raman, and
NMR
spectra
Geometrical isomers may show different spectra, e.g., the intensity of the band in the ultraviolet absorption spectrum depends on the
dipole moment (see Vol. I, Ch. XXXI), and this, in turn, depends on the
distance between the charges. In the trans-iorm of a conjugated molecule,
the distance between the ends is greater than that in the ds-form. Consequently the intensity of absorption of the trans-iorm. is greater than that of
the cis (see also 15. 1). Thus, in cases such as these, it is possible to assign
configurations to pairs of geometrical isomers.
spectra (19a. I) have recently been used to determine configurations of geometrical isomers, e.g., Curtin et al. (1958) have used this method
to distinguish between the cis- and trans-isomers of stilbene and azobenzene
Musher et al. (1958) have assigned configurations to cis- and trans-decaMn
methods.
NMR
[ll(vii)].
(viii) Method of surface films.
Long-chain geometrical isomers which
contain a terminal group capable of dissolving in a solvent will form surface
films, but only the trans-iorm can form a close-packed film, e.g., the longchain unsaturated fatty acids.
H0
II
II
H^ \C0 H
C^ ^H
's-form
(ix)
Method
trans-form
In compounds which
owe
Now
H.
TT
X!0 2 H
.C02 H
CH
II
H0 Cr
2
^H
fumaric acid
H0 C /
succinic acid
Nr
X02 H
II
S< ^C0 H
2
maleic acid
same size and shape tend to form solid solutions. Thus fumaric acid
forms a solid solution with succinic acid, whereas maleic acid does not;
hence the configurations of maleic and fumaric acids may be determined.
(x) Methods based on generalisations of physical properties.
Comparison of the physical properties of geometrical isomers of known configurations has led to the following generalisations:
(a) The meltirg point and intensity of absorption of the cis-isomer are
lower than those of the trans.
(6) The boiling point, solubility, heat of combustion, heat of hydrogenaof the
the
compound is an
95
GEOMETRICAL ISOMERISM
5]
(v)].
e.g.,
EU
'CH
\r
r^Kr
H"
^C0 H
H'
^c
X!02 H
0-toluic acid
cis-crotaflic acid
m.p. 15 5
m.p. 105
CH;
II
rrons-crotonic acid
m.p. 72
^-tohric acid
m.p. 180 9
Thus comparison
C=C
0020^115
CI
b.p. 122
56/l0mm
b.p.
Cl^
b.p.
^C02 C H
2
61/I0mm.
CK ^-^
"C02 C2 H6
b.p. 130
ORGANIC CHEMISTRY
96
[CH. IV
^a 11
Br^
^G
WI
C02 H
C0 H
is
+2H
in
H ^ ^C H
C6 H
a 's-addition, but the problem of reduction of a triple bond is comby the fact that the results depend on the nature of the compound
and the conditions used, e.g., Fischer (1912) found that phenylpropiolic
acid on catalytic reduction gave cw-cinnamic acid, whereas on reduction
with zinc dust and acetic acid, trans-cmnamic acid was obtained.
This
is
plicated
V
TS< NX)2 H
-<
H 2-Pd
C
HI
^,
Zn/CIWCOM.
-
0H
H^
NX) H
2
et al. (1955), on the other hand, have shown that the reduction
of acetylenes with lithium in aliphatic amines of low molecular weight produces trans-oleftns. It appears that, in general, chemical reduction produces
the tfraws-olefin, whereas catalytic hydrogenation produces the cw-olefin.
As a result of a large amount of experimental work, it has been found that
addition reactions to a triple bond where the addenda are halogens or halogen
acids produce predominantly the trans-ethy\enic compound, and so, using
this generalisation, one can determine the configurations of geometrical
isomers when prepared from acetylenic compounds (provided, of course,
the addenda are halogen or halogen acid).
Wislicenus also supposed that removal of halogen, halogen acid, etc., from
olefinic compounds to produce acetylenic compounds was easier in the exposition than in the trans. This again was shown to be incorrect experimentally, and thus the elimination reaction may be used to determine
Benkeser
97
GEOMETRICAL ISOMERISM
5]
Br
Br
.C0 2 H
H^
H_
Br4
JO.
>
,C0 2 H
H.
C02 H
H'
,C0 2 H
ND02 H
Br
VIII
(formed by attack in front) are identical, both being the same weso-dibromoSimilarly fumaric acid would be expected to give ()-oc a'succinic acid.
dibromosuccinic acid. IX and X are mirror images, and since they will be
^0O2 H
Br
VII
Br
Br
H.
H^ /C0 H
/C0 2 H
XT
Br 2
HOC
HOsC^V^-H
H,,
HOgC
"H
,-C0 2
.- %
|
Br
Br
IX
-H
formed in equal amounts (see 7a. II), the racemic modification is produced.
Experimental work, however, has shown that the reverse is true, i.e., maleic
acid gives mainly ()-dibromosuccinic acid (IX and X), and fumaric acid
gives mainly wesodibromosuccinic acid (VII). Thus the addition of bromine
must be trans. In the same way it has been shown that the addition of
halogen acid is also trans. Hence, assuming foam-addition always occurs
with these addenda, the nature of the products indicates the configuration
of the ethylenic compound.
The configuration of the product formed by hydroxylation of a double
bond depends on the nature of the hydroxylating agent used and on the
conditions under which the reaction is carried out. Permanganate and
osmium tetroxide apparently always give cw-addition, whereas permonosulphuric acid (Caro's acid)
Type
Reagent
of
addition
KMn0 4
Os0 4
H a S0 6
C,H 6 -CO-O sH
H aO a Os0 4
H 2 2 SeO a
cis
cis
trans
trans
cis
trans
Maleic acid
Fumaric acid
mesotaxtaxic acid
wesotartaric acid
DL-tartaric acid
DL-tartaric acid
mesotartaric acid
DL-tartaric acid
DL-tartaric acid
DL-tartaric acid
mesotartaric acid
wesotartaric acid
DL-tartaric acid
mesotartaric acid
On
98
ORGANIC CHEMISTRY
[CH. IV
electrophilic; e.g.,
CH 2 ==CH 2 ^
Br-^-Br
*-
CH 2 =tCH 2^ H-Ql
*-
CH2 -CH 2 Br +
CH 2 -CH 3
Br~
CI"
CH
CH
CH 2 Br
2 Br-
2 C1-CH 3
Br
02 H
tt^
+Br2 -^
||
-C0 2 H
tt.
C02 H
H'
'or
|>r*
^C0 2 H
H-.
^c"
-^
D
Br
,C0 2 H
HL
Nr
+1
C0 2 H
H''
Br
Br
(XI)
(XII)
.C0 2H
"C02 H
Since the bromide ion can attack " conveniently " only along the C Br+
bonding line and on the side remote from the bromine, a Walden inversion
occurs at the carbon atom attacked. Since the brominium ion is symmetrical, it can be anticipated that either carbon atom will be attacked
equally well, thereby resulting in the formation of (XI) and (XII) in equal
amounts, i.e., maleic acid will produce ()-dibromosuccinic acid. Winstein
and Lucas (1939) have demonstrated the existence of this cyclic ion (see
6b. III).
we have
seen,
although this predominates, it is not exclusive. The reason for this is not
certain, but it is possible that the cyclic ion is not firmly held, i.e., the ring
opens to give the classical carbonium ion, and this is followed by rotation
about the single C C bond due to electrostatic repulsion between the carboxyl groups. This would explain the experiments of Michael (1892) that
both the maleate ion and fumarate ion add chlorine or bromine to give
mainly wteso-dihalogenosuccinic acid. The configurations of the products
indicate that tfraws-addition has occurred with the fumarate ion but cisaddition with the maleate ion. Roberts and Kimball, however, have
explained these results by assuming that the intermediate maleate brominium ion (cis) changes to the fumarate brominium ion (trans) due to the
powerful repulsions of the negatively charged carboxylase ion groups.
Additions to a triple bond may be assumed to take place by the mechanism
proposed for a double bond.
Now let us consider the mechanism of hydroxylation, i.e., the addition
of two hydroxyl groups to a double bond. With potassium permanganate
99
GEOMETRICAL ISOMERISM
5a]
OH
'
OH
This cyclic intermediate is definitely known in the case of osmium tetroxide
(see Vol. I) ; for potassium permanganate it may be assumed that the permanganate ion, Mn04 - (or the manganate ion, MnO^, behaves in a similar
manner. This is supported by the work of Wiberg et al. (1957), who used
and showed that both glycol
potassium permanganate labelled with 18
oxygen atoms come from the permanganate ion. This also indicates that
fission of the cyclic compound occurs between the O and Mn atoms.
With per-acids the hydroxylation results in iraws-addition. The first
product of oxidation is an epoxide (Prileschaiev reaction; see Vol. I).
Evidence from kinetic studies on solutions of epoxides under high pressure
strongly suggests that acid-catalysed hydrolysis is a bimolecular substitution of the conjugate acid (Whalley et al., 1959). This will result in transhydroxylation. Thus:
/<
/<
/C\
OH 2
NK
J.
OH
_ H+
~^
N^
'
OH
OH
means
^~X
X.
+^0=0^
<H~H
N |
^C0 H
Plf'
cis
trans
cis
ph
C02 H
trans
C02 H
100
ORGANIC CHEMISTRY
[CH. IV
H-CR2 CR^-Z
ijyz
El
H+
E2
^^
+
z- +
Z~
h^cr>cr.2
H^CR^-CR
-^*
CR 2=CR2
Y^H-^CR^CRy^Z
*-
YH
CR 2=CR 2 + Z~
Many examples
readily than
cis, e.g.
as 2.
C02H
H0 Cv /CI
XX
2
(6)
Chavanne
NaOH
HI
(-HC1)
(-HC1)
||
h/
x:o 2H
(1912)
/C0 2H
Ck
NaQH
X/
||
h/N;o h
2
CO aH
fast
as 2.
CI
Hx
.CI
XX
||
NaOH
(-HC1)
HI
is/ \C1
NaOH
\-HCl)
Hx
/CI
X/
||
CK^H
below).
H /i
y' H
1
Cl
k ci
/i
C1\J
Cl
/3-isomer
plane.
GEOMETRICAL ISOMERISM
5b]
101
" liberated " covalent pair of electrons attacks the a-carbon atom from
the rear, thereby forming the double bond with displacement of the halogen
atom. This type of sequence is not possible when the /3-hydrogen atom is
cis to the halogen atom.
Before discussing olefin-forming eliminations, let us consider acetylenicforming eliminations. As already pointed out above, the elimination has
been found to occur more readily in the tfraws-isomer than in the cis. This
may be explained by assuming that the elimination occurs by the E2
mechanism
s-
XT
Al
.H'
+ OH"
II
Br'
Now
III
H 20+Br"
Br'
derivatives,
H
.
+ IBr+Br"
Me
Me
CIS
Me
+ IBr+Br"
Me
trans
In the ()-form, as the transition state changes into the ethylene compound, the two methyl groups become eclipsed; in the meso-form a methyl
group becomes eclipsed with a hydrogen. Thus the energy of activation
of the transition state of the ()-form will be greater than that of the
meso-iorm. and consequently the latter should be formed more readily, i.e.,
the meso-iorm should undergo debromination more readily than the (reform. Winstein et al. (1939) have shown that this is so in practice, the
rate of debromination being about twice as fast. These authors also showed
that the rate of debromination of weso-stilbene dibromide
(Ph-CHBr-CHBr-Ph)
is
ORGANIC CHEMISTRY
102
[CH. IV
Cram et al. (1952) have shown that the base-catalysed dehydrobrornination of the diastereoisomeric 1-bromo-l : 2-diphenylpropanes (I and II)
gives olefins that can only arise by trans elimination.
"Ph-^0^ H
as
Me
Phv
Ph-^~"\^-Me
II
Th
trans
Cram
et al.
(1956)
of the following
PhCHMe-CHPh-NMe3 + }I~
OEt-
> PhMeC=CHPh
This 'onium ion exists in two forms, threo and erythro, and the results were
that the 2&ra>-compound gave the fr-ans-olefin and the ery/wo-compound
H^OEt
Ek
Ph
H^
^O^Me
Ph-
Ph''
r -N/
+
Or
<>
^-Ph
~~Me
trans
NMe 3
threo
H*0Et
r \^ H
Phv
--H
Ph
^O^Me
Ph^-
Ph-~
--Me
CIS
NMe 3
eryithro
the cs-olefm this is in keeping with trans elimination. The rates of elimination, however, were very different, the threo-iorm reacting over 50 times as
In the cw-product, the two phenyl groups become
fast as the erythro.
eclipsed and hence the energy of activation for this product is greater than
that for the tows-product, and consequently the latter is formed more
;
now
arises is:
What
is
the mechanism
when
GEOMETRICAL ISOMERISM
6]
103
CI"
N^ci
y-isomer
should be noted that even if the chair form of the /3-isomer given above
could change to its other chair form, the " ideal " /raws-position of 1,2-HCl
would still not be achieved; the conformations of all hydrogens and chlorines
would be reversed. It is possible, however, when both groups to be eliminated are equatorial, that both become axial if the ring is sufficiently flexible.
Thus the favourable conformation would be produced, but the elimination
would be slowed down since energy must be supplied for this conversion.
When the two groups cannot assume the favourable ^rows-position, the
normal E2 mechanism will not operate. It appears most likely that the
elimination then proceeds via the formation of carbanions. It is possible,
however, that the elimination might proceed by the El mechanism (see
It
more
The
>fumaric acid
maleic acidHNO,
oleic acid-
>elaidic acid
ORGANIC CHEMISTRY
104
[CH. IV
chain reaction, since the conversion does not appear to be effected by bromine
in the dark.
Thus:
hv
Br2
v Br +
Br
Br
H\
H\ ^C0 H
2
>
+Br.
Br'
H\
^C0 H
2
*=
^CL
/C.
H^ ^C0 H
H^'^OOgH
Br
i
H0
JJ^
2
(T
'^H
II
H.
/C0 H
Br
X0 H
+
^C0 H
Hv^
>
II
^C0 H H\ /C0 H
H.
II
^*
II
In free radicals I and II, the upper carbon atom is in a state of tetrahedral
hybridisation, and the lower one (the free radical part) in a trigonal state
(and therefore flat). Owing to the repulsion between the carboxyl groups,
configuration I tends to change into configuration II by rotation about the
If II now reacts with a molecule of maleic acid,
single bond (cf. 4. II).
the latter is converted into a free radical containing the bromine atom,
and II is converted into fumaric acid if " inversion " occurs on the lower
carbon atom; if no " inversion " occurs, II would form maleic acid again.
Similarly, various other reagents are also believed to act by a free-radical
mechanism, e.g., the conversion of cw-stilbene into toms-stilbene by means
In the absence of light, the
of light in the presence of hydrogen bromide.
conversion takes place very slowly, but in the presence of oxygen or benzoyl
peroxide, the conversion is rapid. These reagents are known to generate
free radicals; this supports the free-radical mechanism, the reaction being
BF3
j*v
/C
^C H
6
BF,
H^i/C H
H./CeHs
6
H^ /C H
H^:/C H
6
'-^v
iK+NyH,
CeH^+^H
Crff
^H
Now
GEOMETRICAL ISOMERISM
8]
105
sociation " of a double bond requires energy of about 40 kg.cal., and the
transition is said to be from a singlet ground state to an upper singlet state.
On the other hand, it is also possible for the spins of the jr-electrons to be
parallel (this state is said to be the triplet state), and the energy required
for this " dissociation " is about 25 kg.cal.
It has been observed that
7.
Geometrical and optical isomerism may exist in any sized ring. In the
following account, the saturated rings are treated as rigid flat structures,
and the groups attached to the ring-carbon atoms are regarded as being
above or below the plane of the ring (see also, in particular, cyc/ohexane
compounds, 11). Furthermore, the examples described deal only with
those cases in which the asymmetric carbon atoms are part of the saturated
ring system.
In general, the pattern of optical isomerism followed by cyclic
compounds is similar to that of the acyclic compounds. The main difference between the two is that, since there is no free rotation about ringcarbon atoms, geometrical isomerism may therefore be manifested as well
as optical isomerism. On the other hand, geometrical isomerism may exist
without optical isomerism (see 5 for methods of determination of the configuration of geometrical isomers; see also 9, 10, 11).
8. cyctoPropane types.
Molecule I contains one asymmetric carbon
atom (*), and is not superimposable on its mirror image molecule II. Thus
I and II are enantiomorphs, i.e., a ryc/opropane derivative containing one
asymmetric carbon atom can exist in two optically active forms (and one
racemic modification; cf. 7a. II). Molecule III contains two different
asymmetric carbon atoms, and since it has no elements of symmetry (6. II),
it is not superimposable on its mirror image molecule.
Thus III can exist
in two optically active forms (and one racemic modification).
Structure III,
*X Hi
aH ^2
V
however, is capable of exhibiting geometrical isomerism, the two geometrical
isomers being III and IV. Now IV also contains two different asymmetric
carbon atoms, and these are not disposed towards each other as in III.
Since IV possesses no elements of symmetry, it can also exist in two optically
active forms which are different from those of III. Thus V, which may be
regarded as the non-committal way of writing the configurations III and
IV, is similar, as far as optical isomerism is concerned, to the acyclic molecule Cabd-Cabe, i.e., there are four optically active forms in all (two pairs
of enantiomorphs).
In general, any monocyclic system can exist in 2"
ORGANIC CHEMISTRY
106
optically active forms,
carbon atoms
where n
7c. II).
(c/.
[CH. IV
H,
(110
aH
H
VI
VIII
VII
carbon atoms, and can exist as geometrical isomers VII and VIII. VII
has a (vertical) plane of symmetry and therefore represents a meso-ioim.
VIII, however, possesses no elements of symmetry and can therefore exist
IX contains
in two optically active forms (and one racemic modification).
XII
XIII
3
8
three different asymmetric carbon atoms and can therefore exist in 2
enantiopair
of
Each
enantiomorphs).
pairs
of
(four
optically active forms
morphs is derived from the four geometrical isomers X-XIII. Inspection
of these configurations shows that all of them possess no elements of symmetry. XIV contains two similar asymmetric carbon atoms, and the third
(v)
Ha
aH
xv
XIV
XVI
XVII
is
pseudo-asymmetric
XV
XV-XVII,
a
(vi)
Ha
aH
Ha
XVIII
forms (and one racemic modification). XVIII contains three similar asymmetric carbon atoms which are all pseudo-asymmetric. Two geometrical
isomers are possible, XIX and XX, both of which possess at least one
(vertical) plane of symmetry, and therefore represent wieso-forms.
GEOMETRICAL ISOMERISM
9]
107
type are
butane-1
was obtained.
Truxillic
isolated
from natural
sources.
36
aH
C02 H
C6 H6
Hb
Ml
Ha
H
ho2c/ H q/H
5
HA
H c/
C0 H
C02 H
H
III
-
H0 C/"
2
HZ"
HO,c/
C0 2 H
C H
One
of these is known as the a-acid (m.p. 274) and the other the y-acid
(m.p. 288)
This then raises the problem Which is which? This is readily
answered by the fact that of the anilido-derivatives of these two acids, only
one can be dehydrated to a cyclic iV-phenyl imide, -
N(C g 5)
This reaction can be expected to take place only when the two carboxyl
groups are in the cts-position (see 5. i). Therefore IV is y-truxillic acid,
and VI is a-truxillic acid (since the acid with the melting point 288 has
been called the y-acid). By considering the ease of formation of the cyclic
anhydride, the configurations of the remaining three stereoisomers may be
determined. Two form anhydrides readily, and therefore one of these acids
.
CO
CO
ORGANIC CHEMISTRY
108
[CH. IV
The third acid does not form its own anII and the other III.
hydride, but gives a mixture of the anhydrides produced by II and III.
Thus the third acid, e^'-truxillic acid, is V. The final problem is to decide
which of the two, II and III, is ^>m'-truxillic acid, and which is e-truxillic
acid. ^>m-Truxillic acid, under the influence of aluminium chloride, undergoes an internal Friedel-Crafts reaction to form a truxonic acid, VII, and
a truxone, VIII. This is only possible when the phenyl and carboxyl groups
are in the cj's-position. Thus II is ^m-truxillic acid, and therefore III is
must be
e-truxillic acid.
ftH*
truxone
truxonic acid
VII
VIII
Truxinic acid. This acid can exist theoretically in six geometrical isomeric forms, four of which are resolvable thus ten forms in all are possible
theoretically.
Truxinic acid is of the type IX, and the six geometrical
and XI are meso-iorms (each has a plane
isomers possible are X-XV.
;
viz.,
/?,
d,
and
neo.
C02 H
C6H6
aH
Kb
H
IX
^-f
H
X
to-
C6H5
96 H6
C02 H
\C02 H
H
C6 H5
XI
XII
p.
neo-
C02 H
C 6 H5
HO 2S
t!02 H
C02H
10. eyc/oPentane types. A number of examples involving the stereochemistry of the five-membered ring occur in natural products, e.g., camphoric acid (23a. VIII), furanose sugars (7b. VII). In this section we
shall discuss the case of 2 5-dimethylcyc/opentane-l 1-dicarboxylic acid.
This acid can exist in two geometrical isomeric forms, which may be differentiated by decarboxylation, the cis-isomer giving two monocarboxylic
acids, I and II, and the toms-isomer one monocarboxylic acid, III (see
All three acids contain two similar asymmetric carbon atoms and
5. iii).
one pseudo-asymmetric carbon atom. Both I and II possess a (vertical)
:
GEOMETRICAL ISOMERISM
11]
109
II
II
CH
H,C
II
SfcJT^F
H^<U^H
C02 H
II
^Jp^ *
CH
H
III
I.
determined.
HC
3
H,C
ORGANIC CHEMISTRY
110
[CH. IV
boat form having the higher energy content; see also below). This value,
however, is too small for stability, and consequently neither conformation
retains its identity, each being readily converted into the other.
III
14
"boat" or
C form
._
or
form
"chair
Fig. 4.5.
steric repulsion
(i.e.,
CH
(a)
chair form
boat form
(b)
Fig. 4.6.
in the
vapour phase).
GEOMETRICAL ISOMERISM
11]
On
*<-bonds).
of the boat
various
111
"
(b) it can be seen that the " end
stereochemically from the chair conformation; the
is different
equatorial
(be),
tions.
HH
Conformation
Position
Chair
le:Ze
le:2a
la 2a
2-49
2-49
306
la: 3a
2-51
Boat
2a: 3a
(Fig. 66)
2e: 3e
2-27
2-27
1-83
(Fig. 6a)
(A)
It appears that the boat conformation occurs in relatively few cases, and
so in the following account we shall only study the problem of the chair
conformation. Inspection of the above table shows that a 1 2-interaction
for two adjacent equatorial hydrogens or for an equatorial and adjacent
axial hydrogen is about the same as for a 1 3-interaction for two meta
axial hydrogens. Furthermore, a study of accurate scale models has shown
that with any axial substituent (which is necessarily larger than hydrogen),
the 1 3-interactions are larger than the 1 2-interactions when the same
substituent is equatorial. Using these principles, we can now proceed to
study the conformations of cyc/ohexane derivatives.
Because of the flexibility of the chair conformation, one chair form is
readily converted into the other chair form, and in doing so all a- and
e-bonds in the first now become e- and a-bonds, respectively, in the second.
:
Both forms are identical and so cannot be distinguished. If, however, one
hydrogen is replaced by some other atom or group, the two forms are no
longer identical, e.g., methylcyc/ohexane. In the a-methyl conformation
Me
H-
jj
.
,H
Me-
7/
^-H
H
H
a-methy]
e- methyl
ORGANIC CHEMISTRY
112
[CH. IV
The nature
Here
(geometrical and
the nature of the substituents.
(i)
2-Compounds
Classical formula
Conformations
le:2a
cis-V.2
la:2e
the conformation with the lower energy will be the one in which the larger
group is equatorial, i.e., this is the preferred form. An example of this
type is m-2-methylcyc/ohexanol; the methyl group is larger than the
hydroxyl, and so the preferred form can be expected to be la-hydroxyl 2emethyl. This has been shown to be so in practice. In general, the greater
the difference in size between the two substituents, the greater will be the
predominance of the form with the larger group in the equatorial conforma:
tion.
The
Classical formula
Conformations
le:2e
identical or not, the two conformations are dif3-interactions the e e-form will be the preferred
form. Furthermore, this form will be more stable than the 's-isomer
(a e-form).
An example that illustrates this is 2-methylcycMiexanol. The
:
trans-form has been shown to be more stable than the cis; the latter is
readily converted into the former when heated with sodium, and also the
reduction of 2-methylcycMiexanone (with sodium and ethanol) produces the
trans-Alcohol.
Both the
classical
e-
(and a
a)
conformation of the
GEOMETRICAL ISOMERISM
11]
113
2-compound (whether Yx and Yg are identical or not) are not superimposable on their mirror images and hence should be optically active.
This has been found to be so in practice.
trans-1
(ii)
3-Compounds
Classical formula
Conformations
cis- 1:3
trans -1:3
e:a
The two tows-conformations are identical when the two Y groups are
The cis-e e-form will be more stable than the cis-a a, and will
identical.
also be more stable than the trans-e a-conformation, e.g., the most stable
conformation of 1 3-dimethylcycfohexane has been shown to be the cis:
3-e
It should
e-form.
of the 1
(iii)
4-Compounds
Classical formula
Conformations
o
cis-1.4
trans - 1
a:a
The two
114
ORGANIC CHEMISTRY
[CH. IV
-Br
H
a-Br
e-Br
On
the basis that a substituent preferably takes up an equatorial conformawould therefore be expected that the conformation 2e-bromocyc/ohexanone would be favoured. Infra-red studies, however, have shown that
the fl-bromo conformation predominates. This has been explained as
follows.
The C Br and C==0 bonds are both strongly polar, and when
the bromine is equatorial the dipolar repulsion is a maximum, and a miniwhen the bromine is axial. Since the axial form predominates, this
equatorial dipolar repulsion must therefore be larger than the 1 3-interactions.
When, however, other substituents are present, the 1 3-interactions may become so large as to outweigh the dipolar effect and the
bromine would now be equatorial. Such is the case with 2-bromo-4 4dimethylcycfohexanone (see also 12).
tion, it
mum
*0
Me
(iii)
The energy
barriers
number
from a planar ring with the substituents lying above and below the plane
of the ring.
We shall now, therefore, discuss the stereochemistry of some
cyc/ohexane derivatives from the classical point of view.
(i) Hexahydrophthalic acids
(cyc/ohexane-1 2-dicarboxylic acids). Two
geometrical isomers are theoretically possible, the cis, I, and the trans, II.
:
CO,H
GEOMETRICAL ISOMERISM
11]
115
Molecule I has a plane of symmetry, and therefore represents the mesoform; II has no elements of symmetry, and can therefore exist in two
optically active forms (and one racemic modification). All of these possible
forms are known, and it has been found that the m-compound, I, forms a
cyclic anhydride readily, whereas the ^raws-compound, II, forms a cyclic
anhydride with difficulty (cf. 5. i).
3-dicarboxylic acids). Two
(ii) Hexahydroisophthalic acids (eycMiexane-1
geometrical isomers are possible; the c*s-form, III, has a plane of symmetry,
and therefore represents the meso-iorm; IV has no elements of symmetry,
and can therefore exist in two optically active forms (and one racemic
:
C02 H
Ha
ii0 *9/h
H0 2
H
IV
C02 H
HOjjC
H02 C
C02H
V
optically active.
They may be
distinguished
VI
by the
fact that the cisisomer forms a cyclic anhydride, whereas the trans-isomer does not.
(iv) Inositol (hexahydroxycycMiexane).
There are eight geometrical isomers possible theoretically, and only one of these is not superimposable on
its mirror image molecule; thus there are nine forms in all (and also one
racemic modification). If we imagine that we are looking down at the
molecule, and insert the groups which appear above the plane of the ring,
then the eight geometrical isomers may be represented as follows:
OH
H
HL
/'H
HLJH
H
OH
OH
OH
JH
HL
H
HI
JOH
H
tneso- inositol
OH
OH
HO
OH
OH
resolvable
OH
H
scyllitol
Examination of these configurations shows that all except one the one
labelled resolvable have at least one plane of symmetry, and so are all
[CH. IV
ORGANIC CHEMISTRY
116
All the meso-iorms and both of the optically active forms are
known; of these meso-inositol, scyllitol and (+)- and ( )-inositol occur
naturally.
,
Here again eight geo(v) Benzene, hexachloride (hexachlorocycfohexane)
known,
a,
are
p, y, o,
metrical isomers are possible theoretically; seven
been
have
All
I).
Vol.
(see
insecticide
0*
powerful
a
is
the y-isomer
e v
shown to exist in the chair form, and the conformations that have been
meso-ionas.
assigned are:
a-, aaeeee;
Of these forms,
it is
y-, aaaeee;
eeeeee;
ji-,
d-, aeeeee;
s-,
aeeaee.
the
(3-
which
loses
H
CI
CI
CI
P-
and CI trans).
having
pair of chlorine atoms cis to each other (thus
()-form.
the
as
a-isomer
the
identified
also
has
Cristol (1949)
stereochemistry of the cycfohexane
(vi) So far we have discussed the
are also exhibited by various
stereoisomerism
of
types
same
The
ring
dimethyldiketopiperazine
(6. II), furanose
sized heterocyclic systems, e.g.,
sugars.
VII)
(7a.
pyranose
and
VII)
(7b.
As we have seen, the boat and chair forms
(vii) Decalins and decalols.
and the result is that cycloof cycfohexane are readily interconvertible,
Mohr
(1918), however, elaborated
planar.
were
hexane behaves as if it
fusion of two cycloserine rings,
Sachse's theory, and predicted that the
the cis- and *ras-forms which would be
e s>. as in decalin, should produce
has now been
stable to retain their identities. This prediction
sufficiently
, ,.
,confirmed experimentally.
isomers of decalin
A non-committal way of writing the two geometrical
conventions
several
On the other hand,
VIII
is given by formula: VII and
.
VIII
cis -decalin
rrarcs-decalin
GEOMETRICAL ISOMERISM
11]
117
and
used
T T
XI
XII
Fig. 7 shows the original diagrammatical method of representing cisdecalin by the fusion of two boat forms of cyclohexa.ne, and foms-decalin
by the fusion of two chair forms; these are the forms suggested by Mohr.
m-decalin
trans -decalin
Fig. 4.7.
The
complicated than
as- decalin
trans -decalin
Fig. 4.8.
a's-form
is
ring, whereas the trans-form is produced by joining the two rings by equatorial bonds only; in both cases the cycJohexane rings are all chair forms
(see also below).
118
ORGANIC CHEMISTRY
[CH. IV
tram
The
XV
XX
XIX
nW
Sh
r-c
JJ V^H
^y^y
^
OH
-CD
H
XV
OH
H
XIX
XVII
cis-
,.CH2 -C02 H
OH
H
,--H
CH -C02 H
2
H
XVI
trans
by
XXI
viz. cis-
and XXII
and <rans-cyciohexane-l-carboxyl-2-propionic
formed by scission of the 1 2-bond of
(these are
the decalone).
-C02 H
XXI
,-C0 H
^\><H
2
L'H
^v/^CHz-CHg-CQaH
XXII
I
The conversion of 2-naphthol into two decalols does not prove that the
two decalols are the cis- and tfraws-isomers described above. It is possible
that both compounds could have been the cis- and trans-ioxvns of a given
decalol; since the carbon atom of the CHOH group in the 2-decalol is asym-
119
GEOMETRICAL ISOMERISM
11]
metric,
i.e.,
Had
XV a
XVI
two forms of either XV or XVI, then on their oxidation, only one decalone
would have been produced. Since, however, two decalones were obtained,
the two decalols must be of the types XV and XVI one of each, or even
a mixture of the pairs; further proof of the existence of the types XV and
XVI lies in the fact that the two decalones gave geometrical isomers of
NMR
section).
Various other fused ring systems have also been shown to exhibit the
Ct>
oH
HOH
CK-hydrindanoI.
Two forms; both meso-
trans- hydrindanol
Resolvable
H
NH
Decahydroquinolines
DecahydroJSdquinohnes
ORGANIC CHEMISTRY
120
[CH. IV
same type
XXIII
XXIV
As pointed out above, Musher et al. (1958) distinguished between cisand tfnms-decalin by means of their NMR spectra. The former gives a
sharp band whereas the latter gives a broad spectrum. These differences
are due to the former molecule undergoing relatively rapid interconversion
between the two conformations, whilst the latter molecule has a more rigid
structure and hence the axial and equatorial hydrogen atoms are distinguishable (and so give a broad spectrum).
Now let us consider cw-2-decalol. Here there are four possible conformations which, in pairs, are in equilibrium. Two arise from XXIII (XXIIIa
XXIV*
GEOMETRICAL ISOMERISM
12]
121
to the actual state of the molecule than will XXIVa and XXIII6,
the hydroxyl group in cw-2-decalol should possess more equatorial
character than axial. It is also interesting to note that the two axial
forms do not contain the same energy. In XXIIIZi the a-hydroxyl group
is involved in the normal 1
3-hydrogen interactions (at 4 and 9), but in
XXIVa the interaction is the normal 1 3- with the hydrogen at 4 and the
larger 1 3-interaction with the CH a group at 8. Thus XXIVa should be
more
i.e.,
less stable
than XXIII6.
XXV
XXV
XXVI
of
is
II
The study
ORGANIC CHEMISTRY
122
[CH. IV
group
>Xa
>-
>3=o
-e
yxZ
As we have seen
:
ing diaxial compounds, cis-l 2-Compounds (in which one substituent must
be axial and the other equatorial) undergo elimination reactions slowly.
The steric course of El reactions is more difficult to study than that of
E2 reactions because of the two-stage mechanism. This makes it difficult
to ascertain the geometry of the intermediates involved. The formation
of the carbonium ion will be sterically accelerated if the ionising group is
axial and, if a second group is eliminated to form a double bond, this second
stage will also be sterically accelerated if the second group is axial. Barton
et al. (1951) have pointed out various examples in which El reactions are
favoured by the diaxial conformation.
The arguments used above are satisfactory so long as we know whether
the group under discussion is axial or equatorial. Since, however, the two
chair forms are readily interconvertible and in equilibrium, to study these
predictions experimentally it is necessary to deal with " rigid " conformaThe tf-butyl group, because of its large size, is far more stable in
tions.
the e- than in the a-position (the energy difference between the two forms
:
about 5-6 kg.cal./mole Winstein et al., 1955). Thus almost only the
e-form is present and consequently this position is " locked ". Therefore
4-substituents must be axial when cis to the *-butyl group and equatorial
when trans to this group (11). Working with different substituents in the
4-position with respect to the i-butyl group, various workers have confirmed
the above predictions experimentally, e.g., it has been shown that cis-4-tbutylcydohexanol forms esters more slowly than the trans-isomer, and similarly cs-4-2-butylcycfohexane-l-carboxylic acid is more slowly esterified and
the ester more slowly hydrolysed than the toms-isomer.
Another interesting example is the case of 4-<-butylcyc/ohexyl tosylate
Two forms are possible, cis and trans, but because of
(Eliel et al., 1956).
the large bulk of the -butyl group, this group is always equatorial. Under
is
cis-
trans
the same conditions (sodium ethoxide in ethanol at 70), the cis-iona readily
undergoes bimolecular elimination (E2), but the trans- does not. The latter,
however, does undergo unimolecular (El) elimination.
GEOMETRICAL ISOMERISM
12]
123
certain.
Ph.
I
as
-*
1-ene
2-ene
(88%)
(12%)
(50%)
(50%)
trans
CI
ORGANIC CHEMISTRY
124
[CH. IV
Allinger et al. (1961) have examined the conformations of the 2-halocyc/ohexanones by polarographic methods. It was suggested that since these
compounds are polarographically reduced (Elving et al., 1956), it seems likely
that the reduction potential of such a system will depend on the conformation of the halogen atom. This prediction was shown to be the case in
practice.
The authors showed that for systems with relatively fixed conformation, such as the 2-halo-4--butylcycZohexanones, the epimer with the
axial halogen is reduced more easily. Furthermore, it was found that a
flexible molecule such as 2-chlorocyc2ohexanone, which contains comparable
R-COO
Experimental data has enabled one path to be distinguished from the other
(see also 16. VIII).
In fused, systems, owing to the rigidity of the structure, such interconversions (as described above) are far less likely to occur.
In this chapter, the discussion of conformational analysis has been applied
to cyc/ohexane and its derivatives, and this has been done in order to introduce some of the ideas connected with this problem. The generalisations
applicable to cyclohexsme compounds, however, are also applicable to heterocyclic compounds containing nitrogen, oxygen or sulphur (see, e.g., tropines,
They are also applicable to the poly22. XIV; carbohydrates, 7h. VII).
nuclear compounds, e.g., the Steroids; in fact, much of the work leading to
these generalisations has been carried out on these compounds (see 4c. XI).
READING REFERENCES
Wheland, Advanced Organic Chemistry, Wiley (1960, 3rd ed.). Ch. 7. The Stereochemistry of Additions to Carbon-Carbon Double Bonds.
Ingold, Structure and Mechanism in Organic Chemistry, Bell and Sons (1953). Ch. 12.
Additions and Their Retrogressions.
Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953). Ch. 12. Oxidation Processes.
GEOMETRICAL ISOMERISM
125
Reid, The Triplet State, Quart. Reviews (Chem. Soc), 1958, 12, 205 (see especially
pp. 216-219).
Porter, The Triplet State in Chemistry, Proc. Chem. Soc, 1959, 291.
DePuy and King, Pyrolytic Cis Eliminations, Chem. Reviews, 1960, 60, 431.
Hassel, Stereochemistry of cye/oHexane, Quart. Reviews {Chem. Soc.), 1953, 7, 221.
Bent, Aspects of Isomerism and Mesomerism, /. Chem. Educ., 1953, 30, 220, 284, 328.
Figueras, Stereochemistry of Simple Ring Systems, /. Chem. Educ, 1951, 28, 134.
Klyne (Ed.), Progress in Stereochemistry, Butterworth (1954). Ch. 2. The Conformation of Six-membered Ring Systems.
Barton and Cookson, The Principles of Conformational Analysis, Quart. Reviews {Chem.
Soc), 1956, 10, 44.
Orloff, The Stereoisomerism of cyctoHexane Derivatives, Chem. Reviews, 1954, 54, 347.
Newman (Ed.), Steric Effects in Organic Chemistry, Wiley (1956). Ch. 1. Conformational Analysis.
Angyal, The Inositols, Quart. Reviews {Chem. Soc), 1957, 11, 212.
Brewster, The Optical Activity of Saturated Cyclic Compounds, /. Amer. Chem. Soc,
1959, 81, 5483.
Eliel, Conformational Analysis in Mobile Systems, /. Chem. Educ, 1960, 37, 126.
CHAPTER V
NH-
o
O
N02
C02H
0O2H
NO,
IV
ii
CO.AH6
COAH; NO,
N0
N02
CO2
C02H
NO
N02
C02H
V
(1922) showed that Kenner's acid was resolvable, and pointed out that this
could be explained on the Kaufler formula, IV, since this structure has no
elements of symmetry. These authors, however, also pointed out that the
optical activity could also be accounted for by the co-axial structure, V,
provided that the two benzene rings do not lie on one plane (see also 2).
Kaufler's formula, as we have seen, was based on the assumption that the
two amino-groups in benzidine react simultaneously with various reagents.
Re-investigation of these reactions showed that this was not the case, e.g.,
Turner and Le Fevre (1926) found that the compound produced from
126
2]
127
Hence
it
SH
SH
8H
VI
SH
VII
VIII
J3-S.
IX
derivative, VI, gave the intramolecular disulphide (diphenylene disulphide,
IX). On the Kaufler formula, all three dithiols would be expected to give
the intramolecular disulphides, since the two thiol groups are equally distant
in all three
compounds.
Physico-chemical methods have also been used to determine the con4'figuration of the diphenyl molecule, e.g., the crystal structure of 4 :
diphenyl derivatives shows a centre of symmetry; this is only possible for
the co-axial formula. Dipole moment measurements also confirm this configuration, e.g., the dipole moment of 4 4'-dichlorodiphenyl is zero; this
again is only possible if the two benzene rings are co-axial.
:
resolvable,
but II
Thus
I is
not
is.
-o-oI
<^^
A A
B B
II
(ii) The substituents in the oriAo-positions must have a large size, e.g.,
the following compounds were resolved: 6-nitrodiphenic acid, 6 6'-dinitrodiphenic acid, 6 6'-dichlorodiphenic acid, 2 : 2'-diamino-6 6'-dimethyldiphenyl (see also 4).
The earlier work showed that three groups had to be present in the orthopositions. This gave rise to the theory that the groups in these positions
impinged on one another when free rotation was attempted, i.e., the steric
This theory of restricted rotation about the
effect prevented free rotation.
single bond joining the two benzene rings (in the co-axial formula) was
suggested simultaneously in 1926 by Turner and Le Fevre, Bell and Kenyon,
:
128
ORGANIC CHEMISTRY
and
[CH.
Consider molecule III and its mirror image IV. Provided that
the groups A, B and C are large enough to " interfere mechanically ", i.e.,
to behave as " obstacles ", then free rotation about the single bond is
Mills.
^~0
A
IV
III
IV
is
C02H
C0 2H
COgH
VI
be large enough to prevent the two rings from becoming coplanar, in which
case the molecule would possess a plane or a centre of symmetry, e.g.,
diphenic acid is not optically active. In configuration V the molecule has
a plane of symmetry, and in configuration VI a centre of symmetry; of
these two, VI is the more likely because of the repulsion between the two
carboxyl groups (cf. 4. II).
If restricted rotation in diphenyl compounds is due entirely to the spatial
effect, then theoretically we have only to calculate the size of the group in
order to ascertain whether the groups will impinge and thereby give rise
to optical activity.
In practice, however, it is found that groups (and
atoms) behave as if they were larger than the volumes obtained from group
(and atomic) radii (cf. 15b. I). This behaviour is largely due to the fact
that groups also repel (or attract) one another because of the electric charges
that are usually present on these groups. Thus the actual distance that
the atoms or groups (in the o^o-positions) can approach one another is
greater than that obtained from the atomic and group radii.
Better agreement with experiment is obtained when the van der Waals radii (2. I)
are used for calculating the " size " of a group.
Later work has shown that if the substituent groups are large enough,
then only two in the o- and o'-positions will produce restricted rotation,
e.g., Lesslie and Turner (1932) resolved diphenyl-2
2'-disulphonic acid, VII.
In this molecule the sulphonic acid group is large enough to be impeded
by the or<Ao-hydrogen atoms. Lesslie and Turner (1933) have also resolved
:
S03 H
Br
S03 H
A8(CHs)3
vii
viii
2]
129
_C02II
CQ2 H
(C02 C 2 Hs )2
= 8or"l0
(0O 2 C 2 H 5 ) 2
IX
XI
rings are not coplanar and are held fairly rigid by the large methylene ring.
which
Iffland et al. (1956) have also prepared the optically active diphenyl
has a 2 : 2'-bridge and two amino-groups in the 6 6'-positions. On the
other hand, these authors have also prepared XI in optically active forms
this compound has the 2 2'-bridge but no substituents in the 6 6'-positions.
Mislow (1957) has also obtained the dibenzocyc/o-octadiene acids, XII, in
Similar to
optically active forms; both forms were highly optically labile.
H0 2 C
Ph^
C0 2 H
Th
XIII
XII
_C02 H
OH OH
HO
HO OH
XV
XIII which has been resolved by Bell (1952).
have also resolved the diphenyl derivative XIV.
XII
is
Cxl2
C/H2
Mislow
et al.
(1961)
ORGANIC CHEMISTRY
130
[CH.
XV
Schmidt
persion
method
(12a. I).
Adams
(1931)
et al.
iV'-dipyrryl.
H02 C
C02 H
CII3
H0
CH3
CH3
CH3
'CH3
=N,
=/
0H3
Adams
et al.
(1932)
have
C02H
002H
(ii)
C02H
3'-dipyridyl
C02H
CCfeH
COjjH
This compound gives rise to asymmetric transformation (10 iv. II) resolution with brucine gave 100 per cent, of either the (+)- or ( )-compound.
Other compounds similar to the dinaphthyl which have been obtained
in optically active forms are 1 : l'-dinaphthyl-5 5'-dicarboxylic acid, I
(Bell et al., 1951), the dianthryl derivatives, II and III (Bell et al., 1949),
and the 4 4'- and 5 5'-diquinolyls, IV and V (Crawford et al., 1952).
obtained iV-benzenesulphonyl-8-nitro-l(hi) Mills and Elliott (1928)
naphthylglycine, VI, in optically active forms; these were optically unstable,
;
3]
131
H02 C
C02 H
H0 2C
II
III
9^
N02
/CH^COaH
CH3
CO-CH3
^S03H
VI
VI and VII the optical activity arises from the restricted rotation about
the C N bond (the C being the ring carbon to which the N is attached).
Asymmetry arising from the same cause is also shown by 2-acetomethylamido-4' 5-dimethyldiphenylsulphone, VIII; this was partially resolved
by Buchanan et al. (1950; see also 10 iv. II). It is also interesting to note
in this connection that Adams et al. (1950) have isolated pairs of geometrical
isomers of compounds of the types IX and X; here geometrical isomerism
is
VIII
CN
.SCVCgHs
SOj'CjHs
IX
bonds.
ORGANIC CHEMISTRY
132
[ch.
R
CH3
C6 H5 S02-N
XN^N-SO^CeHs
CH
S02 "C6 H5
(iv) Liittringhaus et al. (1940, 1947) isolated two optically active forms
of 4-bromogentisic acid decamethylene ether.
In this compound the methylene ring is perpendicular to the plane of the benzene ring; the two substituents, Br and C0 2 H, prevent the rotation of the benzene nucleus inside
CH
HO,C
(CH2 )
CH,
1(
CH
^=\
CH,
COoH
the large ring. Cram et al. (1955) have obtained a paracyclophane in optically active forms; there is insufficient space to allow the benzene ring
carrying the carboxyl group to rotate to give the enantiomorph. In this
compound the two benzene rings are parallel and perpendicular to the plane
(CH2 )10
HOC
of the ring.
On the other hand, Blomquist
simple paracyclophane shown.
et al.
(1961)
(v) Terphenyl compounds can exhibit both geometrical and optical isomerism when suitable substituents are present to prevent free rotation about
single bonds, e.g., Shildneck and Adams (1931) obtained the following compound in both the cis- and trans-forms.
Br
CH3 0H 0H CH3
^=fa
OH OH
Br
Ch3
cis
Br CH3
0H 0H
CH3
CH3
OH 0H
CH3 Br
trans
Interference of the methyl and hydroxyl groups in the or^o-positions prevents free rotation and tends to hold the two outside rings perpendicular
to the centre ring.
Inspection of these formulae shows that if the centre
ring does not possess a vertical plane of symmetry, then optical activity is
3a]
CI*3
ch3
Br O H
133
^3 3
uH3
<^3~c>-^=>
^=^ OH Br
CH
CHs
Br
OH
OH
Br
__.
^>-^^-^^CH
CH3
trans
Thus Browning and Adams (1930) prepared the dibromo cis- and
trans-forms, and resolved the 's-isomer; the foms-isomer is not resolvable
possible.
it
(vi)
NH
that
it
salt,
is
tion of the phenyl group about the C phenyl bond, the restriction being
brought about by hydrogen atoms in the wtf/w-positions. The two hydrogen
x overlap in space, and consequently the benzene ring
atoms labelled
cannot lie in the same plane as the 10-methyleneanthrone skeleton.
3a. Molecular overcrowding. All the cases discussed so far owe their
asymmetry to restricted rotation about a single bond. There is, however,
CO,H
ORGANIC CHEMISTRY
134
[CH.
lie
in this plane.
and
5,
and have
Me Me
VI
IV
Newman et al. (1955, 1956) have preoptically stable than I, II and III.
pared V and VI which, so far, are the most optically stable compounds of
the intramolecular overcrowding type.
It will be noticed that in IV and VI the only way in which out-of-plane
distortion can occur is through buckling of the molecule. The simplest
VII
VIII
4]
135
rotation of about 40 around the olefinic double bond (Schmidt et al., 1954).
Even in such simple molecules as tiglic acid (X) the two methyl groups
give rise to molecular overcrowding with the result that the /S-methyl group
Me
\c/
Me
\c/
II
II
Ms/ Nx>,H
HO ac/ NMe
XI
appears to be displaced from the molecular plane, thereby relieving overcrowding which is also partly relieved by small distortions in bond angles.
These results were obtained by Robertson et al. (1959) from X-ray studies,
and these authors also showed similar distortions in angelic acid (XI).
In polynuclear aromatic hydrocarbons in which the strain tends to be
overcome by out-of-plane displacements of substituents and out-of-plane
ring buckling, these effects cause changes in the ultraviolet spectra, but it is
not yet possible to formulate any correlating rules.
studies by Ried
(1957) have shown a shift for the hydrogen atoms in positions 4 and 5 in
phenanthrene itself. A similar phenomenon has been detected by Brownstein
NMR
is
of diphenyl
A B
ORGANIC CHEMISTRY
136
[CH.
that the final product will contain an equimolecular amount of the (+)and ( )-forms. Westheimer (1946-1950) has assumed, in addition to the
above bond-stretchings, that the angles a, /? and y are deformed, and also
is
Plane when
coplanar
Fig. 5.1.
the type Cabde, e.g., from spectroscopic data it appears that the bonds would
break before the vibrations were large enough to permit a planar configuraFurthermore, Kincaid and Henriques (1940), on the
tion to be reached.
basis of calculations of the energy required for the inversion of molecules,
were led to suggest that the molecule Cabde can only be racemised by the
bonds actually breaking. Evete>lso, this theory of racemisation appears to
OCH 3
F C02H
OCHs
H0 2 G F
I
too small to prevent rotation about the single bond. Thus 2 2'-difluoro6 6'-dimethoxydiphenyl-3 3'-dicarboxylic acid, I, is non-resolvable.
These must contain at least two
(ii) Resolvable, but easily racemised.
amino-groups, or two carboxyl groups, or one amino- and one carboxyl
:
C02 H
F
C02 H
II
4]
137
group; the remaining groups may be any of those given in (i) [but not
hydrogen]. Thus 6 6'-difluorodiphenic acid, II, is resolvable, and is readily
:
racemised.
(iii) Not racemisable at all.
Diphenyl compounds which fall in this group
are those which contain at least two nitro-groups the other groups can
be any of those given in (i) but not hydrogen and (ii). Thus 2 2'difluoro-6 6'-dinitrodiphenyl, III, is resolvable, and cannot be racemised.
;
N0
o-o
F
NO,
III
In addition to the size of the groups in the ortho-positions, the nature and
position of other substituent groups also play a part in the rate of racemisation, e.g., the rate of racemisation of IV is much slower than that of
(Adams et al., 1932, 1934). Thus the nitro-group in position 3' has a much
N02 H CO
3
N02 H3CO
NOj;
C02H
IV
C02 H
N02
greater stabilising influence than in position 5'. The reason for this is uncertain, but one possible explanation is as follows.
In VI, the methyl
group of the methoxyl group is probably in the configuration shown. In
VII, the nitro-group in the 3'-position would tend to force the methyl
group away, the resulting configuration being somewhat as shown in VII;
NO,
G/
CH,
C02 H
VI
would be greater interference between the methoxyl
group and the two groups in the other benzene ring.
Adams et al. (1954, 1957) have examined the rate of racemisation of
(VIII).
The rate is increased when R is an electron-attracting group such
in this condition there
PhS0 2
\N/
CH2 C02 H
^CH2 C02H
"
N02
IX
when
N0 2
PhS02v
Me
N0
C=N
ORGANIC CHEMISTRY
138
[CH.
and consequently
it is
R=
transition state.
Adams et al. (1957, 1961) also examined the optical stability of compounds
X; they found that the half-life was in the following order for R:
Me < Et < *'-Pr > M3u. If the effect of R were due merely to the in-
of type
ductive
effect,
this basis.
The
2-Bu group, because of its large bulk, displaces the adjacent Me groups out
of the plane of the benzene ring, thereby causing molecular overcrowding;
C (ring) bond (3a).
this decreases the interference to rotation about the N
A molecular model of this compound showed such an interference. According to Bryan et al. (1960), it is possible that steric repulsion also operates
to cause considerable angle distortion.
Evidence for the obstacle theory. Evidence for the obstacle theory,
interference of groups, amounts to proving that the two benzene rings
direct chemical
in optically active diphenyl compounds are not coplanar.
proof for the non-coplanar configuration was given by Meisenheimer et al.
The method was to unite the " obstacle groups " in optically active
(1927).
diphenyl compounds, thereby forming five- or six-membered rings. Now
such systems are known to be planar, and hence optical activity should
disappear; this was found to be so in practice. Meisenheimer started with
2 2'-diamino-6 6'-dimethyldiphenyl, resolved it and then carried out the
5.
i.e.,
JNH-COCH,
CH,IJ
CH,
CH,-CO-NH
optically active
optically active
form
I
H0
.
Cl
4nh-coch 3
H s S04
CH,CONH(i
optically inactive
CO]
bC02 H
optically active
all the optically active compounds, the rings cannot be coplanar, since
they were, the molecules would possess a centre or plane of symmetry.
If the dilactam, however, is not planar, then it would possess no elements
If the dilactam
of symmetry, and consequently would be optically active.
cannot be
is planar, then it has a centre of symmetry, and consequently
In
if
6]
139
optically active. This compound was, in fact, not optically active, and so
must be planar.
According to Dhar (1932), X-ray analysis studies have shown that in
the solid state the diphenyl molecule is planar. On the other hand, according to Robertson (1961), who also examined crystalline diphenyl by X-ray
This non-planarity has been
analysis, the molecule is not strictly planar.
attributed to steric repulsion between the o-hydrogen atoms. Gas phase
electron-diffraction studies indicate that the two rings are inclined at about
45 to one another (Brockway et ak, 1944; Bastiansen, 1949). In the solid
state, crystal forces presumably tend to keep the diphenyl molecule almost
planar.
6.
Allenes are
I.
6C=C=Ca6
abC==C=Cde
II
Fig. 5.2.
plane of the paper, and the 71,,-bond is in the plane of the paper. In the
trigonal state, the si-bond is perpendicular to the plane containing the three
(r-bonds (see Vol. I, Ch. II); consequently the groups a and b lie in the
plane of the paper, and the groups d and e in the plane perpendicular to
the plane of the paper. This molecule does not possess a plane or centre
of symmetry; this is also true for molecule II. Thus I and II will be
resolvable (see also 3. IV).
The resolvability of allenes was predicted by van't Hoff in 1875, but
experimental verification was not obtained until 1935, when Mills and
Maitland carried out a catalytic asymmetric dehydration on <x : y-di-1naphthyl-a : y-diphenylallyl alcohol, III, to give the dinaphthyldiphenyl-
-HsO^
III
When
IV
the dehydration was carried out with an optically inactive dehydrating catalyst, e.g., ^-toluenesulphonic acid, the racemic modification of the allene derivative was obtained.
When, however, the alcohol
allene, IV.
ORGANIC CHEMISTRY
140
III
[CH.
acid,
The
first
Kohler
et al.,
C6 H5
1-C 10
/G=C=C
C 6 H5
C 6 H5
\C0 H
1-C 10
C=C=C
H^
7
C6 H5
^CO-0-CH2 -C02 H
VI
VI by means
of brucine.
OH
'
(+)-CMe 3 -CMe-C=CH
son*
-^^
CMe 3
CMe^C^CH
-.CH 2 'CH2
ST ^CHs-CH^
JH
^COssH
VII
Pope et al. resolved l-methylcyc/ohexylidene-4-acetic acid, VII in this compound one of the double bonds of allene has been replaced by a six-membered
ring, and the general shape of the allene molecule is retained.
;
It is interesting to note, in
CH^C-(^-CH=C=CH-CH=CH-CH=CH-CH 2-CO aH
7.
If both double bonds in allene are replaced by ring systems, the resulting
molecules are spirans. One method of naming spirans obtains the root
name from the number of carbon atoms in the nucleus; this is then prefixed
by the term " spiro ", and followed by numbers placed in square brackets
7]
141
"
which indicate the number of carbon atoms Joined to the " junction
carbon atom. The positions of substituents are indicated by numbers, the
3
CH2 .
^-CH2
GKf
N^H
^CH CH
pc
":ch
*c\
x CHCr ^CH -CHr
^
/C^i
CH Z \-
II
numbering beginning with the smaller ring and ending on the junction
carbon atom; e.g., I is spiro-[2 2]-pentane, II is l-chlorospiro-[5 3]-nonane.
Examination of these formulae shows that the two rings are perpendicular
to each other, and hence suitable substitution will produce molecules with
no elements of symmetry, thereby giving rise to optically active forms,
e.g., Mills and Nodder (1920, 1921) resolved the dilactone of benzophenone2 2' 4 4'-tetracarboxylic acid, III. In this molecule the two shaded
:
C02 H
C02Na
Ott^C~b
ii'li
ti
J-''!''
>
V
compounds that have been resolved are the spiro-heptane, VI (Backer et al.,
1928, 1929), the spiro-hydantoin, VII (Pope and Whitworth, 1931), and the
spiroheptane, VIII (Jansen and Pope, 1932).
H0 2 C
NH--CCk.
C02 H
^CO--NH
CO--NIT
VI
NH 2
.,NH--CO
1
Vv
VII
/ CH
^CH
CH
'N,/
^CH S ^NH
VIII
ORGANIC CHEMISTRY
142
[CH.
In all the cases so far discussed, the optical activity of the spiran is due
to the asymmetry of the molecule as a whole; thus there is only one pair
of enantiomorphs.
If a spiro-compound also contains asymmetric carbon
atoms, then the number of optically active forms is increased (above two),
the actual number depending on the compound in question, e.g., Sutter
and Wijkman (1935) prepared the spiro-compound IX, which contains two
similar asymmetric carbon atoms (*).
If we imagine the left-hand ring of
IX to be horizontal, then the right-hand ring will be vertical; and if we
represent them by bold horizontal and vertical lines, respectively, then
U
CHa-C-CHs
I*
CH3-C CH^
CH3
CH3
CO O^
^"0
CO
CH,
IX
CH,
XI
XII
there are three different geometrical isomers possible, X, XI and XII (this
can be readily demonstrated by means of models). Each of these geometrical isomers has no elements of symmetry, and so each can exist as a
pair of enantiomorphs. Three racemic modifications were actually isolated
by Sutter and Wiikman, but were not resolved.
Cram et al. (1954) have also prepared the following three spiro [4 4]
nonanediols (as racemates):
:
OH
OH^Xf/OH
HO
as-cts
cis-trans
HO
trans-trans
READING REFERENCES
Stewart and Graham, Recent Advances in Organic Chemistry, Longmans, Green. Vol. Ill
Ch. 11. The Diphenyl Problem.
(1948, 7th ed.).
Adams and Yuan, The Stereochemistry of Diphenyls and Analogous Compounds,
Chem. Reviews, 1933, 12, 261.
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd ed.). Vol. I. Ch. 4,
pp. 337-382.
Crawford and Smyth, The Effect of Groups in Non-Blocking Positions on the Rate
of Racemisation of Optically Active Diphenyls, Chem. and Ind., 1954, 346.
Ann. Reports (Chem. Soc), Stereochemistry of Diphenyl Compounds, 1926, 23, 119;
1931, 28, 394; 1932, 29, 69; 1935, 32, 246; 1939, 36, 2S5; 19S3, 50, 154; 1955, 52, 131.
(Ed.), Progress in Stereochemistry, Butterworth. Vol. II (1958).
CHAPTER VI
was also assumed that a double (and triple) bond repels other bond-pairs
more than does a single bond. The following two tables illustrate these
It
ideas.
Number
of
electrons
in valency
Number
of
bonding
pairs
shell
Number
Hybrid
of lonepairs
orbitals
used
sp 3
HO
sp*d
Trigonal
PC1 6
spH*
bipyramid
Octahedron
SF,
sp*
HgCl,
BCl a
pyramid
V-shape
sp
2
5
Examples
sp*
sp*
molecule
Linear
Triangular
plane
Tetrahedron
Trigonal
Shape of
CH 4
NH,
a
of a-
2.
Quaternary
gen in quaternary
ammonium
ammonium
salts
salts.
later,
144
ORGANIC CHEMISTRY
[CH. VI
Number
Number
of o-bonds and
lone-pairs
of a-
bonds
of lonepairs
Linear
0=C=0;
Triangular
plane
\s^
Shape
of
molecule
Examples
:
Triangular
plane
O
4
Tetrahedron
C1
\c/
II
II
C1
oA<o
ci/^Vo
OH
CI
or
3
H C=N
=v
x OH
X C1
Trigonal
o^|\;i
pyramid
Cl
however, it was shown that one valency was different from the other four.
Thus, using the formula, [Uabcdj+X-, for quaternary ammonium salts, and
assuming that the charge on the nitrogen atom has no effect on the configuration of the cation, the cation may be considered as a five-point system
similar to that of carbon in compounds of the type Cabde. This similarity
is based on the assumption that the four valencies in the ammonium ion
are equivalent, and this assumption is well substantiated experimentally
and
also theoretically.
I,
II
the cation
If
is
planar
(I),
a
I
d N b
I
II
then
CH 3
-i
C 2 H5
IV
showed
was wrong. The first definite resolution of a quaternary amwas that of Pope and Peachey (1899), who resolved allylbenzylmethylphenylammonium iodide, V, by means of (+)-bromocamphorsulphonic acid. This was the first case of optical activity due to a " central "
monium
this
salt
2a]
145
CH3
C6 H5
V
atom other than carbon.
of Jones (1905),
Thus the
tetrahedral.
Bischoff (1890) had proposed a pyramidal structure, and this
configuration was supported by Jones (1905) and Jones and Dunlop (1912).
On the other hand, Werner (1911) had suggested the tetrahedral configurathis was supported by Neagi (1919) and Mills and Warren (1925).
however, Mills and Warren who gave the most conclusive evidence
that the configuration is tetrahedral. Their evidence is based on the following argument. Compounds of the type abC=C=Cab are resolvable since
carbon is " tetrahedral " (see allenes, 6. V), and if nitrogen is also " tetrahedral", then the compound a&C=:N=C& should be resolvable, but will
not be resolvable if the nitrogen is pyramidal. Mills and Warren prepared
4-carbethoxy-4'-phenylbispiperidinium-l l'-spiran bromide, and resolved
it.
If the configuration of this molecule is VI, i.e., a spiran, then it possesses
no elements of symmetry, and hence will be resolvable; if the configuration
is VII {i.e., pyramidal), then it will possess a vertical plane of symmetry,
tion,
and
It was,
CH2 CH2
CH-CH
/ C CH CKf^
C
C6 Hf
^CH CHf^ C
^C0 C H
N\
Br
6
VI
C6H 6
CO2C2H5
VII
and hence will be optically inactive. Since the compound was resolved,
the configuration must be tetrahedral, i.e., VI. This tetrahedral configuration has been confirmed by physico-chemical studies (see 2b). More
recently, Hanby and Rydon (1945) have shown that the diquaternary salts
of dimethylpiperazine exhibit geometrical isomerism, and this is readily
explained on the tetrahedral configuration of the four nitrogen valencies
(cf.
R
CH3
++
CIL-CH,
K.
CH -CH
2
CIS
ch3
2 Br
R
N
++
,CHr-CH2 ^ ( ,H
2 Br
\,
'N
H - CH2
3"l
trans
ORGANIC CHEMISTRY
146
It
II)
(6.
[CH. VI
We
E* "EH
(-)
(+)
CH-
,1=
"JP
(-)
(+)
cis-cis
cis-trans
IX
VIII
jpa< a-q^
(+)
,py s ujp,
meso
(-)
trans-trans
trans-trans
XI
XII
All four have been prepared, and are depicted as shown in IX, X,
XII. The co-axis of each spiran is assumed to be perpendicular
to the plane of the paper, and the intersecting lines represent the two rings.
The short appendages show whether the two substituents (methyl) are cis
or trans. The ring nearer the observer's eye is indicated by the heavy line,
and a uniform orientation has been adopted the front ring is always vertical,
and the back horizontal ring with at least one substituent directed upwards
and the cis ring placed at the back in the case of the cis/trans ring combination.
Racemisation of optically active quaternary ammonium salts is far more
readily effected than that of carbon compounds containing an asymmetric
carbon atom, i.e., compounds of the type Cabde. The mechanism of the
racemisation of the ammonium salts is believed to take place by dissociation
into the amine, which then rapidly racemises (2c):
meso.
XI and
Nabcd}
+X-
^ NZ>c + dX
dX
CH 3
C 2 Hs-N->0
C6 H S
I
C.H. N-K>
CH3
II
2c]
147
N-0
or
IV
R N=0
V
3
also account for the optical activity of these compounds as well as the
tetrahedral.
Consequently these compounds cannot be used as a criterion
for the pyramidal or tetrahedral configuration of the nitrogen atom.
However, by analogy with the quaternary ammonium salts, the configuration
of amine oxides may be accepted as tetrahedral.
Further evidence for
this is as follows. The electronic configuration of nitrogen is (ls 2 )(2s 2 )(2^> 3).
For nitrogen to be quinquevalent, the " valence state " will be derived
from the arrangement (ls2)(2s)(2^>3)(3s).
Now the amount of energy required to promote an electron from a 2s to a 3s orbital appears to be too
large for it to occur, and consequently nitrogen is (apparently) never quinquevalent. The valence state of nitrogen is thus achieved by the loss of one
2s electron and then hybridisation of the 2s and 2p 3 orbitals, i.e., nitrogen
becomes quadricovalent unielectrovalent, and the four bonds (sp3 bonds)
are arranged tetrahedrally. The charged nitrogen atom is isoelectronic
with carbon, and so one can expect the formation of similar bonds. Furthermore, evidence obtained by an examination of the vibration frequencies of
the ammonium ion indicates that the configuration of this ion is tetrahedral.
Recently, Bennett and Glynn (1950) have obtained two geometrical isomers of 1 : 4-diphenylpiperazine dioxide; this is readily explained on the
tetrahedral configuration of nitrogen (c/. 2a).
*^CH -CHf
2
i^-CHjs-CHf
C6 H6
trans
cis
2c.
Amines.
If the tertiary
is
planar,
it will
yCgHs
ORGANIC CHEMISTRY
148
[CH. VI
flk-
images and not superimposable (IV is III " turned over", and it can be
seen that IV is the mirror image of II). Thus this oscillation brings about
very rapid optical inversion. This oscillation theory is supported by evidence obtained from the absorption spectrum of ammonia (Barker, 1929;
Badger, 1930), and the frequency of the oscillation (and therefore the inver10 per second (Cleeton et al., 1934).
sion) has been calculated to be 2-3 X 10
In the foregoing explanation for the racemisation of amines, it has been
assumed that the nitrogen valency angles and the bond lengths change."
This inversion of amines, however, is better represented as an " umbrella
switch of bonds, i.e., the bond lengths remain unaltered and only the nitrogen valency angles change. This interpretation is more in keeping with
the facts, e.g., as the groups a, b and c increase in weight, the frequency of
the inversion of the molecule decreases.
Theoretical calculations have shown that an optically active compound
will not racemise spontaneously provided that the energy of activation for
the change of one enantiomorph into the other is greater than 12-15 kg.cal./
mole. The two forms, II and III, have been shown to be separated by an
energy barrier of about 6 kg.cal./mole, and consequently the two forms are
readily interconvertible.
It has already been mentioned (2b) that the electronic configuration of
3
2
the nitrogen atom is (ls*)(2s ){2p ). According to Hund's rule, electrons
orbital
as far as possible (see Vol. I, Ch. II).
same
the
being
in
tend to avoid
Thus, in ammonia and its derivatives, bonds are formed by pairing with
Since these are mutually at
the three single orbitals 2p x 2p v and 2p z
right angles, the configuration of the ammonia molecule will be a trigonal
pyramid, i.e., a pyramid with a triangular base, with the nitrogen atom
situated at one corner. Oscillation of the nitrogen atom brings about inversion in the tertiary amines, ~Nabc. This picture of the configuration of
the ammonia molecule, however, requires modification. The valency angles
in ammonia have been shown to be approximately 107. The deviation
from the value of 90 (on the assumption that the bonds are pure 2p orbitals)
is too great to be accounted for by repulsion between the hydrogen atoms.
As we have seen (1), according to modern theory the orbitals in ammonia
,
2d]
149
CH,
by chromatographic adsorption on D-lactose (cf. 10 vi. II). In this compound, the nitrogen is tervalent, but the frequency of osculation has been
brought to zero by having the three valencies of nitrogen as part of the
ring system.
Vol.
I)
et at.
by
(1958)
NMR
type of compound
2d.
Oximes.
may
C 6H 6-C(=NOH)-C(=NOH)-C 6H 5
by boiling it in
ethanolic solution;
and then, in 1889, Meyer et al. isolated a third isomer of this compound.
Beckmann, also in 1889, found that benzaldoxime existed in two isomeric
forms, and from that time many aromatic oximes were shown to exist in
two isomeric forms. The existence of isomerism in aromatic oximes was
first explained by structural isomerism, two of the following four structures
corresponding to the two isomers (where R is an alkyl or an aryl group)
II is the modern way of writing the nitrone structure (originally, it was
Ar^ ^R
II
II
oxime
nitrone
II
Ar
,^R
N=0
III
.R
Arv.
l>
IV
written with quinquevalent nitrogen, the nitrogen being linked to the oxygen
by a double bond). Hantzsch and Werner (1890), however, suggested that
the isomerism of the oximes was geometrical and not structural. According to these authors, nitrogen is tervalent (in oximes), and is situated at
one corner of a tetrahedron with its three valencies directed towards the
other three corners; consequently the three valencies are not coplanar (cf.
tertiary amines).
These authors also assumed that there is no free rotation
about the
double bond (cf. 2. IV), and therefore proposed configurations
and VI for the two isomers:
C=N
ORGANIC CHEMISTRY
150
^R
Ar^
/R
Arv.
ii
V
Many
(i)
(ii)
[CH. VI
VI
e.g.,
If
found to be so in
this is not
practice.
(iii)
identical structures.
CH3
Ar.
Ar..
^C=NOCH
BT
^C=1T
R^
VII
"^O
VIII
that on heating with hydriodic acid, VII gives methyl iodide, whereas VIII
gives methylamine. Thus, Semper and Lichtenstadt (1918) obtained four
methyl derivatives of phenyl ^>-tolyl ketoxime, IX-XIL On treatment
.C6 H 6
*>-CH 3 -C 6 H 4 .
^OCH
/>-CH 3 -C 6 H 4
XI
^C H
6
kj
CH 3 Cr
IX
/.-CHsCeH^
'C e
p-CHj-C.H^
^C^
<jxa 3
XII
i.e.,
2e]
Ar
\ G/'
Ar
11
\G / R
=^~
II
and
H^ ^O
^OH
^c^* ^~ Ar \ c /R
II
II
151
II
O^ ^H
HO^
It is possible, however, that none of the nitrone form is present, but its
methyl derivative is formed during the process of methylation
If we assume
that methyl sulphate provides methyl carbonium ions, then it is possible
that these ions attack the nitrogen atom (with its lone-pair) or the oxygen
atom (with its two lone-pairs). This would result in the formation of the
N- and O-methyl ethers, without having to postulate the existence of the
.
CRgQ)- SOjj-OCHg
\c /R
Ar
Ar
\c/R
Al
+
\c^U
+ CHS
|
J.
Nj
Ar
CH^
CH<" ^(P-H
\c/R
Ar
+-
\c /R
Ar
-H +
CH 3
\ c /R
^OCH 3
^CP-H
>(}
"N)
CH,
In the foregoing account, the geometrical isomerism of the oximes is based
on the assumption that the nitrogen atom, in the oximino-form, exhibits the
trigonal pyramidal configuration. Further proof for this configuration is
obtained from the examination of the oxime of cycfohexanone-4-carboxylic
acid
(XHIa
or
b).
If
CH^-CH,
H02 CT
^CHg-CHg
GHrCH^
H02 Cr
^CHg-CH^
OH
XHIa
N O
bond
(i.e.,
the
XIII6
C=N
is
XHIa, and
it will
and
ORGANIC CHEMISTRY
152
C 6 H5
*\rt/ H
Co Hi
JR
/-CH 3 -C 6
HO^"N
N ^OH
first
\o
[CH. VI
II
syn
anti
H4X
'6*1-5
'QHi
HO
III
group named and the hydroxyl group (cf. 4. IV). Thus III may be
as syn-p-tolyl phenyl ketoxime or awfo'-phenyl ^>-tolyl ketoxime.
named
Arx
*v*
Na ' co .
+CH
II
N-OCOCH 3
-C0 2 H
^-OH
syn-
Ar
Ar,
H
Na a CO,
+ CH
-C0 2H
>-
CH 3 -COON
anti-
Brady and Bishop (1925) found that only one of the two isomers of
2-chloro-5-nitrobenzaldoxime readily gave ring closure on treatment with
2
NaOll
0,N
O.N
0,N
Na 2 C0 3
2g]
153
sodium hydroxide.
method
cr
>-
Nu 2 COj
2g. Determination of the configuration of ketoximes. The configurations of ketoximes have been mainly determined by means of the
is
The
ORGANIC CHEMISTRY
154
[CH. VI
the configuration of the oxime, and assumed that the sy-exchange of groups
occurred since they were closer together in this isomer. This, again, was
shown experimentally to be the reverse, i.e., it is the &'-rearrangement
that occurs, and not the syn; thus:
Ar
V/R
V*
NN
Ar
NHAr
AC
MDH
^/E
Arv
/N
-OH
N/-
*L
HCK
NHR
^R
C6 H5-C
C'GeHj;
II
N.
X 0^
c-c6
ozonolysis
C-C6 H 5 CpH
ijiii 5 coci
C 6 HB-C-
-OC6 H5
C6H5"C-
II
O
K "0-COC
H
II
III
C6 H 5 -C-CO-C6 H5
O=C-CO06 H6
pc.
NHC H
6
^OH
IV
III
in the awfo'-position.
The configuration of the /?-monoxime, III,
confirmed by the fact that it may be obtained directly by the ozonolysis
of 3 4-diphenyhso-oxazole-5-carboxylic acid, V (Kohler, 1924).
Meisenheimer et al. (1925) also demonstrated the awfo'-rearrangement as follows.
must occur
is
C6 H 5 -C
CC HS
9
II
II
^CC02 H
N
V
+ C H -C-COCH
ozonolysis
&
III
The a-oxime
2g]
156
Q 2Ni
HO-^
VII
NaOH
OoN
Further evidence for the fo'-exchange of groups in the Beckmann rearrangement has been obtained by studying the behaviour of compounds
exhibiting restricted rotation about a single bond, e.g., Meisenheimer et al,
(1932) prepared the two isomeric oximes of l-acetyl-2-hydroxynaphthalene3-carboxylic acid, VIII and IX, and of these two forms only one was resolvable.
This resolvable isomer must therefore be IX, since asymmetry
H /OH
C6
OH
iCOsH
IX
VIII
due to restricted rotation is possible only with this form (c/. 3. V). Meisenheimer found that the ethyl ester of IX, on undergoing the Beckmann
rearrangement, gave the amide Ar'CONH>CH a (where Ar is the naphthalene
part of the molecule), whereas the ethyl ester of VIII gave the amide
CH 3*CO'NH'Ar. These results are in agreement with the awfo-exchange
of groups in each case.
An
CH,-
-CH2
H,so 4
CH
CH2
CH*
,CH2
CH 2
II
CHo
CHo
NH
_CH2
^CO
NOH
OH
ORGANIC CHEMISTRY
156
[CH. VI
On the other hand, Hill et al. (1956) have shown that the oximes of some
spiro-ketones undergo abnormal Beckmann rearrangements in the presence
of polyphosphoric acid, e.g., spiro-[4 4]-nonanone-l-oxime gives hydrind8 9-en-4-one:
:
NOH
Although aliphatic ketoximes are not known in two isomeric forms, some
CH\
pcu
^C=NOH -^^*-
-h 2 o
C6
H C-H
^C H -NH-CHO+
6
C6 H5
CONH
syn -isomer
fi
H -C
5
-*-C 6 H 5 -CO-NH 2
N
HO'
anti- isomer
form into the anti; aft'-benzaldoxime gives benzamide only. These results
are in agreement with the configurations obtained by other methods (see
2f).
2h]
157
2h. Mechanism of the Beckmann rearrangement. This rearrangement is an example of the 1,2-shift in which the migration origin is carbon
and the migration terminus is nitrogen (see also 1,2-shifts, Vol. I, Ch. V).
As we have seen above (2g), an integral part of the rearrangement is the
Since the oxime itself does not rearrange, it
anti migration of the group.
is reasonable to suppose that some intermediate is formed between the
oxime and the reagent used to effect the rearrangement, and it is this intermediate which then rearranges. Kuhara et M. (1914, 1916) prepared the
benzenesulphonate of benzophenone oxime and showed that this readily
underwent rearrangement in neutral solvents in the absence of any acid
catalyst to give an isomeric compound which, on hydrolysis, gave benzanilide
and benzenesulphonic acid; thus:
Ph-CONHPh
Ph
Ph
Ph-C=N
*2*$.
-> Ph-C=N
OSO.-Ph
OSO.-Ph
+
Ph-SO,H
Kuhara assigned structure I to this intermediate on the fact that its absorption spectrum was almost identical with that of the compound prepared
by reaction between iV-phenylbenzimidoyl chloride and silver benzenesulphonate:
Ph-CCl=NPh
Kuhara
phenone
+ AgOSCyPh
+ AgCl
(1926) also showed that the rate of rearrangement of the benzooxime ester is faster the stronger the acid used to form the ester;
Ph-S03H
Chapman
ethyl methyl ketoxime is treated with sulphuric acid the product, 2V-<xphenylethylacetamide, is almost 100 per cent, optically pure. Thus the
migrating group never separates during the rearrangement, since if it did
a racemised product would have been obtained. Furthermore, this retention
of optical activity might be cited as evidence for the formation of a bridgedion during the migration, since in such an ion the migrating group is not
free and the " new partial " bond is formed on the same side as the bond
which is breaking (see below).
PhMeCH-C-Me
II
NOH
w
-^>
ao
0=C-Me
I
HN-CHMePh
Another problem that arises here is: Does the anion separate completely
during the ionisation or does it also migrate intramolecularly? The work
of
corhplete separation,
and
this
supported by the work of Brodskii et al. (1941), who found that when
benzophenone oxime was treated with phosphorus pentachloride and then
with water enriched with the isotope 18 0, the benzanilide obtained contained some of this isotope. Thus the oxygen atom of the oxime group
is
ORGANIC CHEMISTRY
158
[CH. VI
must have been completely removed in the ionisation stage (see below).
The following mechanism is in agreement with all of the above facts (Y is
PC14 MeCO, etc.); the lower set of equations is the alternative route via
,
YO
R'
/*'
H.O
+ OY"
Ml
R
/*
R'
I
III
+ OY"
--N
R/
'
NHR
/
R
-C
R>
0Y
a bridged-ion. It might also be noted that when acid is used as the re+.
arranging reagent, OY is probably
Support for this mechanism is
2
the evidence obtained for the intermediate formation of the imidoyl ester
(RN
CR-OY) compound II was obtained by Heard el al. (1959), who
examined the rearrangement of a 17-keto-16-oxime (a steroid; Ch. XI):
OH
yys
OAc
OAo
It has been shown that when the migrating group is aryl, the rate of the
rearrangement is accelerated when there is an electron-releasing group,
e.g., Me, in the ^-position.
This may be cited as evidence to support the
formation of a bridged-ion (at least for migrating aryl groups).
On the basis of the above mechanism, we can now explain Brodskii's
results as follows:
Ph
.Ph
Ph
"
+ 0PC1 4
ora<
OPCh
JH.O
Ph x
OH 2
Ph\ .OH
C^
Pli
PhOONHPh
PhCONHPh
Stephen et al. (1956) have shown that one molecule of phosphorus pentachloride, phosphoryl chloride, thionyl chloride, or benzenesulphonyl chloride
rearranges two molecules of the ketoxime to yield the corresponding amide
2R aC=NOH +
PCI.
POCl 8
e.g.,
+ HC1
It has also been shown that hydrogen chloride is essential during the rearrangement, but that it does not itself cause the rearrangement of the
2i]
159
oxime.
R\
2R2C=NOH
-HjO
CR2
cr
N
HC1.
(R 2 C=N 2
anhydride
anhydride salt
.0.
-HCl
RC
II
RN
p*
RC
CR
RN
II
NR
0=CR
RCC1
HCl
-
II
II
RN
NHR
-R
ketoxime imidate
which effect the Beckmann rearrangement may function as dehydrating agents for the formation of the ketoxime
It is also suggested that other reagents
anhydride.
When
The mechanism
is
ism:
^OH
Me X(
J^0H;
Me-03
mO0V
-H,0
The authors
160
ORGANIC CHEMISTRY
[CH. VI
N0 2
C6 H5 -C-CO-C6 H5
II
N-NH-C6 H5
N-NH-CO-NH
II
H0 2 C^ ^CHaCHa^
^COC H
6
III
NMR
NMR
spectra.
Many cases of geometrical isomerism are known in which the two forms
are due to the presence of a nitrogen-nitrogen double bond. Examples of
this type which have been most extensively studied are the diazoates, IV,
the diazosulphonates, V, and the diazocyanides, VI (see Vol. I, Ch. XXIV,
for an account of these compounds).
II
NaCT
also
^S0 K
3
and- form
II
C6H5
CeH 5
syn-azobenzene
m.p. 71 -4"
(in
(1938),
the anti-iorm.
is
II
Azoxybenzene
^CN
VI
own -form
syn-form
is
IV
Azobenzene
II
II
.N'
<ztt'-azobenzene
m.p. 68
C 6 Hb^
C H^
n
II
C6 Hf
N
II
^O
syn -azoxybenzene
m.p. 86
O^ ^C H
6
owtt'-azoxybenzene
m.p. 36
3a]
161
Recently, Le Fevre et al. (1951) have measured the dipole moments and the
ultraviolet absorption spectra of a number of triazens, and have concluded
that these compounds exist in the ara&'-configuration about the nitrogen-
the configuration
i.e.,
is:
E,
II
^NH-R
These authors also believe that this anti-form is converted into an equilibrium mixture of the anti- and syw-forms when exposed to sunlight.
Harley-Mason et al. (1961) have offered evidence to show that they have
isolated the three theoretically possible geometrical isomers of o-nitroaceto-
= o-N0 C H
2
/Ar
Me.
N
*r
Ar/
4-)
Ms
Ai\
A\ /Me
Y
N
.N
Ar^^Me
Me
Me/\A.r
NMR
3.
3a. Tercovalent phosphorus compounds. Since the electronic configuration of phosphorus is (ls 8 )(2s 2 )(2^)(3s )(3^ 8 ), it might be expected
that suitable tercovalent compounds,
3 P, could be resolved, since the
configuration would be a trigonal pyramid (cf. 2c). No tertiary phosphines,
however, have yet been resolved, and the reason for this appears to be the
same as for tertiary amines, viz., that the phosphorus atom is in a state of
!!
ORGANIC CHEMISTRY
162
[CH. VI
oxides,
e.g.,
Meisenheimer
et al.
QH 3
CH 3
P=0
C6 H 5
P=
I
C6H 5
C 2 H6
OH 2 -C6 H5
II
double bond.
Some phosphine oxides that have been resolved recently are:
Me
OEt
0=P H4 -NMe
6
EtP=0
I
}I-
3 (p)
SH
I.
OMe
(McEwen
et al.,
(Aaron
1956)
et al.,
1958)
Kipping (1911) obtained two optically active forms of the 2V-( )-menthyl
derivative of 2-naphthylphenylphosphoramidic acid, III, and Davies and
Mann (1944) resolved M-butylphenyl-/)-carboxymethoxyphenylphosphine
sulphide, IV.
C 6H 6
^-COijH-CHjOCjHP=S
I
1
CH 2*CH2*CH CH
"
IV
III
Michalski
et al.
(1959)
(EtO)EtP(=0)-SCl, in
its
PhEtP(=0)*SH.
its
OC2H5
(C 6
OC 2 H5
H Q P O P C(C H
6
5) S
5) 3
"
II
II
Thus there will be one racemic modification (composed of the pair of enantiomorphs) and one meso-iorm (cf. 7d. II). Hatt (1933) obtained two forms
of compound V; both were inactive and so correspond to the racemic modification and the meso-iorm., but it was not possible to tell which was which.
Many attempts have been made to resolve quaternary phosphonium
compounds, but until recently,
labcdF]+X-
resolve
is
",
^ abcV + dX
carried
4]
163
out on compounds containing at least one alkyl group; consequently dissociation in solution could occur, thereby resulting in racemisation. Holliman and Mann (1947) overcame this difficulty by preparing a much more
stable type of phosphonium compound; these workers prepared a salt in
which the phosphorus atom was in a ring, viz., 2-phenyl-2-^-hydroxyphenyl1:2:3: 4-tetrahydro-wophosphinoliniurn bromide, VI, and resolved it.
^+
Br"
/P
CH i
Nj HiOH(
g
/> ).
VI
resolution of 3-covalent compounds of phosphorus does not prove that
the phosphorus atom has a tetrahedral configuration; it only proves that
the phosphorus atom cannot be in the same plane as the other four groups
The
VII
attached to it. Mann et al. (1955), however, have now synthesised P-spirobis-1 2 3 4-tetrahydrophosphinoliniUm iodide (VII) and resolved it into
(+)- and ( )-forms which have high optical stability. The phosphorus
atom is not asymmetric in this compound; it is the tetrahedral disposition
of the four valencies which produces the dissymmetric cation (c/. nitrogen,
:
R=
HN
phosphine
HNP=0
IX was
4.
was
resolved.
Arsenic, like phosphorus, can exhibit covalencies of 3, 4, 5 and 6; consequently these two elements show a great similarity to each other, and
differ from nitrogen which has a maximum covalency of 4.
164
ORGANIC CHEMISTRY
[CH. VI
first
CH,
CzHg
As CeH
1
1-C
I-C10H7
CH2 C 6 H5
CH^'CgHs
II
naphthylphenylarsonium iodide, I, that had a rotation of +12, but racemised rapidly (in solution). Similarly, Kamai (1933) isolated the (-f)-form
of benzylethyl-1-naphthyl-w-propylarsonium iodide, II, which also racemised
rapidly in solution. This rapid racemisation is believed to be due to a
" dissociation-equilibrium " in solution. This explanation was suggested
by Pope and Harvey (1901) to account for the racemisation of certain
ammonium salts, but definite evidence for this theory was provided by
Burrows and Turner (1921) in their work on arsonium salts. If this dissociation-equilibrium occurs, then in solution there will be:
[abcdAs] + I~
^ abcAs + dl
is
treated
CH3
CH3
is
CH3
CHj As + C2 HS I
CHr-As-C2 H5
As 2 H5 +
C6 H6
CeH5
CH3I
CH6
CH3
CH3
CH3-AsCH3
CHj-As + CH3I
I
C6H5
obtained, but at the same time a considerable amount of trimethylphenylarsonium iodide is also formed. These results are readily explained by the
dissociation-equilibrium theory.
CH.
VH* .CJI
S
Br"
4 -C1(^)
III
Although phosphine oxides of the type abcVO have been resolved (3b),
On the other
similar arsine oxides have not ; the reason for this is obscure.
hand, arsine sulphides have been resolved, e.g., Mills and Raper (1925)
resolved ^-carboxyphenylmethylethylarsine sulphide, IV.
4b]
165
CH3
As=S
C 2 HS
CH.
-ir
0-C
6 H 2 (N0 2) 3
u
-'t
Clfc-As^CgHs
*
CIV-A^-C6 H 5
CB.{
^C^-CHaCHij-CHa
V
C 6 H5
C e Hs
/CHj-CHg-CHg-CH,
/CHg-CHa-CHisCHs
CH^A8=S
|
CH2Aa
CH2-As=S
CjHj^
^CH OH -CH
2
X CH
C6 H^
-CH3
^PdCl
^
2
VI
CH2 CH 2 -CH3
VII
Chatt and Mann (1939) prepared ethylene-1 2-bis(M-butylmethylphenylarsonium) picrate, V, ethylene-1 2-bis(-butylphenylarsine sulphide), VI,
and ethylene-1 2-bis(-butylphenylarsine)-dichloropalladium, VII, and
obtained each compound in two forms. Each of these compounds is of
the type Cabd'Cabd, and hence each should exist in one racemic modification
and one weso-form (cf. 7d. II). As has already been stated, two forms of
each were isolated; both were inactive, but the authors had no evidence
for deciding which was which.
It has already been pointed out above that Holliman and Mann prepared
:
Br"
VIII
the optically stable arsonium compound III. These authors, in 1945, also
resolved an arsonium compound of the spiran type, viz., As-spiro-bis1:2:3: 4-tetrahydro-isoarsinolinium bromide, VIII. This does not contain an asymmetric arsenic atom; the optical activity is due to the asymmetry of the molecule (the two rings are perpendicular to each other), and
this is evidence that the four valencies of arsenic are arranged tetrahedrally
(see also 4b).
Mann et al. (1960) have also resolved compound IX.
4b. Tercovalent arsenic compounds. The electronic configuration
of arsenic is (ls 2 )(2s 2)(2p<i)(3s 2)(3p<i)(3d10)(4s i)(4p 3).
Thus the configuration
of tercovalent arsenic compounds will be a trigonal pyramid (cf. phosphorus,
ORGANIC CHEMISTRY
166
[CH. VI
C02H
CH
CO,H
C2 H5
CH 3
I"
II
III
It might be noted, however,
its mirror image are not superimposable.
that the position of the methyl group with respect to the O As axis is
uncertain (cf. the arsanthrens, below). This folded structure is reasonable
in view of the fact that the valency angle of oxygen is also approximately
104; if the molecule were planar, then the valency angles of both arsenic
and oxygen would be in the region of 120, which is a very large increase
from the normal valency angle. When each enantiomorph of II is treated
with ethyl iodide, the same racemised product is obtained. This is due to
the fact that when the arsonium compound, III, is formed, the asymmetric
quaternary arsenic atom is racemised owing to the dissociation-equilibrium.
and
X) v
.0.
C02 H
CO,H
as
<f
XC H
6
Lesslie and Turner (1936) also resolved 10-phenylphenoxarsine-2-carboxylic acid, IV. This compound was very stable, and oxidation to the
arsine oxide, V, gave a completely racemised product.
Campbell et at. (1956) have resolved some substituted 9-arsafiuorenes,
e.g., 9-/>-carboxyphenyl-2-methoxy-9-arsafluorene (V).
Campbell (1956)
has also resolved 2^>-carboxyphenyl-5-methyl-l 3-dithia-2-arsaindane (Vb).
This compound is optically stable in chloroform solution, but is racemised
in aqueous sodium hydroxide.
Campbell believes that this racemisation is
due to the fission of the AsS bonds by aqueous alkali, and subsequent
reversal of the reaction by acid, a type of behaviour observed in triaryl
:
4b]
Sv
OCH,
167
CO2H
Vb
COjH
thioarsenites (Klement et al., 1938).
Furthermore, Cohen et al. (1931) have
shown that in sodium hydroxide solution, alkyl thioarsenites exist in equilibrium with thiol and arsenoxide:
/
R-As
OH
SR'
\SR'
+ 2H aO
OH"
5==^ R-As
H+
\OH
+ 2R'SH
VII
VIII
pointed out that evidence obtained from models constructed to scale showed
that the two ^>-tolyl radicals (T) in VIII would almost be coincident, and
hence this isomer cannot exist. These authors isolated two optically inactive forms, but were unable to say which was which. When each compound was treated with bromine, both gave the same tetrabromide which,
on hydrolysis, gave only one tetrahydroxide. The loss of isomerism in the
tetrabromide (and in the tetrahydroxide) may be explained as follows.
