Beruflich Dokumente
Kultur Dokumente
Heterocyclic compounds
ISBN: 978-615-5722-01-1
© Gábor Krajsovszky
Moreover, the editor renders many thanks to Mrs. Ferenc Juhász and Ms. Nikoletta Zlatzky
laboratory assistants for drawing material of the figures.
E. Breitmaier, G. Jung:
Organische Chemie
Grundlagen, Stoffklassen, Reaktionen, Konzepte,
Molekülstruktur
Georg Thieme Verlag 1978, 2005
Stuttgart • New York
Clauder Ottó:
Szerves kémia II/2. Egyetemi jegyzet
Semmelweis OTE Budapest, 1980
Bruckner Győző:
Szerves kémia III−1.
Tankönyvkiadó, Budapest, 1964
Szabó László:
Szerves kémia előadások - heterociklusos vegyületek
Semmelweis OTE Budapest, 1978-1996
Three-, four- and five-membered
heterocycles with one heteroatom
and their derivatives
Three-membered heterocycles with
one heteroatom and their
derivatives
Nomenclature
1 1
H
O S N 1
3 2 3 2 3 2
1 1 H
O O N 1
diazomethane
2 2
2
3 O 3 NH 3 NH H2C N N
dioxirane oxaziridine diaziridine
structural
isomers
H 1
1 1 N
O S N N
3 2
2 N
3 2 3
H
H
oxirene thiirene 1H-azirine 2H-azirine 3H-diazirine
2-azirine 1-azirine
Preparation [2+1] intermolecular ring closure
With contribution of atoms from olefin [2] and peracid [1]
O
R CO3H
R CH CH2
R
Br2 / CCl4
R: oxirane derivatives
Br OH
R CH CH2 R CH CH2
Br Cl +HCl
halohydrin
Ethylene oxide is used for gas sterilisation. It must be diluted
with carbon dioxide, otherwise explosive mixture would be
formed with air. Peracids are explosive, toxic compounds!
Br OH
R CH CH2 R CH CH2
Br Cl
halohydrin
OH Cl
H2S NH3 SOCl2
R CH CH2 R CH CH2
aminoalcohol NH2 haloamine NH2
SH
KOH
S
R CH CH2 HBr KOH +HCl
HCl
Br
+HBr R
halothiol H
thiirane derivative N
2
R
CH2 3 1 aziridine derivative
N
C N
carbene Aziridines are carcinogen compounds.
benzonitrile
2H-azirine derivative
O
O C C
H H
CH3(CH2)7 (CH2)7COOH
H H CH3COOH
C C enantiomers
CH3(CH2)7 (CH2)7COOH 20 °C, 3 h H H 1:1
one-step C C
syn-addition CH3(CH2)7 (CH2)7COOH
oleic acid O
O C C
CH3(CH2)7 H
H (CH2)7COOH
CH3(CH2)7 H CH3COOH
C C enantiomers
H (CH2)7COOH 20 °C, 3 h CH3(CH2)7 H 1:1
one-step C C
elaidinic acid syn-addition H (CH2)7COOH
O
Asymmetric oxidation of alkenes
Sharpless epoxidation
A)
diaster eo(enantio-)selective
EtOOC OH O
Ti[OCH(CH3)2]4 H
H O
+ O
HO (CH3)3C O OH
H COOEt CH2OH
O H CH2Cl2
H
O
CH2OH diethyl tartrate enantiomers
H
EtOOC H O
Ti[OCH(CH3)2]4 H
allyl alcohol OH
+ O
derivative H (CH3)3C O OH
HO COOEt CH2OH
CH2Cl2 O
H
B)
O
HO
H OEt
OEt
H
HO S
O
OH
(2S,3S)-(-)-Diethyltartrate
R2
R
R
O
2
R R1
R (CH3)3C-O-O-H / Ti(OiPr)4
molecular sieve R
Z R 1
OH R2
O
HO S
O
R
R1
H
HO OEt
OEt 1 2
HO R<R <R
H
O
(2R,3R)-(+)-Diethyltartrate
O
HO
H OEt
OEt
H
HO S
O
OH
(2S,3S)-(-)-Diethyltartrate
R2
R1
S
O
R2 R
R1 (CH3)3C-O-O-H / Ti(OiPr)4
molecular sieve R
E R OH R2
O
HO R
O R1
R
H
HO OEt
OEt 1 2
HO R<R <R
H
O
(2R,3R)-(+)-Diethyltartrate
Chemical properties 2,2'-iminodiethanol 2,2'-[(hydroxymethyl)imino]diethanol
2-[(2-hydroxyethyl)amino]ethan-1-ol 2-[bis(2-hydroxyethyl)amino]ethan-1-ol
O O
CH2CH2OH CH2CH2OH
HN N CH2CH2OH
CH2CH2OH CH2CH2OH
O δ
NH3 OH NH2
diethanolamine triethanolamine
CH2 CH2
δ In ointment,
lacquer
KOH
H
N
SOCl2 Cl NH2 KOH
CH2 CH2
aziridine
Baeyer strain is greater for 3-membered rings than for 4-membered ones. As
a consequence of this ring opening, reactions are easier for the former ones.