Bromination of VI and VII converts tercovalent arsenic into quinquecovalent arsenic, and in the latter state the ring valency angles of the arsenic
become 120, and so the arsanthren nucleus is now planar. Thus both the
forms VI and VII would give the same tetrabromide, IX (the same is true
for the tetrahydroxide) the tetrabromide should thus be planar, the configuration of each arsenic atom being trigonal bipyramidal in the 5-covalent
;
ORGANIC CHEMISTRY
168
[CH. VI
Phosphorus, which
become
may
and
3d orbitals have energy levels which are close together. Kimball (1940)
showed, by calculation, that this arrangement, i.e., sp sd, could give rise to
the stable trigonal bipyramidal configuration. This consists of three equivalent coplanar orbitals pointing towards the corners of an equilateral
triangle, and two orbitals perpendicular to this plane (see Fig. 2)
Electron
diffraction studies of the vapours of phosphorus pentachloride and pentafluoride indicate the trigonal bipyramidal configuration in these molecules.
The phosphonium ion might possibly be formed from this trigonal bipyramid
by the transference of one of the electrons, or by the transference of a 3s
.
electron and hybridisation of the (3s)(3p 3) orbitals; in either case the tetrahedral configuration of the phosphonium ion can be asymmetric, but only
in the case of the hybridisation of the (3s)(3p s ) orbitals will the four bonds
be equivalent. Since the properties of phosphonium compounds are in
agreement with the equivalence of the four bonds, it therefore appears,
on theoretical grounds, that the tetrahedral configuration with the phosphorus atom at the centre is the probable one.
From the experimental side, the preparation of optically active spirocompounds of phosphorus (3b) and of arsenic (4a) proves the tetrahedral
configuration of these atoms. Earlier work by Mann et al. (1936, 1937)
has also definitely established this configuration. These authors prepared
compounds of the type [R3As Cul] 4 by combination of tertiary arsines or
phosphines with cuprous iodide (or silver iodide) in these compounds the
phosphorus or arsenic is 4-covalent, and X-ray analysis studies of the arsenic
compound showed that the arsenic atom is at the centre of a tetrahedron.
Since the corresponding phosphorus compounds are isomorphous, the configuration of the phosphorus is also tetrahedral.
In the solid state, phosphorus and arsenic compounds may contain a
negatively charged phosphorus or arsenic atom, e.g., PC1 4 + PC1 6 ~ (see above).
In this condition, the phosphorus acquires an electron to become
(3s)(3^)(3i 2 ),
In
arsenic also acquires an electron to become -(As)(Ap s )(Ad z ).
both cases the configuration is octahedral (six sp sd2 bonds), e.g., the following compound has been resolved (Rosenheim et al., 1925).
and the
5a]
169
CO.H
H0 2 C
by Weston
have led him to the conclusion that tervalent antimony, arsenic and
sulphur compounds should be stable to inversion at room temperature. On
the other hand, similar compounds of phosphorus would be optically stable
only at low temperatures, and those of nitrogen not at all.
(1954)
5.
At this time (before the electronic theory of valency, 1916), sulphur was
believed to be quadricovalent, and so Pope and Peachey accounted for the
optical activity of this compound (see below) by assuming that the sulphur
atom was at the centre of a tetrahedron, i.e., the configuration was similar
to carbon. According to the electronic theory of valency, however, sulphur
[CH. VI
ORGANIC CHEMISTRY
170
tercovalent unielectrovalent in sulphonium salts, and the valency disposition is (s 8 ), one orbital being occupied by a lone-pair of electrons
is
A
/
/
/
'
CH 3
\v
'
'
'
'
^V-- -^CH
C0 2 H
C2H 5
Fig. 6.3.
obtained was
fractionally crystallised
as the
the (+)-camphorsulphonate ion is about +52, this leaves +16
Al(see 12. I).
rotation
the
total
to
ion
sulphonium
the
of
contribution
is
compound
sulphur
the
that
conclusively
though this does not prove
favour. Final proof
optically active, it is certainly strong evidence in its
platiniwas obtained by replacement of the camphorsulphonate ion by the
this compound had
chloride ion to give [CH 3 (C 2 6)-S-CH 4 -CO aH] s +PtCl,=
+4-5 in water. In a similar way, Smiles (1900) prepared ethyl-
an [a] D of
methylphenacylsulphonium
CH$v
picrate,
I,
in
SCH,j-CO-C H
6
two
2N|
5
AHf
I
with an
[<x]
Mann and
of
Holliman, 1946).
CH,
Br
/8-CH2-CO-CeH 4
/'
Cl(/))
CH5
II
esters,
5b. Sulphlnic esters. Phillips (1925) partially resolved sulphimc
R-S08R', by means of the kinetic method of resolution (10 vii. II). Two
of ethyl ^-toluenesulphinate were heated with one molecule of
molecules
( )-menthyl alcohol or ( )-sec.-octyl alcohol, i.e., the sulphinate was submodification,
jected to alcoholysis. Now, if the sulphinate is a racemic
then the (+)- and ( )- forms will react at different rates with the optically
Phillips actually found that the (+)-ester
active alcohol (see 2, 7b. II).
If we represent the ester by E, the
)-ester.
reacted faster than the (
equation
alcohol by A, and unchanged ester by E r then the following
alcoholysis:
symbolises the
,
(+)E
(-)E
(-)A-*
[(+)E( _ )A]
+ _ )E( _ )A] +
[(
(+)Er
(_ )Er
5c]
171
Since
(+)Er
[(+)E( )A]
is less
C6H4 -CH,(/>)
So
,S
C.H5O-
CjHsO^^Ce^-CH,^)
O
II
Fig. 3).
In
I,
5c. Sulphoxides.
Sulphoxides of the type R-SOR' have also been
resolved; sulphoxides I and II were resolved by Phillips et al. (1926), and
Karrer et al. (1951) obtained III in the ( )-form and the racemic modification.
C02 H
H 2N
CH 3
s=o
S=0
CHf=CH-CH^
CH
Bell
and Bennett
III
CHs-SOCHa-CHjj-SOCHs.
This molecule contains two similar asymmetric carbon atoms and so is of
the type Cabd'Cabd. Thus it should exist in one racemic modification and
one meso-iona. Bell and Bennett failed to resolve this compound, but
succeeded in resolving the following disulphoxide.
C02H
If the
CH3 S
CH,
4-dithian)
is
converted
ORGANIC CHEMISTRY
172
[CH. VI
into the corresponding ring compound (i.e., into a cyclic 1 4-dithian), then
two geometrical isomers are possible, neither of which is resolvable; these
two forms have been isolated by Bell and Bennett (1927, 1929). Shearer
(1959) has examined the trans-ioim by X-ray analysis and showed that the
in trans and axial positions.
ring is in the chair form with the
:
S=0
,CH2
CIL
^CH
S
//
CHCH
>O
CH2 ^
^O
^CHX <^X1
CHf'
2
as
a,
trans
^O
"\^
^O
S"
p-form
cc-form
of the
form.
When
is
therefore
the same
sulphoxide group.
Chloramine
e.g.,
C02H
CH 3 <^^-S(Vn'
CH
o~
SOg-N-
:S
+ NaCl
6]
173
C02 H
CH 3
^_\S0 -N=S
2
still
be asymmetric
(see 5e).
This
R SJX~
3
R S**0
2
Jl
S OR'
Y
II
O
III
R S=0
2
R S OR'
II
11a
O
Ilia
It has already been pointed out that these multiple bond formulae were
rejected on the grounds that such molecules, on the assumption that the
sulphur atom was quadrivalent and at the centre of a tetrahedron, would
be flat and hence not optically active. If we consider the shapes of optically active sulphur compounds from the point of view of the ideas discussed in 1, then in the formulas (I), (Ila) and (Ilia), the sulphur atom
has one lone-pair of electrons (these are not shown in the formulae), three aand one jr-bond. Thus the bond spatial arrangement will be tetrahedral,
the lone-pair occupying one of these orbitals. Consequently each molecule
will be a trigonal pyramid and is not superimposable on its mirror image
when all three groups are different. It might be noted here that the double
bonds are composed of one a- and one d-fi bond. In these compounds the
d orbitals are produced by promotion of one 3s and one 3p electron to 3d;
this is possible because of the small energy differences between the orbitals
concerned. In sulphonium salts, since only three single bonds and one
lone-pair are present, the hybridisation is sp 3 (tetrahedral); one electron
has been transferred to the halogen atom, thereby producing the positively
174
ORGANIC CHEMISTRY
[CH. VI
^""^CHj-Si O Si CH,
^C H -k
-C3 H 7
c 2 h5
C 2 Hr
_
HOaS^^CHg-^Si O Si^-CHa^^SOaH
C H -
-C H
3
II
C2 H 5
CH,
Si
/ \CH
-C 3 H 7
i<f^Vo H
3
III
*'..,
C,HK
H0 2 C
CKL
,C 2
w-C3H 7
(CH 3) aCH
C 2H/
yC sH 5
x
Br
~~l
^Se-CHjj-COjjH
C6H6
PtCl
10]
Mann
et al.
CHZ
X
CH 2
^eOHjj-CO
So
far,
175
^^
^y
<
>
failed.
I,
and Mann
et al.
(1945)
have resolved
II.
CH3
CH,<C^Te:
,Te-CH 2 CO-C 6 H 4 Cl
(/>)
Br"
II
READING REFERENCES
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd ed.). Ch. 4, pp. 400-443.
Optical Isomerism of Elements other than Carbon.
Dickens and Linnett, Electron Correlation and Chemical Consequences, Quart. Reviews
{Chem. Soc), 1957, 11, 291.
Gillespie and Nyholm, Inorganic Stereochemistry, Quart. Reviews {Chem. Soc), 1957,
11, 339.
Organic Reactions, Wiley. Vol. 11 (1960). Ch. 1. The Beckmann Rearrangement.
Mann, The Heterocyclic Derivatives of P, As, Sb, Bi, and Si, Interscience Publishers
(1950).
Campbell and Way, Synthesis and Stereochemistry of Heterocyclic Phosphorus Compounds, J.C.S., I960, 5034.
Abrahams, The Stereochemistry of Sub-group VIB of the Periodic Table, Quart. Reviews
(Chem. Soc), 1956, 10, 407.
McCasland and Proskow, Synthesis of an Image-Superposable Molecule which Contains
no Plane or Centre of Symmetry, /. Amer. Chem. Soc, 1956, 78, 5646.
Klyne and de la Mare (Ed.), Progress in Stereochemistry, Butterworth. Vol. II (1958).
Ch. 6. The Stereochemistry of the Group
Elements.
CHAPTER
VII
CARBOHYDRATES
This chapter
is mainly concerned with the stereochemistry of the carbohydrates and the structures of the disaccharides and polysaccharides. It
is assumed that the reader is familiar with the open-chain structures and
general reactions of the monosaccharides (for an elementary account of
these compounds, see Vol. I, Ch. XVIII).
1.
Aldotrioses.
There
As we have seen
is
(5. II),
CHO
CHO
HO-
-OH
H-
-H
0H2 OH
CH 2 OH
D (+) -glyceraldehyde
The conventional planar diagrams of the sugars are always drawn with
CHO (or CH aOH-CO) group at the top and the CH 2OH group at the
the
CHO
is also
CHO
L-series
D-series
Aldotetroses.
The
used:
is
CH 2OH-CHOH-CHOH-CHO.
Since this contains two unlike asymmetric carbon atoms, there are four
CHO
-H-
-OH-,
CH2 OH
H-
H-
-OH
COjH
meso-tartaric
aoid
-OH
H-
-OH
C02 H
CHO
CHO
0O2 H
HO-
-H
HO-
-H
[QI
,[0]
-OH
H-
-OH
H-
H-
-OH
C0 2 H
CH2 OH
CH 2 OH
D( )-erythroae
D(-)-threose
L( ) -tartaric
II
acid
176
CARBOHYDRATES
1]
177
Aldopentoses.
CHO-CHOH-CHOH-CHOH-CH 2OH,
and
since it contains three unlike asymmetric carbon atoms, there are eight
optically active forms (four pairs of enantiomorphs).
All are known, *and
correspond to the d- and L-forms of ribose, arabinose, xylose and lyxose.
Their configurations may be ascertained by either of the following two
methods.
D-erythrose
r
CHO
CHO
H-
-OH
HO-
H-
-OH
H-
-OH
HO-
H-
-OH
H-
-OH
H-
CH 2 OH
D( )-ribose
DH
CHO
-OH
HO-
-H
-H
HO-
-H
-OH
D(+)-xylose
-OH
H-
CH 2 OH
CH 2 OH
arabinose
II
CHO
H-
-H
D-threose
CH 2 OH
D()-]yxose
III
IV
V
VI
One method starts by stepping up the aldotetroses by the Kiliani reaction.
Thus D-erythrose gives d( )-ribose and d(-) -arabinose; similarly, D-threose
gives D(+)-xylose and d( )-lyxose.
Ill and IV must be ribose and arabin-
CHO
CH
rV
I][I
,[o]
)0 2
c^0 2
HH-
OH
OH
()O a
ina ctive
II la
C:o 2
IT
H-
H
H
,[o]
,[0]
\r
VI
[0]
HTT
OH
OH HO
OH H
;0 2
1TO
HO
TT
C)0 2
ac ;ive
int ictive
act ive
rVa
Va
V la
:o 2
X> 2
and VI must be xylose and lyxose, but which is which? The former
sugar, on oxidation, gives an optically inactive dicarboxylic acid, whereas
ORGANIC CHEMISTRY
178
[CH
VII
H-
H-
-OH
HO-
H-
-OH
H-
-OH
HO-
H-
-OH
H-
-OH
H-
CH 2 OH
III
-H
CHO
CHO
OHO
CHO
-OH
HO-
-H
-H
HO-
-H
-OH
-OH
H-
CH 2OH
CH 2 OH
CHOH
IV
VI
should be noted that these four configurations have been obtained from
principles (see 7c. II) ; no recourse has been made to the configurations
of the aldotetroses. Arabinose and lyxose, on oxidation with nitric acid,
produce optically active dicarboxylic acids (trihydroxyglutaric acids).
Therefore these two pentoses must be IV and VI, but we cannot say which
is which.
Xylose and ribose, on oxidation, produce optically inactive dicarboxylic acids (trihydroxyglutaric acids). Therefore these two pentoses
must be III and V, and again we cannot say which is which. When each
It
first
IV
S \
/ \
C02H
COjjH
H-
*0H
HO-
-H
-OH
HO-
-H
HO-
-H
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
HO-
H-
-OH
H-
H-
-OH
H-
-OH
-H
C02H
C02 H
C02 H
/X
C0 2 H
-OH
HO-
H-
-OH
H-
H-
-H
-OH
C02H
active
/
C0 2 H
H-
HOH-
-H
C02 H
active
active
active
inactive
HO-
CO.H
CO2H
\
C02H
C0 2 H
H-
-OH
HO-
-H
-OH
HO-
-H
HO-
-H
-H
HO-
-H
HO-
-H
-OH
C0 2 H
active
H-
-OH
C0 2 H
inactive
H-
-OH
C02 H
active
CARBOHYDRATES
1]
179
aldopentose
CHO-CHOH-CHOH-CHOH-CHOH-CHjOH,
and
since it contains four unlike asymmetric carbon atoms, there are sixteen
optically active forms (eight pairs of enantiomorphs).
All are known, and
rD
-ribose
III
D -arabinose
IV
>
CHO
CHO
CHO
1
CHO
H
H
-OH
HO-
-OH
H-
OH
HO-
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
CH 2 OH
-H
H-
-OH
HO-
-H
-H
HO-
-H
CH 2 OH
CH 2 OH
D(+)-allose
D(+)-altrose
D(+)- glucose
VII
VIII
IX
rD
-xylose
CHO
CHO
-OH HO-
-H
H-
-OH
-OH
-H
HO-
-H
H-
-OH
H-
HO-
-OH
H-
CH 2 OH
D( )-idose
XI
XII
allose
and
CHO
-OH
HO
-H
HO-
-H
HO-
-H
HO-
-H
HO-
-H
H-
H-
CH 2 OH
D()-gulose
VI
CHO
mannose
X
D-lyxose
H-
CH 2 OH
D(+)-
-OH
CH 2 OH
CH 2 OH
D(+)-galactose
altrose,
XIII
but which
-OH
H-
D(+)-talose
XIV
is
which?
On
oxida-
tion with nitric acid, the former gives an optically inactive (allomucic)
and
ORGANIC CHEMISTRY
180
[CH. VII
is
XIII
is
The
CH
same; by interchanging the CHO and CH 2OH groups of IX, the enantiomorph of XI, i.e., L-gulose, is obtained. Therefore IX must be glucose (since
we know that glucose is obtained from arabinose), and XI must be gulose.
Consequently X is mannose and XII is idose.
Ketohexoses. All the ketohexoses that occur naturally have the ketonic
group adjacent to a terminal CH 2 OH group, i.e., the structural formula of
all
is
CH 2 OH-CO-CHOH-CHOH-CHOH-CH 2 OH.
Since this structure contains three dissimilar asymmetric carbon atoms,
C =N-NH-C 6 H6
CO
HO-
-H
CHO
CH=N-NH-C6 H 5
CH2 OH
CH.NHNH; HQ-
CgH.-NH-NHa
H-
HO
-OH
-H
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
H-
-OH
CH2 OH
CH 2 OH
Df l-fructose
osazone
XV
[hydrolysis
CHO
I
CO
HO-
-H
H-
-OH
H-
-OH
CH 2 OH
osone
CH 2OH
D(+) -glucose
CARBOHYDRATES
2]
181
there are eight optically active forms (four pairs of enantiomorphs) possible
theoretically; of these the following six are known: d( )- and L(+)-fructose,
(+)- and l( )-sorbose, D(+)-tagatose and l( )-psicose. Only d( )fructose, l( )-sorbose and D(+)-tagatose occur naturally.
Fructose. Natural fructose is laevorotatory, and since D-glucose gives
the same osazone as natural fructose, the latter must be d( )-fructose.
Furthermore, since osazone formation involves only the first two carbon
atoms in a sugar, it therefore follows that the configuration of the rest of
the molecule in glucose and fructose must be the same. Hence the configuration of d( )-fructose is XV, and is confirmed by the fact that d(+)glucose may be converted into d( ) -fructose via the osazone (see chart at
foot of previous page).
The configurations of the other ketohexoses are:
H-
HOH-
CHjjOH
CH.OH
CH 2 OH
GO
CO
CO
-OH
HO-
-H
HO-
-H
-H
HO-
-H
HO-
-H
-OH
HO-
-H
-OH
H-
CH OH
CH2OH
D(+)-sorbose
D(+)-tagatose
CH2 OH
L(-)-psicose
is
OHO
H-
HO-
-OH
-H
H-
-OH
H-
-OH
CH2 OH
D(+)- glucose
The difficulty of this suggestion was that there was no experimental evidence
for the existence of these two forms.
Tanret (1895), however, isolated two
Q
ORGANIC CHEMISTRY
182
[CH. VII
isomeric forms of D(+)-glucose, thus apparently verifying Tollens' supposition (but see 7a, 7f ). The two forms, I and II, are known respectively as
a- and /J-d(+ )-y-glucose (see also 7b for the nomenclature of these forms).
Ring formation of a sugar is really hemiacetal formation, one alcoholic
group of the sugar forming a hemiacetal with the aldehyde group of the
same molecule, thus producing a ring structure which is known as the lactol
form of the sugar.
Mechanism of mutarotation. According to Lowry (1925), mutarotation is not possible without the presence of an amphiprotic solvent, i.e., a
solvent which can function both as an acid and a base, e.g., water. Thus
Lowry and Faulkner (1925) showed that mutarotation is arrested in pyridine
solution (basic solvent) and in cresol solution (acidic solvent), but that it
takes place in a mixture of pyridine and cresol. It has been assumed that
when mutarotation takes place, the ring opens and then recloses in the
inverted position or in the original position. There is some evidence for
the existence of this open-chain form. The absorption spectra of fructose
and sorbose in aqueous solution indicate the presence of open-chain forms;
Solutions of glucose
aldoses gave negative results (Bednarczyk et al., 1938).
and arabinose in 50 per cent, sulphuric acid gave an ultraviolet absorption
spectrum containing the band characteristic of the oxo (carbonyl) group
(Pascu et al., 1948). Aldoses in solution contain a form which is reducible
at the dropping mercury electrode (Cantor et al., 1940). Although the
nature of this reducible form has not been established, it is probably the
open-chain form, either free or hydrated. Furthermore, a relationship was
shown to exist between the amount of this reducible form and the rate of
mutarotation. One interpretation of this observation is that the reducible
form is an intermediate in mutarotation. Rate constants for the conversion
of the ring forms of aldoses to the open-chain form have been calculated from
polarographic measurements, and it has also been shown that the energy of
activation required to open the pyranose ring is the same for glucose,
mannose, galactose, arabinose and xylose (Delahay et al., 1952). The formation of this acyclic intermediate during mutarotation has been confirmed
by isotopic evidence (Goto et al., 1941) and by further polarographic evidence
CH(SCH 3
H 0 OH
HO-C H
H-o-OH
H C OH
CH(SCH 3
)2
H C 0-CO-CH
(CHiCO^o^CHs-CO-O-C-H
Pyridine
H-C-OCOCH
H C 0-CO-CH
CH 2 OH
CHjjO-CO-CHs
glucose dimethyl
mercaptal
CHO
I
H G 0-C0-CH
CH 3 -CO-0 C
HjO/CdCO,
)ij
H C 0-CO-CH
H C O-CO-CHs
I
tt
r,
CHijO-CO-CHs
183
CARBOHYDRATES
2]
H-^-A
^=:
HB+ + A-
6hoh
i
'
Swain
ORGANIC CHEMISTRY
184
is
[CH. VII
itself
Glycosides. Just as simple hemi-acetals react with another molean alcohol to form acetals, so can the sugars, in their ring-forms
(lactols), react with a molecule of an alcohol to form the acetal derivative,
which is known under the generic name of glycoside; those of glucose are
known as glucosides; of fructose, fructosides, etc. The hydroxyl group produced at the oxo group by ring formation is known as the glycosidic hydroxyl
group. This group can be acetylated and methylated, as can all the other
hydroxyl groups in the sugar, but the glycoside derivatives are far more
3.
cule of
product which contained one methyl group (as shown by analysis), and which
did not reduce Fehling's solution or mutarotate, and did not form an osazone.
Thus the hemiacetal structure is no longer present in this compound; in fact,
this compound appears to be an acetal since it is stable in alkaline solution
Furthermore, on boiling with dilute inorganic acids,
(Fehling's solution).
the compound regenerated the original sugar, a reaction again typical of
acetals.
Ekenstein (1894) isolated a second isomer from the reaction mixture
when he repeated Fischer's work, and Fischer explained the existence of
these two isomers by suggesting ring structures for the two methyl glucosides,
viz.,
HCOCH
HC OH
HO C
H CH C OH
TCH OH
2
methyl a-D-glucos,ide
CH,0 C
H C OH
HO C
H CH C OH
I
CH 2OH
methyl (3-D-glucoside
compound
(see 24).
CARBOHYDRATES
4]
185
4.
and
H Cr-OH
II
HO C H
I
p-isomer
ct-isomer
II
The
a-
/9-D-glucose
now
question that
H C OH
H C OH
I
O
I
III
HO C
H C OH
II
IV
ORGANIC CHEMISTRY
186
[CH. VII
93
-f
a
-9 3
-C
dextrorotatory
lsevorotatory
From an examination of 24 lactones derived from aldonic acids, and assuming that they were y-lactones, Hudson concluded that if the lactone ring was
on the right, the compound was dextrorotatory if the ring was on the left,
;
then lsevorotatory.
(in
the D-series)
BO
+A
-OR
C
we
have:
-A
-4
O +B
O +B
a
Molecular rotation of the a-anomer
/?-
P
= +A +B
= -A +B
Thus
Rule
pairs of glucopyranoside
anomers
Cj substituent
OH
OCH,
OC tH s
....
....
.
is fairly
constant.
M/3
+ 202
+ 309
+ 314
+ 34
-66
-69-5
Ma
+ M^ = 2B
+ 236
+243
+ 245-5
CARBOHYDRATES
7]
187
As pointed
7. Methods for determining the size of sugar rings.
out previously, Fischer followed Tollens in proposing the y-oxide ring.
There was, however, no experimental evidence for this ; ihe y-hydroxyl group
was chosen as being involved in ring formation by analogy with the ready
formation of y-lactones from y-hydroxyacids. The problem was further
complicated by the fact that Hudson et al. (1915) isolated four galactose
penta-acetates, none of which had a free aldehyde group. Furthermore,
these four compounds were related to each other as pairs, i.e., there were two
a- and two /J-isomers. The only reasonable explanation for this was that
there are two ring systems present, but once again there is no evidence to
decide the actual sizes of the rings.
The original experimental approach to the problem of determining the
size of the ring present in sugars consisted essentially in studying the methylated sugars. A more recent method uses the methyl glycosides (for this
method, see 7g). Since methylation is so important in the original method,
the following account describes briefly the methods used.
(i) Purdie's method (1903).
The sugar is first converted into the corresponding methyl glycoside (methanol and hydrochloric acid), and this is then
heated with methyl iodide in the presence of dry silver oxide; thus:
i
CHOH
CHOH ?
nvr OH
rm^L.
+ CH
CHOCH.
'
I
c^HOH
CH '
CHOCH,
.
W>+ CHOCH,
I
a3
?+AgI
CHOH +
This method
(CH3 aS04
)
is directly
is eliminated.
A study of the oxidation products of the methylated
sugar then leads to the size of the ring. It should be noted that throughout
the whole method, the assumption is made that no methyl groups migrate
or that any change in the position of the oxide ring occurs (see, however,
later).
The number of methyl groups present in the methylated sugar and
group
ORGANIC CHEMISTRY
188
[CH. VII
the various oxidation products are determined by the Zeisel method (see
Vol. I).
Also, these methyl derivatives are often purified by distillation
in vacuo.
Bishop et al. (1960) have now separated methylated methyl
glycosides by gas chromatography.
7a. Pyranose structure. This structure is also sometimes referred to
as the S-oxide or amylene oxide ring. As an example of the method used,
we shall consider the case of d(+) -glucose (Haworth and Hirst, 1927).
D(+)-Glucose, I, was refluxed in methanol solution in the presence of a small
amount of hydrochloric acid, and the methyl D-glucoside, II, so produced
was methylated with methyl sulphate in the presence of sodium hydroxide
to give methyl tetramethyl-D-glucoside, III, and this, on hydrolysis with
When this was
dilute hydrochloric acid, gave tetramethyl-D-glucose, IV.
dissolved in water and then oxidised by heating with excess of bromine at
90, a lactone, V, was isolated, and this, on further oxidation with nitric
The structure of this comacid, gave xylotrimethoxyglutaric acid, VI.
pound is known, since it can be obtained directly by the oxidation of methylated xylose; thus its structure is VI (see also 7d). The structure of this
C02 H
-OCH 3
H-
CH 30-
-H
-OCH 3
H-
C0 2 H
VI
compound is the key to the determination of the size of the ring in the sugar.
One of the carboxyl groups in VI must be that which is combined in the
formation of the lactone ring in the tetramethylgluconolactone, V. The
other carboxyl group is almost certainly the one that has been derived from
group that is involved
the non-methylated carbon atom, i.e., from the
in the ring formation in the sugar. Therefore there must be three methoxyl
groups in the lactone ring. Thus the lactone cannot be a y-lactone, and
consequently C 5 must be involved in the ring formation. It therefore
follows that the lactone, V, must be 2 3 4 6-tetra-O-methyl-D-gluconolactone.
Working backwards from this compound, then IV must be
2:3:4: 6-tetra-O-methyl-D-glucose, III methyl 2:3:4: 6-tetra-O-methylD-glucoside, II methyl D-glucopyranoside, and I D-glucopyranose (see 7f
It should be noted that the
for the significance of the term pyranose).
question as to whether the sugar is a or /S has been ignored; starting with
either leads to the same final results. The foregoing experimental results
can now be represented by the following equations:
CHOH
-OH
II-
reflux
HO-
-H
-OH
H-
NaOH *
-H
CH S 0-
-OCH
HH-
H-
H-
-OCH3
H(CH,) 2 SQ4
chsQh/hci
-H
OHOCH3
-OH
H-
-OH
110-
OHOCH3
CHOH
H-
CH2 OH
CH2 OH
CHjjOCHs
II
III
CARBOHYDRATES
Va]
189
CHOH
HHC!
*-
CH s O
-OCH,
-H
H-
*-
CH3O
-OCH,
H-
CHjOCHj
IV
CH2 OCH 3
C02 H
C02 H
H-
-OCH3
H-
-OCH3
HNO
HNOj
CH3O-
CH3O-
-H
H-
-6ch3
H-
-OH
-H
H-
-OCH,
COjjH
CH2OCH,
VI
There is a slight possibility that the ring might have been an -ring, i.e.
the oxide ring involves C x and C and that C is converted to the carboxy
6
5
group with loss of C. Haworth, however, made certain that this was not
the case by the following method. Had the ring been 1 6-, then 2:3:4:5tetramethylgluconic acid, VII, would have been obtained (instead of V).
VII was obtained by Haworth et al. (1927) from melibiose and gentiobiose
(see 18, 19) and, on oxidation, gave tetramethylsaccharic acid, VIII, and
not the dicarboxylic acid, VI.
,
C02H
CO,H
H-
H-
-OCH,
CHs O-
-H
-+-
CH3O-
-OCH3
-H
H-
-OCH,
H-
-OCH3
H-
-OCH,
-OCH3
CH2 OH
VII
C0 2 H
VIII
Thus there is a 1 5-ring in the tetramethylgluconolactone, tetra-Omethylglucose, methyl tetra-O-methylglucoside, methyl glucoside, and therefore in glucose itself. This conclusion is based on the assumption that no
change in the ring position occurs during the methylation of glucose. Thus
glucose is a d- or pyranose sugar.
By similar methods it has been shown that hexoses and pentoses all
possess a pyranose structure. There is also a large amount of evidence to
:
ORGANIC CHEMISTRY
190
[CH. Vlt
^NHOH
CH=NOH
(CHOH)4
CH
(CHOH)3
n_
CH
CH2 OH
'
CHjOH
(1951-1955) showed that aldose phenylhydrazones react in
pyridine solution with solutions of diazonium salts to give brilliant-red sugar
diphenylformazans
Mester
et al.
CH=NNHPh
i
/N=NPh
/H
|^N N.^
phN *
PhN
>
c;
CHOH
CHOH
XPh
Formazan formation proves the acyclic structure of the sugar phenylhydrazones. The cyclic structures do not react, e.g., there are three modifications
of D-glucose phenylhydrazone (, m.p. 159-160; p\ m.p. 140-141; y, m.p.
115-116) two of these do not form formazans, but the third does. Hence
the former two are cyclic and the third is- acyclic.
;
191
CARBOHYDRATES
7c]
-OH
H-
-OH
H-
CHOH/HCI^
s
**
O
HO-
CHOCH.
CHOCH3
CHOH
HO-
-H
(CHjfcSO.
NaOH
-H
D-glucofuranose
-OCH3
CH2 OCH$
CH 2 OH
GH2 OH
II
GHOH
H-
-H
CHsO-
H-
-OH
H-
-OH
H-
-OCHj
H-
H-
H-
H-
COgH
H-
CH3O
CH3O-
-OCH3
,
-OCH3
HCl
CH s O-
900
-H
H-
H-
-OCH.
-H
C02H
H-
GH2OCH3
CHaOOHj
III
IV
j/-mannolactone
II y-galactonolactone
III y-gluconolactone
IV <5-mannonolactone
V
VI
12
4
Time
5
in
6
7
days
iO
FIG. 7.1.
<5-gluconolactone
rf-galactonolactone
192
ORGANIC CHEMISTRY
[CH. VII
that this method easily distinguishes a y- from a ^-lactone, but it does not
prove one to be y- and the other 8-. The actual nature of the lactone was
proved chemically the fast-changing lactone was shown to be the d-lactone,
and the slow-changing one the y- (the chemical evidence was obtained by
the degradative oxidation already described). However, having once established the relationship between the rate of hydration and the nature of the
lactone, e.g., in the case of glucose, mannose, galactose and arabinose, the
property can then be used to determine the size of the ring in an unknown
lactone of a sugar acid.
;
OHO
CO
CO
1
i
-OH
H-
HO-
-H
IIO-
-H
H-
-OH
CH 2 OH
CHijOCHj
D -galactose
(-)-lactone;
(+)-lactone;
8-lactone
(open-chain)
Y-lactone
Correlation between the above scheme and Hudson's lactone rule has been
demonstrated in certain cases, e.g., galactose. Preparation of the methyl
galactoside at reflux temperature, then methylation, hydrolysis, and finally
oxidation with bromine water, leads to the formation of a methylated lactone
which is dextrorotatory, and since it is a rapidly hydrated lactone, it must
be 8-. Preparation of the methyl galactoside at 0, etc., leads to the formation of a methylated lactone which is laevorotatory and is very stable to
hydration. Thus, this lactone will have the ring to the left (Hudson's
lactone rule), and hence must be a y-lactone; at the same time, since it is a
slowly hydrated lactone, it must be y- (see the above formulae).
7d* Pyranose and furanose structures of pentoses. The methods
used for determining the size of sugar rings have been described with glucose
(an aldohexose) as the example. It is also instructive to apply these methods
L(+)-Arabinose has been chosen as the example, and
to the aldopentoses.
the following equations and footnotes should now be readily followed:
Glycoside formation at reflux temperature (Haworth et al., 1927).
L(+)-arabinopyranose, and since it is dextrorotatory, the ring has been
drawn to the right. This way of drawing the projection formula is based
on the observation of Haworth and Drew (1926), who pointed out that if a
ring in a sugar is 1 5- (i.e., d-), then Hudson's lactone rule holds good for
(i)
I is
OHOH
HO-
-OH
O
-H
HO-
-H
H-
CH2 I
CHOH
(!)
(ii)
(iii)
CHjOH/HCl; reflux
(CHjJsSOj/NaOH
HCI
H-
-OCH3
CH 3 0-
-H
CH3 0-
-H
CH 2
II
CARBOHYDRATES
7e]
193
GO
HBr,/H,Q
*
90
C02H
H-
-OCH3
CH 3 C-
-H
CHs O-
-H
HNOs
-OCH3
CH3O-
-H
CH 3 0-
-H
CH2-
C02H
III
IV
is
CHOH
CHOH
-OH
H-
HO-
<H)(CH,),S0 1/NaOH
-H
-OCH,
"FT
(QCH.QH/HC1; 18^
(iii)
HC1
CH.O
S
-H
-H
CH 2 OH
CH2OCH3
VI
C02 H
Br a /H,Q^
HNOs
H-
-OCH3
CH3O-
-H
C0 2 H
CH2 OCH,
VIII
VII
7e. Ketose ring structures.
Only D-fructose will be considered; the
method is essentially the same as that for the aldoses, but there is one important variation, and that is in the oxidation of the tetramethylfructose.
This cannot be oxidised by bromine water as can the tetramethylaldose the
fructose derivative is first oxidised with dilute nitric acid and then with
acid permanganate, and by this means the lactone is obtained. The lactone
is then further oxidised by moderately concentrated nitric acid.
The following equations and footnotes explain the method, but before giving these,
;
us first consider the way of writing the projection formula of the ring
structure of fructose. The usual open-chain formula is I, and to form the
ring the ketone group is involved with C in the pyranose form, and with C
6
5
in the furanose form each of these can exist as the a- and /^-isomers.
When
let
ORGANIC CHEMISTRY
194
[CH. VII
CHgOH
CHgOH C OH
c=o
HO-
-H
HOH-
-OH
H-
-OH
-H
H-
-OH
H-
-OH
CH 2 OH
-CH2
II
a-form
HO C CH OH
HO C OHijOH
HO-
HO-
-H
H-
-OH
H-
H-
-OH
H-
CH2
-H
-OH
CHjjOH
IV
III
p-form
p-form
the ring is closed, then if the hydroxyl group is drawn on the right, this will
group now replaces a hydrogen atom in the
be the oc-isomer (the CH 2
aldoses).
Furthermore, since D-fructopyranose is laevorotatory, the oxide
ring is drawn to the left (see the comments on L(+)-arabinopyranose, 7d).
Thus a-D( )-fructopyranose is II, and /3-d( )-fructopyranose is III. The
furanose forms are obtained in a similar manner, but in this case the ring
must be written to the right since the hydroxyl group on C s is on the right
thus /S-D-fructofuranose is IV (see also sucrose, 13).
OH
is
XI
is
D-arabinotrimethoxyglutaric acid.
1
CH 3 0 C CH 2 OH
HO C CHgOH
HO-
HO-
-H
CHaOH/HC^
O H-
-OH
H-
-OH
reflu *
H-
-OH
H-
-OH
GHi!
-CH|j
VI
(CH,),SO
NaOH
CARBOHYDRATES
7e]
HO C CHOGH
CHjO C CHjOCHg
-H
CH3O-
195
HNO,
-H
CH3O-
HCl
O
H-
-OCH3
H-
-OCHs
H-
-OCH 3
H-
-OCH s
-CH.
-CH2
VII
VIII
HO C C0 H
H
CHs O
H-
OCH,
H-
-OCH3
CO.H
CO-
0H3 O-
hso4
-H
q HNO t>
CH 3 0-
-H
H-
-OCH,
H-
-OCH3
H-
-OCHj
H-
-OCH,
CH2
-CH2
C08 H
IX
XI
XII
HO C CHjjOH
HO-
-H
HO C-CHgOCHs
(i)CH,OH/HCl;
18
(ii)(CH,) il SO,/NaOH
(iii)
>
CHjO-
-OH
H-
H-
CH2 OCH,
XII
XIII
-H
CH,0-
H-
-OCH.
H-
and
CO.H
CO-
CH,0-
O
KMnCv
HjSO
H-
-H
-OCH,
CH2 OCH,
H-
-H
-OCH,
XVI
XV
5-tri-O-methyl-D-arabinolactone
so is y-.
is dimethyl-L-tartaric acid.
CH,0HNOa
C02 H
H-
CH2 OCH,
XIV
XVI
-OCH,
CH 2 OH
HO CCOjH
XV is
H-
H-
tone,
HNO.
-H
HCI
ORGANIC CHEMISTRY
196
[CH. VII
From the
Conclusion.
H C OH
.CH=CH ^
CH 2
/
NCH=CH
-OH
H-
HO-
-H
-OH
H-
HOCH2
HCH.jOH
IV
II
H C OH
H
-OH
HO
H
0.
-H
-OH
i
HOCH
-h
VI
VII
CH OH
CH OH
was
as in II).
Comparison of
with II shows that where the
2
originally is now the point of attachment of the oxide ring, the
4
occupying the position where the
atom was, and the latter now where the
without
oxide ring was. Thus, if we consider the conversion of II into
first drawing III and IV, then in effect two Walden inversions have been
is now
effected, and consequently the original configuration is retained.
so that the oxide
transformed into the perspective formula VI by twisting
ring is perpendicular to the plane of the paper and all the other groups are
joined to bonds which are parallel to the plane of the paper. By convention,
Cj is placed to the right and the oxygen atom at the right-hand side of the
part of the ring furthest from the observer. Sometimes the lower part of
the ring, which represents the part nearest to the observer, is drawn in thick
Thus, to change
into VI, first draw the hexagon as shown in VI,
lines.
above the plane of
and then place all the groups on the left-hand side in
the ring in
VI
all
CARBOHYDRATES
197
D-glucose.
In a similar manner,
CH 3 0 C
CH3 0 C H
H-
-OH
CH-CH
-oh!
HO-
//
H-
-H
HO-
-h
!
1
H-
VIII
CH 2OH-CHOH-
H-
-h ;
-OH
CH 2 OH
IX
Two
formula
(i)
are:
<x-d( )-fructopyranose.
fcH2OH
-C OH
HOCH C OH
HO- ^-H
HO-
-H
HOCH C OH
2
HO-
-H
1
H-
- OH
H-
-OH
H-
-OH
O
1
H-
-OH
-CH,
H-
-OH
CH2
H-
-OH
H-
-H
'
ORGANIC CHEMISTRY
198
(ii)
[CH. VII
Methyl p-D(+)-fructofuranoside.
1
CH2 OH
CH3O-
CH3 0 C CH2OH
CH s O-r C
HOH-
-H
C CHjOH!
HO
-H
HOCH,
-OH
-OH
-H
HCH,OH
CHOH
OCHs
^HgOH
Actual size of sugar rings. Since glycoside formation under different
conditions gives compounds containing different sized rings, the important
question then is: What is the size of the ring in the original sugar? Oxidation of an aldose with hypobromite produces an unstable ^-lactone; this is
the first product, but slowly changes into the stable y-lactone (Hudson, 1932).
It therefore follows that the size of the ring in normal sugars is pyranose.
By analogy, ketoses are also believed to exist normally as pyranose compounds. This pyranose structure has been confirmed by X-ray analysis
McDonald et al. (1950)
of various crystalline monosaccharides (Cox, 1935).
examined oc-D-glucose by X-ray analysis, and confirmed the presence of the
six-membered ring, the configuration as found chemically, and also the cis
arrangement of the 1 2-hydroxyl groups in the a-form. Eiland et al.
(1950) subjected difructose strontium chloride dihydrate to X-ray analysis,
and showed the presence of a six-membered ring, and confirmed the conIt might be noted here that furanose sugars
figuration found chemically.
have not yet been isolated, but some furanosides have. It is also interesting
to note that apparently fructose and ribose always occur in compounds as the
:
More
7g.
sugars.
1
of
compounds
R-CHOH-CHOH-R'
R-CHOH-COR'
R-COCOR'
Thus a
free sugar
is
lHIO,
1H10.
1H10.
>
>
>
+ R'-CHO
R-CHO + R'-COgH
R-CO.H + R'-C0 H
R-CHO
CH 2OH-CHOH-CHOH-CHOH-CHO
e.g.,
-^^ >
H-CHO
4H-COaH
CARBOHYDRATES
7g]
199
In all of these reactions, one molecule of periodic acid is used for each pair
of adjacent alcoholic groups (or oxo groups). Thus, by estimating the
periodic acid used, and the formic acid and formaldehyde formed, the number
of free adjacent hydroxy 1 groups in a sugar can be ascertained.
Hudson
(1937, 1939) oxidised " normal " methyl a-D-glucoside, I, with periodic acid,
and found that two molecules of periodic acid were consumed, and that one
molecule of formic acid was produced. It should be noted that although
periodic acid can completely degrade a. free sugar, the oxide ring in glycosides
stable to resist opening by this reagent. The first product
is sufficiently
H C OCH
H C OH
O
HO C
H C OH
H CI
H-
C OCH3
I
CHO
2H10
*-
B^/HnO^
HC0 H +
SrCO,
CHO
H C<
CHgOH
CHgOH
II
H C OCH
C02 H
O CO
I
(0
(ii)
C02 H
IV
H,SO
>
Bn/H,0
+
C02 H
-co
H C-
H-
C OH
I
CH2OH
CHgOH
III
of oxidation of methyl a-D-glucoside was D'-methoxy-D-hydroxyrnethyldiglycolaldehyde, II, and this, on oxidation with bromine water in the presence
of strontium carbonate, gave the crystalline salt, III.
Ill, on acidification
with sulphuric acid (for hydrolysis), followed by further oxidation with
bromine water, gave oxalic acid, IV, and d( )-glyceric acid, V. Isolation
of II, III, IV and
indicates that the ring in I is d-; this is also supported
by the fact that only one carbon atom was eliminated as formic acid, and
that two molecules of periodic acid were consumed. By similar experiments,
it has been shown that all methyl a-D-hexosides of the " normal " type consume two molecules of periodic acid and produce one molecule of formic acid,
and all also give products II, III, IV and V. Thus all these hexosides must
be six-membered rings, and also it follows that all " normal " methyl
a-pyranosides have the same configuration for C x ; this has already been
shown to be VI.
H C OCH
VI
HH
ORGANIC CHEMISTRY
200
[CH. VII
stereoisomer of II,
i.e.,
H C OCH
II
HO C II
H C OH
+
H C OH
2H1Q 4
>
C OCH
CHO
HCOoH +
O
CIIO
CH2I
VIII
VII
sides give the same diglycolaldehyde, they too have the same configuration
for C , viz., VI.
When hexofuranosides, i.e., the " abnormal " glycosides, are oxidised with
periodic acid, two molecules of acid are consumed and one molecule of
formaldehyde is formed. These results are in keeping with the presence of a
five-membered ring,
e.g.,
methyl ot-D-glucofuranoside.
H C OCH3
HHC OH O
HO C
r
H2HIQ4 .
-o- -OCH,
CHO
CHO
I
H CH C OH
H- -c
CHO
+
H-CHO
CH2 OH
H C OCH3
HO C
H C OH
CH 2 OH
IX
H C OCH3
O
1H1O4
CHO
CHO
H CCH< OH
II
CARBOHYDRATES
7h]
201
Mester et al. (1957) have obtained evidence that of these structures the cyclic
hemiacetal (Ila) is the most likely.
OH
H-4-
CH 9-
CH 3
-OL
OCH
I H O
or
L;
II
OCH,
I
OHo
OH
II
Hough et al. (1956) have carried out periodate oxidations on phenylosazones of reducing monosaccharides (X) and obtained formaldehyde, formic
acid and mesoxalaldehyde 1 2-bisphenylhydrazone (XI). These authors
found that XI is obtained from all monosaccharides in which C3 and C4 are
:
CH=N-NH-Ph
CH=N-NH-Ph
1
C=N-NH-Ph
1
CHOH
CHOH
CHOH
CH OH
C=N-NH-Ph
3H10,
>CHO
XI
4-
I"
2H-C0 2 H
CH 2
X
molecule of formaldehyde from the terminal CH 2 OH group when
They also showed that the osazones of the disaccharides maltose
(15), cellobiose (16), and lactose (17) did not give XI but did give formaldehyde. Thus C 3 or C4 are linked in these disaccharides. On the other hand,
the oxidation of the osazone of melibiose (18) gave XI but no formaldehyde;
thus C 6 is linked in this molecule. These oxidations therefore offer a means
of differentiating between the two types of disaccharides.
free,
and
this is free.
'
ORGANIC CHEMISTRY
202
[CH. VII
absent.
It is still usual, however, to use the regular conformations of Reeves
Reeves has shown
since these are readily related to the Haworth formulae.
that the CI conformation is the more stable, and this is supported by Barker
et al. (1959) who studied the ring structures by periodate oxidations in
buffered solutions. Also, according to these authors, the chief exceptions
are /9-D-altrose, /S-D-mannose and /S-D-talose, which are considered to be
0-
IC
CI
,CH 2 OH
HO
We
have also seen that the more stable isomer is the one with the larger
number of equatorial substituents, and so the /S-form can be expected to
be more stable than the a-. Whiffen et al. (1954) have used infra-red spectroscopy to distinguish between a- and jS-anomers; the absorption maxima
H
(i)
CHOMe
O + H sO+:
CH-
CH-^b+Me
fast
CH
CHOH
CH
slow
-*-MeOH
fast
CH-
'I
CH
+ H+
203
CARBOHYDBATES
8]
(ii)
CHOMe
CHOMe
+ H.O+
*
* =?=*
CH
QH
j
j
A*.
H 0CHOMe
H,0
CHOMe
>
>-
I
i
.HOH
CHOH
1^.
~K^
Jff^j
<
CHOH
CH
+MeOH + H+
On
the other hand, axial hydroxyl groups are less reactive (to esterification
reactions) than equatorial groups (12. IV).
In /?-pyranosides, the methoxyl group is equatorial and so mechanism (i) would be more
in keeping with the fact that /S-anomers are more readily hydrolysed than
a- (in which the methoxyl group is axial). However, Bunton et al. (1955)
also showed that the rate of hydrolysis depends on the nature of the aglycon.
In the above example the aglycon is methyl, but when it is phenyl then it is
the a-anomer which is hydrolysed faster.
Since the hemiacetal linkage in the ring-form of reducing sugars is very
labile, reactions involving the carbonyl group may possibly proceed through
the acyclic or the cyclic form (see also mutarotation, 2). Isbell et al.
(1932) have obtained evidence that the oxidation of an aldose with brominewater proceeds to the 1,5-lactone by direct oxidation of the pyranose form.
Isbell et al. (1932-1946) also showed that /S-D-anomers (equatorial
at C x )
are oxidised much faster than the corresponding oc-D-anomers (axial
at
Further experiments on the oxidation of D-glucose by bromine-water
Cj).
appear to show that the a-anomer is first converted into the j8-anomer which
is then rapidly oxidised directly to o-gluconolactone (Perlmutter-Hayman
et al., 1960).
Pentoses (except D-lyxose) are also oxidised in the /3-form
(Overend et al., 1960). Isbell (1961), however, disagrees with Overend's
claim that the rate-determining step is the transformation of oc-D-aldopyranoses into the /3-anomers.
and hydrolysis
OH
OH
ORGANIC CHEMISTRY
204
[CH. VII
gives a trimethylglucose, V.
Methylation of
gives a methyl tetramethylglucoside, and this, on hydrolysis, gives 2:3:5: 6-tetra-O-methyl-D-glucose,
VI, a known compound (see 7b). Thus
must be 2 3 5-, 2 3 6-, or
3:5: 6-tri-O-methyl-D-glucose. Now
forms an osazone without loss of
any methyl group; therefore C 2 cannot have a methoxyl group attached
to it, and so
must be 3 5 6-tri-O-methyl-D-glucose. Thus one wopropylidene radical in di-wopropylideneglucose, I, must be 3 5-, 3 6- or 5 6-.
Monomethylglucose, III, on methylation followed by hydrolysis, gives
2:3:4: 6-tetra-O-methyl-D-glucose, VII, a known compound (see 7a).
Hence III must be 2-, 3-, 4- or 6-O-methyl-D-glucose. Since III gives
sodium cyanate when subjected to the Weerman test (see 11), it therefore
follows that C 2 has a free hydroxyl group. Oxidation of III with nitric acid
produces a monomethylsaccharic acid therefore C 6 cannot have a methoxyl
group attached to it. This monomethylsaccharic acid forms a lactone which
behaves as a y-lactone therefore a methoxyl group cannot be at C4
Thus,
by the process of elimination, this monomethylglucose, III, must be 3-0methyl-D-glucose. It therefore follows that the two isopropylidene groups
2- and 5 6-, the ring being
in the di-wopropylidene derivative must be 1
furanose, and the mono-z'sopropylidene derivative being 1 2-. The foregoing reactions can be written as on opposite page:
O H
H
O
CARBOHYDRATES
8]
<CH,) a CO_
H-C-OH
HC1
jj_
C(CH3)2
l_
O noh
H-<|--0
H-C
H-C
H-C-Q,
CH2
-D(+)-glueose
J
ch2o
)C(CH3 )2
CH2 OH
ii
H C
H-C
HO C
H-C OH
O
CH 0-C
H-C
H C OH
H-C-OH
H C-
CH2 OH
CHjjOH
IV
III
i)(CHJ,SO
1(0
)(CHJ,S04
i)
MCI
CHOH
CHOH
O ()
hci
H COH
H-C-OCH3
O
CH3O-C-H
HCI
CHOH
(i)(CHj,so 4
HCl
CHOH
)C(CH3 )2
CH3O-C-H
:c(ch s ) 2
CH,-COjH
H-C -OCH3
CH 3 0-C-H
HO O-H
H-C-Q^
H C (\
H C-OH
HO-C-H
H-C-OH
205
CH3O-C-H
H C
H-C OCH3
HC
H-C OCH
H C OCHj
H C
CH2OCH 3
CH 2OCH 3
CH2 OCH,
VI
VII
furanose
(I).
The mono-derivative is
2-0-wopropylidene-D-gluc6furanose
HOH
H
O
oH
ORGANIC CHEMISTRY
206
H C
H C OH
H C OH
HO C- -H O
HO C- -H
/C(CH3 ) 2
H C O'
,0 C H
I
(CH 3 2 C
)
o- -c- -H
H C-
H CCH 2 OH
CH 2 OH
IX
VIII
(IV).
[CH. VII
CH 2 OH
CH 2
I
-c
)C(CH3) 2
HO C
O
H C O.
>(CH
H C
I
0H
o-c
(CH 3 ) 2 C N
O C
O
H C Q,
I
3 )2
H-
-C
y C(CH3 ) 2
CH.
1:2-4:5-
2:3-4:5-
CHOH
I
H-G OH
O
HO-C
H C u./
CH'CgHg
H CI
rv
I
CHOCHj
I
H-0 OH
HO 0
H C OH
H C
I
CH2
CH 2 0-C(CH6 s
II
formed much faster with primary alcoholic groups than with secondary,
e.g., methyl glucopyranoside reacts with triphenylmethyl chloride in pyridine
solution to form methyl 6-tritylglucopyrano,side, II.
^-Joluenesiilphonyl chloride (represented as TsCl in the following equations) reacts with sugars in the presence of pyridine to form tosyl esters.
These esters usually produce epoxy-sugars (anhydro sugars) when hydrolysed with sodium methoxide in the cold, provided that there is a free
H H
HH
H H
CARBOHYDRATES
9]
207
hydroxyl group on an adjacent carbon atom and that this hydroxyl and the
tosyl group are trans to each other. This is an example of neighbouring
hydroxyl group participation (6c. Ill), and the mechanism is:
H C OH
HO-C
-Ts~>
On
H C OTs
HO C
TsCl
C,H 6 N
>ATs
H-=C
OMe
OC
X C
V
HCOH
/CH
\C
Na0H
HOC
Na0H
HOC
HCOH
IV
III
In III the configurations of the two carbon atoms are the same as in the
original sugar, but in IV both configurations are inverted (to form a new
sugar).
When the tosyl group is trans to two hydroxyl groups (on adjacent carbon
atoms), two anhydro sugars are formed. At the same time, however, larger
epoxide rings may be produced without inversion, e.g., Peat et al. (1938)
treated 3-tosyl methyl /?-glucoside (V) with sodium methoxide and obtained
a mixture of 2 3-anhydroalloside (VI; with inversion), 3 4-anhydroalloside
(VII; with inversion), and 3 6-anhydroglucoside (VIII; no inversion).
:
CH 2OH
CH 2OH
0.
'H
OMe
O.
MeONa
OMe
OTs
HO
HO
OH
VI (60%)
CH2OH
H J
Ot
Ov OMe
OMe
OH
VII (25%)
OH
VIII (15%)
ORGANIC CHEMISTRY
208
methyl
2
[CH. VII
ac-glucoside
3-anhydro 4
OCH
OCH,
MeONa
PhCH
PhCH
OMe
OMe
OCOPh
IX
For the formation of the epoxide to proceed easily, it is necessary that
the trans
and Ts groups should be diaxial. In the majority of tosyl
derivatives, however, both the tosyl group and the vicinal fraws-hydroxyl
group are equatorial (cf. 7h). Nevertheless, these tosyl derivatives are still
This may be explained on the basis that
easily converted into epoxides.
the' normal chair form (CI) readily changes into the reverse chair form (1C)
consequently both groups are now axial and so epoxide formation proceeds
OH
readily
10.
(cf.
5b. IV).
Glycals are
sugar derivatives which have a pyranose ring structure and a double bond
between
and C 2 e.g., D-glucal is I. Glycals may be prepared by reducing
acetobromo compounds (see 24) with zinc dust and acetic acid, e.g.> D-glucal
from tetra-O-acetyl-D-glucopyranosyl bromide, II, followed by hydrolysis
of the acetyl groups.
Glycosamines are amino-sugars in which a hydroxyl group has been
replaced by an amino-group. All naturally occurring amino-sugars are
CH
II
CH2 OH
H /I
O,
CH
CHO-CO-CH3
CH-NH 2
CHOH
CHO-CO-CH3 O
CHOH
or
CHOH
CHBr
CHOH
CHO-CO-CH 3
CHOH
CH
CH
CH
I
CH 2 OH
I
I
CH 2 0-CO-CH 3
CH 2 OH
III
II
11. Vitamin C or L-ascorbic acid. Ascorbic acid is very closely related to the monosaccharides, and so is conveniently dealt with here.
Hawkins (1593) found that oranges and lemons were effective for treating
CARBOHYDRATES
11]
209
m.p. 192,
[a] D of
+24.
The
-COCHThe presence
-C(OH)=C-
C 6 H,0 6
-^
hci
CH
CH
||
+ C02 + 2H2
||
This reaction suggests that ascorbic acid contains at least five carbon atoms
in a straight chain, and also that there are a number of hydroxyl groups
present (cf. the pentoses). Aqueous iodine solution oxidises ascorbic acid
to dehydroascorbic acid, two atoms of iodine being used in the process arid
two molecules of hydrogen iodide are produced; the net result is the removal
of two hydrogen atoms from ascorbic acid.
Dehydroascorbic acid is neutral
and behaves as the lactone of a monobasic hydroxy-acid; and on reduction
with hydrogen sulphide, dehydroascorbic acid is reconverted into ascorbic
acid.
Since this oxidation-reduction process may be carried out with
" mild " reagents, it leads to the suggestion that since the oxidation product,
dehydroascorbic acid, is a lactone, then ascorbic acid itself is a lactone and
not an acid as suggested previously. Since, however, ascorbic acid can form
salts, this property must still be accounted for.
One reasonable possibility
is that the salt-forming property is due to the presence of an enol group, thfc
presence of which has already been indicated. Thus all the preceding reactions can be explained by the presence of an oc-hydroxyketone grouping
in ascorbic acid:
C OH
C OH
HCOH
I
C=0
=F
h + 2H 8 Q
C(OH)2
+ 2HI
II
C(OH)js
I
I
Reducing;
forms a
phenylhydrazone
Unsaturated
colour with
ferric chloride;
sodium enolate
-2Ha Q^
C=0
c=o
I
ORGANIC CHEMISTRY
210
The
final result is
[CH. VII
ascorbic acid.
CH 8
-> C 6H 6
I*
+ 2HI
Although all these reactions may appear to be speculative, they are known
to occur with dihydroxymaleic acid; hence by analogy with this compound,
the explanation offered for the reactions of ascorbic acid is very strongly
supported.
^C0 H
HO>.
C
II
HO^ ^C0 H
2
Dihydroxymaleic
acid
C0 2H
CO
I
COjsH
C(OH) 2
I
C(OH) 2
H
HO-C
+
C0 2 H
O
|
'
HO C-H
CHjOH
CH2 OH
H2OH
H C-OH
HO G
I
III
II
CHaOH
IV
The ring in ascorbic acid has been assumed to be five- and not sixmembered, because the lactone (i.e., ascorbic acid) is stable towards alkali
In actual fact, however, the same final products would also have
(cf. 7c).
been obtained had the ring been six-membered. It must therefore be admitted that the weakness of the above proof of structure lies in the evidence
used for ascertaining the size of the ring. Structure I, however, has been
amply confirmed by other analytical evidence. Diazomethane converts
ascorbic acid into dimethylascorbic acid (V) these two methoxyl groups are
most likely on Cg and Cs since diazomethane readily methylates acidic (in
This dimethyl derivative is neutral, and
this case, enolic) hydroxyl groups.
dissolves in aqueous sodium hydroxide to form a sodium salt without the
elimination of a methyl group; thus there cannot be a carbomethoxyl group
present, and so it is most likely that two enolic hydroxyl groups are present
Furthermore, the formation of the sodium salt from the
(Hirst, 1933).
neutral compound suggests the opening of a lactone ring (the two enolic
;
CARBOHYDRATES
11]
groups are
211
The
similar-
ity in structure between ascorbic acid and its dimethyl derivative is shown
by the fact that the absorption spectra of both are similar. When this
CO-NH2
CHOH
CNO
NaOCI
>
CHOH
NaOH
>
CHO + NaNCO
I
dioxide.
CO-KH2
I
CHOCH3
NaOCl
NaOH
00^
The dimethylthreonic acid obtained from the ozonised product was converted
into the amide (IX), and this, when subjected to the Weerman test, gave
sodium cyanate as one of the products. Thus this dimethylthreonic acid
contains a free a-hydroxyl group, and consequently must be 3 4-di-0:
ORGANIC CHEMISTRY
212
CO
<
co-
CH3O c=o
-C
HO~
[CH. VII
CO
CO-r
HO-
!
I
CH,N,
CH3O c
H C
CHjO
CII3O c
H C
HO C
O
CH3O
|!M^"" 3 ~ J
Ag!
CH3O c=o
H CCH3O C H
'
HO-C
o3
I
H C
>
CH3O- -C- -H
CH 2OH
CH2 OH
CH2 OCH 3
VI
CH2 OCH3
VII
Ba(OH) 2
C0 2 H
CONH 2
C0 2H
CONH
C02 H
CONH2
I
H C OH
CH3O C H
H C OH
I
CH3O - C
CH 2OCH 3
CH2 0CH3
VIII
IX
An interesting point about ascorbic acid is that it is not reduced by lithium
COH
CO
CH
COH
CH 2
reductic acid
COC(OH)=C(OH)
and examples
and reductic
Many methods
acids.
of synthesising ascorbic
CN
I
CHO
HO CH
I
H-C OH
HO C
I
CH2 OH
CHOH
CHO
I
CO
H C OH
HO C
I
CH 2 OH
XI
KCN
CaCla
CO
I
H C OH
HO-C
I
CH2 OH
XII
CARBOHYDRATES
11]
213
C02H
COsjH
CO -i
CHOH
HoO
oH
r
C OH
CO
H-C OH
HO C
"
HO C
H--J
HO C
H 0 OH
HO C
CH 2 OH
ment
HO
HO
-^+-
CH2 OH
CH 2 OH
XIV
XIII
an atmosphere
of nitrogen with aqueous potassium cyanide containing calcium chloride, gave the 0-keto-cyanide XII, which hydroLyses spontaneously into ^sewio-L-ascorbic acid, XIII. This, on heating for 26 hours
with 8 per cent, hydrochloric acid at 45-50, gave a quantitative yield of
in
L(-j-)-ascorbic acid,
XIV.
CH OH
CH,OH
HOCH
HOCH
HCOH
CH 2OH
HOCH
H,
CO
HOCH
Acetobacter
Cu-Cr
HCOH
HOCH
suboxydans
HCO"H
HOCH
HOCH
HOCH
CHO
D-glucose
CH 2OH
(
+ )-sorbitol
MeXO
H2S01
CH2OH
(-)- sorbose
diacetone - (- )-sorbose
C02 H
CO
KMn04
H 2 SQ4 ,
HOCH
C02 Na
HCOH
I
HOCH
CH 2OH
2-ketogulonic-acid
h -ascorbic acid
CH 90H
ORGANIC CHEMISTRY
214
[CH. VII
Biosynthesis of ascorbic acid (see also 32a. VIII). Horowitz et al. (1952)
and Burns et al. (1956) have shown that rat and plant tissues can convert dglucose into ascorbic acid. A very interesting observation is that glucose
In this way, the
labelled at C x (with 14 C) produces the vitamin labelled at C.
glucose molecule is " turned upside down " to form the glucose derivative (cf.
the stereochemistry of glucose and gulose, 1).
DISACCHARIDES
12. Introduction. The common disaccharides are the dihexoses, and
these have the molecular formula C u 22O u
Just as methanol forms methyl
glycosides with the monosaccharides, so can other hydroxy compounds also
form glycosides. The monosaccharides are themselves hydroxy compounds,
and so can unite with other monosaccharide molecules to form glycosidic
Study of the disaccharides (of the dihexose type) has shown that three
links.
types of combination occur in the natural compounds:
(i)
groups,
(ii)
(iii)
e.g.,
sucrose.
CARBOHYDRATES
13]
215
By
and the
The final problem is to decide whether the glycosidic link is a or /?. This
done by means of enzymes, maltase hydrolysing oc-glycosides and emulsin
/^-glycosides (cf. 3).
In non-reducing sugars, the problem is far more
difficult since the links o^-aa.
x-/?2, /?i-2 would all be hydrolysed by maltase.
Consideration of the optical rotations has given information on the nature
of the link (cf. 6)
Finally, a number of disaccharides have been synthesised,
is
above
facts:
CH2 OH
CH 2 OH
or
CH 2 OH
H CH2OH
,.
i_0-i
CH 2 OH
OH
ORGANIC CHEMISTRY
216
[CH. VII
Oxidation of sucrose with periodic acid confirms this structure (but not
the nature of the glycosidic link). Three molecules of periodic acid are
consumed, and one molecule of formic acid is produced. Subsequent oxidation with bromine water, followed by hydrolysis, gives glyoxylic, glyceric
and hydroxypyruvic acids (Fleury et al., 1942).
HC=
OI
CH 2 OH
-O-j
1 f!
C
HCOH
CH 2 OH
HC=r-0CHO
-C
HOCH O
2-H
HCOH
I
HC
^^HC0 H +
HOCH
3 -I-
HCOH
HC
CHO
CHO
CHO
HC
I
CH 2 OH
CH,OH
CH2 OH
CH2 OH
CH 2OH
CHO
I
C0 2 H
CO
I
(i)
Brg/HaO
(ii)
hydrolysis
C02 H
C02 H
+
C0 2H
HCOH
HCOH
CH 2 OH
CH2 OH
et al. (1947) examined sucrose sodium bromide dihydrate by X-ray
and confirmed the stereochemical configuration found chemically,
showed that the fructose ring is five-membered.
Sucrose has now been synthesised by Lemieux et al. (1953, 1956). Brigl
Beevers
analysis,
and also
(1921) prepared the sugar epoxide, 3:4: 6-tri-O-acetyl-l 2-anhydro-a-Dglucose, II, from tetra-0-acetyl-/?-D-glucose, I (cf. 9; see also 24).
:
CH 2 OAc
CH 2OAc
'H
OAc
AcO
\
H
OAc
x
\i
H A
|/
OAc
I
U/^-~ \
pci 6
CI
(i)
NH 3
in ether
(ii)
NH3
in
OAc
H.
OCOCCI3
AcO
benzene
CARBOHYDRATES
13]
CH2 OAc
CH 2 OAc
A O
217
H X~-O v OMe
H
MeOH.
AcO
AcO
II
Brigl also
showed that
II reacted with methanol to give methyl /9-dglucopyranoside triacetate, III, whereas with phenol, the a-glucopyranoside
was the main product. Other workers showed that secondary alcohols
gave <x,/S-mixtures. Lemieux was therefore led to believe that fructofuranose, a hindered secondary alcohol, would react with anhydroglucopyranose to form an a-glucose linkage. 1 : 2-Anhydro-a-D-glucopyranose
triacetate and 1:3:4: 6-tetra-O-acetyl-D-fructofuranose were heated in a
sealed tube at 100 for 104 hours. The product, sucrose octa-acetate, on
deacetylation, gave sucrose (yield about 5 per cent.)
According to Lemieux,
the reaction proceeds as follows:
.
CH2 OAc
AcO
CH-jOAc
CH2OAc
The CH 2 OAc group at position 6 in the glucopyranose molecule enters into
neighbouring group participation in the opening of the oxide ring, and
consequently shields this side from attack. Thus the fructofuranose molecule is forced to attack from the other side and this produces the desired
a-glucopyranose linkage.
One other point that is of interest is the " inversion " of sucrose on
hydrolysis. Hydrolysis of sucrose gives first of all a-D(+)-glucopyranose
and /S-D(+)-fructofuranose (this is believed to be dextrorotatory), but the
latter is unstable and immediately changes into the stable form, d( )-fructopyranose (the rotation of ( )-fructose is much greater than that of (+)glucose).
CH 2 OH
CH2 OH
OH
HO-
HO-
-H
H-
-OH
HCHjjOH
(+)-
ORGANIC CHEMISTRY
218
[CH. VII
This is believed to be a-D-glucopyranosyl-a-D-glucoa non-reducing sugar which occurs in yeasts and fungi.
It is hydrolysed by hydrochloric acid to two molecules of D-glucose; methylation of trehalose gives octa-O-methyltrehalose which, on hydrolysis, produces
two molecules of 2 3 4 6-tetra-O-methyl-D-glucose (see 7a). The nature
of the glycosidic link is uncertain, but there is some evidence to show that
Thus trehalose may be written.
it is a
a, e.g., the high positive rotation.
Trehalose.
14.
pyranoside.
It is
OJ
H C=J-
CH2OH
OH
II
OH
CH 2OH
5
CHjjOH -Q
HO
2:3:4:
CARBOHYDRATES
15]
219
C02 H
CHOH
CH
H-
-OCH3
0-
-H
H-
-OH
CH,0-
[o]
H-
H-
H-
-OH
H-
-OH
CH sO-
-OCH3
-H
C0 2 H
dimethyl- D-
C02 H
CH2OCH3
2:3:6-trimethylglucose
From
C02 H
-OCH3
H-
(+)-tartaric acid
2:3-dimethylsaccharic acid
can be seen that structure I for maltose satisfies all the above
facts.
This structure, however,. is not the only one that satisfies all the
facts.
The structure of the non-reducing half is certain, but that of the
reducing half need not necessarily be pyranose as shown in I, since a furanose
this it
structure, II,
whether C4
would
2:3:
also give
(as in I) or
C6
(as in II)
GHOH
H-C=
-OH
H-
O
O
-H
HO-
6-tri-O-methyl-D-glucose. To decide
was involved in the glycosidic link,
H-
-OH
HO-
H-
H-
H-
HCH 2 OH
-H
-OH
CH2 OH
reducing
non-reducing
half
half
or
CH OH
CH,OH
Q H
H-OH
"-0
OH
non-reducing
reducing
half
half
HO
HO
H
(a-anomer)
ORGANIC CHEMISTRY
220
CHOH
OH
H-
HO-
[CH. VII
-OH
H-
-H O
HO-
-H
H-
H-
H-
H-
-OH
CH 2 OH
CH 2 OH
II
Haworth
et al.
acid, III,
and
this,
CHoOH
CH 2 OH
CHgOH
CH 2 OH
III
HCl
CH2 OCH 3
CH2 OCH3
IV
C0 2 H
H-
-OCH
0H,O-
CHOH
3
-H
H-
OH3 0-
H-
-OH
H-
H-
-OCH3
H-
GH 2 OCH3
-OCH3
-H
-OCH 3
CH OOH3
2
VI
CARBOHYDRATES
16]
221
agreement of the
ture
I,
specific rotation of
a reducing sugar, Cx
an osazone, C2 is also free,
is
followed by hydrolysis, gives 2:3: 6-trimethyl-D-glucose and 2:3:4:6tetramethyl-D-glucose (these are the same products obtained from maltose,
Oxidation with bromine water converts cellobiose into cellobionic acid,
15).
and this, on methylation followed by hydrolysis, gives 2:3:5: 6-tetramethylgluconic acid and 2:3:4: 6-tetramethylglucose (again the same products as for maltose). Thus cellobiose and maltose differ only in that the
former has a /5-glycosidic link, whereas the latter has an a-. Thus cellobiose
is
(a-form):
H C OH
H-
-OH
H-
O O
HO-
-H
H-
HOH-
CH 2 OH
-OH
-H
J-O
or
-OH
CH2 OH
CH2OH
H-
H-
OH
CH 2 OH
JjCH2 OH^O
Degradation experiments confirm the C 4 linkage (see also 7g), and the
structure has also been confirmed by synthesis {e.g., Stacey, 1946).
17. Lactose (4-0-/?-D-galactopyranosyl-D-glucopyranose).
Lactose is a
reducing sugar, and is hydrolysed by dilute acids to one molecule of d(+)glucose and one molecule of D(+)-galactose. Since lactose is hydrolysed
by lactase (which has been shown to be identical with the /S-glycosidase in
emulsin), the two monosaccharide molecules are linked by a j3-glycosidic
link.
The evidence, given so far, does not indicate which molecule is the
reducing half. On methylation, lactose forms methyl heptamethyl-lactoside, and this, on vigorous hydrolysis, gives 2:3: 6-tri-O-methyl-D-glucose
ORGANIC CHEMISTRY
222
[CH. VII
reducing half.
Lactose
is
CH 2 OH
OH
OH
o.
OH
CH2OH
CH,OH
CH 2 OH
18.
saccharide
CHO0H
CHOOH3
HO-
-H
H-
-Oil
-OH
H-
-OH
H-
HO-
-H
-OH
HH-
H-
CH2 OH
CH
III
IV
0-C(C 8 H 5 ) 3
When hydrolysed
sugar, forms an osazone, and undergoes mutarotation.
by dilute acids, melibiose gives D-glucose and D-galactose. Methylation
converts melibiose into methyl heptamethylmelibioside, and this, on hydrolysis,
2:3:4:
6-tetramethyl-D-galac-
CARBOHYDRATES
19]
223
also 7g]:
CH8 OH
OH 1 (x H
or
0 OH;;
HO VH
I
H-
HOH-
H-
-OH
-H
O HOH-
-OH
CH2 OH
-OH
H
-"
-OH
O GH
Ur \
OH
2
-o.
or
OH
OH
OH
H
OH
II
H-
H-
CHjjOH
CHr
is
primeverose
(26).
ORGANIC CHEMISTRY
224
[CH. VII
glucosefructose
galactose
H OH
OHJ
OH
OH
H
CH2 OH
^-CH
melibiose part
glucose
glucosefructose
of gentianose is:
sucrose part
CH2OH
gentiobiose part
CH2 OH
POLYSACCHARIDES
Polysaccharides are high polymers of the monosaccharides, and may be
roughly divided into two groups: those which serve as "structures" in
plants and animals, e.g., cellulose, and those which act as a metabolic
reserve in plants
and animals,
e.g.,
starch.
CARBOHYDRATES
21]
225
per cent, yield (Irvine el al., 1922) therefore the structure of cellulose is
based on the D-glucose unit. Methylation, acetylation, or " nitration " of
cellulose produces a trisubstitution product as a maximum substitution
product, and it therefore follows from this that each glucose unit present
has three hydroxyl groups in an uncombined state. When fully methylated
cellulose is hydrolysed, the main product is 2 3 6-tri-O-methyl-D-glucose
Thus the three free hydroxyl groups in each glucose unit
(90 per cent.).
must be in the 2, 3 and 6 positions, and positions 4 and 5 are therefore
occupied. Now, if we assume that the ring structure is present in each
unit, then this would account for position 5 (or alternatively, 4) being
occupied. Furthermore, if we also assume that the glucose units are linked
by Cz of one unit to C4 of the next (or alternatively, C 5), then the following
tentative structure for cellulose would account for the facts:
;
CHOH
H-
HCl
CHjO-
H-
-OCH,
-H
-OH
H-
OH a OH
CH 2 OCH
CH 2 OCH
glucose unit
2:3:6-trimethyl-
glucose
It should be noted, however, that if the linkages at 4 and 5 were interchanged, the same trimethylglucose would still be obtained on hydrolysis
(cf.
maltose,
etc.).
(this is carried
CH
CHOH
H-
HO-
-OH
-H
H-
HO-
H-
H-
H-
HCH.OH
-OH
-H
-OH
CH2 OH
cellobiose
glucose units are the same (all /?-) or alternate (a and /?), since all the links
could be /S-, or each pair of cellobiose units could be joined by a-links; the
latter possibility is not likely, but it is not definitely excluded.
Very careful
acetolysis of cellulose, however, has produced a cellotriose, cellotetraose and
ORGANIC CHEMISTRY
226
[CH. VII
H-
-OH
H-
-H
H-
-OH
HO-
-II
-0-0
H-
-OH
HO-
r O C
-O-C
CHOH
IIO-
-II
HO-
H-
H-
H-
II-
H-
H-
H-
H-
CH 2 OH
CH,OH
-OH
CH 2 OII
-II
-OH
CH2 OH
It should be noted that in the structure given for cellulose, the first glucose
unit in la (i.e., the one on the left-hand side; this unit is on the right-hand
side in 16) has a free reducing group, but since this group is at the end of a
very long chain, its properties tend to be masked; thus cellulose does not
exhibit the strong reducing properties of the sugars.
The cellulose molecule is not planar, but has a screw-axis, each glucose
unit being at right angles to the previous one. Although free rotation about
C link might appear possible at first sight, it apparently does
the
not occur owing to the steric effect. This and the close packing of the atoms
give rise to a rigid chain molecule. The long chains are held together by
hydrogen bonding, and thus cellulose has a three-dimensional brickwork.
This would produce strong fibres with great rigidity but no flexibility, and
consequently, although the fibres would have great tensile strength, they
could not be knotted without snapping. Since the fibres can be knotted
without snapping, they must possess flexibility, and the presence of the
latter appears to be due to the partly amorphous character of cellulose.
The chemical structure of cellulose appears to be more complicated than
the one given above. Schmidt et al. (1932) showed that carboxyl groups are
present in carefully purified cotton fibres. Kleinert et al, (1944) have suggested that various other groups, which are not necessarily carbohydrate in
CO
CARBOHYDRATES
21]
227
In nitrogen
rr
.
1
,__:
\
\
V.
r-*>
CXXDOZO
r->-
o::d
1r->-|}-"
*-i -e-i
CD CD
228
ORGANIC CHEMISTRY
[CH. VII
By means of chromatography, McGilvray (1953) has detected 2:3:4:6tetra-O-methyl-D-glucose in the hydrolysate after the methylation of celluThus degradation of the chain has occurred
lose in an atmosphere of nitrogen.
under these conditions, and so there is no evidence for the linking of the end
groups in the absence of oxygen. Furthermore, McGilvray determined the
degree of polymerisation from viscosity and osmotic pressure measurements,
and also from the end-group assay. The values obtained from the first
two methods were greater than that obtained from the third method, and
McGilvray suggests these results may be accounted for by assuming a
slightly branched structure for the soluble methylcelluloses.
A number of other chemical methods have been used for estimating the
molecular weight of cellulose, e.g., that of Hirst et al. (1945) this is based on
the periodate oxidation (7g). Examination of the formula of cellulose
shows that the terminal reducing unit would give two molecules of formic
acid and one of formaldehyde (this reducing unit, which is left in la, behaves
as the open-chain molecule, since it is not a glycoside), whereas the other
terminal unit (right in la) would give one molecule of formic acid; i.e., one
cellulose molecule gives three molecules of formic acid and one of formaldehyde. Estimation of the formic acid produced gives the value of the chainlength as approximately 1000 glucose units. There appears, however, to be
some uncertainty with these results, since " over-oxidation " as well as
normal oxidation with periodic acid results, the former possibly being due
to the progressive attack on the chain-molecules from their reducing ends
(Head, 1953).
Physical methods. Ultracentrifuge measurements have given a value
of 3600 glucose units for native cellulose; lower values were obtained for
purified cellulose and its derivatives (Kraemer, 1935). These differences
are probably due to the degradation of the chains during the process of
Viscosity measurements on
purification and preparation of the derivatives.
cellulose in Schweitzer's solution give a value of 2000-3000 glucose units;
lower values were obtained for viscosity measurements on derivatives of
Osmotic prescellulose in organic solvents (Staudinger et al., 1935-1937).
sure measurements on derivatives of cellulose have given values of approximately 1000 glucose units (Meyer, 1939). Schulz et al. (1954, 1958) have
determined the molecular weight of cellulose nitrate by measurements of
viscosity, etc., and obtained results varying from 1400 to 7800 glucose units,
the value depending on the source of the cellulose.
From the foregoing account, it can be seen that the values obtained
chemically and physically are not in agreement. This indicates the uncertainty of the value of n, and also that the value of n depends on the source
and treatment of cellulose. However, the more recent work of Schulz (see
above) is reliable in that evidence was obtained that no degradation occurred
in the course of purification and conversion into the nitrates.
;
Hydrolysis
22. Starch. The molecular formula of starch is (C 6 10 O B ).
of starch with acids produces a quantitative yield of D-glucose (cf. cellulose)
thus the structure of starch is based on the glucose unit. Methylation of
starch gives the trimethylated compound (maximum substitution), and this,
on hydrolysis, produces 2:3: 6-tri-O-methyl-D-glucose as the main product,
and a small amount (about 4-5 per cent.) of 2 3 4 6-tetra-O-methyl-Dglucose.
Oxidation studies (periodic acid) have also shown the presence of
:
1
4-linked D-glucopyranose residues. Starch is hydrolysed by the enzyme
diastase (/5-amylase) to maltose (see also below). Thus the maltose unit is
present in starch, and so we may conclude that all the glucose units are
joined by a-links (cf. cellulose). The following structure for starch fits these
:
facts
CARBOHYDRATES
22]
CH 2 OH
CH 2 OH
229
CH 2 OH
CH 2 OH
maltose unite
or
pH 2 OH
H J
O H
A
NJ
H
CH OH
h/L JV>h
OH
H
(1932)
CH 2 OH
J
L/H
O.
J Q H
iy\
OH
OH J
H
is
OH
composed of
230
ORGANIC CHEMISTRY
[CH. VII
gives only about 70 per cent, of maltose, and this has been confirmed by
other workers. Since /J-amylase only attacks a-1 : 4-glucosidic linkages, it
thus appears that a-amylose contains a small number of other linkages.
Careful purification of " crude " soya-bean /5-amylase showed the presence
of two enzymes, |?-amylase and another which was named Z-enzyme; it is
the latter which was shown to hydrolyse the non a-1 4-linkages. Thus
unpurified /3-amylase (which contains both enzymes) degrades a-amylose
completely to maltose. It has also been shown that Z-enzyme has /S-glucosidase activity and that emulsin can hydrolyse these " anomalous " linkages.
These observations suggest that a-amylose contains a small number of
/3-glucosidic linkages.
Another difficulty arises from the fact that the structure of potato amylose
depends on its method of preparation, e.g., one sample is completely degraded
by purified /3-amylase, whereas other samples are not. The first sample
represents about 40 per cent, (by weight) of the total amylose in potato
starch, and thus it follows that potato amylose is heterogeneous both in
large proportion is completely linear (and contains
structure and in size.
about 2000 glucose units), and the remainder (which contains about 6000
The nature of
units) contains a small number of these anomalous linkages.
these anomalous linkages is still uncertain.
:
Amylopectin (B-fraction). Molecular weight determinations of amylopectin by means of osmotic pressure measurements indicate values of 50,000
Larger values have also, been reported,
to 1,000,000 (Meyer et al., 1940).
e.g., Witnauer et al. (1952) have determined the molecular weight of potato
amylopectin by the method of light scattering, and report an average value
Let us consider an amylopectin having an average
of 10,000,000 or more.
molecular weight of 550,000; this corresponds to about 3000 glucose units.
The end-group assay by methylation shows the presence of one unit with
four free hydroxyl groups per 24-30 glucose units; the same results are also
obtained by the periodate method. Thus the 3000 units are joined in such
a manner as to give about 100 end units it therefore follows that the chain
must be branched,. The problem is further complicated by the fact that
Hirst (1940), after methylating amylopectin and hydrolysing the product,
obtained, in addition to tri- and tetra-O-methyl-D-ghicose, about 3 per cent,
of 2 3-di-O-methyl-D-glucose.
This has been taken to mean that some
glucose units are also joined by C t and C g atoms. Furthermore, in certain
experiments, enzymic hydrolysis has given a small amount of 1 6 a-linked
diglucose, i.e., womaltose is also present in amylopectin (Montgomery et al.,
1947, 1949). Wolfrom et al. (1955, 1956) have obtained evidence that there
3-bond in amylopectin the principal bond is a-D-1 4, and
is also an a-D-1
branching occurs through a-D-1 6-bonds.
The branching of the chains in amylopectin is supported by the following
evidence:
(i) Amylopectin acetate does not form fibres; fibre formation is characteristic of linear molecules.
(ii) /?-Amylase hydrolyses amylopectin to give only about 50 per cent, of
maltose. Thus there are " blocked " points, and these will occur at the
;
branch points.
(iii) Amylopectin solutions do not show an orientation of the molecules
in the direction of flow in the concentric cylinder technique; the molecules
are therefore not linear.
The detailed structure of amylopectin is still not settled. Haworth and
Hirst (1937) suggested a laminated formula for amylopectin; each line
represents a basal chain of 24r-30 glucose units joined by a C x
4 links,
and each arrow head represents the joining of the terminal reducing group
(C x ) of each chain to the central glucose member (at C 6 ) of the next chain.
CARBOHYDRATES
23]
231
1.
n *
x
18 f
^maltose +
II
12
18
12
^^
4-
12
dextrin
In support of this explanation, it has been found that dextrin has a unit
chain-length of 11-12 glucose units.
Further work has shown that the Haworth laminated formula does not
satisfy the behaviour of amylases on amylopectin; the formula is far too
regular (c/. Hirst's work, above). Meyer (1940) proposed a highly branched
structure; this fits the behaviour of the amylases better. Furthermore,
ORGANIC CHEMISTRY
232
[CH. VII
CHOH
H-
HOH-
CH OH
-NH2
-H
-OH
H-
H
CH2 OH
NH-CO-CH3
A -acety]glucosamine
r
D -glucosamine
iV-Methyl-L-glucosamine
is
a component of streptomycin
(see 7.
XVIII).
is
CARBOHYDRATES
23a]
233
CH OH
CH 2OH
CO
CO
H OH
H OH
HO !
H OH
H j OH
H : OH
ribulose
CH 2OH
sedoheptulose
algae
extract.
tial
are as follows
(i)
of water.
(ii) The product now splits
(CH20-P03H 2 -CHOH-C0 2H)
into
two molecules
of phosphogryceric acid
(iv)
CHO-(CHOH) s -CHOH-CH 2 OH
oxidat ">n
>
CHO-(CHOH) 3 -CHOH-C0 2H
decarboxylation
>
The foregoing account of photosynthesis describes the various intermediates produced. In green plants the presence of chlorophyll (6. XIX)
is necessary for photosynthesis, but its exact function is not certain.
It
appears that all the light energy is used in the " light phase " to raise chlorophyll a from its ground state to an excited state, and then this energy of
the excited state is used in the " dark phase " to convert carbon dioxide
into carbohydrates (Trebst el al., 1958-1960). Furthermore, the same series
of dark-phase reactions has also been shown to occur in non-chlorophyllous
cells (inter alia, McFadden el al., 1957, 1959).
What is peculiar to photosynthesis
is its light
phase.
ORGANIC CHEMISTRY
234
[CH. VII
GLYCOSIDES
H-COCO-CH
CHOH
I
(GHOH)3
(CHOCOCH3 3
)
I
I
CH
CH
CH2 C-COCH3
CH2 OH
a-glucose penta-acetate
glucose
(CH 3 CO) 2 0;
CH,C02 Na;
(CH 3 CO),0;
2nCl 2 /U0
heat
CH 3-COO- C-H
O
(CHO-COCH 3
)3
CH
I
CH 20-COCH 3
p-glucose penta-acetate
^-compound
(1. III).
CARBOHYDRATES
25]
235
H-C-C-CO~CH 3
(GHO-CO-CH 3
CH,0-C-H
(CHO-CO-CH3
)3
O
)3
CH
CH2OCOCH3
CH20-CO-CH3
a-penta-acetate
<%.
(3-glycoside
H-C-Br
O
(CHO-COCH3
)3
CH-
CH2 OCOCH
o-acetobromohexose
CH3 -COO-C-H
(CHOCC~CH3
)3
H C-GCH,
(CHO-CO-CH 3 ) 3
I
CH-
CH
CH G~CC-CH3
OH OCC~CH 3
(3-penta -acetate
25. Indican.
a -glycoside
and in the woad plant. When the leaves are macerated with water, the
enzyme present hydrolyses indican to glucose and indoxyl, and the latter,
on exposure to air, is converted into indigotin (see Vol. I).
The molecular formula of indican is C14H 17 0N, and since it gives D-glucose
and indoxyl on hydrolysis, it is therefore indoxyl D-glucoside. When indican
is methylated (with methyl iodide in the presence of dry silver oxide), tetramethylindican is obtained, and this, on hydrolysis with methanol containing
1 per cent, hydrogen chloride, gives indoxyl and methyl 2:3:4: 6-tetra-Omethyl-D-glucoside. Thus the glucose molecule is present in the pyranose
form, and since indican is hydrolysed by emulsin, the glycosidic link must
be p. Thus the structure of indican is III, and this has been confirmed by
synthesis from indoxyl, I, and tetra-O-acetyl-a-D-glucopyranosyl 1-bromide,
II,
as follows:
ORGANIC CHEMISTRY
236
[CH. VII
u~
Ag s C0 3
CH 2OCOCH3
II
CH 2 OH
CH OCOCH3
2
III
Ruberythrlc acid. This occurs in the madder root, and on hydrowas originally believed to give one molecule of alizarin and two
molecules of D-glucose. Jones and Robertson (1933), however, showed that
two molecules of D-glucose were not present in the hydrolysate a mixture
Thus the moleof two sugars was actually present, D-glucose and D-xylose.
cular formula of ruberythric acid is C 25 H 26 13 and not, as was originally
Thus the hydrolysis is:
believed, C 26 H 28 14
26.
lysis, it
CaHasOu+aHgO^CgHjiA, +
OH
OH
C s H 10 O 5 +
Jones and Robertson also showed that the two monosaccharide molecules
were present in the form of the disaccharide primeverose. Now, this
disaccharide
is
CHOH
1
HHOH-
-OH
-H
-OH
HHOH-
H-
CH,
C-H
OH
H
OH
CH<r
primeveros
CARBOHYDRATES
27]
237
therefore follows that alizarin is linked to the glucose half of the primeverose molecule. Further work has shown that the glucosidic link is /S,
and that it is the 2-hydroxyl group of alizarin that is involved. Thus the
structure of ruberythric acid is:
it
is
two molecules
of D-glucose,
C20H 27 OuN
and one
+ 2H 0-* C H
2
of
5
hydrogen cyanide.
-CHO
2C 6H 12
+ HCN
Since emulsin also brings about this hydrolysis, amygdalin must contain a
On the other hand, the enzyme zymase hydrolyses amygdalin into one molecule of glucose and a glucoside of (+)-mandelonitrile
/J-glycosidic link.
(this
compound
is
C2oH a7 O uN
+ H 02
C 6H 12
C 6H 5 -CH(CN)-OC 6H uO s
identical with prunasin, a naturally occurring glucoside). Thus the aglycon of amygdalin is (H-)-mandelonitrile, and the sugar is a disaccharide.
Haworth et al. (1922, 1923) have shown that this disaccharide is gentiobiose
Gentiobiose, I,
(19), and have synthesised. amygdalin (in 1924) as follows.
was converted into hepta-acetyl-bromogentiobiose, II, by means of acetic
anhydride saturated with hydrogen bromide, and then II was condensed
with racemic ethyl mandelate in the presence of silver oxide, whereby the
^-glycoside, III, was obtained. Treatment of this with ethanolic ammonia
hydrolysed the acetyl groups, and at the same time converted the ester
group into the corresponding amide; thus the ()-amido-glycoside, IV, was
obtained. IV was then treated with acetic anhydride in pyridine solution,
and the (ij-hepta-acetyl derivative of the amide, V, was then separated
into its diastereoisomers by fractional crystallisation (the mandelic acid
portion is
and
the gentiobiose portion is +; hence the two forms
,
present are
and
[-, i.e., they are diastereoisomers).
The (-f-)-form
was then dehydrated with phosphorus pentoxide to give the (+)-nitrile, VI,
++
ORGANIC CHEMISTRY
238
-OH
GHOH
H- -OH
HO- -H
OO
H-I-OH
H-C-Br
H- -OH
-C-H
OCOCH,
OOCH.COO
CH,000
II
H-(-OCOCH3
H-j-OCOCH3
CH 2 OH
CH,
II-l-OCOCHj
0-
HO- -H
H-I-OH
H-
[CH. VII
CH OCOCH 3
CH,
II
C6H5
CH
0-
C02 C 2H5
OCOCH3
OO CH3COO
CH3COO-
"O-*-
-C-H
OCOCH3
-C-H
H-|-OCOCH,
H-I-OCOCH3
H
CH
CH.0C0CH,
III
C6H5
O C-H
CH
C-H
C0NH2 H- -0H
HO- -H
00
H-}-OH
HO- -H
CH 3 CO) a O
()-heptaacetyl
of
derivative
H- -OH
H-I-OH
H-
H-
p3 o 6
(+)-form
pyridine
'
CH,OH
CH,
IV
CeH5
CcHc
r 5
CH-O-C-H
CN H OH
CH-O-C-H
C-H
H- OCOCH,
CN
H-+-OCOCH3
00 CH,000
CH3COO-I-H
-OH
HO--H 00H0
H- -OCOCH3
H- -OCOCH,
H+OH
H+OH
H-
H-
H-
CH 2 OCOCH 3
GH 2
CH,OH
CH,-
VI
28.
C-H
VII
Arbutln
is
hydrolysed by cmulsin
to give one molecule of D-glucose and one of quinol; thus arbutin is a /?glucoside.
When methylated (with methyl sulphate in the presence of
sodium hydroxide), arbutin forms pentamethylarbutin, and this on hydrolysis with methanolic hydrogen chloride, gives methyl 2:3:4: 6-tetra-Omethyl-D-glucoside and monomethylquinol (Macbeth et al., 1923) ; structure I
for arbutin accounts for all these facts.
239
CARBOHYDRATES
29]
O-C-H
rio<f~~j>
CH3
(CH,) a sot
0<<> O-C-H
XT.rtll
NaOH
-011
HO-
'
II-
-H
CH3 0HH-
-OH
HH-
-OCH3
-H
-OCH3
CH2 OCH 3
CH2 OH
I
CHOCH3
OCH,
H-
HCI
CH3O-
CHjOH
HH-
-OCH,
O
-H
-OCH3
CH 2OCH 3
Pentamethylarbutin has been synthesised by converting 2:3:4: 6-tetraO-methyl-D-glucose into tetra-0-methyl-ix-D-glucopyranosyl 1-bromide, and
condensing this with monomethylquinol; the product is identical with the
methylated natural compound.
Methylarbutin. This is hydrolysed by emulsin to one molecule of dglucose and one molecule of monomethylquinol; thus methylarbutin is a
/?-glucoside,
and
its
structure
cHs0
is:
0"
~~ ~~**
H-
HOH-
-OH
-H
-OH
H-
CH2 OH
Methylarbutin has been synthesised by condensing tetra-O-acetyl-a-D-glucopyranosyl 1-bromide with monomethylquinol in the presence of silver
carbonate, followed
by
de-acetylation.
and one
This structure has been confirmed by condensing tetra-0-methyl-a-D-glucopyranosyl 1-bromide with salicyl alcohol.
ORGANIC CHEMISTRY
240
[CH. VII
CH2OH
-OH
H-
HO-
-H
H-
-OH
H-
CH 2 OH
and then methylating the product. The pentamethylsalicin so obtained
was identical with the methylated natural product (Irvine et al., 1906).
30. Sinigrin. This glycoside occurs in black mustard seed, and on
hydrolysis with the enzyme myrosin, D-glucose, allyl wothiocyanate and
potassium hydrogen sulphate are obtained.
K+0 3S-0-C-S-C 6H uO a
II
N-CH 2-CH=CH 2
N-OSO.-K+
II
structure of sinigrin, but Ettlinger et al. (1956) have proposed II, since
these authors have shown that allyl wothiocyanate is produced by rearrangement when the glycoside is hydrolysed by myrosin (cf. the Lossen
rearrangement; see Vol. I).
READING REFERENCES
Handbook for Chemical
of Carbohydrates.
Rosanoff, On Fischer's Classification of Stereoisomers, /.
114.
Haworth, The Constitution of Sugars, Arnold (1929).
Honeyman, Chemistry of
Ch.
5.
Nomenclature
CARBOHYDRATES
241
Manners, Structural Analysis of Polysaccharides, Roy. Inst. Chew,., Lectures, Monographs and Reports, 1959, No. 2.
Wiggins, Sugar and its Industrial Applications, Roy. Inst. Chem., Lectures, Monographs
and Reports, 1960, No. 5.
Bassham, Photosynthesis, /. Chem. Educ, 1959, 36, 548.
Park, Advances in Photosynthesis, /. Chem. Educ, 1962, 39, 424.
Arnon et at., Photoproduction of Hydrogen, Photofixation of Nitrogen and a Unified
Concept of Photosynthesis, Nature, 1961, 192, 601.
Roderick, Structural Variety of Natural Products, /. Chem. Educ, 1962, 39, 2.
CHAPTER
VIII
TERPENES
Introduction. The terpenes form a group of compounds the majority
which occur in the plant kingdom; a few terpenes have been obtained
from other sources. The simpler mono- and sesquiterpenes are the chief
constituents of the essential oils; these are the volatile oils obtained from
the sap and tissues of certain plants and trees. The essential oils have
been used in perfumery from the earliest times. The di- and tri-terpenes,
which are not steam volatile, are obtained from plant and tree gums and
resins.
The tetraterpenes form a group of compounds known as the carotenoids, and it is usual to treat these as a separate group (see Ch. IX).
Rubber is the most important polyterpene.
Most natural terpene hydrocarbons have the molecular formula (C 5H 8),
and the value of n is used as a basis of classification. Thus we have the
following classes (these have already been mentioned above):
1.
of
(i)
(hi)
(v)
(vi)
Monoterpenes, CxoH^.
Diterpenes, C 20 3a
Tetraterpenes, C 40
Polyterpenes, (C 5
Sesquiterpenes, C^H^.
Triterpenes, C 30 48
(these are the carotenoids).
(ii)
(iv)
H
Hg
64
).
compounds C]0H 16
The thermal decomposition of almost all terpenes gives isoprene as one
of the products, and this led to the suggestion that the skeleton structures
of all naturally occurring terpenes can be built up of isoprene units; this is
known as the isoprene rule, and was first pointed out by Wallach (1887).
Thus the divisibility into isoprene units may be regarded as a necessary
condition to be satisfied by the structure of any plant-synthesised terpene.
to the
Furthermore, Ingold (1925) pointed out that the isoprene units in natural
terpenes were Joined " head to tail " (the head being the branched end of
isoprene).
This divisibility into isoprene units, and their head to tail union,
may conveniently be referred to as the special isoprene rule. It should be
noted, however, that this rule, which has proved very useful, can only be
used as a guiding principle and not as a fixed rule. Several exceptions to
it occur among the simpler terpenes, e.g., lavandulol is composed of two
isoprene units which are not joined head to tail; also, the carotenoids are
joined tail to tail at their centre (see Ch. IX).
>c=CH-GH 2 -cn-c^
cii3
'
ClI 2 OH
CII?
J_CK=CIl2
isoprene
lavandulol
242
TERPENES
1]
243
C
I
C C-
are
C C-
head
C C
head
tail
tail
C
i
I.
c
-h-
-K
C
1
cA
</\
acyclic
/>-cymene
structure
structure
c4Xc
/
1 C-ChC'.
A
c
<>
c
.
,'j'c-c-ci
|
i
;0
\\y
If we use these ideas with the sesquiterpene acyclic structure, then we find
that only three monocyclic and three bicyclic structures are possible (not
all are known; see the sesquiterpenes).
ORGANIC CHEMISTRY
244
[ch. VIII
C
I
\ C
/\ c
c
,1^
-Rx
C N \C^C-C-C-C
;C-c-c
/\
^ c
K"V^
c
'
'
V
c-hc-c-c
/N
c
J> v
/
c-c\
c
:
AA
c
k.
^^-A
\
>
--c
<
V\
C-C
c
Xc
o-C'
c-c
a
,c. 9
V< x \l/\
;T\
,','
c.-.'-c';
(/ xc
is
Wc.
c-c
c
/.c'v.
V
c
-CH 2 CH2
tail.
Me
O
Plants contain2. Isolation of monoterpenes and sesquiterpenes.
ing essential oils usually have the greatest concentration at some particular
In general, there are four methods of extractime, e.g., Jasmine at sunset.
tion of the terpenes: (i) expression; (ii) steam distillation; (iii) extraction
by means of volatile solvents; (iv) adsorption in purified fats (enfleurage).
Method (ii) is the one most widely used; the plant is macerated and then
steam distilled. If the compound decomposes under these conditions, it
may be extracted with light petrol at 50, and the solvent then removed
by distillation under reduced pressure. Alternatively, the method of adsorption in fats is used. The fat is wanned to about 50, and then the
flower petals are spread on the surface of the fat until the latter is saturated.
The fat is now digested with ethanol, any fat that dissolves being removed
by cooling to 20. The essential oils so obtained usually contain a number
of terpenes, and these are separated by fractional distillation. The terpene
hydrocarbons distil first, and these are followed by the oxygenated deDistillation of the residue under reduced pressure gives the
rivatives.
sesquiterpenes, and these are separated by fractional distillation.
TERPENES
4]
245
is
XIV).
4.
by
acid.
MONOTERPENES
The monoterpenes may be subdivided
ACYCLIC MONOTERPENES
Myrcene, C10H16 is an acyclic monoterpene hydrocarbon which occurs
and bay oils. It is a liquid, b.p. 166-168. Catalytic hydrogenation (platinum) converts myrcene into a decane, C^H^; thus myrcene
contains three double bonds, and is an open-chain compound. Furthermore,
since myrcene forms an adduct with maleic anhydride, two of the double
4.
in verbena
bonds are conjugated (Diels et al., 1929; see the Diels-Alder reaction, Vol. I).
This conjugation is supported by evidence obtained from the ultraviolet
spectrum of myrcene (Booker et al., 1940). These facts, i.e., that myrcene
contains three double bonds, two of which are in conjugation, had been
established by earlier investigators (e.g., Semmler, 1901). Ozonolysis of
myrcene produces acetone, formaldehyde and a ketodialdehyde, C 5 6 3
and the latter, on oxidation with chromic acid, gives succinic acid and
carbon dioxide (Ruzicka et al., 1924). These results can be explained by
assigning structure I to myrcene. In terpene chemistry it has become
customary to use conventional formulae rather than those of the type I.
In these conventional formulae only lines are used; carbon atoms are at
the junctions of pairs of lines or at the end of a line, and unsaturation is
indicated by double bonds. Furthermore, the carbon skeleton is usually
ORGANIC CHEMISTRY
246
[CH. VIII
OH,
CH3
CH=CH 2
C
;c=CHGH 2 CH2
CH
used in this book. Thus the process of ozonolysis and oxidation of the
ketodialdehyde may be written:
+ 2CII 2
XiHO
formaldehyde
acetone
H0
ketodialdehyde
/CO-jH
CHO
CH2
CH
.CHO
CO-
\o H
2
4a. Ocimene, Ci
b.p. 81/30 mm.
When catalytically hydro16
genated, ocimene adds on three molecules of hydrogen to form a decane.
Thus ocimene is an acyclic compound which contains three double bonds.
Furthermore, since ocimene forms an adduct with maleic anhydride, two
of the double bonds are conjugated.
On ozonolysis, ocimene produces
formaldehyde, methylglyoxal, lsevulaldehyde, acetic and malonic acids, and
some acetone. All of these products, except acetone, are accounted for by
structure I for ocimene (this has an wopropenyl end-group).
In order to
account for the appearance of acetone in the oxidation products, ocimene
,
/CHO + CH2
0.
I
CHO
CH.,
C02H
CH3CO ,H +
C^f,
COjjH
is
247
TERPENES
5]
is
mixture of I and
yGO^l
CH3 COCHO + CH 2
-
CH,
/
CH
CH,
N />
C
/\
r
CH
CH
CH
C
C
CH 3
II
isoprene units joined head to tail). Citral can be reduced by sodium amalgam to an alcohol, geraniol, C10 18O, and is oxidised by silver oxide to
geranic acid, C^H^Oa; since there is no loss of carbon on oxidation to the
acid, the oxo group in citral is therefore an aldehyde group (Semmler, 1890).
Oxidation of citral with alkaline permanganate, followed by chromic acid,
gives acetone, oxalic and laevulic acids (Tiemann and Semmler, 1895). Thus,
if citral has structure III, the formation of these oxidation products may be
CHO
C02H
CH3 CH3
C
II
CH 2
1
CH 2
COaH
C0 2 H
CO
CH 3
supported by the work of Verley (1897),
6-methylhept-5-en-2-one, IV, and acetaldehyde. The formation of these products
accounted
for.
This structure
is
ORGANIC CHEMISTRY
248
[CH. VIII
CHO + H 2
CHO
k 2 co 3
CH 3
CBr
CBr
I
CH,
C
CH 3/ CH3
CH3 /CHs
NaOH
+ NaCH(COCH3)r
CH
.CH 2
.CH 2
CH,
CH 2
CH 2 Br
CH3
CH.
CH(COCH3 2
)
CO
I
CH3
and Bouveault (1896) then converted methylheptenone into geranic ester, V,
by means of the Reformatsky reaction, using zinc and ethyl iodoacetate.
The synthesis of citral was completed by Tiemann (1898) by distilling a
/CHjj-COjjEt
'OH
(CH 3 CO) a O
-H0
,CH-COEt
(ca represents
TERPENES
5]
CH ,CH 3
"
tt
Tp
l^ila
O
V/
CHO +
+ H-COiCa
CH-COjjca
Methylheptenone was
249
QH, ,CH,
(ONa-liquidNHs
*rrrrr^
(ii)
H,0
"VV"^
"
C^-OH
CaCO,
Zn-Cu
"h^*~
(1948).
CH
tt 3
3
~\^./~
^OH
^CH
CH
CH2
CH3 CH 3
PBrj
II
CH
CH,
CH,
E.A.A.
synthesis
II
/ill
/
CH2 Br
CH
CH2
CO
I
CH3
Then the methylheptenone was treated with ethoxyacetylene-magnesium
bromide, the product reduced and then de-alkylated. It should be noted
CMgBr
+
CO
111
COC 2 H5
COC 2 H5
CHOC 2 H 5
Pd-BaSOi
^OH
HCl.
CHO
that an aUylic rearrangement occurs in both parts of this synthesis (see also
Ethoxyacetylenemagnesium bromide may conveniently be prepared
8).
from chloroacetaldehyde diethyl acetal as follows (Jones et al., 1954):
CH
Cl-CH(OC 2H 5 ) 2
i^ CH=C-OC H ^X BrMgC=C-OC H
2
250
Examination
ORGANIC CHEMISTRY
of the formula of citral
[CH. VIII
are possible:
mzHS- form;
as -form;
citral-a;
citral-6;
geranial
neral
CHO
CHO
has been regarded as a mixture of four substances, two geranials and two
Assuming, then, that both the wopropylidene and wopropenyl forms
nerals.
are present, it is possible that these two structures form a three-carbon
tautomeric system:
CH3
CH-C=CH~
CH,
=F^=
CH 2 =C-CH2
Recent work, however, has cast doubt on the existence of these two forms
According to infra-red spectroscopic studies, it appears that
naturally occurring acyclic monoterpenes as a class possess only the isopropylidene end-group structure (Barnard, Bateman et al., 1950). According to these authors, during oxidative degradation, partial rearrangement
from the t'sopropylidene to the wopropenyl structure occurs, and so this
in citral.
method
TERPENES
6]
251
CH3 CH 3
CH, /CH,
eft
CHCHO
CH 2 C-CH3
N
CH a
+ CH 3 COCH3
CH-CH=CHCOCH
CH
Ba(OH)j
CHjt
CH
h s so 1
(+2H s O)
C-CH3
2
f/-ionone
CH3 CH 3
X
; H
CH -CH=CHCOCH,
,CH=OHC6CH3
CH=CHCOCH,
:^>
p-ionone
a-ionone
since
.CH=CHCOCH 3
C0 2H
C02H
CO-CH3
C0 2 H
III
p-ionone
gave geronic acid, I, a a-dimethyladipic acid, II, and a a-dimethylsuccinic acid, III. On the other hand, a-ionone gave a mixture of
wogeronic acid, IV, /? 5-dimethyladipic acid, V, and a a-dimethylglutaric
acid, VI.
/5-ionone
CH=CHCO-CH3
C02 H
s
CO-CH3
COH
C02H
^COjjH
ORGANIC CHEMISTRY
252
Theimer
et al.
(1962)
[CH. VIII
,CH=CHCOCH,
graphy) from the mixture of ionones obtained above (this ionone corresponds
to the y-irone; see below).
The ionones are related to irone, C14 2aO; this occurs in the oil obtained
from the orris root. The structure of irone was established by Ruzicka
et al. (1947), who showed that on ozonolysis, irone gives formaldehyde and
y-trimethylpimelic acid, VIII also, reduction of irone with hydriodic
/3
/?
acid and red phosphorus, followed by dehydrogenation with selenium, gives
1:2: 6-trimethylnaphthalene, IX. Ruzicka therefore proposed structure
CH-CO-CH 3
fr
VII
VII
CH=CH-COCH,
,OH=CHCOCH
PH=CH-COCH3
y-irone
(J-irone
a-irone
The structural identity of geraniol and nerol is shown by the following facts.
Both add on two molecules of hydrogen when hydrogenated catalytically;
thus both contain two double bonds. Both give the same saturated alcohol,
C 10H22 O. Also, on oxidation, geraniol and nerol give the same oxidation
products which, at the same time, show the positions of the double bonds
to be 2 and 7 (cf. citral, 5). Thus geraniol and nerol are geometrical isomers. Geraniol has been assigned the trans configuration and nerol the cis
on the fact that cyclisation to a-terpineol (11) by means of dilute sulphuric
acid takes place about 9 times as fast with nerol as
it
253
TERPENES
8]
to the carbon
with nerol
(*)
which
is
is
OH
a-terpineol
geraniol
(trans-)
Nerol also occurs naturally in various essential oils, e.g., oil of neroli, bergamot, etc.; its b.p. is 225-226.
Knights et al. (1955) have found that, on ozonolysis, geranyl acetate gives
less than 3 per cent, of formaldehyde, and have concluded that the acetate
and geraniol itself have predominantly the isopropylidene structure (cf.
citral, 5).
toluene solution at 100 produces geranyl chloride, and this, when treated
with moist silver oxide in benzene solution, is reconverted into linalool.
These reactions are parallel to those which occur when crotyl alcohol is
treated with hydrogen bromide; a mixture of crotyl bromide and methylvinylcarbinyl bromide is obtained. When either of these products is treated
with moist silver oxide, a mixture of crotyl alcohol and methylvinylcarbinol
is
obtained.
H3-CH:CH-CH 2OH-i^CH3-CH:CH-OH2 Br +
CH3 CHBr-CH:CH2
CH 2 OH
geraniol
linalool
ORGANIC CHEMISTRY
254
[CH. VIII
NaNH 2
C2 H a
et al.,
C-ONa
Na
moist ether
(+)-linalool
step
by the
action of vinyl-
et al.,
1900).
OHO
crf\
C02H
( 0O 2 H
on oxidation.
rhodinal.
Thus structure
On
,C0 2 H
IHO
(
j
-2^CH20+CH3-C0 2 H +
C02 H
255
TERPENES
10]
compound
9a. Citronellol
and geranium
oils,
( )-Citronellol
occurs in rose
is
CH,OH
CH 2 OH
The (+)-form
MONOCYCLIC MONOTERPENES
10. Nomenclature.
For the purposes of nomenclature of the monocyclic monoterpenes, the fully saturated compound ^-methyHsopropylcyc/o-
10
CH3 CH3
CH
CH
CH2
af*
CH
CH 3
l
contains one or
a number which
To prevent ambiguity, the second carbon atom joined to the double bond is also shown,
A2 -^-menthene
/Kmenth-
p-mentha-
2-^-menthene;
i(7)-ene
l:4(8)-diene
-<menth-2-ene;
p-menthene-2.
256
ORGANIC CHEMISTRY
[CH. VIII
a-Terpineol
'->
Trihydroxy compound
V [Ketohydroxyacid]
II
>-
III
Keto-lactone
IV
warm
alk.
KMnO,
Terpenylic acid
^->Terebic acid
VI
+
CH3 -C02H
Oxidation of a-terpineol, I, with 1 per cent, alkaline potassium permanganate
hydroxylates the double bond to produce the trihydroxy compound II,
C 10 20O 3 This, on oxidation with chromic acid (chromium trioxide in
acetic acid), produces a compound with the molecular formula C 10 16 O 3
(IV).
This compound was shown to contain a ketonic group, and that it
was neutral, e.g., it gave no reaction with sodium carbonate solution. When,
however, IV was refluxed with excess of standard sodium hydroxide solution, and then back titrated, it was found that alkali had been consumed, the
amount corresponding to the presence of one carboxyl group. Thus compound IV appears to be the lactone of a monocarboxylic acid. Furthermore,
since it is the lactone that is isolated and not the hydroxy acid, this spontaneous lactonisation may be interpreted as being produced from a y-hydroxyacid, i.e., IV is a y-lactone, and therefore III is a y-hydroxyacid.
It is
possible, however, for (5-hydroxyacids to spontaneously lactonise, and so
whether IV is a y- or (5-lactone is uncertain at this stage of the evidence.
Now, since IV is formed from II by scission of the glycol bond, and since
TERPENES
lla]
257
OH
-OH
OH
OH
-CH3 C02 H +
/\
HO,C
CO>
there is no loss of carbon atoms in the process, the double bond must therefore be in the ring in I.
On warming with alkaline permanganate, IV gave
acetic acid and a compound C 8H, 2 4 (V).
The formation of acetic acid
suggests that IV is a methyl ketone, i.e., a CH 3 'CO group is present. Thus
IV is a methyl ketone and a lactone it is known as homoterpenyl methyl
ketone, and the structure assigned to it has been confirmed by synthesis
(Simonsen et al., 1932).
study of the properties of terpenylic acid, V,
showed that it was the lactone of a monohydroxydicarboxylic acid. Further
oxidation of terpenylic acid gives terebic acid C 7
10 O 4 (VI), which is also
the lactone of a monohydroxydicarboxylic acid.
The above reactions can be formulated as shown, assuming I (p-meaih.l-en-8-ol) as the structure of a-terpineol.
These reactions were formulated
;
CH 3
CH3
CH3
I
CO
CO
c s H,ONa
CO
CH 8 a-CQ 8 Ca H5
CH
OHNa
CH,
/ \
COsCijHs CH
C0 2C2H6
ICHsMgl
CO2C2H5
C02C2H 5
CH3
1
CH3
OH
hydrolysis
C02C2Hs CH2
C02 C2 H5
C0 2H
C02 H
ORGANIC CHEMISTRY
258
CHs
OH,
CO
CO
+ 2CH2 C1-C02 C 2 H 5
CH
[CH. VIII
90.
^"'^%
(2 steps)
CO2
C02C2 H 6 CH 2
C02C2H 5
CO2 2 H 6
CH,
CII 3
CO
HC1
CH
CH
C02H
CH
/ \CH
CH
II
COjCzHg
\zOH
hydrolysis
C-OMgl
1CH.M*!
CH
CH3
CH3
/ \ CH
CH
I
C02H
->.
hydrolysis
CH2
CH2
ketonic
,c-
C02 C2H5
COAH5 C02C 2 H6
lactonises
0O2 H
C02H
C02H
CO
terpenylic acid
It is of interest to note here that Sandberg (1957) has prepared the
/?-acetotricarballylate in one step from acetoacetic ester and ethyl bromoacetate in the presence of sodium hydride (in benzene solution).
These syntheses strengthen the evidence for the structure assigned to
This
a-terpineol, but final proof rests with a synthesis of a-terpineol itself.
has been carried out by Perkin, junior (1904), and by Perkin, junior, with
Meldrum and Fisher (1908). Only the second synthesis is given here; this
starts with ^-toluic acid.
C0 2H
CO,H
CO,H
C02 H
C0 2 H
KOH
H 2 SO,
feOjH
CH,
CH,
C0 2H
OH
C,H B OH
heat in
pyridine
HC1
f^HBr)
VII
() -a-terpineol
259
TERPENES
12]
Compound VII was also resolved with strychnine, each enantiomorph treated
as
shown above
(+)- and
(esterified, etc.),
and thereby
It should
( )-terpineol.
C0 2 H
C0 2 H
pyridine
CH,
VIII
the removal of a molecule of hydrogen bromide from 3-bromo-4-methylcycfohexane-1-carboxylic acid to give VII is an ambiguous step; instead of
VII, compound VIII could have been formed. That VII and not VIII is
formed rests on the analytical evidence for the position of this double bond;
VIII cannot give the products of oxidation that are actually obtained from
a-terpineol.
CH3
CH3
CO
CO
Hi
CH
>
^
w
^->.
(i)
CH
/ \
V-OH
CH2 ^pH
yPH
CHj
CH3
Two
CH.MgBr
(i,)acid
viz.,
OH
p-terpineol
m.p. 32-33
12.
\)H
-y-terpineol
m.p. (38-70
Carvone, CiH140, b.p. 230/755 mm. This occurs in various essenspearmint and caraway oils, in optically active forms and also
ORGANIC CHEMISTRY
260
QH3
A
i
.CH 3
OH
[CH. VIII
c=o
c
carvone
skeleton
The
H a so 4
may
be
NOH
The addition
hydrogen chloride from III by means of sodium ethoxide produces IV, and
on warming with dilute sulphuric acid, loses a molecule of water with
simultaneous hydrolysis of the oxime to form carvone, V. Thus, according
to this interpretation of the reactions, carvone is ^>-menth-6 8-dien-2-one.
Actually, these reactions show that carvone has the same carbon skeleton
as a-terpineol, and also confirm the position of the keto group. They do
not prove conclusively the positions of the two double bonds; instead of
position 6 (in IV), the double bond could have been 1(7), and instead of
position 8 (as in V), the double bond could have been 4(8). Thus the above
reactions constitute an ambiguous synthesis of carvone (a-terpineol has
already been synthesised). The exact positions of these two double bonds
have been determined analytically as follows.
The double bond in the disposition. The following reactions were carried
this,
out
vc
*
(+iH
(1895).
ui
Vi c
>
10
KMn 4
VII
Cio
COjjH
CrO s
cH,cOaH*
Ketonic
alcohol
Hydroxy
NaOBr
*
acid
Bra/HjO
190
|
.
VIII
c9
IX c
JoH
CH3
TERPENES
12]
261
CH3 CH2 OH
N
^-OH
CH3
X
C=0
JOH
VIII
OH
Had the double bond been in the 4(8)-position (structure V<z), then compound VIII, and consequently X, could not have been obtained, since
three carbon atoms would have been lost during the oxidation.
CH3-COCH3 +
>GR
ORGANIC CHEMISTRY
262
[CH. VIII
1900).
bond in the
6-position.
Had
.CO,H
C02 H
I
C02 H
CO
I
CH3
XIV
XIII
C02 H
COjjH
C02 H
CH3
XII
formic acid and not pyruvic acid would have been obtained. Further
support for the 6-position is provided by the work of Simonsen et al. (1922),
who obtained /9-wopropylglutaric acid and acetic acid on oxidation of carvotanacetone with permanganate.
known.
Since limonene adds on four bromine atoms, it therefore contains two
double bonds. (+) -Limonene may be prepared by dehydrating (+)-aterpineol with potassium hydrogen sulphate, and limonene (or dipentene)
may be converted into a-terpineol on shaking with dilute sulphuric acid.
OH
-HaO^
or
Thus the carbon skeleton and the position of one double bond in limonene
are known. The position of the other double bond, however, remains uncertain from this preparation; I or II is possible.
Proof for position 8. Structure I contains an asymmetric carbon atom
(C4 ), and hence can exhibit optical activity.
II is a symmetrical molecule
and so cannot be optically active. Therefore I must be limonene.
Chemical proof for position 8 is afforded by the following reactions:
Limonene
KOH
NOCl
> Limonene
nitrosochloride
f*-
carvoxrme
C.H.OH
I
III
IV
263
TEEPENES
13]
noci
OH
OH
+ 2HC1
(+)-
or (-)-
limonene
CH,
(CH3 2CC1
CI
CI
CH,
(CHskCCl
as
trans
-OCO-CH
CHs-COjAg
^OCO-CHa
264
ORGANIC CHEMISTRY
[CH. VIII
by the
action
OH
NaOH
^OH
p-terpinene
o-terpinene
b.p. 180-182
b.p.
173-174
all
give
y-terpinene
b.p.
69-73/20mm.
-OH
-H s O
Phellandrenes, C^H^.
are optically active,
and
all
o-phellandrene
b.p. 58-59/ 16
mm.
p-phellaudrene
b.p. 171-172
TERPENES
14]
265
It is isomeric
-OH
-H,Q
-OH
Further support for this structure is afforded by a study of the products
obtained by oxidation (Wallach et al., 1888, 1890, 1892). When oxidised
with potassium permanganate, cineole forms cineolic acid, II, and this, on
distillation with acetic anhydride, forms cineolic anhydride, III.
When
distilled at atmospheric pressure, cineolic anhydride forms 6-methylhept5-en-2-one, IV, a known compound (5). These reactions were interpreted
by Wallach
as follows:
C02 H- Hi,o O
Co],
jC02
II
Further work on the structure of cineolic acid has confirmed the above
sequence of reactions (Rupe, 1901,
).
It seems most probable that the 1 8-terpins have chair conformations,
but when they form 1 8-cineole, the latter possesses the boat conforma-
tion; thus:
cis-terpin
There
is also
l:4-cineole
b.p. 172
8-cineole
ORGANIC CHEMISTRY
266
[CH. VIII
Ascaridole, C 10 H 16 O s b.p. 96-97/8 mm. The cineoles are oxides ascarihowever, is a peroxide, the only known terpene peroxide, and it occurs
naturally in, e.g., chenopodium oil. When heated to 130-150, ascaridole
decomposes with explosive violence. When reduced catalytically, ascaridole forms 1 4-terpin (Wallach, 1912), and this led to the suggestion that
;
dole,
work.
( )- and ()-forms;
\ C
c
\ c-c
W-cymene skeleton
Subsequent work, however, showed that sylvestrene does not occur in pine
In the extraction of sylvestrene, the pine oil is heated with hydrogen
chloride to give sylvestrene dihydrochloride. This compound was shown
oil.
car-3-ene
sylvestrene
car-4-ene
TERPENES
16]
267
(see 21).
vestrene dihydrochloride.
16. Menthol and menthone. Menthol, C 10H ao O, is an optically active
compound, but only the ( )-form occurs naturally, e.g., in peppermint oils.
( )-Menthol, m.p. 34, is a saturated compound, and the functional nature
of the oxygen atom is alcoholic, as shown by its reactions, e.g., menthol
forms esters. Furthermore, since oxidation converts menthol into menthone, a ketone, the alcoholic group in menthol is therefore secondary. Also,
since reduction with hydrogen iodide gives />-menthane, menthol most probably contains this carbon skeleton. Finally, since (+)-pulegone gives menthol on reduction, and since the structure of pulegone is known to be I
(see 17), it therefore follows that menthol must be II.
This structure,
OH
^>-menth-3-ol, for menthol has been confirmed by consideration of the oxidation products of menthone (see below), and also by the synthesis of menthol.
Examination of the menthol structure shows that three dissimilar asymmetric carbon atoms (1, 3 and 4) are present; thus eight optically active
forms (four racemic modifications) are possible theoretically. All eight
enantiomorphs are known and their configurations are as follows (the horizontal lines represent the plane of the cycloh.exa.ne ring):
CH,
OH
CH,
OH CH(CHS 2
H(CH3
c:
)Z
Menthol
CH,
H(CH 3
O]
neo Menthol
)2
CH 3 OH CH(CH
li
OH H
/so Menthol
H H
I
neoiso Menthol
3)2
ORGANIC CHEMISTRY
268
[CH. VIII
menthol
These are the orders of rates actually obtained by Read et al. (1934). The
following conformations have been assigned by Eliel from chemical studies,
and are supported by Cole et al. (1956) from their infra-red spectra and
conformation studies.
'-Pr
OH
weoMenthol
Menthol
H
z-Pr
OH
Me
Me
woMenthol
OH
weoMoMenthol
In menthol, all of the substituents are equatorial, and in the rest one is
It should also be noted that the larger of the two alkyl groups {isopropyl) is always equatorial (cf. 11. IV).
Menthone, C10 18 O, b.p. 204/750 mm. ( )-Menthone occurs in peppermint oil, and it may readily be prepared by the oxidation of ( )-menthol
with chromic acid. Menthone is a saturated compound which has the
When heated with hydriodic acid
characteristic properties of a ketone.
and red phosphorus, menthone is reduced to ^-menthane; thus this skeleton
Oxidation of menthone with potassium permanis present in menthone.
ganate produces a compound C 10 18 O 3 this compound was shown to contain a keto-group and one carboxyl group, and is known as ketomenthylic
acid (IV). Ketomenthylic acid itself is very readily oxidised by permanganate to /?-methyladipic acid (V) and some other acids (Arth, 1886; Manasse
The foregoing oxidative reactions may be formulated as
et al., 1894).
This
follows, on the assumption that III is the structure of menthone.
axial.
C02 H
_[]_
TERPENES
17]
269
structure for menthone has been confirmed by synthesis, e.g., Kotz and
Schwarz (1907) obtained menthone by the distillation of the calcium salt of
/J'-methyl-a-/sopropylpinielic acid, which was prepared as follows.
3-Metbylc^c/ohexanone, VI, was condensed with ethyl oxalate in the presence of
sodium, and the product VII then heated under reduced pressure; this gave
the ethyl ester of 4-methylcyc/ohexan-2-one-l-carboxylic acid, VIII. VIII,
on treatment with sodium ethoxide followed by wopropyl iodide, gave IX,
and this when boiled with ethanolic sodium ethoxide and the product then
acidified, gave j8'-methyl-a-/sopropylpimelic acid,
(note the acetoacetic
ester fragment in VIII).
Structure III contains two dissimilar asymmetric carbon atoms (1 and
4), and so four optically active forms (and two racemic modifications) are
possible.
All are known, and correspond to the menthones and womenthones; these are geometrical isomers, each one existing as a pair of enantiomorphs. The configurations have been assigned on physical evidence; the
's-isomer has the higher refractive index and density (Auwers-Skita rule;
see 5 x. IV).
H 5\
!0 2 C 2
(i)C a HONa
+ (0O2C2 H5 2 J^
)
(ii)(CH 5 )jCHI
VII
VIII
C0 2 C 2 H 5
30 2 H
CjHONa
(i)
(ii)
HC1
Ca
CH -C02 H
2
o
(ch 3 ) 2 ch1L
"xf*
(CH 3 )2 CHl
H
CH,
as-isomer
trans- isomer
z'soMenthone
Menthone
oils.
3-one.
ORGANIC CHEMISTRY
270
[CH. VIII
pulegone
This structure has been confirmed by synthesis, starting from 3-methylcyc/ohexanone (Black et al., 1956: cf. menthone, 16).
(p-MeCH 4 'S03 H
catalyst)
pulegone
cyclic ketal
iwpulegone
This occurs in
18. (-)-Piperitone, C10 16 O, b.p. 232-233/768 mm.
eucalyptus oils, and is a valuable source of menthone and thymol. Piperitone contains one double bond, and behaves as a ketone. Piperitone, on
catalytic hydrogenation (nickel), gives menthone in almost quantitative
yield; on oxidation with ferric chloride, thymol is obtained (Smith et al.,
1920). These reactions show that piperitone is j!>-menthene-3-one, but do
C02 H
not show the position of the double bond. This had been shown by Schimmel (1910), who found that on oxidation with alkaline permanganate, piperitone gave a-hydroxy-a-methyl-aWsopropyladipic acid, II, y-acetyl-a-t'sopropylbutyric acid, III, and oc-t'sopropylglutaric acid, IV. These results
can be explained only if piperitone is -menth-l-en-3-one, I. This structure for piperitone has been confirmed by various syntheses (e.g., Henecka,
271
TERPENES
19]
1948; Birch
is
ketone.
BICYCLIC
The
19. Introduction.
MONOTERPENES
bicyclic
monoterpenes
may
Class
I (6-
+ 3-membered
ring).
CH 3
CH3
^CH
CH
l\
l\
CHA
>
^CH,
ClC
1
1
CH
.CH2
CH
^j^CH
CH3
CH3
CH3
carane
thujane
Class II
(6-
be divided into
being a six-
first
4-membered
ring).
CH 3
CH
CH2
-CH
CHj-C^HsJ
CH2
CH,
CH
pinane
Class III
(6-
+ 5-membered
ring).
CH3
CH2
|
CH 2
CHs-C-CHjl
CH 2
CH 2
..
CH3
CH2
CHg
^CH"Cji3
^CH
^CH
ixocamphane
camphane
CH
CH2
CH2
1
CH2
I/CH3
>
CH2
.C
^CH^
fenchane
CH2
CH2
CH3 C-CH3
CH-CH 3
CH2
|
^CH
zsobornylane
272
ORGANIC CHEMISTRY
[CH. VIII
It is important to note that the two rings do not lie in one plane, but are
almost perpendicular to each other (see, e.g., 23b).
The members
of this group
which
OH
a-thujene
21.
thujyl alcohol
Carane and
thujone
its derivatives.
umbellulone
It
sabinene
sabinol
car-3-eno
car-4-ene
car-3-ene-5:6-epoxide
Car-3-ene occurs
when
(+)-Car-4-ene,
It
(15)-
Car-3-ene-5 6-epoxide,
:
b.p. 83-85/14
mm., occurs
in certain essen-
tial oils.
dihydrocarvone
carone
TERPENES
22]
273
C0
V U2H
[Q]
>
HO
CH 3
CIJ3
CH 3
^ CN
Jl
CH
+ CH2 -COAH5
(Michae
condensation)
C02 C2 H5
^NxtfT^
OHTf
C a H B ONa
CH2 -C02 H
.CH3
^H
CH2
hydrolysis
^cOhCtH.
'
>
'
C02 C2H5
CH2 C 2H
CH 3/ f~
CH2 -C02 H
'
<
"
p:p-dimethylglutaric acid
^X CHErC0B
,m,
(CH3 ,)2C
c a H 8 OH
/CHBr-C02C2H5
.....
"(CH^Ctf
KOH
CHg-COBr
CH-C0 2 H
(CH&CT
^CHC0 H
2
An
trum
interesting point about carone is that its ultraviolet absorption specshows similarities to that of a : /9-unsaturated ketones (Klotz, 1941).
o-pinene
pinane
in
cis
and
p-pinene
tran$,
trans
and each
of these exists
ORGANIC CHEMISTRY
274
[CH. VIII
22a. a-Pinene.
It occurs in
oils; it is
acid (V). All these facts can be explained as follows, based on I being the
structure of a-terpineol (see also 11).
IV
pinol
pinol
hydrobromide
(III) is
sobrerol
sobrerythritol
terpenes
22a]
Thus,
275
the formula for oc-pinene is VI, then the formation of the above
substances can be explained. This structure also accounts for other reactions of a-pinene, e.g., its ready hydration to oc-terpineol (see later).
if
Although the Wagner formula (VI) for a-pinene readily explains all the
no direct evidence for the existence of the cyc/obutane ring.
Such evidence was supplied by Baeyer (1896)
This is described in method 2.
Method 2. As in method 1, a-pinene was shown to be bicyclic. When
treated with ethanolic sulphuric acid, a-pinene is converted into a-terpineol
(Flavitzky, 1879). Therefore a-pinene contains a six-membered ring and
another ring (since it is bicyclic), the carbon skeleton of pinene being such
as to give a-terpineoi when this second ring opens. Since, in the formation
of a-terpineol, one molecule of water is taken up and the hydroxyl group
becomes attached to C 8 this suggests that the C 8 of a-terpineol is involved
in forming the second ring in a-pinene. There are three possible points of
union for this C 8 resulting in two three-membered and one four-membered
ring (see VII) at the same time the position of the double bond in a-pinene
facts, there is
is
also
a-terpineol
(I).
A-OH
VII
Vila
A point of interest here is that there are actually four possible points of
union for C 8 the three shown in VII and the fourth being at the double
bond to form a four-membered ring (Vila)
This one, however, was rejected
on the grounds of Bredt's rule (1924) which states that a double bond cannot
be formed by a carbon atom occupying the bridge-head (of a bicyclic system).
The explanation for this rule is that structures such as Vila have a large
,
amount
of strain.
Xa0Br
1%
*
Pmene
alt.
a-Pinene
warm alk. .
KMnOj
glycol
J
Pio
Vio
VI
VIII
j
Pimc acid
t>-
r-TT-o
+ CHBr
,
c9
X
Pinene glycol, C 10H 18 (OH) a
who
(i)
KMn04
>-Pmomc
C10
acid
IX
Br,
(ii)
Ba(OH),
>
as-Norprnic acid
C8
XI
bond
ORGANIC CHEMISTRY
276
[CH. VIII
CH3
HOj
HO
[Q3
>
A
Y>|
C<
1
J?I^ C02H>
-*-CHBr3 +
VIII
C0 2 H
Ba(OH)2
CQ2H
COIpj
COjjH
[o]
H0 Cn
hcAK
hydroxypinic
bromopinic
acid
acid
The synthesis of norpinic acid (to confirm the above reactions) proved
to be a very difficult problem, and it was not carried out until 1929, when
Kerr succeeded with the following ingenious method (apparently the presence
of the gem dimethyl group prevents closure to form the cyc/obutane ring).
The norpinic acid obtained was the trans-isomer this is readily converted
into the 's-isomer (the isomer obtained from the oxidation of a-pinene)
;
by heating the trans acid with acetic anhydride, whereupon the cis anhydride
formed and this, on hydrolysis, gives the cis acid (Simonsen et ak, 1929).
is
CN
- TTT
CH2'C0 C2H5 +NH
3
(CHs CO +
_
CH2 C0 C2H6
2
)2
e thanol
'
solution
CN
-' CHCCk
ln C
NH
(CH
3 2
^CH-CO)
CN
CN
,C COv.
CN
lWcC>
C,H,ONa
Hch
3 )2
;nh
cv
"CNa-CO
I
CN
CH 2
Ia
(CH 3 ) 2 C^
pH
"CWX)'
CN
:nh
TEEPENES
22a]
277
/C02H
C^OjjH
(i)NaOH
^CI^COgH
ntf
/CH2
"(CH&C.
(15)Hci
C;C02 H
(CH 3
)2
C^ /CH
CH-C02H
C02 H
The
Guha
et al.
,C02 H
(i)HBr
.CH 2 OH
as-anhydride
rraMS-norpinic acid
^C02 H
hydrolysis
C0 2 H
C02 H
[C
"
.CH 2 -C^
(ii,KCN
l^CH
C02 CaH5
C02 C 2H5
C 3 H 5 OH
S^
^pCH
^^
partial
1
2
pinic acid
/!02 C 2 H5
/C0 C2 Hs
CO,H (i)soa.
*'
(ii)(c,H B a NH
|C
/COaH
QQ-NfCJi, v, H a so 4
{nr)
CH 3
CH3
CO
CO
CO-N(C6 H6 ) 2 (i)KOH^K
(i)SOCl a
(\
(ii)CH 3 CdCI
LT~J
0O-N(CS.l
[nr)
92H
(ii)HCl
rraws-pinonic acid
CH3
,0
ethyl pinonate
CHS
:
/C^ ^1CH-C0 2 C2H 5
j^COAHj
ac d
,-
>
glycidic ester
jas^j^pg^g^K^S.
278
ORGANIC CHEMISTRY
(Dieckmann
"T
/n/,N(CH
1
(ii)
A S OH
>
[\
OH^/\-^
\|/\x3 2C,H B
reaction)
(i)CH 3 I
)NH 8
(")
[CH. VIII
+
3 ) 3}
OH
distil
U nder
l"T~ J
j
reduced
pressure
,
a-pinene
8-pinene
The
final step gives a mixture of two compounds, a- and <5-pinene.
former was identified by the preparation of the nitrosochloride; this proves
that one of the products is a-pinene, but does not prove which is a and which
is d.
These are differentiated by consideration of the analytical evidence
the following evidence also supports the structure given for a-pinene. This
evidence is based on the fact that diazoacetic ester combines with compounds
containing a double bond to form pyrazoline derivatives, and these, on
heating alone or with copper powder, decompose to produce cyclopropane
When the two pinenes were subjected to this
derivatives (see also 2a. XII)
The
CHC0 C H
2
CH3 /G02 H
[o]
H0
C02H
COgH
CH-CQAHfr'
H0
8-pinene
treatment, and the resulting compounds oxidised, a-pinene gave 1-methylcyc/opropane-1 2 3-tricarboxylic acid, and <5-pinene cycfopropane-1 2 3tricarboxylic acid. These products are in accord with the structures assigned
to a- and <5-pinene.
Examination of the a-pinene structure shows that two dissimilar asymmetric carbon atoms are present; thus two pairs of enantiomorphs are
possible.
In practice, however, only one pair is known. This is due to
the fact that the f our-membered ring can only be fused to the six-membered
one in the m-position; trans fusion is impossible. Thus only the enantiomorphs of the cw-isomer are known.
Isomeric with a-pinene are |3- and <3-pinene; the former occurs naturally,
the latter is synthetic (see Ruzicka's synthesis)
Crowley (1962) has obtained
a small amount of /J-pinene by irradiating a one per cent, ethereal solution
of myrcene (4) with ultraviolet light. This is of some interest in connection
with the biosynthesis of terpenes (see 32a).
:
TERPENES
23a]
p-pinene
279
8-pinene
Camphane and its derivatives. Camphane, C^Hjg, is a syncompound, and may be prepared from camphor, e.g.,
(i) By reduction of camphor to a mixture of bomeols (23t>), these then
converted to the bornyl iodides which are finally reduced to camphane
23.
thetic
(Aschan, 1900).
Zn
CH,-CO a H
camphor
(ii)
camphane
Camphor may
also
Wolff-Kishner reduction
N-NH2 C,H,ONh
heat
Camphane
23a.
is
solid,
m.p. 156;
it is
"-
+N2
optically inactive.
Camphor. This
and Japan.
It is
solid,
to camphor.
The molecular formula of camphor is C10H 16O, and the general reactions
and molecular refractivity of camphor show that it is saturated. The
functional nature of the oxygen atom was shown to be oxo by the fact that
camphor formed an oxime, etc., and that it was a keto group was deduced
from the fact that oxidation of camphor gives a dicarboxylic acid containing
10 carbon atoms; a monocarboxylic acid containing 10 carbon atoms cannot
be obtained (this type of acid would be expected if camphor contained an
ORGANIC CHEMISTRY
280
(or
camphor) with
[CH. VIII
camphoronic
acid,
C 9H 14O e
(Bredt,
1893).
CH 3
CH3
CHjj C C0 2H
CHs C C0 H
\ H-2
7'A,(CH3) 2
9(CH3) 2
C02 H
it!0 2 iH
co2 h
,coh
I
Iheat
QH3
C02 + 2CH 3
CH3
CH-C0 H
\
C0 2 +
H C C0 H
2
II
C(CH3) 2
C02 H
III
2H
+C
Hence, if camphoronic acid has structure I, then camphoric acid (and camphor) must contain three methyl groups. On this basis, the formula of
The
camphoric acid, C 10 l6O4 can be written as (CH 3) 3C 5 5 (C0 2H) 2
parent (saturated) hydrocarbon of this is C 5 1? which corresponds to
CH 2, i.e., camphoric acid is a ryctopentane derivative (this agrees with
the previous evidence that camphoric acid is monocyclic). Thus the oxidation of camphoric acid to camphoronic acid may be written:
CH3
CH3
C(CH3
2C
-^U-
,0O2 H
CHjf C
+ 2 C02
C(CH 3 2
)
^X
C0 H C0 H
2
TERPENES
23a]
281
This skeleton, plus one carbon atom, arranged with two carboxyl groups,
will therefore be the structure of camphoric acid.
Now camphoric anhydride forms only one monobromo derivative (bromine and phosphorus)
therefore there is only one a-hydrogen atom in camphoric acid. Thus the
carbon atom of one carboxyl group must be X C (this is the only carbon atom
joined to a tertiary carbon atom). Furthermore, X C must be the carbon of
the keto or methylene group in camphor, since it is these two groups which
produce the two carboxyl groups in camphoric acid. The problem is now
to find the position of the other carboxyl group in camphoric acid. Its
position must be such that when the cyc/opentane ring is opened to give
camphoronic acid, one carbon atom is readily lost. Using this as a working
hypothesis, then there are only two reasonable structures for camphoric
H
H0
/
2 C'
IV
IVa
acid, IV and V.
IV may be rewritten as IVa, and since the two carboxyl
groups are produced from the
CH a CO group in camphor, the precursor
of IVa [i.e., camphor) will contain a six-membered ring with a gem-dimethyl
group. This structure cannot account for the conversion of camphor into
^>-cymene.
On the other hand, V accounts for all the facts given in the
foregoing discussion. Bredt therefore assumed that V was the structure
of camphoric acid, and that VI was the structure of camphor, and proposed
the following reactions to show the relationships between camphor, camphoric acid and camphoronic acid.
/V) H
'V) H^/\30 H
\s, C02 H
-CO.
H02C C02H
OH
Bredt, however, realised that if camphor had structure VII, then all the
foregoing facts would be equally satisfied, but he rejected VII in favour of
VI for a number of reasons. One simple fact that may be used here for
OH
CH(CH3 2
)
VII
VIII
rejection of VII is that camphor gives carvacrol, VIII, when distilled with
iodine.
The formation of this compound can be expected from VI but
Formula VI for camphor was accepted with reserve at the time when Bredt
proposed it (in 1893), but by 1903 all the deductions of Bredt were confirmed
by the syntheses of camphoronic acid, camphoric acid and camphor.
ORGANIC CHEMISTRY
282
[CH. VIII
00
(i)C a H,ONa
CH 3 I
(ii)
CH.
CH 3
CH3
CH,
C0
(i)C 3 H,ONa
CHCH3
(ii)
Zn + CH a BfCOjCjH|
*-
GH S
(Reformatsky
\
A/ntr
Xj(\/ki$)2
reaction)
coah
CO2C2H5
C02C2H B
CH3
CH3
^OH
/^^c^
C(CH
/C\
s'
Cm
^OZnBr
C(CH3 ) 2
CH2
acid,
(i)PCi.
3 )2
(ii)KCN
COAH5
C02C2H6
CO,H
C0 2H C02 H
Komppa (1899)
/S-dimethylglutaric ester as follows, starting with mesityl
synthesised
/3
CO2C2H5
(CH3)2 C=CHCOCH 3 +
CH 2 (C02 C 2 H5 )2
C'" 5 Na
>
^C02C2H5
(OH 3 ) 2 C
CH
^CH,
C0 2 C 2H6
^CH
^CH^
CO
(CH 3 ) 2 C
CjH 5 ONa
(i )
CH2
,CH 2
Ba(OH) a
OOHci
CH
*"
/CH -C0 H
-CHBr3+
(CH,) 2
C^
CH 2
^CO
T!0
NaOEr
^CO
(CH3) 2 C
.CH2 -C02C2H6
CiH , OH
2 rl5
oxide and ethyl malonate. The product obtained was 6 6-dimethyleycfohexane-2 4-dione-l-carboxylic ester (this is produced first by a Michael
condensation, followed by a Dieckmann reaction). On hydrolysis, followed
by oxidation with sodium hypobromite, /? /S-dimethylglutaric acid was
obtained (c/. carone, 21).
Komppa (1903) then prepared camphoric acid as follows:
:
CH2 C02C2 H6
CO2C2H5
C(CH S) 2
C02C2H6
CH2-C02C2H5
diketoapocamphoric
ester
TERPENES
23a]
HO.
V'VjO-A H5
(i)Na
(ii)CHjI
283
Na-Hg
NaOH
0^\ /C02C H5
2
HO
diketocamphoric
ester
/NjObH
/\x) H
2
HBr
C02H
J^ / C0 H
/^COgH
Zn
CH,C0 S H^
TpQM
\ /C<
The structure given for camphoric acid can exist in two geometrical
isomeric forms, cis and trans, neither of which has any elements of symmetry. Thus four optically active forms are possible; all are known, and
correspond to the (+)- and ( )-forms of camphoric acid and wocamphoric
acid.
Since camphoric acid forms an anhydride, and wocamphoric acid
does not, the former is the as-isomer, and the latter the trans- (5 i. IV).
CH 3
CO2H
C0 2 H
C0 2 H
CH 3
CH 3
camphoric acid,
m.p.l87
Synthesis of
acid prepared
thesised later
camphor
MO-camphoric acid,
m.p. 171-172
(Haller, 1896).
C0 2H
2
/N>CO
CH,COCl
KCN
camphoric
camphoric
anhydride
acid
J2 1
hydrolysis
X!H2 -CN
o-campholide
Ca
CH C02 H
salt
<lr
homocamphoric
acid
This
is
not
have had
an unambiguous
|/\iH -C02H
2
*\/C02H
p- campholide
IX
might
ORGANIC CHEMISTRY
284
[CH. VIII
In this case, homocamphoric acid would have had structure X, and this
would have given camphor with structure VII which, as we have seen,
was rejected. Sauers (1959) has now oxidised camphor directly to oc-campholide by means of peracetic acid. It is also of interest to note that
Otvos et al. (1960) have shown, using labelled
CH a -C*O aH (14 C), that in
the pyrolysis of the calcium salt of homocamphoric acid to camphor, it
is the labelled carboxyl group that is lost.
Camphor has two dissimilar asymmetric
Stereochemistry of camphor.
carbon atoms (the same two as in camphoric acid), but only one pair of
enantiomorphs is known. This is due to the fact that only the cw-form
is possible trans fusion of the gew-dimethylmethylene bridge to the cyclohexane ring is impossible. Thus only the enantiomorphs of the a's-isomer
camphor
way
of
borneol
isoborneol
is
is
obtained
by the sulphonation
()-Camphor-ji-sul-
acid.
is
iv
a-Pinene
...
(1)
HCl gas
>-
10
Bornyl
chloride
J
MoBornyl acetate
....
(n)
v
HCl
-r,.
gas
oc-Pmene
10
'
t.
-HCl
> woBorneol
> Bornyl
chloride
J
tsoBornyl
formate
J
CH-C0 2 Na
NaOH
> Camphene
r
'>
CH,-CO,Na
-HCl
> woBorneol
CH,-CO a H
>
HSO
Camphor
> Camphene
r
H-CO.H
O,
Ni; 200
> Camphor
r
>
TERPENES
23c]
285
borneol
m.p. 208-5
woborneol
m.p. 217
of the cyc/ohexane ring and the hydroxyl group is below the plane,
isoBorneol has the e#o-configuration in which the bridge and the hydroxyl
group are both above the plane of the cycfohexane ring (see also 23a).
Kwart et al. (1956) have now obtained direct evidence on the configuration of bornyl chloride.
Bornyl dichloride (I), the structure of which has
been established by Kwart (1953), is converted into bornyl chloride (II)
ethanol,
(III)
by sodium and
ethanol.
Na-Hg
EtOH
1^7*^^ I/
I
Na
EtOH
III
Both borneol and woborneol are produced when camphor is reduced, but
the relative amounts of each are influenced by the nature of the reducing
agent used, e.g., electrolytic reduction gives mainly borneol, whereas catalytic
hydrogenation (platinum) gives mainly woborneol; woborneol is also the
main product when aluminium wopropoxide is used as the reducing agent
(the Meerwein-Ponndorf-Verley reduction; see Vol. I).
Borneol is converted into a mixture of bornyl and wobornyl chlorides by the action of
phosphorus pentachloride. Borneol and wobomeol are both dehydrated to
camphene (23c), but the dehydration occurs more readily with woborneols
than with borneol. Both alcohols are oxidised to camphor, but whereas
borneol can be dehydrogenated to camphor by means of a copper catalyst,
woborneol cannot.
286
ORGANIC CHEMISTRY
[CH. VIII
apocamphoric acid when heated above its melting point implies that the
former contains two carboxyl groups attached to the same carbon atom
C02H
CH,CONa
-HC1
*"
*"
l^ C02H
iT^COaH
bornyl
camphene
carboxyapocamphoric
chloride
acid
apocamphoric
acid
malonic ester syntheses). These facts were explained by giving camphene the formula shown (I). The structure of apocamphoric acid was
later proved by synthesis (Komppa, 1901; cf. camphoric acid, 23a).
This structure for camphene, however, was opposed by Wagner. The
oxidation of camphene with dilute permanganate gives camphene glycol,
C10H 16 (OH) 2 [Wagner, 1890]. This glycol is saturated, and so camphene is
a tricyclic compound (so, of course, is structure I). On further oxidation
of camphene glycol, Wagner (1896, 1897) obtained camphenic acid, C10 16 O 4
(a dibasic acid), and camphenylic acid, C 10 16 O 3 (a hydroxy-monobasic
acid), which, on oxidation with lead dioxide, gave camphenilone, C 9 14
According to Wagner, it was difficult to explain the formation
(a ketone).
(c/.
of these
compounds
if
Wagner
I.
(1899) therefore
camphene
C=CH
H l/OH
?
a
CH.
\I/
N CH
N CH
,OH
vCH,OH
camphene
0Ji
A\yr-G0
H
(7
A\yO
camphenylic
camphenilone
glycol
III
carbocamphenilone
Camphenic
acid
VII
III,
IV
and
V, it was
Although it was easy to explain the formation of
The formation of VII was exdifficult to explain the formation of VII.
VI
287
TERPENES
23c]
plained by later workers, who suggested it was produced via carbocamphenilone, VI. Another difficulty of the camphene formula, II, is that it does
not explain the formation of apocamphoric acid when camphene is oxidised
with nitric acid (see above). The course of its formation has been suggested
by Komppa (1908, 1911), who proposed a mechanism involving a Wagner
rearrangement.
Structure II for camphene is supported by the fact that treatment of
bornyl iodide with ethanolic potassium hydroxide at 170 gives bornylene,
C10 16 (m.p. 98), as well as camphene (Wagner et al., 1899). Bornylene
is readily oxidised by permanganate to camphoric acid; it therefore follows
that bornylene has the structure I, the structure originally assigned to
camphene; no rearrangement occurs in the formation of bornylene.
KOH
to]
C,H e OH
bornyl
camphoric
bornylene
iodide
acid
et al.,
camphene.
+ CH2
II
Further support for this structure for camphene is afforded by the work of
Buchner et al. (1913). These workers showed that camphene reacts with
diazoacetic ester, and when the product is hydrolysed and then oxidised,
CO2C2H5
(i)
hydrolysis
Cxi)
oxidation
(Df
><L
COjjH
VIII
cycZopropane-1
COjJI
(i)
hydrolysis
(ii)
oxidation
CO,H
0O2 H
IX
C02 C,H5
ORGANIC CHEMISTRY
288
[CH. VIII
Lipp (1914) has synthesised camphenic acid (VII), and showed that it
has the structure assigned to it by Wagner. Finally, camphene has been
synthesised as follows (Diels and Alder, 1928-1931).
CHO
CHCHO
+
>-
11
CHO.
H 2 -Pd
(CH 3 CO),0
CH2
CHO-COCH,
CH 3 M g I
(i)NaNHa
(ii)
CH S
acid
(-H s O)
23d.
Wagner-Meerwein rearrangements.
(ii)
The conversion of
-,,
[~ :
^i
k
-a*_
*r=^
('
"J
*(-
TERPENES
23d]
(i) and (ii) are
same carbonium
289
Why
see later).
(iii)
to
camphene (with
acids).
$?*
(iv)
^=H^
0?'
cr
Me
Me 3 C CH 2 OH
-*
^- Me C CHr^Hg
Me 2 C CH2 Me
""'"-
Br"
Mef-C
CH
Me 2 0BrCH2 Me
Wagner-Meerwein rearrangement.
uct
CI
Their evidence for this mechanism was that the rate of the rearrangement was
and that the rate depended on the nature of the solvent, the rate
being faster the greater the ionising power of the solvent. The order observed
for some solvents was:
first order,
SO a > MeN0 8 > MeCN > PhOMe > PhBr > PhH > Et a O
This dependence of rate on solvent was more clearly shown by also studying
the solvolysis rates of triphenylmethyl chloride in the same solvents. It was
found that the rate of the rearrangement of camphene hydrochloride was faster
in those solvents in which triphenylmethyl chloride undergoes solvolysis more
readily.
Meerwein also found that the rearrangement was strongly catalysed
by Lewis acids such as stannic chloride, ferric chloride, etc. All of these form
complexes with triphenylmethyl chloride. Furthermore, halides such as phosphorus trichloride and silicon tetrachloride, which do not form complexes with
triphenylmethyl chloride, did not catalyse the rearrangement. Further evidence
ORGANIC CHEMISTRY
290
[CH. VIII
by Meerwein et al. (1927) and by Ingold (1928) also supports the mechanism
given above.
Meerwein, however, recognised a difficulty in his proposed mechanism. The
carbonium ion formed in the rearrangement of camphene hydrochloride would
presumably be the same as that formed in the rearrangement of pinene hydrochloride to bornyl chloride (example i). The reason why the epimers are obtained is not certain; one possibility is that the ions are not the same, and as
we shall see later, the ions are not identical if we assume there is neighbouring
group participation producing a non-classical carbonium ion.
Bartlett et al. (1937, 1938) showed that the rearrangement of camphene hydrochloride in non-hydroxylic solvents is strongly catalysed by hydrogen chloride,
and pointed out that the formation of Mobornyl chloride requires a Walden
inversion at the new asymmetric carbon atom. According to these authors, the
function of the hydrochloric acid is to help the ionisation of the chloride ion
(from the camphene hydrochloride). Evidence for this is that phenols have a
catalytic effect on the rearrangement rate of camphene hydrochloride, and that
the order of this catalytic activity of substituted phenols is the same as the
order of the increase in acid strength of hydrogen chloride which phenols promote
in dioxan as solvent. These catalytic effects were explained by Bartlett et al.
(1941) as being due to hydrogen bonding between the phenolic hydroxyl group
and the receding chloride ion.
Nevell et al. (1939) suggested that the type of resonance hybrid Z is involved
in the rearrangement. Thus the hydrogen chloride-catalysed reaction in the
_
Z+ can
inert solvents used would produce an ion-pair [Z+][HC1 2 ] (2e. III).
now
experimental work.
86 C1) exchange
(i) Nevell et al. found that the rate of radioactive chlorine (
between HC1* and camphene hydrochloride is 15 times faster than the rate of
rearrangement to isobornyl chloride. It therefore follows that the rate-determining step of the rearrangement is not the ionisation step, but is the reaction
It also follows, from the principle
of the bridged-ion with HCl a - at position 2.
of microscopic reversibility (Vol. I), that the rate-determining step of the rearrangement of wobornyl chloride back to camphene hydrochloride is the reaction with hydrogen chloride to produce the ion-pair directly.
(ii) On the basis of the bridged-ion being an intermediate in the rearrangement
in inert solvents and also for solvolytic reactions of both camphene hydrochloride
and wobornyl chloride, then both isomers should give the same products Meerwein et al. (1922) found that methanolysis, in the cold, of camphene hydrochloride
gave at first the J-methyl ether (attack at position 1) and this, on long standing,
gave Mobornyl methyl ether. woBornyl chloride also gave Mobornyl methyl
These results can be explained
ether, but in this case the reaction was slower.
by the presence of the liberated hydrogen chloride which would make the methanolysis reversible.
(iii)
23d]
TERPENES
291
CI
isobornyl
chloride
bornyl
chloride
attack the C+ (of the C CI) at the rear, thereby assisting ionisation; this neighbouring group participation cannot occur with bornyl chloride. Various representations of this bridged-ion are possible; I has been proposed by Winstein
et al.
(1952).
for the participation of a neighbouring saturated hydrocarbon radical has been obtained by Winstein et al. (1952) in their detailed
examination of some reactions of the parent norbornyl systems.
e#o-norbornyl
alcohol
endo-norbornyl
alcohol
These authors showed that the relative rates of acetolysis of the brosylates
(^-bromobenzenesulphonates) of exo/endo norbornyl alcohols in acetic acid at
25 are 350/1. The explanation offered for the large relative rate of the exoisomer acetolysis was neighbouring group participation to form the non-classical
carbonium ion (la). As the OBs~ ion is leaving from the front, the neighbouring
group (group C) can attack from the rear to form the bridged-ion. This
OBs
sequence
not possible as such for the <2o-compound, and so the latter reacts
Further support for the formation of (la) is as follows. This
ion has a plane of symmetry (see 16) and hence is optically inactive.
It has
been shown that solvolysis of e#o-norbornyl brosylate in aqueous acetone,
ethanol or acetic acid gives only &*o-products, but in these products the carbon
atoms have become " shuffled " (see below). Winstein et al. (1952) also showed
that acetolysis of optically active e#o-norbornyl brosylate gave racemic exonorbornyl acetate. Attack must be from the back of the CH bridge and so
2
this results in the e#o-product; also, since positions 1 and 2 are equivalent, equal
amounts of the enantiomorphs (i.e., racemate) will be produced.
When ewao-norbornyl brosylate undergoes acetolysis, ionisation of the OBsgroup leaves the ewao-norbornyl carbonium ion. This is probably originally the
far
is
more slowly.
292
ORGANIC CHEMISTRY
[CH. VIII
classical carbonium ion, but it then rearranges to the more stable e#o-bridgedion.
The formation of the latter is shown by the fact that acetolysis of the opti-
C-bridging
H-bridging
have both carbon and hydrogen bridging. Winstein (1955) has pointed out that
''
extra " carbon shuffling (to positions 5 and 6) depends on the nucleophilic
activity of the solvent, and is zero for very reactive solvents in which the life
of the carbonium ion is short. This suggests that the hydrogen shift competes
with the solvent attack and so occurs after the formation of the purely carbon
the
bridgedrion.
CO aH
CHO
HOC
(CH S
CH
L-glyceraldehyde
CH-C
-C0 2 H
l( )-methylsuccinic acid
l(
)-isopropylsuccinic acid
TERPENES
24]
(+)-camphor
H.
(+)-a-pinene
Me
293
(+)-limonene
(+)-aterpineol
H. Me
(-)-carvone
I
H Me
Hv Me
(X
OHC
O
Me2CH
CMe2
(-)-menthone
(+)-citronellal
trans-(+)-
tetrahydro-
carvone
Me 2CH 'H
d-(+)- methyl-
Me2CH
(+)-piperitone
phellandrene
succinic acid
HO,0
D-(+)-isopropyl-
succinic acid
Fenchane and
its derivatives.
The most important natural terfenchone; this occurs in oil of fennel. It is a liquid,
192-193, and is optically active, both enantiomorphs occurring
24.
is
b.p.
naturally.
ORGANIC CHEMISTRY
294
[CH. VIII
or
II
III
/Nx> h
^/X> H
2
IV
-H 1
The
or
by
UCOAH
,C02 C 2 H 6
(i)
Zn+CH 3 Br CO a C3H 8
(ii)
() PBr 3
(ii)
acid
HO
H
I0 2
(i)
CHg-COgCgHs
^
!0 2
HrPt
heat
y
(ii)
hydrolysis
CH2 C02H
CH2 C02H
co2 v
CH2 vv/
c2 ri5
H
j
Pb
salt
heat
(i)
Na
(ii)
CH,I
295
TERPENES
26]
SESQUITERPENES
25. Introduction. The sesquiterpenes, in general, form the higher boiling fraction of the essential oils; this provides their chief source. Wallach
(1887) was the first to suggest that the sesquiterpene structure is built up
of three isoprene units; this has been shown to be the case for the majority
of the known sesquiterpenes, but there are some exceptions.
The sesquiterpenes are classified into four groups according to the number
of rings present in the structure.
If we use the isoprene rule, then when three
isoprene units are linked (head to tail) to form an acyclic sesquiterpene
hydrocarbon, the latter will contain four double bonds. Each isoprene unit
contains two double bonds, but one disappears for each pair that is connected:
zingiberene (27a).
Class of
sesquiterpene
Number
Acyclic
Monocyclic
Bicyclic
Tricyclic
....
....
.
Molecular
of
double bonds
refractivity
|
4
3
69-5
67-8
66-1
64-4
2
1
1
J
This type of information can also be used with the monoterpenes, but in
this case it has not been so useful as in the sesquiterpenes.
It might be
noted here that the non-acyclic members of the sesquiterpenoid group may
have rings of various sizes: 4, 5, 6, 7, 9, 10 and 11 and in many of these the
;
ACYCLIC SESQUITERPENES
26. Farnesene, C^H^, b.p. 128-130/12 mm., is obtained by the dehydration of farnesol with potassium hydrogen sulphate (Harries et al.,
;-farnesene
/3-farnesene
ORGANIC CHEMISTRY
296
[CH. VIII
This compound is the oc-isomer, and it has now been shown that
1913).
the /S-isomer occurs naturally (in oil of hops), and Sorm et al. (1949, 1950)
have assigned it the structure shown. /S-Farnesene is also obtained by the
dehydration of nerolidol.
NH,OH
(i)
(ii)
(CHs-CO)sO
farnesal
farnesol
KOH
farnesenonitrile
geranylacetone
farnesenic acid
CH 2OH
o
CHO
CHO
(cf.
linalool, 8).
TERPENES
27]
nerolidol
297
farnesol
,CH 2 C1
+ CHjCOCHa-COaCaHs
CH-COAHs
COCH
geranyl chloride
(i)
(ii)
Ba(OH) a
HC1
(i)
co-cH3
*
NaNH
c "; CH
;i:'
(in) HjO
geranylacetone
() -nerolidol
MONOCYCLIC SESQUITERPENES
27. Bisabolene, C^H^, b.p. 133-134/12 mm., occurs in the oil of
myrrh and in other essential oils. The structure of bisabolene was determined by Ruzicka et al. (1925). Bisabolene adds on three molecules of
hydrogen chloride to form bisabolene trihydrochloride, and this regenerates
bisabolene when heated with sodium acetate in acetic acid solution. Thus
bisabolene contains three double bonds and is therefore monocyclic (see 25).
Nerolidol may be dehydrated to a mixture of a- and /?-farnesenes (cf. 26).
This mixture, on treatment with formic acid, forms a monocyclic sesquiterpene (or possibly a mixture) which combines with hydrogen chloride to
form bisabolene trihydrochloride. Removal of these three molecules of
ORGANIC CHEMISTRY
298
[CH. VIII
OH - H >
p-farnesene
a-farnesene
nerolidol
l/Cl
(i)
H-COgH
(ii)
+ 3HC1
Lei
-3HC1
/CI
biaabolene trihydrochloride
III
II
y-bisabolene
p-bisabolene
-bisabolene
Ruzicka et al. (1929) showed that synthetic and natural bisabolene conmainly of the y-isomer (III), since on ozonolysis of bisabolene, the
products were acetone, laevulic acid and a small amount of succinic acid.
These products are readily accounted for by III; and this structure has
been confirmed by synthesis (Ruzicka et al., 1932).
sisted
bonds
fact that zingiberene shows optical exaltation* whereas dihydrozingiberene does not. The absorption spectrum of zingiberene also shows
the presence of conjugated double bonds (Gillam et al., 1940).
Ozonolysis of zingiberene gives acetone, laevulic acid and succinic acid
(Ruzicka et al., 1929). Since these products are also obtained from bisabolene (27), it appears probable that zingiberene and bisabolene have the
same carbon skeleton. Oxidation of dihydrozingiberene, I, with permanganate gives a keto-dicarboxylic acid, C 12 20O 5 (II), which, on oxidation
by the
TERPENES
28]
299
C0 2 H
C02H
CO-CH3
XC 2H
CO,H
III
Thus
will
G02 CH3
C
III
C-C02CH3
C-C02CH3
C02CHs
COuCHs
C02 CH3
27b.
Humulene
(o-caryophyllene),
membered
C 15H 24
b.p.
264,
is
an eleven-
Its structure is
OAc
humulene
pyrethrosin
which con-
BICYCXIC SESQUITERPENES
b.p. 134-136 /11 mm.,
d^,
Catalytic hydrogenation
28. Cadinene,
in oil of cubebs, etc.
hydrocadinene,
C15 Hag
ORGANIC CHEMISTRY
300
[CH. VIII
bicyclic.
On dehydrogenation with sulphur, cadinene forms cadalene,
C15 H 18 (Ruzicka et ah, 1921). Cadalene does not add on bromine, and
forms a picrate. This led to the belief that cadalene was an aromatic
compound, and its structure was deduced as follows. Ruzicka assumed
that the relationship of farnesol (26a) to cadinene was analogous to that
Furthermore, since dipentene gives
of geraniol (7) to dipentene (13).
^>-cymene when dehydrogenated with sulphur, then cadalene should be, if
the analogy is correct, 1 6-dimethyl-4-wopropylnaphthalene; thus:
:
CH2 OH
geraniol
farnesol
p-cymene
dipentene
cadalene
cadinene
skeleton
et
al.
(1922),
CH 2
CH2 -C0 2 C 2 H5
Zn
acid
CH 2 BrC02 C 2 H 6
(-H 2 0)
C02 H
OH
!H2
(i)
HBr
(ii)
CHyCNafCOaCaHaJa
C(C0 2 C2 Hs 2
)
0H3
CHCH3
C02 H
301
TERPENES
yCH*CH3
COGl
(i)
Na-C t H u OH
(ii)
distillation
CH3
Thus cadinene has the carbon skeleton assumed. The only remaining
is to ascertain the positions of the two double bonds in cadinene.
Since the molecular refractivity shows no optical exaltation, the two double
problem
bonds are not conjugated (11. 1) this is supported by the fact that cadinene
not reduced by sodium and amyl alcohol. Ozonolysis of cadinene produces a compound containing the same number of carbon atoms as cadinene.
The two double bonds are therefore in ring systems, but they cannot be in
the same ring, since in this case carbon would have been lost on ozonolysis.
Ruzicka et al. (1924) were thus led to suggest I (a or /?) for the structure of
cadinene, basing it on the relationship of cadinene to copaene, which had
been given structure II by Semmler (1914). I was proposed mainly on the
;
is
II
two molecules
of
H-C=C-C
c
I
CH,
COOaH
>
H-C-Cc-c
CH 3 -MgCI
H-C C-C
I
c
c' H '
-H a O
c=c-c
I
I
OH
CH,
Thus the positions of the additional methyl groups show the positions of
the double bonds in cadinene. The Ruzicka formula for cadinene would
give dimethylcadalene III (from the a isomer) or IV (from the /?), and the
monomethylcadalenes would be
(from a or /9), VI (from a) and VII (from
Campbell and Soffer oxidised their dimethylcadalene, first with chromic
fi).
acid and then with nitric acid, and thereby obtained pyromellitic acid
302
ORGANIC CHEMISTRY
[CH. VIII
VIII
VII
the two methyl groups at positions 6 and 7 in ring B, could give VIII.
Therefore the double bond in cadinene in ring B is 6 7. From this it
follows that VI is also eliminated. If the double bond in ring A is as in
structure I, then dimethylcadalene is IV, and monomethylcadalene is
or VII. Campbell and Softer synthesised IV and VII, and found that each
was different from the methylcadalenes they had obtained from cadinene.
Thus IV and VII are incorrect; consequently the double bond in ring
cannot be 3 4. The only other dimethylcadalene which could give VIII
on oxidation is IX. This was synthesised, and was found to be identical
with the dimethylcadalene from cadinene. Cadinene must therefore be X,
and the introduction of one or two methyl groups may thus be formulated
:
V
A
as follows:
X could
oxidised)
TERPENES
28a]
303
It should be noted, in passing, that this new structure for cadinene has
necessitated revision of the structure of copaene. Briggs and Taylor (1947),
using a technique similar to that of Campbell and Soffer, have assigned
the following structure to copaene.
copaene
The
now
28a. Selinenes, C 1B M
Selinene occurs in celery oil; when treated
with hydrogen chloride, it forms a dihydrochloride which, when warmed
with aniline, is converted into the compound C^H^. This is isomeric with
selinene, and the natural compound was called /3-selinene, and the synthetic
isomer a-selinene (Semmler et al., 1912). Semmler showed that the catalytic
hydrogenation of the two selinenes gives the same tetrahydroselinene, C 1S 28
Thus they each contain two double bonds, and are tricyclic. Ozonolysis
of /3-selinene produces a diketone (I) with the loss of two carbon atoms,
and oxidation of I with sodium hypobromite gives a tricarboxylic acid (II),
with the loss of one carbon atom. From this it follows that I contains a
group. Ozonolysis of a-selinene gives a diketo-monocarboxylic
CHg'CO
acid (III) with loss of one carbon atom, and III, on oxidation with sodium
hypobromite, loses two carbon atoms to form II. Thus III contains two
CHj'CO groups (Semmler et al, 1912). Ruzicka et al. (1922) distilled
/S-selinene with sulphur, and thereby obtained eudalene (see 28b for the
evidence for the structure of this compound). If we use the isoprene rule,
all the foregoing facts are explained by giving the selinenes the following
structures (Ruzicka et al., 1922). The relationship of the selinenes to
eudesmol (28b) confirms the nature of the carbon skeleton given to the
.
selinenes.
eudalene
NaOBr
NaOBr
CHg-CO
C02H
CH3 -CO'
C02 H
H0 C
2
II
ORGANIC CHEMISTRY
304
[CH. VIII
Catalytic hydro28b.
genation converts eudesmol into dihydroeudesmol, C 15 28 0. Thus one
double bond is present in the molecule, and since eudesmol behaves as a
tertiary alcohol, the parent hydrocarbon is Ci 6 28=CH2,i-2; eudesmol is
therefore bicyclic. When dehydrogenated with sulphur, eudesmol forms
eudalene, C 14 16 and methanethiol (Ruzicka et al., 1922). Eudalene behaved as an aromatic compound (cf. cadalene, 28), and its structure was
deduced as follows. Since eudalene was a naphthalene derivative, and
since it contained one carbon atom less than cadalene, it was thought to
be an apocadalene, i.e., cadalene minus one methyl group. Thus eudalene
is either l-methyl-4-wopropylnaphthalene (II) or 7-methyl-Wsopropylnaphthalene (la). To test this hypothesis, Ruzicka oxidised cadalene with
in eucalyptus
oil.
2,
which must
C0 2 H
JU
C02 H
cadalene
soda lime
be I or II. Distillation of this acid with soda-lime gives a methyh'sopropylnaphthalene which must be la or Ha. Ha was synthesised from carvone
(the synthesis is the same as for cadalene except that ethyl malonate is
used instead of ethyl methylmalonate see 28). The synthetic compound
(Ha) was found to be different from the hydrocarbon obtained by the
Thus the apocadalene
distillation of the naphthoic acid from cadalene.
obtained must be la, i.e., 7-methyl-l-wopropylnaphthalene.
Ruzicka now found that eudalene was not identical with either la or lla.
On oxidation, however, eudalene gives the same naphthalenedicarboxylic
acid as that which is obtained by the oxidation of la. This is only possible
if in eudalene the two side-chains in la are interchanged, i.e., eudalene is
;
l-methyl-7-Mopropylnaphthalene
thus
[o].
COH
la
CO,H
2
eudalene
et al.,
1922).
28b]
TERPENES
HO
v_|T
+ BrCH2 -COAH5+
305
CHOH
N
CH8
Zn^^^
COjCjHs
cuminal
CH
-HjjO
y-\J
Na-C 2 H 6 OH
(i)HBr
C02C 2 H,
CH2 CN
eudalene
To develop the
is
^C
III
Now
A
c
combines with hydrogen chloride to form selinene dihydrois also obtained by the action of hydrogen chloride on
eudesmol (Ruzicka et al., 1927, 1931). Since eudesmol contains one double
bond and a tertiary alcoholic group, it follows that the double bond must
be in the side-chain, and the hydroxyl group in the ring, or vice versa, i.e.,
/S-selinene
chloride,
IV,
or
which
VI
HCl
CI
p-selinene
selinene
dihydrochloride
or
OH
ORGANIC CHEMISTRY
306
[CH. VIII
Hydrogenation of eudesmol forms dihydroeudesmol, VII, and this, on treatchloride followed by boiling with aniline (to remove
a molecule of hydrogen chloride), gives dihydroeudesmene, VIII. VIII, on
ozonolysis, forms 3-acetyl-5 9-dimethyldecalin, IX, with the elimination of
one carbon atom. These results are explained if IV or V is the structure
of eudesmol, but not by VI. Thus the hydroxyl group is in the tsopropyl
side-chain.
VIII
VII
The final problem is to ascertain the position of the double bond in eudesmol,
Ozonolysis of eudesmol showed that eudesmol
i.e., Is the structure IV or V?
is a mixture of IV (a-eudesmol) and V (/3-eudesmol), since two products are
obtained: a hydroxyketo-acid X, with no loss of carbon, and a hydroxyketone XI, with the loss of one carbon atom (but cf. citral, 5).
OaH
OH
IV
CH,
o-eudesmol
O,
CHjjO
OH
V
p-eudeamol
The proportions
OH
y -eudesmol
28c. Caryophyllene,
C 15H 24
b.p. 123-125/10
mm.,
is
a bicyclic sesqui-
caryophyllene
TERPENES
29]
isocaryophyllene
307
santonin
and y-caryophyllene, but it has now been shown that the a-isomer is
identical with humulene (27b) the /S-isomer (the main hydrocarbon) is called
caryophyllene; and the y-isomer (which is believed to be produced by thermal
a-,
ft-,
isomerisation) is
Santonin
Acorone
is
known
as isocaryophyllene.
(cf.
pyrethrosin,
a most interesting bicyclic sesquiterpene in that it is a carboexample of such a compound to be found in nature.
is
or
may
OH
Na a CQ 3
solution
ryc/odecane-1 6 -dione
:
C,H B OH
azulene
Azulene
is
decane.
Two
its systematic name is bicyclo[5 3 0]sesquiterpenes containing this bicyclodecane skeleton are
OH
Azulene
is
vetivone
guaiol
2 (aromatics
0@>
dipolar structure
I,
Ch.
XX).
It
ORGANIC CHEMISTRY
308
[CH. VIII
DITERPENES
30. Phytol, C 20 H 40 O, b.p. 145/0-03 mm.,
produced from the hydrolysis of chlorophyll
an acyclic diterpene; it is
XIX), and it also forms
part of the molecules of vitamins E and K (see Ch. XVII). The reactions
of phytol showed that it is a primary alcohol (Willstatter et al., 1907), and
since on catalytic reduction phytol forms dihydrophytol, C 20 H 42 O, it thereThus the parent hydrofore follows that phytol contains one double bond.
carbon is C 20H 42 (=C B H 2m+2 ), and so phytol is acyclic. Ozonolysis of phytol
(F. Fischer et al.,
gives glycolaldehyde and a saturated ketone, C 18 H 36
1928). Thus this reaction may be written:
Ci 8
is
(6.
36
The formula
CH3
CH3
CH3
CH3
CH 3
CH3
JHj-Pd
CrLi3
CILi
CH3 -CH-(CH 2
(-*H 3
I
)3
|PBr 3
CHq3
OHo
Cxi5
I
CHa-CH-CCH^-CH-CCHj^-CH-CHa-CHaBr
III
CH 3 -CH-(CH2
)3
CH s CO-CHNhCOjCjH 6
CH3
CH3
CH3
CH3 -CH-(CH2
C0 2 C 2 H 5
hydrol\-sis
ch 3
ch3
CHq
^CO-CHj
IV
phorus tribromide, gives hexahydrofarnesyl bromide, III. Ill, on treatment with sodio-acetoacetic ester, followed by ketonic hydrolysis, forms
the saturated ketone, IV. This ketone (IV) was then converted into phytol
as follows (F. Fischer et al., 1929) it should be noted that the last step
involves an allylic rearrangement (cf. linalool, 8).
;
TERPENES
31]
CH3
CH3
CH3
CH3
309
CH3
IV
|0>)
NaNHj
)CH=CH
CH 3
CH 3 -CH-(CH2
)3
CH-(CH2
Oxio3
CH-*3
CH 3 -CH-(CH2
)3
vri*
i
OH
(CH 3 CO) 2
CH3
CH3
C=CH
OH
CH-(CH2 ) 3 C
-
Crln3
CH,
CH,
CH,
CH3
CH3
phytol
It
appears that natural phytol has a very small optical rotation; Karrer
(1943) have isolated a (-f)-form from nettles.
et al.
C20H 30O 2
m.p. 170-174,
is
tricyclic
diterpene.
The non-steam volatile residue from turpentine is known as rosin (or colophony), and consists of a mixture of resin acids which are derived from the
diterpenes.
Abietic acid is one of the most useful of these acids.
C02 H
abietic acid
Me'
C02 H
great amount of work was done before the structure of abietic acid
elucidated.
For our purpose it is useful to have the structure of abietic
acid as a reference, and then describe the evidence that led to this structure.
I is the structure of abietic acid; the system of numbering is shown, and
also the four isoprene units comprising it.
This way of numbering abietic
acid follows the phenanthrene numbering. There has been recently, however, a tendency to bring the numbering of all diterpenes in line with the
steroids (3. XI); this is shown in la.
In the following discussion I has
been used (the reader should work out the change-over for himself).
The general reactions of abietic acid showed that it was a monocarboxylic
acid.
On dehydrogenation with sulphur, abietic acid gives retene (Vesterberg, 1903) ; better yields of retene are obtained by dehydrogenating with
selenium (Diels et al., 1927), or with palladised charcoal (Ruzicka et al.,
Retene, CigHjg, m.p. 99, was shown by oxidative degradation to
1933).
was
ORGANIC CHEMISTRY
310
[CH. VIII
CIVCO^
+ (CH3 ) 2
CHBr^UCH3)2CH ~Y
(CH3) 2CH
ch 3 oh
H0 C
A1C1 3
(CH 3 ) 2CH
CH2
(i)CH 3 M g I
CH
C N /XR^
CH a
CH,
(CH 3 ) 2 CH-
CH,-CC~
fl
HI _ P
(CH3 ) 2 CH
HjSO
C-CH,
H0
GH
CH,
(OH3) 2 CH
(CH 3
)2
Zn-Hg (CH 3 ) 2
CH
CH-XV\
XXX
CH.
retene
V
N
cr
Now
this
carbon skeleton
is
present in abietic
Thus:
it is
known
CH(CH3
)2
Nc
and
TERPENES
31]
311
vii.
X).
It is therefore
atoms lost may have been originally the carband an angular methyl group.
Abietic acid is very difficult to esterify, and since this is characteristic of
a carboxyl group attached to a tertiary carbon atom, it suggests that abietic
acid contains a carboxyl group in this state. This is supported by the fact
that abietic acid evolves carbon monoxide when warmed with concentrated
sulphuric acid; this reaction is also characteristic of a carboxyl group
attached to a tertiary carbon atom.
possible that the two carbon
oxyl group (in abietic acid)
C2oH 34
C^H^
.C0 2 H
J2L
C0 2H
II
III
312
ORGANIC CHEMISTRY
aCHs
j^
XJOaH
C0 2H
*"
[o]
H
C-C0 2H
x-COgH
CH,
II
COoH
/\0O H
C02H
Structure
[CH. VIII
VI
1937).
H
H
Thus:
,CH,OH
/X^CHg
CoH
PC1 5
_EL
methyl abietate
abietinol
"methyiabietin"
DCH(CH3) 2
homoretene
It has already been pointed out that abietic acid has two double bonds.
Since abietic acid forms an adduct with maleic anhydride at above 100, it
was assumed that the two double bonds are conjugated (Ruzicka et al.,
It was later shown, however, that levopimaric acid also forms the
1932).
same adduct at room temperature. It thus appears that abietic acid isomerises to levopimaric acid at above 100, and then forms the adduct.
Thus this reaction cannot be accepted as evidence for conjugation in abietic
Nevertheless, the conjugation of the double bonds in abietic acid
acid.
has been shown by means of the ultraviolet spectrum, which has not only
shown the conjugation, but also indicates that the two double bonds are
not in the same ring (Kraft, 1935; Sandermann, 1941).
Oxidation of abietic acid with potassium permanganate gives, among
other products, wobutyric acid (Ruzicka et al., 1925). This suggests that
one double bond is in ring C and the 6 7- or 7 8-position. If the double
bond is in the 6 7-position, then the other double bond, which is conjugated with it, must also be in the same ring (5 13 or 8 14) if 7 8,
then the other double bond could be in the same ring C, but it could also
:
TERPENES
32]
313
,C02H
,CO(,H
CH(CH3
CH(CH3
)2
:7-
)2
7:8-
be in ring B.
0 H
COjjH
CH-CO
abietic acid
sapietic acid
(levopimaric acid)
adduct
TRITERPENES
32. Squalene, C 30 50 b.p. 240-242/4 mm., has been isolated from the
liver oils of sharks.
Other sources are olive oil and several other vegetable
,
(nickel) converts
in squalene:
CH3
=CH-CH2-CH2 -C=
Since squalene cannot be reduced by sodium and amyl alcohol, there are
no conjugated double bonds present in the molecule. Perhydrosqualene
was found to be identical with the product obtained by subjecting hexahydrofarnesyl bromide to the Wurtz reaction. This led Karrer et al.
(1931)
to synthesise squalene itself from farnesyl bromide by a Wurtz reaction.
ORGANIC CHEMISTRY
314
[CH. VIII
CH 3
CH3
CH 3
CH3
CH3
>-
CH3
+
MgBr2
be noted that the centre portion of the squalene molecule has the
two isoprene units joined tail to tail (cf. the carotenoids, Ch. IX). Squalene
forms a thiourea inclusion complex, and hence it has been inferred that it
It should
is
the
a.U.-trans
stereoisomer (Schiessler
et al.,
1952).
This
is
supported by
1954).
When the units have been chosen, the next problem is to consider the
types of reactions whereby the natural products are synthesised in the
organism. The general principle is to use reactions which have been developed in the laboratory. The difficulty here is that some types of laboratory reactions require conditions that cannot operate in the organism, e.g.,
carboxylation and decarboxylation are known biological processes, but when
carried out in the laboratory, these reactions normally require elevated
temperatures. Deamination is also a known biological process, but in the
laboratory this reaction is usually carried out under conditions of (pB)
which would be lethal to the living organism. These differences between
laboratory syntheses and biosyntheses are due to the action of enzymes in
the latter. According to Schopf (1932), syntheses in plants may take place
through the agency of specific or non-specific enzymes (see 12-17. XIII),
or without enzymes at all. Chemical syntheses (these do not involve the
use of enzymes) must therefore, from the point of biosynthetic studies, be
carried out under conditions of pH and temperatures comparable with those
operating in plants. Chemical syntheses performed in this way (with the
suitable units) are said to be carried out under physiological conditions (which
involve a pH of about 7 in aqueous media and ordinary temperatures).
Reactions which are commonly postulated in biosynthesis are oxidation,
hydrogenation, dehydrogenation, dehydration, esterification, hydrolysis,
carboxylation, decarboxylation, amination, deamination, isomerisation, condensation and polymerisation. It might be noted here that the choice of
TERPENES
32a]
315
and type of reaction are usually dependent on each other. Furthermore, other reactions which are known to occur in biological syntheses are
O- and iV-methylation or acylation. These may be described as extra-skeletal
processes, and can occur at any suitable stage in the postulated biosynthesis.
Another extra-skeletal process is C-methylation, but this is much rarer than
those mentioned above.
Now let us apply these principles to the biosynthesis of terpenes. As
we have seen, according to the special isoprene rule, terpenes are built up
of isoprene units joined head to tail (1).
Assuming then that the isoprene
unit is the basic unit, the problem is How is it formed, and how do these
units join to form the various types of terpenes?
At present it is believed
that the fundamental units used in the cell in syntheses are water, carbon
dioxide, formic acid (as " active formate "), and acetic acid (as " active
acetate "). These " active " compounds are acyl derivatives of coenzyme A
(written as CoA H in the following equation); e.g., acetoacetic acid is
believed to be formed as follows:
units
in the methyl group (Cm ) and in the carboxyl group (C c) has led to the suggestion that the carbon atoms in the isoprene unit are distributed as follows:
Cm.
CmCc
-Cc
Cm/
This distribution
)CH-CH 2 -"C0 2H
"CHj/
Tavormina et al. (1956), however, have shown that the lactone of mevalonic
acid (/3-hydroxy-/3-methyl-<5-valerolactone) is converted almost completely
into cholesterol by rat liver, and is a much better precursor than senecioic
acid.
The following scheme has therefore been proposed for the early stages
in the biosynthesis of terpenes; it is in agreement with the distribution of
the carbon atoms in cholesterol (see above):
Me
Me
CO
CoA
Mc COCoA
Me
\ /
HO^
CO
>-
CH 2
>
CH
CH,
HO
\ c ^-Me
CH,
^CH,
COCoA
COCoA
C0 2 H
CHO
CO.H
HMG
leucine
Me
Me
CH
Me
COCoA
=^^=
CH
I
COCoA
HO.
CH 2
I
C0 2 H
CH 2
.Me
^CH 2
CH 2 OH
MVA
C0 2 H
senecioic acid
ORGANIC CHEMISTRY
316
[CH. VIII
acid (MVA), possibly through the intermediate mevaldic acid (Rudney et al.,
1958; Lynen, 1959). Support for this sequence is afforded by the following
facts.
has been isolated from natural sources (Wolf et al., 1957), and
it is also known that
may be formed from leucine by the route shown
(Lynen et al., 1958, 1959).
The biosynthesis of terpenes can be subdivided into three definite steps:
(i) the formation of a biological wopentane unit from acetate
(ii) the condensation of this unit to form acyclic terpenes (iii) the conversion of acyclic
into cyclic terpenes.
The stages leading to
have been discussed above. What happens
after this is uncertain.
One suggestion is that
forms a pyrophosphate
(at the primary alcoholic group), and then the carboxyl and the tertiary
hydroxyl group are eliminated simultaneously to form wopentenyl pyrophosphate (I). This isomerises to the wopropylidene compound, /? /3-dimethylallyl pyrophosphate, which combines with (I) to form the pyrophosphate of the acyclic terpene geraniol (in the following equations P
represents the pyrophosphate residue, P 2 6 3 ):
MVA
HMG
MVA
MVA
CHO
CH
/OH
CH/
CO aH
|
CH,
NMe
CH
^J\Nvie
I
XH OP
Hv
-t>
POCH
il
Me/
Nvie
This
is
labelled
PhCOCH(C0 2 Et) 2
SS^U-
PhC=C(C0 2 Et) 2
-^^*-
OBs
p>
\C r X
CoBs
C0""2
This provides one of the mildest known methods for making an acetylenic bond,
and this reaction may be regarded as support for the mechanism proposed by
Jones (1961) as a possible route for the biosynthesis of acetylenic bonds:
TERPENES
33]
317
C0 2 H
MeCOCH
XiOCoA
enzyme
**
ft
Me^
J^
^j>
"
+ OP
bOCoA
POLYTEKPENES
33. Rubber. Rubber {caoutchouc) is obtained from latex, which is an
emulsion of rubber particles in water that is obtained from the inner bark
of many types of trees which grow in the tropics and sub-tropics. When
the bark of the rubber tree is cut, latex slowly exudes from the cut. Addition of acetic acid coagulates the rubber, which is then separated from the
liquor and either pressed into blocks or rolled into sheets, and finally dried
in a current of warm air, or smoked.
Crude latex rubber contains, in addition to the actual rubber hydrocarbons (90-95 per cent.), proteins, sugars, fatty acids and resins, the amounts
of these substances depending on the source.
Crude rubber is soft and
sticky, becoming more so as the temperature rises.
It has a low tensile
strength and its elasticity is exhibited only over a narrow range of temperature.
When treated with solvents such as benzene, ether, light petrol, a
large part of the crude rubber dissolves the rest swells but does not dissolve.
This insoluble fraction apparently contains almost all of the protein
impurity. On the other hand, rubber is insoluble in acetone, methanol, etc.
When unstretched, rubber is amorphous; stretching or prolonged cooling
causes rubber to crystallise.
Structure of rubber. The destructive distillation of rubber gives isoprene as one of the main products; this led to the suggestion that rubber is
a polymer of isoprene, and therefore to the molecular formula (C
This
6
8) n
molecular formula has been confirmed by the analysis of pure rubber. Crude
rubber may be purified by fractional precipitation from benzene solution by
the addition of acetone. This fractional precipitation, however, produces
molecules of different sizes, as shown by the determination of the molecular
weights of the various fractions by osmotic pressure, viscosity and ultracentrifuge measurements; molecular weights of the order of 300,000 have
been obtained.
The halogens and the halogen acids readily add on to rubber, e.g., bromine
gives an addition product of formula (C
5
g Br 2 ), and hydrogen chloride
the addition product (C 5 9 C1). Pure rubber has been hydrogenated to the
fully saturated hydrocarbon (C
5
10)this is known as hydrorubberby
heating with hydrogen in the presence of platinum as catalyst (Pummerer et
al., 1922).
Rubber also forms an ozonide of formula (C 5 8 3). All these
addition reactions clearly indicate that rubber is an unsaturated compound,
and the formulae of the addition products show that there is one double
bond for each isoprene unit present.
Ozonolysis of rubber produces laevulaldehyde and its peroxide, lsevulic
acid and small amounts of carbon dioxide, formic acid and succinic acid
(Harries, 1905-1912).
Pummerer (1931) showed that the hevulic derivatives
comprised about 90 per cent, of the products formed by the ozonolysis.
This observation led to the suggestion that rubber is composed of isoprene
units joined head to tail. Thus, if rubber has the following structure, the
formation of the products of ozonolysis can be explained:
;
ORGANIC CHEMISTRY
318
CH3
[CH. VIII
CH,
CH,
CH,
13
CH,3
^Xl
CH3
Some
of the laevulaldehyde
is
-C=O + OCHCH2
acids.
CH 3
\
.CH 2
\ /
C
4-72 A (obs.)
5:04 A (theor.)
II
8-10 A
fobs.)
9-13A
(theor.)
/CH2
CH2
,CH3
CH 2
\
C
CH^
CH3
/\H
CH,
yCH
c
II
CH2
CH2
rubber
gutta-percha
cis-form
trans-iorm
1942) have shown that rubber is composed of long chains built up of isoprene
units arranged in the cw-form, whereas gutta-percha is the trans-iorm.
TERPENES
33b]
319
sticky than crude rubber, and is not so soluble and does not swell so
in organic solvents.
Furthermore, vulcanised rubber has greater
tensile strength and elasticity than crude rubber.
The mechanism of vulcanisation is still not clear. Vulcanised rubber is
not so unsaturated as rubber itself, the loss of one double bond corresponding
approximately to each sulphur atom introduced. It therefore appears that
some sulphur atoms enter the chain, vulcanisation thus occurring through
intramolecular and intermolecular cross-links; it is the latter type of reaction
that is desirable in vulcanisation. It should be noted that not all the
sulphur is in a combined state some is free, and this can be readily extracted.
Vulcanisation may be accelerated and carried out at lower temperatures
These compounds are conin the presence of certain organic compounds.
sequently known as accelerators, and all of them contain nitrogen or sulphur,
or both, e.g.,
is less
much
NH=CT
.NH-C8H 5
ff
(CH3 ) 2 N-C-S-S-C-N(CH3 ) 2
NHCe*H
H,
6
tetramethylthiuram
diphenylguanidine
II
II
(CH3 ) 2 N- C-S-Zn-S-C-N(CH3 )2
disuJphide
C-SH
zinc dimethyldithiocarbamate
mercaptobenzothiazole
320
ORGANIC CHEMISTRY
[CH. VIII
of hydrogen chloride to form Chloroprene (2-chlorobuta3-diene), the addition taking place in accordance with Markownikoff's
rule (see also Vol. I).
1
2CHEEECH
>
CH 2=CHC=CH
HC1
>-
CH
=CHCC1=CH
Chloroprene readily polymerises to a rubber-like substance known as Neoprene. Actually, the nature of the polychloroprene depends on the conditions of the polymerisation.
Silicone rubbers. These are chemically similar to the silicone resins.
The chief silicone rubber is prepared by treating the hydrolysis product of
dimethyldichlorosilane, (CH 3 ) 2 SiCl 2 with various compounds capable of increasing the molecular weight without the formation of cross-links, i.e.,
they produce long-chain molecules.
,
Si(CH OSi(CH
3) 2
3)
j-0-Si(CB,) 2
Silicone rubbers have very high electrical insulating properties, and do not
deteriorate on exposure to light and air, and are resistant to the action of
acids and alkalis.
READING REFERENCES
The Terpenes, Cambridge University Press (2nd ed.). Sir John Simonsen and Owen.
Vol. I (1947); Vol. II (1949). Sir John Simonsen and Barton. Vol. Ill (1952).
Sir John Simonsen and Ross. Vol. IV. (1957); Vol. V. (1957).
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1953). Vol. IV, Ch. 7. The Terpenes.
Rodd (Ed.), Chemistry of the Carbon Compounds, Elsevier, (i) Vol. IIA (1953). Ch. 11.
Rubber and Rubber-like Compounds (p. 407). (ii) Vol. IIB (1953). Chh. 12-16.
Terpenoids.
Mayo, Vol.
I.
Mono- and Sesquiterpenoids. Vol. II. The Higher Terpenoids. Interscience (1959).
Pinder, The Chemistry of the Terpenes, Chapman and Hall (1960).
Ruzicka, History of the Isoprene Rule, Proc. Chem. Soc, 1959, 341.
Ginsburg (Ed.), Non-Benzenoid Aromatic Compounds, Interscience (1959). Chh. V, VI.
Azulenes.
Streitwieser, Solvolytic Displacement Reactions at Saturated Carbon Atoms, Chem.
Reviews, 1956, 56, p. 698 (Wagner-Meerwein Rearrangements).
Barton, The Chemistry of the Diterpenoids, Quart. Reviews (Chem. Soc), 1949, 3, 36.
Gascoigne and Simes, The Tetracyclic Terpenes, Quart. Reviews (Chem. Soc.), 1955,
9, 328.
Barton and Mayo, Recent Advances in Sesquiterpenoid Chemistry, Quart. Reviews
(Chem. Soc), 1957, 11, 189.
Halsall and Theobald, Recent Aspects of Sesquiterpenoid Chemistry, Quart. Reviews
(Chem. Soc), 1962, 16, 101.
Progress in Organic Chemistry, Butterworths. Vol. 5 (1961). Ch. 4. The Chemistry
of the Higher Terpenoids.
Ciba Foundation Symposium on the Biosynthesis of Terpenes and Sterols, Churchill
(1959).
Robert Robinson, The Structural Relations of Natural Products, Oxford Press (1955).
Downes, The Chemistry of Living Cells, Longmans, Green (2nd ed., 1963).
Birch, Some Pathways in Biosynthesis, Proc. Chem. Soc, 1962, 3.
Gee, Some Thermodynamic Properties of High Polymers and their Molecular InterSir
CHAPTER IX
CAROTENOIDS
The carotenoids are yellow or orange pigments which
1. Introduction.
are widely distributed in plants and animals. Chlorophyll is always associated with the carotenoids carotene and lutein the carotenoids act as photosensitisers in conjunction with chlorophyll.
When chlorophyll is absent,
e.g., in fungi, then the carotenoids are mainly responsible for colour.
Carotenoids are also known as lipochromes or chromolipids because they are
fat-soluble pigments.
They give a deep blue colour with concentrated sulphuric acid and with a chloroform solution of antimony trichloride (the
Carr-Price reaction) this Carr-Price reaction is the basis of one method of
the quantitative estimation of carotenoids.
Some carotenoids are hydrocarbons; these are known as the carotenes. Other carotenoids are oxygenated derivatives of the carotenes; these are the xanthophylls. There are
also acids, the carotenoid acids, and esters, the xanthophyll esters.
Chemically, the carotenoids are polyenes, and almost all the carotenoid
hydrocarbons have the molecular formula C40 66
Also, since the carbon
skeleton of these compounds has a polyisoprene structure, they may be
regarded as tetraterpenes (cf. 1. VIII).
In most of the carotenoids, the central portion of the molecule is composed
of a long conjugated chain comprised of four isoprene units, the centre two
of which are joined tail to tail. The ends of the chain may be two openchain structures, or one open-chain structure and one ring, or two rings.
The colour of the carotenoids is attributed to the extended conjugation of
the central chain (see Vol. I). X-ray analysis has shown that in the majority
of natural carotenoids, the double bonds are in the tfras-position a few
natural carotenoids are cis-. Thus, if we represent the ends of the chain by
(where
may be an open-chain structure or a ring system), tfraws-caroteHes
may be written:
;
CH 3 H
CH 3 H
AVvSVvvvy*
i
If
we
H
i
CH3 H
i
CH3 H
(4.
will
Carotenes.
carrots (this
two
ORGANIC CHEMISTRY
322
[CH. IX
Biosynthetic studies of the carotenes have been carried out, and the pathways
are those for the terpenes (32a. VIII). Thus Braithwaite et al. (1957) and
Grob (1957) have shown that labelled mevalonic acid is incorporated into /Scarotene. Scheuer et al. (1959) have also shown that this acid is incorporated
into lycopene. Furthermore, Modi et al. (1961) have isolated mevalonic acid
from
carrots.
p-Carotene, C40 66 When catalytically hydrogenated (platinum), /3carotene forms perhydro-/S-carotene, C 40 78 Thus /J-carotene contains eleven
double bonds, and since the formula of perhydro-/?-carotene corresponds to
the general formula CH 2 -2, it follows that the compound contains two rings.
When exposed to air, /?-carotene develops the odour of violets. Since
this odour is characteristic of jS-ionone, it was thought that this residue is
present in /J-carotene (see 6. VIII). This was confirmed by the fact that
the oxidation of a benzene solution of /3-carotene with cold aqueous potas3.
among
/3-ionone.
Now
/3-ionone,
!H=CH-CO-CH3
o.
on ozonolysis,
I,
et al.,
gives,
1929).
CO-C02 H
COCH
II
/S-Carotene,
"
CH,3
.CH=CH-C=
CH3
=OCH=CH
l:
TOjjH
CO-CH,
II
C02 H
[O]
\ H [o] H0 C ^XJOjH
C0 H
2
>
IV
CAROTENOIDS
3]
323
CH
CH=
(a);
CH
CH
CH
CH
CH
CH
CH
toluene
CH C / \>CHS
N
CH
or
1
CH
CH
CH3-cL
C-CH
^CH
^CH
GB. 3
"
CH
f\
L
\/
7K-xylene
1:5
1:3
(c)
CH yCH
CH CH C-CHj
ch 3 -c
II
II
/CH
xm
xm
CH
CH /C
CH
-C
CH
^CH
CH CH /-CHj
X CH 'CH
2:6- dimethylnaphthalene
1:6
1:8
ORGANIC CHEMISTRY
324
[CH. IX
The
following symmetrical structure for /S-carotene would satisfy the require(a), (b) and (c)
the tail to tail union of the two isoprene units at
the centre should be noted.
ments of
CH3
<?H3
CH3
=CH-C=CH-CH=CH-C=CHCH=CH-CH
234
10
11
<jJHs
C-CH= =CH-CH=C-CH=CH12 13
14
15
-1:5-
-1:6-
-1:5-
(*)
(c)
(*)
16
17
18
This symmetrical formula for /S-carotene has been confirmed by the following oxidation experiments (Kuhn et al., 1932-1935). When /S-carotene is
oxidised rapidly with potassium dichromate, dihydroxy-/5-carotene, VI, is
obtained and this, on oxidation with lead tetra-acetate, gives semi-/3carotenone, VII, a diketone. Since both VI and VII contain the same number
of carbon atoms as /S-carotene, it follows that the double bond in one of the
fi-ionone rings has been oxidised; otherwise there would have been chain
scission had the chain been oxidised.
Oxidation of semi-/S-carotenone with
chromium trioxide produces /S-carotenone, VIII, a tetraketone which also has
the same number of carbon atoms as /S-carotene. Thus, in this compound,
the other /S-ionone ring is opened. Now only one dihydroxy-/S-carotene
and one semi-|S-carotenone are obtained, and this can be explained only by
assuming a symmetrical structure for /S-carotene. Thus the oxidations may
be formulated:
,CHCH-
p-carotene
\X)-CH CHCO-CH3
VII
O-CH CH-CO
,COCH3 CH3-CON
VIII
This structure for /S-carotene has been confirmed by synthesis, e.g., that of
Karrer et al. (1950). The acetylenic carbinol IX is treated with ethylmagnesium bromide and the product is treated as shown on opposite page.
CAROTENOIDS
3]
325
CH3
H=CH-C-CH2 -C=CH
OH
IX
CjHjMgBr
CH3
!H=CH-C-CH2 -C=C-MgBr
OMgBr
CH,
CH3
CH3
OH
OH
Hj-Pd
CH3
CH,
OH
OH
J2
p-CH 3 -C 6 H 4 'SO s H
(-H a O>
CH3
CH,
p -carotene
jg
prepared by Isler (1949) by treating pMonone with propargyl
bromide in the presence of zinc (cf. the Reformatsky reaction):
IX has been
CH,
CH=CHCO + CH 2 BrCHCH
Zn
CH3
CH=CHC-CH 2-C=CH
OH
A/
IX
ORGANIC CHEMISTRY
326
[CH. IX
.'__> CH 3 -CHOH-CeeC-Ce^C-CHOH-CH 3
2CH 3 -CHOH-C=CH - CuCl-NH.Cl
7-dione)
UAIBt
>
,,
MnO,
CH 3 -CHOH-CH=CH-CH=CH-CHOH-CH 3
Zn
CH 3 -CO-CH==CH-CH==CH-CO-CH 3 CH.COjH
CH 3 -CO-CH 2 -CH=CH-CH 2 -CO-CH 3
>
^V C(OH)-CH=CH
C(OH)-CeeeC
worth while at
methods have been divided into four groups according to the carbon content
+ C + C 19
An example
(1957)
[% =
by the
C 16
OH
BrMgC s=CMgBr
OHO
OH
OEt
HC(OEt),
P5SJ
OEt
B/ \f
CH(OEt) a +
(EtO) 4
CHv/\/Rp
jzhCl,
EtO
OEt OEt
0Et
OEt
OEt OEt
lAcOB
I'
Im-1P-Y reduction
H
(i) allylio rearr.
(ii)
and dehydration
partial hydrogenation"
(MY
stereomutatioit
jS-carotene
jS-ionine ring]:
+ C + C16
327
CAROTENOIDS
5]
An
example of the fourth group makes use of the Wittig reaction (see crocetin,
9 for an illustration of this method).
[Karrer
et al.,
1933].
,CH=CH-CO-CH,
CH-C0 2H
[O],
COCH
CO-CH3
'COjjH
a-ionone
isogeronic acid
of a-carotene is:
CH
CH3
CH
CH
!H=CH-C=CH-CH=CHC=CHCH=CHCH=CCH=CH-CH=CCH=CH N
3
As we have
CH,
=CH-OCH2-C=CH
I
OH
It is interesting to
et al.,
1947); this
is
an example of
three
carbon prototropy.
175, is a carotenoid that is the tomato pigSince the structure of y-carotene depends on that of lycopene, the
latter will be discussed here, and the former in the next section.
On catalytic hydrogenation (platinum), lycopene is converted into perhydrolycopene, C 40 82 Therefore lycopene has thirteen double bonds, and
is an acyclic compound (Karrer et al., 1928).
Ozonolysis of lycopene gives,
among other products, acetone and lsevulic acid; this suggests that lycopene
contains the terminal residue:
5.
ment.
H.C
CH,^
I
i
CH3
I
I
acetone
-
methylheptenone
[CH. IX
ORGANIC CHEMISTRY
328
facts.
CH 3
CH 3
CH
=
CH-CH=CH-C=CH-CH
(CH3 2 C=CH-CH2 -CH z -C=CH-CH=CH-i
3
CH 3
CH 3
CH3
lycopene
Cr 03
J
CH3
CH3
CHO-CH=CH-C=CH-CH=CH-C=CH-CH
(CH 3 2 C=CH-CH2 -CH 2 -C=0 +
CH
methylheptenone
(CH3 )
CH
2 C=CH
|l
CH3
CH3
lycopenal
Cr0 3
i
CH
CH3
CHO-CH=CH-C=CH-CH=CH-C=CH-CH
+
(CH^C^HCHs-CTVcUo CHO-CH=CH- C=CH-CH=CH-C=CH-CH
CH 3
CH3
methylheptenone
3
CH3
bixindialdehyde
(i)
NH 2 0H
(HXCHa-COJaOG-HjO]
)
hydrolysis
CH3
CH3
C0 2 H-CH=CH-C=CH-CH=CH- C =CHCH
0O 2 H- CH=CH-C=CH-CH=CH- C=CH-CH
CH3
norbixin
CH
CAROTENOIDS
6]
329
The
CH3
^C(CHS 2
OH CH-CH=CH-C-CH 2 CsCH
OH
CH2 C-CH,
)
y-Carotene, C40 H 66
into perhydro-y-carotene,
C40H 80
CHS
<j!H 3
CH,
CH3
(CH^q
H=CH-C=CH-CH=CHC=CH-CH=CH-CH=CCH=CH-CH=C-CH=CH-CH
CH3 C
y-carotene
CHS
CH,
This structure for y-carotene is supported by the fact that the absorption
maximum of y-carotene in the visible region lies between that of /5-carotene
and that of lycopene. Final proof for this structure has been obtained by
the synthesis of y-carotene (Karrer et al., 1953) the following reactions are
written with the conventional formulae (see 1):
;
,CsCMgBr
OMgBr +
BrMgO
.0
y-carotene
BrMgC=C
ORGANIC CHEMISTRY
330
<5-carotene
isolated,
and
this
et al.,
[CH. IX
human
that of /3-carotene. This provitamin nature of /3-carotene led to the suggestion that vitamin A t is half the molecule of /3-carotene.
On catalytic hydrogenation, vitamin Ax is converted into perhydrovitamin
C20 40O; thus vitamin t contains five double bonds. Since
t
vitamin x forms an ester with ^-nitrobenzoic acid (this ester is not crystalThus the
lisable), it follows that vitamin A x contains a hydroxyl group.
parent hydrocarbon of vitamin t is C 20 H4 and consequently the molecule
molecule of
contains one ring. Ozonolysis of vitamin
produces one
geronic acid (3) per molecule of vitamin A lt and so there must be one /Sionone nucleus present (Karrer, 1931, 1932). Oxidation of vitamin x with
permanganate produces acetic acid; this suggests that there are some
C(CH 3)=?= groups in the chain. All of the foregoing facts are in keeping
with the suggestion that vitamin x is half the /3-carotene structure. When
heated with an ethanolic solution of hydrogen chloride, vitamin A x is converted into some compound (II) which, on dehydrogenation with selenium
Heilbron
forms 1 6-dimethylnaphthalene, III (Heilbron et al., 1932).
assumed I as the structure of vitamin A lt and explained the course of the
reaction as follows:
A
A
HCl-CjH 5 OH
CH3
CH
CH3
CH=CH-C=CH-CH2 OH
CHs
CH3T
OH=CH-C=CHCH2 OH
II
Se
At
Perhydrovitamin
identical
CAROTENOIDS
7]
331
The following synthesis is that of Isler et al. (1947). This starts with methyl
vinyl ketone to produce compound IV, one stage of the reactions involving
Preparation of IV.
CH3
CH3
N
CH^CH-C^O
;;?,
NHj
T^H
CH2=CH-C-C^CH
ONa
OH3
CHi=CH-C-C=CH
H,S *
>
^+
CH3
CH2 OH-CH=C-CsCH
OH
CH 3
C a H B M s Br
^BrMgOCH2 CH=C-C=CMgBr
IV
Preparation of V.
<pH3
CH=CH-O0
+
,ON
Hr C Hhquid
>
CHj,C]
C0z2 C*^
z
2
CH3
CH=CH-C CH-C0
.
2 C 2 H6
'
,'
in
NH,
CH3
CH3
.CH=CH-CH-CO-COs|H
heat with
hydrolysis
!H=CH'CH-CHO
Cu
powder under
red. press.
CH3
CH2 -CH=C-CHO
isomerises
an
Compound
is prepared from
(cf. 8. VIII).
of the Darzens glycidic ester reaction (see also Vol. I).
The following chart shows the steps of the synthesis, and it should be noted
that another allylic rearrangement is involved in one of the later steps.
allylic
/S-ionone
rearrangement
by means
ORGANIC CHEMISTRY
332
Combination of
IV and
V,
[CH. IX
etc.
CH3
CH3
BrMgCsC-0=CH-CH 2 OMgBr
CH2 -CH=OCHO + BrMeCsOO=(
IV
CH
CH 3
CH9 -CH=C-CH-C=C-C=CH-CH2 OH
3
OH
VI
iH a -Pd- BaSOa
CH3
OH
/ CH 2 -OH=C- CH- CH=CH-C=CH-CH
OH
vil
CH3
l(CH,-CO) a O
CH
CH3
OH
vm
trace of Ig in benzene solution
?H3
CH3
,-CHC=CHCH=CH- C=CH -CH2 0- CO CH 3
I
'
I
OH
j_H a O
CH 3
CH 3
H=CH-C=CH-CH=CH-C=CH-CH 2 0-CO-CH3
'
IX
hydrolysis
CH3
CH=CH-C=CH-CH=CH- C=CH-CH2 OH
CH
CAROTENOIDS
7]
333
CH 3
CH=CHCO + CH 2 BrCH=CHC0 CH 3
2
Zn (Reformatsky)
CH3
CH= CH- C CH 2 CH= CH- C02 CH 3
OH
(i)
(C0 2 H) 2 11-HjO]
(li)
KOH
CH3
CH=CH-C = CH-CH = CH-C02 H
SOCl 2
(i)
(ii)
CH 3 Li
CH 3
CH 3
,CH=CHC = CHCH = CHCO
CH 2 Br-CO s C 2 H 5 /Zn
(
Reformatsky)
CH,
CH,
CH=CH-C = CHCH=CHC-CH
CO.
C H,
>
OH
(i)
(ii)
-H 3
KOH
CH 3
CH3
,CH=CHC = CHCH=CHC = CHCOoH
LiAlH 4
CH3
CH3
ORGANIC CHEMISTRY
334
Attenburrow
et al.
(1952)
[CH. IX
Ax
starting from
2-methylcyc/ohexanone.
NaNH 2
3
CH S I
r
ft
CHSCH,
Na/NH
'
CH,
CEU
= C-C-CH=CHCH = CH-C-CH=CH,i
(i)
(ii)
OH
EtMgBr
CH a
CH 3
CO-CH=CH-CH=CCH=CH 3
XI
CH 3
,C
acid
CH,
C-C=CH-CH=CH-C=CH'CH 2 OH
\)H
XII
(rearr.)
CH,
CH,
(i)
(il)
LiAiH 4
(CH 3 CO) 2
xnl
Ca
CH,
CH,
pMeC6 H4 S03 H
'
(-H 20)
Two
also
CH 2 OH
CH2 OH
vitamin
CftjOH
neovitamin
t>
neovitamin a
335
CAROTENOIBS
8]
Vitamin
a.
dehydrovitamin
x.
CH3
CH=CH-C=CH- CH=CH- C=CH-CH2 OH
CH,
vitamin Ag
Jones et al. (1955) have also introduced a method for converting vitamin x
into vitamin
Vitamin Aj may be oxidised to vitamin x aldehyde (retin2
enej) by means of manganese dioxide in acetone solution (Morton et al., 1948),
and then treated as follows:
/ [CH
CH 20H
A9
8. Xanthophylls. The xanthophylls occur naturally, and all have the same
carbon skeletons as the carotenes or lycopene (except flavoxanthin).
Cryptoxantbin, C^I^O, m.p. 169, is monohydroxy-/S-carotene; it has
provitamin-A activity.
r
Rubixanthin,
xanthin,
C^H^O,
C 40H 5 jO,
CH
fXPBtk
(CH S ) 2 C
CH
CH
II
CH;
HO
rubixanthin
Rhodoxanthin, C M H52
2,
m.p. 219,
o^\A
CH3
CH;
lycoxanthin
is
y\A>
ORGANIC CHEMISTRY
336
[CH. IX
known
as xanthophyll;
it is di-
Zeaxanthin, m.p. 205, and lycophyll, m.p. 179, are the corresponding
hydroxy derivatives of )3-carotene and lycopene, respectively.
,C(CH S ) 2
di-
(CHa^C.
CH
OH
HO
CH3
zeaxanthin
OH
CH,
lycophyll
217.
When boiled with potassium hydroxide solution, bixin produces one molecule of methanol and a dipotassium salt which, on acidification, gives the
dibasic acid norbixin, C 24 28 4
Thus bixin is a monomethyl ester, and
can be esterified to give methylbixin.
On catalytic hydrogenation, bixin is converted into perhydrobixin,
C 25 48 4 ; thus there are 9 double bonds present in the molecule (Liebermann el al., 1915). Perhydrobixin, on hydrolysis, forms perhydronorbixin.
Oxidation of bixin with permanganate produces four molecules of acetic
acid (Kuhn et al., 1929) ; thus there are four
C(CH 3) groups in the chain.
Furthermore, since the parent hydrocarbon of perhydronorbixin, C 24 46 4
is C 22 46 (the two carboxyl groups are regarded as substituents), the molecule is acyclic.
The thermal decomposition of bixin produces toluene, w-xylene, w-toluic
acid and the methyl ester of this acid (Kuhn et al., 1932). Hence the following assumptions may be made regarding the nature of the chain (cf. j3carotene, 3).
JCH 3
CH3
=CH-CH=CH-C=CH-CH=
^H
CH3
=CH-C=CH-CH=CH-C=
3
CH3
H0 2 C-CH=CH-C=CH-CH=CH-
C02 H
CH,
CH ,O2 C-CH=CH-C=0H-CH=CH-
C02CH3
337
CAROTENOIDS
9]
The
foregoing facts
for bixin
(Kuhn
may
et al.,
CH3
CSHs
<pH3
<j)Hj
H0 2C-CH=CHG=CH-CH=CH-C=CH-CH=CH-CH=CCH=CH-CH=C-C!H=CH-C02CH,
supported by the fact that perhydronorbixin has been
to be identical with the compound obtained from
the reduction of bixin (Karrer et al., 1933). Further proof is the synthesis
of norbixin (Isler et al., 1957).
Jackman et al. (1960) have shown, from an examination of the
spectra (19a. I) of many carotenoids, that the positions of the absorption
bands resulting from the methyl groups give some indication of the molecular
environment of these groups. " Natural " methylbixin is the cw-isomer of
the following trans-isomer:
This structure
synthesised,
is
and shown
NMR
C02 Me
Me0 2 C
The methyl
ester of crocetin (see below) also probably has the a's-configuration at the corresponding 2,3-position.
Crocetin, C 20 24 O 4
Crocetin occurs in saffron as the digentiobioside,
crocin. The structure of crocetin was elucidated by Karrer et al. (1928) and
Kuhn et al. (1931). Crocetin behaves as a dicarboxylic acid and has seven
double bonds (as shown by catalytic hydrogenation to perhydrocrocetin,
C 20 38O4). On oxidation with chromic acid, crocetin gives 3-4 molecules
of acetic acid per molecule of crocetin; thus there are 3-4 methyl sidechains. The structure of crocetin was finally shown by the degradation of
perhydronorbixin, C 24 46 4 , by means of the following method:
R-CIVC02 H
CHaNa
^U-R-CHBrC0 H
> RCHOH-CO 2 0H 3
(CH 3 -co, )4 Pb
hytlrolysis
>
> ;R
CHO
CHaMgI
>
RCHOHCOjjH
R-CHOH-C(OH)(CH3) 2
_m_^ R C02H
.
therefore
CH3
CH3
CH3
CH3
H02CC=CH-CH=CH-C=CHCH=CH-CH=C-CH=CHCH=C-C02 H
This structure is supported by the fact that the removal of two carbon atoms
from perhydrocrocetin by the above technique (one carbon atom is lost
from each end) resulted in the formation of a diketone. The formation of
this compound shows the presence of an oc-methyl group at each end of the
molecule. The structure of crocetin is further supported by the synthesis
of perhydrocrocetin, and by the synthesis of crocetin diesters by Isler et al.
These diesters probably have the c*s-configuration at the 2,3(1957).
position (see bixin, above). The tfraws-crocetin dimethyl ester has been
synthesised by the Wittig reaction (a carbonyl group is exchanged for a
methylene group; Vol. I) between the dialdehyde and two molecules of the
phosphorane (Buchta et al, 1959, 1960).
ORGANIC CHEMISTRY
338
Me0 2 C
PPh 3 OHC
CHO
[CH. IX
Ph3P<
v^X/G0 Me
2
CO, Me
MeO,C
READING REFERENCES
Karrer and Jucker, Carotenoids, Elsevier (translated and revised by Bfaude, 1950).
Rodd (Ed), Chemistry of the Carbon Compounds, Elsevier. Vol. 11A (1953). Ch. 10.
The Carotenoid Group.
Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953). Ch. 7. The
Terpenes (see the section on Tetraterpenes)
Bentley, The Natural Pigments, Interscience (I960).
CHAPTER X
Introduction.
Naphthalene,
anthracene,
phenanthrene,
fluorene,
have been described in Volume I. All these compounds occur in coaltar, but also present are many polycyclic hydrocarbons containing four or
more rings, and others of this type have been synthesised.
etc.,
CH 2 Br
Br
BrCH2/
Br
"
-fY
+ 4Na +
CO]
anthracene
H,c c;
BrUH 2
sifr
^>
[o]
phenanthrene
(ii) Ullmann diaryl synthesis.
This method results in the formation
of isolated polynuclear compounds, e.g., heating iodobenzene with copper
powder in a sealed tube produces diphenyl.
2C 6 II 5 I + 2Cu
Compounds
+ 2CuI
ORGANIC CHEMISTRY
340
[CH.
CH,
+ H2
tube, but a much better yield is obtained when the dimethyldiphenyl is
heated with sulphur. The latter is an example of cyclodehydrogenation
(see also
method
oo
CH 3
CH3
vii).
CH
+ 21L
CH 3
+ 2H2S
/y
CH2C1
MCI.
C1CHJ
o o
co-co,
^^_^^y_^>^
A very important case of the internal Friedel-Crafts reaction is that in which
ring closure is effected on acid chlorides,
butyryl chloride to a-tetralone.
e.g.,
Aicu
O
This type of ring closure may be effected by the action of concentrated
sulphuric acid on the carboxylic acid itself, e.g.,
H a SQ 4
2]
341
-H a O
(vi)
Phenanthrene syntheses.
is
partifor
methods
CFt=C^CQ 2H
CHO
N02 +
(i)
(CJVCOJjO
N0
<Q
(ii)NaNO,/H,S04
heat
-CO*
A"^>A
ORGANIC CHEMISTRY
342
[CH.
>0
CH2 CO
A1CI,
CO
CH 2
H02C
CH,
CO,H
HCI
Zn-Hg;
1 HCI
H,SOt
H 2 SO
Zn-Hg:
(i)
f()
Zn-Hg/HCI
Se'
3
OH
CH.3 Pd-C
2]
343
CH^CH
N
CH2
H0 2C
CO
CH 3 -CH-C(X Aids
+
>0
I
CHjj-CO
OH -CH -COCl
3
CO-CH2 -CH3
>
Br 8
inC6H ; NO
main product
CH-CH3
'CHBr CHNa(COjCjH 6 )a
CH(COAH
yCH\CH-CH
6)2
H0 C
2
CO
KOH
(i)
HC1
(ii)
(iii)heat
(c)
Johnson
Vol. I);
e.g.,
CO-CH3
CHjj-COaCuHs
(ch,) s
cok
f)fV-C==C-CH
\XJ
CHa-CO,
-C0 2 H
HBr-CH,-C0 2 H
reflux
C-CHa-CI^C O
i)NaOH
(
CH,
H *
CH-CHa-CHa-OQiH
ORGANIC CHEMISTRY
344
[CH.
"*^/i H
__
C6 H6Br-^C
6
6 MgBr
(i)
/K
HBr
^i^Vc H -CH -CH OH^^C
H -CH -CH Br
6
o
,COC02 C 2 H5
(ii)
(OOAH&
iCOAHs
>
/)H2Br
CH2 CH.2
moist
ether
(e)
Bogert-Cook synthesis
(1933).
pre-
paration of phenanthrene.
^CHjCHjMgBr
2
*f
HO
H;,S04
It
2]
345
both proceed via the formation of olefin III, which then gives a mixture of
octahydrophenanthrene IV and the spiran V.
OH
HO
III
+ 3H,
cyc/ohexane
+ 5H,
4H
H
hydrindane
indene
Perhydro-compounds, i.e., fully hydrogenated compounds, are readily dehydrogenated catalytically, but are very little affected, if at all, by the
chemical reagents sulphur and selenium. Partially unsaturated compounds,
however, are readily dehydrogenated by sulphur and selenium.
ORGANIC CHEMISTRY
346
[CH.
Alcoholic groups
hydrocarbons,
e.g.,
OH
S or Se
When
CH,
Se
eyc/oheptane
Ring expansion may occur, e.g., cholesterol gives chrysene (see 1. XI).
(c) Compounds containing an angular methyl group tend to eliminate this
methyl group as CH 3SH or CH 3SeH, e.g., eudesmol gives eudalene (28b.
In some cases, the
VIII), cholesterol gives Diels' hydrocarbon (1. XI).
angular methyl group enters a ring,
(b)
CH3
CH,
3]
347
thereby bringing about ring expansion [c/. (6) above]. On the other hand,
a normal substituent methyl group may migrate to another position, e.g.,
5:6:7: 8-tetrahydro-l 5-dimethylphenanthrene gives 1 8-dimethylphenanthrene on dehydrogenation with selenium.
(d) Side-chains larger than methyl may remain intact, or be eliminated
or be degraded, e.g.,
:
V ^]CH
-CH2-GgH5
Se
HO
cholesterol
(e)
Dehydrogenation
may
Diels'
(c/.
hydrocarbon
method
iii);
e.g.,
Pd-C
cm
ch.
BENZANTHRACENES
3.
Naphthacene
m.p. 357.
1931).
H 2 S0 4
(2
ORGANIC CHEMISTRY
348
When
[CH.
quinone.
3a.
by heating
CsHs
or
better,
with
C6H5
CeH5 CeHj
but changed
it
the fluorescence slowly disappears, and a white solid can now be isolated.
This is rubrene peroxide, and when heated to 100-140 in a high vacuum, it
emits yellow-green light and evolves oxygen, reforming rubrene.
CeHij
C 8H5
airsunlight
heat
in
a vacuum
3b.
viz.,
Two
pentacene
[Clar, 1930,
1939].
3d]
IS
14
12
UC
10$
13
14
349
15
pentacene
Clar (1942) thought he had prepared heptacene, but in 1950 he showed that
the compound he had isolated was 1 2-benzohexacene. Bailey et al. (1955)
have synthesised heptacene.
:
heptacene
3c. 1 2-Benzanthracene, m.p. 160, occurs in coal-tar, and has been
synthesised as follows (Bachmann, 1937).
:
xxco
iMgBr
1-naphthalene-
magnesium
bromide
3d.
Cook
et al.
COOl
2-naphthoic
acid
2-methylnaphthalene
ORGANIC CHEMISTRY
350
Buu-Hoi
1:2:5:
et al.
(1960)
[CH.
6-dibenzanthracene
\\i
ch2-cq
>o
CH2-CO
1
MCI3
C 6 HjNOj
(
1
Zn-10%NaOH
200
J3
XX)
CH
pyrene
H02C
'Ho
Zrt dust
distil
HO2 0.
CR.
XIH,
3f.
20-Methylcholanthrene
is
a pale yellow
solid,
m.p. 180.
It is
steroid derivative, and has been prepared by the degradation of, e.g., cholCook (1934) showed that methylcholanthrene has
esterol (see 3 iii. XI).
powerful carcinogenic properties, and Fieser et al. (1935) synthesised it in
4]
351
CI
AIC1,
+ COCl-CH2-CH2Cl -^J
CH
COCH2-CH2Cl CH3
'
CO-CHaCI^Cl
CH3
The alternative way of writing the formula shows more clearly the relationship of methylcholanthrene to the steroids (see 3. XI for the method of
numbering in cholesterol). The steroids are phenanthrene derivatives, and
so methylcholanthrene may also be regarded as a phenanthrene derivative
(instead of an anthracene derivative).
PHENANTHRENE DERIVATIVES
4. Chrysene (1
It occurs in coal-tar,
(i)
By
ORGANIC CHEMISTRY
352
(ii)
By
a Bogert-Cook synthesis
(cf.
2.
(vi)
[CH.
e).
/CHjjMgBr
CH,
HjS04
(iii)
(iv)
By
a Pschorr synthesis
(H)
NaN0 2 -HCl
(iii)
Cu powder
Phillips (1956)
[cf.
(vi)
a].
(i)
(II)
pci 6
A1C1 3
is produced by the pyrolysis of indene, and also by the dehydrogenation of steroids with selenium.
Chrysene
4c]
synthesised
353
3d).
IT
i
s
\
CH3 CH3U
13
12
J.
11
5^v
1
l)
II
^/
T
7k
CH 2
COC1
n
x^
1
Buchta
et al.
reaction [2
(vi)
Alcia
C0CI c6 h b nox2
(1958)
c]:
C0 2 Et
^2
C0 2 Et
CH
J30
_MfONa^
QH2
C0 2 Et
Zn
heaT
OH
Perylene is a very pale yellow solid, m.p.
and has been synthesised in several ways.
4c.
tar,
273.
It occurs in coal-
ORGANIC CHEMISTRY
354
[CH.
10
8-di-iodonaphthalene
(ii) Perylene may also be prepared by heating 1
with copper powder (i.e., by an Ullmann synthesis; cf. 2. ii).
:
120-260
(iii)
is formed when
under pressure.
Perylene
fluoride
l'-dinaphthyl
is
HF
Robertson et al. (1953), by X-ray analysis of perylene, have shown that the
two bonds connecting the two naphthalene units are longer (1-50 A) than the
usual aromatic C C bond (1-38-1-44 A). The existence of these long bonds is
supported by some magnetic susceptibility measurements (Hazato, 1949).
4d.
Coronene, m.p.
benzene solution;
:
it
4d]
355
CH3
p-co
CI
CH3
+
alkaline
1GR
CO-O
c H NO
KMn0 4
C02 H
C02 H
CI
C02 H
COoH
C0 2 H
C02 H
ORGANIC CHEMISTRY
356
|CH.
C02 H
C02 H
C02H C02H
Newman
tetralone,
and proceeding as
OH
OH
heat
(-2HaO)
from 7-methyl-
4d]
357
(i)
(i)
(ii)
(ii)
READING REFERENCES
Deof Preparative Organic Chemistry, Interscience Publishers (1948).
hydrogenation with Sulphur, Selenium and Platinum Metals (pp. 21-59).
Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953), pp. 1232Dehydrogenating Agents.
Genie, La Cyclodeshydrogenation Aromatique, Ind. chim. belg., 1953, 18, 670.
Cook, Polycyclic Aromatic Hydrocarbons, J.C.S., 1950, 1210.
Part II (1949).
Traiti de Chimie Organique, Masson et Cie., Vol. XVII.
Encyclopaedia of Organic Chemistry, Elsevier. Vol. 14 (1940). Tetracyclic and HigherCyclic Compounds. See also Vol. 14 Supplement (1951).
Cocker, Cross et al., The Elimination of Non-angular Alkyl Groups in Aromatisation
Reactions. Part II. J.C.S., 1953, 2355.
Cook (Ed.), Progress in Organic Chemistry, Butterworth. Vol. 2 (1953). Ch. 5. The
Relationship of Natural Steroids to Carcinogenic Aromatic Compounds.
Badger, The Structures and Reactions of Aromatic Compounds, Cambridge Press (1954).
Newer Methods
CHAPTER XI
STEROIDS
The steroids form a group of structurally related
1. Introduction.
compounds which are widely distributed in animals and plants. Included
in the steroids are the sterols (from which the name steroid is derived), vitamin D, the bile acids, a number of sex hormones, the adrenal cortex hormones,
some carcinogenic hydrocarbons, certain sapogenins, etc. The structures
of the steroids are based on the 1 2-cjyc/opentenophenanthrene skeleton
(Rosenheim and King, 1932; Wieland and Dane, 1932). All the steroids
:
1:
2-cyc/opentenophenanthrene
among
Diels'
358
hydrocarbon
STEROIDS
3]
359
STEROLS
They are crystalline
2. Sterols occur in animal and plant oils and fats.
compounds, and contain an alcoholic group; they occur free or as esters of
the higher fatty acids, and are isolated from the unsaponifiable portion of
oils
and
animal
fats.
Cholesterol, cholestanol
sterols; ergosterol
The
sterols that are obtained from animal sources are often referred to as
the zoosterols, and those obtained from plant sources as the phytosterols.
third group of sterols, which are obtained from yeast and fungi, are referred
to as the mycosterols. This classification, however, is not rigid, since some
sterols are obtained from more than one of these groups.
and
oleate.
Cholesterol is a white crystalline solid which is optically active (larvorotatory). Cholesterol (and other sterols) gives many colour reactions, e.g.,
When concentrated sulphuric acid is
(i) The Salkowski reaction (1908).
added to a solution of cholesterol in chloroform, a red colour is produced in
is
HO
have the established structure of cholesterol at the beginning of our discussion.
I is the structure of cholesterol, and shows the method of numbering.
The molecule consists of a side-chain and a nucleus which is composed of
four rings; these rings are usually designated A, B, C and D or I, II, III and
ORGANIC CHEMISTRY
360
[CH. XI
IV, beginning from the six-membered ring on the left (see also (iii) below).
It should be noted that the nucleus contains two angular methyl groups, one
at C 10 and the other at C 13
(i) Structure of the ring system.
Under this heading we shall deal
with the nature of the ring system present in cholesterol; the problem of
the angular methyl groups is dealt with later [see (iv)].
The usual tests for functional groups showed that cholesterol contains one
double bond and one hydroxyl group. Now let us consider the following
set of reactions.
.
Cholesterol
> Cholestanol
'->
Cholestanone
> Cholestane
^27"4*~'
^27^48^'
^-'27"46^-'
^27X143
II
III
IV
The conversion of
one double bond in
section).
>
>
>
>
STEROIDS
3]
361
for the ease of hydrolysis or acetylation when these positions are occupied
by hydroxyl groups (see also testosterone, 13). More recently, it has been
minium
Me
I
CH(CH 2 3 CHMe 2
)
These two " homeless " carbon atoms were not placed until Rosenheim and King first proposed that steroids contained the chrysene nucleus
and then proposed the cycfopentenophenanthrene nucleus (see above).
Bernal (1932) also showed, from the X-ray analysis of cholesterol, ergosterol,
etc., that the molecule was thin, whereas the above structure for the steroid
nucleus would be rather thick.
(ii) Positions of the hydroxyl group and double bond.
Let us conposition.
Cholestanone
C27H46O
III
y Ketone
C 2gH 44
VI
Since the dicarboxylic acid V contains the same number of carbon atoms as
the ketone (III) from which it is derived, the keto group in III must therefore
be in a ring. Also, since pyrolysis of the dicarboxylic acid V produces a
ketone with the loss of one carbon atom, it therefore follows from Blanc's
rule that V is either a 1 6- or 1 7-dicarboxylic acid. Now we have seen
that the nucleus contains three six-membered rings and one five-membered
ring.
Thus the dicarboxylic acid V must be obtained by the opening of
ring A, B or C, and consequently it follows that the hydroxyl group in
cholesterol (which was converted into the keto group in cholestanone; see
(i) above) is in ring A, B or C.
Actually two isomeric dicarboxylic acids are obtained when cholestanone
is oxidised.
The formation of these two acids indicates that the keto group
:
ORGANIC CHEMISTRY
362
[CH. XI
in cholestanone
HO
Cholesterol
C27xi 46 (J
(i)
(ii)
CrO
>
-H,0
Zn OH.-COjH
'
>
Cholestanetriol
'->
Hydroxycholestanedione
C^H^C^
L 27 xi 44 U3
VII
VIII
CrO,
Cholestanedione
IX
In the conversion of I into VII, the double bond in I is hydroxylated. Since
only two of the three hydroxyl groups in VII are oxidised to produce VIII,
these two groups are secondary alcoholic groups (one of these being the
secondary alcoholic group in cholesterol), and the third, being resistant to
oxidation, is probably a tertiary alcoholic group. Dehydration of VIII (by
heating in vacuo) and subsequent reduction of the double bond forms IX,
and this, on oxidation, gives a tetracarboxylic acid without loss of carbon
atoms. Thus the two keto groups in IX must be in different rings had they
not obtained.
been in the same ring, then carbon would have been lost and
It therefore follows that the hydroxyl group and double bond in cholesterol
must be in different rings. Furthermore, since IX forms a pyridazine
derivative with hydrazine, IX is a y-diketone. Since we have already
tentatively placed the hydroxyl group in ring A, the above reactions can
be readily explained if we place the hydroxyl group at position 3, and the
double bond between 5 and 6. In the following equations only rings A and
B are drawn; this is an accepted convention of focusing attention on any
part of the steroid molecule that is under consideration (also note that full
lines represent groups lying above the plane, and broken lines groups lying
below the plane; see also 4, 4a, 4b). Noller (1939) has shown that the
pyridazine derivative is a polymer, and so the interpretation that IX is a
y-diketone is rendered uncertain. Supporting evidence, however, for the
above interpretation is afforded by the fact that when cholesterol is heated
with copper oxide at 290, cholestenone, XI, is produced, and this on oxidation with permanganate forms a keto-acid, XII, with the loss of one carbon
atom. The formation of XII indicates that the keto group and the double
bond in cholestenone are in the same ring. The ultraviolet absorption
spectrum of cholestenone shows that the keto group and the double bond
are conjugated (Menschick et al., 1932). These results can be explained if
we assume that the double bond in cholesterol migrates in the formation
of cholestenone, the simplest explanation being that the hydroxyl group
;
VIII
363
STEROIDS
3]
HOjC
HQjC,
J4T
pyridazine
derivative
in position 3
to both rings
is
6,
position 5 being
common
+ CO,
XI
XII
It might be noted here that the orientation of the two hydroxyl groups
(introduced across the double bond in cholesterol) depends on the nature
of the reagent used. With hydrogen peroxide, or via the oxide, the cholestanetriol is trans-5 6 (VII)
with potassium permanganate or osmium
:
ORGANIC CHEMISTRY
364
[CH. XI
These orientations
tetroxide, the product is cis-5 6 (Vila; cf. 5a. IV).
may be explained as follows. When the addition of the two hydroxyl groups
occurs via the oxide (the 5 6-oxide), the oxide ring will be formed behind
the plane of the molecule due to the steric effect of the methyl group. Since
opening of the epoxide ring occurs by attack on the conjugate acid (5a. IV),
:
the water molecule will attack from the back of the ring {i.e., from the front
of the molecule), and also preferably at position 6 due to the steric effect
Thus the orientation of the two hydroxyl groups
of the methyl group.
With permanganate (and osmium tetroxide),
(trans) will be as shown in VII.
HO-^/?\/
Vila
HO
VII
the plane of the cyclic compound will lie at the back of the molecule, again
due to the steric effect of the methyl group. Moreover, since in the formation of the dihydroxy compound, both glycol oxygen atoms come from the
permanganate ion (5a. IV), it follows that both hydroxyl groups will be at
the back of the molecule (Vila).
The addition of bromine, occurring via a brominium ion (5a. IV), will
produce the dibromide Vllb, the reasons for the orientation being the same
as those for the formation of VII (via the epoxide).
Since secondary alcoholic groups in steroids are readily oxidised to keto
groups, and the latter may be located by mass spectra measurements (see
4b), this offers a very good way of locating secondary hydroxyl groups in
the steroid molecule.
Acetylation of cholesterol
(iii) Nature and position of the side-chain.
produces cholesteryl acetate and this, on oxidation with chromium trioxide,
forms a steam-volatile ketone and the acetate of a hydroxyketone (which is
not steam volatile). The ketone was shown to be wohexyl methyl ketone,
CH 3 'CO(CH 2 )3-CH(CH 3 ) 2 Thus this ketone is the side-chain of cholesterol,
the point of attachment of the side-chain being at the carbon of the keto
group. These results do not show where the side-chain is attached to the
nucleus of cholesterol, but if we accept that the position is at 17, then we
may formulate the reactions as follows:
.
365
STEROIDS
3]
CH3 -COO
HO'
CrOj
CrO,
CHsCOO'
CH.3
\
CHirCHaCHgCH
XCH
CH3COO'
The nature of the side-chain has also been shown by the application of
the Barbier-Wieland degradation. Since this method also leads to evidence
that shows which ring of the nucleus is attached to the side-chain, we shall
consider the problem. of the nature of the side-chain again.
The Barbier-Wieland degradation offers a means of " stepping down "
an acid one carbon atom at a time as follows:
K*CH 2 'C0 2 H
HCl
>
R-CH 2 -C(OH)(C 6H 5) 2
>
*->
R-CH=C(C 6H 5
CrO,
)
R-C0 2H
(C 6
H CO
5) 2
R-CH 2 -C(OH)(CH 3
'+
R-C0 2H
(CH 3) 2CO
366
ORGANIC CHEMISTRY
the side-chain as
as follows
(B-W
CM then we may
,
[CH. XI
Coprostane
ArC
(C 6
(C 6
(C 6
'->
CH s*COCH 3 +
H s CO +
)
Norcholanic acid
Ar
n_ 4
H 2CO
5)
-f-
B-W
>
Bisnorcholanic acid
Ar
n _5
B-W
>
CtO
H CO + ^tiocholyl
methyl ketone
ArC_ 6
5) 2
>
Cholanic acid
Ar M _ 3
'->
Etianic acid
ArC_7
(i)
(ii)
S0C1
TTC1
'-*
CHjN,
Z"
>
AcOH
>
('
Ar-CHMe-CH=CH-CO-CH 3
CrO
)Br
*
(ii)
>
-HBr
V Ar-CHMe-C0 H
2
2PhMgBr
>
^""""""V
succinimide
Ar-CHMe-CHBr-CH=CPh 2
Ar-CMe=CH-CH=CPh 2
^%
CrO
V Ar-COMe
(iii) Jones et al. (1958) have carried out the fission of a steroid side-chain with
an acid catalyst and have then subjected the volatile products to chromatography. This method has been used with as little as 30 mg. of material.
367
STEROIDS
3]
The problem now is: Where is the position of this side-chain? This is
by the following observation. The dicarboxylic acid, setioThus
bilianic acid, forms an anhydride when heated with acetic anhydride.
partly answered
12-ketocholanic acid
20-methylcholanthrene
dehydronorcholene
C08 H
C02H
CrO.
CrO,
HOjC
HOijC
5:6-dimethyl-l:2-
benzanthraquinone-
It should be noted that the isolation of methylcholanthrene affords additional evidence for the presence of the cycfopentenophenanthrene nucleus
in cholesterol.
Thus, now that we know the nature and position of the side-chain, we
can formulate the conversion of coprostane into setiobilianic acid as follows:
ORGANIC CHEMISTRY
368
[CH. XI
002H
OH 3 -COCH3 +
B _.
coprostane
cholanic acid
C02H
CO-H
B-W^
B--W
bisnorcholanic
norcholanic acid
CrO,
aetiocholyl
methyl
ketone
acid
C02H
.CO a
?OaH
setiobilianic acid
setiocholanone
etianic acid
M/
hno 3
B-w
A point
when
is
that
:
tained (Butenandt et
of the phenanthrene nucleus in cholesterol, and also evidence for the position
of the C 13 angular methyl group (see iv).
ffitiobilianic
anhydride
1: 2-dimethyl-
acid
phenanthrene
XV
XVI
Positions of the two angular methyl groups. The cyc/opentenophenanthrene nucleus of cholesterol accounts for seventeen carbon atoms,
and the side-chain for eight. Thus twenty-five carbon atoms in all have been
accounted for, but since the molecular formula of cholesterol is C 27 46 0, two
more carbon atoms must be fitted into the structure. These two carbon
atoms have been shown to be angular methyl groups.
In elucidating the positions of the hydroxyl group and double bond, one
of the compounds obtained was the keto-acid XII. This compound, when
subjected to the Clemmensen reduction and followed by two BarbierWieland degradations, gives an acid which is very difficult to esterify, and
evolves carbon monoxide when warmed with concentrated sulphuric acid
(iv)
(Tschesche, 1932). Since these reactions are characteristic of an acid containing a carboxyl group attached to a tertiary carbon atom (cf. abietic
acid, 31. VIII), the side-chain in XII must be of the type
369
STEROIDS
3]
C
L
C-C-C C-C0 H
2B-\V
C
Thus there must be an alkyl group at position 10 in XII. This could be
an ethyl group (as originally believed by Windaus and Wieland) or a methyl
group, provided that in the latter case the second " missing " carbon atom
can be accounted for. As we shall see later, there is also a methyl group
at position 13, and so the alkyl group at position 10 must be a methyl
group. On this basis, the degradation of XII may be formulated:
H02<I
Zn-Hg
HCl
CO.H
The position of the other angular methyl group is indicated by the following evidence. When cholesterol is distilled with selenium, chrysene is
obtained as well as Diels' hydrocarbon (see 1). How, then, is the former
produced if the latter is the ring skeleton of cholesterol? One possible
explanation is that there is an angular methyl group at position 13, and on
selenium dehydrogenation, this methyl group enters the five-membered
ring
to form a six-membered ring; thus:
HO
cholesterol
Diels'
hydrocarbon
chrysene
This evidence, however, is not conclusive, since ring expansion could have
taken place had the angular methyl group been at position 14. Further
support for the positions of the two angular methyl groups is given by the
following degradative experiments (Wieland et al., 1924, 1928, 1933) (see
overleaf).
ORGANIC CHEMISTRY
370
[CH. XI
C0 2 H
HNO3
dehydrodeoxycholic
deoxycholic acid
acid
CO,H
KMn0 4
H0 C
2
pyrodeoxybilianic acid
deoxybilianic acid
C02H
CO,H
C02H C02 H
XVII
diketo-dicarboxylic
acid
C02H
HO,
HNO a
heat
HO.C
compound
XX was
Thus
this
is
also shown to be a
Furthermore, one carb-
STEROIDS
3]
371
XX
oxyl group in
was shown to be attached to a tertiary carbon atom, and
so it follows that there is a methyl group at 13 or 14.
was then shown
to have the trans configuration, i.e., the two carboxyl groups are trans.
Thus its precursor XIX must have its two rings in the trans configuration
(the methyl group and hydrogen atom at the junction of the rings are thus
trans).
Theoretical considerations of the strain involved in the cis- and
trans-iowas of XIX suggest that the m-form of XIX would have been
obtained had the methyl group been at position 14. Thus the position of
this angular methyl group appears (from this evidence) to be at 13, and this
is supported by the fact that aetiobilianic acid (XV, section iii) gives 1
2dimethylphenanthrene (XVI) on dehydrogenation with selenium. Had the
angular methyl group been at position 14, 1-methylphenanthrene would
most likely have been obtained.
(v) Synthesis of cholesterol.
Two groups of workers, viz., Sir R.
Robinson et al. (1951) and Woodward et al. (1951), have synthesised cholesterol.
One of the outstanding difficulties in the synthesis of steroids is the
stereochemical problem. The cholesterol nucleus contains eight asymmetric
carbon atoms and so 256 optical isomers are possible (see also 4 for further
details)
Thus every step in the synthesis which produced a new asymmetric
carbon atom had to result in the formation of some (the more the better) of
the desired stereoisomer, and at the same time resolution of racemic modifications also had to be practicable. Another difficulty was attacking a particular point in the molecule without affecting other parts. This problem
led to the development of specific reagents. The following is an outline of
the Woodward synthesis. 4-Methoxy-2 5-toluquinone, XXI, was prepared
XX
if\(CH3+
Ho(J
Sn-HCl
CH3 Of
CH3 Ol
CH3
H3
^H
FeC
'NO,
^m
T nCH
'\Ao
XXI
XXI was condensed with butadiene (Diels-Alder reaction) to give XXII.
This had the cis configuration and was isomerised (quantitatively) to the
trans-isomer XXIII by dissolving in aqueous alkali, adding a seed crystal of
the trans-form, and then acidifying. XXIII, on reduction with lithium
aluminium hydride, gave the glycol XXIV, and this, on treatment with
aqueous acid, gave XXV. Conversion of
to XXVI by removal of
the hydroxyl group was carried out by a new technique
was acetylated
and the product, the ketol acetate, was heated with zinc in acetic anhydride
to give XXVI (reduction with metal and acid usually reduces <x ^-unsaturated bonds in ketones). XXVI, on treatment with ethyl formate in
the presence of sodium methoxide, gave the hydroxymethylene ketone
XXVlI (Claisen condensation). When this was treated with ethyl vinyl
ketone in the presence of potassium fert.-butoxide, XXVIII was formed
(Michael condensation). The object of the double bond in the ketone ring
in XXVI is to prevent formylation occurring on that side of the keto group,
and the purpose of the formyl group is to produce an active methylene
XXV
XXV
ORGANIC CHEMISTRY
372
[CH. XI
The necessity
(this is now flanked on both sides by carbonyl groups).
for this " activation " lies in the fact that ethyl vinyl ketone tends to selfcondense, and consequently decrease the yield of XXVIII. XXVIII was
now cyclised (quantitatively) by means of potassium hydroxide in aqueous
group
dioxan to the single product XXIX. This is the desired compound; the
other possible isomer (XXIX with the two hydrogens cis instead of trans
as shown) is not formed since the cw-isomer is less stable than the trans-.
XXIX was then treated with osmium tetroxide to give two cw-glycols of
structure XXX. These were separated, and the desired isomer (the one
insoluble in benzene) was treated with acetone in the presence of anhydrous
copper sulphate to give the wopropylidene derivative XXXI. This, on
catalytic reduction (H 2 Pd/SrC0 3 ) gave XXXII which was condensed with
ethyl formate in the presence of sodium methoxide to give XXXIII, and
The
this was then converted into XXXIV by means of methylaniline.
purpose of this treatment was to block undesired condensation reactions
on this side of the keto group (at this position 3). When XXXIV was condensed with vinyl cyanide (cyanoethylation) and the product hydrolysed
with alkali, the product was a mixture of two keto acids. These were
(methyl group in front and propionic
separated and the stereoisomer
acid group behind the plane of the rings) was converted into the enol
lactone XXXVI which, on treatment with methylmagnesium bromide, gave
XXXVII, and this, on ring closure by means of alkali, gave XXXVIII.
When this was oxidised with periodic acid in aqueous dioxan, the dialdehyde
XXXIX was obtained, and this, when heated in benzene solution in the
presence of a small amount of piperidine acetate, gave XL (and a small
amount of an isomer) This ketoaldehyde was oxidised to the corresponding
acid which was then converted into the methyl ester XLI with diazomethane. XLI, a racemate, was resolved by reduction of the keto group
with sodium borohydride to the hydroxy esters [()-3a- and ()-3/S-].
The (+)-form of the 3/3-alcohol was preferentially precipitated by digitonin, and this stereoisomer was now oxidised (Oppenauer oxidation) to
give the desired stereoisomer (+)-XLI. This was catalytically reduced
(H 2 Pt) to XLII, which was then oxidised to XLIII which was a mixture
of stereoisomers (from the mixture of XLII; H at 17 behind and in front).
These were separated, reduced (sodium borohydride), and hydrolysed. The
jS-isomer, XLIV, was converted into the methyl ketone by first acetylating,
then treating with thionyl chloride and finally with dimethylcadmium. This
acetylated hydroxyketone, XLV, on treatment with wohexylmagnesium
bromide, gave XLVI. This was a mixture of isomers (a new asymmetric
carbon has been introduced at position 20). XLVI, on dehydration, gave
one product, XLVII, and this, on catalytic hydrogenation (H 2 Pt), gave a
mixture of cholestanyl acetates (the asymmetric C 20 has been re-introduced).
These acetates were separated and the desired isomer, on hydrolysis, gave
The
cholestanol, XL VIII, which was identical with natural cholestanol.
conversion of cholestanol into cholesterol, LIII, is then carried out by a
series of reactions introduced by various workers: XLVIII to XLIX (Bruce,
1943) XLIX to L (Butenandt et al., 1935) L to LI (Ruzicka, 1938) LI to
LII (Westphal, 1937); LII to LIII (Dauben et al., 1950).
XXXV
373
3]
CH,
CH;
/>H2
CH
+
CH
LiAlH,
CH3O
/CH3
^Q-CH=CH 3
C a H 8 -CO
(CH s)aCOK
CH2
KOH
pQ
CH^oHd H
!HO
XXVIII
(CHs)aCO
os o4
XXX
XXIX
:C(CH3 ) 2
C(CH,) 2
XXXI
XXXII
ORGANIC CHEMISTRY
374
C>
(ii)
hydrolysis
HOoC
XXXV
(CH3 )2
0^\}
XXXVII
XXXVI
XXXIX
XXXVIII
C02 CH3
CHO
XL
XLI
STEROIDS
3]
C02 CH3
375
C0 2CH3
L--H
HO
CH3 -COO
XLVI
XLVIH
cholestanol
XLVII
XLIX
ORGANIC CHEMISTRY
376
[CH. XI
(CH 3 CO)jO
CH3COO'
LII
LIII
cholesterol
4.
sterol,
we
If
256 optical
the nucleus (3, 5, 8, 9, 10, 13, 14 and 17). Thus there are 2 8
isomers possible. If we also include the asymmetric carbon atom in the
side-chain (20), then there are 512 optical isomers possible.
atoms
trans-decakn, 11 vii. IV); rings A/B and C/D could be cis or trans.
It has been found that all naturally occurring saturated steroids, except
those of the heart poisons, belong either to the cholestane series or to the
coprostane series; in the former the rings A/B are trans, and in the latter
By convention a
cis, the rings B/C and C/D being trans in both series.
full line represents groups above the plane of the molecule, and a dotted
(or broken) line represents groups below the plane (see also 11 vii. IV for
(cf.
STEROIDS
4a]
377
analysis has shown that the hydrogen atom at C 9 is trans to the methyl
group at C10 (Bernal et al., 1940), and this conclusion is supported by chemical
evidence. Thus cholestane must be I or III. Further chemical work has
shown that the methyl groups at C10 and C13 are cis, and so cholestane is I,
and consequently coprostane is also I, except that in this case the hydrogen
atom at C 5 is above the plane (rings A/B are cis in coprostane). The final
point to be settled in connection with this problem of the configuration of
cholestane is the orientation of the side-chain
at C 17
Chemical evidence
and X-ray analysis studies have shown that this side-chain is above the plane
of the molecule (i.e., cis with respect to the two angular methyl groups).
Thus cholestane and coprostane are:
Cholestane
A/B
B/C
C/D
trans
trans
trans
alio series
Coprostane
A/B
cis
B/C
C/D
trans
trans
normal
series
known
are
as the a/to-compounds,
the prefix alio being reserved to indicate this configuration at C 6
Compounds derived from coprostane are known as the normaZ-compounds,
but it should be noted that it is not customary to prefix compounds of this
series by the word normal, e.g., aWocholanic acid can be derived from cholestane, whereas cholanic acid can be derived from coprostane.
.
378
ORGANIC CHEMISTRY
[CH. XI
OH
I
pairs of epimeric, allylic steroid alcohols, and found that the differences
were those which may be predicted on the basis that the conventional steroid
formulae represent the absolute configurations. Thus the configuration of
the 3/S-hydroxyl group in cholesterol corresponds to that of d(+) -glycer-
aldehyde.
Barton (1944r- ) has also applied the method of optical rotations to steroid
chemistry, and has called his treatment the Method of Molecular Rotation
Differences (this is a modification of the Rule of Shift, 12. I). The basis
of this method is that the molecular rotation of any steroid is considered
as the sum of the rotation of the fundamental structure (which is the parent
hydrocarbon cholestane, androstane, or pregnane) and the rotations contributed by the functional groups (these are called the A values). The A
STEROIDS
4c]
379
The preparation
(platinum)
cholesterol
(cholestan-3/S-ol).
On
(cholest-5-en-3/?-ol)
the
H.-Pt
H
cholesterol
cholestanol
solution
HO
Hj-Pt
H
cholestanol
(main product)
H
epicholestanol
(main product)
cholestanone
ORGANIC CHEMISTRY
380
[CH. XI
The corresponding C 5
epimers, coprostanol (coprostan-3/?-ol) and epicoprostanol (coprostan-3-ol), may be prepared from cholesterol as follows,
the first step being the conversion of cholesterol into cholest-4-en-3-one by
means of the Oppenauer oxidation (aluminium tert.- butoxide in acetone;
see also Vol. I).
Oppenauer
oxidation
HO
H
cholesterol
cholest-4-en-3-one
H s -Pt
coprostanol
coprostanone
neutral
H
epicoprostanol
A detailed study of
381
STEROIDS
4d]
out, the product is usually
mainly
cis
and hence the exceptions can only be ascertained as such by other evidence.
Barton (1953) has restated this Auwers-Skita rule of catalytic hydrogenation as follows: Catalytic hydrogenation of ketones in strongly acid media
(rapid hydrogenation) produces the axial hydroxyl compound, whereas
hydrogenation in neutral media (slow hydrogenation) produces the equatorial alcohol if the ketone is unhindered or the axial alcohol if the ketone
is very much hindered.
All the evidence obtained has shown that all the cycJohexane rings in
the steroid nucleus are chair forms; thus I
is
cholestane,
II is coprostane.
Coprostane
(A/B as)
Cholestane
(A/B
and
trans)
II
effect of conformation on the course and rate of reactions has been
discussed in 12. IV. The following is a summary of the generalisations
that have been formulated:
Thus, when
(i) Equatorial groups are normally more stable than axial.
a (polycyclic) secondary alcohol is equilibrated with alkali, it is the equatorial
isomer that predominates in the product. Similarly, when a (polycyclic)
ketone is reduced with sodium and ethanol, the predominant isomer in the
product is the equatorial alcohol (the more stable form). Furthermore,
because of the rigidity of the system (which prevents interconversion of
chair forms), the stable configurations of hydroxyl groups at different positions in the cholestane series will be as shown in III (compare this with I).
The
a
III
The
Cholestanol
[30(e)]
io%i
* 80%
Coprostanol [30(a)]
90%
Epicholestanol
(ii)
[3<x(a)]
Epicoprostanol
[3oc(e)]
ORGANIC CHEMISTRY
382
[CH. XI
torial groups.
(or
esters, e.g.,
gives I; thus:
iii),
!0 2
Ergostanol
fe
op,
>
COJI
CH,-COO
STEROIDS
5]
383
Thus ergostanol and cholestanol have identical nuclei, the same position
of the hydroxyl group and the same position of the side-chain.
The only
difference must be the nature of the side-chain, and hence it follows that
ergosterol contains one more carbon atom in its side-chain than cholesterol
Ozonolysis of
(the former compound is CjgH^O and the latter C 27 H 46 0).
ergosterol gives, among other products, methyh'sopropylacetaldehyde, IV.
This can be accounted for if the side-chain of ergosterol is as shown in V
(Windaus
et
al, 1932).
C02H
CHO
I
CH-CH(CH 3 ) 2
CHS
IV
'C0 2
3/3-
CH3
CO-CHfCHak
CHvCOO'
ergostanyl acetate
We have now accounted for all the structural features of ergosterol except
the positions of the three double bonds. The position of one of these is
actually shown in the above account it is C 22 C^. The side-chain must
contain only one double bond, since if more than one were present, more
than one fragment (IV) would have been removed on ozonolysis. Thus
the other two double bonds must be in the nucleus. When heated with
maleic anhydride at 135, ergosterol forms an adduct, and so it follows that
the two double bonds (in the nucleus) are conjugated (Windaus et al., 1931).
Now ergosterol has an absorption maximum at 2810 A. Conjugated acyclic
dienes absorb in the region of 2200-2500 A, but if the diene is in a ring
system, then the absorption is shifted to the region 2600-2900 A. Thus
the two double bonds in the nucleus of ergosterol are in one of the rings
(Dimroth et al., 1936). When ergosterol is subjected to the Oppenauer
oxidation (aluminium totf.-butoxide and acetone), the product is an a /?unsaturated ketone (as shown from its absorption spectrum). This can
only be explained by assuming that one of the double bonds is in the 5 6position, and moves to the 4 5-position during the oxidation (c/. cholesterol,
3 ii). The other double bond is therefore 7 8 in order to be conjugated
with the one that is 5 6. Thus the conjugated system is in ring B and
:
the oxidation
is
explained as follows:
ORGANIC CHEMISTRY
384
[CH. XI
HO
ergosterol
6.
for
Vitamin D.
bone formation,
its
metabolism.
Steenbock et al. (1924) showed that when various foods were irradiated
with ultraviolet light, they acquired antirachitic properties. This was then
followed by the discovery that the active compound was in the unsaponifiable
fraction (the sterol fraction).
At first, it was believed that the precursor of
the active compound was cholesterol, but subsequently the precursor was
shown to be some " impurity " that was in the cholesterol fraction {e.g., by
Heilbron et al., 1926). The ultraviolet absorption spectrum of this " impure
cholesterol " indicated the presence of a small amount of some substance
that was more unsaturated than cholesterol. This led to the suggestion
that ergosterol was the provitamin
in the " impure cholesterol ", and
the investigation of the effect of ultraviolet light on ergosterol resulted in
the isolation from the irradiated product of a compound which had very
strong antirachitic properties. This compound was named calciferol by
the Medical Research Council (1931), and vitamin D t by Windaus (1931).
This potent crystalline compound, however, was subsequently shown to be
a molecular compound of calciferol and lumisterol (one molecule of each).
Windaus (1932) therefore renamed the pure potent compound as vitamin D 2
but the M.R.C. retained the original name calciferol. The Chemical Society
(1951) has proposed the name ergocalciferol for this pure compound.
A detailed study of the irradiation of ergosterol with ultraviolet light
has led to the proposal that the series of changes is as follows (R
C 9 17)
HO
ergosterol
pre-ergocalciferol
OH
tachysterol
HOergocalciferol
HO
lumisterol
Velluz
385
steroids
6a]
(1949) isolated the pre-ergocalciferol (P) by irradiation of ergoand showed that it formed ergocalciferol (E) on heating (see
et al.
sterol at 20,
hv
Ergosterol
hv
D2
is
an optically active
crystal-
m.p. 115-117.
forms esters, the oxygen
line solid,
Its
1936).
ORGANIC CHEMISTRY
386
[CH. XI
FH
.^COjH
X-ray analysis studies of the 4-iodo-3-nitrobenzoate of ergocalciferol confirm structure I for ergocalciferol (Crowfoot et al., 1948).
The presence of the two double bonds 5 6 and 7 8 gives rise to the
possibility of various geometrical isomeric forms for ergocalciferol.
Ultraviolet spectroscopic studies (Braude et al., 1955) and other work (6) have
led to the conclusion that ergocalciferol has the configuration shown in the
chart in 6. This is further supported by the work of Crowfoot et al. (1957)
who, from calculations of electron densities in the ester crystal (the 4-iodo3-nitrobenzoate), have shown that their results agree with the configuration
given in the chart.
Lythgoe et al. (1957) have carried out a partial synthesis of ergocalciferol
:
D
D
II.
STEROIDS
7]
387
and by
Fieser
et al.,
1950).
Cr0 3
CH,CO
CHs-COO'
cholesteryl
acetate
uaih 4
C8 H6 COO
HO'
OCOC H
6
C t H.N(CH)a
reflux
6 Hfi-COO
7-dehydrocholesterol
6).
HO
HO
vitamin
7.
oil.
D3
vitamin
Dt
ORGANIC CHEMISTRY
388
[CH. XI
double
C02H
CH3 -00O/
CH3-000
stigmastanyl acetate
CHO
I
CH-CH(CH3)2
C2 H 6
ethyhsopropylacetaldehyde
position of the second double
to be 5 6 by the method used
Stigmasterol, on hydroxylation with hydrofor cholesterol (Fernholz, 1934)
gen peroxide in acetic acid, gives a triol which, on oxidation with chromium
This, on dehydration followed by retrioxide, forms a hydroxydiketone.
ii):
hydroxydiketone
X.
pyridazine
dione
is
389
STEROIDS
7a]
stigmasterol
7a. Biosynthesis of sterols. It has long been known that animals
can synthesise cholesterol, but the possible pathways were unknown until
biosynthetic cholesterol was prepared from acetic acid labelled isotopically
(with "C) in either the methyl (m) or the carboxyl (c) group, or labelled in
both groups ( 13 CH 3a4C02H). These tracer studies were carried out mainly
by B\och etal. (1942- ) and by Cornforth et al. (1953- ), and the results established that the distribution of the carbon atoms is as shown in I. Thus
/m
V
m
-tn
m^ /m\ /m
C
Evidence was also
acetic acid can be regarded as the fundamental unit.
obtained that isovaleric acid can serve as a precursor for cholesterol, and
then Tavormina et al. (1956), using labelled mevalonic acid (MVA), showed
that this is converted almost completely into cholesterol by rat liver; the
route from acetic acid to MVA has been described in 32a. VIII. The probis converted into cholesterol.
lem now is to discover the route whereby
As far back as 1926 Heilbron et al. suggested that squalene (32. VIII) is a
precursor of cholesterol, and Robinson (1934) proposed a scheme for the
cyclisation of the squalene molecule with the loss of three methyl groups.
Woodward et al. (1953), however, suggested that squalene is first cyclised
to lanosterol, and then this loses three methyl groups to give cholesterol.
Bloch et al. (1952) showed that squalene is a precursor of cholesterol in the
intact animal. Furthermore, Bloch et al. (1955) showed that lanosterol is
converted into cholesterol in rats, and in 1956 carried out the biosynthesis
of lanosterol from labelled acetate. Thus we have evidence for the suggested
route from squalene to cholesterol. As mentioned above, Woodward et al.
(1953) suggested that squalene ring-closes to form lanosterol, and proposed
a 1,3-shift of the methyl group at C 8 to C 13 (the squalene molecule is numOn the
bered to give the numbering in the closed-ring system in the steroid)
other hand, Ruzicka etal. (1955) and Bloch et al. (1957) proposed a 1,2-shift
of the methyl group from C M to C 13 and another 1,2-shift from C 8 to C 14
Further work by Bloch et al. (1958) showed that the 1,2-shifts were correct;
this is also supported by the work of Cornforth et al. (1958).
MVA
390
ORGANIC CHEMISTRY
squalene
[CH. XI
lanosterol
HO'
cholesterol
Bloch et al. (1957) also found that the three methyl groups of lanosterol
are eliminated as carbon dioxide (via oxidation to carboxyl groups). Several
intermediates and new precursors which function between lanosterol and
cholesterol have now been identified (Cornforth, 1959; Crabbe, 1959).
Finally, studies with yeast extracts have shown the mevalonic acid 5-pyrophosphate, isopentenyl pyrophosphate, geranyl pyrophosphate and farnesyl
pyrophosphate are successive intermediates in the biosynthesis of squalene
(see 32a. VIII).
The biosynthesis of ergosterol from acetate has been carried out by Bloch
et al. (1951), and the distribution pattern corresponds to that of cholesterol.
Bloch et al. (1957) also showed that formate is an efficient source for the
methyl group at C 28
BILE ACIDS
The bile acids occur in bile (a secretion of the liver
stored in the gall-bladder) of most animals combined as amides with
either glycine (NH 2 *CH 2 'C0 2 H) or taurine (NH 2 *CH 2 "CH 2 -S0 3 H), e.g., glycocholic acid (= glycine
cholic acid), taurocholic acid (= taurine
cholic
8.
which
Introduction.
is
C02H
cholanic acid
a/Zocholanic acid
391
STEROIDS
9]
The bile acids are present as sodium salts, and they function as
emulsifying agents in the intestinal tract, e.g., fats, which are insoluble in
water, are rendered " soluble ", and so may be absorbed in the intestine.
The bile acids are hydroxy derivatives of either cholanic acid or allocholanic acid (but see 10). Dehydration of a bile acid by heating in a
vacuum, followed by catalytic reduction, gives either cholanic or a//ocholanic
acid).
acid.
bile acids
Name
Deoxycholic acid
Hydroxyl
M.p.
Lithocholic acid
Chenodeoxycholic acid
Hyodeoxycholic acid
Source
groups
195
172
186
140
197
3a
3a
3a
3a
3a
7a 12a
12a
:
7a
6a
Man,
Man,
Man,
Man,
ox
ox
ox
ox,
hen
Pig
These
9. The structures of cholanic acid and Af/ocholanic acid.
acids may be derived from coprostane and cholestane, respectively, as
follows (cf. 4c). At the same time, these reactions show the relationship
between the bile acids and the sterols (Windaus, 1919).
AZ/ocholanic acid.
HO'
H
cholesterol
cholestanol
H
cholestanone
C02 H
cholestane
a/focholanic acid
ORGANIC CHEMISTRY
392
[CH. XI
Cholanic acid.
cholesterol
cholest-4-en-3-one
coprostanol
C02 H
(!)
CrOa
(ii)
Zn-Hg/HCl
coprostane
cholanic acid
Since all the bile acids can be con10. Structure of the bile acids.
verted into either of the cholanic acids, the former are therefore hydroxy
derivatives of the latter, e.g., lithocholic acid can be converted into cholanic
acid as follows:
HO
H
lithocholic acid
cholenic acid
C02 H
H 2 -Pt
cholanic acid
According to Fieser et al. (1955), cholenic acid is a mixture of the two compounds shown, the chol-3-enic acid being the main constituent.
The positions of the hydroxyl groups in the bile acids have been determined by means of oxidative degradation, e.g., the position of the hydroxyl
group in lithocholic acid is shown to be at 3 as follows. Cholesterol can be
"
STEROIDS
10]
393
viz.,
position 3.
Thus:
C02 H
C0 2H
is not conclusive, since had the hydroxyl group in lithocholic acid been at position 4, III could still have been obtained.
In practice,
however, the oxidation of I produces two isomeric acids for II, one being II
as shown, and the other Ila, in which the ring
is opened between C 2 and
C 3 ; this acid, on further oxidation, gives wolithobilianic acid, Ilia. Since
the oxidation of lithocholic acid, IV, also produces a mixture of the same
two acids, III and Ilia, there can be no doubt that the hydroxyl group is
at position 3.
The configuration of the hydroxyl group in lithocholic acid has been shown
to be a by, e.g., the oxidative degradation of the acetates of lithocholic
acid and epicoprostanol to 5-Moandrosterone (formerly known as 3a-hydroxysetiocholan-17-one).
Since all of the natural bile acids except one (" /?
ORGANIC CHEMISTRY
394
H0
H0
HO
[CH. XI
C02 H
Ilia
all
have there-
H
5 - jsoandrosterone
lithocholic acid
epicoprostanol
see Vol.
The
I).
SEX HORMONES
Hormones are substances which are secreted by the
11. Introduction.
ductless glands, and only minute amounts are necessary to produce the
various physiological reactions in the body. As a group, hormones do not
resemble one another chemically, and their classification is based on their
physiological activity. There appear to be about 60 different hormones
recognised so far, and more than half of these are steroids. The sex hormones
395
STEROIDS
12]
belong to the steroid class of compounds, and are produced in the gonads
Their activity appears to
(testes in the male, and ovaries in the female).
be controlled by the hormones that are produced in the anterior lobe of the
pituitary gland. Because of this, the sex hormones are sometimes called
the secondary sex hormones, and the hormones of the anterior lobe of the
pituitary (which are protein in nature) are called the primary sex hormones.
The sex hormones are of three types: the androgens (male hormones),
the cestrogens (female or follicular homones) and progesterone (the corpus
luteum hormone). The sex hormones are responsible for the sexual processes, and for the secondary characteristics which differentiate males from
females.
ANDROGENS
It was
12. Androsterone, C 19H 30 O 2 m.p. 184-185, is dextrorotatory.
first isolated by Butenandt et al. (1931) from male urine (about 15 mg. from
15,000 litres of urine). Androsterone behaves as a saturated compound,
and since it forms mono-esters, one oxygen atom is present as a hydroxyl
group. The functional nature of the other oxygen atom was shown to be
oxo, since androsterone forms an oxime, etc. The parent hydrocarbon of
androsterone, C^rl^Oa, is therefore C 19 H 32 and since this corresponds to
,
the general formula CH 2 _6, the molecule is tetracyclic. This led to the
suggestion that androsterone probably contains the steroid nucleus, and
since it is a hydroxyketone, it was thought that it is possibly related to
CHs -COO
epiandrosterone
cholestanyl acetate
CH,-COO'
epicholestanyl acetate
HO'
H
androsterone
ORGANIC CHEMISTRY
396
[CH. XI
TsO'
HO-'
5-z.s0androsterone
dehydroepiandrosterone
testosterone
397
STEROIDS
13]
(1935) and Ruzicka (1935) the Oppenauer oxidation step in this method
was introduced by Oppenauer (1937). This preparation of testosterone
This method has been improved
establishes the structure of this hormone.
;
CrOa-CKs-COsH
cholesterol
HO
CH,COO
dehydroepiandrosterone
OH
OCO-CH5
(i)
(ii)
CeHfCOCl
mild hydrolysis
(CH 3 OH-NaOH)
HO
CH3-COO'
0-CO-C6 H5
testosterone
398
ORGANIC CHEMISTRY
[CH. XI
HO'
VV
O"
dehydroepiandrosterone
V \y
O*
androst-4-ene-3:17-dione
testosterone
the other hand, Norymberski et al. (1954) have shown that if there is a double
bond in position 4 5, then the keto group at 17 or 20 is preferentially reduced
to that at 3. Thus androst-4-ene-3 17-dione is reduced to testosterone by
sodium borohydride {cf. 3 i). Johnson et al. (1960) have adapted Johnson's
synthesis of equilenin (17) to provide an improved synthesis of testosterone.
It appears that testosterone is the real male sex hormone in the body;
the others are metabolic products of testosterone. The ketonic steroids are
separated from the non-ketonic steroids (all from urine) by means of Girard's
reagents (P and T); the ketonic compounds form soluble derivatives, and
may be regenerated by hydrolysis (see also Vol. I). Many other hormones
:
have
also
(ESTROGENS
14. (Estrone.
It
has been known for a long time that there are hor-
mones which control the uterine cycle, but it was not until 1929 that
Butenandt and Doisy independently isolated the active substance cestrone
from the urine of pregnant women. (Estrone is the first known member of
the sex hormones, and soon after its discovery two other hormones were
isolated, cestriol and cestradiol.
%U]
STEROIDS
399
/CH 2 OH.
,CH2 MgBr
CH 3
CH3O'
7-methoxy-l:2-cyc/opentenophenanthxene
in oestrone is ring A, and the (phenolic) hydroxyl
'
at position 3; hence the skeleton of oestrone is:
is
Into this skeleton we must fit the keto group, and since this skeleton contains only 17 carbon atoms, another carbon atom must also be placed. The
position of the keto group was shown to be at 17, and the extra carbon atom
was shown to be an angular methyl group at position 13, as follows (Cook
et al., 1935).
When the methyl ether of oestrone, I, is treated with methylmagnesium iodide, compound II is obtained. When II is dehydrated with
potassium hydrogen sulphate to III, this catalytically reduced to IV, and
then IV distilled with selenium, the product is 7-methoxy-3' : 3'-dimethyl1 : 2-cyc/opentenophenanthrene, V.
The formation of
can be explained
only if there is a keto group at position 17 and an angular methyl group at
position 13. It should be noted that in the given equations, the dehydration
is accompanied by the migration of the angular methyl group; this assumption is based on the analogy with known examples in which this occurs
(see overleaf).
400
ORGANIC CHEMISTRY
[CH. XI
HO,
y CH,
(-H a O)
GH 3
CH,0
II
CH3, /CH3
CH3 \ yCH3
CH3O
CH,0
The structure of
Thus the structure
et al.,
1935).
of cestrone is:
cestrone
This has been confirmed by the synthesis of Anner and Miescher (1948).
These authors started with the phenanthrene derivative VI, which had been
prepared previously by Robinson et al. (1938), and by Bachmann et al. (1942).
The first step of the Anner-Miescher synthesis involves the Reformatsky
reaction, and a later one the Arndt-Eistert synthesis.
The stereochemical problems involved in the synthesis of cestrone are not
so complicated as in cholesterol, since only four asymmetric carbon atoms
are present in the hormone (c/. 3). VI contains 3 asymmetric carbon atoms,
and so four racemates are possible. Three have been isolated by Anner and
Miescher, and one of these was converted into () -cestrone (C/D trans) and
the stereoisomer (C/D cis) as shown above. These were separated and the
401
STEROIDS
15]
^^COjCHs
C
,C02CH3
CUJBr-COJJH.n+Zrt-*-
/\ZV/rCH,<XV3H,
CH30*
CH 3
C02 CH3
POClj
CH.N
^W^CHC0 CH
2
aq.
methanolic
AyAcH^COjCHs^"
/\l/C0 2CH3
^
<\Vm3H -C0 H
2
C02 CH3
AgOH ^
CH s OH
(COCI)j
(\>AcH -COCl
CH 2 -CO-CHN2
diazoketone
^C
C02H
/C0 2 CH3
Pb(CO),
160
CH -CH2 C0 H
2
HBr
CH 3 -COjH
CH
HO
()-oestroDe
()-cestrone resolved with ( )-menthoxyacetic acid. The (+)-enantiomorph that was obtained was shown to be identical with the natural com-
pound.
Johnson et al. (1958, 1962) have carried out a total synthesis of cestrone;
each step in their synthesis was stereoselective. Hughes et al. (1960) have
reported total syntheses of cestrone which appear to be simpler than any
previous
method and
just as efficient.
urine
cestrone),
diketone
is
ORGANIC CHEMISTRY
402
[CH. XI
and
cestrone is produced.
It therefore follows that cestriol has the same
carbon skeleton as cestrone, and that the two alcoholic groups in cestriol
are at positions 16 and 17. Structure I for cestriol fits the above facts,
and is supported by the following evidence. When fused with potassium
hydroxide, cestriol forms marrianolic acid, II, and this, on dehydrogenation
with selenium, is converted into a hydroxydimethylphenanthrene, III, which,
on distillation with zinc dust, gives a dimethylphenanthrene, IV. The structure of IV was shown to be 1 2-dimethylphenanthrene by synthesis, and
since marrianolic acid forms an anhydride when heated with acetic anhydride,
it therefore follows that cestriol contains a phenanthrene nucleus and a fivemembered ring, the position of the latter being 1 2 (where the two methyl
groups are in IV). Finally, the structure of III was shown to be 7-hydroxy1 2-dimethylphenanthrene by synthesis (Haworth et al., 1934), and so if I
is the structure of cestriol, the degradation to the phenanthrene derivatives
may be explained as follows:
:
C02 H
..OH
Hg-COgH
HO
Se
HO
II
HO
III
is
cestrone, cestriol
and
cestradiol (16)
HO
cestrone
cestradiol
403
STEROIDS
15]
NOH
Zn
dust
CH 3 -COjH
CH 3
methyl ether of cestrone
/OH
HBr
Na
(CH,) s CHOH
CUs-COjH
CH3O
CH3O
OH
Leeds
method:
et
al.
(1954)
cestriol
by a simpler
OAc
HO
and
is
ORGANIC CHEMISTRY
404
16. (Estradiol,
and
j8;
[CH. XI
(Estradiols,
the a-isomer
HO.
OH
,H
HO
HO
ot-cestradiol
p-oestradiol
(oestradiol-17(3)
(cestradiol-17et)
a-(Estradiol was first obtained by the reduction of cestrone (see 15), but
was isolated from the ovaries of sows (Doisy et al., 1935). When
the phenolic methyl ether of cestradiol is heated with zinc chloride, a molecular rearrangement occurs, the angular methyl group migrating to the
This compound, when dehydrogenated
(c/. 2 viii. X).
cycZopentane ring
with selenium, produces 7-methoxy-3'-methyl-l 2-cyc/opentenophenanthrene, the structure of which has been ascertained by synthesis (Cook et al.,
Thus the structure of cestradiol is established.
1934).
later it
OH
CHjN a
HO
CH 3
-oestradiol
CH3O
7-methoxy-3 -methyl-1: 2cyc/opentenophenanthrene
Velluz et al. (1960) have synthesised cestradiol starting from 6-methoxy1-tetralone; this is therefore a total synthesis of the hormone.
/?-(Estradiol has been isolated from the pregnancy urine of mares (Wintera-QEstradiol is much more active than cestrone, whereas
steiner et al., 1938)
It appears that cestradiol is the real
/5-cestradiol is much less active.
hormone, and that cestrone and cestriol are metabolic products. It might
be noted here that when the second cestradiol was discovered, the earlier
.
"a
"-isomer.
Subsequently, this
STEROIDS
17]
405
17/? configuration,
fi
"-isomer the
17a configuration.
A very active synthetic oestrogen is 17ce-ethinyloestradiol, and has the
advantage that it is very active when taken orally. This synthetic compound has been prepared by the action of acetylene on cestrone in a solution
of liquid
ammonia
containing potassium.
OH
/C=CH
K-NH.
C 2 H2
HO
HO
cestrone
17.
1 7a-ethinylcestradiol
(+)-Equilenin, C18H 18
2,
double bonds (cf. cestrone, 14). When the methyl ether of equilenin is
treated with methylmagnesium iodide, then the alcohol dehydrated, catalytically reduced and then dehydrogenated with selenium, the product is
7-methoxy-3' 3'-dimethyl-l 2-cycZopentenophenanthrene, II (cf. cestrone,
Thus the structure of equilenin is the same as that of cestrone, except
14).
that the former has two more double bonds than the latter (Cook et al.,
Now the absorption spectrum of equilenin shows that it is a naph1935).
thalene derivative. Thus, since ring A in cestrone is benzenoid, it appears
probable that ring B in equilenin is also benzenoid, i.e., rings A and B form
the naphthalene nucleus in equilenin. All the foregoing reactions of equilenin may be readily explained by assuming that I is its structure, and
further evidence that has been given to support this is the claim by Marker
et al. (1938) that equilenin may be reduced to cestrone, III, by sodium and
ethanol. This reduction, however, has apparently never been substantiated
:
(cf.
Dauben
et al.,
1956).
Cxi v
CHoO
CxLj
HO
equilenin
[CH. XI
ORGANIC CHEMISTRY
406
who
NH-CO-OHs
NH,
(CH 3 -CO) s O
HO
H03 S
Cleve's acid
NH,
(i)(CH3)aS04 -NaOH
(ii)
hydrolysis
(i)
(ii
CH..0
>
N aN02-H 2 S04
KI
CH3O
/ CH
CH.OH
CH 2
PBr 3
CH 3
CH3
.CH^
OH.
QH2
C02 H
(i)SOCla^
(ii)SnCU
CH3O
CH
IV
Br
STEROIDS
17a]
407
OHO
) HCOjCjH.
CH.ONa
n ^
'
CH3o
CH,0
CH
vN.
[c
vy
X
r
l
NHaOHHCl
CHj'COjH
"1
>OH
OH
CH 3
CH3
Pd-C
Reduction of
17a. (+)-Equilin, C 18 20O ?) m.p. 238-240, has also been isolated from
the urine of pregnant mares (Girard et al., 1932), and its structure has been
shown to be:
ORGANIC CHEMISTRY
408
[CH. XI
HO
equilin
(1939) as follows:
anisaldehyde
de
anisoin
<r~^CH CO^T~^OCH
CH3
deoxyanisoin
C2H5
C 2 H 6 ONh
c2 h b i
QHsMgl
* CH
OOH 3
CH-CO
Q2HS C2H5
*-
CH,0
CH
OCH3
I
OH
C2H5 C 2
PBr 3
->-
(-H2O)
CH3O
C==C
OCH,
O2H5 CjHs
ethanolic
KOH
HO
C=C
OH
stilboestrol
The above
HO
rrans-stilboestrol
STEROIDS
19]
Kharasch
409
et al.
The
presence of alkali.
the one given.
structure of I
uncertain, but
is
-^
CH 0<^
it is
believed to be
J)>CHBrCH2 -CH 3
anethole
NaNH 3
liq.
NH 3
H30Yy-CH-CH-<^y>0CH3
CH
CH 2
II
Hexoestrol (dihydrostilbcestrol)
bromide as follows:
may
=
2CH3o/~ ~\cHBrC 2H 5 -^+
CHaO^^^CH-CH-^^^OCHs
m^t c2h6
KOH
HO^-CH-C^^^OH
C2H 6 C2H5
hexoestrol
The
Crowfoot
GESTOGENS
C 21H 30O 2 m.p. 128, was
19. Progesterone,
form by Butenandt et
[CH. XI
ORGANIC CHEMISTRY
410
absorption spectrum of progesterone, however, shows that it is an a /Sunsaturated ketone, and this suggests that the position of the double bond
is 4
5 (see below). Finally, progesterone has also been synthesised from
diosgenin and from pregnanediol, and the preparation from the latter, taken
in conjunction with the others, definitely shows that the position of the
double bond in progesterone is 4 5.
(i) Progesterone from stigmasterol (Butenandt et al., 1934, with improvements by other workers).
:
CHj-COO
CH CO
3
CH3
N
C=C(C6 H 5
pregnenolone
CH 3
CO
)2
progesterone
STEROIDS
19]
411
(ii)
first
(i)(CH 3 -CO) 2 Q
(ii)
HCN
HO
HO'
dehydroepiandrosterone
cholesterol
HO
CN
CH 3COO
CH,M g Br
HO
pregnenolone
progesterone
ORGANIC CHEMISTRY
412
[CH. XI
Diosgenin
Progesterone from diosgenin (Marker et al., 1940, 1941).
sapogenin) occurs as a glycoside in the root of Trillium erectum.
(iii)
(a
diosgenin
CrO,
CH,COO
pregnenolone
progesterone
is
known
STEROIDS
19]
(iv)
Progesterone
413
et al.,
1930).
CH,
CH,
I
CHOH
IHO-COCH.
KOII
HO
CH,COO
H
pregnanediol
CH3
CHO-COCH
(ii)CrOa
HO'
CH3
CO
CH3
CO
C,H 6 N
(-HBr)
<y
O"
-I
Br
pro jesteroiu*
[CH. XI
ORGANIC CHEMISTRY
414
(v)
et al.,
1955).
This appears to
HO
ergosterone
ergosterol
MeO
jjoergosterone
CHO
C 6 H 10 NH
CH,
progesterone
20. Pregnane-3ot 20a-diol, C^HsgOa, was isolated from human pregnancy urine by Marrian (1929) it is biologically inactive, and is the main
metabolic product of progesterone. The functional nature of the two oxygen
atoms was shown to be secondary alcoholic, and since pregnanediol is saturated, the parent hydrocarbon is C 21 H3 6 and so the molecule is tetracyclic.
Pregnanediol gives the haloform reaction; thus a CH 3 'CHOH- group is pre:
415
STEROIDS
22]
I)
When oxidised, pregnanediol is converted into the diketone
pregnanedione and this, on the Clemmensen reduction, forms pregnane,
C 21 H 36 This is identical with 17-ethylsetiocholane, a compound of known
structure.
Thus pregnanediol contains the steroid nucleus, and the position
of the side-chain is 17.
Finally, the relationship between pregnanediol and
progesterone shows that the former contains one hydroxyl group at position 3.
Further work showed that the configuration of the 3-hydroxyl group is a.
Thus:
CH
CHOH
3
HO'
H
pregnanediol
pregnanedione
Zn-Hg
;
HCl
gesterone
produced by oxidation during the isolation of the hormones from the cortical
extract. Adrenosterone is as shown, and possesses androgenic activity
(see overleaf).
416
ORGANIC CHEMISTRY
[CH. XI
andrenosterone
The
six active
letters as well as
Substance
compounds are as
named
follows (they
systematically).
2 1 -Hy droxyprogesterone
Corticosterone
11 21-Dihydroxyprogesterone
:
l-Deoxy-17-hydroxy-
1 1 -Dehydrocorticosterone
2 1 -Hydroxy- 1 1 -ketoprogesterone
Substance M;
Substance S;
1
Compound A;
Substance H;
1 1 -Deoxycorticosterone
Substance F;
Compound E;
7-Hydroxycorticosterone
corticosterone
1 1 -Dehydro- 1 7-hydroxy-
corticosterone
cortisone
Owing
The
STEROIDS
22]
417
tion and by partial syntheses from sterols of known structure, e.g., deoxycorticosterone from stigmasterol (Reichstein et al., 1937, 1940). The first
step is the conversion of stigmasterol to pregnenolone (see 19 i).
C02 H
(i)(CHyCO)Q
(ii)
SOCl a
HO
HO
pregnenolone
O-0HN2
COC1
(i)CH 2 N g
(ii)KOH
HO
CHa-COO'
CH2OH
COCHN
/\
X
^nn
Oipenauer
CO
2
y\
\
H 2 SO t>
ov
0'
deoxycorticosterone
above synthesis
is
leaf).
ORGANIC CHEMISTRY
418
[CH. XI
CH2OCOCH3
CH 2 0-COCH3
I
CO
C(OH)-CN
CH 3 COO
vH
CH3-COO'
CH2 OH
CH2 0-COCH3
OCN
C-CN
(i)
(ii)
POClf-CH,N(-H a O
KOH
HO'
CH2OCOCH3
I
CHoOH
/ON
->o
-o
CH 2 0-COCH3
CHjOH
00
-OH
(i)(CH,-CO) a O
(i)-HBr
cortisone
A UXINS
23. It had been suggested for some years by botanists that various substances
had plant growth-promoting properties, but it was not until 1933 that such
compounds were actually isolated. In 1933, K6gl et at. isolated an active compound from human urine, and they named it auxin a and showed that its structure is I. Soon afterwards, Kogl et al. isolated auxin b (II) from maize germ oil.
419
STEROIDS
23]
C,H,-CH-^
^-CH-CsHs
^CHOH-CHuCHOHCHOHCOjH
I
auxin a
>- CH-C H
C.H.- CH~<;
^CHOH-CHjCOCHjCOjH
II
auxin b
The name auxin is now taken as the generic name for the plant hormones.
Auxins generally occur in the plant kingdom, but are also present in urine, etc.
Further work by Kogl et al. (1934) led to the isolation from urine of another
growth-promoting substance which the authors named " hetero-auxin ", and
subsequently showed that this compound is indole-3-acetic acid.
CH,-C0 8 H
to
indole-3-aoetic acid
V.
pH2 -COjH
CHjCOjH
^jOCHjCOaH
IV
Recent work has suggested that indole-3-acetic acid is the natural plant
hormone, and not auxins a and b. In fact, there now appears to be some doubt
as to the existence of auxin a (auxentriolic acid) and auxin b (auxenolonic acid)
neither of these compounds has been isolated since Kogl obtained them.
The relation between chemical structure and growth-promoting properties has
still to be solved, but nevertheless much progress has been made in this direction.
Koepli et al. (1938) believe that a plant hormone must have a ring structure
containing at least one double bond, and a side-chain containing a carboxyl
group (or a group capable of being converted into a carboxyl group) removed
from the ring by at least one carbon atom (cf. compounds I-V)
These requirements, however, have been modified by Veldestra (1944- ).
.
READING REFERENCES
Fieser and Fieser, Steroids, Reinhold (1959).
Gilman (Ed.), Advanced Organic Chemistry, Wiley
ORGANIC CHEMISTRY
420
[CH. XI
Cook
Steroids.
Skoog
Growth Hormones
(p.
5).
Plant
CHAPTER
XII
or
of precedence established
by
rule
(i).
e.g.,
The hetero-atoms in
e.g., O by oxa, S by
by
prefixes,
AZOLES
Azole is the suffix used for five-membered rings containing two or more
hetero-atoms, at least one of which is nitrogen.
2.
PYRAZOLE GROUP
Pyrazole may be synthesised in
of the
(i)
III
CH
CH- CH
+ CH 2 N2
ti*
CH5
2N
H
(ii)
By
CH2 ^
> + NH \NH
ch/
2
CH2 -NH-NH
CHOH -CH2
CHOH
CH 2
*-
CH2 C1
N2 H4
CH2C1
^
II
+ 2NH 3
H
421
NH
\NH/
422
ORGANIC CHEMISTRY
[CH. XII
HO,C
|C0 2
gjjO
HO
(iv)
e.g.,
by
o-
3 CO,
by the condensation
of
1:1:3:
(C a B 0) aCH.CH a -CH(OC a 6 ) a
with hydrazine dihydrochloride.
Properties of pyrazole. Pyrazole is a colourless solid, m.p. 70. It
is a tautomeric substance; the existence of tautomerism cannot be demonstrated in pyrazole itself, but it can be inferred by the consideration of pyrazole derivatives. If pyrazole is tautomeric, then the positions 3 and 5 will
be identical; if pyrazole is not tautomeric, then these positions are different.
Now Knorr et al. (1893) showed that on oxidation, both 3-methyl-l-phenylpyrazole and 5-methyl-l-phenylpyrazole gave the same product, viz., methylpyrazole. Thus positions 3 and 5 must be equivalent in pyrazole, and this
II
^H
H
II
-Q
H
v"
H
3-substitution
stable,
4-substitution
HETEROCYCLIC COMPOUNDS
2a]
423
Orgel el al. (1951), however, have calculated the electron distribution in pyrazole, and it can be seen from their results that 4-substitution will be favoured by electrophilic reagents. Brown (1955, 1960) has
also calculated the electron densities in pyrazole.
stitution.
-Oil,
,0-07
0-06 k
/N-0-38
W
H
0-36
note that pyrazole-4-diazonium salts are stable to boiling water. Pyrazole is feebly basic, and forms salts with inorganic acids;
the imino hydrogen may be replaced by an acyl group. Pyrazole is very
resistant to oxidising and reducing agents, but may be hydrogenated cataBoth of these comlytically, first to pyrazoline, and then to pyrazolidine.
pounds are stronger bases than pyrazole.
It is interesting to
VH
^N
catalyst
CH2 /NH
catalyst
pyrazolidine
pyrazoline
2a. Synthesis of
(i)
pyrazole derivatives.
/CO
CH2
X
=^^=
CO
COH
HNR
CH
+
V
CO
H2 N
|
* CH
X
I,
I,
',
R'
/CO
CH2
N
=?=^
CH
"^COH
R'
/C=N
HN
CO
CO
+ 2H 2
C=N
R
I
(b)
R
^C NR"
(a)
by the
and hydrazines (Knorr
CH
*I
+ 2H 2
^C NR"
HNR"
R'
R'
Thus, according to the above, a mixture of isomeric pyrazoles will be produced. Contrary to general opinion, the product is usually only one of
the isomers, e.g., benzoylacetone and phenylhydrazine form only 3-methyl1
5-diphenylpyrazole (Drumm, 1931).
:
CH COCH
CH2-CO-CH 3
T
C6 H5-CO
=f=*=
II
C 6 H5 COH +/NH 2
*~
C6 H5
NH
CH-C-CH 3
1 Q xt
Cs ^N
||
||
^"^
C6 H5
CeH5
In a few cases, two isomers have been isolated, e.g., 3-a-benzoylacetyl-l 5diphenylpyrazole, I, reacts with phenylhydrazine to produce a mixture of
1'
5 : 5'-tetraphenyl-3 : 3'-dipyrazolyl, II, and 1 1' 3' 5-tetraphenyl1
3 5'-dipyrazolyl, III (Finar, 1955).
:
424
ORGANIC CHEMISTRY
CH
II
||
C-C 6 H 5
[CH. XII
+ C 6 H5 NH-NH 2
C6 H 5
CH C C
C6H
II
-0
5
OH
VIIV
II
CC H5
.N
C 6 H 5 -C
II
II
C6H5
11
CH
VIN.
II
C-C
CH
II
6 6 H5
\ N/
C6 H5
II
ll
X>C 6 H5
C 6 H5
III
CH2
C2H 5
>-H 20+
CH
C'Cri3
Jl
C 2H 5
C'CH3
-|
+C H OH
II
CO
JZ
HN
/NH 2
2
CH2
C'Gri3
1T
W
H
(ii) Pyrazolecarboxylic acids are produced by the reaction between diazoacetic ester and acetylenic compounds, e.g., with ethyl acetylenedicarboxylate, ethyl pyrazole-3 4 5-tricarboxylate is formed.
:
C 2H5
C 2 H5
2 C-C
III
C-C
2
CH-C0 2 C 2H5
C 2H5
C-C
*-
II
C 2H6
N2
C-C0 C H
2
II
II
2 C-C
y
H
s
3:4:
5-tricarboxylate.
C 2 H5
C-CH
CH-002 C 2H6
CH-C02 C2 H6
N" 2
C 2H6
H5 CCH 1
/
'
\lN
N
r-c=c-co-r'
R-C=CC-r'
r"-nh-nh 2
R"-NH
R-CCH C0R'
2
'nh-r"
CH C-R'
II
II
R-C
/N
CH
R-C
II
II
C-R'
1*
i-
i-
HETEROCYCLIC COMPOUNDS
2a]
425
OH
CHO
CH 2
NH
NH
CH CH
CH 2 N
CH2OH
CH2 #
VH
lT
Pyrazole-3-
and 5-carboxylic
H5
by heating
^
V
e.g.,
HO^
HO.C^CO.H^
H0C
stable,
J!N
V
H
Although pyrazole
e.g.,
o
N/
CHr-CH
^*/
C,H,OH
CeH5
CeHs
are produced,
CH 3 V
CH3
+ CH 2
HC
*-
N/
H
n
nCH3
?
CH 2 OH
HOOH
nCH 3
2n
HOCH
2n
[rCH 3
7
CH 2 OH
(main product)
ORGANIC CHEMISTRY
426
[CH. XII
CH 2 C1
+ CH 2
+ HCI
N
I
C,H 6
4-Chloromethyl-l-phenylpyrazole can be converted into 1-phenylpyrazole4-aldehyde by means of the Sommelet reaction (see Vol. I). The 4-aldehyde
is more conveniently prepared by the direct formylation of 1-phenylpyrazole with dimethylformamide and phosphoryl chloride (Finar et al., 1957).
1-Phenylpyrazole can also be mercuratedin the 4-position (Finar et al., 1954).
When boiled with concentrated aqueous potassium hydroxide, quaternary
pyrazoles are converted into hydrazines (Knorr et al., 1906), e.g.,
+ cH 3
i-^riSCHsfr-^V
N
I
C6 HB
cbHs
Knorr used
same time,
salts.
CHC0
R-CH
R-CH
RCH,
I
RCH
RCH C-C0 2 C 2 H 5
RCH-
C 2 H6
RCH
N.
Cu
heat
H
CH-C0 2 C 2 H5 + N 2
Antipyrine
is very
prepared industrially by condensing ethyl acetoacetate with phenylhydrazine, and methylating the product, 3-methyl-l-phenylpyrazole-5-one, with methyl iodide in alkaline
ethanolic solution, or with methyl sulphate in the presence of sodium
hydroxide.
much used
(2
in medicine as
CH 3 C OH 2
-
febrifuge.
It is
CO.C 2 H 5
+ C.H.NH-NH,
Oxlg" C
"
CHg
N C02C2H6
NH
C H5
I
-CH 2
CH,C-
+ C 2 H5 OH
CH 3 I
CH,C=
?H
CH 3 JJ
CO
N
I
C 6H5
3-methyl- l-phenylpyrazol-5-one
CeHs
antipyrine
At first sight one might have expected to obtain the O-methyl or the 4-methyl
derivative, since the tautomeric forms IV (keto) and V (enol) are theoretically
HETEROCYCLIC COMPOUNDS
2b]
possible.
methane
Methylation
of
0H2
CO
HN
i
i
CsHs
C 6 H5
IV
diazo-
(this is also
CH3 C=CH
11
II
NT
0-methyl derivative
OH
COH
CH3 C
i-
with
3-methyl-l-phenylpyrazole-5-one
CH3 C
427
CO
C6 H5
VI
CH3 C
CH. rc=c:
OH
CO
OC 2H5
'
CH + H
CH3 N
CH3-NH VN
+ C 2H6 OH
CO
I
NH
CH
C 6H6
The pyrazole nucleus has always been considered to be a synthetic one,
but Fowden et al. (1959) have now isolated a-amino-j8-l-pyrazolylpropionic
acid from water-melon seed; this acid has been synthesised in good yield
by Finar
et al.
(1960).
H
-HjO
Indazole
may
conveniently be prepared
by heating
o-2V-nitroso-2V-benzoyl-
CO-C6 H5
NO
J*+C 6 Hs -C0 2 H
kAcH
Indazole, m.p. 146, exhibits the same type of tautomerism that exists
in pyrazole, since two series of 2V-derivatives (1 and 2) are known:
Nitration
ORGANIC CHEMISTRY
428
[CH. XII
IMIDAZOLE GROUP
This group of compounds
is also
known
CHO-CHO + H 2
(ii)
CHO
CHO + H- C0 2H
H-
>-
CH-N
NH
h-CHO
NH
3
CHO
>-
II
II
CH /CH
\
N
+ 3H 2
amount
certain
may
glyoxaline
hyde.
A general method for preparing imidazoles is by the reaction between
an oc-dicarbonyl compound, ammonia and an aldehyde (Radziszewsky, 1882).
R c=0
+2NH
R C=0
,
RC
+ R-CHO
->
,||
||
RC
CR
+ 3H2
H
Imidazole itself is best prepared by the action of ammonia on a mixture of
formaldehyde and tartaric acid dinitrate (" dinitrotartaric acid "), and then
heating the dicarboxylic acid thereby produced.
C0 2 H
co
C0 2 H
I
cho-no2
_ 2MN0
<W>,
C0 2 H
"Ao
a
n
^^H0 CC 1h~^U
2NH3
ho
c-c
ann
2
C0 2 H
3oo,
CH O.
>H.CH 2Br
CH.-0 7
|
CHO
I
CH2 Br
-S
NHs
is
(positions 5,
Imidazole
-N
3H5
2CHf
CH* 2Cf
$CH*2CHm
HETEROCYCLIC COMPOUNDS
3a]
429
o^a
W
ch 3 i
KOH
1))CH
'N
i.
!
An
CH3-CO
I
+2NH 3 +CH
CHO
/
xr/
CH3n
+ 3H2
H
The imidazole ring is extremely stable towards oxidising and reducing
agents hydrogen peroxide, however, readily opens the ring to form oxamide.
;
CONH
h 3 q,
CO-NH2
'N'
CH-NH-COC 6 H:
+ 2C6 H6 -COCl+3NaOH
+ H-C0 2 Na+2NaCl
H|
CH-NH-COC6 H,
[J
ntnj/
li
Nitration
"
:
|
[=N
f=^
II
III
IV
is
2:4:
5-tribromoimidazole.
Brn
+ 3HBr
Br
Imidazole couples with diazonium salts in the 2-position, but iV-alkylimidazoles do not couple at all.
3a.
Benzimidazoles (benziminazoles).
e.g.,
benzimidazole
itself
ORGANIC CHEMISTRY
430
(m.p. 170)
is
[CH. XII
acid.
jm
(f
NH2
CH+2H
OXAZOLE GROUP
tso-Oxazoles are formed by the dehydration
4. wo-Oxazoles.
monoximes of /?-diketones or /?-ketoaldehydes.
R-C
I
ft
CH2
T
COR
OH
CH
R-C
^=^
>
RC,
C-R
N2
OH OH
C-CHO
III
NH OH2
CH
by the
III
II
5CR
O'
action of hydroxylamine on
CH CH
CH
II
II
CH
.CH
II
of the
II
CH
HO
wo-Oxazole is a colourless liquid, b.p. 96, and smells like pyridine; it is
weakly basic. wo-Oxazoles, when substituted in the 3 5-positions, are
stable to alkalis, but when the 3-position is vacant, the ring is opened to
form ketonitriles (cf. oximes, 2f, 2g. VI).
:
OH CH
II
-Ss^R-CO-CH^ON
II
RC.
2T
XT
4a. Oxazoles. Oxazoles may be prepared by the condensation of acid
amides with oc-halogenoketones, e.g., acetamide and co-bromoacetophenone
form 2-methyl-4-phenyloxazole the mechanism of the reaction is not certain
but it may occur through the enol forms.
;
__
NH2
C 6 H 5 -CO
C 6 H 5 -C0H
CHBr
CH 2 Br OC-CH s
C 6 H5 C-ijN
II
(coCHs
+ HBr +
II
NH
HOCCH
2CCH3
CH-NH
R-CO
COR'
^_
CH
_ Hl0
>
RC VX
C-R
OH HO'
VJ R
Oxazoles have basic properties similar to those of pyridine, but are less
They possess aromatic properties, and the stability
resistant to oxidation.
of the ring towards hydrolytic reagents depends on the nature of the sub-
431
HETEROCYCLIC COMPOUNDS
5]
(c/.
t'so-oxazoles).
oxazole, has
4b. Benzoxazoles.
%^CH
NH>
+
OH
>-
/
H0
Ay\.^CH+aHjO
[
VN/
|
THIAZOLE GROUP
r-co
>R"
R'-CHC1
R |r- N
_
r
R'&,
PR"
^b-coh
HC1
CR*
R'CCl
N S/
HS'
S^
Thiazole itself may be prepared from chloroacetaldehyde and thioformamide.
CHO
NH
+1 2
CH2 C1 CH
I
QH0H
^=^
n11
*
II
tf
+H 0+HC1
II
^/
JCH
CHCI
CHO
CH2 C1
NH2
NH
CHOH
+
II
i-NH2 "
\\
l^
C-NH2
CHCI
^NH
H 0+HC1
2
OL *- n
NaNO;
HCI
Another general method for preparing thiazoles is by the action of phosphorus pentasulphide on a-acylamidocarbonyl compounds.
CH2 NH
R-CO
CO-R'
"
CH
R-C
C-R'
\>H HO
2-Mercaptothiazoles may be prepared by the condensation between achloroketones and ammonium dithiocarbamate.
R-CO
I
R'-CHC1
NH2
|
C-SNH4
Rn
>-
N
I
R'V >SH
. + XTTI
+H
NH C1
_,
432
ORGANIC CHEMISTRY
[CH. XII
CH,
+ Br2
OOH
5a. Thiazolines.
These
may
e.g.,
CH.
II
OR
HS
A characteristic reaction
of acids,
II
CHjjBr
+ HBr
NH
CHjj-NH,
Br'
CH 3 n
chci 3
CR
NH
Br
S
of the thiazoles
is
by the
action
e.g.,
CH2
CH 2 -NH
HCl
II
CH2 SH
.CCH3
2 -ami noethanethiol
2-methylthiazoltne
H0
,HO- 2 C-CH-NH 2
+ R-CO-R
CH2 SH
C-CH
*"
'
NH + H,0
J,
The
XVIII).
/y
NH
CH
(CH 3 -CO)jO
2JCH+2H 2
/
HO
by the
p s s
NH-CO-CH.
C-CH,
HETEROCYCLIC COMPOUNDS
6]
433
it
may
C-SH+H2
+ CS 2
\AoH
5d. iso Thiazoles. Benzwothiazoles have been known for many years,
but no derivatives of isothiazole itself have been obtained until very recently
when Adams
its
et al.
is
of
e.g.,
iNH,
/soThiazole
simple derivatives,
[o]
-2co2
OC0
fCOjH
2
TRIAZOLE GROUP
Triazoles are five-membered rings
6. Osotriazoles and triazoles.
which contain two carbon and three nitrogen atoms. Two structural isomeric triazoles are known, the 1:2: 3-(l 2 5-) and the 1 2 4- (1 3 4-),
the former being known as osotriazole, and the latter as triazole. Each
exists in two dissimilar tautomeric forms.
:
CH-
iNH
CH
HNj
CHs zN
CHz
H
of the imino
osotriazole
FT
Replacement
CH^N
H
CH=N
3
Ill
triazole
triazoles
and two
hydrazoic acid.
CH
HN
CH
S
CH
CH
On
the other hand, a general method for preparing osotriazoles is the condensation of azides with j8-ketoesters, e.g., phenyl azide and ethyl acetoacetate form ethyl 5-methyl-l-phenylosotriazole-4-carboxylate.
C6 H 5 -N3 +
CH2 -C02 C 2H 5
J^
TI
CO-CH
3
*-
CC0 2 C 2 H6
N
I
N
CCH
|c 3
N
CHS
ORGANIC CHEMISTRY
434
[CH. XII
benzilosazone gives
1:3:
4-triphenylosotriazole.
C 6 H5-C=N-NH-C 6 H6
C 6 H6 -C=N-NH-C6 H6
C6 H5-C=N
>C H
C 6 H5-C=N
+ C6 H5 -NH2
e.g.,
OCH
NH
NH,
HC=0
N=
CH
CH
NH
H,N
+ 2H 2
NHNH
I
N-
CH3-CO
-N
+2H2
II
CH 3-C
CO-CHs
ZnCla
^C-CHs
CH3C
OH HO
NN
^CCHa
CH,
v-
CH,
CH,
Both
triazoles are
Benzotriazole
is
diamine.
=NC1
HCl
HNO,
+HC1
\K
CH
II
II
CH
\>'
1:2:3-
oxadiazole
f
c
N
CH
ff
II
\/
N
6h
II
\>
1:2:4-
1:2:5-
1:3:4-
oxadiazole
oxadiazole
oxadiazole
R-C CH
NaOH
R|? _
-C-B
V
II
NOH noh
of
sodium
+ h2 o
O O
HETEROCYCLIC COMPOUNDS
8]
435
2
'
*
/y CHiC0
^\m
CH 0=0
T
W^l
/
(CH,CO),0
_ Ha0)
(
Earl (1946) proposed the name sydnone for compounds of this type; thus
the above compound is iV-phenylsydnone.
Sydnones are white or pale yellow crystalline compounds, which are
hydrolysed by hot 5 per cent, sodium hydroxide to the original iV-nitroso2V-ary]glycine, and by moderately concentrated hydrochloric acid to an
arylhydrazine, formic acid and carbon dioxide.
The structure proposed by Earl is similar to that of a yS-lactone, but
Baker
et al.
number
e.g.,
(i)
system containing fused three- and four-membered rings would be
highly strained, and consequently is unlikely to be produced by dehydration
with acetic anhydride; /?-lactones are not produced under these conditions.
(ii) Many /3-lactones are unstable to heat; sydnones are stable and so
the /S-lactone structure is unlikely.
(iii) If the /S-lactone structure is correct, then sydnones should be capable
of existing in optically active forms.
Kenner and Baker (1946) prepared
(+)-2V-nitroso-2V-phenylalanine, and when this was converted into a sydnone, the product was optically inactive. If Earl's structure were correct,
then the sydnone would be expected to be optically active.
CH3
CH,
Jm>C0 H
C 6H B-KX
CO
*"
Ctf.-N
N0
NN
by
an
+/
CH=C-0
Ar-N
^N
I
--
^=0-0
X
N=0 +
Ar-N.
CH-C-0
+/
- - Ar-N.
^N
II
III
Now Simpson (1945) had proposed structure IV for 3-methyl-5 6-dimethoxyanthranil; Baker et al. (1949) adopted this
sign and suggested
that sydnones be represented by structure V. Baker also proposed the
:
CH C=0
Ar-N^
ORGANIC CHEMISTRY
436
[CH. XII
CHC
Ar-N
(+)
Va
"
is
CH-C=0
Ar-N/.
NN
5h-c=o
Ar-IST _
X
VI
VII
TETRAZOLE GROUP
Tetrazole is a five-membered ring which contains one
9. Tetrazole.
carbon and four nitrogen atoms. There are two tautomeric forms of tetrazole, and replacement of the imino hydrogen by, e.g., an alkyl group gives
rise to
two iV-alkyltetrazoles
triazoles, 6).
(cf.
CH
N5
||
CH=N
^=^
||
2N
*|
HNi
H
Tetrazole may be prepared by heating hydrogen cyanide with hydrazoic
acid in benzene solution at 100.
CH
CH
I +HN
"I
\n-
HETEROCYCLIC COMPOUNDS
11]
437
C6 H5 -CH=N-NH-C6 H5 r H ON C6 H 6 -C=N-NH-C6 H6
C a 5 QNa^
N=N-NH-C 6H 5
C 6 H 6 -N3
^_
<
>C H
+ C6H,NH 2
6
AZINES
The suffix azine is used for six-membered rings which contain two or
more hetero-atoms, at least one of which is nitrogen.
DIAZINE GROUP
10. Introduction. The diazines are six-membered rings containing two
nitrogen atoms. Three isomeric diazines are theoretically possible, and all
three are known.
o-diazine
-diazine
/>-diazine
pyridazine
miazine;
piazine;
pyrimidine
pyrazine
i.e.,
Pyridazines.
11.
on
These
may be
by atmospheric oxygen.
CO
COH
R
Pyridazine
hydrate.
itself
may
NH
CH
H^N
CH
CH 2
/\
R
CHO
CH
II
CH
NH
NH
+1
CHO
Pyridazine
is
ORGANIC CHEMISTRY
438
[CH. XII
PYRIMIDINES
Ureides. Ureides are acylureas, and may be prepared by the action
an acid anhydride or acid chloride on urea, e.g.,
12.
of
/.NH2
XNH
(CH,-CO),0
/NH-00-CH3
^VNH
/JSIH-COCHs
(CH,-CO),0
>
NNHCO-CH3
acetylurea
diacetyJurea
The simple
NH 2-CONH +
2
(ii)
By
Cl-CO a
free state,
but
Rv NH -CONH-C0 R + HC1
2
-C0 2R
NH
TTTWO
>
-CONH-C0 2R
O
0.
naturally
W ^0^
H0 C
.NH2
^x
It
ho 2 c
nh2
.CO.
\CH
fH
/C
%ra
A much
.CO.
C2 H 6
/NH2
CO
\H
+
2
>H
C '" ONa
2
C^Ac'
j^
>
|
\H +
|
CO
X
CO
NH X
2C2 H5 OH
HETEROCYCLIC COMPOUNDS
13b]
439
Barbituric acid is a solid, m.p. 253, and is not very soluble in water. It
strongly acidic due to enolisation (lactam-lactim tautomerism) ; some
Structure IV represents barbituric acid
possible lactim forms are II-IV.
is
OH
/a\
NHi
5CH2
COa
4CO
NH
__
CH 2
HOC.
__
CO
N
HOC!
Ctt,
CO
A
V
N
HOC
CH
COH
IV
III
II
OH
C \
as 2 4 6-trihydroxypyrimidine, and this structure has been proposed because of the acidic nature of barbituric acid. On the other hand, barbituric
acid contains an active methylene group, since it readily forms an oximino
derivative with nitrous acid. Thus barbituric acid behaves as if it had
structure I, II or III. Furthermore, it is very difficult to acylate hydroxypyrimidines containing hydroxyl groups in the 2-, 4- or 6-positions, thus
indicating that structure I is more probable than II or III. This is supported by the fact that methylation of hydroxypyrimidines with, e.g.,
methyl iodide in the presence of sodium hydroxide, results in the formation
of iV-methyl derivatives this indicates the probable presence of imino groups.
On the other hand, it is possible to replace three hydroxyl groups by three
chlorine atoms by means of phosphoryl chloride; this suggests barbituric
acid behaves as IV. Barbituric acid also forms O-alkyl derivatives, thereby
indicating structures II, III and IV.
Barbituric acid can be nitrated and brominated in the 5-position, and
By means of the sodio
also forms metallic derivatives (at position 5).
derivative, one or two alkyl groups may be introduced at position 5 (this
reaction is characteristic of the
CH 2 *CO group). Barbituric acid and
5 5-dimethylbarbituric acid have no hypnotic action. On the other hand,
5 5-diethylbarbituric acid (Barbitone, Veronal) has a strong hypnotic action
it is best prepared as follows:
:
/NH2
CO
\ra2
c2 h
(C 2 H5) 2
ch.on
CiH,ONa
>
Ac^
C(C 2
5/2
5
)2
5-cycZoHexyl-3
than Barbitone
nal) is
/CO\
C2 H5 2C x
13b. Derivatives of barbituric acid. Violuric acid (5-oximinobarbituric acid) is formed when barbituric acid is treated with nitrous acid;
Violuric acid gives a violet colour
it is the oxime of alloxan (see 2. XVI).
CO
NH
I
CO
/C
CH 2
CO
X NH 7
HN0
NH
2
C=NOH
I
CO
+ H,0
CO
^H^
and forms deeply coloured salts with various metals, e.g., the
potassium salt is blue and the magnesium and barium salts are purple.
Dilituric acid (5-nitrobaibituric acid) may be prepared by nitrating
barbituric acid with fuming nitric acid, or by the oxidation of violuric
in water,
440
ORGANIC CHEMISTRY
C0
NH
CH2 hno
CO
NNH/
C0
NH
>
/*\
CH-N02
^NH 7
barbituric acid
<hno
II
NH
C=NOH
CO
CO
CO
CO
[CH. XII
CO
XNH
dilituric acid
Uramil
(5-aminobarbituric acid)
dilituric acid or violuric acid.
/C o
violuric acid
is
CO
NH
CHN0
CO
CO
[h]^
NNHX
CO
NH
CHNH
CO
CO
XNH X
jh]_
NH
C=NOH
CO
N
CO
NH /
uramil
dilituric acid
violuric acid
CO v
CO
NH
CO
|
CO
NNIT
NH
CO
NH
-HS0 3
>-
CO
MTT
xS0
CO
H0
H -^^-
XNH X
alloxan
thionuric acid
/ C0 \
NH
OH'
H-NH 2
CO
CO
XNff
S04
uramil
/CO\
NH
CH-NH
co
/C O
HWOi>
" bo
do
\NH/
urainil
14.
NH
Pyrimidine, m.p.
DO
CHOH
^^
co
NH
CO
co
Co
^NH/
^NH^
dialuric acid
alloxan
22-5, b.p.
first
prepared from
/C0
\CH
?
C
/ X
CI
/ C6H N
Ni' '
CH
/ \
__ n' CH pqc^ N^ CH
CO
CO
vu
jy
Hoi
hou
ooh
JloH
*~ClA
cic
CC1
cci
xnh/
<*n'
NH
V
'
Zn dust
^
h twater
.CHt.
cm,
^/CH
4.CH
pyrimidine
HETEROCYCLIC COMPOUNDS
14]
441
1953).
Ha
Pd-C
is
~v~
Thus the
When
acid, 13a,
A very important general method for preparing pyrimidines is the condensation between /3-carbonyl compounds of
the type R-COCH a -COR', where
and R'
H, R, OR, CN, and compounds having the amidine structure R>C(= NH)*NH 2 where
R (an
R=
NH
OH
amidine),
(urea), SH or SR (thiourea or its S-derivative),
3 (guanidine) the condensation is carried out in the presence of sodium hydroxide
or sodium ethoxide. Thus:
;
R'
XNH
R-C.
^NH
/ NH
OC<R'
-CH,
OC;R'
%H
OCXR"
HOC^R"
by
+ 2H2
N-
R'
= OC H
2
5,
and R"
= CH
3)
to
form
C2 H6
yNH2
CH 3 -o(
"^NH
CO.
2(I
-tfcr
\H -Hhm* f
CH C
HOC^CH 3
y>h1
,
f
CCH
3
CH;
(see 4.
ORGANIC CHEMISTRY
442
[CH. XII
NH e
NH
4X NH
CN
+
*^> aN=N-CH
"NH
>H-N=N-C 6 H B
NC X
NH,
Schaeffer
amidine
et al.
salts
4 5-disubstituted pyrimidines
(yield:
VNH
15.
Uracil
(2
2,
NX
Z =
CN, COPh
It
(i)
C 2H6
/NH.J
tip
/ C0 \
/C0 \
Cx
CH2
*H
ao
^CH
NH2
NH
Br t
CH s -CO s H
CH 2
CH2
Nra'
ethyl
acrylate
urea
dihydrouracil
.CO
boil in
C6 H C N
NH
"CH
Ao
Ah
(-HBr)
XNH
uracil
(ii)
Y or NH,
6-dihydroxypyrimidine)
cent.):
N^N
/*
X CHg-C
X = C0 R, CONH
Y = NH OR, SR
51-100 per
CS
thiourea
c 2H 5 o2 a
/NH 2
\NH
(1908).
CH
CH
CS
\nh/
.CH
II
NaO<CH
sodioformylacetic ester
2-thiouracil
/C \.
CH
_ + CH 2 SH-C0 2 H
CQ
CH
CI
NH
aq.
CHjCI-CO a H
eo
NH
]|
^nh'
uracil
CH
CHBr
CH
\nh'
CO
HETEROCYCLIC COMPOUNDS
17]
Four
443
OH
OH
/ C0 \
NH
CH
co
ch
\nhx
A\CH
ch "
co
/ C0 \
CH
NH
__
^~"
ch
hoc.
//
_^
"~
IT
\NCH
hoc
ch
\kh/
"Ni/
%/
II
III
IV
The
13b. XVI).
16. Thymine (5-methyluracil, 2 6-dihydroxy-5-methylpyrimidine) is a
hydrolytic product of the nucleic acids.
It has been synthesised by methods
similar to those used for uracil.
(i) Fischer and Roeder (1901); in this case ethyl methacrylate is used
instead of ethyl acrylate.
:
/CO N
CO
/NH
nn
CO
C a H,0,C N
+
r-rn
^OCHs
+
CH2
^NH2
^^
(-HBr)
_/
h ' at
NH
CH-CH3
>
"l
I
I
l
Br
2a
NH
ch,-co,h*
Vh^
Br
(f
|'
N CH
/W
OH
COv
NH
\jOH.
C0
CH
__
"
H0
^nh/
(ii)
is
/NH 2 C2H5
+
08
^NH
/
C^^ ^^NH
*-|
>CH
NaOci?
_
^v
NH XCCH
\>CH
H, a -co,H
C
"*"">
>
CS
S
^SK
II
CH
CO
N NIT
C
CH
ORGANIC CHEMISTRY
444
[CH. XII
CI
.CO
/NH2 C 2 H
C2 H 5 S-C
NH
NH
CH
NaOCH
^CH
C 2H 6 SC
CH
fi
CH
SC..
CH
"
%'
c7h 6 SC
.CH
NH,
SK.
C,H
CH
NH,
NHs
c,HfOH
pocu
II
N
"*"
CH
CO
HO^
""
.CH
N'
\nh/
cytosine
Pyrazlnes
18. Pyrazines may be prepared by the self-condensation of an a-aminoketone in the presence of an oxidising agent such as mercuric chloride; the
intermediate dihydro compound is readily oxidised to the pyrazine (Gabriel
et al.,
1893).
/NH
RCO
H CR
OO-R
THg
.CH,
H,N /
\S
Hgci
>
Pyrazine
itself
may
as follows (Wolff
H in the
be prepared from aminoacetaldehyde (R
best method, however, for preparing pyrazine is
The
above equations).
et
al, 1908).
JSTHv
CH 2 C1
2
CH(OC 2 H5
NH
CH(OC 2 H 5
NHN
heat
)2
CH(OC 2 H B ) 2
diacetalylamine
ehloroacetal
HCl
CH2
CH 2
3
CH
3H,2
HOCH
)CH
CH 2
NH 2 OH-HCl
CHC
CHOH
2:6-dihydroxymorpholine
a-amino-
acid with acetic anhydride in the presence of pyridine, hydrolyse the product
(an acetamidoketone) with acid and then warm with sodium hydroxide in
the presence of mercuric chloride (Dakin et al., 1928). This method is thus
similar to the first general method given above, but offers a convenient
method of preparing a-aminocarbonyl compounds.
HETEROCYCLIC COMPOUNDS
19]
NH
,NH-CO-CH3
(CH,-CO)tO
R-C
iC0 H
C HBN
../
/NHu-HCl
* R-CH
CO-CH3
CO-CH,
r/\ch
HgCI.
HCl
*~R-Cf
445
^ch^JJr
is
solid,
Na
CjH 5 OH
C!H 2
CH 2
CH2
CHjj
Nir
piperazine
BENZODIAZINES
The
phthalazine
quinazoline
quinoxaline
Cinnolines may be prepared by the cyclisation of diazotised o-aminoacetophenones (Schofield el al., 1948), e.g.,
CO-CH,
2
N
+ HCl
N2 C1
of benzalde-
0.H,
ORGANIC CHEMISTRY
446
aco-c"CH,
[CH. XII
NH 3
+
NH-CO-CHg
+ 2H2
of o-phenylenediamines
e.g.,
glyoxal
The formation
1
2-diketones
of quinoxalines is
(see, e.g., 9.
^.NH
OC-R
+
\Anh
+ 2H2
OC-R
NH
9
2
10
HC
+ 3H2
^A
I).
ATOM AND
Morpholine
20. Oxazines.
prepared as follows:
is
tetrahydro-1
"
ethylene
oxide
4-oxazine,
'
OH
HO
2CH2CH 2 + NH 3
CH2
CH 2
(fH 2
-!iF-
and
it
may
be
+H
XN
.CH.
XNH
diethanolamine
Phenoxazines.
aNH
OH
e.g.,
yX
ho
HO
H
^ ^
i\
A/
phenoxazine
+2H
HETEROCYCLIC COMPOUNDS
24=]
by the action
447
of alkali on 2-hydroxy-2'-
,NH
\J 0H W\J
Phenoxazine
is
solid,
may
\AsH HO^V
phenothiazine
Phenothiazine
may
also
.NH.
cno
+ 2S
Phenothiazine, m.p. 185, is used as an insecticide; it is the parent substance of a number of dyes, e.g., Methylene Blue (see Vol. I).
Three triazines are theoretically possible; the parent compounds are unknown, but derivatives of each have been prepared.
23.
l:2:3-triazine;
l:2:4-triazine;
l:3:5-triazine;
p/c.-triazine;
(W.-triazine;
sym.-triazine;
p-triazine
a-triazine
cyanidine
Cyanuric acid, cyamelide and hexamethylenetetramine are derivatives of sym.triazine (see Vol.
24.
I).
Tetrazines.
V
l:2:3:4-tetrazine;
osotetrazine
l:2:4:5-tetrazine;
sym.-tetrazine
ORGANIC CHEMISTRY
448
25.
[CH. XII
systems are:
These occur in natural products (see Ch. XVII, Vitamins). It appears that
isoalloxazine, the tautomer of alloxazine, does not exist as such; only when the
hydrogen atom is substituted is the isoalloxazine form retained (see 6. XVII).
READING REFERENCES
Gilman
Vol.
IV
(1953).
Ch.
8.
Hetero-
).
Wright, The Chemistry of the Benzimidazoles, Chem. Reviews, 1951, 48, 397.
Wiley, The Chemistry of the Oxazoles, Chem. Reviews, 1945, 37, 401.
Organic Reactions, Wiley, Vol. VI (1951). Ch. 8. The Preparation of Thiazoles.
Benson and Savell, The Chemistry of the Vicinal Triazoles, Chem. Reviews, 1950, 46, 1.
Potts, The Chemistry of 1,2,4-Triazoles, Chem. Reviews, 1961, 61, 87.
Baker and OUis, Meso-ionic Compounds, Quart. Reviews [Chem. Soc), 1957, 11, 15.
Benson, The Chemistry of the Tetrazoles, Chem. Reviews, 1947, 41, 1.
Nineham, The Chemistry of Formazans and Tetrazolium Salts, Chem. Reviews, 1955,
55, 355.
CHAPTER
AND PROTEINS
AMINO-ACIDS
1. Classification of the
alkalis or enzymes, proteins
XIII
amino-acids.
When
hydrolysed by acids,
pages 452 and 453 shows a convenient classification; the letters g, I and e
which follow the name of the acids indicate that the acid is respectively of
general occurrence, lesser occurrence and essential (to man).
The a-amino-acids listed in the table have been isolated from proteins.
Plants have continued to provide new amino-acids of diverse structure;
between 1950 and 1960 about fifty amino- or imino-acids have been identiAbout 20 more have been recognised
fied as components of higher plants.
as constituents of micro-organisms or have been obtained as fragments of
the antibiotics excreted by the micro-organisms. These discoveries are the
result of the application of paper and ion-exchange chromatography to the
examination of plant extracts.
There are
2. General methods of preparation of the amino-acids.
many general methods for preparing a-amino-acids, but usually each method
applies to a small number of particular acids many acids are also synthesised
;
(a)
it
An
a-chloro- or bromo-acid
is
e.g-,
449
ORGANIC CHEMISTRY
450
[CH. XIII
CH a
?^
\ NK+BrCH-COiAHs3
aNCH-C0 C H
2
-&&**
CO
,C0 2 Na
HCI
-A
C0 2 H
L1)co h
'CO-NH-CH'C02 Na
CH,
cyanide),
r 3"
CH,-CHO
e.g.,
CH -CH(
-^U
KCN
\
3
HCI
CN
This method
phenylalanine.
(iiia)
(i)
a;
of
it offers
CH 2 (C0 2C2H 6
)a
R-CBr(C0 2H) 2
6) 2
(ii)
HCI
HCHO +
HCI
-*"C 6 H 5
CH 2 -S-CH 2 C1
benzylthiomethyl chloride
benzylthio]
0c> K
CO
\
N-CHtCOAHs),
)2
CO
CO
CNa(C0 2 C2 H5 ) 2
C.Hp-CHs-S-CHaCl
\N-C(C0
C2 H 5 ) 2
CHa-S-CHjj-QsHs
2]
C02 H
COgH
(ii)
451
NH CH-CH SH
2
HCI
S- benzyl cysteine
C0 2H
C02H
NH
() -cysteine
() -cystine
Proline.
;N-0Na(CO2
)2
N-C(COAH6
+-Br(CH2 ) 3 Br
CH2-CH2 CH2Br
CO
\^N-C(C0 C H
2
(i)NaOH
B)2
CH 2 -CH 2 CH
CH2 CH
<">
HC1
>
*
)2
NH
CH-C0 2 H
0-CO-C!H3
-GOgH
NH a-CH(COaCaH
B) a
-^^H
CH3-CO-NH-CH(COaCaH 5 a
C'
OTa
RBr
ethyl acetamidomalonate
HBr
>
>
CHa-CO-NH-CR^OaQjH^a
'
H
.
R-CH(NH a)-CO aH
The
ctfuoN^
Ccr
CH2-0(CO2C 8 H5 2
)
NH-COC.H,
(;)
(ii)
CH2 -CHC02H
Na OH.
HCI
NH,
H
tryptophan
ORGANIC CHEMISTRY
462
[CH. XIII
u
X
ffio
a
u
o
gag 15.
Soyo
""
XX
XX iuo
Ocn
ssg
d
o
a a
^a ga
'i
.^h
j
S
P*
"^
<->
f,
ST-
gllskS
-flu
g^
'S 'o
_g
'55
h o o u
\'H
s a 2 ,&
Soj.8 aa.aa.
ta
;&.
o o o o o o o
n d
fa 'a 'a 1 'a 1 1
<
vj
J' 8
-M
.3.3
o o 9 o o
a a <? a a
.g
<3 <
.52 *<!
&
0)
l?a\lra
n
a aa-T-a
vu
<?
"S88S88
?.
2^
<
.
u
s
.
.3
aa.
6
d
8 8
8 8
ffl
-52
*&
(H
ph
cm'
si*" -PI
So-
'% '3 5
.9 -H r3
Mi
co ^' i co i> oo
-22
00'
toll
'
'
a!
XI
Ph
-M
S d
- -M
3 a S
5 *Tj
.S o
d ^J
4)
C m &
oi
.d
Iri
d h ' m
o
o
O
bo
t3
ft
M^
2]
Km
453
o
o
w.8o
ffi
d'
o
o
X
o--x
X
<_>--o
\
K
X w
o--o
ffi
C3^H
&W y-0 K
j_j
gag
\K
/
o--o
o
X
ffi
tij66
oooo
ooffiWo
B,
3
'<3
-t-
>1
>>
o
s
is
-s
"S
'o
<U
a'cii
o s
is
"C
.2
"
a
rt
s
.S3 Sin
>.
'o o
s s
4-> _h
o o 3 $ >3
Co
3 3
w &0
bo
O O
a a a a a
1'S S S a
-(->
"*
>>
Al
ri
T)
-M
3 s
u
c
tS
ri
Ph
t J3
a>
j)
ni
O 3
p<
o
o o
N
T3
o'g
60
is
X
p
u
OOO
ffi
Ph
J-.
8a
8 8 8
.a
*|
"
^1
Tl
w
S-1 a Ph
^1
,g
-u
a,
8 8
t/J
-t->
Ph
c
3+> a
to
'BJ-
J3
Ph
u
d
rt
.y
xi
rn
C8
n
c
a
<u
!>.
1-1
Ph
Jl >,
ua-xi
ti
OX)
O 9> a
a U Ph
rn 3
ni
OS
^0
ft
>
.
f
'S
c1<
13
aj
-^h "-*
8
a
.a o x b
y sea p '2
'D
(H
'So
too
>
"
gl
"S
3 3
43
c/i
eft
^.g
&-i
Oi
r-l
fh (N P5
<o
bo
Si *1H
t!
92
tf
>o
o<u
SP
k4W
o tIN <M
3
ri
(M
'**
.H
HOHOe
XI
ORGANIC CHEMISTRY
464
[CH. XIII
)2
c * H Na
>
"
R
rx
C0* K
R-CH(C0
" uinwjvji^
2C 2 H6 )2
/
^^*- R-CH(
a^
o.v
N H
-^*-
CO2C9H5
C0 2 H
C02 H
C0 2 K
c ' H ' OH
-i2^R. CH
R-Ch'
CONHNH
RCH
>
X
CON3
^*-
NH-C0 2 C 2 Hs
acid azide
R-CH(NH2 )-C02 H
Glycine, alanine, phenylalanine and valine can be prepared by this method.
Instead of malonic ester, the starting material can be ethyl cyanoacetate.
CN
CN
/
CH
% RCH
X
CiH ' M
\>0 2 C2H 5
ON
Na " 4
Vr
/
c
oh
N
CON3
RCh'
CO 2 2 H6
CN
hno
>
CONH-NH 2
CN
H ' OH
r-ch
>
N NHC0
-^U-R-CH(NH2 )-C02 H
2
C2 H 6
C0 2 C2 H 5
'
C0 2C 2 H 6
\CO-NH
-mh*" R CH
'
*"
NH
R-CH(NHg -C02 H
)
/CN
CN
R-CHO+CH
-$-*- R-CH.-CH
C0 2 C 2 H 6
C0 2C2 H5
US/
CN
R-CH 2 CH
11?)
hci*"
R-CHg-CHfNHjJ-COjH
CON3
may
Amino-acids
455
2]
R-COCO aH
R-CH(NH a)-C0 2H
ROC0 2H"
+ NH 3 M
.-
II
NH
This method works well for alanine and glutamic acid.
Oximes of oc-keto-acids may also be reduced to a-amino-acids. The
advantage of this method is that the oximes may readily be prepared in
good yield by the action of sulphuric acid on a mixture of an alkylacetoacetic
and an alkyl
ester
nitrite
(Hartung
et
ah, 1942).
H SO
+ CH 3 -CO H + ROH
a
II
NOH
The reduction of phenylhydrazones made by the action of a diazonium
salt on an alkylacetoacetic ester also may be used to prepare a-amino-acids
(c/.
e.g.,
COCH 3
CH3 -COaH + CH3 -C-CO aCaH 5
Zn CjH.OH
II
N-NH-C 6H 5
CH 3-CH-CO aC2H 5 J^^Lt. CH 3 -CH(NH a)-CO aH
NH a
Thus
may
and hydroxyproline
by means
of the
H SO
C,Hs
CHO + CH 2 -C0 2 H
NH-CO-C6H5
C o) a o
CH > COjNa
(CHs
rr
C,H5-CH=
N< 2 >
I
C6 H 5
is usually referred to as the Erlenmeyer azlactone synthesis.
Aceturic acid (acetylglycine) may also be used instead of hippuric acid.
Furthermore, it has been found that aliphatic aldehydes may condense with
hippuric acid to form azlactones if lead acetate is used instead of sodium
acetate (Finar et al., 1949).
When azlactones are warmed with one per cent, sodium hydroxide solution, the ring is opened, and if the product is reduced with sodium amalgam
followed by hydrolysis with acid, an a-amino-acid is produced, e.g.,
This reaction
ORGANIC CHEMISTRY
456
CO
II
N^
CeEt-CH^
C6 H5 -CH=C C0 2 H
[CH. XIII
NaOf^
NH-CO-C6 H5
Na-H g>
CgIi5*CPl2' CH'COgH
NH-CO-C6 H5
C6 Hs
HCI
CeHj-CHg-OEKNH^-COaH + C 6 H5 -C0 2 H
The azlactone
synthesis offers a convenient means of preparing phenylalanine, tyrosine, tryptophan and thyroxine.
(v&) Aromatic aldehydes also condense with hydantoin, and reduction of
the product with sodium amalgam or ammonium hydrogen sulphide, followed
by hydrolysis, gives an a-amino-acid, e.g., tryptophan may be prepared by
first
Tiemann
by means
of the
Reimer-
I).
OHO
-NH
(CH
+ T
>coCH2-NH
CH=C
3 -CO).jO,
NH>;co
CO-NH
hydantoin
CH 2 -CHC0 H
CH 2 CH-NH
hci
^CO-^
CO-NH
NH,
CO NH
>
CHN-CO-CHj
I
acetylthiohydantoin
The above method may be used to prepare phenylalanine, tyrosine, tryptophan and methionine.
Another modification of the hydantoin synthesis is the Bucherer hydantoin synthesis (1934). In this method an oxo compound is converted
into the cyanohydrin and this, on treatment with ammonium carbonate,
produces a 5-substituted hydantoin which, on hydrolysis, gives an a-aminoacid.
RCHO + HCN
HCI.
-^R-CHOH-CN
fNH,) C 3
>
RCH CO
>NH
NH CO
R-CH(NH8 )-C02 H
3]
/C0
457
/CO
r
C H -CH=C
?^j2^v
awoHotf
CH
NH
\o'
HI
BsoH o H
NH
CO
may
Many
3. Isolation of amino-acids from protein hydrolysates.
amino-acids can be detected colorimetrically, and these colour reactions
have now been developed for quantitative estimation. Also, amino-acids
containing a benzene or pyrrolidine nucleus have characteristic absorption
spectra; thus the presence of such acids can readily be ascertained.
The actual quantitative isolation of amino-acids from their mixtures is a
The earliest method was the fractional distillation of the
difficult problem.
amino-acid esters in vacuo (Fischer, 1901). This method is very little used
now, and is only satisfactory for the neutral amino-acids {i.e., those containing one amino-group and one carboxyl group).
Neutral amino-acids may be extracted by w-butanol saturated with water,
and then separated by fractional crystallisation or by the fractional distillation of the esters. After the butanol extraction, the residue may be treated
with phosphotungstic acid, whereupon the basic amino-acids are precipitated
(Dakin et al., 1913).
A number of individual amino-acids can be obtained by means of selective
precipitation as salts, e.g., lysine is precipitated by picric acid.
Mixtures of amino-acids may be separated into fractions consisting of
the neutral, basic and acidic acids by means of the electrical transport method.
In this method a P.D. is applied to the mixture at the proper pK; the basic
acids (positively charged) migrate to the cathode compartment, the acidic
acids (negatively charged) migrate to the anode compartment, and the
neutral acids remain in the centre compartment.
The most satisfactory method of analysing amino-acid mixtures is partition chromatography carried out on paper (Martin et al., 1944). The mixture
of amino-acids is partitioned between a stationary water phase adsorbed on
a strip or sheet of filter paper and a moving phase of some organic solvent
(butanol, phenol, etc.). The moving phase either ascends or descends the
paper
way
the experiment
is
performed).
small
amount
Coloured spots are produced at the positions of the various aminoThe ratio of the distance travelled by the amino-acid to the distance
travelled by the solvent is characteristic of each amino-acid, and is known
as the R F value (this value depends on the experimental conditions).
A very interesting analytical method is the microbiological assay. This
depends on the fact that micro-organisms can be " trained " to feed on a
The rate of growth of the
specific amino-acid in the nutrient medium.
micro-organism is first measured by breeding in a medium containing the
particular amino-acid, and then the rate of growth is measured in the
mixture of amino-acids to be analysed. In this way it is possible to determine the amounts of various amino-acids in protein hydrolysates without
4C).
acids.
isotopic dilution.
468
ORGANIC CHEMISTRY
[CH. XIII
specimen
4.
The amino-acids
are
Gross et al. (1955) have shown that sublimation is possible with a number of
amino-acids. All except glycine contain at least one asymmetric carbon
atom, and all (except glycine) occur naturally in their optically active forms.
It has been mentioned in 5b. II that natural ( )-serine was chosen as the
arbitrary standard for correlating the configurations of amino-acids, the
relationship to this acid being indicated by D g or ts
It has now been shown
that l,
L 8 i.e., natural ( )-serine belongs to the L-series (with glyceraldehyde as absolute standard). The correlation between the two standards
was established as follows. (+)-Alanine has been correlated with l(+)lactic acid (for the correlation of the latter with l( )-glyceraldehyde see
5b i. II); and L(+)-alanine has been correlated with l( )-serine:
.
C02 H
HO-
-H
-*^-H-
Me
C02 H
C0 2 H
C0 2 H
-Br
-*&*+
-H
N,-
-%+
cat.'
Me
Me
Me
C02 H
NH 2
NH;
-""j
l(+) -alanine
C02 Me
C02 Me
MeOH
ClNHg"
HC1
H
CH2 OH
CH2 OH
PCI.
ClNHs
CH2 Cl
l( )-serine
C02 H
(!)
NaOH
NHr
-H
Me
!.(+) -alanine
459
4]
H-C-NH
HO-C-H
NHj-G-H
H-G-OH
C0 2 H
C0 2 H
C0 2 H
C02 H
H~C-NH
H-C-OH
NHrC~H
HO-C-H
L(-)-threonine
CH
CH 3
CH S
CH 3
D-a/Zothreonine
L-atfothreonine
D(+)-threonine
Since they contain amino and carboxyl groups, the amino-acids possess
the properties of both a base and an acid, i.e., they are amphoteric.
acids, e.g.,
liberated
from
by means
its salt
Amino-acids
may
anhydride.
R-CH(NH 2)-C0 2H
->
RCH(NH-COCH3)-C02H + CH s -C02H
(CH3-CO) 2
These acetylated
Similarly, benzoylchloride produces the benzoyl derivative.
derivatives are acidic, the basic character of the amino-group being effectively
eliminated by the presence of the negative group attached to the nitrogen.
It should also be noted that the carboxyl group of one molecule can react
with the amino-group of another molecule of an amino-acid to form a
peptide (see 9). Sanger (1945) has shown that l-fluoro-2 4-dinitrobenzene
combines with amino-acids to form dinitrophenyl derivatives (see 11).
:
(iii)
R-CH(NH a)-C0 2H
The nitrogen
is
+ HNO
-*.
R-CHOH-CO aH
+N +H
2
van
(or
bromo)
acids.
R-CH(NH2)-C02H
+ NOC1-* R-CHC1-C0 H + N + H
2
+ NH
is elimi-
460
ORGANIC CHEMISTRY
[CH. XIII
NH 2 -CH
The
-C0 2H
C2 H 6 OH
-C0 2C 2 H 5
+H
may
in this case
UAm'>
R-CH(NH 2 )-CO aH
et al.,
1952).
(iii) When suspended in acetyl chloride and then treated with phosphorus
pentachloride, amino-acids form the hydrochloride of the acid chloride.
R-CH(NH 2)-CO aH
(iv)
Dry
PC1 5
distillation, or better
Cl{H 3N-CHR-COCl
+ POO,
oxide, decarboxyl-
+ C0 2
When
R-CH
NH2
(CHj-CO)aO
c,h 5 n
C02 H
>
NH-CO-CHs
R'CH
COCH3
When measured
an inner
exists, in solution, as
salt:
-c6 2
+H
is
4]
461
electrode
glycine
formed.
is
NH
-CH2 -C02H
2 -C0 2
H + H2
These glycine derivatives are strong acids (the basic character of the aminogroup being now suppressed), and can be titrated with alkali. This method
known
is
When
(ii)
CH2 -C02 C H 5
NH
+
C2H 5
NH
(iii)
acid,
/CH2-CO\
*-
OCH
NH
esters give
NH + 2C H OH
2
XJO-CH^
iV-alkyl or arylamino-acids
(see 8. XII).
CH-C0 2 H
ArN
(CH3CO)3 >
(iv)
Betaines.
itself
may
Ar-N
XN
NN0
betaine
/C
C=0
methanolic solution. The betaines exist as dipolar ions; thus the formation
of betaine may be written:
Betaine
is
solution of
(CH 3) 3N
+ C1CH
2 -C0 2
-f-
HC1
Betaine
is
toins (see 2.
Ph-NCO
solid,
XVI):
C0 2H
If
phenyl wothiocyanate
is
\co
CONPh
ORGANIC CHEMISTRY
462
(vi)
Ninhydrln reaction.
[CH. XIII
Ninhydrin (indane-1
3-trione hydrate)
CO
CO +
RCHNH2 -C02 H
>~
RCHO+ C02 + NH
CO
\hoh
ni
drin
:i
2NH,
>
The amino-acid
is
replaced
On
(thyronin), C 1B 15 4N. This behaves as a phenol and an oc-amino-acid.
fusion with potassium hydroxide in an atmosphere of hydrogen, thyronine
gives a mixture of ^-hydroxybenzoic acid, quinol, oxalic acid and ammonia.
When fused with potassium hydroxide at 250, thyronine gives ^-hydroxy-
H MOa
m \^/- ~\^y>~CH
is I.
CH-C02 H
NH,
I
thyronine
Thyronine (provisionally structure I) was subjected to the Hofmann exhaustive methylation (see 4. XIV) and the product thereby obtained was
then oxidised. The final product would be III (on the assumption that I
is
thyronine).
HO \__\-0-\__\ C0 2 H
III
The
structure of III
anisole
and
^>-cresol.
was confirmed by
p-bTomo-
5]
cH*
C3
<
>Br+K0<
Cu
C3
>cH3
*3
bronze
^~
0<^>-0-^>C0 H- ^
chso<j3^- o
CH3
463
HO
-<3
>ch
\^y O
\__y 0 H
>
>
III
CH3
established.
is also
0<3-0-<3cH3-^ H0<^O^3cH
II
is
IV.
I
HO \
NH
IV
thyroxine
464
ORGANIC CHEMISTRY
[CH. Xllf
1927).
Clj-HCl
?0-\
>0H3\
KoCO.in
/JNOa
(ii)C
C 5t
HuONO-HCr
SnCla-HCI
-, yf
^v__^
ch
-o \
o \^y
3
N\
C t H s CONH-CH a CO,H
^ cho
CO
CCjHs
1
azlactone
1
CH-CO2H
NH
() -thyroxine
1938).
The
,7t.
,C02 H
"
L-tyrosine
NH
e.g.,
by Hems
et al.
s?-\^
/C0 2 H
noT
(1949).
6]
N*
P)(ch,-co),o-n.oh
(ii)
W
^
I, in
^ CH 0<>==^^0-<^=^VCH CH
CjHjNHj
NzzrzX
Nv
g^
NH-CO-CH3
l
caofVo/
\ / ^\==/>-CH GH\xm
0l3U
2
*
'
HI-CH3 -CO,H
(ii)
no
heat
(iii)Ij-Nal
(i)
/COAH
^_CH -CH
X NH-CO-CH
=,/
>SO.CI:
>so 3 ci;
H '- W
NaN0 2 -H 2 S0 4
(ii)
H0<
c,H a oH;cH,^^so,n
ch,<
<"
465
Y^
'
HO^^-0-^^CH
rrv rw
NH-CO-CH
3
.
C0 2H
2 -CH
NH2
L-thyroxine
is
myxcedema.
PROTEINS
General nature of proteins.
Mulder
(1839),
who
globin).
and
ORGANIC CHEMISTRY
466
[CH. XIII
to
is
are coagulated
with
by heat.
ammonium
Albumins
Globulins.
and
They
(from barley).
7]
467
Submembers
haemoglobin.
(iii) Glycoproteins.
In these the prosthetic group contains a carbohydrate
or a derivative of the carbohydrates.
(iy) Phosphoproteins.
These are conjugated proteins in which the prosthetic group contains phosphoric acid in some form other than in the nucleic
acids or in the lipoproteins.
(v) Lipoproteins.
In these the prosthetic group is lecithin, kephalin,
etc.
(vi) Metalloproteins.
These are heavy metal-protein complexes; all the
heavy metals can form complex ions with proteins, e.g., calcium caseinate
occurs in blood.
enzymes on
Protein
>.
\
Primary
by the
action
proteins.
phate.
Secondary proteoses; soluble in water, not coagulated by heat, and are precipitated by saturation with ammonium sulphate.
^
~\
Peptones
j,
Polypeptides
>
phate.
,J,
Simple peptides
Amino-acids
468
ORGANIC CHEMISTRY
[CH. XIII
protein.
It appears that, in general, three or four types of amino-acid
residues make up the bulk of a given protein molecule, and minor amounts
of fifteen or more other acids are also present.
Fischer (1902) and Hof-
CONH
R'
"
II
tl
The examination
NH
stituted
On
amide group
is
when the
N-H
0=C
CHR
H-N
C=0
7
/
O=0
N-H
N-H
CHR
C=0
0=C
CHR
H-N
V=0
-H-N
8]
469
NH
Nil
CO
CO
CH-CH -S-S-CH CH
2
NH
NH
ix
P
.CH />-H,
^<f
N^CH^C^
.a
NH^
^CH
\>--H
N^
CH
^(f
I
^N^
P"
-H
CH
It
XV
JC
^N^
Oh'
CH
I
On
the other hand, Pauling et al. (1951) have proposed a coiled chain
form of a helix containing either 3-7 or 5-1 acid residues.
The folded (coiled) form of a fibrous protein is known as the a-form, and
the extended as the /3-form. Elliott et al. (1951, 1953) have observed that
the frequency of the CO stretching mode in synthetic polypeptides and
natural proteins depends on the configuration of the polypeptide chain.
Thus this offers a means of distinguishing between the a- and /5-forms.
It has been shown that in the solid state many synthetic polypeptides
form stable helical structures which correspond closely to the a-helix form.
With other synthetic polypeptides, this a-helical configuration appears to
be less stable (Elliott et al, 1960; Blout et al, 1960). It has been shown
that in poly-/3-benzyl-L-aspartate, steric interference between the side-chain
and main-chain makes the a-helical configuration fairly unstable (Elliott
et al., 1959, 1962).
When this compound is heated, it adopts a new helical
form, which has been termed the co-helix. Fraser et al (1962) have prepared another polypeptide which, although not identical in form with that
of the aspartate polymer, also is conveniently described as an co-helix.
in the
ORGANIC CHEMISTRY
470
CONH
[CH. XIII
C(OH)N
C(OH)NH
NH
CON
I
II
NH
CO
CO
This
is
known
C(OH) O
C(OH)S
NH
NH
CH 2
xCO /CH\NH
OH
/
CH
2
Bz-nh/
\co
bz-nh/
N:o
nh,
NH V
NH
/CO
XCH/
The globular (corpuscular) proteins are more compact than the fibrous
proteins, but their shape is not spherical; e.g., X-ray studies have shown
that haemoglobin has a cylindrical shape. The chains in globular proteins
are folded many times, and in order to account for certain properties, this
folding must follow some definite pattern. An interesting point in connection with globular proteins is that infra-red methods may be used to
detect the presence of carboxylate groups in them at the isoelectric point
(Ehrlich
et
al, 1954).
of crystallisation ".
One other point about the nature of these polypeptide chains will now
be mentioned briefly. Let us consider a dipeptide composed of two different
amino-acids, A and B. These may be combined in two different ways:
NH 2ACONHBCO aH
and
H0 2CANHCOBNHa
9]
9.
Synthesis of polypeptides.
471
e.g.,
(i) The partial hydrolysis of a diketopiperazine with hydrochloric acid
gives a dipeptide (Fischer, 1901), e.g.,
NH CH .,
-iii^NH
0H NH
\ c^
2
glycylglycine
2:o-diketopiperazine
The methyl
to form
esters of di-
and
methanol
>-
By means
of this reaction, Frankel et al. (1942) prepared polypeptides containing up to 110 glycyl units.
(iii) When two different amino-acids are joined to form a dipeptide, two
possibilities occur (cf. 8) ; thus, if glycine and alanine are linked together,
the two possibilities are:
CaH 5
'
'
hea't
'
'>
C2H 5
C2H B
2
C-NH-CH a-COaC2H 6
Hence by
be prepared.
hydrolysing the peptide link. This difficulty was overcome by Fischer (1915)
by using ^-toluenesulphonyl chloride as the " blocking agent " instead of
ethyl chloroformate; the former group can be removed (as the thiophenol)
by warming with hydriodic acid, without hydrolysis of the peptide link, e.g.,
>
NH.-CH.-CO.C.H,
heat
agent,
ORGANIC CHEMISTRY
472
[CH. XIII
C 6H 5 -CH 2 OH
The procedure
is
+ COCLj--* C H
6
-CH 2 OCOC1
then as follows:
C 6H 6 -CH 2OCOC1
+ R-CH(NH )-C0 H
>
PCI
C 6H 5 -CH 2OCONH-CHR-C02 H
'->
B'-0H(NH,)-CO,H
C KH ,-CH,OCONH>CHR-COCl
+ HC1
NaOH
H Pd
H -CH0-CO-NH-CHR-CO-NH-CHR'-C0 H
C H -CH 3 + C02 + NH -CHR-CO-NH-CHR'-C0 H
2
fi
C B H s -CH,0-CO-NH-CHR-CO-NH-CHR'-COH
C 6 H B -CH 2Br
COg
+ BrNH
-CHR-CONH-CHR'-C0 2 H
Weisblat et al. (1953) have also shown that the ^-toluenesulphonyl group
can be removed by means of hydrogen bromide in acetic acid containing
phenol.
Stevens
et
al.
(1950)
have used
allyl
(cf.
ib.).
CO
'v
/
CO
N-CHRCOC1
(i)NaH 4 -C 2 H 5 OH
fii)
HC1
PCX
N-CHRCOaH-
O+NHjj-CHR-COjjH
\N-CHRCONH-CHR-COgH
NH,-CHR-CQ 2 H^
*
Mg(5
NH CHRCO-NHCHR-C0 H
2
AMINO-ACIDS
9]
(iv)
AND PROTEINS
473
chloride with
1903).
ClCHa-COCl
+ NH 2 -CH
-C02 C 2 H 5
>-
-^
PCI
CH,-CH(NH,)-C0 2 H
C1CH,-CONH-CHx 2 -COC1
NH,
>
C1CH 2-C0-NH-CH 2-C0-NH-CH(CH 3)-C0 2H
NH 2 -CH 2-CO-NH-CH 2 -CO-NH-CH(CH 3)-C0 2H
glycylglycylalanine
its
+
group to form the group (^{HgN'CHR-, which
chloride present;
-^ NH
NH 2 -CHz2 -C0 H
2
z
is
not acetylated
by the
acetyl
e.g.,
CHycoci
WH CH
''
2
i
-CH 2 .C0C1
''
C ' H
>
NH 2-CH -CONH-CH
2
-C0 2H
glycylglycine
By
this
(of
HO/^SCHO +
N=/
C02H
^CH -CO.O^>CH=C-CO
^==
3
NHCOCHs
co-CH3
r
RCH[UH f yco^
(l)H *- pd
(ii)HCl
c^. G0 o
.
>
c0 SH GnR c02H
^ ^^ CH=cNHCO-CH,
HO<f
\
.'
/>CH
CHCONH-CHR-C0 2 H
I
NH
On the other hand, Beyerman et al. (1961) have used the ^-butoxy group
to protect the hydroxyl group in the synthesis of peptides containing hydroxyamino-acids. This group is removed readily by acid without fission of the
>
ORGANIC CHEMISTRY
474
[CH. XIII
peptide bond, and the optical activity is completely maintained during the
process.
The 2-butoxy group is conveniently introduced by the acidcatalysed addition of t'sobutene to the hydroxy group of the iV-acylated
hydroxyamino-acid
(vii) A very recent method of building up peptides
et al.
NH
(1955); this
is that of Schwyzer
of chloroacetonitrile as follows:
NH,-CHE'-CO,H
-
NH
-CHR-CONH-CHR'-C0 2H
As we have seen (4), all the amino-acids except glycine contain at least
one asymmetric carbon atom. Furthermore, the a-acylamino-acids are
readily racemised, and hence a very important point about the syntheses
described above is that racemisation will occur during the syntheses. The
actual extent of racemisation depends on the nature of the acyl group and
the type of condensation used. According to Boissonas et al. (1955), the
benzyloxycarbonyl group gives very resistant derivatives (to racemisation)
and is therefore the best one to use.
10. Properties of the polypeptides. The polypeptides are solids which
usually decompose when heated to 200-300. They are soluble in water,
but are insoluble in ethanol, and have a bitter taste similar to that of the
proteins.
They are hydrolysed by acids, alkalis and enzymes, and they
very closely resemble the polypeptides actually obtained by the partial
hydrolysis of proteins. Polypeptides (synthetic) also give the biuret test.
Many peptides have been found as the products of metabolism of microorganisms.
It has already been pointed
11. Degradation of the polypeptides.
out that a necessary requirement for the elucidation of the structure of
proteins is a knowledge of the " order " of the amino-acid residues in the
molecule (8). Chemical methods have been introduced whereby the terminal amino-acid residue of a polypeptide may be removed in a stepwise
fashion.
Consideration of the following structure of a polypeptide shows
that the two ends of the molecule are not alike; the end on the left-hand
side is known as the " amino-end ", and that on the right-hand side as the
" carhoxyl-end " ; the former is said to be iV-terminal and the latter C-
terminal.
NH 2 -CHR-CO-NH-CHR'-CO-NH-CHR"-CO-NH
CONH-CHR"'-C02H
carboxyl-end
amino-end
and Kumpf
(1926).
11]
475
NHj-CHR-CO-NH-CHR'CO-NH -OHR* C0 2H
-i.-coci
|c,h,
C6H5 -GONHCHRCONHCHR
with
CONHCHR -C0 H
2
NH4NCS
Iheat
and (CH 3 -CO)jO
CHR"
II
SO
C.H 5 -CO-NH-CHR-CONHCHll'-CON
,00
\N /
!aOH
CHR
II
SO
CO
C,H5 CO-NH-CHRCO-NH-CHR-C0 2 H+
NH
X
NH
thiohydantoin
JBa(OH),
NH CHR"C0 2H
2
Thus the terminal amino-acid can be identified, and the process can now
be repeated on the degraded peptide.
Reduction of proteins with lithium aluminium hydride (or lithium borohydride) converts the free terminal carboxyl group to a primary alcoholic
group (c/. 4b). Hydrolysis produces an amino-alcohol, which is then
identified.
NH-CHR-CO-NH-CHR'-CO aH
4.M1H.
NH 2-CHR-CONH-NH + NH
2
-CHR'-C0 2H
ORGANIC CHEMISTRY
470
ch5 -ncs +
nh
[CH. XIII
-chr-co-nh-chr'-co-nh-chr"-co 2 h
phenyl zsothiocyanate
,,,
CO-NHCHR -CO H
C6H5 -NHCS-NHCHRCO-NH-CHR
i!
Ihci
i"
NH CHR
I
NHaCHRCONHCHR-CO^H
CO
SC
\ N/
I
C6H5
thiohydantoin
Ba(OH) a
NH
-CHR-C0 2 H
Thus the terminal amino-acid can be identified, and the process can now
be repeated on the degraded peptide.
More recently, Asai et al. (1955) have investigated the infra-red spectra
of polypeptides and have shown that certain bands depend largely on the
sequence of the amino-acids in the chain. These authors have concluded
that the crystalline part of silk fibroin contains glycine and alanine residues
arranged alternately.
DNP
N02
ROHNH,
CO-NHCHR'0O2 H
f</_\no
N02
HF
R-CH-NH
/NO;
CONHCHR'C02 H
N02
R-CH-NH
>NO.
NH 2 CHR'C02 H
CO,H
Thus, when a peptide is first treated with the reagent and then the product
hydrolysed with acid, a number of amino-acids will be obtained as their
dinitrophenyl derivatives (which can be separated by chromatography;
of.
3).
14]
477
The exact sequence of amino-acid residues has been worked out only for
the hormone insulin, the enzyme ribonuclease, and for the unit protein of
the tobacco mosaic virus. The arrangement of the acid residues is random,
and consequently synthesis is made difficult.
In protein chemistry, to facilitate writing out the amino-acid sequence,
the general practice is to use the first three letters of the names of the acids
as abbreviations. When the sequence is not known, the abbreviations are
enclosed in brackets, but the N- and C-terminal residues may be differentiand
respectively, e.g.,
ated from residues within the chain by
OH
H-Ala-(Gly-Val-Leu)-OH.
ENZYMES
12.
Enzymes
which bring about chemical reactions in living cells. They are produced
by the living organism, and are usually present in only very small amounts
in the various cells (about 0-01 per cent.). They can also exhibit their
The
activity even when they have been extracted from their source.
enzymes are all organic compounds, and a number of them have been
obtained in a crystalline form. Those so far obtained crystalline are proMost enzymes are colourless
teins and have very high molecular weights.
solids, but some are yellow, blue, green or greenish-brown; most are soluble
Some enzymes are purely protein in nature,
in water or dilute salt solution.
but many contain a prosthetic group (see 7 B) which has a relatively low
molecular weight. The prosthetic group of some enzymes is readily separated
{e.g., by dialysis) from the protein part and the latter, in this condition, is
known as an apoenzyme, e.g., peroxidase is composed of ha^matin (prosthetic
names,
e.g.,
particular enzymes,
pH
ORGANIC CHEMISTRY
478
[CH. XIII
{e.g.,
17.
Mechanism
by an enzyme is
the enzyme (cf. the theories of catalysis).
The details of the mechanism of the catalysis
still
not certain.
effected
by enzymes
are
a transition state by combination with its substrate, and then the enzyme
regenerated with the simultaneous formation of the products (cf. the
transition state, Vol. I). A number of these transition states have been
shown to exist from, e.g., spectroscopic evidence; during the reaction the
absorption spectrum of the enzyme is altered. It is also believed that the
protein part of the enzyme has an " active centre ", and it is this which
combines with the substrate. Assuming this be the case, it is now necessary to explain why neither the protein part of the enzyme nor the prosthetic group can act separately, but both must be present (apparently in
is
17]
479
represented
ZH + E t > Z + EjH 2
"
> Cyt. + H 2
Cyt. H 2 + 0 2
EjtHj
,._
-.
oxidase
Most of the dehydrogenases contain a prosthetic group (which is the hydrogen acceptor). Thus a number of vitamins (1. XVII) function as part of
pyridino-enzymes (pyridine nucleus), flavo-enzymes
the other hand, cytochrome and catalase are hsemcontaining enzymes, and ascorbic acid oxidase and phenolase are copper
protein enzymes.
When small molecules are converted into large molecules containing more
energy than the units from which they were built, then energy must be
supplied to bring about these syntheses. Enzymes are involved in these
syntheses, and it is believed that certain organic compounds contain energyrich phosphate bonds, and when dephosphorylation occurs energy is liberated,
is used to repree.g., acetyl phosphate contains such a bond (the symbol
sent an energy-rich bond):
prosthetic groups,
(riboflavin), etc.
e.g.,
On
O
II
CH, CO
~ POH
II
OH
are inactive unless an activator is present. The inactive
as a zymogen, and the activator as a kinase (if this is inorganic), e.g., trypsinogen (the zymogen) together with enterokinase (the
kinase) forms the enzyme trypsin. Some activators may be metallic or nonmetallic, e.g. salivary amylase requires chloride ions for activity. Activators,
however, are not co-enzymes. Originally, co-enzymes were understood to
include a small number of organic compounds of relatively low molecular
weight which are required in catalytic amounts in enzyme reactions; the
co-enzymes have no enzymic properties of their own. This description of
a co-enzyme, however, is now losing this " definition "; most of the metalloporphyrin catalysts [i.e., the so-called prosthetic groups (12)] are covered
by the foregoing definition. On the other hand, nucleotide co-enzymes are
only catalytic in enzyme reactions in which they can be regenerated continuously. From this point of view, it would seem that a co-enzyme behaves
as a substrate for the " true " enzyme (cf. dehydrogenases above).
Many substances may behave as inhibitors, i.e., in their presence the
enzyme fails to act; e.g., saccharase is inactivated by copper ions (cf.
" poisons " in catalysis). Sometimes purely physical means may inactivate
an enzyme, e.g., crystalline pepsin is inactivated by sound waves with a
frequency of 9 kilocycles per second.
Many enzymes
enzyme
is
known
ORGANIC CHEMISTRY
480
[CH. XIII
The Krebs
involved and mechanisms
enzymes
CH 3 -CO-C0 H
CH 2 -C0 H
pyruvic acid
*
CH,-C0
a
2H
LoH
x
CO
X0 H
-C0 H
2
CO-CO 2 H
CH
citric acid
oxalacetic acid
k
CH-C0 2 H
CH 2 -C0 H
II
C-C0 2 H
CHOH-CO aH
|
CH 2-C0 H
1
malic acid
cJ5-aconitic acid
X
CHOH-C0 2H
CH-C0 2H
CH-CO aH
1
II
2 C-C H
fumai ic acid
H0
CH 2 -C0 2H
iiocitric acid
11
H
co +
cH
C
-C0 2 H
-C0 2 H
CO-CO 2H
"
CH 2
+ C0
CH 2 -CO aH
succinic acid
a-ketoglutaric acid
C0 2 H
C0 2H
CH-NH
CH
C0 2H
en2yme
C=NH
=v
CH 2
H
2 -C0 2
CH
CO
H,0
+ NH 3
*.
1
CH 2
CH
-C0 2 H
CH
-C0 2
i8]
481
CH 3
CH 3
CH-NH.
transaminase
+ CO
CH 2
^-*
I
+ CH-NH a
>
I
CH 2
C0 2H
CH 2 -C0 H
I
glutamic
pyruvic
acid
acid
alanine
a-ketoglutaric
acid
We
have already seen (32a. VIII) how various keto-acids could be synthesised in the organism. Thus, with the formation of a-ketoglutaric acid
from the break-down of carbohydrates, its direct amination to glutamic
acid, and the latter now capable of aminating other keto-acids by transamination, the cycle of events is set up for the biosynthesis of amino-acids
point to be noted in this connection is' that some aminoin general.
acids are essential (1), e.g., man cannot synthesise the benzene ring. Since,
however, plants and bacteria synthesise aromatic compounds, a great deal
of work has been carried out to elucidate the possible pathways. Two
distinct routes have been recognised: (i) from acetate; (ii) from carbohydrates. The latter is believed to be the more important, and Davis et al.
(1955, 1958), from their work with bacteria, have proposed the following
route for the biosynthesis of phenylalanine and tyrosine; the two starting
orthomaterials are phosphoenol pyruvate and D-erythrose 4-phosphate (P
phosphate residue):
C0 2 H
CO
CHO
co 2 h
H-
c-op
H-
OH,
-OH
HOH-
CH2OP
H-
-OH
C0 2 H
HO,,
H
OH
OH
\y OH
or"
OH
(JH2 OP
dehydroquinic acid
\>H
I
OH
HO-
PO'\/X>H
OH
OH
OH
dehydroshikimic
shikimic
acid
acid
CO.H
0O,H
COH
CH 2 C0CO 2 H
CH,CHNH,CO,H
H0 2C, /CH2-CO-CO.JH
phenylalanine
CH2 COC02 H
CH2 CHNH 2 C0 2 H
OH
OH
tyrosine
ORGANIC CHEMISTRY
482
[CH. XIII
Bahadur
exposing a
(1954),
READING REFERENCES
Schmidt, The Chemistry of the Amino-Acids and Proteins, Thomas (1943, 2nd ed.).
Sahyum (Ed.), Outline of the Amino-Acids and Proteins, Reinhold (1948, 2nd ed.).
Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. II (1943, 2nd ed.). Ch. 14.
Natural Amino-Acids.
Rodd (Ed.), Chemistry of Carbon Compounds, Elsevier. Vol. IB (1952). Ch. 22.
Proteins.
and
Proteins, p. 140.
(1947,
2nd
ed.).
483
Avison and Hawkins, The Role of Phosphoric Esters in Biological Reactions, Quart.
Reviews {Chem. Soc), 1951, 5, 171.
Klyne (Ed.), Progress in Stereochemistry, Butterworth (1954). (i) Ch. 7. The Stereochemistry of Compounds of High Molecular Weight, (ii) Ch. 8. Stereospecificity
of
Enzyme
Reactions.
CHAPTER XIV
ALKALOIDS
Definition of
an
means
alkali-like)
alkaloid.
was given
it
3.
(Reinecke's solution
is
General properties. The alkaloids are usually colourless, crystalwhich are insoluble in water, but are soluble in
484
4]
485
ALKALOIDS
betaine.
(e) The Zerewitinoff active hydrogen determination may be applied to the
alkaloid (see Vol. I).
The presence of methoxyl groups and their number
(/) Methoxyl group.
may be determined by the Zeisel method. The alkaloid is heated with concentrated hydriodic acid at its boiling point (126) ; the methoxyl groups are
thereby converted into methyl iodide, which is then absorbed by ethanolic
Only methoxyl groups have
silver nitrate and the silver iodide is weighed.
been found in natural alkaloids.
*0 ). The presence of this group
(g) Methyleneiioxyl group (
2
is indicated by the formation of formaldehyde when the alkaloid is heated
with hydrochloric or sulphuric acid.
(iii) The functional nature of the nitrogen.
\a) The general reactions of the alkaloid with acetic anhydride, methyl
iodide and nitrous acid often show the nature of the nitrogen.
(b) Distillation of an alkaloid with aqueous potassium hydroxide usually
leads to information regarding the nature and number of alkyl groups
attached to nitrogen. The formation (in the volatile products) of methylamine, dimethylamine or trimethylamine indicates respectively the attachment of one, two or three methyl groups to a nitrogen atom; the formation
Only iV-methyl groups
of ammonia shows the presence of an amino group.
have been shown to be present in alkaloids with one exception, viz., aconitine,
OCH
their
number may be
When
the alkaloid
is
deter-
heated
ORGANIC CHEMISTRY
486
[CH.
XIV
with hydriodic acid at 150-300 under pressure, iV-methyl groups are converted into methyl iodide (cf. the Zeisel method, ii/).
(d) The results of hydrolysis will show the presence of an amide, lactam
or betaine
(e)
iid).
(cf.
/\ch
/CH
CH2
H.-Ni.
CH2
CH2
(i)
CH,l
(ii)
AgOH
*?Hjjf\
heat
(-H,0)
XJHj
pyridine
(CHsUfOH;
piperidine
/CH,
CH,
CH 2
CH
(i)
CH,
N(CH3
CH 3
CH2
CH
heat
(ii)AgOH
CH2
(-H.O)
CH,
CH
CH
CH,
CH,
*-(CII 3 ) s N+
N(CH 3 ) 3 OH
/5
CH T!H
II
CH2 CH3
piperylene
Hofmann's method fails if there is no /3-hydrogen atom available for elimination as water; in such cases the Emde modification (1909, 1912) may be
used. In this method the quaternary ammonium halide is reduced with
sodium amalgam in aqueous ethanol or catalytically hydrogenated, e.g.,
NH
(ilCH,^
(ii)AgOH
isoquinoline
l:2:3:4-tetrahydrof'soquinoline
N(CH 3 ) 2 l OH
487
ALKALOIDS
4]
CH
(-H a O)
nX
CHij-N(CH3) 2
oh-nkih.u
CH
I
2 -N(CH 8 3i t
)
'
CK
KIT
Na-Hp
HjO-C.
"
+ (CH 3
)S
<K.
,CH 2
CH 2 \
/CH 2 'CH 2 \N
NR+BrCN
CH 2
CH,
H2
XCH
CH2 'CH 2
yCH.2
'
->-
CH 2 CH2 /
CgHs-COCl
NaOH,
yCHjj
amines
N-CO-C6H5
/
2 CH 2
-
CH2V
CH2
CIi2'
CH 2
\ CH
(iii)
)4
CH2 "CH 2
NH +
PBrj-Bt*
/ CN J
,r >
CH2"CHjgv
CH,
-CH 2
Br
CHgBr
CH 2
N
CH2 -CH 2 NRCN
(ii)
N-Rl +
N-CBr 2 C6H6
under
reduced
distil
pressure
CHg
acid at 300,
e.g.,
-555**-
ORGANIC CHEMISTRY
488
[CH.
XIV
CHOH
CH
Ha so 4
(-H,0)
-CHC1
I
CH 2
More recently, mercuric acetate has been used to dehydrogenate certain
alkaloids, thereby introducing olefinic bonds.
(vi) Fusion of an alkaloid with solid potassium hydroxide often produces
relatively simple fragments, the nature of which will give information on
the type of nuclei present in the molecule (cf. iiib).
This usually gives the same products as (vi),
(vii) Zinc dust distillation.
except that when the alkaloid contains oxygen the oxygen is removed.
(viii) Physical methods are also now being used, in conjunction with
chemical methods, to elucidate structure, e.g., infra-red spectra studies are
used to identify many functional groups; ultraviolet spectra are used to
indicate the likely type of structure present and X-ray analysis has offered
a means of distinguishing between alternative structures that appear to fit
equally well the alkaloid in question.
The foregoing analytical work will ultimately lead to the
(ix) Synthesis.
proposal of a tentative structure (or structures) for the alkaloid under conThe final proof of structure, however, depends on an unsideration.
ambiguous synthesis of the alkaloid.
;
Phenylethylamine group.
Pyrrolidine group,
Pyridine group,
(iv) Pyrrolidine-pyridine group.
(v) Quinoline group,
(vi) MoQuinoline group,
(vii) Phenanthrene group.
(ii)
(iii)
ALKALOIDS
7]
489
PHENYLETHYLAMINE GROUP
Many compounds of this group are known, some natural and others
synthetic. Their outstanding physiological action is to increase the bloodpressure; hence they are often referred to as the pressor drugs.
6.
(5-Phenylethylamine.
This
C 6H 5 -CH 2C1
+ KCN -+ C H
6
pVPhenylethylamine
7.
it is
Wo
5
-CH a -CN
>
( )-Ephedrine, m.p.
Ephedra;
drug).
is
is
meat
38-1.
( )-Ephedrine
is
Ma
C10H 15ON
-^> CH
-NH 2
C 6H B -COCH 2 -CH 3
either I or II.
C 6H 5 -CHOH-CH-CH 3
II
NH-CH 3
It has been observed, however, that compounds of structure II undergo
the hydr amine fission to form propiophenone when heated with hydrochloric
acid.
Thus II is more likely than I. This is supported by the fact that when
subjected to the Hofmann exhaustive methylation method, ephedrine forms
sym. -methylphenylethylene oxide, III this cannot be produced from I, but
is to be expected from II.
;
C eH 5 -CH-CH-CH 3
^S
(CH 3 ) 3N
III
ORGANIC CHEMISTRY
490
[CH.
XIV
group by hydrogen will result in the formation of an optically inactive compound. Structure II, however, contains two asymmetric carbon atoms, and
so the replacement of the hydroxyl group by hydrogen should still give a
compound that can be optically active. Experimentally it has been found
that when this replacement is effected in ( )-ephedrine, the product, deoxyephedrine, is optically active. Thus II agrees with all the known facts,
and this structure has been confirmed by synthesis, e.g., Spath et al. (1920)
CH.OH
>
HBr
>CH,
OCH,
CH.-NH,
C,H,MgBr
> CH 3-CHBr-CH:
CH3 -CHBr-CH;
C BH B
Br
,OCH
HI
ch 3 -ch-c:
<,CbH5
C 6H 6 -CHOH-CH(CH ?)-NH-CH 3
(
-y-ephedr ine
NH-CH,
of tartaric acid.
() -ephedrine
ically possible.
CH3
CH,
H-
-NHCH3
H-
-OH
-H
CH -NHHO3
C 6H5
-H
(+) -ephedrine
H-
-H
-OH
()-4> -ephedrine
-NH-CH3
HOC6
CeH 5
CeHs
( ) -ephedrine
CH 3
CH,
CH 3-NHH-
(+)-J>
H
H5
-ephedrine
Various mechanisms have been proposed for the hydramine fission. Chathave suggested two different mechanisms according to whether
the aryl nucleus contains (i) an electron-releasing group in the o and /or pterjee et al. (1961)
position,
e.g.,
R=
c-ch 2 nh 2
^^
MeNH 2 HCl
0^-H
C-'-OHj-NH 3
OH
OH
CHO
491
ALKALOIDS
10]
(ii)
in the m-position:
-NH,
\__\ -C-CHjfNH.
OH
COMe
CgHB-CH.-COCHj
ways,
e.g.,
Mingoia (1940):
ergot,
tion
0<^
CH 3o
">CHO+
(
CH3 -N02
W *">
CH3
<^_
_\ CH=CH-N02
anisaldehyde
-^-CH O
CH2 CH2-NH2 -
-O
C02H
CH3
GH=CH2
CH3O
II
HO
CH 2 -CH 2-N(CH3 2
)
III
ORGANIC CHEMISTRY
492
^^XcHijCHaOH
[CH.
XIV
Barger (1909):
e.g.,
-^^<^J>CH
CH 2 C1
(CH 3 ) 3 NH
>
2-phenylethanol
g">
HN 3
3)2
HO<^^>CH OH
2
N0 2
>
N(CH,) 2
OCH,
CILjO
^OCH ^
>CH2
CH2 -NH2
0 H3
OCH,
OH 3
OCH3
OCH3
BaS0 4
(Rosenmund
reduction)
0CH
OCH,
CH 3 0<f
H 2 -Pd
;r
c "3- NO '>
>CHO-^oh
,3
CH -3 0</ ^\cH=CH-N0 2
\__/
OCH,
OCH,
3:4:5-trimethoxyto-nitrostyrene
OCH
Na-Hg
* CH 0<
>CH -CH
2
-NH 2
OCH 3
mezcaline
A
this
of Banholzer
et al.
(1952)
493
ALKALOIDS
12]
OCH 3
CH 3
0^^C0C1
OCH3
SbSU- CH 3 0<^>C0CHN2
"H
^"
>
OCH3
OCH3
diazoketone
OCH 3
OCH3
CH30<^^>CH2 CQ-NH 2
OCH
UA, "*>
CH,0<A^\cH -CH NH
2
OCH3
Adrenaline (Epinephrine), C 9H 13
non-steroid hormone.
3 N, is a
the source of the hormones adrenaline and noradrenaline. Adrenaline was the first hormone to be isolated in a crystalline
form (Takamine, 1901; Aldrich, 1901). Adrenaline is active only when
given by injection; it raises the blood-pressure, and is used locally to stop
haemorrhage.
Adrenaline is a colourless crystalline solid, m.p. 211, and dissolves in
acids and alkalis (it is insoluble in water) ; it is also optically active, having
12.
is
a lsevorotation.
of adrenaline
is
indicated
by
its
solubility in
On
present.
product
is
OH
OCH3
0"
0"
C02 H
C0 2 H
OH
I
OH
CHOH-CH2 -NH-CH
III
II
by fusion with potassium hydroxide, gives veratric acid, II, and trimethylamine (Jowett, 1904). The formation of trimethylamine indicates that the
nitrogen atom must occur at the end of the side-chain. Since adrenaline
is optically active, it must contain at least one asymmetric carbon atom.
Now adrenaline contains three hydroxyl groups, two of which are phenolic
(as shown by the formation of I and II).
The third hydroxyl group was
shown to be secondary alcoholic by the fact that when adrenaline is treated
with benzenesulphonyl chloride, a tribenzenesulphonyl derivative is obtained
which, on oxidation, gives a ketone (Friedmann, 1906). To account for the
CHOH group
oxidation of adrenaline to the benzoic acid derivative, the
CH2 -CH0H>, then a
must be attached directly to the nucleus had it been
phenylacetic acid derivative would have been obtained. AH the foregoing
facts are in keeping with structure III for adrenaline, and this has been
confirmed by synthesis by Stolz (1904) and Dakin (1905), with improvements by Ott (1926).
;
ORGANIC CHEMISTRY
494
[CH. XIV
OH
OH
+ CH 2 C1-C0 2 H
POC
OH
'
CH,-NH t>
>
GO-CH 2 -NH-CH3
CO-CH 2 Cl
catechol
io-chloro-3:4-
dihydroxyacetophenone
OH
Hj-Pcl
CHOH-CH2 -NH-CH 3
()-adrenaline
of (+)-tartaric acid.
OGO-CHj
0-CO-CH 3
^O-CO-CHj
+ CH3 -N0 2
OCO-CH 3
-^L>-
CHO
CHOH-CfI 2 -N0 2
diacetylproto-
catechualdehyde
OH
O-CO-CH,
Zii-CH 3
CO a H^
HCHO
^0-CO-CH 3
hci
OH
-0
CHOH-CH 2 -NH-CH3
CHOH-CH 2 -NH-CH 3
() -adrenaline
is
CH2 -NH-CH 3
HO-C-H
13]
OH
OH
CHO
ALKALOIDS
495
OH
OH
^0
OH
CHOHCN
OH
CHOH-CHjfNHjj
() -noradrenaline
is
CH2 -NH2
HO 0
PYRROLIDINE GROUP
Its
13. Hygrine, C 8 15 ON, b.p. 193-195, is one of the coca alkaloids.
reactions show the presence of a keto group and a tertiary nitrogen atom,
and when oxidised with chromic acid, hygrinic acid is formed.
C gH 15ONiU 6H u
hygrinic acid
Hygrinic acid was first believed to be a piperidinecarboxylic acid, but comparison with the three piperidine acids showed that this was incorrect.
When subjected to dry distillation, hygrinic acid gives 2V-methylpyrrolidine
hence hygrinic acid is an iV-methylpyrrohdinecarboxylic acid. Furthermore, since the decarboxylation occurs very readily, the carboxyl group
was assumed to be in the 2-position (by analogy with the a-amino-acids).
This structure, l-methylpyrrolidine-2-carboxylic acid, for hygrinic acid was
confirmed by synthesis (Willstatter, 1900).
Br ,
Na
vBr(CH
CHCH
CHf-CH
>
ch N " 2
CHa
-CH(C0 2 C 2 H5
'
*~GTI,
Br
C(C0 2C 2 II6 ) 2
>
G(C02 C 2 H5
CH 2
^N^
Br
CH3
(i)Ba(OH)
(h)hci
2 )3
^H,
CH
C h2
CH -C0 H
CH3
(+)-hygrinic acid
2>
496
ORGANIC CHEMISTRY
Thus a
CH 2
CH
II
CH
2
[CH.
XIV
is
CH-CH 2 -CO-CH3
CH,
Hess (1913) claimed to have confirmed this structure by synthesis; his
synthesis starts with pyrrylmagnesium bromide and propylene oxide to form
pyrrylpropanol (note the rearrangement that occurs). This compound is
then catalytically hydrogenated and then treated with formaldehyde; the
imino nitrogen is methylated and the secondary alcoholic is oxidised to a
keto group.
CH 3 Mgflr
CHVCH-CH 3
FloOH -CHOH-CH,
2
MgBr
CHo
H 2 -Pt
CHn
II
H-CHO
'
CH2
CHCH -CHOHCH
2
CH3
() -hygrine
Lukes
(1959)
et al.
product
is
(I); it is
pK
CH2 -CH 2
I
GH2
CHO
C02C 2 H5
CH2 COCH 3
pHl
II
NH
I
CH3
CH,
ester:
497
ALKALOIDS
15]
CH CH
I
CHO
CH2
CH
+ CHO CH
CH2
NNH
COoEt C0 2 Et
+|
CH2 -CO-CH 2
PHT,
HN
I
CH,
CH,
CH2 CH 2
CH 2 CH2
II
CH 6H-CH
2
2 -CO-
IICH
CH 2-CH
CH,
CH,
cuscohygrine
13b. Stachydrine
orange leaves,
etc.
monium compound
is
It is the betaine (4 C.
of hygrinic acid.
CH 2
CH 2
CH 2
CH-COr
X 1T
(CH3) 2
14. Gramine has been found in barley mutants; it raises the bloodpressure in dogs when administered in small doses. Gramine has been
synthesised by allowing indole to stand in an aqueous solution containing
et al.,
1944).
GH,-N(CH,)
HCHO+(CH NH
3) 2
+^0
PYRIDINE GROUP
C,H 7 O gN, m.p. 130, is widely
distributed in plants;
15. Trigonelline,
the best source is the coffee bean. When boiled with barium hydroxide
solution trigonelline produces methylamine; thus the molecule contains an
iV-methylamino group. On the other hand, when heated with hydrochloric
acid at 250 under pressure, trigonelline forms methyl chloride and nicotinic
acid; this suggests that the alkaloid is the methyl betaine of nicotinic acid.
This structure for trigonelline has been confirmed by synthesis (Hantzsch,
When heated with methyl iodide in the presence of potassium
1886).
hydroxide, nicotinic acid, I, is converted into methyl nicotinate methiodide,
II, on treatment with " silver hydroxide " solution, forms nicotinic acid
II.
methohydroxide, III, which then spontaneously loses a molecule of water
to give trigonelline (a betaine), IV.
^C0,H
chi
C02CH3 _AgOH_
CO gH -h
q,.
[|\C0
N'
I
CH 3
IV
ORGANIC CHEMISTRY
498
[CH.
XIV
Spath
e.g.,
H
*)C0 H
!iC0 2
KMnQ 4
(1923);
CI
CI
CI
et al.
(CH 3 CO) 2
4-chloropyridine2:3-dicarboxylic acid
4 -chloroquinoline
CI
CI
CI
(f\c0 H
Brj-KOH
CC-NH2
fjSc0 H
NH
C02 H
NaNOj
H a S0 4
poci 3
PC1
OH
HI
II
2-carbonamido-4-chloropyridine-3-carboxylic acid
d^ScOCl
/A,CO-NH
NH ,
"
Jci
II
OCH3
CI
CI
:H s ON a>_
pocj^r
^ CN
CH3OH
100
OCH,
Jci
2:4-dichloro-
pyridine-3-carbonamide
OCH 3
CH S I
heat in vacuo
This is not an unambiguous synthesis, since II could have been 3-carbonamido-4-chloropyridine-2-carboxylic acid, II, and consequently III would
have been
Ilia.
CI
CI
JcO'
l[
XN
CI
JC0,H
CI
Jc0 H
H ' so
JcOoH
^N
II
III
499
ALKALOIDS
17]
The
Ha
Pd
-BaS0 4
NO.
OCH
al.
(1956).
OCH,
CH,
2
H,S0'
O
OCH.,
5|CONH2
l'Cls
POCl 3
17. Areca (or Betel) nut alkaloids. The betel nut is the source of a
number of alkaloids which are all partially hydrogenated derivatives of
H
guvacine,
m.p. 271-272
C0 2 H
C08 CH3
CO,H
guvacoline,
.p.H4/l3mm.
C02CH3
N^
I
0H3
arecaidine
m.p. 223
arecoline,
b.p. 209
ORGANIC CHEMISTRY
500
CH(OC 2 H5
CHO
CH +
CH 2
2C 2 H 5 0H+HC1-
[CH. XIV
(C 2
)2
6 0) 2
CH 3 NHj
-CH 2
CH(OC 2H5 ) 2
CH 2
CH2
CII 2
II
CH
CH2C1
CH3
II
CH
III
,CH
CHO CHO
CH2 CH2
CH2 CH2
HCl
- 2 X>CN
CH2 C-CHOjj) NH2 oH^ CH
CH
CH
(ii)
SOCIj
"cH, CH
I
CH,
CH3
CH3
IV
V
.CH
N C-C0
CH 2
I
2H
CH 2 CH 2
\ X
N/
I
CH 2
c-co 2
or
CH.
CH,
CH3
CH3
VI
Via
a al.
(1946).
C0 2 C2 H5
C02 C2 H6
+NH
CH
CH
+ CH
CH 2
CH 2
CH
II
II
COjAHs
C 2 H50 2 C
Cxig
\'
(Dieckmann
reaction)
XvXA2
NH
ethyl
acrylate
,C0 2 C 2
c 6 h,coci
C02 C2 H 5
Hj-Ni
dry
iC02 H
HCl
CO-C6 H5
CO-CgHs
3-carbethoxypiperid4-one
>C0 2 H
180
H
guvacine
SCO2C2H5
CH3
arecaidine
601
ALKALOIDS
18]
Hemlock
coniine;
it
'CH=CH-CH3
2-propenylpyridine
Na
^_ 9 Ha
ch 6 oh
qjj^
CH-CH2-CH 2-CH3
H
() -coniine
hydriodic acid at 300 under pressure, coniine forms M-octane. Had the
side-chain been isopropyl, then the expected product would be wo-octane.
From this evidence it therefore follows that coniine is 2-M-propylpiperidine,
and this has been confirmed by synthesis (Ladenburg, 1885). The racemic
coniine was resolved by means of (+) -tartaric acid, and the (+)-coniine so
obtained was found to be identical with the natural compound.
The reactions of coniine described above can therefore be formulated as
follows:
H
CH2 CH 2
.HI
CH3 CHgCHgCHgCHj
CH^'CHs CHg
n -octane
KMnOi
^CM2"CIi2"Ofi3
conyrine
C02 H
pyridine-2carboxylic acid
Coniine has also been synthesised from 2-methylpyridine and phenyllithium as follows (Bergmann et al., 1932):
EtBr
EtOH
CH,Li
ORGANIC CHEMISTRY
602
[CH.
XIV
H,
R0
is
2
V/^riimH.r!B
.rrw
IT
V-r^^n
CH2' Oxi2*Cri3
conhydrine
^"Conhydrine
Y-comceine
and
pseudo-pelletierine.
The
H
CH
-CH 2 -CHO
pelletierine
H
H
wopelletierine
o
N
CH 2 -CH CH2
CH2 n-chs co
CH CH CH2
I
CH2 -COCH3
CH,
pseudo-pelletierine
methylzsopelletierine
CH(OC2 H 5
)2
C 6 HB
Li
CH 2 CH2-CH(OC 2H5 )2
)2
()-form
to hydrolyse
it
/$CH,
H,C
H 2C
Cja2
H,C
2
|
CHCH 2 CH 2 CHO
HaC
CH,
503
ALKALOIDS
20]
H2C
H 2C
CH 2
CH
N
I
CH,
HOCH
CH
I
C17H18
N + N aO
J-C^oO*
C 5HUN
piperidine
piperic acid
piperic acid and piperidine ; thus the alkaloid is the piperidine amide of piperic
acid (Babo et al., 1857). Since piperidine is hexahydropyridine, the structure of piperine rests on the elucidation of that of piperic acid. The routine
tests show that piperic acid contains one carboxyl group and two double
bonds. When oxidised with permanganate, piperic acid gives first piperonal
and then piperonylic acid. The structure of the latter is deduced from the
fact that when heated with hydrochloric acid at 200 under pressure, piperonylic acid forms protocatechuic acid (3 4-dihydroxybenzoic acid) and
:
formaldehyde.
C8 H 6
-^
11+
V
HO(f\cO,H
HO
piperonylic acid
H-CHO
protocatechuic acid
Since one atom of carbon is eliminated, and there are no free hydroxyl
groups in piperonylic acid, the structure of this acid is probably the methylene
ether of protocatechuic acid, i.e., piperonylic acid is 3 4-methylenedioxybenzoic acid; this has been confirmed by synthesis:
:
CH 2 I 2
-^>
hut
piperonylic acid
O-YXCHO
CH,
KMn0<>
c^;fVH
piperonal
is
ORGANIC CHEMISTRY
504
all of
[CH.
XIV
=CH-CH=CHC0 2 H
[o]
C0 2 H
+ H0 2 C-CHOH-CHOH-C0 2II
CHO
NaOH
+ CHO,
CH a(a
NaOH
CHO
%
QIl.Q|
catechol
ch
^-0
1 ^r irNcH=CH- CHO
NaOH^-WzH
(CH CO),0 QH 2
JCH^COJsO
CH;
:H *
!lCH=CH- CH=CH- G0 2H
CH 3 -C02Nr
When the acid chloride of piperic acid (prepared by the action of phosphorus
pentachloride on the acid) is heated with piperidine in benzene solution,
piperine is formed; thus pipeline is the piperidine amide of piperic acid.
^--O
,CH2
r\cH=CHCH=CHCOCl
CH2v
+ HN.
Gfi2*CH 2
CH.
.CH 2 -CH 2 v.
x^
^-~( ^CH=CH-CH=CH-CONv
.CH2
-<AJ
piperine
PYRROLIDINE-PYRIDINE GROUP
Many alkaloids have been isolated from the
21.
tobacco leaf, e.g., nicotine, nicotimine (anabasine), nornicotine, etc.
Nicotine, C 10 14N a b.p. 247, is the best known and most widely distributed of the tobacco alkaloids; it occurs naturally as the ( )-form. When
oxidised with dichromatesulphuric acid (or permanganate or nitric acid),
nicotine forms nicotinic acid (Huber, 1867).
Tobacco alkaloids.
C 10 H 14 N2
KWnOt
^C0 2 H
.
nicotine
nicotinic acid
505
ALKALOIDS
21]
It is instructive, at this point, to see how the orientations of the three isomeric
pyridinecarboxylic acids have been elucidated.
CO,H
C0 2 H
NN 'COjH
"N
picolinic acid,
nicotinic acid,
wonicotinic acid,
m.p. 137
m.p. 234-237
m.p. 317
CHjOH
11011
,CO,H
CO s H
C.H.NO,
CH.OH
NH.
Co]
H0 2C
thylamine.
CHjOH
NH2
+ GHOH
H a SO,
CHjOH
C]
HOs C<*
.
nicotinic acid
ORGANIC CHEMISTRY
506
[CH.
CO,H
CO,H
[o].
XIV
CO.H
N
nicotinic acid
quinolinic acid
quinoline
C0 8 H
to].
CO>H
C0 2 H
cinchomeronic acid
MOquinoline
wonieotinic acid
C 5 H10 N
CH 2 CH 2
CB H10N
-CH CH.
or
-CH
'
I
Of 2
CH,2 CH
CHg
\,
a-/
I
CHS
CH,
The
(1892, 1893).
Treatment of nicotine with bromine in acetic acid gives, among other products, the hydrobromide perbromide, CinH^ONgBra-HBr-Brg, which, when
treated with aqueous sulphurous acid, is converted into dibromocotinine,
C10H 10 ON 2Br2 This, on heating with a mixture of sulphurous and sulphuric
acids at 130-140, forms 3-acetylpyridine, oxalic acid and methylamine.
.
of nicotine
must account
structures:
C-C
C 5 H,N
^N
C-C
(oxalic acid)
N-CH
(methylamine)
(3-acetylpyridine)
Now
507
ALKALOIDS
21]
C 5 H10 N
N
N'
C-C-C
N-CH
(methylamine)
(malonic acid)
"N"
(nicotinic acid)
These two sets of reactions, taken in conjunction with one another, are
satisfied
by the
C-C-C-C
N-CHs
The problem now is Where is the position of the N-methyl group? Nicotine
behaves as a di-tertiary base, and forms two isomeric " methyl iodide addition
products ". Thus the nitrogen atom in the side-chain must be of the type
:
CN(CH )C
3
Furthermore,
it is
extremely
difficult to
reduce nico-
tine
H N=C
H8'NCHj^C4Hg).
chain is cyclic, i.e., iNT-methylpyrrohdine (C 5 u
4
The presence of this pyrrolidine nucleus also accounts for the formation of
pyrrole when nicotine zincichloride is distilled (see above). All the foregoing facts are satisfied by the following structure for nicotine.
CHg
CH 2
rV<CH
^CHj
nicotine
On
/\
1
(I
CH2 -CH2
CH
CH,
H * m Br,-CH
Rr ._cH.-co.H
3 -CQ 3 H^
P
"V
(ii)H,SO,
N
(i)
N'
CII,
CH 2 -CHBr
>~CBr CO
if
H a SO
I
CH3
dibromocotinine
l0
OCH s+ CO2 H
+
COaH
3-acetylpyridine
CO CHBr
CHsr- CH2
,fV- CH
CH,
Brj
HBr
X 1T
/\-CBr
||
CO
N'
CHS
CH,
dibromoticonine
jCOoH
B a(OH),
:
508
ORGANIC CHEMISTRY
XIV
[CH.
The most direct analytical evidence for the presence of the pyrrolidine
nucleus has been given by Karrer (1925, 1926) nicotine hydriodide forms
nicotine isomethiodide when warmed with methyl iodide and this, on oxidation with potassium ferricyanide, is converted into nicotone which, on
oxidation with chromium trioxide, gives hygrinic acid (13).
;
CH2 CH2
H0 2CCH CH2
CH3}V
CH3
nicotine /somethiodide
hygrinic acid
CH2-CO\
>/
CH2 -CO'
CH2 -CH \
nil./
CH2 CO
succinimide
2-pyrrolidone
electroIytic
\C0 C H
2
(ii)
||
CH 2-CH 2
,cHJ.so t
9 H"GH^
NaOH
CH,-CO /
/\-0O-GH CH
C2 H 6 oNa
>
CO
\r
CH,
e.g.,
CH2
CO
\r
CHs
CH.,
CH. CH.
COCHCH CH NH-CH
C0 H
HCl
II
-^(X CO NH
^jCKt
^N
(5-ketonic acid
-CH.
CH2 CH 2
CHOH CH2
CHI CH.
CH,
Zn
dust
CjHjOH-NhOH
II
NH
NH
V
CH,
CH2
NaOH
CH,
CH2
ov
CH2
CH3
(+)-nicotine
( )-nicotine
509
ALKALOIDS
22]
Craig (1933).
+ BrMgCH 2
CH 2 CH 2 OC 2 H 5
Y -ethoxypropylmagnesium bromide
CH 2 CH2
CH 2
CO
OC 2 H 5
3-pyridyI y-ethoxypropyl
nicotinonitrile
ketone
CH
CH 2
CH2
NOH OC,H5
C
NHjOH
||
CHo
GH2 CH2
CH CH 2
*
z"
u >
CH 3 -CO a H
/\
]
H.
J NH
CHg
CHg
'CHo
-a ^
CH
HBr
150-155
OC 2 H 5
CH.2
(i)CH 3 l
(ii)
NaOH
(+)-nornicotine
CH2 CI12
(f\ CH
CH2
V Y
N
CH3
() -nicotine
Spath
et al.
have resolved
(1936)
methylation of the
acid gave () -nicotine, identical
r r )-nornicotine;
|
When warmed
is
is
hydrolysed
the tropine
C6 H5
CH=CH-C0 2H
I
C6 H 5 -C-COi,H
CH2
II
gives benzoic acid. Thus tropic and atropic acids contain a benzene ring
with one side-chain. It therefore follows that atropic acid could be either
Since, however, I is known to be cinnamic acid, II must be atropic
I or II.
Addition of a molecule of water to II would therefore give tropic
acid.
ORGANIC CHEMISTRY
510
CeH 6
XIV
OH
C-C02 H
[CH.
C 6H 5
C 00,-H
I
CH 2 OH
CH3
IV
III
shown to be IV by
Wood
(1919), starting
from acetophenone.
6Hs
~
\n
JJ=0
"cn.*~
CH 5
^^OH
CH 3
CHf
yk
C6 H 5
*"
XN
GH"
^/
OH
\ COaH
heat
reduced
pressure
III
atrolactic acid
CH^^COgH
HQS
CH,^ dX 0H,01
K>c%
CeH^^CH.OH
CH2
"
tropic acid
j-r
by means
of quinine.
Blicke et al. (1952) have synthesised tropic acid by boiling phenylacetic
acid with tsopropylmagnesium chloride in ethereal solution, and then treating the product, a Grignard reagent, with formaldehyde.
.CH 2 OH
>MgCl
C,H6-CH 2 -C0 2 H
>
2L^C H -Ch(
O.H.-OHr
\:o 2H
C0 2 MgCl
Ph
H C0 H
2
CH-OH
Tropine (tropanol), C 8H16ON, m.p. 63, behaves as a saturated compound which contains an alcoholic group. The structure of tropine was
investigated by Ladenburg (1883, 1887), who showed that the molecule
contained a reduced pyridine nucleus:
Tropine
CgH 16ON
->-
hydrochloride
<
CH3CI
>
Dihydrotropidine
C 8H15N
C8 HUNI
+ wrDihydrotropidine
C H1SN
7
iml
* 2-Ethylpyridine
C 7H,N
511
ALKALOIDS
22]
Merling (1891),
()-tropinic acid.
C 8H13
C 8H15ON-^V
(^-tropinic acid
tropine
CH 3 -N
fa*
Tropine
C 8H 16ON
or
CH S-N
CH2
CHOH CH 2
I
> Tropinone
C 8H 13ON
'-*
of tropine
()-Tropinic acid
C 8H 1S
CH2
CH
CH 2
OH,,
NCH3 CHOH
CH CH 2
I
(i)
Willstatter formula.
ORGANIC CHEMISTRY
512
[CH.
XIV
CH2 CH
CH
CH 2~~* C
NCH3 CHOH
I
Hr
OH
GH2
jFx
NCH, CHI
CH2
CyX''
[H]
NCH, CH 2
CH
I
Cri2^~ CH
"
CH 2
CHg
CH2
dihydrotropidine
tropine
(tropane)
CHo
CHg"-~CH
HCI
NH CH
*-CH3 Cl +
/CHo'OHfl
CH
CH2 CH
2-ethylpyridine
Kordihydrotropidine
CH CH CH
CH
92
NCH, CHOH- ^
CH CH CH
CH CHCH
CH2 CH
tropine.
CH 2 CH CH 2 -C02 H
NCH3
-CH-<
CH-C0 *H
CH 2
2
tropinic acid
tropinone
ch b -cho
CH2 CH
C=CHC
H5
NCHS CO
CH 2 CH
C=CHC H
6
dibenzylidenetropinone
CH2 CH
CH
CH
NCH,
CH2 CH
CH2 CH
CHOH-g^.
CH
CH
CH-|^>
NCH 3
CH
CH2 CH=CH
MCH^CHdistillation
(i)
(ii)
(iii)
CH
CH2
HON(CH3 2 CH
)
CH2 CH
CHg CH
CH
CH2 CH=CH
CH3
AgOH
I
CH
vacuum
CH=CH CH
II
CH 2 CH
CH
distillation
tropilidene
CHf- CHCH 2 C0 2 H
I
CH2
NCH 3
CHC02H
CH2
(i)
CH 3 I
acid.
CH-CH
C0 2H
HONtcHs),
(ii)AgrOH
CHg CH-C02 H
tropinic acid
N(CH 3 ) 2
CH2 CHC0 2 H
(iii)
CH2-CH2 CH2-C0 2H
AgOH^
heat
CH=CHC0 H
2
CH2-CH2 -C0 H
2
piraelic acid
ALKALOIDS
22]
513
"
K H
CHI CjH
B OH
\so^m+
HI
(ii)
CH2
"
CH
>
~^^
CHg* OHg
cycloheptene
suberone
0x12*0x12"
Will-
CHg* GHg'GHg
by
CH2
CH,-
CIV CH
GHo
exhaustive
II
CHI (^2V
CHBr
CH
Oxxg * GxX
Bra ,
II
CH
methylation
CH 2 CH=CH
CH2 -CH2-CH-N(CH3 )2
CHjj-CHj-CHBr
"
cyc/oheptadiene
CHr-CH=CH
CH
quinoline
CH
150
CH2-CHBrCH2
HBr
CH
*-
(CH 3 8 NH
)
II
II
CHjj-CHBr-CH
CH=CH CH
(l:4-addition)
cyc/oheptatriene
CH=CH CH
(tropilidene)
CH2 CH
-CH
CH2 CHigmrv
JN(OH
CIT
yti
3)2
(QW.-C.H.OH
(ii)Br,-HBr
CH2 -CH=CH
CH2CH-
CH2
CH,-CH
+
Br"N (CH3 )2
I
CH2
~^^
CH* CH-
-CHBr
CH CH-
-CH2
ClN{CHs)2
CH2
N(CH 3)2
warm in
yH*
ether
Br
CHBr
CHj CH
-QH,
()Kl(Br->.I)
CH
BrN(CH3)2
CH2 CH
(ii)AgCl(I-*C1)
CH
CH CH
CHg^GH"" CH2
heat
CH
CH 8
NCH3 CHBr
>
CH GHg
I
CH, CH-
CH
CHj CH
-CH
CHg
tropidine
Cxi2~~
H3SO4.
CH~~~ GH2
NCH3
200
CH2CH
iji
C<
H -^V
xOH
CH
|
-tropine
CH2--CH
CH
Zn
HI
NCH3 GO
CH2 CH
CH
tropinone
CHj CH
CH,
.-OH
|Sl
GH CHg
I
NCH3 C
CH2
tropine
ORGANIC CHEMISTRY
514
[CH.
XIV
Robinson's synthesis.
When a mixture of succinaldehyde, methylamine and acetone is allowed
to stand in water for thirty minutes, tropinone is produced in very small
yield.
CH2 CHjO
h
+ NCH
HiCH2
CH2 OHIO
CO
IH
CH,-
..J,
-*-2H 2
'
CH2
HiCHj
NCH3 CO
*l
CH CH
.Ah- -CH,
A much
better yield (40 per cent.) is obtained by using calcium acetonedicarboxylate or ethyl acetonedicarboxylate instead of acetone; the calcium
salt or ester so produced is converted into tropinone by wanning with
hydrochloric acid, e.g. (ca
Ca/2)
CH CH
CH2 -C02 ca
CH2 -CHO
CH-C02 ca
I
+ CHs-NHjj + CO
NCH CO
>-
CHjj CH
HCI
CH
C%- CH
CH 2 -C02 ca
CH2 -CHO
CH-C02 ca
NCH3 CO
CH2 CH
I
CH
i
Schopf et al. (1935) have obtained a yield of 70-85 per cent, by carrying out
Robinson's synthesis at a pB. of 7. Elming et al. (1958) have also synthesised tropinone using methylamine hydrochloride, acetonedicarboxylic
acid and generating succinaldehyde in situ by the action of acid on 2,5-di-
methoxytetrahydrofuran
CH3OI
^?
^OCH3
"s
H,CHO
CH 2 -CHO
CH 3 NH2 HCI
co(CH s co2 H) 2
XT
CH,
CHj-CH
NCH 3 CO
CH CH CH,2
I
"
The yield was 81 per cent., but in this case " physiological conditions
were not necessary (see 28).
The final problem is to combine tropine with tropic acid; this has been
done by heating the two together in the presence of hydrogen chloride
(Fischer-Speier esterification; see Vol.
I).
CH 2 CH CH2
/C0H5
XCH,OH
CH CH
2
CH
HCI,
CbHr
NCH133 CHO-CO-CH
CH CH
I
CH,
"t!H2 OH
gi
atropine
y)-tropine,
515
ALKALOIDS
22]
acid, the best combination being zinc dust and hydriodic acid; or by means
of electrolytic reduction. On the other hand, reduction with sodium amalgam converts tropinone into y-tropine. According to Mirza (1952), lithium
aluminium hydride reduces tropinone quantitatively to y-tropine, but according to Beckett et al. (1957), 54 per cent, of y-tropine and 45 per cent, of tropine
are obtained.
larger yield of the former (69 per cent.) is obtained with
sodium borohydride, and reduction with sodium and wobutanol (in toluene)
gives the maximum yield of y-tropine (88 per cent.).
Tropine and y-tropine are geometrical isomers, one isomer having the
hydrogen atom on C 3 on the same side as the nitrogen bridge, and the other
isomer has this hydrogen atom on the opposite side (cf. the borneols, 23b.
VIII) ; Fig. 1 shows the two possible forms. Neither of these forms is optically
CH 2
CH;
CH
NCH,
CH-
CH 2
CH,
,OH
CH'
1
,CH,
HO'
NCH,
CH-
CH'
(a)
.cT
^CH,
CH(b)
Fig. 14.1.
has a plane of symmetry. C and C 6 are asymmetric, but the molecule is optically inactive by internal compensation (see
7b. II), and so each isomer is a meso-iorm; C 3 is pseudo-asymmetric (see
It should also be noted that another pair of optically active forms
8. IV).
would exist if the fusion of the nitrogen bridge were trans; this, however,
is not possible (cf. camphor, 23a. VIII; also cocaine, 23).
The problem now is to decide which geometrical isomer (of the two forms
shown in Fig. 1) is tropine and which is y-tropine. Fodor (1953) has given
evidence to show that y-tropine is the sy-compound (nitrogen bridge and
hydroxyl group are in the ct's-position; Fig. 1 b), and that tropine is the anticompound (nitrogen bridge and hydroxyl group are in the iraws-position;
Fig. la). The problem, however, is more involved than this, since the conformation of the piperidine ring has also to be considered. Fodor gives
the configuration of the piperidine ring as the boat form in both isomers
active, since the molecule
(Fig. 2).
CH 3 ho
V- H
/CH 3
>
(b)
tropine
Fig. 14.2.
Zenitz et al. (1952) and Clemo et al. (1953) support these configurations
from evidence obtained by measurements of the dipole moments of these
two isomers y-tropine has been shown to have a higher dipole moment than
tropine. Zenitz et al. have also shown from infra-red absorption spectra
measurements that y-tropine has intramolecular hydrogen bonding; this is
only possible in the sy-form. Bose et al. (1953), however ^ have assumed
the chair form for the piperidine ring by analogy with the chair conformaThus these
tion of cyc/ohexane compounds and pyranosides (see 11. IV).
authors have suggested that y-tropine is Fig. 3 (a), in which the hydroxyl
;
ORGANIC CHEMISTRY
516
group
group
is
equatorial,
is Fig.
[CH.
(6),
in
XIV
is axial.
/CH 3
/CH 3
N
(a)
<]i
(b)
tropine
-tropine
Fig. 14.3.
The
esters
acids.
itself)
Cxio
CH CHo
I
NCH3 CHO-0O-CHOH-C H6
6
CH
CH2 CH
homatropine
22b. Hyoscine (scopolamine), C 17 21 4 N, is a syrup and is laevorotatory; it is obtained from various sources, e.g., Datura Metel. Hyoscine
is a constituent of travel sickness tablets, and when administered with
morphine, produces " twilight sleep ". Hyoscine is the () -tropic ester of
the aminoalcohol scopine; these two compounds are produced by the hydrolysis of hyoscine with ammonia.
CH CH
\ CH
CH2
CH2 0H
NCH3 CHO-CO-CH
CH2
CH
^-
C6Hs
li3'oscine
CH CH
CH,
/ CH OH
2
<CH-CH
NCH CHOH +
3
scopine
0H 2
C 6 H5
CH
COzH
tropic acid
517
ALKAtOIDS
23]
,CH CH CH2
CHOH CH
NCH
oscine
CH,
acid
NCH3 CHOH
IICH
\m_ ch
c
>
CH-,
CH
CH
o
CH
scopine
oscine
It is interesting to note, in this connection, that
latter
NMe
R = COCHPh-CH
OH).
C17H 21
N+H
cocaine
benzoylecgonine
Thus cocaine contains a carbomethoxyl group, and benzoylecgonine a carboxyl group. When benzoylecgonine is heated with barium hydroxide solution, further hydrolysis occurs, the
and ecgonine.
C 16H19
N+H
7MSSB)t
2
>
benzoylecgonine
C 9 H 15
N+
C 6 H 5 -C02 H
ecgonine
Ecgonine
C 9H 15
From
V Tropinone
C H ON
8
13
^>-
Tropinic acid
C 8H 13
Ecgoninic acid
C 7Hu
518
ORGANIC CHEMISTRY
[CH.
XIV
CH
III
CH2
CH-COJI
NCH3 OHOH
CH
I
GH2 CH
ecgonine
On
CH2 -
H.o
benzoylecgonine
cocaine
CH CH CHCOjH
CH-C02 H
CHj CH
Ba(QH)
CH CH
CHr-
therefore be written:
CH2 CH CH-C02 H
NCH3 CHO-COC6 H5
CH3OH +
CH CH-COjCHs
NCHj CHO-COC6 H5
may
NCH3 CO
I
CHjCH CHz
CHj- CH CH,!
ecgonine
CH*- CH CH2
NCH3 COI
CHj CH CH2
tropinone
CrO,
NCH3
CH2 CH-C02 H
tropinic acid
^CHj
CHj CO
ecgoninic acid
The
CHa CH3CH-COjjH
NCH,*CHOH
Is
/I
16 optically
asymmetric carbon atoms present {*), and so there are 24
active forms (eight pairs of enantiomorphs) possible (cf. tropine, 22). Since,
however, only the cis fusion of the nitrogen bridge is possible in practice,
Cx and C s therefore have only one configuration (the cis-form), and so there
are only eight optically active forms (four pairs of enantiomorphs) actually
possible (cf. camphor, 23a. VIII) ; three pairs of enantiomorphs have been
prepared synthetically.
In the original synthesis of Willstatter, the racemic ecgonine obtained
was not identical with the ( )-ecgonine from ( )-cocaine, but its chemical
properties were the same.
519
ALKALOIDS
23]
CHg CH CH
I
NCH3 CONa
NCH3CO
-^
CHj CH CH2
CHj CH CH 2
I
tropinone
CH 2 CH CH-C02 H
CHj CH CH-C02 Na
Na-Hg
NCH3 CO
Later, Willstatter
et
al.
CH CH CH
a ()-ecgonine
sodium tropinonecarboxylate
Robinson method
CH CH CH
NCH3 CHOH
acid
by means
of the
(see 22):
GHz CH CHC02 C 2H 5
CH2 C0 C2 H 5
CH 2 CHO H
KOH
+ NCH3 + CO
NCH3 CO
CH2 CH CH-C02H
I
CH2 -CHO H
CHj-COaH
CH2 CH CH-C02H
CH2 CH CH-C02C2 H5
NCH3 CO
I
NCH3 CHOH
hydrolysis
CH CH2
I
CHg
(0 [H]
(ii)
CH
CH2 CH
final product was shown to be a mixture of three racemates, ()ecgonine, (ij-y-ecgonine and a third pair of enantiomorphs (Willstatter
et al., 1923).
The racemic ecgonine was resolved, and the ( )-form esteri-
The
fied
CHg CH CH-C02H
I
NCH CHOH
3
CH2 -CH
(OCH3OH-HC1
(ii)CH-COCl
CH2
CH2CH
( )-cocaine.
CH-C0 CH
2
NCH3
CHr-CH
CHO-CO-C8H5
CH
(-)-cocaine
(-) -ecgonine
In a similar way, the (+)- and ( )-y-cocaines were obtained from the
corresponding y-ecgonines. An interesting point in this connection is that
Einhorn et al. (1890) showed that the prolonged action of 33 per cent,
aqueous potassium hydroxide converts ecgonine into y-ecgonine, and Findlay
(1953) has found that cocaine gives y-ecgonine methyl ester by the action
of sodium methoxide in hot methanol.
Fodor et al. (1953, 1954) and Findlay (1953, 1954) have established the conformations of ecgonine and y-ecgonine (R = CO aH; R' = H) and the corresponding cocaines (R = COjMe; R' = COPh) (c/. 22):
Nil*
OR
cocaine
(and ecgonine)
y-cocaine
(and y-ecgonine)
ORGANIC CHEMISTRY
520
[CH.
XIV
Hardegger et al. (1955) have correlated ( )-cocaine with L-glutamic acid and
have shown that the formula represents the absolute configuration of l( )cocaine.
When
CHs CH CH 2
NCHsCHO-CO-Cft^^
CH CH CH
-CH CH
CHa
NCH3
CHCH
CHj
tropacocaine
lM
<X*
OH
+ CeHs'CO^I
t{<-tropine
to give /3-eucaine.
H HCH
2CH3-CO-CH3+NH3^H^O+NH
I
(CH3 )2C
ch 3 -ch(qc 8 h 5
CO
CH 2
n
yn
NH
CH
CH
^C-
io i;;^. coc?
CH2
(CH3 )2 C
)cHO-CO-C6H6
CH,
p-eucaine
(c ' HB)aNH
>ISrO 2
^ N0 <f^\cO-OCH
2
NH 2 <^_^>CO-OCH2 CH
-N(C 2
5)2
-CH2Cl
>
5) 2
procaine
QUINOLINE GROUP
24.
Angostura alkaloids.
e.g.,
521
ALKALOIDS
24]
Cusparine, C19H 17 3N, m.p. 90-91, has been shown to contain one
methoxyl group (Zeisel method), and when fused with potassium hydroxide,
protocatechuic acid
obtained.
is
19
17
O 3N
,OH
KOH
CO.H
On
and 4-methoxyquinoline-2-carboxylic
C 19 H17
acid.
-^i*.
C0 2 H
Consideration of this information led to the suggestion of the following
structure for cusparine.
OCH 3
O
SHa-CHr^f
CH
^-0
cusparine
by
synthesis (Spath
OCH3
CH,
et al.,
O CH
-^V
OCH
1924).
piperonal
4-methoxy-2methylquinoline
OCH,
^~f
OCH,
CH CH
2
CH,
cusparine
Galipine, C 20H 21 O 3N, m.p. 113, contains three methoxyl groups (Zeisel
method). When oxidised with chromic acid, galipine produces 4-methoxyquinoline-2-carboxylic acid and veratric acid. Thus the formula of the
alkaloid is probably:
ORGANIC CHEMISTRY
522
[CH.
XIV
OCH,
OCH 3
/-CHCHr-/^\oCH
galipine
by
synthesis (Spath
et al.,
1924).
OCH3
OCH3
+
>CH3
OCH^^OCHr^^
veratraldehyde
OCH,
NCH-^VOCH3
CH=CH-
0CH3
CHf-CH
galipine
C19H19
OCH,
When
U^CH^^>Ch7\An^CTI=CH-^3>OCH3
O-CHj-CeHs
CH8 QNa
-Pd-C
(i)C,H t
(ii)H 2
OCH,
"^ je^
c^-chK7och
rcH.V
7
523
ALKALOIDS
25a]
member of this
group,
its
Thus cinchonine
,HlgON
CO,H
contains a quinoline nucleus with a side-chain in position 4 (III) this sidechain was referred to by Skraup as the "second-half" of the molecule.
The hydroxyl group in cinchonine must be in this " second-half ", since if
it were not, then a hydroxy derivative or a carboxy derivative (sjnce the
hydroxyl is alcoholic) of cinchoninic acid would have been obtained.
Oxidation of cinchonine with permanganate gives cinchotenine and formic
acid (Konigs, 1879).
;
C19H MON s
+ 4[0]
KMnO,
> C18H ao
N +
!,
H-C0 2H
cinchotenine
is
CH=CH
When treated with phosphorus pentachloride, followed by ethanolic potassium hydroxide, cinchonine is converted into cinchene which, when heated
with 25 per cent, phosphoric acid, forms lepidine and a compound Konigs
named meroquinene (Konigs et ah, 1884). With the information obtained
so far, we may formulate the work of Konigs as follows:
/ OH
N CH=CH
PCI
cinchonine
!
H N-CH=CH
11
KOH
i!
H 3 PO
CjHOH
+ C 9 H16
+ 2H a O)
meroquinene
cinchene
lepidine
524
ORGANIC CHEMISTRY
Meroquinene (meroquinenine)
acid, wjien cinchonine is
[CH.
XIV
CioIImON
COJI
/\
?\
^
v^V
1
Jsu
CI
\sy\K y
[
+ C 9 H 15
cinchonine
meroquinene
cinchoninic
acid
Thus the key to the structure of the " second-half " is the structure of
meroquinene. The routine tests showed that meroquinene contains one
carboxyl group and one double bond; the presence of the latter indicates
that the
Oxidation
2 side-chain is still present in meroquinene.
of meroquinene with cold acid permanganate produces formic acid and
cincholoiponic acid, the latter being a dicarboxylic acid (Konigs, 1879).
The formation of formic acid confirms the presence of the
2 side-
CH=CH
CH=CH
C 9H 15 O aN
*S C H
8
meroquinene
13
N + H-C02H
cincholoiponic acid
'
chain in meroquinene. The presence of this group has also been demonstrated by the ozonolysis of meroquinene; formaldehyde is produced (Seekles,
Oxidation of cincholoiponic acid with acid permanganate produces
1923).
loiponic acid, C 7 11 4 N (Konigs, 1890). This is also a dicarboxylic acid,
and since it contains one methylene group less than its precursor cincholoiponic acid, this suggests that the latter contains at least a side-chain
CH -CO H.
2
The
reactions of the above three acids indicated that they were all secondary bases that they all contained a piperidine ring is shown by the following
reactions.
;
(i)
C 2H5
Hcl
Meroquinene
-,
240
CH,
(ii)
H a SO t
Cincholoiponic acid
heat
co
.CH
(iii)
Loiponic acid
-.
isomenses
>-
x CH-C02 H
CH2
CH,
CH,
II
hexahydrocin chomeronic
acid
alkaloids
25a]
The
(cf.
525
is
known from
its
synthesis
21).
meroquinene
is:
C
I
/\
C
C C
}
+c
\N /
The problem then is to find the position of the remaining carbon atom.
This carbon atom cannot be an JV-methyl group, since all three acids are
secondary bases. As we have seen, meroquinene contains a
CH=CH 2
group in the side-chain. A possible position for the extra carbon atom is
structures
CH2 -C02 H
CH 2 -C0 2 H
CH
?H2 X CH-CH=CH2
CH2 CH2
"
*-
CH 2
N CH-CH
CH
CH2
-CH 3
meroquinene
cincholoipon
CO]
C0 2 H
CH2 -C02H
U
/(
+ H-C02 H-I1^
CH 2 X!H-C0 2 H
II
H
cincholoiponic acid
/(
!3
CH 2 X CH-C0 2H
'I
H
Ioiponic acid
ORGANIC CHEMISTRY
526
GH(OC 2 H5) 2
2
0H2
NH
->-
0H2 C1
CH2
CH2
CH2
CH
/
NH
p-chloropropionacetal
XIV
CH(OC2 H 6)2
(C 2 H s O) 2 CH
[ch.
HCI
iminodipropionacetal
CHO
CHO
y
CH
.CH
/ "^
CH C-CN
I
CH
CH
\ N/
H
CH2
CH2
\V
H
CH2
C-CHO
CH2
CH2
(i)NHgOH
W***
H
CH(C02 C 2 H5) 2
CH a ( CQ 3 C 3 H) a - C a HONa
{Michael condensation)
CH2
CH2 -C02H
CH2
CH'CN
(i)Ba(OH)a
rrrr
PTT
(ii)
HCI
-l
CH-C0 2 H
I
CH2
CH2
(+) - cincholoiponic
acid
The racemic cincholoiponic acid was acetylated, and then this derivative
was resolved by means of brucine; the (-j-)-form was identical with the
acid obtained from meroquinene.
Since meroquinene is obtained from cinchonine by oxidation, the carbon
atom of the carboxyl group in meroquinene will be the point of linkage to
the " quinoline-half " at which scission of the " second-half " occurs. Since
cinchonine is a di-tertiary base, the " second-half " therefore contains a
But meroquinene is a secondary base, and it theretertiary nitrogen atom.
fore follows that in its formation the tertiary nitrogen atom is converted
into a secondary nitrogen atom, a carboxyl group also being produced at the
same time.
possible explanation for this behaviour is that the tertiary
bond being broken
nitrogen atom is a part of a bridged ring, one C
when cinchonine is oxidised:
.CH
7
?H*
CH2
CH-CH-CH=CH2
6
CH*j.CH2
H,S0 4
CH
CHL
CH'CH=CH,
II
C0 H CH ^CH
CH.
I
3-vinylquimielidine
meroquinene
Thus, in cinchonine, the " quinoline-half " must be joined via its side-chain
at position 4 to the " quinuclidine-half " at position 8. The remaining
problem is to ascertain the position of the secondary alcoholic group in the
" second-half ". Rabe et al. (1906, 1908) converted cinchonine into the
ketone cinchoninone by gentle oxidation (chromium trioxide). This ketone,
in which both nitrogen atoms are still tertiary, on treatment with amyl
ALKALOIDS
25a]
527
nitrite
-CO Ah-,
i.e.,
R-CO -CHR2
II
OH
-NO
HO-
NOH
NO
The
/CH
CH
CH 2 ch2 CH-CH=CH 2
IIICH
IHOH CH
CH,
\\7
CO
CH2 C H^CH-CH=CH 2
CH CH CH2
I
Tf
CrQ 3
cinchonine
cinchoninone
CO,H
CH2 ch^CH-CH^H,
I
HON=C
N'
cinchoninic
X N^
acid
oxime
.CH
.CH
CH
CH=CH 2
H2C
2 nwNH-CH=
H2
I
0=C
acid
ch2 CH2
CH 2 CH2
CH-CH=CH 2
CH, CH,
CO,jH
CH2
CH2
HN^^
amide
meroquinene
1909).
ORGANIC CHEMISTRY
528
[CH.
XIV
.CH
CH2 CH^OH-CH=CH2
CH,
ch7 chch=ch2
CO-CH CH2JC1I
CHOH-CH CI^CH2
HIT
CH3CO2H
VAn
V^N
cinchotoxine
cinchonine
CH 2 CH2 CH-CH^H,
O CH 2 CH 2/ cH 2
HN
'I
CO CHBr CI*^CH
HN
NaOBr
cinchotoxine
OH ci^CH-CH=CH 2
2
CO CH ^^CHj
I
NaOH
Al
C 2 HjONa-CjH 5 OH
{-HBr)
cinchoninone
CH
CH2 CH^CH-CH=CH2
CHOH-CH
9H2^CH 2
() -cinchonine
25b.
none, a ketone.
C 20H MO aN 2
quinine
Cr0
h>-
C aoH 2aO aN a
quininone
ALKALOIDS
25b]
529
Quinine also contains one ethylenic double bond, as is shown by the fact
that it adds on one molecule of bromine, etc. (cf. cinchonine). Oxidation
of quinine with chromic acid produces, among other products, quininic acid.
H 24 O N 2
20
quinine
CrO,
> Cu H 9
H.SO,
quininic
acid
On
the other hand, controlled oxidation of quinine with chromic acid gives
quininic acid and meroquinene. Thus the " second-half " in both quinine
and cinchonine is the same, and so the problem is to elucidate the structure
of quininic acid. When heated with soda-lime, quininic acid is decarboxylated to a methoxyquinoline, and since, on oxidation with chromic acid,
quininic acid forms pyridine-2 3 4-tricarboxylic acid, the methoxyl group
must be a substituent in the benzene ring (of quinoline), and the carboxyl
group at position 4 (Skraup, 1881). The position of the methoxyl group
was ascertained by heating quininic acid with hydrochloric acid and then
:
C02H
C02 H
[Q]
H0 C
H0 CH
2
>
quininic acid
C0 2H
C0 2 H
^CH3C1+ HOrNf
CH sO
_co,
HO
6-hydroxyquinoline
quininic acid
This structure for quininic acid has been confirmed by synthesis (Rabe
at.,
1931).
CH3O,
CH,0,
+ CH3-CO-CH2 C02C2Hb-
CH,
0H30,
pocu
OH
PC1 <
CHjO
CHjO,
)qI
C02 H
CHCH' C0H5
CH^-CHO^
ZnCU
CH3|
KMnQ4
CH 3 -COjH
CH3O
,
If
630
ORGANIC CHEMISTRY
[cH.
XIV
The
is:
GHOH-CH Hs CH
CH,0^
xx
quinine
This formula contains the same four asymmetric carbon atoms as cinchonine;
thus the same number of pairs of enantiomorphs is possible. One pair is
()-quinine, and another pair is ()-quinidine the configurations of C and C
3
4
are the same in quinine, quinidine, cinchonine and cinchonidine, since all
four give the same 8-oximino-3-vinylquinucHdine (see 25a).
Rabe et al. (1918) carried out a partial synthesis of quinine starting from
quinotoxine, which is prepared by heating quinine in acetic acid (c/. cin;
chotoxine). Woodward and Doering (1944) have synthesised (-f-)-quinotoxine, and so we now have a total synthesis of quinine.
The following is
Woodward and Doering's work up to (+)-quinotoxine, and from this to
ALKALOIDS
25b]
NH
531
H,SQ 4
III
CH2 -C5H10N
axo(CH 3 -CO),0
(ii)
IV
CHs
CH3
f)f
CO-CH,
H,- RM.y N.
(i)
YN/
f CO-
separated ^
H
VI
VII
VrH
*r
CH3
VY
N-CO-CHs CjHtONO
C0 2 C 2 H5
Vila
N-CO-CH3 Jh]_
f
VIII
CH,
'
OH
COAH5
CH,
CH2
N C ,CH
'
AVJ
CH2
~~
CH,
CHs
C02 C 2 HB
^
CH
N^
IX
CH-CH-CHs
exhaustive ^
methy lotion
OH,
CH
2
CO-CHj
IX
.CH
CH 2
CH2
C02H
CH2
CH2
HN
.CH
CHCH=CH
CH2
CH2
(i)CaH 8 OH-HCl,
(ii)C,H 6 -COCI
"CH,
J"*
CH2
CH'CH=CH 2
CH
ch.
C02C2 HB f
COC H6
6
XI
ORGANIC CHEMISTRY
532
CH2 CH2
!OOC 2 H 5
CH
|\
CH2 CH-OH=CH2
C0 2 C2 H5
CH3
CH. XIV
CH2
C 3 H e ONa
W/
I
COC H
XII
XI
CO-CH CH -CH
2
C!^CH-CH=CH2
C02 C 4H5
CH3
HC1
f
C -
xni
6H5
\
CH2 c H CH-CH=CH2
\
CO CH
9 H2
CH2
HIT
CH,0
resolved
>- (+)-isomer
(i)NaOBr
(ii)'NaOH
XIV
()-quinotoxine
.CH
CH2 CH^CH-CH=CH 2
co ch C^y^h
Al
CHjO
C2H 5 ONa-C 2 H 5 OH
(+)-quininone
.CH
CHac^CH-CH^CH,
CHOH
CH
CH2 C h
resolved
CH,0
W
()-quinine
*-(-)-quinine
ALKALOIDS
26]
533
ISOQUINOLINE GROUP
Opium alkaloids. Many alkaloids have been isolated from opium, and
they are divided into two groups according to the nature of their structure
isoQuinoline group,
(i)
(ii)
e.g.,
Phenanthrene group,
e.g.,
morphine
(see 27).
C 20H 2lO 4N
is
known
as papaveroline.
papaverine
C16H 13
papaveroline
When
(C 19
H 19
N)CH 2 -L>
papaverine
(C19
papaverinol
N)CO
papaveraldine
synthesis.
C02 H
C0 2 H
C0 2H
C0 2 H
ch 3
^
NaOH
i
0H
0CHs
OCH3
veratric acid
acid
is
either I or II.
Now
534
ORGANIC CHEMISTRY
[CH.
XIV
different monoesters.
Thus II is metahemipinic acid; I is actually hemipinic acid (this isomer was known before metahemipinic acid).
CO-0
C0 2H (CH.-CO) l0
^do/V-.
CO
hemipinic acid
CH3
CQjH cH 3 co),o
CH 3
C02 H
CHp'
P<K.
:o
CH,0
n
metahemipinic
acid
G0 2H
kmo
HO^
H0
2 Cll
6 : 7-Dimethoxyisoquinoline-l-carboxylic acid.
The usual tests
showed that this compound contains one carboxyl group and two methoxyl
groups. On oxidation, this acid forms pyridine-2 3 4-tricarboxylic acid;
when decarboxylated, the acid forms a dimethoxywoquinoline which, on
oxidation, gives metahemipinic acid; thus the structure is established.
:
KMnO,
CaO^
C02H
C02 H
6:7-dimethoxy-
pyridine-2:3:4tricarboxylic acid
isoqainoline-
1-carboxylic acid
KM.O,,
CI^o/Sco,!!
CH 3 ol|JcG 2 H
metahemipinic acid
ALKALOIDS
26]
535
We may now
(i)
The
papaverine.
The presence
papaverine
we can
ORGANIC CHEMISTRY
536
[O]
CH3
[O]
CH3
[CH.
H0
H0
XIV
OCH 3
OCH3
papaverinic acid
papaveraldine
first
CHs o/%,CH 2 Cl
(i)
(i)HCl
H a -Raney Ni
(ii)PCl,
CH 2-CH 2-NH2
CH3iOjjXcHii-COCl
CH 3
(.
v.
homoveratrylamine
homoveratroyl
chloride
papaverine
ALKALOIDS
27]
26a.
Some
537
CH 3,or
CH 3
GH 2
CH,
CH3O1/Y
CH,
laudanosine
laudanine
narcotine
hvdrastine
PHENANTHRENE GROUP
Morphine, codeine and thebaine.
opium
alkaloids
it
it is
ORGANIC CHEMISTRY
538
[CH.
XIV
-OH
C16H 16ON<;
C16 H 16 ON
CHOH
I
ICHOH
I
A
codeine
.
morphine
fOCH3
C 16H 16 ON^
f OCH 3
ClaH 15 ON
co
fOCH3
L00CH3
II
thebaine
codeinone
So far, we have accounted for the functional nature of two of the oxygen
atoms; the unreactivity of the third oxygen atom suggests that it is probably
of the ether type (Vongerichten, 1881).
All three alkaloids are tertiary bases (each combines with one molecule
When heated with hydrochloric
of methyl iodide to form a methiodide).
acid at 140 under pressure morphine loses one molecule of water to form
apomorphine, C 17 H 17 2 N. Codeine, under the same conditions, also gives
apomorphine (and some other products). Thebaine, however, when heated
with dilute hydrochloric acid, forms thebenine, C 18 19 3N (a secondary base),
and with concentrated hydrochloric acid, morphothebaine, C 18H 19 3N (a
tertiary base).
Thus in the formation of thebenine from thebaine, a terFor this change
tiary nitrogen atom is converted into a secondary one.
to occur, the tertiary nitrogen must be of the type >N*R, where the nitrogen
NR 2 then the
is in a ring system; had the nitrogen been in the group
formation of a primary base could be expected.
When morphine is distilled with zinc dust, phenanthrene and a number
This suggests that a
of bases are produced (Vongerichten et al., 1869).
phenanthrene nucleus is probably present, and this has been confirmed as
follows.
When codeine methiodide, I, is boiled with sodium hydroxide
solution, a-methylmorphimethine, II, is obtained and this, on heating with
acetic anhydride, forms methylmorphol, III, and ethanoldimethylamine,
IV (some of II isomerises to jS-methylmorphimethine).
f=NCH 3
J^C
C 16 H 16 0^-OCH 3
ICHOH
16
H 15 0i-0CH
LCHOH
3
>
'n
C 16H 12
III
The
ALKALOIDS
27]
539
et al. (1900)
,CH
CH
HOjjC
CII3O
(CH 3 -C0) 2 O
CHO
N0 2
phenylacetic acid
3 4-dimethoxy-2-nitro:
(sodium
salt)
benzaldehyde
CH30(
(0
(ii)
(iii)
NaN0 2 -H 2 S0 4
CH3O
CH3 ^
CH3O
heat
Cu powder
C0 2 H
dimethylmorphol
Then Pschorr
it
3-acetoxy-4-methoxy-2-nitrobenzaldehyde).
Ill
methylmorphol
>NCH
ORGANIC CHEMISTRY
540
oxygen atom.
[CH.
XIV
et al.,
1906).
The
structure
of 3
CH3
*-0
morphenol
methylmorphenol
morphol
Codeinone, on heating with acetic anhydride, gives ethanolmethylamine
and the diacetyl derivative of 4 6-dihydroxy-3-methoxyphenanthrene.
:
C 18 H19
(CH3,CO)2O
>
codeinone
The
structures.
ALKALOIDS
28]
541
CH3o
CH
XJ"
\\ /|\14/
N
I
>H
OH.
CHrl
16
15
.CH
codeine
morphine
CH
CH,
o/\
CH.
o/N
/NCHs
CEfc
"CHj
HO
CH ,o
codeinone
(enol form)
codeinone
{keto form)
Gates
et al.
(1956)
NOH
/
Y^CHj
CHj
\/
thebaine
28. Biosynthesis of alkaloids. As more and more structures of alkaloids were elucidated, it became increasingly probable that the precursors
in the biosynthesis of alkaloids were amino-acids and amino-aldehydes and
We
ORGANIC CHEMISTRY
542
[CH.
XIV
HO
H0
phenolase
\ ^CH
HO
HO^_\cO-CH(NH
C-H(NH 2 )-CO-2H
HO
)-C0 2
HO<^J%CO-CH 2 -NH 2
HO
HO
HO^^ScHOH-CHg-NHa
^>CHOHCH 2 -NH-CH 3
HO<f
adrenaline
noradrenaline
Leete et al. (1952-) have shown, using labelled compounds, that phenylalanine, tyrosine and 3,4-dihydroxyphenylalanine are precursors for the
alkaloids of the phenylalanine and woquinoline groups (see also later).
study of the formulae of hygrine (13) and cuscohygrine (13a) shows
that the two most reasonable units are acetone and pyrrolidine. The biosynthesis of acetone occurs via acetoacetic acid (see 32a. VIII), but the
precursor of the pyrrolidine fragment is less certain. The most likely aminoacid precursor appears to be ornithine, which could undergo the following
reactions to give 4-methylaminobutanal (see also later):
CH 2--CH
CH --CH
2
CH 2--CH
CH 2--CH 2
CH
I
1
CH CHO
-^CH CHO -
CH, -NH
NH CO H NH
1
CH a CH-NH 2
CO
NH CO H
2
This compound
acetic acid) to
CHo
II
H
CHO
2
CH 2
HC
H 2C
hygrine
+ CH
CHo2
I
CO CH3 + CHO CH 2
NH
CHCH2 COCH3
CH3
H^C
2
(or aceto-
H2C
CH2
^
CH 2
H 2C
CH-CH2 CO-CH2 -CH
CH2
CH
y 2
I
CH3
CH 3
cuscohygrine
In the same way, the pelletierine group of alkaloids (19) may all be
imagined to be formed from 5-aminopentanal, e.g., Anet et al. (1949) have
condensed this aldehyde with acetoacetic acid at pH 11 to give wopelletierine; and 5-methylaminopentanal with acetoacetic acid at pK 7 to give
methyh'sopelletierine.
The amino-acid precursor of 5-aminopentanal is most
likely lysine (the homologue of ornithine).
It should also be noted that
conversion of the keto group in wopelletierine into a methylene group gives
coniine
ALKALOIDS
28]
/\
H2CV
543
cr
CHO
+ CO
NH,
CH2 C02 H
CH 2 COOH 3
wpelletierine
CH 2 CH 2 CH 3
coniine
mode
as the precursor:
CH aCH
tf-CH 3
CH 2CH 2
CH 2CH
CH 2
CO
CH 3
N-CH 3 CO
CH
CH 2CH
CH 2
CHOH CH
>-
CH
N-CH 3 CO
CH 2CH
CH 2
/CHO
CH3 CH3CHO
CHO CH 2
CHO
H 2C
CH2 CHO
H 2C
CH 2
NH
0H 3
CH 3
ORGANIC CHEMISTRY
544
[CH.
XIV
.OH,
CH-NH 2
OCH Q
OCHo
Support for the plausibility of this mechanism is given, e.g., by the formation
of the tetrahydrowoquinoline from the condensation between 3 4-dihydroxy3-5 (Schopf et al., 1934).
phenylethylamine and acetaldehyde at
:
pH
CH,
Rapoport et al. (1960), using labelled carbon dioxide (14C), have shown
that the primary product of synthesis in the morphine alkaloids is apparently
thebaine, which is later converted into codeine and morphine.
READING REFERENCES
Henry, The Plant Alkaloids, Churchill (1949, 4th ed.).
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd
Vol. II.
ed.).
Ch. 15.
Alkaloids.
Cook (Ed.), Progress in Organic Chemistry, Butterworth. Vol. I (1952). Ch. I. Molecular Structure of Strychnine, Brucine and Vomicine.
Vol. Ill (1955). Ch. 5.
Indole Alkaloids.
Manske and Holmes (Ed.), The Alkaloids, Academic Press. (Vol. I, 1950;
.)
Bergel and Morrison, Synthetic Analgesics, Quart. Reviews (Chem. Soc), 1948, 2, 349.
Stern, Synthetic Approaches to the Morphine Structure, Quart. Reviews (Chem. Soc),
1951, 5, 405.
Gates and Tschudi, The Synthesis of Morphine, /. Amer. Chem. Soc, 1956, 78, 1380.
McKenna, Steroidal Alkaloids, Quart. Reviews (Chem. Soc), 1953, 7, 231.
Bentley, The Chemistry of the Morphine Alkaloids, Oxford Press (1954).
Bentley, The Alkaloids, Interscience Publishers (1957).
Glenn, The Structure of the Ergot Alkaloids, Quart. Reviews (Chem. Soc), 1954, 8, 192.
Saxton, The Indole Alkaloids Excluding Harmine and Strychnine, Quart. Reviews
(Chem. Soc), 1956, 10, 108.
Sir Robert Robinson, The Structural Relations of Natural Products, Oxford Press (1955).
Morgan and Barltrop, Veratrum Alkaloids, Quart. Reviews (Chem. Soc), 1958, 12, 34.
Rodd (Ed.), Chemistry of the Carbon Compounds, Elsevier. Vol. IVC (1960). Alka-
loids,
Chh.
XXIII-XXIX.
Sangster, Determination of Alkaloid Structures, /. Chem. Educ, 1960, 37, 454, 518.
Battersby, Alkaloid Biosynthesis, Quart. Reviews (Chem. Soc), 1961, 15, 259.
Huisgen, Richard Willstatter, /. Chem. Educ, 1961, 38, 259.
Ray, Alkaloids the World's Pain Killers, /. Chem. Educ, 1960, 37, 451.
CHAPTER XV
ANTHOCYANINS
Anthocyanins are natural plant pigments; they are
1. Introduction.
glycosides and their aglycons, i.e., the sugar-free pigments, are known as the
anthocyanidins. The anthocyanins, which are water-soluble pigments,
generally occur in the aqueous cell-sap, and are responsible for the large
variety of colours in flowers; red violet blue. Willstatter et al. (1913- )
showed that the various shades of colour exhibited by all flowers are due
to a very small number of different compounds. Furthermore, these different compounds were shown to contain the same carbon skeleton, and differed
only in the nature of the substituent groups. The anthocyanin pigments
are amphoteric ; their acid salts are usually red, their metallic salts usually
blue and in neutral solution the anthocyanins are violet (see also 5).
in anthocyanidins is
benzopyrylium
flavylium chloride
chloride
shown
chlorides).
Various sugars have been found in anthocyanins; the most common are
glucose, galactose and rhamnose, and the most important of these is glucose,
which occurs as the diglucoside. Some pigments, as well as being glycosides, are also acylated derivatives, two common acids being ^-hydroxybenzoic acid and malonic acid. The acid radical may be attached either
to a phenolic hydroxyl group in the flavylium nucleus or to a hydroxyl
group in the sugar residue.
number of qualitative tests have been introduced to identify the various
anthocyanins without actually isolating them (Robinson et al., 1931-1933,
1938);
e.g.,
The pigment
545
ORGANIC CHEMISTRY
546
[CH.
XV
Aglycon
Trivial
name
Pelargonidin
Chemical name
Occurrence
4' 5 7-Tetrahydroxyflavylium
chloride
:
Cyanidin
Delphinidin
Peonidin
4'
7-Tetrahydroxy-3'-
methoxyflavylium chloride
Malvidin
(Syringidin)
Hirsutidin
may
3'
offer
Primula
viscosa.
OH
+ H0 2C
HO
o
OH
cyanidin chloride
This method suffers from the disadvantage that the fusion (or boiling with
concentrated potassium hydroxide solution) not only degrades the anthocyanidin, but also often demethylates it at the same time. Thus the positions of the methoxyl groups in the original compound are now rendered
uncertain. This difficulty was overcome by Karrer et al. (1927), who degraded the anthocyanidin with a 10 per cent, solution of barium hydroxide
or sodium hydroxide in an atmosphere of hydrogen in this way, the methoxyl groups are left intact.
;
ANTHOCYANINS
3]
547
Karrer
et al.
OG
OG
OG
,OG
OCH,
HO
(CH s) a so t ^
X)l^j-^yocn
NaOH
OCH3
erf
Cl,
OCH3
II
OH
OH
OCH3
Ba(OH) g
atmosphere of
Ha
OCH3
cT
01}
OCH3
+ H0 2C
CH3O
OCH3
0CH3
The problem is: Which of the two hydroxyl groups in monomethylphloroThe above results do not lead to
glucinol was originally attached to G ?
a definite answer, since had the structure of the anthocyanin been IV instead
of
I,
III
would
still
OCH3
0CH3
OCH3
+ HO !C
*-
OH
HO
OH
<3
0CH3
0CH3
OCH,
(ii)
Hydrogen peroxide
(Karrer
et al.,
1927):
ORGANIC CHEMISTRY
548
[CH.
XV
4.
(i)
+ ArMgBr-
The
original
method
of
e.g.,
CH2 OOH 3
cH 3(y
oh o
3
QCH3
OCH 3
OCH3
nci
ANTHOCYANINS
4]
549
Robinson (1928, 1931) then modified this method so that the product could
have both hydroxyl and methoxyl substituent groups, e.g.,
O-C0-C 6 H5
0CHO +
OH
CH 2 0-COCH3
CO^^^>0-COCH
^^
3
OCH3
0-CO-C6 H5
OH
OCH3
HCl
V" n s)
HO
peonidin cliloride
to
3 4-Triacetoxyacetophenone.
:
OH
OH
o-
CH2C1-C0 2H
OH
pocis
(CH 3 -CO) 2 Q
0-CO-CH 3
CH 3 -CO a K
CO-CH2 Cl
catechol
to
O-CO-CH,
O-CH20-C0-CH3
4-Diacetoxyacetophenone.
OCH3
+ CH2 C1-C0C1
anisole
OH
''
>
0-CO-CH3
(CH 3 CO) 3 Q
CH 3 -C03 K
CO-CH 2 Cl
CO-CH20-CO-CH3
ORGANIC CHEMISTRY
550
to
[CH.
4-Trimethoxyacetophenone.
OCH.s
OCH3
OCH3
0CH3
OCH 3
socia
C02 H
OCH3
CH a N 2
CO-CHNz
COC1
diazoketone
veratric acid
OCH3
OCH,
OCH;3
aqueous
OCH3
(CH 3 ) 2 S0 4
NaOH
H-CO-H
CO-CH2OCH3
COCH2OH
to
4-Dimethoxyacetophenone.
(i)
^CH 0-CH
3
-CN
cyanodimethyl
ether
OCH 3
(ii)
OCH,
CH30-CH2-CN +
MgBr
to
CO-CH2OCH3
4-Triacetoxy-5-methoxyacetophenone.
Mi
OH
)/\oH chjOhJIo/SoH
HO,
gallic acid
O
)
CH 3 0|
C(C 6
-O
C(C 6
OH
_HcipH 0||
3
^OH
(i
)(CH,-co) a o
(ii)
NaOH
COCl
SOCI2
CO,H
0-CO-CH3
0-CO-CH3
CHsOff ^0-CO-CH 3
6) 2
C0 2 CH 3
5) 2
C0 2CH3
HO ( X-6
C0 2 CH3
C0 2H
(CH 3 ,so 4
C6 H 5)2 cc la ,
(i)CHlN ,
(ii)CH 3 -CO,H
0H 30(f ^0-00-CH3
C0-CH20-C0-CH 3
XV
ANTHOCYANINS
5]
551
OH
OH
+ HCN +
HO
HC1c
'
'
JoH
HolJ
phloroglucinol
2-Hydroxy-4 6-dimethoxybenzaldehyde.
0C0C H
(f%CHO
OH
5]CHO
HO
C.H.-COC1
KOH
JoH
JoH
HOll
phloroglucinaldehyde
2 -benzoylphloroghicinaldehyde-(2-benzoyloxy4 6-dihydroxybenzaldehyde)
:
0-C0-C 6 H5
if%CHO
(CH 3 ) 3 SO t
NaOH
CH
OH
hvdrolvsis
piyOCH,
CH3
C 27H 31
19 C1
+ 2H
-^i> C16H U
6 C1
+ 2C H
6
ia
Since cyanidin chloride forms a penta-acetate, the molecule therefore contains five hydroxyl groups. No methoxyl groups are present, and so the
potassium hydroxide fusion may be used to degrade this compound; this
gives phloroglucinol and protocatechuic acid. Thus cyanidin chloride has
the following structure:
OH
HO
OH
+ H0 2C
OH
OH
Cl>
<3oH
cyanidin chloride
OCH3
CHO
OH
CH2 OCH3
CH3*COaC2H|j
CO
(^ ^OCH
HC1 gas
3
OCH,
OH
OCH
(i)HI
CH3O
OCH 3
(ii)HC1
HO
solution
et al.,
1928):
ORGANIC CHEMISTRY
552
[CH.
XV
The formation
OH
OH
HO
HO'
Oxonium
Red
Colour base
Purple in neutral solution
salt
in acid solution
HO
Salt of the colour base
Thus a variation
On
OH
OH
HO
OH
OH
pseudo-base
base), and according to Markakis, it is this form which probably predominates
at the isoelectric point.
This structure has an interrupted conjugated bond
system, and hence will be less coloured than the colour base itself.
Cyanin was the first anthocyanin to be isolated and its structure determined. It has been synthesised by Robinson et al. (1932). Phloroglucin-
ANTHOCYANINS
6]
553
C6 H 10O4-O-COCH3
CHO
+ (CHs-COOVCeHTOBr 2H*-
(i)
HO
HO
OH
II
CHjjOH
(ii)
CO
O-CO-CHs
II
O-CO-CH,
IV
CH20-C6 H7 (0-CO-CH 3 4
)
CO-<f
^O-CO-CHs
O-CO-CHs
OCa Hi O4 -O-CO-CH
OC H7 O(O-C0-CH3
3
)4
(iii)
III
0-CO-CH3
HO
0-CO-CH 3
0-C 6 H u
(i)
KOH
(ii)
HC1
O-C6 Hai
HO
OH
VII
C 27 H 31
15 C1
+ 2H
-^> C^H^OsCl + 2C H
6
ia
ORGANIC CHEMISTRY
554
[CH.
XV
present, the potassium hydroxide fusion or boiling with concentrated potassium hydroxide solution may be used to degrade the compound; the products
are phloroglucinol and ^>-hydroxybenzoic acid, and so the structure is probably as shown:
H0 C
HO
OH
pelargonidin chloride
by
synthesis,
e.g.,
Robinson
et al.
(1928).
0-CO-C 6 H 6
ff^ScHO
HOll
CHjOCO-CHs
JoH
CO-^^^>OCOCH
0-CO-C 6 H 5
NaOH
OH
HO
(inNs)
HO
UL
co
OH
OC6H n
O-C 6 H 10 O4 -O-CO-CH 3
CeHnOs
(f
HO
HO
OH
11
^CHO
JOH
II
GH2 OC 6 H7 0(0-CO-CH3
CO
)4
\o-CO-CH 3
III
555
ANTHOCYANINS
8]
net
CH8 9 a Cl+4H g O-2^Ci6H
u
7 Cl
+ 2C 8 H 12 O 6 + 2
C0 2 H
Delphinidin chloride contains six hydroxyl groups, and no methoxyl groups;
on fusion with potassium hydroxide, the products are phloroglucinol and
gallic acid.
OH
OH
KOH
+ H0 2 C
HO
OH
OH
OH
OH
delphinidin chloride
This structure has been confirmed by synthesis, starting from 2-benzoylphloroglucinaldehyde and et> 3 4 5-tetra-acetoxyacetophenone (Robinson
:
al, 1930).
8.
cules of glucose,
when peonin
C28H33
16 C1
6 C1, is
chloride
+ 2H
is
> C^gHijOgCl
+ 2C H12
6
When
OH
KOH
OH
HO
OH
+ H0 2C
OH
OCH,
OCH,
peonidin, chloride
This structure has been confirmed by synthesis from 2-benzoylphloroglucinaldehyde and co 4-diacetoxy-3-methoxyacetophenone (Robinson et al.,
:
1926).
ORGANIC CHEMISTRY
556
XV
[CH.
OC H 0(OCO-CH
OCHiA
AjCHO
JOH
(|
HO
3 )4
II
II
CO?
nOCO-CH,
OCH3
III
9.
cules of glucose,
when malvin
C29H 35
17 C1
chloride
+ 2H
is
is
-^> C17H 15
7 C1
2C 6H 12
Malvidin chloride contains four hydroxyl groups and two methoxyl groups.
When degraded by boiling barium hydroxide solution in an atmosphere of
hydrogen, the products are phloroglucinol and syringic acid (4-hydroxy-3 5dimethoxybenzoic acid). Thus:
:
OCH3
HO
H0
V^ 0H
+ H0 2 C
OH
OCH,
malvidin chloride
OC^A
O06 H nO5
OCH
OH
3
CO4(
\,0-CO-CH 3
OCH 3
OCH,
II
produced.
C3oH 37
17 Cl
+ 2H
HCl
2
> C 18 H 17
C1
2C 6H 12
557
ANTHOCYANINS
11]
hydroxide solution in an atmosphere of hydrogen, the products are monomethylphloroglucinol and syringic acid. The formation of these products
OCH3
OCH3
Ba(OH) 2
OH
CH3
+ HO,C
OCft
0CH3
cr;
OH
CH30
hirsutidin chloride
does not prove conclusively that the methoxyl group at position 7 is actually
there; had this position been interchanged with the hydroxyl group at
position 5, monomethylphloroglucinol would still have been obtained (cf.
The formula given for hirsutidin chloride, however, has been confirmed
3).
by synthesis, starting from 2-benzoyl-4-0-methylphloroglucinaldehyde and
eo-acetoxy-4-benzyloxy-3 5-dimethoxyacetophenone (Robinson etal., 1930).
:
0-COC 6H 5
0CHO
OH
CH0 C0 CH
.
OCH
OCH3
CO-^
HCl
"\ 0-CH
2 -C 6
OCO-C6 H5
OH
CH 3
(in N)
OCfcH,A
pC 6 Hu
OCH3
CH30
OCH3
CI
J"
hirsutin cliloride
FLAVONES
11. Introduction. The flavones, which are also known as the anthoxanthins, are yellow pigments which occur in the plant kingdom. Flavones
ORGANIC CHEMISTRY
558
[CH.
XV
occur naturally in the free state, or as glycosides (the aglycon is the anthoxanthidin and the sugar is glucose or rhamnose), or associated with tannins.
Chemically, the flavones are very closely related to the anthocyanins the
flavones are hydroxylated derivatives oiflavone (2-phenyl-4-chromone) which
may be partially alkylated. In almost all cases positions 5 and 7 are
;
flavone
hydroxylated, and frequently one or more of positions 3', 4' and 5'. The
general method of ascertaining the structure of the flavones is similar to
that used for the anthocyanins: the number of free phenolic groups and
the number of methoxyl groups are first determined, and then the products
obtained by alkaline fusion or hydrolysis are examined. Finally, the structure is confirmed by synthesis. Recently, Simpson et al. (1954) have shown
that methoxyflavones may be demethylated selectively by hydrobromic
4'
These authors have also shown
acid, the relative rates being 3'
7.
that the relative rates of methylation of flavone-hydroxyl groups with
methyl sulphate and sodium hydrogen carbonate in acetone solution are
4'
3'
7
3.
With methyl sulphate and aqueous alcoholic sodium
carbonate, the exact reverse of this order is obtained. These results thus
offer a method of ascertaining the positions of methoxyl groups in various
methoxyflavones.
>
>
>
>
Flavone, C15 H10 O 2 occurs naturally as " dust " on flowers, leaves,
When boiled with concentrated potassium hydroxide solution, flavone,
12.
etc.
>
'QH 2
OH COC H 5
CkH s
II
COpH
+ CH3 -CO-C 6 H 5
IV
COCH
+
H
C 6 H 6 -C0 2 H
VI
559
ANTHOCYANINS
12]
In general, all the flavones give a mixture of four products when degraded
with potassium hydroxide. The intermediate o-hydroxy-/3-diketone can be
if cold alkali or an ethanolic solution of sodium ethoxide is used.
the other hand, if a normal solution of barium hydroxide is used as the
degrading agent, then the products are usually salicylic acid and aceto-
isolated
On
The structure given for flavone has been confirmed by synthesis. Many
syntheses are known, e.g., the Kostanecki synthesis (1900). This is a general
method for synthesising flavones, and consists in condensing the ester of
an alkylated salicylic acid with an acetophenone in the presence of sodium
(this is an example of the Claisen condensation; this synthesis is a reversal
of the formation of III and IV). Thus, for flavone itself, the reaction is
carried out with methyl o-methoxybenzoate and acetophenone.
J002GH3
CH3
C - C H *
^OCH3
CH2
_^^
~^
OCH
COC6 H5
CH
OH
CnHn
^J-CaH,
HO
The most
method
CH3
+
v\
(C 6
-CO) 2
CnHe-COgNa
s
'
180
GeH
and VI
is
illustrated
CH3O
OH3O
CO-CH,
OCH,
+ C6 H5-002 C2 H 5
OCH3 CO-C6 H 5
HO
This preparation involves a Claisen condensation, and the following is also
another general method which involves an " internal " Claisen condensation.
560
ORGANIC CHEMISTRY
[CH.
CO-CH,
CO-CH 3
C6 HS COO
HO
Na 2 C03
XV
POOC-CgH,
CH,
rvG H -C00kji0H CO-C H
I
recent
method
HO
2-benzylidenecoumaran-3-ones (Wheeler
by the
1955),
et al.,
ring expansion of
e.g.,
C,H,OH
Most flavones are yellow solids which are soluble in water, ethanol and
dilute acids and alkalis. The oxonium salts are usually more highly coloured
than the free bases; the flavones do not occur naturally as salts (cf. anthocyanins). The structure of flavone salts is not certain; VII, VIII and IX
are possibilities, and according to calculations of charge distribution (in
y-pyrone salts), IX appears to be most likely (Brown, 1951).
C G HS
VII
IX
VIII
KOH
CbHs
XCHOH
)OR
COC6HB
COH
HO
CO-CH 2OH
+ C6 H 5 -C02 H
ANTHOCYANINS
13]
561
HCl
CH C6H 5
-
in
C 2 H B OH
H 2 SO,
flavanone
OH
C6H6
O
enol form;
flavonol
The
synthesis, starting
paration of flavones.
CcH5
CfiH 5
flavone
An
aCO-CH
NaOH
TT
+ C6 xi
H 56 CHO
-
OH
CO-
CHBr
(i)(CH3-CO) a O
(ii)
koh
in
Br,
6
|
COCH3 Br
CH,
ORGANIC CHEMISTRY
562
XV
[CH.
This synthesis has been simplified by Wheeler et al. (1955) these authors
prepared flavones by condensing co-chloro-o-hydroxyacetophenones with
aromatic aldehydes in the presence of ethanolic sodium hydroxide, e.g.,
;
+ C6 H 5
NaOH
CHO
in
C6 H 5
C,H 5 0H
H O
C21H 20O u
+H
TTPI
2
> C15H 10 O 7
+ CH -(CHOH) 4-CHO
3
pentahydroxyflavone.
OH
+
fuse
OH
H0
OH
HO
[(CHjJjSOi
3H3
KOH
OCH,
CjHOH
OCH,
OCH,
CH3
Or
CH 2 OCH s
H0 2 C
<z.
OH
OH
quercetin
CHs O
OCH,
OCH,
ANTHOCYANINS
14]
k/OCH
563
e.g.,
Kostanecki
et al.
(1904).
OCH3
OCH3O
HCI
OCH3 CH3O
HaSO,
OCHgO
HI
OCH,
CHsO
HO
OH
OCH,
Another synthesis
for flavonols
(cf.
ORGANIC CHEMISTRY
564
[CH.
XV
HO
4?
&
OH
Ho
OH
\Ao^-0
OH
OH
H OH
OH
HO
-V^AoH
quercetin
HC1
OH
HCl
HO
cyanidin chloride
OH
ANTHOCYANINS
14a]
Bauer
et
al.
(1954)
565
cyanidin cMoride
King
et al.
followed
by the
anthocyanidin
of a navonol,
action of hot hydrochloric acid, gives the corresponding
thus:
(i)Zn-AcOKa; Ac 2
quercetin
...
,,
.,
ISOFLAVONES
14a. woFlavones are hydroxylated derivatives of woflavone (3-phenyl4-chromone) which may be partially alkylated. The woflavones occur
ttoflavone
naturally, but are not so widespread as the flavones; they occur either in
the free state or as glycosides. The general method of ascertaining the
structure of woflavones is similar to that used for the flavones (see 3, 11).
Thus fusion with potassium hydroxide breaks down the molecule into two
fragments, and hydrolysis with ethanolic potassium hydroxide permits the
This may be illustrated with daidzein (Walz,
isolation of intermediates.
1931):
HCO H
a
HO
/>
Oxidation with alkaline hydrogen peroxide may also be used in degrading
woflavones recognisable fragments are not usually obtained by this method,
but sometimes information may be obtained about the substituents in the
3-phenyl nucleus, e.g., genistein (4' 5 7-trihydroxyMoflavone) gives p;
hydroxybenzoic acid.
The
general
e.g.,
method
an woflavone
isofiavone itself
may
of synthesising woflavones
is
566
ORGANIC CHEMISTRY
fCH.
/>*.
'CH 2
I
OH CKO H5S
OH CHONa
acid
CO
'
Na
+H-CO0H.2 2
5
XV
H5
By
^\/C0\
OH
HO
C0 2 C 2 H 5
C1B
OH
^\
HO'
^OH
HO
>OH
OH
OH
C,
OH
C 16
C,
was shown
that:
Me
lC02 H
CH3 -C02 H
>
OH
DEPSIDES
15. Depsides. Phenolic acids, by the interaction of the carboxyl group
of one molecule with the hydroxyl group of another, give rise to depsides:
HQ C2
^ ^
>Q--CO-<
>Q
--CO-h^
'n
;>0H
ANTHOCYANINS
16]
567
compound.
0 CO
3H
HOff
N*OH
0'
HOf]
+ C0C1 2
>-
C02H
C02 H
HO<f^>C0 H
2
*~ CH S OjC'Of
CHAC'Of
HO <f~^CO,H
^v
-^^
^COCl
>/
CH,0 2C-0^
>C0 H
may
10
CHsOjC-O-CjHi'COCI +
HO
OCOjjCHj
CHO
CH s
COC,,H 4 COO<
OC02 CHj
These are widely distributed in plants; many are glycobest sources of tannin is nutgall. The tannins are colourless non-crystalline substances which form colloidal solutions in water; these
16.
sides.
Tannins.
One of the
ORGANIC CHEMISTRY
568
[CH.
XV
solutions have an astringent taste. Tannins precipitate proteins from, solution, and they form a bluish-black colour with ferric salts, a property which
is used in the manufacture of ink.
Tannins also precipitate many alkaloids
from their solutions.
All tannins contain polyhydroxyphenols or their derivatives. Some tannins are hydrolysable by acids, and others are not; those which can be
READING REFERENCES
Gilman
(Ed.),
ed.).
Vol. II.
Ch. 18.
II
(i)
Ch. 10.
Robinson, Natural Colouring Matters and their Analogues, Chem. and Ind., 1933, 737.
Robinson, Uber die Synthese von Anthocyaninen, Ber., 1934, 67 A, 85.
Robinson, Chemistry of the Anthocyanins, Nature, 1935, 135, 732.
Warburton, The isoFlavones, Quart. Reviews (Chem. Soc), 1954, 8, 67.
Jain and Seshadri, Nuclear Methylation of Flavones and Related Compounds, Quart.
Reviews (Chem. Soc), 1956, 10, 169.
Seshadri, Recent Developments in the Chemistry of Flavonoids, Tetrahedron, 1959,
6, 169.
CHAPTER XVI
is
also shown):
N=CH
YGH CH
CNH,
CH C
=f^
1NJC IT>CH
Nv
JCH
N CNH
||
||
purine
is
These formulae have been written as in A, but more recently, the practice
to write the nitrogen of the pyrimidine ring at the top as in B (cf. diazines,
A
.
Nx
,N
.N
Nr
H
is
used (B
is
translate
portions.
+H
2.
C4H 2
N 2 + 2H 2
^> NH -CONH
2
+ C0 H-COC0 H
2
ORGANIC CHEMISTRY
570
NH H0
2
CO
\ NH
* HN
.00
H0 2 C /
O
/
[CH.
XVI
Y
[+21^0
0^ N A)
H
alloxan
O
CH-Ph
HN
PhCHO
CrO,
A.
AcOH
alloxan
barbituric
acid
monohydrate
Alloxan is a strongly acid compound (in the enol form) it crystallises with four
molecules of water of crystallisation. Three of these are readily lost on warming, but the fourth is lost only when the monohydrate is heated to 150. Because of this, it is believed that the fourth molecule of water is not water of
crystallisation but water of constitution (c/. chloral hydrate, Vol. I).
Alloxan stains the skin purple (due to the formation of murexide). The
5-oxime of alloxan is violuric acid (13b. XII), and when reduced with zinc and
hydrochloric acid, alloxan forms dialuric acid (13b. XII). When alloxan is
reduced with hydrogen sulphide, the product is alloxantin. According to Tipson
et al. (1951), however, if excess of hydrogen sulphide is used, the product is
Alloxantin is produced by reducing alloxan (one molecule)
dialuric acid only.
with half a molecule of hydrogen sulphide, or by mixing aqueous solutions of
alloxan and dialuric acid.
;
/COx
CO
NH
II
CH-0-C(OH) NH
|lCO
CO
CO
XNrf
00
NH
alloxantin
When
0NH 4
/X>
.CO
KH
C=NCH ^H
Cp
CO
CO
K
Nb"
1}6
/X)
^Ov
C=N
II
CO
CO
CO
NH
CO
XNH.
NH
NH
nh"
NH
co
S*
N
NH
murexide
purpuric acid
Murexide
N4 + H
[0]
-* C4H 6 3N 4
CO,
2]
571
Structure of allantoin, C4 6 3N 4 (Baeyer, 1861-1864). When hydrolysed with alkali, allantoin forms two molecules of urea and one molecule
of glyoxylic acid.
C4H 6
N4 + 2H
+ CHOC0 H
2
The formation
C4H 6
N4 +
^X NH -CONH
[O]
+CH
3
N2
Now
parabanic acid, on hydrolysis, gives urea and oxalic acid, and since
there are no free amino or carboxyl groups present in the molecule, this
suggests that parabanic acid is oxalylurea.
^NH-CO
CO
V
+ 2H 2
**
NH -CO
y
N
NH
H0 2C
CO
H0
NHi,
parabanic
acid
This structure has been confirmed by synthesis, e.g., oxalyl chloride condenses with urea to form parabanic acid (Bornwater, 1912).
^^NH CO
CICO
NHj!
CO
+ 2HC1
CQ^
I
NH
NH-CO
CICO
Thus, from the above facts, it can be seen that allantoin contains the parabanic acid nucleus joined to a molecule of urea. The point of the attachment is. deduced from the following experimental evidence. When reduced
with concentrated hydriodic acid at 100, allantoin forms urea and hydantoin.
C4H 6
_NH
CI^
CO
HO
-NIT
CIVNH-CO-NH,
CH2 -NH2
C2H
C2H
hydantoic acid
hydantoin
e.g.,
West
(1918).
CH2 -NH 2
I
C02H
CHNH
CHjj-NH-CO-NHjj
KNCO >
CH 3 -COjH
HC1
boil
>
C0 2 H
\KnJ
co
CO
NH/
COBr
CH 2 Br NH2
NH8
CHuBr
\lO
NH,
>-HBr+
CO
CO
NH
CHr- NH
>-HBr +
CONH
CO
ORGANIC CHEMISTRY
572
[CH.
is
acidic
XVI
and forms
salts.
CHf-NH
CONH
Hydantoin
NH
yCOH
C(QH)-N /
Oil
I
by bromine
is
NH
CO + CO-NH\
NH
<
HN 8
CH-NH>0
CO + CO-NH
I
NH
CO-NIT
-2*-*-
CO-NH.
CO
>0
NH
NHs!
water.
would account
NH
>0
CHj-NH
allantoin
|h 2 o
/NH 2
CO
XNH
+
2
C0,H NHK
+
0
GHO NH/
I
This has been confirmed by synthesis by heating urea with glyoxylic acid
at 100 (Grimaux, 1876).
NH
NH
C02 H
CO
I
NH
+
2
CO
00+2H.0
>-
NH,/
CHO
CONH N
CO
NH \
+
NH-CH-NH'
Examination of the structure of allantoin shows that it contains an asymmetric carbon atom; hence two optically active forms are possible. Both forms
have been obtained, and they have been found to racemise rapidly in solution
the racemisation probably occurs via enolisation (cf. 8 iii. II).
NH
NH
II NH>o ^
NH CHNH'
CO
CO
C(OH)-NH.
CO
NIK>
NH C
II
atom
00
NH
K
if
>
L
NH-C
Medicus formula
NH
NH-
CO CO
I.
NH
Fittig formula
2]
573
CO
n
NH,
CO
C.HAC
NH
/ 2
+
,CH
T_
//
HO-C
NH
HgSQ 4 ,
heat
CH
C-CHS
CO
NH
fuming
hno 3
II
C-C0 2 H
CO
\ NH/
CH 3
5-nitrouracil
-4-carboxylic
4-methyluracil
ethyl aceto-
C\N0 2
acetate
acid
C \
NH
H3O
boil in
NO 2
NH
Sn-HCI
If
CH
C-OH
CH
CO
N
NH
5-aminouracil
5-nitrouracil
NH
CO
\
CH
CO
C-NH 2
Nll
5-hydroxyuracil
The mechanism
NH
C-NH 2
_^
"^~~
CO ^CH
C=NH
c=o
C-OH
CH,
.CH,
.CH
The
,NH
NH
CO
<l
C'OH
Brj-H 2
CH
X NH
5-hydroxyuracil
NH COH
CO
l-OH
h-<L
\ /
NH
4:5-dihydroxyuracil
H 2 S0 4
r
CO
(
CO
s
C-
n6
-ss.
uric acid
574
ORGANIC CHEMISTRY
[CH.
XVI
/ 00
NH
CO
CO
CO
H02 C
/0 ^
C=NOH
NH t HS
JDO
NH
NH
violuric acid
barbituric acid
C >_
/.CO\
NH
r
CO
h,%hci
C
NHs
\rfl OH
4>-uric acid
uramil
^r
J\
.NH
v
^n/
s
NH
(iii) Traube's synthesis (1900) is the most important method, since it can
be used to prepare any purine derivative; it is also the basis of various
commercial methods for preparing the purines synthetically.
XNH,
NC /
CN
CO
XNH
CO
thyl
cyanoacetate
cyanoacetylurea
.CO
NH
__
/.
CH
C-NO
NH 4 HS
CNH
CO
XNH
/CO
NH C-NH
CO.
NH
hno,
2
CO
JC-NH 2
/C Q
2
^C-NHa
XNH
C i-co a c a H 6
NaOH
CO
/NHC0 C H
2
1?
\^^NH
4:5-diamino-
heat at
i0
uracil
^H\
/\
nh tr
II
CO
.c.
xnh ^nh
C-NH
XNH
CO
3]
575
15
CO
/
NH \ C-NHj
c
NH 2
/
CO
NH
CO
NH 2
NH
||
NH.
NH
CO + 2NH 3
NH
(e.g.,
&
NH
/r NH/C\
AA
X
HO
urate).
COH
NH
HN
CO
HO
2:8-
2:6-
2:6:8-
be uncertain. Fischer thought that the di-enol form is the 2 6-. Evidence
that may be quoted to support this is that in this arrangement the pyrimidine
ring will be " aromatic " and so stabilised by resonance. There is, however,
a certain amount of evidence which suggests the 2 8- di-enol form (c/.
:
13a, 15).
It is also interesting to consider the path followed in the oxidation of uric acid
to allantoin. Behrend (1904) suggested that the alkaline permanganate oxidation of uric acid (I) gives allantoin (Ilia and b) via the symmetrical intermediate
II.
Cavalieri et al. (1948) have carried out this oxidation using uric acid labelled
with 1S at x and s and found that the allantoin produced had this isotopic
nitrogen distributed uniformly among all the four nitrogen atoms. This is in
keeping with the intermediate formation of II.
NH2
CO /N
.. H^
NHCHN
NH C NH
*/ \ /
C
NH
NH
CO
"CO
II
CO
OH
II
NH
Ilia
\
/
NH CNH
NH
\co
CO3
CO
.1
CO,H
NH2
^NH
L.
0^
CO
I
CH
CO
NH
I
NH
lit b
> >
ORGANIC CHEMISTRY
576
NH
XVI
OH
S\ ^NH
N V^
.NH
CO
II
CO
[CH.
/!,
"ho^JL^
-NH
"^NH
2:6:8 -trichloropurine
NH
boiling
"2
purine
6 -di-iodopurine
Purine is a fairly strong base and forms salts with acids; it has been found
to occur naturally as its 9-D-ribofuranoside, nebularine (Lofgren et al., 1953).
PURINE DERIVATIVES
4.
Synthesis of purines.
Fischer (1897, 1898) prepared various purines starting from 2:6: 8-trichloropurine. There are, however, two general synthetic methods in which
the pyrimidine ring is synthesised first and then the imidazole ring " built
up " on this, or vice versa.
This consists of synthesising a 4 5-diaminopyri(i) Traube's method.
midine (see 14. XII) and then condensing with formic acid to produce
the imidazole ring; the formyl derivative is ring-closed by heating alone
or by heating its sodium salt.
:
NHCHO
NH,
This synthesis leads to the preparation of purines that are unsubstituted
in position 8.
This type of purine may also be prepared by heating a 4 5diaminopyrimidine with dithioformic acid in the presence of sodium hydroxide solution, and then heating the product with a methanolic solution of
sodium methoxide.
:
R
NH,
0t
H-CS 2 Na
^\/NHCHS
ff
CH 3 ONa
nAt-\
NH,
8-Hydroxypurines
of formic acid.
5]
heating.
Finally, diaminopyrimidines
may
577
8-hydroxypurines
NH-C0 2 C 2 H5
/vNH
Uk
R,
NH
COH
NNH,
(Xs
^
i T
^Vn
Co
R'
(-2nh 3
(cf.
-NH 2
H2 N
;CMe
vv
>Me
E,
X NH2 HjlT
less
derivative,
e.g.,
CH,
H NOCv,N
2
,CH+(C 2 H5 0) 2 CO
H^l/^N//
(i)
Adenine
5.
and
and
in tea extract.
NH
NH.
<o-~oo
2:6:8-trichloro-
purine
adenine
ORGANIC CHEMISTRY
578
Traube
(ii)
XVI
[CH.
(1904).
NH
A/NH
CN
.NH,"
W-^221*.
(
+
\NH,
(i)
HS^Awn
^N' NNH
Ci*
HNO a
" ,NHtHS
hs
VAnh
NH,
(i)H-COjH
Na
(ii)
(iii)
salt at 250
Todd
ci
CN
+
NH
v-
formamidine
(1943).
et al.,
NH8
7T>^ if
NH
>N=N-C H fgg^
CN
6
S\Y,N=NC H
H,-RaneyNi_
100
pressure
\kS*h.
phenylazomalononitpile
NH-CHS
[CS,H
NH,
6. Hypoxanthine (6-hydroxypurine), d. 150, occurs in tea extract and
Its formation by the action of nitrous acid on adenine
in animal tissues.
establishes its structure, and this is confirmed by synthesis.
(i)
OH
CI
OH
i3c>^<c> Co
.CH
hypoxanthine
(ii)
Traube
,NH2
(1904).
QjHsOjC^
OH
NHCHO
H-COH
hs a nA
^k^NH
/V V
NH
CH
8]
579
new useful synthesis of hypoxanthines and adenines involves the condensation between 1,2,2-trimethylaminoacrylamide and ortho-esters (Richter
et al.,
1960),
e.g.,
hypoxanthine:
OH
/NH,
C0
h n// \
Y
h n/ xNH
+ 2HC(OEt),
and
OCjHg
CI
CD
VCC1
X^CjH.ON,
01'
OK
NH
NH
HI
CO-
heat
HO-
N^
CjH,
xanthine
(ii)
Traube
(1900).
OjHgOjC.
JSTHj
fH
CO
+
Nth,
POCI.
NH
CH2
CO
ON
NaOH
NC
HO
NH
OH
OH
NH.
(ii)
Hott
N x NNH,
NHiHS
Xanthine
is
NH
(i)HNO,
(ii)
heat
Na
salt
*N'
number
of
compounds
KOH^
NH 8
in
CjHjOH
A^
NH
0O
\
.001
100
CI
Ar \
NH
HI
(see later).
OH
aqueous
CH
Ns
HO
guanine
ORGANIC CHEMISTRY
580
(ii)
Tra*be
XVI
(1900).
NH,
HN=C
[CH.
/
+
NNH
HOC
5
0)HNO 3
(ii) NH 4 HS
C3HsONa
.CH,
NC /
NH
guanidine
OH
NH
V
11/
H^^N^N^
H-CO,Na+H-CO,H
[I
H.n'StAnH,
XANTHINE BASES
Three important methylated xanthines that occur naturally are caffeine,
theobromine and theophylline. All three have been prepared from uric
acid by Fischer and all have been synthesised by means of the Traube
method.
Caffeine (1:3: 7-trimethylxanthine), m.p. 235-237, occurs in tea,
Its molecular formula is C 8 10O 2N 4 and its relationship to uric
acid is shown by the fact that on oxidation with potassium chlorate in
hydrochloric acid, caffeine gives dimethylalloxan and methylurea in equimolecular proportions. The structure of the former product is established
by its conversion into sym.-dimethylurea and mesoxalic acid on hydrolysis,
and is confirmed by synthesis from these two compounds.
9.
coffee, etc.
PIT
1
"s'"NT
]
CO
CO
CO
-2^CH
-NH-CO-NH-CH3 + C0 2 H-CO-C0 2 H
\N/
CH3
These results indicate that caffeine and uric acid have the same skeleton
structure; at the same time the positions of two methyl groups and one
oxygen atom in caffeine are also established. Thus the problem, now is to
ascertain the positions of the remaining methyl group and oxygen atom.
The following skeleton structure for caffeine summarises the above information; the third methyl group is at either position 7 or 9, and the remaining
oxygen atom at 6 or 8.
,C V
CH.
V
O' NN
CH3
Position of the methyl group. As we have seen above, the oxidation of
caffeine gives dimethylalloxan and methylurea.
Fischer, however, also iso-
9]
581
iV-methylhydantoin
CH2 N-CH
\co
CH2 -NHCH
+ NM3 + co 2
C0 2H
GOMil
It therefore follows that caffeine contains two ring structures, that of dimethylalloxan and that of methylhydantoin. The following two skeleton
structures for caffeine are both possible, since each could give the required
oxidation products. Actually, the isolation of methylurea suggests I or II
/Cn -N
C
\
ilc
Ks^
X
CH 3-l/ C "**\
CH 3 N
CH,
CH3
CH 3
II
^3
CO
CH 3-N
I
CO
CH
\CH
2
||
C.
X C^
CH.-N
3
CO
</
CH3
c.
\CO
CH3
IV
III
By analogy with uric acid, III would appear the more likely one; this,
however, is not proof. Fischer showed that III is caffeine as follows.
Caffeine
C 8H 10 O 2N4
^-> Chlorocaffeine
C 8H 9
N 4C1
Na0H
Oxycaffeine
C 8H 10 O 3N 4
>
Methoxycaffeine
C 8H 9O aN 4.OCH 3
>-
taU
+ CH C1
3
ORGANIC CHEMISTRY
582
[CH.
OH.s
.a
COCHs
II
or
CH 3
methoxycaffeine
9H
CH3
I
XVI
COH
or
CHS
CO
^N /
CH3
CH,
VII
VI11
oxycaffeine
When
oxycaffeine, as its silver salt, is heated with methyl iodide, it is converted into a mixture of tetramethyluric acid (which contains four iV-methyl
groups) and methoxycaffeine (which contains three N-methyl groups and
one methoxyl group). The simultaneous formation of these two products
suggests that oxycaffeine is a tautomeric substance, i.e., it contains the
qmido-imidol triad system:
NHC=0 ^ N=COH
Now this triad system can exist only in the imidazole nucleus in oxycaffeine,
since neither nitrogen atom in the pyrimidine nucleus is attached to a
hydrogen atom (VII can give rise to the above tautomeric system, whereas
VIII cannot). Thus the methoxyl group in methoxycaffeine is in the
imidazole nucleus, and consequently the chlorine atom in chlorocaffeine
is also in this nucleus; hence caffeine is IX and chlorocaffeine is X.
qHi
jco
(K
CH3-N
I
co
\CH
^N s
CH3
co
CH3-N
I
Ya
co
CHs
\
S
N
XIC1
CH3
IX
caffeine
chlorocaffeine
e.g.,
10]
(i)
583
CH3
CO
I
l:3:7-trimethyluric acid
CH3
CH
CH3-N
CH 3 N
Ht
CC1
c-
CH
/
CH3
CH3
caffeine
chlorocaffeine
CH 3 -NH
CjjH6
POCI3
CH3
uric acid
(ii)
PC1
CO
Vn/
C-
CHj-N''
ch 3 i.
NaOH
oo
II
CO +
NaNHg
CH2
CH 3-N
in
xylene
"
CO
CH
hno
is
as follows:
CH 3-N
C-NO
co
p-NH2
CH3
NH,
Zn
HjS04
CH3-N
l-NH,
c-:
ON
CHs-NH
h-coh
II
Jo
V'
CH,
H
.CO
V.^
/
CH N
3
reflux
NNH2
CH S
.CH
CO
J'
in
C 3 H,OH
CHgONa
equivalent of
CH3
CH3
QH3
CO
CH,
theophylline
CH
CH3
caffeine
Theobromine
10.
Thus theobromine
is
CH,
!0
CH 3-N
\ CH
CHj
/C
HN
or
II
~y
CH,
II
^CH
ORGANIC CHEMISTRY
584
[CH.
The
T^
f
CH NH
C2H6
c0
CO
poo.
CO
T*
f
J**^
shown
.ili-o^
Jo
\f
\u
CN
^Vj^H?
*
XVI
CHs
CH 3
W
prr
II
reflux
ou
1/
ch
>
CO
>
i
,y
ch,
6h s
CH,
"
theobromine
,<%
.CD
CO
CH 3
CH3
uric acid
3-methyluric acid
f>
Y Xoo-^ %/^
V^
H
.ja^T
" ,OH
CH 3
It should
CH 3
11]
585
/NH-CONH.;
HN
HCONHj
:/\.
NHCHO
caffeine
<
NaOH
^^_r
15
theobromine
AcONa
H
xanthine
Me 2 SO-NaOH
3-dimethylxanthine), m.p. 269-272, occurs in tea.
(1
has been deduced from the fact that it is converted into caffeine
on methylation, and that it forms dimethylalloxan and urea on oxidation.
Thus theophylline is 1 3-dimethylxanthine, and this structure has been
confirmed by synthesis.
11.
Theophylline
Its structure
(i)
Fischer (1899).
.CD
NaOH
/VS>
I-
CD
C.
N
CH3
fr
n
.CO
POCIj
II
co
uric acid
1
CO
3-dimethyluric acid
CO
CHS-N
CO
\r \
CH 3
chlorotheophylline
CH3-N
CI
co
\K \
CH
a
CH,
theophylline
by means
of
ORGANIC CHEMISTRY
586
[CH.
XVI
NH-CH 3
CO(NH2
14"-160
+ 2CH 3 -NH2
>
ch, ( cn)-co,h
cb
N
>
50_7
NHCH
co
/X)
CH3-N
CH
aqueous
Na , co ,
70 - 80
CN
CO
CO
CH3
/CQ ^NH 2
C
/ P
HaSO *
cp
^NH
Xjjj/
()Zn-H j0
.NH-CHO
cp
\jj^>NH
CH 3
queous
C-NH 2
(i)HNOi|
N /
N
GH3
NH
CH
GH3-K
CH3
uil 3
KOH
"
CH 3
lla. Biosynthesis of purines. Most of the work on the biosynthesis
of purines has been carried out on uric acid by means of enzymes from
bird liver. Sonne et al. (1946, 1948), working with the following labelled
compounds ( 13C), showed that carbon dioxide supplies C 6 formic acid C 2
and C 8 and glycine C4 , C 5 and 7 Thus all the carbon atoms in uric acid
are accounted for. It has also been shown that the carbon atoms in hypoxanthine are derived from the same precursors as those in uric acid. Furthermore, it was also shown that in the hypoxanthine biosynthesis in liver
,
OH
OH
HOP op o
^\
This fragment
<K H
H 2 N,H<OH H0>|
is
CH 2 OPO s H 2
cor
l
$ffV
CH2 OPCH
CI
fonnat .
NH2
/NHX
ATP
K?HH>
CH.
CO^
0H
>^
Jl
CHO,
^./
J*.
HOjC
H0
A!
NUCLEIC ACIDS
PURINES
13a]
X
H* N
spuute
(]
HNOO^/'
587
X
NX
H,N
if
>
HjNOcliv^
HO,CCH,CHC(VH
HjNOC^j/
>
""*"
N^/IL-
OH
OH
hypoxanthine
Or6 (1961) has shown that adenine and the purine precursors 4-aminoimidazole-5-carboxamidine and formamidine are formed spontaneously from
hydrogen cyanide in water-ammonia systems under conditions assumed to
have existed on primitive Earth (c/. 18. XIII). Or6 has also suggested
a mechanism for the formation of adenine from hydrogen cyanide under
the above conditions.
NUCLEIC ACIDS
Nucleoproteins are one of the classes of conjugated
12. Introduction.
proteins (7 B. XIII); the nucleic acid part is the prosthetic group, and
the protein part consists of protamines and histones. These latter compounds are basic and form salt-like compounds, the nucleoproteins, with
the nucleic acids. On careful hydrolysis, nucleoproteins are broken down
into the nucleic acid and protein.
Genes are the units of inheritance, and there is now a great deal of evidence
to show that a gene is a nucleic acid molecule.
all of
aqueous
T
> Nucleotides
,
enzymes (nucleinase)
aqueous
Nucleic acid-
NH,
at 175
.._
..
> Nucleosides
__
xx
P04
+H
3
Inorganic acid
Sugar
+ Purines +
Pyrimidines
Hayes (1960) has shown that ribonucleic acids (13a) may be rapidly and
quantitatively degraded to ribonucleosides by refluxing with 50 per cent,
aqueous formamide.
13a. Sugars. Only two sugars have been isolated from the hydrolysates of nucleic acids; both are pentoses: d( )-ribose and 2-deoxy-D( )ribose.
ribose
2-deoxyribose
i!
nucleic acids are classified according to the nature of the sugar present:
the pentose nucleic acids or ribonucleic acids (R.N. A.), and the deoxypentose
Ribonucleoproteins are
nucleic acids or deoxyribonucleic acids (D.N.A.).
The
588
ORGANIC CHEMISTRY
[CH.
XVI
Aldridge (1960) has shown that the addition of indium chloride solution
to acetate-buffered solutions of nucleic acids in the presence of sodium
chloride produces a precipitate containing indium and nucleic acid.
Furthermore, by varying the concentration of the sodium chloride, it is possible to
precipitate either the R.N.A. or the D.N.A. from aqueous solution.
13b. Bases. Until very recently, only two purines had been isolated
from nucleic acids, adenine and guanine. In 1958, however, Littlefield et al.
found 2-methyladenine and 6-methylaminopurine in R.N.A.s from several
sources, and Adler et al. (1958) and Dunn et al. (1958) have shown that 2methylamino- and 2-dimethylaminoguanine are widespread in R.N.A.s.
Nil,
CH
^
adenine
OH
H
L
HUN
H,
guanine
OH
Nl
HO
HO
NH
NH
\V/
5-methylcytosine
^VCH 0H
jjAyCH,
HO'
cytosine
thymine
uracil
A^/
HO'
5-hydroxymethylcytosine
13c]
589
13c.
ammonia
HN
I
CO
C-NH-NH-C6 H 6
II
C-NH-NH-C 6HS
C5H9O4
I
ORGANIC CHEMISTRY
590
[CH.
XVI
cytidine).
NH2
ArNa Cl.
+ CHO-(CHOH)3-CH 2 OH
<X.NH
NH-C 5 H 9
JH
(i)(CHyco) a o
0(0-CO-CH 3 ) 3
NH
(i)H-CS,Na
(ii)CH a ONa-C a H e OH
I
C5H 9
adenosine
It might be noted, in passing, that glycosides are compounds formed by
the linking of a sugar (at CJ with a COH group. Thus the nucleosides are,
strictly speaking, not glycosides; they should be called ribosyl-pyrimidines
and ribosyl-purines.
The final problem
13c]
591
-O
>N CH-CHOH-CHOH-CH-CH OH
2
(CH,) s SO,
O
>N SCHCHOCH 3-CHOCH 3-CH-CH 2OCH 3
r
acid
-o
CHOH-CHOCH a -CHOCH 9-CH-CH 2OCH 3
[O]
CHO
H10 t
,H1Q
CHO
I
CH
CH g OH
9-p-D-manno-
CHgOH
dialdehyde
CH2 OH
adenosine
pyranosidyladenine
the sugar residue is at position 9, has the furanose structure and that the
linkage is /?-. Similar experiments with other ribonucleosides suggest that
Also, Todd et al. (1946-1948)
all these compounds have a /S-configuration.
have synthesised adenosine, guanosine, cytidine and uridine, and thereby
ORGANIC CHEMISTRY
592
NH
H C CI
H C O-CO-CH3
HC OCO-CH
XVI
[CH.
CC1CI
C:-H
H C-O-COCHs
O
H C-0-CO-CH
H CI
CH 2 OCO-CH
II
NH,
NH,
CH 20-CO-CH 3
^ "UT"V
-N.
NH 3
in
OH OH
adenosine
e.g., adenosine has been synthesised as follows
(Todd et al., 1948). Acetochloro-D-ribofuranose, II (cf. 24. VII), is condensed with the silver salt of 2 8-dichloroadenine, III, and the product
deacetylated with a methanolic solution of ammonia to give 2 8-dichloroIV, on catalytic reduction (palladium), is
9-/J-ribofuranosyladenine, IV.
When nucleotides are carefully hydrobe isolated from the products; thus the
phosphoric acid is attached to the sugar residue in nucleotides. Examination of the nucleoside structures shows that the point of attachment may
be 2', 3' or 5' in the ribose molecule, and 3' or 5' in the deoxyribose molecule.
On reduction with hydrogen in the presence of platinum, ribose phosphate
is converted into an optically inactive phosphoribitol (Levene et al., 1932,
This product can be optically inactive only if the phosphate residue
1933).
is attached to the centre hydroxyl group of the ribose molecule, i.e., at the
13d. Structure of nucleotides.
lysed, ribose
3'-position.
monophosphate
may
13d]
593
CHjjOH
^CHOH
H C OH
H C OPO(OH)
H COH
I
H C OH
H C OPO(OH)
H C OH
3
..I
5
H '~ Pt
>
CH 2 OH
CH 2
It should be remembered that the furanose structure occurs only when the
sugar is in the form of a glycoside; on hydrolysis, the furanose sugar first
liberated immediately changes into the stable pyranose form (see 7f. VII).
Until recently, it was believed that the 3 '-position was the only one occupied by the phosphate radical. Emden et al. (1929) claimed to have isolated
a 5 '-phosphate (from muscle nucleic acid). Carter and Cohn (1949) isolated
two isomeric adenylic acids from the alkaline hydrolysates of R.N.A.s, and
called them " a " and " b " adenylic acids.
These authors, in 1950, also
isolated two isomers of guanylic, uridylic and cytidylic acids.
Carter and
Cohn found that one of their adenylic acids was identical with adenosine-3'phosphate, but the other was not the same as the 5'-compound of Emden.
These authors therefore believed that their two isomers were the 2'- and
3'-phosphate. Todd et al. (1952) synthesised adenosine-2'- and 3'- phosphate,
and showed that their synthetic compounds were identical with the "a"
and " b" acids obtained by Carter and Cohn, but were not able to say
which was which. Loring et al. (1952) showed that the " a " and " b "
cytidylic acids resist oxidation by periodic acid, and hence it follows that
they must be the 2'- and 3'-phosphates (but there is no indication from this
which isomer is the 2'- and which is the 3'-); had one isomer been the 5'eompound, then it would have been oxidised by periodic acid (the two
hydroxyls on 2' and 3' are free and adjacent). A study of the solubility,
acidity and absorption spectra of these two cytidylic acids led Loring et al.
to suggest that the "a" acid is the 2'-phosphate. This conclusion has
been supported by Harris et al. (1953) from their study of the infra-red
spectra of these compounds. Todd et al. (1954) have synthesised deoxycytidine-3'- phosphate, and comparison of its infra-red spectra and other
"
properties with cytidine phosphates provides strong evidence that " b
cytidylic acid is cytidine-3'-phosphate, and therefore that " 6 " uridylic
acid is uridine-3'- phosphate. Brown et al. (1955) have shown that hydrazine
splits "a" and " b" cytidylic acid to give ribose 2- and 3-phosphate respec" b " Uridylic acid yields the same ribose phosphate obtained from
tively.
" 6 " cytidylic acid. Thus the " a " and " b " isomers of these nucleotides
are the 2'- and 3'-phosphates, respectively, of the ribonucleosides.
Experiments using enzymic hydrolysis of nucleic acids have shown that
these acids also contain 5'-phosphoester links. Cohn et al. (1951) have
isolated the 5'-phosphates of adenosine, guanosine, uridine and cytidine.
These authors have also shown that the nucleotides in calf thymus D.N.A.
are 3'- and 5'-phosphates (position 2' is not possible since this is a CH 2
group).
ORGANIC CHEMISTRY
594
o
I
[CH.
XVI
/xo
CH- CH CHoOH
I
Base CH CH
also isolated thymidine-3' 5'- diphosphate and deoxycytidine-3' 5'diphosphate from herring sperm deoxyribonucleic acid.
Heppel et al. (1955) have shown that these cyclic esters are converted
into the 3'-phosphate in the presence of methanol or ethanol and ribonuclease provided the base is a cytosine or a uracil residue, e.g.,
have
Base
OH i OH
CH CH-CH OH CHOH
I
CH CH-CH CH CH 2 OH
CH 3 OH
Base
-O-
L_
et al. (1955) have shown that this reaction occurs only if the alcohol
contains a primary alcoholic group, and suggest that if such a reaction is
concerned in the biosynthesis of ribopolynucleotides from simpler units,
then this requirement {i.e., the primary alcoholic group) might explain why
only 3' 5'-diester links are present in these polynucleotides (see 13e).
Barker
Nucleotides have been synthesised in various ways, e.g., Levene et al. (1937)
synthesised adenosine-5'-phosphate from 2',3'-0-isopropylideneadenosine. This
was phosphorylated with phosphoryl chloride in pyridine, followed by careful
hydrolysis with acid to remove the isopropylidene residue. 2'- and 3'-phosphates are more difficult to synthesise because of their ready interconversion. Todd et al. (1954) synthesised adenosine-2'-phosphate by phosphorylating
3',5'-di-0-acetyladenosine in the 2'-position with dibenzylphosphochloridate
[(PhCH 20) 2POCl] and removing the benzyl groups (as toluene) by hydrogenation (Pd), and finally removing the acetyl groups by treatment with alkali.
Under these conditions no phosphate migration is possible.
NH.
NH 2
AcOH 2 C
AcOHjO
.
H
VH
H\|
AcO
KH
OH
^O
H
AcO
/OCHjPh
OP:X
OH 0-PO,H 2
o O0HjPh
13e]
595
(HO)gP0-0R, -Adenine
0P-OR Uracil
0POR Guanine
f/ OH
O P OR-Cytoaine
I
OH
This simple structure for nucleic acids has, however, been shown to be
incorrect by more recent work, e.g.,
(i) It has been found that alkaline methods of purification degrade nucleic
acids; thus the molecular weight varies with the methods used for the isolation of the acid. Furthermore, fractionation experiments on both R.N.A.s
and D.N.A.s (from the same and from different sources) have shown that
these nucleic acids are complex mixtures (see also iv).
(ii) Various methods for determining molecular weights, e.g., diffusion and
the ultracentrifuge, have shown that the molecular weights of the nucleic
acids are very high; they range from about 105 to 10 7 , e.g., a value of about
2 X 106 has been found for the R.N.A. from tobacco mosaic virus.
(iii) X-ray studies have shown that D.N.A.s are composed of two polynucleotide chains wound as spirals round a common axis but head in opposite
directions (Wilkins et al., 1953; Watson et al., 1953).
The two chains are
held together by hydrogen bonds, thus producing a long, thin, relatively
rigid molecule.
Less is known about the structure of R.N.A.s, but according to Gierer (1957, 1958), the R.N.A. from tobacco mosaic virus is in the
form of a flexible, moderately coiled chain.
(iv) The analysis of the hydrolysates of nucleic acids, particularly by
chromatography, has shown that the acids from different sources have
different chemical compositions (cf. i).
According to Chargaff (1950), not
one specimen of a nucleic acid gave analysis results corresponding to a
tetranucleotide thus the " statistical tetranucleotide " theory is untenable.
Chargaff found that in D.N.A.s, the sum of the total purine nucleotides is
equal to that of the pyrrolidine nucleotides, and that the molar ratios of
adenine to thymine, and of guanine to cytosine (or its analogues) are unity.
Chargaff et al. (1954) also found the same regularities in R.N.A.s, with uracil
taking the place of thymine. Chargaff estimated the nucleotide content
from spectral data (as well as by some of the earlier methods), and pointed
out that the regularities are not usually observed with purified samples
of pentose nucleic acids, but only when, e.g., whole cells are subjected to
;
hydrolysis.
(v) Levene et al. (1926), from electromeric titration experiments, concluded that R.N.A.s show four primary and one secondary phosphate dissociation for each set of four phosphorus atoms present.
On this evidence,
and on the results of analysis, Levene put forward his tetranucleotide theory
(see above).
More refined titration experiments, however, have shown that
R.N.A.s exhibit only three primary and one secondary phosphate dissociation (Gulland et al., 1944). These latter findings are also supported by
methylation experiments (Anderson et al., 1949).
(vi) Various structures have been proposed for the nucleic acids, e.g.,
Todd (1952) has suggested the following for deoxyribonucleic acids:
OH
OH
OH
D.N.A.
ORGANIC CHEMISTRY
596
[CH.
XVI
The deoxyribose units are in the furanose form and attached to the phosphate molecule by the C 3 and C B hydroxyl groups; the base is attached
to C r of the sugar. The structure of the R.N.A.s is less certain, but the
linkages are believed to be similar to those of the D.N.A.s. All work so
far reinforces Todd's suggestion that both types of nucleic acid are 3',5'-
linked polynucleotides.
Since the nucleic acids are complex mixtures, the problem of determining
nucleotide sequence is very difficult indeed. One method has been the use
of enzymes, but used alone, this method has yielded little information.
Enzymic methods, however, have been successful in synthesising large polynucleotides, e.g., Romberg et al. (1958) have carried the biosynthesis of
D.N.A. by means of enzymes. On the other hand, chemical methods which
have been developed are giving some information. The most thoroughly
studied stepwise degradation method is the one which depends on the
periodate oxidation of the 2',3'-glycol system in the terminal nucleoside
residue of a polynucleotide chain (Todd et al., 1953). This method may
be used for R.N.A.s, but the absence of the 2'-hydroxyl group in D.N.A.s
precludes its use for these acids.
Jones et al. (1956) have also developed a chemical method for the specific
degradation of deoxyribonucleic acids. These authors have found that on
treatment with mercaptoacetic acid (CH a SH-C0 2 H), purines are removed
and replaced by carboxymethylthio groups. By this means it is possible
to obtain information on the relative positions of purines. and pyrimidines.
Thus the results have shown that in calf-thymus deoxyribonucleic acids
there are regions in which at least three pyrimidine nucleotides occur in
adjacent positions.
READING REFERENCES
Fischer, Synthesen in der Puringruppe, Ber., 1899, 32, 435.
Stewart, Recent Advances in Organic Chemistry, Longmans, Green. Vol. I (1931,
6th ed.). Ch. 13. The Purine Group.
Lythgoe, Some Aspects of Pyrimidine and Purine Chemistry, Quart. Reviews (Chem.
Soc), 1949, 3, 181.
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1938, 1st ed.). Vol. II. Ch. II.
The Chemistry of Pyrimidines, Purines and Nucleic Acids.
Levene and Bass, Nucleic Acids, Chemical Catalogue Co. (1931).
Davidson, The Biochemistry of the Nucleic Acids, Methuen (1953, 2nd ed.).
Ti$$on, The Chemistry of the Nucleic Acids, Advances in Carbohydrate Chemistry,
Academic Press, Vol. I (1945).
Schlenk, Chemistry and Enzymology of Nucleic Acids, Advances in Enzymology, Interscience Publishers, 1949, 9, 455.
Rodd (Ed.), Chemistry of Carbon Compounds, Elsevier. Vol. IVC (1960). Ch. XX.
Purines and Related Ring Systems. Ch. XXI. Nucleosides, Nucleotides and
Nucleic Acids.
Avison and Hawkins, The Role of Phosphoric Esters in Biological Reactions, Quart.
Reviews (Chem. Soc), 1951, 5, 171.
Baddiley and Buchanan, Recent Developments in the Biochemistry of Nucleotide Coenzymes, Quart. Reviews (Chem. Soc), 1958, 12, 152.
Fairley. Nucleic Acids, Genes, and Viruses, /. Chem Educ, 1959, 36, 544.
597
Roth, Ribonucleic Acid and Protein Synthesis, /. Chem. Educ., 1961, 38, 217.
Todd, Some Current Problems in Polynucleotide Chemistry, Proc. Chem. Soc, 1961, 187.
Verwoerd et al., Specific Partial Hydrolysis of Nucleic Acids in Nucleotide Sequence
Studies, Nature, 1961, 192, 1038.
Molecules
et al., Determination of the Helical Configuration of Ribonucleic Acid
by X-Ray Diffraction, Nature, 1962, 194, 1014.
Spencer
CHAPTER XVII
VITAMINS
In addition to oxygen, water, proteins, fats, carbo1. Introduction.
hydrates and certain inorganic salts, a number of organic compounds are
also necessary for the life, growth and health of animals (including man).
These compounds are known as the " accessory dietary factors " or vitamins,
and are only necessary in very small amounts. Vitamins cannot be produced by the body and hence must be supplied. Vitamin D, however,
may be supplied in food or may be produced in the skin by irradiation
(ultraviolet) of sterols.
Many vitamins have now been isolated and their structures elucidated.
As each vitamin was isolated, it was named by a letter of the alphabet, but
once its structure had been established (or almost established), the vitamin
has generally been renamed (see text).
"
The vitamins have been arbitrarily classified into the " fat-soluble group
"
"
(the remainder
water-soluble group
(vitamins A, D, E and K), and the
of the vitamins).
number of vitamins
VITAMIN B COMPLEX
Eijkman (1897) found that birds developed poly2. Introduction.
neuritis when fed with polished rice, and were cured when they were given
Then Grijns (1901) found that rice polishings cured beriberi
rice polishings.
in man (beriberi in man corresponds to polyneuritis in birds; it is a form of
Grijns suggested that the cause of this paralysis was due
paralysis).
to some " deficiency " in the diet, and this was confirmed by Funk (1911,
1912), who prepared a concentrate of the active substance from rice polishFunk believed that this active substance was a definite chemical
ings.
compound, and since he separated organic bases when he prepared his conIt was then
centrate, he named his " deficiency compound " a vitamine.
found that " vitamine B " was a complex mixture, and when a number
of " vitamines " were obtained that contained no nitrogen, the name vitamin
was retained for them. The name vitamin B is now reserved for the complex mixture of vitamins in this group.
598
599
VITAMINS
3]
Thiamine is obtained crystalline in the form of its salts ; the chloride hydrochloride has been shown to have the molecular formula C 12 18
4 C1 2 S
(Windaus et al., 1932) ; this salt is isolated in the form of its hemihydrate,
d. 248-250.
When treated with a sodium sulphite solution saturated with
sulphur dioxide at room temperature, thiamine is decomposed quantitatively
and B (R. R.
into two compounds which, for convenience, we shall label
Williams et al., 1935).
H 0N
C12H180N 4C1 2S
+ Na S0
2
this oxidation product was a monocarboxylic acid, and found that it was
identical with 4-methylthiazole-5-carboxylic acid, I, a compound already
described in the literature (Wohmann, 1890). From this it follows that
has a side-chain of two carbon atoms in place of the carboxyl group in I
OCH
II
II
II
CH
CH
C-COjjH
C-CH3
II
CCH,-CH,OH
II
(one carbon atom is lost when A is oxidised to I). Since it is this sidechain which must contain the alcoholic group, the side-chain could be either
CH 2'CH a
or
CHOH>CH3 Either of these could lose a carbon atom
to form a carboxyl group directly attached to the thiazole nucleus. The
CHOH*CH 3 was excluded by the fact that A does
second alternative,
not give the iodoform test, and that A is not optically active (the second
alternative contains an asymmetric carbon atom). Thus A was given structure II, and this has been confirmed by synthesis (Clarke et al., 1935).
OH
ORGANIC CHEMISTRY
600
CH3
(i)
++Br CH
?_
CH Na
-CH 2OC 2 H5
[CH. XVII
CH3
?^
CO-CH-CH2 -CH 2 OC 2 H B
^V
C0 2 C 2 H,
CH 3 CO2 H 6
CO-CCl-CH 2 -CH 2 OC 2H 5
(ii)
NiH
CH 3
"ketonic
CO-CHCl-CH 2 -CH 2 OC 2 H 5
h6J-C-CH
s
""""
'/
*-
CH
C-CH2 -CH 2 OC 2 H 6
+ HC1 +
C-CH3
Clj
SIS
II
It
CCH
CH
thioformanude
-CH 2 OC 2 H 5
_HO^
C-CH,
y
|,
C-CH2 CH 2 C1
CH
J^^.
H '
C-CH 3
||
|,
C-CH 2 CH 2 OH
CH
A
The hydrochloride
of this
compound
is
and
fission),
nitric acid.
Londergan
et al.
n
(1953)
V/
have synthesised
CH "
a.
CH 3
H/t>d-C
HOI *
CHj CHCI
_
"
HCS-NH.,
CH*2
-H0
CH 2 OH COCH 3
Clo
^"
CH
-CH
*~
CH 2 C-CH 3
nCH,"
II
CH !/CC1
'
CH 'inHCO H
!
>
jlCHj-CHjOH
solution.
On treatment with nitrous acid, B evolves nitrogen ; thus contains one or more amino-groups.
Analysis of the product showed that one
amino-group is present in
(the product contained only one hydroxyl
group). Furthermore, since the evolution of nitrogen was slow, and the
reaction of B with benzoyl chloride was also slow, this suggests that
contains an amidine structure (Williams et al., 1935). Williams et al. (1935)
then heated B with hydrochloric acid at 150 under pressure, and obtained
C 6H 9
N 3S + H 2 -^> C 6H 8 4N 2 S + NH 3
C
compound C and ammonia. The formation of ammonia indicates the replacement of an amino-group by a hydroxyl group. This type of reaction
is characteristic of 2- and 6-aminopyrimidines it was therefore inferred that
B is a pyrimidine derivative (cf. 14. XII). This is supported by the fact
that the ultraviolet absorption spectrum of compound C was similar to that
of synthetic 6-hydroxypyrimidines thus B is probably a 6-aminopyrirnidine.
;
VITAMINS
3]
601
When B
group
is
et
al, 1937).
NH
(WV3
^NH
N^\CH
CHOH
acetamidine
Xr
formylpropionic
ester
NH
(i)
(ii)
POCla
NH3 - C2 H,OH
>
CH
|JCH3
JJ
with the absorption spectra of methylated aminopyrimidines of known structure (Williams et al., 1937). This is confirmed by the synthesis of Grewe
(1936); Williams et al. had arrived at their conclusion independently of
Grewe's work (see below for this synthesis). Thus, in compound D, there
is an amino-group instead of the sulphonic acid group in B.
Williams
therefore concluded that the sulphonic acid group (in B) is joined to the
methyl group at position 5. This was confirmed (in 1937) by treating
5-ethoxymethyl-6-hydroxy-2-methylpyrimidine (see the synthesis described
for thiamine) with sodium sulphite, whereby 6-hydroxy-2-methylpyrimidyl5-methanesulphonic acid was obtained, and this was shown to be identical
with compound C.
hCH 2 OC 2 H5
Na , S Q,
-.
ORGANIC CHEMISTRY
602
Thus
[CH. XVII
NH2
rtCHii-SOaH
.0'
CH^
B
This structure
is
et al.,
1937).
CN
NH2
<f
%H
acetamidine
^'/
c ' H ' 0Na
6-CN
C2H 6
\ rN
^V
>
-^
6-amino-5-cyano2-methylpyrimidine
ethoxymethylenemalononitrile
NH
NH 2
CH 2 NH2
N^CH Br NaHS0
2
(;)HNOj
("'"^^CHs^
H^W-ayi
so.
6-amino-5-aminomethyl2-methylpyrimidine
J$
The final problem is: How are fragments A and B united in thiamine?
As we have seen, the sulphonic acid group in B is introduced during the
fission of
fragment
of
in this position, the nitrogen atom of the thiazole ring is in a quaternary state, and so accounts for the chloride hydrochloride of thiamine. Had
B been connected to A through a carbon atom of the latter, it would not
be easy to account for the ready fission of this carbon-carbon bond by
means of sodium and liquid ammonia, nor for the fact that thiamine does
not form a dihydrochloride. Thus the chloride hydrochloride of thiamine
ment A;
is
NH
HT
_r
Y-CH N
II
CH 3L
HC1
II
CH
OH
CCH
II
,CCH
C
2 -CH 2OH
e.g.,
that of Williams
et al.
VITAMINS
5]
603
nh,
COjAHjs
C0 2 C 2 H 6
(i)
(0
CH2 -CH2 OC 2 H5
HC0
C 2 H5
^^H
Na
>
CHO
NH2
CH
C,HONa
OH
\cH OC H
N'
CH,'C=NH
'
J^ t
tt
-==-*. CH-CH
s
2 OC 2
(i)
pocu
NH
-HBr
NH
-HBr
CH 3
j|CH 2 OC 2
HBr
^n )
CH
N^\cH Br
2
(ii,
-U
C-CH 3
OH
C-CH2 -CH2OH
\S
NH HBr
Br
CH
N/\-CHj N
C-CH S
KJ
0-CH 2 -CH2 0H
NH
CH
-HC1
^N'T
in
CH 3 OH
CI
nAp CH N
3
AgCI
II
I)
CH3
CCH -CH 0H
CH
II
\g/
Co-carboxylase.
This
is
CH 3 -CO-C02H
Co-carboxylase
car"oxylMe
>
CH 3 -CHO
+ G0
is
NH2
CT
SrNr CH N
QH
CH 3 k
2
1J
5.
Thiochrome was
C-CH 3
CCH CH OPO(OH)OPO(OH)
2
its
ORGANIC CHEMISTRY
604
is
also
[CH. XVII
cyanide (Todd
ferriet al.
(1936).
CH 2 -CH OH
2
thiochrome
Riboflavin is a
riboflavin (lactoflavin), C 17 20 O 6 4
6. Vitamin
8,
water-soluble, thermostable vitamin which occurs in the vitamin B complex.
It is necessary for growth and health, and occurs widely distributed in nature,
Chemically, vitamin 2 is
e.g., in yeast, green vegetables, milk, meat, etc.
closely related to the yellow water-soluble pigments known as the flavins
(isoalloxazines), and since it was first isolated from milk, vitamin
2 is also
known
as lactoflavin.
Riboflavin is a bright yellow powder, m.p. 292, showing a green fluorescence; it is soluble in water and in ethanol, but is insoluble in chloroform
and other organic solvents.
When exposed to light, lactoflavin in sodium hydroxide solution forms
mainly lumi-lactoflavin, C13 12 2 4 (this is soluble in chloroform). Lumilactoflavin, on boiling with barium hydroxide solution, is hydrolysed to one
molecule of urea and one molecule of the barium salt of a /3-ketocarboxylic
The nature of this acid is
acid, I, C 12 12 3 2 (Kuhn et al., 1933, 1934).
shown by the fact that, on acidification of the barium salt, the free acid
immediately eliminates carbon dioxide to form the compound, II, C u 12 ON 2
This compound showed the properties of a lactam, and on vigorous hydro-
lysis
H N
C17 H 20O 6N 4
>
Hght
Ba(OH) s
>
lumi-lactoflavin
lactoflavin
CO(NH 2
_
C13H 12 2N 4
NaOH
[C 12
N
H 12 ,,
3
acid
2]
_ co
>
CaHaON,
>
CHOC0 2H +
C 9H 14N a
III
II
The structure of III was elucidated as follows (Kuhn et al., 1934). Preliminary tests showed that III was an aromatic diamino compound. Then
it was found that it gave a blue precipitate with ferric chloride, and since
this reaction is characteristic of monomethyl-o-phenylenediamine, it suggests
that III contains the following nucleus, IV. The molecular formula of IV
N 2 and since III is C 9H, 4N 2 two carbon and four hydrogen atoms
is C
H 10
NHCH
IV
/V /NHCH
HI
must be accounted
605
VITAMINS
6]
carried out a series of synthetic experiments and showed that III has the
structure given, iV-methyl-4 5-diamino-o-xylene. Kuhn then proposed II
as the structure of the precursor of III, since this would produce the required
products of hydrolysis.
:
NH-CHj
',00
NaOH
CH;
CH
1??
H0 C
2
OCH
III
II
II could therefore
CH 3
-co2
/!-C02 H
II
Since I and a molecule of urea are obtained from lumi-lactoflavin, the latter
could be 6:7: 9-trimethyh'soalloxazine (6:7: 9-trimethylflavin).
CH
3i
9
M^O
C-0O2 H
K
,00
NH, /
lumi-lactoflavin
CH 3
NH
HO
OH;
CH,
(X
(Karrer
for lumi-lactoflavin
et al.,
methylalloxazine (A).
ORGANIC CHEMISTRY
606
[CH. XVII
NHV
lumichrome
The woalloxazine
NH
NH
lactoflavin is:
CH 2 -(CHOH) 3 -CH 2 OH
N
N
NH
O
lactoflavin
This side-chain contains three asymmetric carbon atoms, and so there are
eight optically active forms possible. Which configuration is actually present
was solved by synthesising a number of pentose derivatives, and it was
finally shown by Karrer et al. (1935) that the configuration is that of d( )The following syntheses are due to Karrer et al. (1935).
ribose.
NH
OH OH OH
+ cho-c-c-^-ch^H
I
(i)
(ii)
condensation
H ,_ Pd
H H H
OH OH OH
CH C C C CHjjOH
H H H
I
NOj^^NjCl
607
VITAMINS
6]
CH2 -(CHOH)
CH 2 -(CHOH) 3 -CH2OH
-CH2 OH
,NH
pressure
N=n_^ XnO,
N
hoj^
Js.
NIL,
CHj^CHOHJs-CHitOH
Y
NH
/yv
.V
H 3 BO s
HNOj
>
+ C1-C02 C 2 H5
NH-C02 C 2 H6
NH,
NO,
H a -Pd
'
NH-C02 CH,
<
^^3
D()-ribose
^WjNH00
C2H 5
CH 2 (CHOH) 3 -CH2 OH
N=CH-(CHOH) 3 CH2 OH
Hg-Ni
NHC0
*"ch 3
C 2 H5
CH2 -(CHOH)
CH 3 ^
-CH2 OH
NaOl^
ANHC0
LN^/ x
C 2 n.55
^2 ^
NH
alloxan
HjBOj
NH
(Folkers
et
al, 1951).
ORGANIC CHEMISTRY
608
[CH. XVII
Cresswell and
units (Plaut, 1954; Birch et al., 1957; Goodwin et al., 1958).
Wood (1960) have synthesised riboflavin by a method which has possible implications in the biosynthesis of this vitamin.
When warmed
into
compounds
and
Investigation of
II.
C 9H 17
HC1
>
C3H 7
showed that
it
is
hydrolysed
was
/^-alanine
N + C H 10O 3
6
II
+
Cl{H 3N*CHyCH 2 'C0 2H).
On the
other hand, when hydrolysed with alkali, pantothenic acid forms /S-alanine
(I) and the salt of an acid which, on acidification, spontaneously forms the
lactone II. Thus the free acid of II is probably a y- or (5-hydroxycarboxylic
acid also, since the rate of lactonisation is fast, II is more likely a y-lactone
than a ^-lactone (cf. 7c. VII). As pointed out above, pantothenic acid
contains two hydroxyl groups. One of these has now been accounted for,
and so the problem is to find the position of the second one. This was
shown to be a- by the fact that the sodium salt of the acid of the lactone II
gives a canary-yellow colour With ferric chloride (a test characteristic of
oe-hydroxyacids), and also by the fact that II, on warming with concentrated
sulphuric acid, liberates carbon monoxide (a test also characteristic of <xhydroxyacids). Thus II is most probably the y-lactone of an a-hydroxyacid
(actually present as the hydrochloride,
/3-dimethyl-y-butyrolactone
CH 2 C(CH 3
CHOHCO = C H
6
10
O3
'
II
Treatment
actions
may
be formulated as follows:
m *
CH 2 -C(CH 3 2 -CHOH.CO
H,u
)
ry
II
()
>
VITAMINS
7]
609
(CH '- c0 ' ) 'Fb
CH 2OH-C(CH 3 2-CHOH-C(OH)(CH 3 2
CH 3-COCH 3 + CH 2OH-C(CH 3 2-CHO
CH 2OH-C(CH 3 2 -C0 2H
>
-^
III
Examination
The
lactone,
it
has
/CHjjOH
(CH3 ) 2CH-CHO
K' 3
CH2
CHO
formalin
zsobutyralrlehyde
^^>
(CH 3 ) 2 C
>
CH 2 OH
(CHs^C
>
(CH 3 ) 2 C
CHOH-CN
/ CH
CO
N CHOH
() -lactone
The (i) -lactone (as the sodium salt of the acid) was resolved with quinine
and the ( )-form was identical with the lactone obtained
hydrochloride,
from pantothenic
acid.
In pantothenic acid, the nitrogen atom is not basic. Also, since hydrolysis
of pantothenic acid produces a free amino-group (in /3-alanine), this suggests
that the group
is present, i.e., pantothenic acid is an amide.
Thus the hydrolysis may be formulated:
CONH
pantothenic acid
HCl
+ NH
lactonises
CH 2 -C(CH 3 2 -CHOH-CO
)
'
This interpretation of the results has been proved by the synthesis of pantothenic acid. Stiller et al. (1940) warmed pantolactone (synthesised as described above) with the ethyl ester of jS-alanine, and removed the ester
group by hydrolysis with a cold solution of barium hydroxide.
Ba(OH) a
ORGANIC CHEMISTRY
610
[CH. XVII
(ii)
(iii)
Vitamin B conjugate.
Vitamins B 10 B u and factors R, S and U.
(vii) Vitamin M.
(v)
(vi)
by
e.g., iv).
Angier et
vitamin B c)
al.
(1946)
is:
jH 2N
-0O 2
|2-amino-6-hydroxypteridine
/>-aminobenzoic
glutamic acid
acid
pteroic acid-
pteridine
shown
VITAMINS
8a]
611
numbering frequently used in American publications). A further examination of compound I showed that it also contained one hydroxyl and one
amino-group. Oxidation of I with chlorine water, followed by hydrolysis
with hydrochloric acid, produced guanidine, NH=C(NH 2) g as one of the
products. The formation of this compound suggests that the amino-group
is at position 2.
Finally, I was shown to be 2-amino-6-hydroxypteridine,
8-carboxylic acid
by
synthesis.
C02 H
A*
OHO
|AcH
h n/\n ^
1CH,
VI
The reactions of compound II showed that it was a primary aromatic
amine, and on hydrolysis it gave one molecule of ^-aminobenzoic acid and
three molecules of glutamic acid.
Hydrolysis of the fermentation L. casei factor with sulphurous acid gave
an aromatic amine, III, and an aldehyde, IV. Ill, on hydrolysis, gave one
molecule of ^-aminobenzoic acid and three molecules of glutamic acid, i.e.,
II and III are identical.
When the aldehyde IV was allowed to stand in
dilute sodium hydroxide solution in the absence of air, compound I and
another compound, V, were produced. V, on vigorous hydrolysis, gave
2-amino-5-methylpyrazine, VI. From this it was concluded that V is 2amino-6-hydroxy-8-methylpteridine, and IV is 2-amino-6-hydroxypteridine8-aldehyde. Consideration of this evidence led to the suggestion that the
liver L. casei factor has the structure given in 8; this has been confirmed
by synthesis, e.g., that of Angier et al. (1946).
/NHa C 2H B 2C
(i)
NH CH
0.
-/C=NH
HN^VNH
2
+
NH=C
X NH,
OH,
Nc/
OH
NH
HNO,
>-
HN
2
NH,
HoN
2 :4 5-triamino-6hydroxypyrimidine
:
ORGANIC CHEMISTRY
612
A/
A%/A
(u)
CHBrCH.Br
n nh
HoN/
+i
+CHO
[CH. XVII
CO-NH-CH-(CH2VC02H
+ NH*
C02 H
2:3-dibromopropionaldehyde
/>-aminobenzoyl-L(+)-
glutamic acid
ait
jCH3'COaNa
l<
CO-NH-CH-CCHijJa-COijH
C02 H
H
liver
L.casei factor
isr
n'
leucopterin
xanthopterin
egg-yolk oc-biotin, and that from liver j8-biotin. Both compounds have
the same molecular formula C 10 16 O 3N 2 S.
(B-Biotin (Bios IIB or biotin), m.p. 230-232, behaves as a saturated
compound (the usual tests showed the absence of an ethyleijic double bond).
/S-Biotin forms a monomethyl ester C u 18 3N 2 S which, on hydrolysis, gives
an acid the titration curve of which corresponds to a monocarboxylic acid;
thus the formula of /3-biotin may be written C 9 15 ONjjS-C0 2 H. When
heated With barium hydroxide solution at 140, )3-biotin is hydrolysed to
carbon dioxide and diaminocarboxylic acid C 9 18 2N 2 S which, by the action
of carbonyl chloride, is reconverted into |3-biotin (du Vigneaud et al., 1941).
These reactions suggest that /5-biotin contains a cyclic ureide structure.
Furthermore, since the diaminocarboxylic acid condenses with phenanthraquinone to form a quinoxaline derivative, it follows that the two amino-
613
VITAMINS
9]
/CO
NH NNH
at-a
coc
'
NH2
NH2
Ba(OH),
Ar^ \
c
diamino-compound
p-biotin
When
NH
lysed with barium hydroxide solution, a triamine was obtained which did
not give adipic acid on oxidation with alkaline permanganate (du Vigneaud
It was therefore inferred that /3-biotin contains a
et al., 1941, 1942).
(CH 2) 4'C0 2 side-chain (w-valeric acid side-chain).
The absorption spectrum of the quinoxaline derivative (formed from
phenanthraquinone and the diaminocarboxylic acid) showed that it was a
quinoxaline, I, and not a dihydroquinoxaline, II thus the diaminocarboxylic
NH
NH2
CH
CH
IV
III
cannot be attached
amino-group.
an
joined
to
atom
carbon
a
to
The nature of the sulphur atom in /S-biotin was shown to be of the thioSC) since:
ether type {i.e.,
peroxide produced a sulphone.
(i) Oxidation of /3-biotin with hydrogen
with methyl iodide,
(ii) When the methyl ester of /3-biotin was treated
a sulphonium iodide was formed.
As we have seen, /3-biotin does not contain a double bond; hence, from
contains two rings
its molecular formula, it was deduced that /3-biotin
(du Vigneaud et al., 1941; Kogl et al., 1941). The sort of argument that
may be used is as follows. The molecular formula of /3-biotin is C10H 16O 3N 2 S.
The carboxyl group may be regarded as a substituent group, and so the
groups are preparent compound will be C 8H 16 ON 2 S. Also, since two
is
sent, these may be replaced by CH 2 groups; thus the parent compound
Cu lgOS. The CO group may be replaced by a CH 2 group and the sulphide
atom also by a CH a group. This gives a compound of formula C12 22
which has the same " structure " as /3-biotin. Now the formula C12H 22
corresponds to the general formula CH g _ 2 and this, for a saturated compound, corresponds to a system containing two rings.
When heated with Raney nickel, /8-biotin formed dethiobiotin by elimination of the sulphur atom (this is an example of the Mozingo reaction, 1943).
It therefore follows that the w-valeric acid side-chain
NH
614
ORGANIC CHEMISTRY
[CH. XVII
atom
is
CO.
NH
Raney
NH
NH
Ni
CH
CH-
CH-(CH2)4 -C0 2 H
CH 2 -(CH2
CH,
)4
-C0 2
dethiobiotin
p-biotin
NH2
NHjj
HCl
C02H
HI0 4
GH- -CH
CH S CH2 -(CH 2 4 -C02 H
CH2 -(CH2
)4
-C0 2 H
pimelic acid
Further evidence for this structure is given by the fact that the exhaustive
methylation of the diaminocarboxylic acid (produced from /3-biotin), followed
by hydrolysis, gave (5-(2-thienyl)-valeric acid (du Vigneaud et al., 1942);
the structure of this compound was confirmed by synthesis.
'
+ (CH 2 3
thiophen
Zn-H
4-
Aicu
CO
glutaric
CO-(CH2)s-C02H
HCl
anhydride
NH2 NH,
<
[1
P(CH2 ) 4 -C0 2 H
(i)(CH,),
)aS04-NaOH
(ii)conc -
CH -OH
HCl
^ /
CH 2
CH-(CH 2 )4 -C0 2 H
8-(2-thienyl)valeric acid
The above
et al.,
NH
NH 2
CH-C0 2 Na+ CH 2Cl-C0 2 Na
*-
synthesis (Harris
2
(i) C 6 H,-COCl
(ii)CHsOH-HCl'
CH-C02 H
CH 2 SNa
Na
by
salt of
L- cystine
NH-CO-C6 H 6
CH-CO 2 0H 3
I
CHj
NHCO-Ce H 5
NH-CO-Ce H 5
CH,ONa
CHjOH
CONa
HCl
CHj-COjH*
CHaCOjCHj
CH2
G*C0 2 CH3
'
CO
CH2
0H2
615
VITAMINS
10]
NH-CO-C 6 H s
CHO-(CHa ),-CQ 8 CH^
piperidine acetate
C 8H 5 -CO
NH
(ii)
(Hi)
C 8 H 6 -CO
H '" Pd
>
aq
CH CH
II
CKu
NH
NH
CH
CH
|
.
NH
II
coci,-nhco,
Zn-CH,-CO,H/(CH,-CO),CT
CC-CH,
NH
>
C-(CH 2 ) 4 -C0 2 CH 3
Ba(OH) *
HjSO,
NH.OH
(i)
(ii)
NH
CH2
>
CH
V"
CH 2
OO-CH,
'
*"*
GH2
CH-(CH2 )4 -C02 H
Two
resolved via
(Traub, 1956).
The structure of a-biotin
is
uncertain.
it
616
ORGANIC CHEMISTRY
[CH. XVII
hydrolysis to its corresponding acid, did not give a red colour with ferrous
sulphate, there is no carboxyl group in the 2-position.
It therefore follows
that, on decarboxylation, the tricarboxylic acid eliminates the 2-carboxyl
group to form the anhydride; thus the tricarboxylic acid could have either
of the following structures.
C0 2 H
C0 2 H
H0 2 C 0OCH3
H0 C / ^OCH
Ho c
or
Now pyridoxin
CH2 OH
CH2 OH
HOCH
/\^OH
HOCH
f[
uyoH.
A
or
When
C0 2H
C02 H
H0 2C(f\oCH 3
HO,jC<f%OCH 3
CH,
v<
JcH 3
V
II
Kuhn
et al.
(1939)
OCH 3
OCH,
0H 3 KMn0s H0 2 C
3
C*jCH
H0
,N
CH 2 OH
HOCH
2 f[
^iOH
pyridoxin
C
is
from
its
forma-
(a synthetic
com-
617
VITAMINS
12]
e.g.,
Folkers (1939):
CH2 0C2 H 5
CH2 OC 2 HB
OH 2 CN
CO
9H
CH2 OC 2H
CH2 OC2 H6
N
/XcN
CH3
[Jon
p C1 ,
Q2
CH,^
H N,f\cH NH
W
J
HNOs
(CH 3 -CO) a O
QH
CH2 OC 2 H5
n/\cN h^H^/XcN
Ha _ Pt+Pd-C
C^l^Cl
Jci
CH 2 OH
CH 2 OH
CH2 OC 2Hg
CH,
CH
cyanoacetamide
ethoxyacetylacetone
ff\cN
A.
"
H,*^
12
CH3-CO
c 2 hoh
^CO
hci
H Nff\cH NH
2
CH,
HNO|)
HOr|^\cH OH
2
pyridoxin
C02 H
0'
Still
acid,
V ^0
COCl
CONHa
Vitamin B 12 Cyanocobalamin.
C0(NH,
C0 2 H
ORGANIC CHEMISTRY
618
[CH. XVII
B lg
ribofuranoside (III) and the 3'-phosphate of III (Folkers et al., 1949, 1950;
Todd et al., 1950). Compound IV (a succinimide derivative) has also been
isolated by the chromic acid oxidation of hydrolysed vitamin B 12 (Folkers,
1955).
CH 3 CHOH CH2 NH 2
II
3-
CH 2OH
\O/ H
C'OH HO
I
Me
H
x
c6 co
I
CHCH^CHo-COoH
:c-
m/
IV
III
Other work has shown that six amido groups are present in the molecule.
Also, alkaline hydrolysis of vitamin
12 gives a mixture consisting mainly
of a penta- and a hexacarboxylic acid, in both of which the nucleotide
fragment is absent. As the result of a detailed X-ray analysis of the hexacarboxylic acid, vitamin B ia has been assigned the structure shown.
NH 2 COCH 2 CH 2 Me
NH2 -COCH 2
Me/CHa-CONHj
>CH2-CH 2-CONH 2
Me
Me
NH2 -COCH 2
'
CH2CH2CONH2
NH-CO-CH 2 -CH2
CH 2
I
MeCH
YV
Vitamin Bj 2
619
VITAMINS
15]
point of interest
is
is
13.
(ii)
11 iv. IV).
The absence of this
(iii) Choline.
a fatty liver in animals.
OH
NH,
compound
OH
H
H
HO |(CH N-CH
OH
3) 3
-CH 2 OH
HO
0O 2 H
choline
OH
/>-amino-
myoinositol
benzoic acid
said to exist
VITAMIN E GROUP
Vitamin E is the anti-sterility
factor; it occurs in
14. Introduction.
seed germ oils. It is now known that there are three closely related compounds comprising " vitamin E " ; all three are biologically active, and are
known as a-, /?- and y-tocopherol. The main source of a- and ^-tocopherol
Wheat
is wheat germ oil; the y-compound is obtained from cotton seed oil.
germ oil was first subjected to chromatographic analysis to remove sterols,
etc., and then the a- and /3-tocopherols were purified by conversion into their
Hydrolysis
crystalline allophanates (see 12. XII) or 3 5-dinitrobenzoates.
of these derivatives gave the tocopherols as pale yellow oils.
:
15. a-Tocopherol, Cs9 B0 O a When a-tocopherol is heated at 350, duroquinol is obtained (Fernholz, 1937). On the other hand, when heated with
selenium, a-tocopherol forms duroquinone (McArthur et al., 1937). Finally,
when heated with hydriodic acid, ^cumenol is formed (John et al., 1937).
.
C29H50O2
a-tocopherol
CH
ORGANIC CHEMISTRY
620
[CH. XVII
C2xH 40O2
0H
C2 9
5(
A -^^
VC^
O + CaHaA
If
may
R'
I
R OCHj-CHjj-CO
I
Now
Clg H 32
R=
(i)
'
'
'
CH S
(ii)
QeHss-C/CHa-CHij-CO-^1
'
'
Fernholz then showed that the acid (I) contained methyl groups (c/. 3. IX),
and was led to propose a structure based on the isoprene unit, viz.
CH 3
CH 3 -CH-(CH 2
CH 3
)
CH 3
621
VITAMINS
15]
CH,
,CH 2
XCH
HO
CH 3
H0
CH,
\Ao
CH
.cr
,/
NC H
16
CH 3
.CH 2
)3H-CH-C M H
fl
33
CH3
coumaran structure
chroman structure
CH3
BrCH2
CH
0-
HO,
ZnClj
light petrol
CH 3
OH .C
CH3
/C'CisH33
CH,
CH,
CH,
HO
CH
CieHs3
CH,
rr
CH2
CH3
CH,
O',/l
CH3
CH,
() -a-tocopherol
is
follows:
CH3
CH3
(i)
CH r
CH
CH CH 2H
CH2 CH 2 MgBr
;
2'
(i)PBr.
fi
(ii)
OCH3
Mgr
OCH3
CH3
CH,
CH,
CH,
CH,
HO
CH.
/V^i
)
CHa-COjH*
VjisH 3;
Cjj
CH3
() - a-tocopherol
622
ORGANIC CHEMISTRY
Smith
et al.
[CH. XVII
by oxidation
C28H 48
16. (3-Tocopherol,
pherol
by
quinol,
I,
differs from that of a-tocoof /9-tocopherol gives trimethylheating with hydriodic acid ^>-xylenol, II (John et al., 1937).
CH 2
and
This formula
2.
Thermal decomposition
H3
2.
HO
HO
OH
CH 3
Ml
OH3
CH3
II
When
H40O
(C 2l
CH,
HO
CH
\
CH.
QH 3
CH,3
CH 3
CH,
p-tocopherol
BrCH2
OH
+
CH 3-COO
OH
CH3
ZnClj
CH
HO
CH2
CH3
/C-(CH 2
CH3
(CH2) 3 -CH-(CH2 ) 3 -CH(CH3 ) 2
)3
CHS
y-Tocopherol, C 28H 48
only difference
is
CH.
CH 2
HO
CH 3
/
CH3
0H3
CH 3
CH 3
y-tocopherol
623
VITAMINS
20]
This structure has been confirmed by synthesis, starting from the monoacetate of o-xyloquinol and phytyl bromide.
CH
CH,
CH3
18.
HO
C"Ci 6 H33
CH,
Stern
CH
BrCH
CH
CH3 COO
8-Tocopherol, C27H4e 2
(1947) it is a yellow
.
et al.
structure of ^-tocopherol
a
'
CH,
C'CxsHm
CH3
and
inactive physiologically.
is
by
The
oil
is
/CHj
II
.C-(CH 2) 3 -CH-(CH
CH 3
)S
!S
-CH-(CH 2 )3-CH(CH S ) 2
H *
8-tocopherol
VITAMIN
GROUP
19. Introduction. Dam et al. (1939) and Doisy et al. (1939) isolated
vitamin K from alfalfa, and called it vitamin K x to distinguish it from a
substance called vitamin K 2 which had been isolated from putrefied fish
meal by Doisy et al. (1939). Both are antihaemorrhagic vitamins; they are
connected with the enzymes involved in blood clotting, a deficiency of them
lengthening the time of blood clotting. Kegel et al. (1962) have obtained
chemical evidence for the presence of vitamin K x in extracts from spinach
chloroplasts.
Vitamin
ORGANIC CHEMISTRY
624
[CH.
XVI
When
\/
C31H46O0
CH,
/\ CO,H Ai
\J C0 ^ VA/Wco h
2
o
Thus the presence of the 1 4-naphthaquinone structure is confirmed, and
at the same time these products show that one ring is unsubstituted and that
the other (the quinonoid ring) has substituents in the 2- and 3-positions.
When the diacetate of dihydrovitamin K x (see above) was subjected to
ozonolysis, a compound C lg H 36
was obtained, which was then shown to be
identical with the ketone produced by the oxidation of phytol (McKee et al.,
1939; cf. Smith's synthesis of a-tocopherol, 15). Hence, on the evidence
obtained above, vitamin Kj is 2-methyl-3-phytyl-l 4-naphthaquinone.
:
CH,
CH3
CH,
vitamin
625
VITAMINS
21]
0H 3
CH 3
-- 3
CH
CH3
^CH
CH3
CH 3
AgjO
CH3
CH3
Cl
(?Hs
I=C-(CH.),-C]
CH2-CH=C-(CH
2 ) 3 -OH-(CH 2 )3-CH-(CH 2 )3-CH(CH 3 ) 2
(C0 2 H) 2
0H3
CH3
0H 3
Wendler et al. (1954) have obtained vitamin Kj in good yield by condensing the 1-acetyl derivative of 2-methyl-l 4-naphthaquinol with phytol
in the presence of boron trifluoride.
:
Vitamin
than vitamin
x.
2,
It
and
ORGANIC CHEMISTRY
626
[CH. XVII
O-CO-CHs
,,CH 3
CuHaA-H^
CHyCHO
OCOCH
CH
CH 3
vitamin
3 )2
natural vitamins.
also
READING REFERENCES
A
(i)
(ii)
(iii)
Todd
et al.,
CHAPTER XVIII
CHEMOTHERAPY
Introduction. The term chemotherapy was introduced by Ehrlich
and it now appears to be used in the sense of the treatment of diseases
due to bacterial invasion by chemical compounds which destroy the microorganisms without affecting, to any material extent, the tissues (of the host).
Many compounds, e.g., formaldehyde, phenol, iodine, etc., are also active
in destroying bacteria. These compounds, however, are applied externally,
and tend to destroy the tissues ; thus they are not included under the heading
of therapeutic agents, but are known as disinfectants.
The first compounds to be used by Ehrlich (1907) were organic dyes.
From then onwards, organic compounds of diverse chemical structures have
been used in chemotherapy. It has now been found that a given compound
The relationis specific in its toxicity towards a particular micro-organism.
ship between chemical structure and chemotherapeutic action is extremely
complicated, but some progress has been made in this field.
Compounds which exert various physiological effects of therapeutic value
are collectively known as drugs. The ideal requirement of a drug is that,
on administration (to the host), it should be localised at the site where it
In practice, however, no drug behaves in this way, but tends
is required.
to distribute itself anywhere in the tissues of the host. Another difficulty
is that cells, which were originally susceptible to a particular drug, may
acquire a tolerance (resistance) to that drug. In some cases it has been
found that the drug actually reverses its original action, i.e., it stimulates
the cell instead of inhibiting it.
There have been three approaches to the problem of finding a drug to
combat a particular disease:
This involves the trial of all kinds
(i) The method of trial and error.
1.
(1909),
(ii)
2.
Sulphonamides.
Sulphanilamide (^-aminobenzenesulphonamide)
and
its
H N
2
^-SO,j-NH 2
sulphanilamide
627
ORGANIC CHEMISTRY
628
Sulphanilamide
may
[ch. XVIII
CH.-CO-NH
CH 3 -CO-NH
>-
SCVNHg
CH s -CO-NH
NaOH
NH
>
S o 2 ci
-^V
S08 -NHij
CH 3 0ONH<f^
\=S>S0
CHoOONH
2 C1
HN<.
SOj-NH-
NaOH
and B 693.
name of
Sulphathiazole (^ 1 -2-thiazolylsulphanilamide) is more potent than
Sulphapyridine and less toxic; it is used mainly in severe infections. It is
This compound was introduced under the trade
NH,^~\sOr-NH-j|^
^h
is
NH
Sulphamezathine
<^ ^SO-NH-IJ^ J
(iV'-2(4
6-dimethylpyrimidyl)-sulphanilamide)
is
also
629
CHEMOTHERAPY
2]
Sulphaguanidine, since
tract,
of bacillary dysentery.
,NH
J'
NH2
Prontosil (4-sulphonamido-2' 4'-diaminoazobenzene) was the first sulphonamide to be used in medicine. It is prepared by diazotising sulphanilamide and then coupling with w-phenylenediamine.
:
NHj^
>
+ C1N2<^
>S0 NH
>-2=N-^
>S0 NH
NH,
NH2^
NH,
It was suggested that Prontosil broke down in the body to sulphanilamide;
this led to the discovery that the latter compound is very active against
bacteria.
Prontosil S is more soluble than Prontosil.
CHj-CONHj^
Na03 sL
Y
11
V-N=N-^;
N=N-^
Js03 Na
^>S
>S02 -NHs
Some compounds
active, e.g.,
CH3 CO-NH^
>S0 H
2
in which the amino-group is ortho or meta to the sulphonamidogroup are either less active or completely inactive.
^-Aminobenzoic acid is an essential growth factor for most bacteria
susceptible to the sulphonamides. The theory of action is that, owing to
the similarity in structure, bacteria absorb a sulphonamide " by mistake ",
and once this compound is ingested, the bacteria cease to grow in numbers
(Woods, 1940). Thus the sulphonamides are not bactericidal but bacterio-
Compounds
static.
ORGANIC CHEMISTRY
630
[CH. XVIII
known
CH2 OH
CH3
CHOH
hso
CeHn-NOj
CH3 0|
["].
CHjjOH
CH3O
CH,-CHBr'(CH,)-N(C 4 H 5 ),
CH3O
NH'CH(CH3
-CHis-CHu-CHa'NfCijHss),,
Mepacrine (Atebrin, Quinacrine) is 2-chloro-5-(4'-diethylamino-l'-methylbutylamino)-7-methoxyacridine. It is better than quinine, and it has been
prepared as follows:
(i)
[CHs-CO-CH-COijCjHs]
i!
NH
-f-
C1CH 2 -CH,-N(CH B
)2
C2 H6
CHs-CO-CH-CH CH
H2 Raney Ni
Na+
ketonic
l!
-N(C 2 H6) 2
*-
hydrolysis
) j!
CH 3 -CO-(CH2 )3-N(C 2 H 5
)2
631
CHEMOTHERAPY
4]
CH3O
+ CH3 -CH-(CH
(iii)
CI
NH
CH3
NH-CH(CH2
)S
-N(C 2
i!
)s-N(C H5) 2
i!
6) 2
CH3
CH
NH-CH-(CH 2 3-N(C2 H 5 2
)
Ny
Chloroquine
/r-_
CI
4.
is
Arsenical drugs.
NH
NH
y^-WR- C -NH-C-NH-CH(CH3
)2
(1909)
it is
3'-diamino-4
pared as follows:
OH
NH.
As0 3H 2
Arsphenamine
NH,
As=^j
is
>_ NagSaOj^
A803 H 2
As0 3 H 2
NH.
HO
f\m
HXQ 3?
NaNO,
H,SO t
an unstable compound;
OH
it is
which, however, cannot be used as such but must be converted into the
soluble sodium salt. Ehrlich (1912) overcame this difficulty by preparing
neoarsphenamine (Neosalvarsan), a soluble compound, which may be produced by condensing arsphenamine with sodium formaldehydesulphoxylate,
CH 2OH-S0 2Na.
I;
632
ORGANIC CHEMISTRY
Wit
HO^
[CH. XVII
NH-CHjjOSONa
^OH
>-As=As%
neoarsphen amine
Vol.
I).
NH
Tryparsamide
As04
>-
NHj
Ab0 3 H 2 +
it is less
is
NU
NH COCH
2
^
2
AaOaHjj
+ ClCH2 -CONH2
NH^ ^As0 H
3
v-
+ HC1
5. Antibiotics.
Many micro-organisms produce within themselves
chemical substances which, when excreted, interfere with the growth or
metabolism of other micro-organisms. Such compounds are known as antibiotics, and need be present only in low concentration to bring about this
antibiotic action.
Antibiotics are thus chemotherapeutic agents.
In 1929, Fleming discovered a mould of the Penicillium species which
inhibited the growth of certain bacteria. This observation was investigated
later by a number of workers and culminated in the isolation of the active
principle penicillin.
At the same time, research along this line led to the
isolation of many other antibiotics.
Chemical
Name
Pent-2-enylpenicillin
Benzylpenicillin
....
^-Hydroxybenzylpenicillin
....
-Heptylpenicillin
M-Amylpenicillin
Penicillin-I or F
Penicillin-II or
Penicillin-III or
Commercial preparations
Penicillin-K
Dihydro-Fpenicillin
lins in
Other Names
CH -CH=:CH-CH -CH
CH -C H
CH -C H -OH(l
(CH -CH
(CH -CH
2
2
2) 6
2) 4
4)
of penicillin contain one or more of the penicilIt has been found that the addition to the
varying proportions.
633
CHEMOTHERAPY
6a]
6a. Structure of the penicillins. The penicillins are all strong monobasic acids, e.g., they form salts. The penicillins are hydrolysed by hot
dilute inorganic acids; one carbon atom is eliminated as carbon dioxide,
and two products are obtained in equimolecular amounts, one being an
amine, penicillamine, and the other an aldehyde, penilloaldehyde. All the
penicillins give the same amine, but different aldehydes; it is the latter
group.
N SR + 2H
D-Penicillamine, C H u
C 9H u
HCl
C 8H u
NS + C 3H 4 2NR
e.g.,
(CHjOsCH-CH-COijH
NH2
CHjjCl-COCl
NaOH
(CHjJjjCH-CH-COjjH
>
NH-CO-CH2 Cl
DL-valine
(CH3 ) 2 C=C
(CH s -CO),0
CO
H,S
(aEW,0-C-00,H
N=C-SH
CH3
C]
azlactone
CHC02H ho
(CH 3 ) 2C
(CH3) 2C CHC0 2 H
SHNH-CO-CHj
boil
(i)
HCl (boil)
() pyridine
^H 3
2:5:5-trimethyl-2thiazoline-4-carboxylic
acid
8H
NH
DL -penicillamine
The racemic amine was resolved as follows: the amine was converted into
the formyl derivative, which was then resolved by means of brucine. dPenicillamine was obtained after removal of the formyl group by hydrolysis.
(CH 3) 2CCH-C0 2H
H-C0 s H
> (CH 3
C CH-C0 H
(i)
(ii)
SH NH 2
SH NH-CHO
DL-form
DL-form
brucine
HCl
(Hi) pyridine
(CH 3) 2CCH-C0 2H
SH NH 2
D-penicillamine
ORGANIC CHEMISTRY
634
[CH. XVIII
On
vigorous hydrolysis,
all
R-CONH-CH 2-CHO
+ H -> R-C0 H + NH
2
-CH 2 -CHO
R-COC1
+ NH
R-CONH-CH 2 -CH(OC 2H 5
+ R-CONH-CH
R-CONH-CH-CHO -^ C0 2
-CHO
C0 2H
penaldic acid
The problem now is: How are the two fragments, penicillamine and
penilloaldehyde, combined in penicillin? The hydrolysis of penicillin with
dilute alkali or with the enzyme penicillinase produces penicttloic acid (a
dicarboxylic acid), which readily eliminates a molecule of carbon dioxide
to form penilloic acid. This suggests that a carboxyl group is in the imPenilloic acid, on
position with respect to a negative group (c/. above).
hydrolysis with aqueous mercuric chloride, gives penicillamine and penilloaldehyde. This hydrolysis is characteristic of compounds containing a
thiazolidine ring (c/. 5b. XII). Thus penilloic acid could be I, since this
structure would give the required products.
RCONHCHjCHO
.g
R-CO-NH-CHVCH yCH^
hiCH-C0 H
H ,o
^
Hg *
Nj!(CH8) 2
HjjN-CHCOijH
Hence,
if
I is penilloic acid,
HS
RCONHCH
002H
CH
|
C(CH3) 2
>-mj
CH-C0 H
|
nh
II.
II
This structure (II) is supported by the fact that the treatment of penicillin
with methanol gives methyl penicilloate which, on hydrolysis with aqueous
mercuric chloride, gives methyl penaldate (see also above) and penicillamine.
635
CHEMOTHERAPY
6a]
/\C(CH
R-CO-NH-CH CH
Penicillin
H80
h^ci,*
On
CH' OH
>
HS N
R-CO-NH-CH -CHO
C02 CH s
3) 2
Ah CHC0 H
CH,02 C
C(CH3)2
H,NCH-C0 2H
the basis of the foregoing evidence, two structures are possible for
and IV.
RC
CH CH
CO
C(CHS
R-CONH-.CH
)2
NH CHC0 H
CO
CH
C(CH3 )2
CHCO H
IV
III
oxazolone structure
(S-lactam structure
It was not possible to decide between these two on chemical evidence alone,
since penicillin readily undergoes molecular rearrangements, e.g., on treatment with dilute acid, penicillin rearranges to penillic acid. It was therefore
necessary to examine the molecule by physical methods (thereby leaving
C=0
C=0
RC'
I
CHR
c=o
I
oxazolone
ORGANIC CHEMISTRY
636
CH
HO ,C-CH
[CH. XVIII
G<(CH 3) 2
;
CHC0 H
KS-
*C
t
R
peniUic acid
[dilute
|
RCONHCH
acid
-CH
f
CO-
C(CH 3
)2
CHCO.H
Npeniciilin
CO- NH- CH
H0
CH/\C(CH
NH
2C
R- CO-NH- CH-
3) 2
CHC02 H
penicilloic acid
CH
CH-C0 H
2
h 2 o-h s ci 2
CH
C(CH3 ) 2
NH
CHC0 2 H
R- CO-NH- CH-CHO
I
C0 2 CH3
methyl penaldate
penilloic acid
HaO-HgCla
HS
R-CO-NHCH -CHO +
C(CH3
HS-C(CH3
penilloaldehyde
C(CH 3) 2
methyl penicilloate
-co2
RCONHCH
CH
NH
2C
H NCHC0 H
2
H NCHC0 H
2
penicillamine
penicillamine
Penicillin has been synthesised by condensing synthetic D-penicillamine
with a suitably substituted oxazolone containing a potential aldehyde group,
e.g.,
R.-C
I
O
" Synthetic "
C=CHOR
I
CO
R=C H
R=CH
6
-CH 2
637
CHEMOTHERAPY
7]
(1959) isolated pure 6-aminopenicillanic acid from fermentawhich no precursors had been added. This acid had already
been synthesised by Sheehan (1958); it is the amino-compound (I) with
the RCO group removed.
Batchelor
et al.
tion liquors to
^V
(i)
CH
RCO- -NH- CH
CMe 2
-CHC0 2 H
CO-j-N(2)
It has also been shown that (1) is the site of action of the enzyme penicillin
amidase (Rolinson et al., 1960; Claridge et al., 1960) and, as mentioned
(2) is
Many
6c. Biosynthesis of penicillins. This has been studied and much progress
has been made the structure of penicillin can be dissected into an acid, cysteine,
;
and
valine.
RCO- -NH-CH
i:
CH '^CMej
r-V"
CO-^-N*
aliphatic or
*l
?CHC02 H
aromatic
cysteine
acid
(a)
been used
(see
above and
valine
6).
NHC-NH2H
NH
NH-OKHjj
OH
III
NH
ORGANIC CHEMISTRY
638
[CH. XVIII
The following is a very brief account of the evidence that led to this structure for streptomycin. The molecular formula was shown to be C 2 iH 39 1 gN 7
Three nitrogen atoms are strongly basic (the molecule forms a trihydrochloride), and on mild acid hydrolysis, streptomycin gives one molecule of
streptidine, C 8 18 4 6 , and one molecule of streptobiosamine, C 13 23 9N
(Folkers et al, 1946).
.
III),
NH,
HO
OH
HO
NH,
OH
streptamine
a diaminotetrahydroxycyc/ohexane, and examination of the oxidation products of dibenzoylstreptamine with periodic acid led to the suggestion that
streptidine is 1 3-diguanido-2 4 5 6-tetrahydroxycyc/ohexane (Carter
Streptidine has been synthesised from streptamine (Wolfrom
et al., 1946).
et al., 1948).
Since streptidine is not optically active, the configuration of
the molecule must be meso, with the two guanido groups cis (see unit III).
N-Methyl-L-glucosamine (unit II). When streptomycin is treated
with methanolic hydrogen chloride (methanolysis), and then subjected to
acid hydrolysis followed by acetylation, the penta-acetate of iV-methyl-Lglucosamine is obtained; the parent compound is obtained by hydrolysis.
The structure of iV-methyl-L-glucosamine was confirmed by synthesis from
L-arabinose (Kuehl et al., 1946, 1947).
Streptose (unit I). The streptose fragment has not been isolated from
streptomycin by degradation. It appears to be too unstable, but its structure was elucidated by various degradative experiments, e.g., the alkaline
:
OH
CH,
maltol
hydrolysis of streptomycin gives maltol (Schenck et al., 1945), and this is
produced by the conversion of a furanose ring into y-pyrone.
Streptobiosamine (units I and II). Analytical work showed that this
compound was a disaccharide, and from it was isolated iV-methyl-L-glucosamine (see above). The formation of maltol and other analytical work led
to the structure (I
II) for streptobiosamine, and then the points of attachment between streptobiosamine and streptidine were found, and so led to
the structure given above for streptomycin (Kuehl et al., 1947, 1948).
639
CHEMOTHERAPY
8]
fever, etc.
and
is
antibiotics are
(Woodward
et al.,
1952):
Aureomycin:
Terramycin:
R = C1;
E.'=H
R=H; R=OH
moulds. It is an
8. Patnlin. This has been obtained from various
optically inactive solid, and it inhibits Staphylococci and coliforms. The
molecular formula of patulin is C 7 6 4 ; it is a neutral substance and forms
a monoacetate. Hydrolysis of patulin with acid produces one molecule of
formic acid and a small yield (10 per cent.) of tetrahydro-y-pyrone-2carboxylic acid (I). Catalytic reduction followed by further reduction with
hydrogen iodide and red phosphorus gives 3-methylhexoic acid (II) and
the lactone of 4-hydroxy-3-methylhexoic acid (III) [Birkinshaw et al., 1943].
CH2
X
CH CHMe
'
I
\/
C02 H
CH 3 CH 2 C02 H
II
CH
X
CH, CHMe
I
CH 3 CH 2 CO-
III
640
ORGANIC CHEMISTRY
Woodward
et al.
(1949, 1950)
[CH. XVII t
OH
C(C02 Et)2
C02 Et
(i)
hydrolysis
CO
(II)
mesoxalic
y -pyrone
ester
AcOx
\O
C02 Et
tetrahydro-
AcO. O-
<>
follows:
AcOH-Ac 2
AcO O
CO
CH
AgOAo^
N- bromosuccinimide
VSr
OAc
T>
lactol acetate
CO
.CH
AcOH-Ao 2
OAc
patulin
\A,H
patulin
monoacetate
(1-2% yield)
et
al, 1949).
641
CHEMOTHERAPY
9]
These products
may be
l--nitrophenylpropane-l
,NH2
^^\cHOHCH
^GHOHCP
N02 <f
2H 04
'"'"*>
'
>
NQ
N0
^CH
CHoOH
2 OH
^*
Thus chloramphenicol
^ ^>
>CHO+
CHO + CH
CII 2 + NH3
<f
be
will
OmcO'CHCij
CHOH-CH
X CH OH
2
e.g.,
that of
Long
et al.
(1949).
NO,
:
^^
NOg <T
C0 .CH3^
>CO-CH2 -NH2
N0,^3c0-0H B iffSaSU
2
(CH3CO) '>
NH 2
'-*NO^
COsaq.
"\
>COC^
/
\
3
"
[(CM3)aCMO]3A
'
NH-COCHs
-i^NOj,^
*
(ii)CHCI 2 -C0 2 CH 3
>y
no 2 :
>
CH2 OH
^>CIIOHCH
(i) resolved
>CO-CH NH-CO-CH3
N0 2<^
NHCOCH
CH
/MI*
<n
^>CHOHCH
/NHCOCHC1,
_/_
>CHOHCII
^v
CH.OH
( ) -chloramphenicol
H
N02 <^
T-
NHCOCHCl 2
CCH OH
2
OH H
It is interesting to note that
chloramphenicol
is
the
first
natural
compound
is also
most
ORGANIC CHEMISTRY
642
[CH. XVIII
READING REFERENCES
Advanced Organic Chemistry, Wiley. Vol. Ill (1953). (i) Ch. 5. Some
Aspects of Chemotherapy, (ii) Ch. 6. Antibiotics.
Raiziss and Gavron, Organic Arsenical Compounds, Chemical Catalog Co. (1923).
Work and Work, The Basis of Chemotherapy, Oliver and Boyd (1948).
Northey, The Sulphonamides and Allied Compounds, Reinhold (1948).
Northey, Structure and Chemotherapeutic Activities of Sulphanilamide Derivatives,
Chem. Reviews, 1940, 27, 85.
Haynes, Physiologically Active Unsaturated Lactones, Quart. Reviews (Chem. Soc),
Gilman
(Ed.),
1948, 2, 46.
Cook, The Chemistry of the Penicillins, Quart. Reviews (Chem. Soc), 1948,
The Chemistry of Penicillin, Princeton University Press (1949).
Knox, A Survey of New Penicillins, Nature, 1961, 192, 492.
Antibiotics, Oxford Press (2 volumes; 1949).
2, 203.
Brink and Folkers, Some Aspects of Streptomycin and Other Streptomyces Antibiotics,
Advances in Enzymology, Interscience Publishers, 1950, 10, 145.
Birkinshaw, The Chemistry and Biochemistry of Streptomycin and Related Compounds,
/. Pharm. Pharmacol., 1951, 3, 529.
Rebstock el al Chloramphenicol, /. Amer. Chem. Soc, 1949, 71, 2458, 2463.
Long et al.. Chloramphenicol, /. Amer. Chem. Soc, 1949, 71, 2469, 2473.
Brink and Harman, Chemistry of Some Newer Antibiotics, Quart. Reviews (Chem. Soc),
CHAPTER XIX
catalysts (biological) in
many
biological pro-
cesses.
HAEMOGLOBIN
Haemoglobin occurs in all
2. Degradation products of haemoglobin.
vertebrates (with certain exceptions) and in many invertebrates; it has also
been found in certain strains of yeasts, moulds, etc. It is a chromo-protein
and the prosthetic
(7 B. XIII), the protein part being globin (94 per cent.),
group being hsem (6 per cent.). The composition of haemoglobin varies
slightly, depending on the species from which it is isolated; the variation
occurs only in the globin part of the molecule. It is interesting to note
that haemoglobin was the first protein to be obtained in a crystalline form.
The way in which the globin part is bound to haem has been the subject
of much discussion. There appears to be agreement that the iron atom is
bound to some part of the protein. The iron atom (bivalent) in haem uses
four co-ordination valencies in this molecule, and since iron has a coordination number of six, it is believed that it is these two valencies (which
are perpendicular to the other four) that are joined to the globin molecule.
Keilin (1960) has shown that only the basic nitrogen atoms in amino-acids
can combine with haem.
In the animal body, haemoglobin readily combines with oxygen to form
oxyhemoglobin, and this, when treated with glacial acetic acid, forms haematin,
The chloride of haematin is known as haemin its moleC34H3 2 4N 4Feni
cular formula is C34H 3 g0 4N 4Fe Cl (the chlorine is ionised, and the iron atom
Haemin may be prepared by warming blood with
is in the ferric state).
acetic acid and sodium chloride (Teichmann, 1853). The iron can be re-
OH
moved from
643
between an a-aminoketone
ORGANIC CHEMISTRY
644
CH3
C 2H5
CH3
[CH.
CH3
CaH,
2-n-6
XIX
C 2 H6
u
H
opsopyrrole
haemopyrrole
cryptopyrrole
phyllppyrrole
II
III
IV
CH 3
CH3
'CH3
and a ketone containing an active methylene group, i.e., a compound conThe mechanism of the reaction is not
CH a -CO
taining the group
known; possibly the enol forms are involved, and so we may write the
HCR
RCOH
H CR
RCO
,11
II'-
CH
C-R
R-C
C-R"
VNH,
NH,
O'
/
HO'
-C-R"
**1
II
RC.
C-R
2H 2
H
A
detailed study of this reaction has shown that the yields depend on the
nature of R, R', R" and R'" when R' and R" are acyl or carbalkoxyl groups,
the yields are usually very good. As examples of the Knorr synthesis, let
us consider the preparation of ppsopyrrole (I) and cryptopyrrole (III).
Opsopyrrole may be synthesised by condensing aminoacetone with ethyl
2: 4-diketopentanoate, and then subjecting the product to the Wolff-Kishner
reduction, i.e., first converting the product into the hydrazone and then
heating the latter with sodium ethoxide at 160. By this means a ketogroup is converted into a methylene group (see also Vol. I). By using an
excess of sodium ethoxide, decarboxylation is also effected at the same
;
time.
CH 3 CO
COC0 2 C 2H5
CH2
NH 2
HCCOCH
CH3 -COH
CHj-CO-CIIs
CH
C-C0 2C 2 H5
NH
CO-CH 3
CH,
NsH,
/
HO
C(=N-NH2 )-CH3
CH,
C0 2 C2H 5
C0 2 C 2 H5
H
C a HONa
CHo*
CH;3
2 ^"
CH,
160
C02C2H5
C 2 H s ONa
CH2 CH3
CH,
\J
H
opsopyrrole
645
2]
Cryptopyrrole
may
oc-aminoacetoacetate
4-dione).
HCCOCH3
CHvCOH
CH2 C0CH3
CH,CO
C2 HB
OCH
CO-CH 3
\'NH,
NH,
|COCH 3
CH;
OH,
C2H5O2C
.C-CH3
CaHjjOaC-q
(;)
(ii)
n2 h 4
C 2 H s ONa
CH
./
HO'
CH2
at 160
OH3
'CH3
H
cryptopyrrole
When reduced with tin and hydrochloric acid, haemin is again degraded
carboxylic
into four pyrrole derivatives, but in this case the products are all
group
carboxyl
a
contains
pyrroles
I-IV
four
the
acids in which each of
attached to the ethyl group:
CH,
iCH2
CH 2 C0 2 H
CH 2 'CH 2 C0 2H
CH3
CH3
N'
opsopyrrolecarboxylic acid
hseraopyrrolecarboxylic acid
VI
CH<
CH 2 -CH2 C02 H
CH 3
CH,
CH,
CH2 -CH2 00 2 H
'CH 3
'N'
H
cryptopyrroJecarboxylic acid
phyllopyrrole-
carboxylic acid
VIII
VII
When oxidised with chromic acid, haemin gives two molecules of h&matinic
On the other hand, mesoporphyrin (see below) gives, on oxidaacid (IX).
tion,
two molecules
of ethylmethylmaleimide (X).
CH CH 2 C02 H
CH
CH
C2 H 5
O'
hsematinic acid
ethylmethyimaleimide
IX
The treatment of haemin with iron dust and formic acid results in the
removal of the iron atom and the formation of protoporphyrin, C3 4 H 34 4 N 4
The iron atom is also removed from haemin by the action of hydrobromic acid
in acetic acid, but in this case the product is hsematoporphyrin, CaJrlggOgNj.
If, however, haemin is treated with hydriodic acid in acetic acid, the iron
atom is again removed and mesoporphyrin, Cg^jgC^N^ is obtained.
Finally, when porphyrins containing two carboxyl groups are decarboxy.
known
as
ORGANIC CHEMISTRY
646
[CH.
XIX
when protoporphyrin is decarboxylated, and the product then reduced, the final product is setioporphyrin, C 32 3 gN4 , which is
also a degradation product of chlorophyll.
Thus haemin and chlorophyll
aetioporphyrins, e.g.,
Compound
Haemoglobin
Atmospheric oxidation
.
CHj-COjH
CHs-COjH
NaCl
Osopyrrole, Haemopyrrole,
Cryptopyrrole and Phyllopyrrole
Opsopyrrole-, Haemopyrrole-,
Cryptopyrrole- and Phyllopyrrolecarboxylic acids
Haematinic acid
SnHC1
Haemin
Mesoporphyrin
CrO a
CrO s
Haemin
Haemin
Haemin
HBr CH -C0 H
HICHj-COjH
S0 4
S0 4
FeH-CO sH
a
Decarboxylation
(and then reduction,
if
Oxyhaemoglobin
Haematin
Haemin
Haem
Na 2 S a 4
HI + PH 4I
Haemin
Porphyrin
Products
Reaction
Oxyhemoglobin
Oxyhemoglobin
Haemin
Haemin
Ethylmethylmaleimide
Protoporphyrin
Haematoporphyrin
Mesoporphyrin
iEtioporphyrins
necessary)
From the foregoing evidence (the molecular formula and the degradation
products of haemin), it is reasonable to infer that haemin contains four substituted pyrrole nuclei linked together. The isolation of the pyrroles I-IV
suggests that each of the four pyrrole nuclei contains a methyl group in the
(oxidation
The isolation of the oxidation products IX and
/^-position.
at the a-position), and of the reduction products I-VIII (appearance of a
methyl group at the a-position), suggests that the pyrrole nuclei are linked
at the a-positions via one carbon atom. The isolation of two molecules of
IX suggests the presence of two propionic acid residues each in the /J-position
of two pyrrole nuclei (this would also account for the two carboxyl groups
present in haemin). The appearance of ethyl groups in I-IV on the reduction of hsemin could be explained by the presence of two vinyl groups in
the /?-position of two pyrrole nuclei (haemin contains two ethylenic double
bonds). A possible structure for haemin is thus a ring structure containing
four pyrrole nuclei linked at the a-positions via one carbon atom, with
four /^-positions occupied by methyl groups, two ^'-positions by vinyl groups
and the remaining two ^'-positions by propionic acid residues. Ktister (1912)
was the first to propose that the four pyrrole nuclei formed a cyclic structure,
and this has been proved correct by synthetic work; the porphyrins so
obtained had the same absorption spectra as the natural porphyrins. At
the same time, this synthetic work established the nature and the positions
of the substituent groups.
The parent substance of all the compounds mentioned above is porphin
In this
(XI), and this may conveniently be written as XII (H. Fischer).
porphin molecule there is an eighteen-membered ring containing a complete
arrangement of conjugated double bonds. Thus many resonating structures
contribute to this molecule, and consequently its stability will be great; this
is observed in practice, e.g., the molecule has a very large heat of combustion.
Also, the resonance gives rise to the colour in porphin derivatives (see
Ch. XXXI, Vol. I); porphin itself does not occur naturally. It has been
shown, by analogy with the X-ray data on phthalocyanines (9), that the
HAEMOGLOBIN, CHLOROPHYLL
3]
AND PHTHALOCYANINES
647
XII
6
porphin
XI
porphin molecule is planar, and this planar structure is also in agreement
with magnetic measurements.
The artioporphyrins, C32 38N4 are derivatives of porphin in which the
3- and 4-positions of each pyrrole nucleus are substituted by methyl and
ethyl groups. Four isomers are possible, and these are known as setioporphyrin I, II, III and IV, respectively.
CH3C2H5
C 2Hs
CH3
CH3
CH3
C2H5
C 2 H5
C 2 H6
II
CH 3
C 2 Ih
c3HS
"2H5
c)H 3
(3 2
CH3
CH
0,1is
()H3
JH 3
CH3
C2H6
IV
III
C 2H6
C2H6
C2H5
CH 3
CH.
CH3
CHj
C2H6
setioporphyrins
ORGANIC CHEMISTRY
648
CH,
n^"*
fl
JcH
[CH.
XIX
+ Br2
C 2H 5 CH3
CH3
CH3
C2HB
CH3
C2H5
|
CH=
Br
Br
H
H^
,.
BF
According to Corwin
nCH3
C,H
-2 -US'
sn
II
et al.
_2
Br
(1944), the
mechanism
C^ 2a xi
H 5K n
r.CH 3
CH3
Br
C2H 5
CH
CH3
BT
of this reaction
C*HS
CH$
CH2 Br
is:
nCH.,
BKmJMlBr
CH3
CaHs
+ HBr
CH=
Br
Br"
(ii) When pyrroles, in which the 5-position is vacant, are coupled by means
of formic acid in the presence of hydrobromic acid, dipyrrylmethenes are
C 2H6
CH,
n^"3
u
1
et al.,
1922);
e.g.,
C 2H50 2 C
+ H-CO.H-H2V
(
nUH3
UH 3 c=|iqCOAHs
CH,
w
H
Br~
(iii) Piloty et al. (1914) showed that dipyrrylmethanes may be oxidised
to the corresponding methenes by means of bromine, e.g.,
C2H6
rCH 3 CH31
2 C,
CH,
chJ
C0 2 C 2H 5
CH
Br2
H. Fischer et al. (1923) modified the above procedure as follows. A dipyrrylmethane containing carbethoxyl groups was first prepared, this then hydrolysed and then treated with bromine in acetic acid. In this way the methane
3]
649
derivative
|C0 2 C 2
CHji
C 2H6
H _b^
Bri
5
C2 H 5
CH3
iCO^Hs
CH 3 n
boi ]
wate
C\
J0H2 Br
J)
C0 2 C2 H5
CH3 n
C 2H5
C02C2H5
"^C2H 6
CH,OH
C02C 2 H5
CH3
CH,
2
C^
C02C2Hs
:h2
H
+
H O+0H O
C02H
0O2H
CH3
(i)NaOH
(ii)Brj-CH 3
C0 2 H
CH,
-CH=
Br
H^
_
Br
CH,
+ HCN+HC1
(i)
AICU
>
C2 H
w
n6
H
C 2 H5
mo+
\J \J
1
H3
CH-
CHO
CH3
CH,
(ii)
CH 8
'
[|
|= CH
K/- cHj\y CH
CH3H Br> c ^n
>
CH3
H
-r-'+
Br"
ORGANIC CHEMISTRY
650
CH3
Br
riCgHj
CH8
1C2H5
[CH.
succinic acid
XIX
CHaBr
Br
CH3
C 8 H5
CH
C aH s
CH 3
<
CH3
CH=7/
C 2H 5
CH
C 2 HB
CH3
setioporphyrin I
CH,
-CH,
^NH
y
4CH2
/
HN
H
CH2
-CHs
-CH
CH-
H
CH
CH
porphin
It should be noted that the two imino hydrogen atoms are replaced
the iron atom in the hsems, and the iron atom is covalently bound.
by
4]
4.
651
1929).
et al.,
CH,
(i)
CH
OCHll
CH3
JICH3
CH2
Br 2
(ii)
y CHs
CjHsO^C
C02 H
OH2
C02 H
CH 2
QH2
v-Hg
CH3
C2H5
CH
H o cll
H
])
(i)
boil in
CHoBr
NaOH
(ii) Bi-2
-CH3 -CO*H
II
C02 H
C0 2 H
CH2
<J!H 2
CH,2
V"^
CH S
Br
cl|
2
/C0 C2H5
JLcht-II
Br"
CH2 -C02 H
CH
CH,
0H
H
CH 2 C02 H
J>CH
1-CH=L
<1
J
XWJUh=LXN)+
Br
HU
HfBr"
II
CH.
CH-
-CH
CH,
CH,
,...
(ill)
v.
II
succinic acid
...
....
_
*~
180-190
CH,
CH2
I
=CH
CO.
CH,
CH2
CO.H
deuteroporphyrin
ORGANIC CHEMISTRY
652
[CH.
CH3
CH-
ch
CH
Ferrous acetate
K-r.^N
NaCl-HCl-CH 3 -C0 2 H
cr
*CH
C02H
nrr.t=
CH.
CH2
COaH
deuteroheemin
CH3
CH
Jl
C O-CH3
I
CH
CH
CH,
CH,
COCH3
(CHj-COJjO
cr
SnCU
CH2
CO.H
CH2l='CH,
CH 2
C02H
diacetyldeuterohsemin
CH3 COCH3
CH
CH-
CH3
CH,
HBr
CHj-COjH
,N
CH 2
CH2
Nv
COCH3
C02H
CH
CH
CH.
CH,
CH2
I
C0 2 H
diacetyldeuteroporphyrin
XIX
AND PHTHALOCYANINES
HAEMOGLOBIN, CHLOROPHYLL
4]
653
CH3
CH3CHOH
CH-
KOH
CjHjOH
CH
-CH
<
.N
CH
CH2
CH3
CHOHCH3
CO.
=(
rvpCH, fc=
CH
CH*
CH 2
C02H
hjematoporphyrin
CH2
CH3CH
CH
CH-
H
CH,
CI I,
distil at
in
105
,
'
25% HC1
CH,
N.
CH2
C0 2 H
CH=CH
=CH
CH=
CH 2
en.
CH
C02II
protoporphyrin
CH,
CH 2
CH
CH
C1IS
FeCU
CH
N'
|CH,
3
CI"
CH3 -COjH
CH=CH
CH.
'
CH.
COo H
CR=/ \=CH
CH,>='CH 3
CH
I
'
CH,
002H
hsemin
ORGANIC CHEMISTRY
654
[CH.
XIX
It should be noted that the introduction of the iron atom into deuteroporphyrin to give deuterohaemin renders the pyrrole nuclei more reactive.
Bloch et al. (1945), using acetic acid labelled with deutero atoms, showed
that deuterohaemin was produced. Thus at least the methyl carbon of acetic
acid is involved in the biosynthesis of haem. Then Shemin et al. (1950) and
and
Neuberger et al. (1950) carried out experiments with 14 CH 3-C0 2
in
CH 3 14C0 2H, and showed that both carbon atoms of acetate participate
14
the synthesis of haem. The latter authors also showed that with CH 3 -CO aH,
about half of the radioactive tracer atom appeared in the two pyrrole nuclei
carrying the vinyl radicals, and the other half in the two pyrrole nuclei
When, however, CH 3* 14 C0 2 was
carrying the propionic acid residues.
cent, of the tracer atom appeared
per
used as the precursor, then about 20
in the vinyl pyrrole nuclei and 80 per cent, in the propionic acid pyrrole
In neither case of the labelled acetates was there any significant
nuclei.
radioactivity in the methine carbon of the haem. Thus the carbons of the
C02 H
CO,H
CH,
2
2
!
C02 H
CO,H
2
,
<Jh 2
COX
CH 2
COX
s
H
I
"
CH2 C02 H
NH 2
II
pyrrole of the type I was formed first. Also, consideration of the distribution of the radioactivity of the carbon atoms of the propionic acid residue
and the (pyrrole) nuclear carbon to which it was attached led to the suggestion
HAEMOGLOBIN, CHLOROPHYLL
5]
AND PHTHALOCYANINES
655
that succinic acid was a precursor, and that two molecules of this, on condensation with one molecule of glycine, could form the common pyrrole (I).
The tracer distribution of the labelled succinic acid could arise by acetate
entering the Krebs cycle (18. XIII). Two molecules of " active " succinate
CH2 C02 H
I^OH
CH2 -C02 H
COOOoH
CH 2 C02 H
CH3 002 H
I^COjjH
\t
i;
COC02 H
CH 2 -C02 H
C02 + CH -C0 H
2
2
CH 2
+C02
CH 2 -C02 H
C02 H
C02H
CH a
CH
.
NH2-CH2-CO
C02H
CH 2
CH 2
*~
CO
j
CH2
CH2
CH 2
CH
C --^Protoporphyrin
CO.H
NH 2 -CH2
NH 2
ii
Jm
C
^N
porphobilinogen
The problem
has
still
Bile pigments. Several pigments occur in bile, e.g., bilirubin, mesobilirubin, etc. the most important one is bilirubin, CsjHsjOjN^.
On vigorous
5.
ORGANIC CHEMISTRY
656
[CH.
XIX
C02H
C02 H
CH 2
CH2
CH
CH 2
CH2
CH,
>CH 3
i-
CH
>CH3
CH
II
CH2
bilirubin
CHLOROPHYLL
the green colouring matter of leaves
Photoessential for photosynthesis.
synthesis is the process in which light energy is used by plants to synthesise
carbohydrates, proteins and fats. In green plants it is the chlorophyll
which absorbs the light energy.
The name chlorophyll was given to the green pigment in leaves by Pelletier
and Caventou (1818). There the matter rested until 1864, when Stokes
showed, from spectroscopic evidence, that chlorophyll was a mixture. This
paper apparently did not attract much attention, and it was not until Willstatter entered the field that any progress in the chemistry of chlorophyll
6.
Introduction.
Chlorophyll
presence
its
is
is
was made.
When dried leaves are powdered and then digested with ethanol, a
" crystalline " chlorophyll is obtained after concentration of the solvent.
If, however, ether or aqueous acetone is used instead of ethanol, then the
product is " amorphous " chlorophyll (Willstatter et al., 1908). The extraction of chlorophyll is also accompanied by the extraction of two other pigments, carotene and xanthophyll (see Ch. IX). Willstatter et al. (1910)
then showed that " crystalline " chlorophyll was produced during the extraction of chlorophyll by means of ethanol, a molecule of phytyl alcohol
being replaced by ethanol under the influence of an enzyme, chlorophyllase
(which is present in leaves). Nettle leaves are the main source for the
extraction of chlorophyll on a large scale.
6]
657
Willstatter et
C 55H 72
al.
N4Mg,
KO
CO,H
^C H ON 4 Mg^
32
+ C20H40O+ CH sOH
30
CO,H
.CO 2 0H 3
chlorophyllide-a
C32 H 30 ON 4 Mg
C0 2 C2oH39
,CO,CH,
chlorophyll -a
(COiH)s
CjHjOH
/
CsJUOK
COjCajHsg
III
phytyl phseophorbide-a
C0 2H
^^C^HagO.NiMg
+-
CsjoHmO + CH3 OH
C02 H
yC0
II
CH3
CjaHajOjNaMg.
chlorophyllide-i
COoCmHs,
.C0 2 CH 3
chlorophyll-6
C 3 HOH *
C32H3o0 2 N^
CO 2 C20 H39
IV
phytyl phfcophorbide-ft
ORGANIC CHEMISTRY
658
[CH.
XIX
6a. Nomenclature of the chlorophyll degradation products. Porphyrins are substituted porphins (see 2). Phyllins, phyllides and chlorophylls contain magnesium, whereas phorbins, phorbides and phytins are
magnesium-free compounds, the magnesium atom having been removed
and replaced by two hydrogen atoms. 7 8-Dihydroporphin is the nucleus
of the chlorin series of compounds (tricarboxylic derivatives) which are
derived from chlorophyll-a; rhodins are the corresponding compounds derived from chlorophyll-6. The introduction of the extra ring two methylene groups across the 6 /-positions (see 7) gives rise to the phorbins.
The prefix phaeo designates those compounds which have the same substituents that occur in chlorophyll. Chlorin itself is dihydroporphin, and
the natural red porphyrin pigments are derivatives of porphin, whereas
the gfeen chlorophylls and their derivatives are derivatives of chlorin.
(in 7) shows that
Furthermore, examination of formulae XIV and
there is still complete conjugation in chlorin as in porphin (formula XI, 2).
Chlorin has been synthesised by Linstead et al. (1955), and has been dehydrogenated to porphin.
:
XV
7. Structure of chlorophyll-a. When phytyl phseophorbide-a is hydrolysed with boiling methanolic potassium hydroxide (30 seconds), the product
This is a tricarboxylic acid (e.g., it forms a trimethyl ester), and
is chlorin-e.
Chlorin-e,
its molecular formula may thus be written as C 3 iH 33 4 (C0 2 H) 3
on oxidation with chromic acid or with Caro's acid, gives hsematinic acid, I,
and ethylmethylmaleimide,
CH;
nn
H
I
CH3
CaH 5
|
CH3
chJ
H
IV
When
chlorin-e is
C 2Hg
CH31
C 2 H,
"6
CH3'
Ao
A)
CH
II
III
CH
C 2HS
OH,
H
V
reduced with hydriodic acid in acetic acid, hsemopyrrole, III, and phyllopyrrole, IV, are produced (Willstatter et al., 1911). When phylloporphynn
are now III,
(see below) is reduced under the same conditions, the products
that
IV, and cryptopyrrole, V. From these results it is reasonable to infer
chlorophyll-a contains four pyrrole nuclei, each probably having a methyl
group in the /3-position (see II-V). It is also reasonable to suppose that at
the ^'-position
least one pyrrole nucleus contains a propionic acid residue in
in
the molecule
present
is
vinyl
group
a
that
likely
It also appears
(see I).
on reduction; at
(this would account for the presence of an ethyl group
the same time, the presence of an ethyl group, as such, is not excluded).
Furthermore, the isolation of I and II on oxidation (giving oxidation at the
methyl
a-position), and of III and IV on reduction (the appearance of a
group at the a-position), can be interpreted as meaning that the four pyrrole
atom
nuclei are joined to each other at their a-positions via one carbon
one,
cyclic
be
could
a
chlorin-e
structure
for
skeleton
Thus a possible
(cf. 2)
VI; the positions of the various substituent groups cannot be assigned on
acid
the evidence obtained so far, e.g., a methyl group at 1 and a propionic
residue at 2 would produce the same oxidation product I had the positions
.
7]
659
CH3
C2 H5
C 8 H5
CH3
a
V-
CH-
N'
SCH
CH(J
V
VII
Y
8
CH 3 CH 2
CH 2
CH,
C0 2H
VIII
pyrroporphyrin
H N
ORGANIC CHEMISTRY
660
[CH.
XIX
C
C
c
ot
s/
8
-c-
VI
op
C
,tt
sK
Y
-CI
can <**
CO,H C
c
9
C0 2H
IX
?
c
9
c
Aj
/
c
c
C
i
\.
CO
CO 20H 3
C0 2H
XI
7]
group
group
(at
is
When
group
661
is
C02 CH 3
C0 2 CH 3
4
\C0 C2oH
2
+ CgoH^O
C02 H
39
phytyt phasophorbide-o:
phasophorbide-a
When
CH2
OH
OH.,
OHa
O2H
2n5
0H 3
C2H5
^CHS
H
CH
CH
CH
A=c-V^
irrF 0H
CH
2
CH2
yr
X CO
CH.
C02 CH 3
C02H
XII
pliajophorbide-a
CHZ C0 2 CH3
C0 2 C2oH 39
XIII
phytyl phasophorbide-tf
662
ORGANIC CHEMISTRY
XIX
[CH.
former.
this is
XIV.
Chlorophyll-6
Q2H5
<? 2
H'CH,
I
CH 2
CH
N
CO~
C0 2 CH3
|
CH3
COjCaiHsg
XV
chlorophyll -b
The total synthesis of chlorophyll-^ has now been carried out by Woodward et al. (1960) and by Strell et al. (1960). Chlorin-e 8 trimethyl ester was
synthesised, and since this had already been converted into chlorophyll-a,
a total synthesis.
chlorophyll, chlorobium chlorophyll, has been isolated from the
culture Chlorobium thiosulphatofilium (Holt et al., 1960).
this constitutes
new
PHTHALOCYANINES
8. Preparation of the phthalocyanines.
Phthalocyanines are a very
important class of organic dyes and pigments; they are coloured blue to
green. They were discovered by accident at the works of Scottish Dyes Ltd.
in 1928.
It was there observed that some lots of phthalimide, manufactured
by the action of ammonia on molten phthalic anhydride in an iron vessel,
were contaminated with a blue pigment. The structure and method of
formation of this compound were established by Linstead and his co-workers
(1934).
The phthalocyanines form metallic complexes with many metals, and the
colour depends on the nature of the metal (copper, magnesium, lead, etc.)
greener shades are obtained by direct chlorination or bromination. The
8]
663
They
are
made
water-soluble
by
sulphonation,
and these
used as dyes.
Metal phthalocyanines
By
metallic salts.
(iii) By heating phthalic anhydride or phthalimide with urea and a
metallic salt, preferably in the presence of a catalyst such as boric acid.
Phthalocyanine, I, the parent substance of this group, may be prepared
by heating phthalonitrile with a little triethanolamine. It can be seen
from formula I that phthalocyanine contains four woindole nuclei Joined in
a ring by means of nitrogen atoms. If we ignore the benzene nuclei, then
we have four pyrrole nuclei linked by nitrogen atoms, a structure similar
II
porphin
phthalocyanine
to the porphyrins, in which the pyrrole nuclei are linked by methyne groups
(II is porphin; cf. 2).
Both types of compounds are coloured, and both
contain two imino hydrogen atoms which can be replaced to form metal
complexes. Because of these similarities the phthalocyanines are often
known as the tetra-azaporphyrins. The first commercial phthalocyanine
is
copper phthalocyanine
BS
(III).
664
ORGANIC CHEMISTRY
[CH.
XIX
that in the
CO-NH 2
CO-NHo
0CH CN
2
CH2 -CN
VI
formation of phthalocyanines, the two nitrile groups involved must be in
the o^Ao-position. Thus there are probably four C g 4N 2 units, each having
an isoindole structure, VII, or a phthalazine structure, VIII. VIII was
N
VIII
VII
This suggests that in metal phthalocyanines, the metal has replaced two
imino hydrogen atoms. A reasonable structure for phthalocyanine is one
in which the four woindole units are joined through nitrogen atoms to form
9]
665
HN H
It seems unlikely
in this case the molecular formula would be (C 8 4 2 ) 4 4
that
could be rejected on these grounds alone, since in a large molecule
of this type it appears to be difficult to estimate the hydrogen with certainty
3-9 per cent.).
(IX contains approximately 3-5 per cent, hydrogen, and
X, however, is unlikely, since phthalocyanine is a very stable substance;
the presence of an imino group at the end of the molecule could be expected
Furthermore, the
to render the compound unstable to, e.g., acid reagents.
oxidation of phthalocyanine with eerie sulphate in dilute sulphuric acid
proceeds according to the following equation (over 90 per cent, of the
.
H 4N 4H +
(C 8
2)
7H 2
[O]
- 4C H
8
N + 4NH
This agrees with IX, but had the structure been X, then the molecule would
have required two atoms of oxygen.
H4N H4 + 6H
(C 8
2) 4
2[0]
- 4C H
8
N + 4NH 3
chemical evidence.
READING REFERENCES
Stewart and Graham, Recent Advances in Organic Chemistry, Longmans, Green. Vol. Ill
Some Natural Porphyrins and Related Compounds,
(i) Ch. 5.
(1948, 7th ed.).
The Azaporphyrins.
(ii) Ch. 6.
666
ORGANIC CHEMISTRY
[CH.
XIX
Phthalocyanines.
(i) Linstead et al., J.C.S., 1934, 1016; 1936, 1745.
(ii) Robertson, J.C.S., 1935, 615; 1936, 1195; 1937, 219; 1940, 36.
(iii) Dahlen, Ind. Eng. Chem., 1939, 31, 839.
Elderfield (Ed.), Heterocyclic Compounds, Wiley. Vol. I (1950).
Ch. 6. Chemistry
of Pyrrole and its Derivatives.
Fischer and Orth, Die Chemie des Pyrrols, Leipzig. Vol. II (Part I, 1937; Part II, 1940).
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd ed.). (i) Ch. 16. The
Chemistry of the Porphyrins, (ii) Ch. 17. Chlorophyll.
Lemberg and Legge, Hasmatin Compounds and Bile Pigments, Interscience Publishers
(1949).
(Ed.), Chemistry of
Rodd
Vol.
IVB
(1959).
Ch. XIII.
Interscience (1960).
Maitland, Biogenetic Origin of the Pyrrole Pigments, Quart. Reviews (Chem. Soc), 1950,
4, 45.
INDEX OF AUTHORS
Names associated with reactions, syntheses, etc., are not listed here
cribed in the Subject Index.
Aaron, 162
Abderhalden, 473
Adams, A., 433
Bastiansen, 139
Batchelor, 637
Bateman, 250
Adams,
Battersby, 541
Bauer, 565
Baxter, 330
Beckett, 55, 515
Beckmann, 149
Bednarczyk, 182
Beets, 602
Beevers, 216
Akabori, 475
Albertson, 53, 451
Alder, 259, 288
Aldrich, 493
Aldridge, 588
Alexander, 24
Allinger, 110, 113, 124
Almquist, 624
Altaian, 654
Ambrose, 469
Amos, 588
Andersag, 602
Anderson, 472, 595
Andriani, 49
Anet, 496, 542
Angell, 589
Angier, 610, 611
Angyal, 111
Anner, 400
Arago, 21
Archer, 516
Arens, 249
Armstrong, 184
Arshid, 8
Arth, 268
Asai, 476
Aschan, 279
Aston, 109
Attenberg, 266
Attenburrow, 334
Austin, 75
Auwers, von, 93, 94, 380
Averill, 231
Bentley, 637
Bergkvist, 78
Bernhauer, 619
Bernstein, 27, 107
Beyerman, 473
Bide, 536
Bijvoet, 32
Binkley, 624, 626
Biot, 8
Birch, 271
Birkinshaw, 639
Bischoff, 145
Bishop, C. T., 188
Bishop, G., 152
Black, 270
Blicke, 510
Bloch, 389, 390, 654
Blomquist, 132
Blout, 469
Boeseken, 141, 185
Babo, 503
Bachmann,
Backer, 141
Badger, 148
Baeyer, von, 266, 272, 273, 275, 571, 573
Bahadur, 482
Bailey, 54, 349
Bain, 151, 160
Baker, 55, 435, 436
Balbiano, 421
Bamberger, 156
Banholzer, 492
Barber, 127
Barbier, 248
Barger, 492
Barker, E. F., 148, 594
Barker, G. R., 198, 202
Barnard, 250
Boissonas, 474
Booker, 245
Bornwater, 571
Bose, 515
Bothner-By, 82
Bouveault, 248, 254
Bradley, 54
Brady, 150, 152
Braithwaite, 322
Braude, 386
Braun, 85
Braun, von, 487
Bredereck, 428, 584
Bredt, 279, 281
Brenner, 470
Bretschneider, 508
Briggs, 303
Brigl, 216
667
668
INDEX OF AUTHORS
Brink, 638
Crowley, 278
Brockman, 387
Brockway, 139
Curtin, 94
D
Dakin, 444, 457, 460, 493
Dalgliesh, 494, 495
Dam, 623
Dane, 358, 360
Darmon, 468
Dauben, H.
Dauben, W.
J., (Jun.),
G., 372,
61
405
Davies, 162
Davis, B. D., 481
Davis, E. F 592
Davis, T. L., 85
Dawson, 543
Debye, 2, 11
Delahay, 182
Dewar, 422
Dhar, 139
Buser, 387
Dimroth, 383
Djerassi, 379
Dodds, 408
Cahn, 35
Drew, 192
Drumm, 423
Dubrunfaut, 181
Dufraisse, 348
Casanova, 55
Cavalieri, 575
Caventou, 656
Celmer, 140
Challenger, 174
Chapman, 157
Chargaff, 595
Chatt, 165, 167
Chatterjee, 490
Chavanne, 100
Christie, 126
Clar, 348, 349
Claridge, 637
Clarke, 599
Cleeton, 148
Clemo, 24, 551
Close, 438
Clusius, 575
Cohen, 167
Cohn, 592, 593, 596
Cole, 268
Cook, 349, 350, 367, 398, 399, 400, 404,
405
Cornforth, 378, 389, 390
Corwin, 648
Cotton 85
Coulson, 11, 26, 134
Cox, 198
Crabbe, 390
Craig, 509
Cram, 84, 102, 132, 142
Crawford, 130
Cresswell, 608
Cristol, 100, 103, 116
Crowfoot, D. C, 386, 408, 409
Dunitz, 641
Dunlop, 145
Dunn, 588
Dvoretzky, 425
Eaborn, 174
Earl, 434, 435, 436
Eascott, 612
Easty, 54
Edman, 475
Emiich, G., 470
Ehrlich, P., 627, 631
Eijkman, 598
Eiland, 198
Einhorn, 519
Eisenlohr, 79, 119
Ekenstein, 184
Eliel, 24, 122, 268
Elisberg, 398
Elliott, A., 469
Elliott, K. A. C, 54,
Elming, 514
Elving, 124
Emden, 593
Erlenmeyer, 24
Eschenmoser, 299
Ettinger, 240
Evans, 235
Everest, 552
Falk, 655
Faraday, 10
Faulkner, 182
Fear, 187
Ferguson, 135
130
358
INDEX OF AUTHORS
Fernholz, 382, 388, 620, 621, 626
Ferreira, 55, 85
Fieser, 347, 350, 367, 387, 392, 624
Finar, 423, 425, 426, 427, 455
Findlay, 519
Fischer, E., 25, 30, 31, 32, 69, 96, 178, 184,
187, 190, 234, 235, 442, 443,
471, 473, 567, 569, 572, 573,
576, 577, 578, 579, 580, 581,
Fischer, F., 308
Fischer, H., 646, 647, 648, 649,
660, 662
Fisher, 258
Fittig,
572
457, 468,
574, 575,
583, 584
651, 659,
669
Hartung, 455
Harvey, 164
Hass, 54
Flavitzky, 275
Fleming, 632
Fleury, 216
Fodor, 515, 517, 519
Folkers, 617, 618, 638
Hatt, 162
Havinga, 385
Hawkins, 208
Haworth, R. D., 310, 312, 402
Haworth,
Fonken, 360
Fowden, 427
Frankel, 471
Hayes, 687
Hazato, 364
Head, 228
Heard, 158
Fraser, 469
Fredga, 50
Fresnel, 56, 57
Freudenberg, 9, 490
Friedmann, 493
Frolich, 209
Fulmer, 612
Funk, 598
Furberg, 589, 592
Heggie, 85
Heilbron, 330, 384, 385, 389
Heifer, 120
Helferich. 236
Hems, 464
Henderson, 54
Henecka, 270
Henriques, 136, 149
Heppel, 694
Herzig, 564
Hess, 496
Hesse, 537
Hibbert, 227
Higuchi, 482
Hill, 156, 159, 183
Hinshelwood, 66
Hirs, 469
Gadamer, 240
Gafner, 135
Galat, 460
Gallagher, 366
Gams, 536
Gates, 541
Geissman, 545
Gierer, 595
Gillam, 298
Girard, 405, 407
Glynn, 147
Gold, 62
Hofmann, 501
Hofmeister, 468
Goidschmiedt, 533
Goodwin, 608
Goto, 182
Graebe, 6
Granick, 662
Green, 162
Greenberg, 586
Grewe, 602
Grignard, 250
Griins, 598
Hunter, 3
Hurd, 200
H
Haller, 283
Hammett, 69
Hanby, 145
Iffland, 129
Ingold, 24, 35, 47, 48, 60, 61, 62, 66, 67,
68, 69, 71, 72, 73, 74, 75, 103, 242, 243
INDEX OF AUTHORS
670
Ingram, 133
Inhoffen, 326, 385
Irvine, 225, 239, 240
203
Isensee, 449
Isbell,
Ives,
337
24
Kraemer, 228
Kraft, 312
Krause, 159
Krebs, 480
Krfiger, 251
Kuehl, 638
Kuhara, 157
Kuhn, L. P., 15
Kuhn, R., 321,
Jackman, 81
Jahns, 499
Jamison, 53, 55
Jansen, 141
Jensen, 112
John, 619, 621, 622
85, 91
Kuster, 646
Kwart, 285
Jowett, 493
K
Kaczkowski, 543
Kamai, 164
Karabatsos, 160
Karagounis, 65
Kargl, 330
Karrer, 171, 172, 309, 313, 322, 323, 324,
327, 328, 329, 330, 337, 808, 547, 605,
606, 621, 623
Kaufler, 126
Keesom, 2, 5
Kegel, 623
Keilin, 643
Kekule, 22
Kelham, 131
Kendall, 415, 462
Kenner, 126
Kenyon,
Kerr, 276
Kerschbaum, 296
Kharasch, 409
Kimball, 76, 98, 168
Kincaid, 136, 149
King, H., 358, 360
King, H. G. C, 565
Kipping, 147, 162, 173, 174
Kistiakowsky, 104
Kleinert, 226
Klement, 167
Klotz, 273
Knights, 253
Knopf, 85
Knorr, 235, 422, 423, 424, 426, 538, 643
Koepli, 419
Kogl, 418, 419, 612, 613
Kohler, 140, 154
Komppa, 282, 283, 286, 287
Kon, 270, 358, 363
K6nigs, 235, 484, 523, 524
Kopp, 4, 5
Kornberg, 596
Komblum, 129
Lander, 140
Lapworth, 140
Laqueur, 396
Le Bel, 21, 144
Lee, 484
Leeds, 403
Leete, 542, 543
Le Fevre, 109, 126, 127, 161, 436
Lemieux, 216, 217
Lesslie, 128, 166
Lcuclis 54
Levene, 589, 590, 592, 594, 595
Levy, 24
Lewinsohn, 174
Lewis, 516
Lichtenstadt, 150
Liddle, 442, 443
Liebermann, 336
Liebig, 569, 570
Lindlar, 332
Lindsay, 354
Linstead, 117, 658, 662, 664
Lipp, 288
Littlefield, 588, 589
LSfgren, 576
Lohmann, 603
Londergan, 600
London, 2
Long, 641
Lorentz, 7
Lorenz, 7
Loring, 593
Lowry, 175, 182, 183
Lucas, 76
LukeS, 496
Luttringhaus, 132
Lynen, 315, 316
Lythgoe, 591
M
McArthur, 619
Macbeth, 113, 238
McCasland, 39, 146
McDonald, 198
McElvain, 500
McEwen, 162
McFadden, 233
McGilvray, 228
671
INDEX OF AUTHORS
McKee,
Nodder, 141
McKenzie, 55, 81
Mackenzie, 510
Noller, 362
Macleod, 6
McNutt, 607
McQuillin, 306
Magat, 64
Maitland, 139
Malaguti, 279
Malaprade, 198
Mamoli, 397
Manasse, 268
Norymberski, 398
Mann,
Normant, 254
O
Oeda, 52
Ogawa, 52
Oliver, 250
Olivier, 68
Mannich, 543
Manske, 490
Manson 592
Marckwald, 55, 79
Marion, 543
Markakis, 652
Marker, 405, 412
Marrian, 401, 414
Marsh, 285
Martin, 457
Matthiessen, 537
Medicus, 572
Meerwein, 288
Oppenauer, 397
Orgel, 423
Or6, 482
Oroshnik, 334
Ostwald, 1
Ott, 493
Otvos, 284
Overend, 183
Parikh, 458
Park, 316
Pascu, 182
Pasteur, 22, 61, 52
Paterno, 22
Pauling, 29, 469
Meier, 79
Mingoia, 491
Mirza, 515
Mislow, 50, 129,130
Mitchell, 85
Mizushima, 28
Modi, 322
Mohr, 116
Momber, 31
Montgomery, 230
Morton, 335
Mosher, 82
Motl, 303
Moureu, 424
Mulder, 465
Mumford, 6
Musher, 94, 120
N
Nagai, 494
Nakamiya, 322
Neagi, 145
Nerdel, 53
Neuberger, 654
Nevell, 290
Newman,
Quilico, 244
INDEX OF AUTHORS
672
Raper, 164
Rapoport, 544
Rappoldt, 385
Read, 268
Rebstock, 640, 641
Reeves, 201, 202
Reichstein, 415, 417
Reid, 81
Richter, 579
Ried, 135
Riniker, 378
Roberts, 76, 98, 149
Robertson, A., 236
Robertson, G. B., 162
Robertson, J. M., 135, 354, 664, 665
Robeson, 334
Robinson, 371, 389, 400, 513, 514, 540,
541, 545, 548, 549,
555, 556, 557, 563
Roeder, 442, 443
551,
552,
554,
Rolinson, 637
Roosen, 573
Roozeboom, 49
Rosanoff, 31
Roth, 323
Rothemund, 650
Ruber, 185
Rupe, 265
Ruzicka, 245, 252, 254, 277, 294, 296,
297, 298, 300,
307, 309, 312,
395, 397
Rydon, 145, 312
301,
313,
Schimmel, 270
Schlack, 474
Schlenk, 55
Schmid, 172
Schmidt, E 226
Schmidt, G. M. J., 134
Schmidt, J., 126
Schmidt. O. T 130
Scboch, 229
Schofield, 445
Scholl, 354
Schopf, 314, 514, 544
Schreiber, 392
303,
372,
304,
380,
305,
389,
Schuetz, 380
Schultz, 126
Schulz, 228, 318
Steenbock, 384
Steinberg, 482
Stephen, 158, 159
Stern, F., 58
Stern, M. H., 606, 623
Stevens, 472
Stiller, 608, 609
Stokes, 656
Stolz, 493
Streitwieser,
24
662
Sugden, 6
Sutter, 142
Sutton, 7, 436
Swain, 183
Swart, 62
Strell,
Symons,
60, 61
Szent-GiSrgi, 209
Takamine, 493
Tanret, 181
INDEX OF AUTHORS
Tavormina, 315, 389
Taylor, E. C, 499
Taylor, W. I., 303
Teichmann, 643
Theimer, 252
Thorpe, 273, 282
Tiemann, 247, 248, 251, 254, 260
Tipson, 570
Tishler, 333, 451
Tobie, 183
Traub, 615
Traube, 574, 578, 580
Trebst, 233
Treibs, 659
Tschesche, 368
Tschugaeff, 10
Tuli, 7
Tulinsky, 135
Turner, E. E., 53, 55, 81, 126, 127, 128,
134, 164, 166
Turner, R. B., 110
U
Underhill, 566
Wendler, 625
Werner, 95, 136, 145, 149, 152
Wessely, 566
West, 571
Westall, 655
Westheimer, 136
Weston, 169
Westphal, 372
Weygand, 472
Whalley, 99
Wheeler, H. L., 442, 443
Wheeler, T. S., 560, 562
Whiffen, 202
Whitfield, 596
Whitmore, 288
Whittaker, 441
Whitworth, 141
Wibaut, 502
Wiberg, 99
Wicker, 380
Wieland, 149, 358, 359, 360, 361, 367,
369
Wijkman, 142
Wildiers, 612
Wilkins, 595
Wilkinson, 536
Williams, R. J., 608, 610
Williams, R. R., 599, 600, 601, 602
Willstatter, 119, 308, 321, 495, 511, 518,
519, 545, 546, 548, 564, 656, 657,
673
139
Veldestra, 419
Velluz, 385, 404
Verley, 247
Verwoerd, 596
Vesterberg, 309, 345
Vignau, 454
du Vigneaud, 612, 613, 614
Vocke, 311
Vogel 460
Vogt, 259
Vongerichten, 538, 539
658
Wilson, 319
Wohmann, 599
Wolf, 316
Wolff, 444
Wood, 510
Wackenroder, 321
Wagner, 257, 274, 286, 287, 288
Woods, 629
Woodward,
Waksman, 637
Walden, 69
Wallach, 242, 256, 257, 265, 266, 269,
274, 293, 295
Walz, 565
Warren, 145
Watson, 595
Wechsler, 140
Weisblat, 472
Zemplen, 221
Zenitz, 515
Ziegler, 266
Zimmermann, 126
INDEX OF SUBJECTS
Names beginning with the prefixes cyclo and iso are listed under C and I, respectively.
Salts of acids are listed under the parent acid, acetates of sugars under the parent sugar,
and essential oils under Oil. Many ethyl esters are listed as acid esters. Deuterocompounds are listed under Deuterium compounds. Name reactions which have been
used in the text are listed in this index. Page numbers printed in bold type are the
more important references, and substituted derivatives have often been listed under
the parent compound by numbers in italics
more important substituted derivatives
have been listed separately.
;
Addition
double
bonds,
stereoto
chemistry of, 96-99, 363-364, 379-380
Additive properties, 1, 5, 6, 7, 9, 10
Adenine, 577-579, 588, 589, 593, 595
Adenosine, 589-592, 594
Adenylic acid, 589, 593
Adermin, see Pyridoxin
Adrenaline, 493-494
Adrenosterone, 415
miobilianic acid, 366, 367, 371
661
Infra-red, 3, 13-15, 30, 94, 114, 147,
148, 202, 245, 250, 268, 318, 468, 469,
470, 476, 515, 593, 635
Raman,
16, 94,
Ultraviolet
245
and
Albumins, 466
Aldoses, 176-180, 181-184
Aldoximes, stereochemistry of, 149-153
Alginic acid, 232
Alizarin, 236
Alkaloids, 52, 55,
Acetochlororibofuranose, 592
Acetolysis, 225
derivatives
Acetophenone,
Alloxazines, 448
Allylbenzylmethylphenylammonium
iodide, 144
424
3-Acetyl-5:9-dimethyldecalin, 306
iV-Acetylglucosamine, 232
l-Acetyl-2-hydroxynaphthalene-3carboxylic acid, 155
y-Acetyl-a-Mopropylbutyric acid, 270
iV-Acetyl-Ar-methyl-^)-toluidine-3sulphonic acid, 131
Acetylthiohydantoin, 456
Acorone, 307
Acraldehyde, 425, 499
Acridines, 630
ACTH, 415
Activators (enzyme), 479
484-544
Allantoin, 570-572
Allenes, stereochemistry of, 139-140
Alio- series in amino-acids, 459
in steroids, 377
^Wocholanic acid, 360, 390, 391
Aluminium
2-butoxide,
see
Oppenauer
oxidation
Amidines, 441
see also
Acetamidine and
Formamidine
Amine oxides,
stereochemistry
Amino-acids, 53, 449-465, 467
of,
146-147
674
INDEX OF SUBJECTS
6-Aminopenicillanic acid, 637
o-Aminophenol, 431, 433, 466
l-Aminopropan-2-ol, 618
a-Amino-/J-l-pyrazolylpropionic acid, 427
o-Aminothiophenol, 432
5-Aminouracil, 573
Amphetamine, see Benzedrine
Amygdalin, 237-238
Amylase, 228, 230, 231, 477, 479
Amylopectin, 230-231
a-Amylose, 229-230
/J-Amylose, see Amylopectin
Anaesthetics, 520
Anchimeric assistance, 74
Androgens, 395-398
see also individuals
Androstenedione, 398
Androsterone, 395-396
Aneurin, see Vitamin B t
Angelic acid, 135
Anhaline, see Hordenine
Anhydro-sugars, 206, 208
Anomers, 183, 185, 187
Anthocyanidins, 545-557
Anthocyanins, 545-557
Anthoxanthins, see Flavones
Anthracene, 339, 340, 341
Antibiotics, 140, 632-641
Anti-compounds, 151
Antimony compounds, stereochemistry
of, 169
Antipyrine, 426
Apocadalene, 304
Apocamphoric acid, 286, 293
Apoenzyme, 477
Apomorphine, 538
Arabinose, 177-179, 182, 192-193, 200,
232
Arabinotrimethoxyglutaric acid, 193, 194
Arbutin, 238
Arecaidine, 499-500
Arecoline, 499
Arginine, 452, 467, 478
Arndt-Eistert synthesis, 401, 417, 492, 550
Arrhenius equation, 64
Arsanilic acid, 632
Arsanthren, 167
Arsenicals (in medicine), 631-632
Arsenic compounds, stereochemistry of,
163-169
Arsphenamine, 631
Ascaridole, 266
Ascorbic acid, 208-214
Asparagine, 453
Aspartic acid, 52, 453
Association, 2,4, 5, 9, 12, 14, 15, 16
As-spiro-bis- 1:2: 3: 4-tetrahydroiso
arsinolinium bromide, 165
Asymmetric carbon atom, 23, 30, 31, 32,
40, 41, 141, 142, 261, 263
Asymmetric decomposition 85
Asymmetric solvent action, 54
Asymmetric synthesis, absolute, 85
partial,
79-85
675
Atoxyl, 632
Atrolactic acid, 46, 81, 82-83, 510
3:4-Benzophenanthrene, 134
Benzopyrylium
chloride,
545
^-Benzoquinone, 6
Benzothiazole, 432-433
Benzotriazole, 434
Benzoxazoles, 431
Benzoylacetone, 423
3-a-Benzoylacetyl-l 5-diphenylpyrazole, 423
Benzoylecgonine, 517, 518
Benzoylformic acid, 81, 82-83, 154
Benzoylglycine, see Hippuric acid
3:4-Benzpyrene, 350
Benzyl chloride (hydrolysis of), 68
Benzyl chloroformate, 471
:
Benzylethylmethylphenylammonium
iodide, 144
INDEX OF SUBJECTS
676
Bilirubin, 655
Calciferyl-4-iodo-3-nitrobenzoate, 386
Camphane, 279, 285
Bimolecular mechanism, 60
Bios, 612
Biosynthesis, 314-315
alkaloids, 541-544
amino-acids and proteins, 480-482
carbohydrates, 232-233
porphyrin, 654-655
purines, 586
sterols, 315, 389-390
terpenes, 315-317
Biotins, 612-615
a-Biotin, 612
fl-Biotin, 612-615
Bisabolene, 297
Bisnorcholanic acid, 366
Biuret reaction, 462
Bixin, 336
Bixindialdehyde, 328
Blanc's rule, 361, 367
Boat-axial bonds, 111
Boat-equatorial bonds, 111
Bond lengths,
Bromofumaric
acid, 98
4-Bromogentisic acid decamethylene
ether, 132
jS-Bromolactic acid, 34
a-Bromo-0-methylvaleric acid, 41-42
2-Bromo-5-nitroacetophenone, 154
a-BromopropioniC acid, 40, 71, 74-75
Bromosuccinic acid, 87
1-Bromotriptycene, 65
Biicherer hydantoin synthesis, 456
Buna rubber, 319
Buna rubbers, 319
Buna S rubbers, 319
M-Butane, 28, 110
Butan-2-ol, 82
Butenes, 101
sec-Butyl bromide, 55, 56
4-2.-Butyk;ycfohexyl tosylate, 122
teri.-Butyl -hexyl ketone, 81
5-Butylmercuric bromide, 24
Calciferol,
384-386
Camphene, 285-288
Camphenic acid, 286, 288
Camphenilone, 286, 287
Camphenylic acid, 286
Campholide, 283
Camphor, 49, 55, 82, 279-284, 285
Camphoric acid, 279-281, 282, 287
Camphoronic acid, 280-281, 282
Camphoroxime, 50
Camphorsulphonic acids, 52, 85, 140, 170,
284
Carboxyapocamphoric
acid, 285
2-o-Carboxybenzyl-l-indanone, 47
Carboxymethylethylmethylsulphonium
bromide, 169
Carboxymethylmethylphenylselenonium bromide, 174
9--Carboxyphenyl-2-methoxy-9arsafluorene, 166
2--Carboxyphenyl-5-methyl-l 3-dithia2-arsaindane, 166
^-Carboxyphenylmethylethylarsine
sulphide, 164
Carcinogenic hydrocarbons, 349, 350
Car-3-ene, 266, 272
Car-4-ene, 266, 272
Carene epoxide, 272
Carone, 272-273
Caronic acid, 273
Caro's acid (permonosulphuric acid), 97,
99, 658
Carotenes, 321-330
a-Carotene, 321, 322, 327, 330
0-Carotene, 321-327, 329-330
y-Carotene, 322, 330
Carotenoids, 321-338
jS-Carotenone, 324
Carr-Price reaction, 321, 330
Carvacrol, 259, 281
:
Carvotanacetone, 261
Carvoxime, 49, 262
Caryophyllene, 306-307
Cellobiose, 201, 221, 225
Cellotriose, 224, 225
Cellulose, 16, 224-228
Centre of symmetry, 37-38
INDEX OF SUBJECTS
677
Channel complex, 55
Chemotherapy, 627-641
Chenodeoxycholic acid, 391
Chitin, 232
Chitosamine, see Glucosamine
Chloramine T, 172
Chloramphenicol, 640-641
Cinnamic
Citraconic acid, 91
Citral, 247-251, 252
1-Chloroapocamphane, 65
Chlorobutane, 24
Chlorocaffeine, 581-582, 583
Chlorocrotonic acids, 92
Chlorocycfohexane, 111, 123
Chlorocyc/ohexanones, 124
a-Chloroethylbenzene, 47-48
Chloromethylation, 425, 426, 536
Chloromycetin, see Chloramphenicol
2-Chloro-5-nitrobenzaldoxim.es, 152
2-Chloro-octane, 55
2--Chlorophenacyl-2-phenyl- 1:2:3:4tetrahydroiso-arsinolinium bromide,
164
Chlorophylls, 321, 467, 646, 656-662
Chlorophyll-a, 657-662
Chlorophyll-6, 657, 658, 662
Chlorophyllase, 656
Chlorophyllide-a, 657-658, 659
Chlorophyllide-6, 657-658
Chloroprene, 320
Chloroquine, 631
Chlorosuccinic acid, 69
Chlorosulphinates, 73-74
Chlorotheophylline, 585
3-Chloro-l:3:3-triphenylprop-l-yne, 348
Cholanic acid, 360, 366, 367, 390, 392
Cholestanedione, 362
Cholestanetriol, 362, 363-364
Cholestanol, 359, 360, 363, 372, 378, 379,
380, 381, 383, 391, 395
Cholestanone, 360, 361, 363, 379, 391
Cholestenone, 362, 380, 392
Cholesterol, 315, 359-376, 379, 380, 387,
389, 391, 392, 397, 411
Cholic acid, 391, 394
Choline, 619
Chromans, 621
Chromatography, 54, 55, 149, 188, 214,
227, 228, 233, 322, 366, 457, 476, 482,
545, 595, 619, 657
Chromoproteins, 464, 643
Chrysene, 351-352, 358, 360, 369, 398
Chrysin, 559
Cinchene, 523
Cincholoipon, 525
Cincholoiponic acid, 524-526
Cinnamaldoxime, 156
Cinnolines, 445
Circular dichroism, 85
Cis-addition, 96-99
Cisoid conformation, 27
Cis-trans isomerism, see Geometrical iso-
merism
Citral-a, 250
Citral-b, 250
Citric acid cycle, see
Citronellal, 254
Citronellic acid, 254
Citronellol, 255
Krebs cycle
Clemmensen reduction,
Cocaine, 517-520
^-Cocaine, 519
Co-carboxylase, 603
Codehydrogenase
Codeine, 537-541
and
II,
617
Colophony, 309
Compensation, external, 40, 57-58
internal, 42, 57-58
Configuration, 11, 17, 20, 29, 32, 41, 70-71,
91, 185-187
absolute, 17, 32, 130, 140, 510, 520
correlation of, 34-37, 50, 55, 70, 82,
292, 378, 379, 458
specification of, 35-37
1, 6, 7,
10
of,
678
INDEX OF SUBJECTS
Corticosterone, 416
Cortisone, 417-418
564
Cyanin, 551, 552-553
Cyanoacetic ester, see Ethyl cyanoacetate
Cyanocobalamin, see Vitamin B l2
Cyc/obutane derivatives, stereochemistry
of, 107-108, 276
Oyc7odecane-l:6-dione, 307
Oyc/oheptatriene, see Tropilidene
Cycloh.exa.ne, 109-112, 345
Gyc/ohexane-l-carboxyl-2-propionic acid,
118
Cycldhexaxie derivatives, stereochemistry
of, 100, 103, 109-116, 121-124
CyeZohexane-l:2-diacetic acid, 118
C;)/Zohexanone-4-carboxylic acid, oxime
of, 151
Cyc/opentane derivatives, stereochemistry
of, 108-109, 283, 371
287
Cysteine, 432, 450, 452, 633
Cystine, 450, 452, 466, 468, 614
Cytidine, 589, 592
Cytidylic acid, 589, 593
Cytochrome, 479
Cytosine, 443-444, 588, 589, 595
D
Daidzein, 565, 566
Debye
forces, 2
Decahydroisoquinolines, 119
1 1 -Dehydrocorticosterone, 416
Dehydrodeoxycholic acid, 370
Dehydroepiandrosterone, 396, 397, 411
Dehydrogenases, 477, 479, 480
Dehydrogenation (with metals), 307, 311,
342, 344, 345-347, 357, 536
see also Selenium and Sulphur dehydrogenation
Dehydrolithocholic acid, 393
Dehydronorcholene, 367
Delphinidin chloride, 545, 546, 555
Delphinin, 555
Denaturation, 465, 467
Dendrolasin, 244
Deoxybilianic acid, 370
Deoxycholic acid, 367, 370, 391
11-Deoxycorticosterone, 416
1 1-Deoxy-l 7-hydroxycorticosterone, 416
Deoxyribonucleic acids (D.N. A.), 587,
595-596
Deuterium compounds, 24
Deuterohsemin, 652
Deuteroporphyrin, 651
Dextrin, 231
Dextrose, see Glucose
<o:4-Diacetoxyacetophenone, 549, 554
Dialuric acid, 440, 570
Diamagnetism, 13
2:2'-Diamino-6:6'-dimethyldiphenyl,
127,
138
4:5-Diaminouracil, 574
Dianthronylidene, 134
Diastase, 228, 229
Diastereoisomers, 20, 41, 80
Diazines, 437-445
Diazoacetic ester, 278, 424, 426, 662
Diazoates, 160
Diazocyanides, 160
Diazoketones, see Arndt-Eistert synthesis
Diazomethane, 187, 210, 366, 401, 404,
417, 421, 427, 522, 550, 590, 615, 634
Diazosulphonates, 160
1:2:5:6-Dibenzanthracene, 349
2:3-Dibromobutane, 76, 101
a:^-Dibromobutyric acid, 40
Dibromocotinine, 506-507
Dibromofumaric acid, 96
Dibromomaleic acid, 96
2:4-Dibromo-2-methylbutane, 248
a:a'-Dibromosuccinic acid, 97
Dibromoticonine, 506-507
Dichloroadenihe, 592
6:6'-Dichlorodiphenic acid, 127
4:4'-Dichlorodiphenyl, 127
l:2-Dichloroethane, see Ethylene chloride
2: 6-Dichloro-3-nitrobenzaldoxime, 153
2:4-Dichloropyrimidine, 440
Dieckmann reaction, 278, 282, 500
Dielectric constant, 2, 67
Diels-Alder reaction, 99, 259, 288, 299,
312, 313, 322, 356, 371, 383
Diels' hydrocarbon, 358, 360, 367, 369, 412
2:2'-Difluoro-6:6'-dimethoxydiphenyl3:3'-dicarboxylic acid, 136
2:2'-Difluoro-6:6'-dinitrodiphenyl, 137
6:6'-Difluorodiphenic acid, 137
Digitonin, 359, 412
679
INDEX OF SUBJECTS
Diosgenin, 412
Dipentene, see Limonene
Diphenic acid, 128
Diphenyl, 16, 126, 139, 339
Diphenyl compounds, stereochemistry
126-139
Diphenyl-2:2'-disulphonic acid, 128
Diphenylene disulphide, 127
Diphenylguanidine, 319
Dihydrocarveol, 260-261
Dihydrocholesterol, see Cholestanol
9:10-Dihydro-3:4-5:6-dibeirzophenanthrene, 134
22:23-Dihydroergosterol, 387
Dihydroeudesmene, 306
Dihydroeudesmol, 304, 306
Dihydro-tp-ionone, 296
Dihydroxy-/}-carotene, 324
Dihydroxymaleic acid, 210
3:4-Diphenyliso-oxazole-6-carboxylic
4:5-Dihydroxyuracil, 573
2:6-Di-iodopurine, 576
3:5-Di-iodotyrosine, 452, 465
Diketogulonic acid, 210
Diketopiperazines, 456, 461, 471
Dilituric acid, 439-440
Dimercaptodiphenyl, 127
a):4-Dimethoxyacetophenone, 550
6:7-Dimethoxyisoquinoline-l-carboxylic
acid, 534, 535
/?:0-DimethylacryIic ester, 273
a:a-Dimethyladipic acid, 251
/?:/?-Dimethyladipic acid, 251
Dimethylalloxan, 580, 585
2-Dimetbylaminoguanine, 588
Dimethylbenzimidazole, 618
3:3-Dimethylbutan-2-ol, 82
3:3-Dimethylbutan-2-one, 81
Dimethylcadalene, 301-302
l^-Dimethylcye/ohexane, 113
l:3-Dimethylcycfohexane, 113
6:6-Dimethylcyctohexane-2:4-dione-lcarboxylic ester, 282
2:6-DimethyleyeZopentane-l-carboxylic
acid, 93,
of,
acid, 154
1:4-Diphenylpiperazine dioxide, 147
DPN, 598
Dipolar ions, 460, 461, 500
Dipole-dipole effect, 2
Dipole moments, 2, 4, 9, 11-13, 15, 25, 27,
29, 30, 67-69, 72, 93, 94, 95, 127, 147,
166
Dissymmetry, 20-22
Distance
rule,
10
5:10-Di--tolyl-5:10-dihydroarsanthren,
167
Duroquinol, 619, 620
Duroquinone, 619, 620
108-109
363
Dimethyldiketopiperazine, 38
Dimethyldithiocarbamate (zinc
2:3-Dimethylglucose, 227, 230
salt),
319
300
Dimethylmaleic acid, 620
Dimethylmalonic acid, 322
1:6-Dimethylnaphthalene, 330
2:3-Dimethylnaphthalene, 385
2:6-Dimethylnaphthalene, 323
1:2-Dimethylphenanthrene, 368, 371, 402
Dimethylphenylarsine, 164
Dimethylpiperazine, 145
Dimethylsaccharic acid, 218
a:a-Dimethylsuccinic acid, 251, 322
Dimethyltartaric acid, 190, 193, 195, 218,
591
Dimethylthreonic acid, 211
Dimethylurea, 580, 583
Dimethyluric acid, 584
l:l'-Dinaphthyl-5:5'-dicarboxylic acid,
130
l:l'-Dinaphthyl-8:8'-dicarboxylic acid,
130
a:y-Di-l-naphthyl-a:y-diphenylallene, 139
a:y-Di-l-naphthyl-a:y-diphenylallyl
alcohol, 139
6:6'-Dinitrodiphenic acid, 126, 127, 139
Ebonite, 319
Ecgonine, 517-518
y-Ecgonine, 519
Ecgoninic acid, 517, 518
Eclipsed form, 26-30, 101, 102, 110
Elastins, 467
Elbs reaction, 341, 351
Electron diffraction, 3, 17, 25, 30, 111, 135,
166, 168
Electron paramagnetic resonance, 17
Electron spin resonance, 17
Elements of symmetry,
see
Symmetry
Enzymes,
215,
232,
449,
694,
Ephedrines, 489-491
y-Ephedrines, 490
Epi-series {in Steroids), 378
Epiandrosterone, 395, 396
Epicholestanol, 379, 381, 395
Epicoprostanol, 380, 381, 393
Epimerisation, 46
218,
235,
467,
698,
221,
237,
475,
603,
INDEX OF SUBJECTS
680
a-Fenchocamphorone, 293
Fenchone, 293-294
Fenchyl alcohol, 293
Fibrous proteins, 469-470
Ergostanol, 382
Ergosterol, 359, 382-384, 414
Ergosterone, 414
Erythro-3-bromobutan-2-ol, 76-77
Erythrose, 176-177
Essential oils, 242, 244
Ethyl a-bromopropionate, 85
Ethyl oc-chlorocrotonate, 95
Ethyl chloroformate, 471, 567, 574, 577,
607
64
FAD, 598
Faraday
effect, 10
Farnesal, 295, 296
Farnesene, 295, 297
Flavanone, 561
Flavins, 604
Flavone, 558-560
Flavones, 557-565
Flavonol, 560-562
Flavonols, 560, 563
Frequency
factor, 64
Furazans, 434
Furfuraldehyde, 209
Galactans, 232
Galactose, 179-180, 182, 187,
191,
205,
C=C,
408
C=N, 149-160
160-161
reduced ring systems, 105-124, 263, 264,
276, 283, 530
terphenyls, 132
see also Additive reactions. Elimination reactions, Stereomutation
N=N,
INDEX OF SUBJECTS
Germanium compounds, stereochemistry
of, 174
Geronic acid, 251, 322, 329, 330
Gestogens, 409-415
Girard's reagents, 398, 416
Globin, 643
Globular proteins, 468-469
Globulins, 466
Glucal, 208
Glucosamine, 208, 232, 637
Glucose, 30, 31, 37, 179-180, 181-182, 183,
184, 185, 188-192, 198, 199, 203-208,
610-612
Glutamine, 453
Glutelins, 466
Glyceraldehyde, 31-36, 176, 233, 458
Glyceric acid, 34, 199, 216, 233
Glycidic esters, see Darzens glycidic ester
condensation
Glycine, 390, 434, 449, 454, 460, 461, 466,
571, 581
Glycocholic acid, 390
Glycogen, 231
Glycoproteins, 464
a-Glycosans, see Anhydro-sugars
Glycosides, 15, 172, 184, 186, 187, 234-240,
412, 545, 558, 567, 589
Glycylglycine, 471
Glyoxalines, see Imidazoles
Gramine, 451, 497
Grignard reagents, 81-84
Guaiol, 307
Guanidine, 580, 611
Guanine, 579-580, 588, 590, 595
Guanosine, 589, 590, 591
Guanylic acid, 589, 593
Gulose, 179-180
681
Hexachloroeye/ohexane, 116
Gums, 232
Gutta-percha, 318
Guvacine, 499
Guvacoline, 499
Haem, 643
Hydrindanols, 120
Hydrocarbostyril-3-carboxylic acid, 54
Hydrogen bonding, 2-3, 4, 8, 15, 226,
468-469, 515
Hydrorubber, 317
Hydroxyaetiocholanone, see 5-7soandro-
Hemimellitene, 311
303,
sterone
551
7-Hydroxy-l:2-dimethylphenanthrene,
402
a-Hydroxyethylbenzene, 71, 73
/}-Hydroxyglutamic acid, 453
7-Hydroxyisoquinoline, 530
5-Hydroxymethylcytosine, 588
a-Hydroxy-a-methyl-a'-isopropyladipic
acid, 270
7-Hydroxy-8-methyljsoquinoline, 530
INDEX OF SUBJECTS
682
isopelletierine,
317
a-Jsopropylglutaric acid, 270
/?-/sopropylglutaric acid, 262
Idose, 179-180
Imidazoles, 428-429, 569, 576, 577
Indoxyl, 235
Induced dipoles,
2,
Induction
effect,
sugars),
433
Isotopic asymmetry, 24
Isotopic indicators, 24, 47, 62, 71, 73, 214,
232, 315, 316, 389, 458, 566, 575, 586,
654-655
12
460
Inositols, 115
Inner
502
isopentanethiol, 53
Jsopentyl carbamate, 49
Isoprene, 242, 259, 317
Isoprene rule, 242, 266, 295, 305, 308, 315,
salts,
Intensity of magnetisation, 12
Internal compensation, see Compensation
Inulin, 232
Inversion, see Walden inversion
Invertase, 215, 224
Invert sugar, 217
Iodogorgic acid, 452
2-Iodo-octane, 71
a-Ionone, 251, 327
0-Ionone, 251, 322, 323, 326, 327, 330, 333
y-Ionone, 252
y-Ionone, 251
Ion-pairs, 67
Irone, 252
/soalloxazines, 448, 604
Isobutylethylmethylpropylammoniura
chloride, 144
isocamphane, 271
isocamphoric acid, 283
Jsocrotonic acid, 90, 92
Isoelectric point, 461, 466
Jsoequilenin, 407
Zsoergosterone, 414
Jsoflavones, 565-566
Isogeroaic acid, 251, 327
Isohexyl methyl ketone, 364
Jsoindole, 664
Zsoleucine, 450, 452, 455
IsolithobiUanic acid, 393
Isomaltose, 230
Isomerism, rotational, 28
see also Conformational analysis
Jsonicotinic acid, 505-506
iso-oxazoles, 153, 154, 430
Keesom
of,
149-151,
Lactase, 221
Lactic acid, 35, 46, 54, 70-71, 81
Lactoflavin, see Vitamin B,
Lactols, 182
Lactose, 54, 149, 201, 221
Lsevulaldehyde, 246, 250, 296, 317, 318,
625
Laevulic acid, 247, 248, 298, 313, 317, 318,
327, 329
Laevulose, see Fructose
Lanoline, 359
Lanosterol, 389
Latex, 317
Laudanine, 537
Laudanosine, 55, 537
Lavandulol, 242
L casei factors, 610-612
Lepidine, 523, 534
Leucine, 450, 451, 452, 455
Leucopterin, 612
Levopimaric acid, 312, 313
INDEX OF SUBJECTS
Lithium aluminium hydride
565
Lithobilianic acid, 393
Lithocholic acid, 391, 392-394
London
Lumi-lactoflavin, 604^605
Luminal, 439
Lumisterol, 384
Lutein, 321, 336
Lycopenal, 328
Lycopene, 327-329
Lycophyll, 336
Lycoxanthin, 335
378-379
Methoxycafleine, 681-582
7-Methoxy-l:2-eye/opentenophenanthrene, 390
7-Methoxy-3':3'-dimethyl-l:2-cyciopentenophenanthrene, 399, 405
Lyxose, 179-180
M
628
M and B,equation,
6
Macleod
Magnetic induction, 13
Magnetic optical rotation, 10
Magnetic permeability, 13
Magnetic susceptibility, 12-13, 354
Malamic acid, 33
Maleic acid, 87-88, 91, 94, 97, 98, 103
Maleic dialdehyde, 437
Malic acid, 33, 34, 50, 69, 87
Malonic ester syntheses, see Ethyl malonate syntheses
Maltase, 184, 215, 218
Maltol, 638
Maltose, 201, 218-221, 228, 229, 230, 231
Malvidin chloride, 546, 556
Malvin, 556
Menthone, 268-269
Menthoxyacetyl chloride, 53
Menthylhydrazine, 53
Menthyl mandelate, 55
N-( ) -Menthy l--sulphamylbenzoyl
chloride, 53
Mepacrine, 630
2-Mercaptobenzothiazole, 319, 433
Mercaptosuccinic acid, 50
Meioquinene (meroquinenine), 523-527,
529
Mesaconic acid, 91
Mescaline, see Mezcaline
Mesityl oxide, 282
Mesobilirubin, 656
115, 116
619
Meso-ionic compounds, 434-437
Mesomechanism, 62
Mesoporphyrin, 645, 659
Afesotartaric acid, 33, 43, 58, 97
Mesoxalic acid, 569, 570, 580
forces, 2
Lumichrome, 605-606
JVfesoerythritol, 177
Afesoinositol, 115, 612,
Methoxyhydroxymethyldiglycolaldehyde,
199, 200
7-Methoxy-3'-methyl-l:2-cytfopentenophenanthrene, 404
4-Methoxy-2-methylquinoline, 521
6-Methoxy-4-methylquinoline, 529-530
4-Methoxyquinoline-2-carboxylic acid,
521
4-Methoxy-2:5-toluquinone, 371
Methyl
abietate, 312
Methylabietin, 312
2-Methyladenine, 588
/S-Methyladipic acid, 254, 268, 269
2-Methylaminoguanine, 588
6-Methylaminopurine, 588
Methyl arbutin, 239
Methylbixin, 337
Methylcadalene, 301-302
20-Methylcholanthrene, 350, 367
Methyleyefohexane, 111
2-Methyliyrfohexanol, 112
2-Methyleyc/ohexanone, 112, 334
3-Methyleye/ohexanone, 269, 270
4-MethylcycZohexan-2-one-l-carboxylic
ester,
269
3-Methylcyc/ohexylamine, 113
l-MethyUycfohexylidene-4-acetic acid, 140
l-Methykyc/opropane-l:2:3-tricarboxylic
acid, 278
5-Methylcytosine, 688, 589
i^-Methyl-4:5-diamino-o-xylene, 605
3-Methyl-5:6-dimethoxyanthranil, 435
3-Methyl-l:5-diphenylpyrazole, 423
Methyleneglycine, 461
Methyl fructoside, 194, 198, 215
W-Methylglucosamine, 232, 637, 638
1-Methylguanine, 688
3-Methyleptane, 48
Methylheptenone, 247, 248, 254, 265, 327
Methyltsopelletierine, 502
Methyltsopropylacetaldehyde, 383, 385
l-Methyl-4-sopropylnaphthalene, 304
7-Methyl-l-isopropylnaphthalene, 304
/S-Methyl-a-tsopropylpimelic acid, 269
Methylmorphenol, 539, 640
a-Methylmorphimethine, 538, 539
fl-Methylmorphimethine, 538, 539
Methylmorphol, 538, 539
2-Methyl-l:4-naphthaquinone, 626
INDEX OF SUBJECTS
684
a-Hydroxyethylbenzene
Methylphenylmethyl chloride,
see
a-Chloroethylbenzene
3-Methyl-l-phenylpyrazole, 422
5-Methyl-l-phenylpyrazole, 422
3-Methyl-l-phenylpyrazolone, 426
Methylphenyl--tolyltelluronium iodide,
175
3-Methylpyrazolone, 424
Methylsuccinic acid, 50
Methyl tartrate, 49
Methyl tetramethylfructoside, 194
Methyl tetramethylglucoside, 188, 189
4-Methylthiazole-5-carboxylic acid, 599
4-Methyluracil, 573
Methylurea, 573, 580, 583, 584
Methyluric acid, 572, 573, 584
/5-Methylvaleric acid, 41-42
Methylvinylcarbinyl bromide, 253
Methyl vinyl ketone, 259, 331
7-Methylxanthine, 577
Mevalonic acid, 315-316
Mezcaline, 492-493
Michael condensation, 273, 282, 371, 526
Micro-wave spectroscopy, 15
Millon's reaction, 466
Mirror image forms, 20-21
Molecular compounds, 2, 12
Molecular overcrowding, 133-135, 138
Molecular refractivity, 7-10, 185, 245, 279,
295, 298, 301, 398
Mozingo reaction,
Mucic acid, 180
61
Neoprene, 320
Neosalvarsan, 631
Neovitamin a, 334
Neovitamin b, 334
Neral, see Citral-b
Nerol, 252-253
Nerolidol, 297, 298
Neutron crystallography, 17-18
Newman projection formula, 26
Niacin, see Nicotinic acid
Nicotinamide, 617
Nicotine, 21, 504-509, 617
Nicotinic acid, 497, 504-506, 617
Nicotone, 508
Ninhydrin reaction, 462
6-Nitrodiphenic acid, 127
Nitrogen compounds, stereochemistry
143-161
o-Nitrophenylglyoxylic acid, 159
o-AT-Nitroso-TV-benzoyltoluidine, 427
Nitrosolimonene, 262
5-Nitrouracil, 573
5-Nitrouracil-4-carboxylic acid, 573
Noradrenaline, 494
Norbixin, 328, 336
O
Ocimene, 246-247
Octan-2-ol, 71, 170
(Estradiols, 402, 404-405
CEstriol,
Mucilages, 232
bergamot, 253
camphor, 279
caraway, 259
celery, 303
chenopodium, 266
citronella, 254, 255
cubebs, 299
N
Naphthacene, 347
Naphthalene-2-carboxylic acid, 385
2-Naphthol, 118, 354
y-l-Naphthyl-a:y-diphenylallene-acarboxylic acid, 140
2-Naphthylphenylphosphoramidic
401-403
(Estrogens, 398-409
(Estrone, 398-401, 402, 415
Oil of ambrette, 296
bay, 245
Murexide, 570
Mutarotation, 181-183
Mycomycin, 140
Mycosterols, 359
Myrcene, 245-246, 278
Myrosin, 240
ester,
162
Narcotine, 55, 537
Nebularine, 576
of,
geranium, 255
ginger, 298
lemon, 260
lemon grass, 247
myrrh, 297
neroli, 253, 297
organge, 253, 262
orris root, 252
pennyroyal, 269
peppermint, 262, 267, 268
INDEX OF SUBJECTS
pine needle, 266, 267, 272
rose, 252, 253,
255
spearmint, 259
turpentine, 262, 274, 309
verbena, 245
Opacity, 14
Oppenauer oxidation, 372, 380, 383, 392,
397, 410, 411, 412, 414, 417
Oxadiazoles, 434
Oxazines, 446
Oxazoles, 430-431
Oxazolones, see Azlactones
Oxidases, 477
see
Oximino compounds,
625
685
Pentan-2-ol, 54
Pentosans, 232
Pentoses, aldo, 177-179, 192-193
Peonidin chloride, 546, 549, 555
Peonin, 555-556
Peptides, 467, 468
Peptones, 467
Perbunan, 319
Perhydrocarotene, 322, 329
Perhydrocrocetin, 337
Perhydrolycopene, 327
Perhydronorbixin, 336, 337
Perhydrosqualene, 313
Perhydrovitamin A, 330
Periodic acid (use of), 198-201, 216, 228,
230, 372, 591, 593, 641
Perkin reaction, 341, 352, 504
Perylene, 353
Phaeophorbide-a, 657, 661, 662
Phaeophorbide-6, 657
Phaeophytin a, 657
Phseophytin b, 657
Phasoporphyrin-a 5 661
a- and /?-Phellandrenes, 264
Phenanthrene, 339-345, 538
,
of),
Phenyl
^-Phenylenebisiminocamphor, 54
o-Phenylenediamine, 430, 434, 446, 604
Paludrine, see Proguanil
Plasmoquin
Pantoic acid, 608-609
Pantolactone, 608-609
Pantothenic acid, 608-610
Pamaquin,
see
Papain, 53
Papaveraldine, 533, 536
Papaverine, 533-536
Papaverinic acid, 533, 536
Papaverinol, 533, 535
Papaveroline, 533
Parabanic acid, 571, 572
Parachor, 6
Paramagnetism, 13
Patulin, 639-640
Pectin, 232
Pelargonidin chloride, 546, 553-554
Pelargonin, 553, 554
Pelletierine, 502
y-Pelletierine, 502
Penaldic acid, 634,
636
Penicillamine, 633-634, 636
Penicillins, 632-637
Penicilloic acid, 634, 636
Penillic acid, 635, 636
Penilloaldehyde, 633, 634, 636
Penilloic acid, 634, 636
2:3:4:5:6-Penta-acetylaldehydoglucose,
183
Pentacene, 348
iV-oc-Phenylethylacetamide, 157
j8-Phenylethylamine, 489
Phosphoproteins, 467
Phosphoranes, 337
INDEX OF SUBJECTS
686
Pyrene, 353
Pinol, 274
Pinol glycol, 274
Pyrethrosin, 299
Pyridazines, 362, 388, 437
Pyridine-2:3:4-tricarboxylic acid, 529, 534
Pyridoxin, 615-617
Pyrimidine, 437, 440, 569
Pyrimidines, 438-444, 576, 577, 588-589,
600-602, 603, 611-612, 628
Pulegone, 269-270
Psicose, 181
Pteridines, 448, 610-611
Pterins, 612
Pteroic acid, 610
Pteroylglutamic acid, see
Purine, 575-576
Purines, 569-587, 588
630
Quinolinic acid, 506, 617
Quinotoxine, 530, 532
Quinoxalines, 445, 612
Quinuclidine, 526
R
(iJ)-compounds, 36
Rjf value,
457
Reformatsky reaction,
Refrachor, 7
Refractive index, 7-8
see also Molecular refractivity
Reimer-Tiemann reaction, 456, 504
Replacement reactions, 60
Vitamin
Bc
Residual valencies, 2
Resin acids, 309
INDEX OF SUBJECTS
687
Resonance,
Sinigrin, 240
Retene, 309
Retinene 1( 335
Rhamnose,
Solubility,
Solvent
B,
Rosin, 309
Rotational isomers, 28
S
SS) -compounds, 36
(Sg reaction, 60
Sn reaction, 74
Sabinene, 272
Sabinol, 272
Saccharic acid, 30, 43, 180, 189, 204, 218
Sachse-Mohr theory, 116
Salicin, 239
Salicyl alcohol,
239
Salkowski reaction, 359
Salvarsan, 631
Santonin, 307
Sapietic acid, 313
Sapogenins, 412
Saponins, 412
Schmidt reaction, 455
Scleroproteins, 466
Scopine, 516-517
Scopolamine, see Hyoscine
Scopoline, see Oscine
Scyllitol, 115
Secondary valencies, 2
Sedoheptulose, 233
Selenium compounds, stereochemistry of,
174-175
Selenium dehydrogenations, 245, 252, 301,
307, 309, 330, 342, 344, 345-347, 352,
358, 360, 363, 367, 368, 369, 386, 399,
400, 404, 405, 412, 619
Selinenes, 303, 305
Semi-/S-carotenone, 324
Senecioic acid, 315
Serine, 34, 449, 450, 451, 452
of,
27, 110
Sodium borohydride
Rhodinal, 254
Rhodinol, 254, 255
Rhodoporphyrin, 659
Rhodoxanthin, 335
174
Skew conformation,
effects, 9, 14,
67-69
Solvolysis, 65
Sommelet reaction, 426
Sorbitol, 213
Sorbose, 181, 213
Sorensen formol titration, 461
Specific rotation, 9
Spirans, 140-142, 145-146, 156, 163, 165
Squalene, 313-314, 316, 389
Stachydrine, 497
Staggered form, 27
Starch, 228-231
Stereochemical conventions, 26-28, 30-37,
97, 116-117, 176, 376-378
Stereochemistry, 20-175
addition reactions, 96-99, 363-364
aldoximes and ketoximes, 149-159
alkaloids, 490, 494, 495, 514-516, 518,
519, 527, 530
allenes, 139-140
antimony compounds, 169
arsenic compounds, 163-169
dianthryls, 130
dinaphthyls, 130
diphenyls, 126-139
dipyridyls, 130
dipyrryls, 130
diquinolyls, 131
elimination reactions, 100-103
germanium compounds, 174
nitrogen compounds, 143-161
olefinic compounds, 87-105
phenylpyrroles, 130
phosphorus compounds, 161-163, 168169
polynuclear compounds, 133-135
reduced ring compounds, 105-124
restricted rotation (other than dipheny
type), 129-138, 155
selenium compounds, 174-175
silicon compounds, 174
spirans, 140-142
steroids, 376-381
sugars, 176-187
sulphur compounds, 169-173
tellurium compounds, 175
terpenes, 267-268, 269, 278, 283, 284,
285, 288-293
terphenyls, 132-133
tin compounds, 174
see also Geometrical isomerism
Stereoisomers, numbers of, 40-45
Stereomutation of geometrical isomers,
103-105
Steric acceleration, 64, 121
Steric control of asymmetric induction,
rule of, 84
Steric factor, 3, 63-65
Steric hindrance, 2, 3, 63-65, 121, 124,
127-139, 226, 469, 567
Steric repulsion, 29, 63, 110-112
Steric strain, 30, 63, 110-112, 133-135
INDEX OF SUBJECTS
688
Steroids, 358-418
408-409
Stobbe condensation, 343
Strainless rings, 109-124
Strecker synthesis, 450
Streptamine, 638
Streptidine, 638
Streptobiosamine, 638
Streptomycin, 637-638
Streptose, 637
Styrene, 48, 319
Styrene dibromide, 48
Suberone, 513
Substances, F, H, M, Q, S, 416
Substrates, 477
Succinaldehyde, 514, 519
Stilbcestrol,
Sulphamezathine, 628
Sulphanilamide, 627-629
Sulphapyridine, 628
Sulphathiazole, 628
Sulphilimines, 172
Sulphinic esters, 170-171, 173
Sulphonamides, 627-629
salts, 72, 169-170, 173
Sulphoraphen, 172
Sulphoxides, 171-173
Sulphur compounds, stereochemistry of,
169-173
Sulphur dehydrogenations, 245, 300, 303,
304, 305, 307, 309, 312, 340, 345-347,
353
Surface tension, 6-7
Sydnones, 434-436, 461
Sylvestrene, 266-267, 272
Symmetry, elements of, 37-39
Sulphonium
Sy-compounds, 151
Syringic acid, 556
Tautomerism,
209,
430,
569,
611,
250,
431,
570,
644,
645
222
2:3:4:6-Tetramethylgluconolactone, 188
2:3:4:6-Tetramethylglucose, 183, 187-189,
204, 215, 218, 220, 221, 223, 227, 228,
229, 230, 234, 235, 238, 239
2:3:5:6-Tetramethylglucose, 190, 204
Tetramethylspiro-(l:l')-dipyrrolidinium
^-toluenesulphonate, 39, 146
l:l':3':5-Tetraphenyl-3:5'-dipyrazolyl, 423
l:l':5:5'-Tetraphenyl-3:3'-dipyrazolyl, 423
Tetramethylthiuram disulphide, 319
Tetramethyluric acid, 581, 582
Tetrazines, 447
Tetrazoles, 436
Tetroses, 176-177
Thebaine, 537-541
Thebenine, 538
Theobromine, 583-585
Theophylline, 583, 585-586, 590
Thiamine, see Vitamin B t
Thianthren dioxide, 172
Thiazole, 431-432
Thiazoles, 431-432
Thiazolidines, 432, 634
Thiazolines, 432, 633
8- (2-Thienyl) -valeric acid, 614
Thioamides, 431, 432, 600
Thiochrome, 603-604
Thioglucose, 240
Thiohydantoins, 461, 475
Thionuric acid, 440
Thioureas, 431, 441, 442, 443, 578
Thorpe reaction, 407
Three-centre reaction, 72
Threo-3-bromobutan-2-ol, 76
Threonic acid, 210
Threonine, 449, 452, 459
Threose, 176-177, 210
Thujane, 271
689
INDEX OF SUBJECTS
Tropilidene, 512, 513
a-Thujene, 272
Thujone, 272
Traube
174
585
Trehalose, 218
co:3:4-Triacetoxyacetophenone, 549
co:3:4-Triacetoxy-5-methoxyacetophenone, 550
Triazines, 447
Triazoles, 433-434
Trichlorocrotonic acid, 92
2:6:8-Trichloropurine, 576, 577, 578, 579
Trigonelline, 497
Trihydroxycoprostanic acid, 394
Trihydroxyglutaric acid, 43, 177, 178, 179
co:3:4-Trimethoxyacetophenone, 550, 551
2:3:4-Trimethylarabinolactone, 193, 194
2:3:5-Trimethylarabinolactone, 193, 195
2:3:4-Trimethylarabinose, 192
2:3:5-Trimethylarabinose, 193
3:4:6-Trimethylfructose, 232
3:4:5-Trimethylfructuronic acid, 194
3:4:6-Trimethylfructuronic acid, 195
2:3:4-Trimethylglucose, 218, 222, 223, 224
2:3:6-Trimethylglucose, 218-219, 221, 225,
228, 230
3:5:6-Trimethylglucose, 204
Trimethylisoalloxazine, 605
1:2:6-Trimethylnaphthalene, 252
4:5:8-Trimethyl-l-phenanthrylacetic acid,
133
Trimethylphenylarsonium iodide, 164
j3:6:y-Trimethylpimelic acid, 252
Trimethylquinol, 621, 622
Trimethylsuccinic acid, 280
Trimethylthreonamide, 210, 211
a:a:/S-Trimethyltricarballylic acid, 280
Trimethyluric acid, 581, 582, 583
2:4:6-Trinitrostilbene, 85
Triphenyliso-oxazole, 154
Truxone, 108
Truxonic acid, 108
Tryparsamide, 632
Tryptophan, 451, 452, 456
Tyramine, 491
Tyrosine, 450, 452, 454, 456, 457, 464, 491,
U
Ullmann
464
Ultracentrifuge measurements, 228, 317,
466, 595
Ultraviolet absorption spectra, see Absorption spectra
Umbelhilone, 272
Unimolecular mechanism, 60
Uracil, 442-443, 588, 595
Uramil, 440, 570, 574
Urea, 438, 439, 442, 443, 478, 569, 570,
571, 572, 573, 574, 575, 579, 586, 604,
617, 663
Ureides, 438
cyclic, see Pyrimidines, Purines
Uric acid, 569-575, 583, 584, 585
y-Uric acid, 573-574
Uridine, 589
Uridylic acid, 589, 593
Uronic acids, 232
Uroporphyrinogen, 655
Valeric acid, 79
Valine, 449, 450, 451, 452, 454, 455
van der Waals forces, 1-2
van der Waals radii, 2, 128
Vitamins, 598-626
Vitamin A r 330-334, 335
A a 335
B complex, 598-619
Bj, 599-603
,
604-608
B B 4 B 619
B see Pyridoxin
B 10 B, 610, 619
B 12 617-619
B 13 B 14 619
3,
6,
6,
Be, 610
C, see Ascorbic acid
T> 1 and
2 , see Calciferol
D3 D4
,
386-387
INDEX OF SUBJECTS
690
Vitamin H,
K
K
see
Biotins
623-625
a 626-626
M, 610
x,
,
Volatility, 3
Vulcanisation, 318
W
Wagner rearrangement, 287
Wagner-Meerwein
rearrangement, 284,
288-292, 294, 312
Walden inversion, 69-74, 98, 234-235
Wave-mechanical effect, 2
Weerman test, 204, 211
Wittig reaction, 337
Wolff-Kishner reduction, 119, 279, 398,
644
X-ray analysis,
Xanthine, 579
Xanthophylls, 321, 335, 656
Xanthoproteic reaction, 466
Xanthopterin, 612
Xanthosine, 590
Xylans, 232
-Xylenol, 622
Xylo-glucans, 232
o-Xyloquinol, 623
^-Xyloquinol, 622
Xylose, 177-179, 182, 188, 232, 236
Xylotrimethoxyglutaric acid, 188
Zeaxanthin, 336
Zeisel method, 188, 485, 521, 522, 528, 533,
537, 546, 555
Zymase, 237
Zymogens, 479