Ring opening – it may occur with acid or with base
Different regiochemistry:
with acid: SN1-like mechanism (alkyl cation of higher order is more stable)
with base: SN2 mechanism (for sterical reasons, the nucleophile attacks the
carbon of lower order)
H H H
O O O O
H Y Y OH
R CH CH2
R R R R
Nu
O Nu OH Nu
H
R CH CH2 R CH CH2
OH
CH2 CH3
LiAlH4
OH OR
RO
CH2 CH2
O OH
HO
CH2 CH2
OH
RMgBr
MgBr
O R NH4Cl OH R
O CH3 O
(CH3CO)2O
+ N CH3 HOCH2CH2N(CH3)3 H3C COCH2CH2N(CH3)3
CH3 Cl Cl
HCl choline chloride acetylcholine chloride
Ar OH competing reaction
O O
OH Cl
b) pathway HO
Ar OH + Ar O CH2 CH CH2
CH2 Cl a) pathway HCl Ar O CH2
a) pathway (main pathway)
epichlorohydrin RNH2
steric reason
RNH2 OH NHR
prototypes:
Ar O CH2 CH CH2
CH3
CH propranolol
CH3
CH3
CH pindolol
N
H CH3
Four-membered heterocycles with
one heteroatom and their
derivatives
Nomenclature
1 2
O S HN
4 3
Hantzsch-Widman name oxetane thietane azetidine
Radicofunctional name trimethylene oxide trimethylene sulfide trimethylene imine
Replacement name oxacyclobutane thiacyclobutane azacyclobutane
1 2 1 2 1 2 1 2
O S N HN N
4 3 4 3 4 3 4 3
1 2 1 2
S S HN NH
4 3 4 3
1,2-dithiet 1,2-dihydro-1,2-diazet
Preparation
By intramolecular ring closure
OCCH3 Cl HS
Cl O Cl H2S Cl KOH S
HO
AlCl3 HCl
H3C SO2NH2
Br Ts
Br Ts NH2 N LiAlH4 HN
ether
Chemical properties
RMgX
R CH2CH2CH2OH
LiAlH4
CH3CH2CH2OH
O HBr
Br CH2CH2CH2 Br
RNH2
RNHCH2CH2CH2OH
HO O O
OH O pr opano-3-lactone
1
β-propiolactone
H2O cyclic ester
β β α
α 3 2
EtO O O
pr opano-3-lactam
NH2 NH
ether β-propiolactam
EtOH cyclic amide
β α β α (antibiotics)
O
O S pr opano-3-thiolactone
[2+2]
S C β-propiothiolactone
cycloaddition
C C H3C Ph cyclic thioester
H3C Ph Ph Ph Ph Ph
HY O O Nu O
Nu Y Nu H YH
Nu H
Some important derivatives
β-Lactam antibiotics
• Penicillins
• Cephalosporins
Antibiotics: natural compounds produced either by microorganisms (e.g., fungi), or by
a higher organism against other microorganisms (e.g., bacteria) to block the life and
reproduction of the bacteria. Antibiotics are efficient in low concentration.
β-lactame ring of penicillins is sensitive to acids, bases, or penicillinase enzyme.
Nowadays penicillins with broad therapeutic range also exist (see microbiology).
Cephalosporins (1948) makes the other main group of the β-lactame antibiotics.
These are resistent to penicillinase enzyme.
The bacterium produces penicillinase/cephalosporinase enzyme in order to be resistent
against the given penicillin/cephalosporin derivative. Thus, newer and newer penicil-
lin/cephalosporin derivatives must be synthesized. Their total synthesis is possible, but
it would be too expensive, thus new derivatives are produced by semisynthetic me-
thods. The fermentation processes are combined by chemical methods (beginning of
biotechnology).
Clavulanic acid: inhibitor of the β-lactamase with low antibiotic effect. Clavulanic acid
is produced by Streptomyces clavurigeus (the same fungus also produces penicillin as
well as cephamycin).
Augmentin® contains amoxycillin and potassium clavulanate.
β -Lactam antibiotics
Basic skeletons
7 8
N 3 N 3
4 5
O O 4
penam cepham
lactam lactam
Penicillium notatum Cefalosporium acremonium
O O
penicillins "-cillin" cephalosporins "ceph(a)-" O OH
O NH2 O
H H
CH2 C NH CH C NH
3
6 7 CH3
benzylpenicillin cephalexin
G-penicillin
O O
H
H S NH
NH O CH3
3
7
N 6
O CH3 O
oxacillin cephalotin
O
N OH
H O
RNH COOH RNH X
S Y
CH3 Clavulanic acid
N CH3 N Z
O O
COOH
Penicillins COOH
N SO2O K
O
Monobactams
Five-membered heterocycles with one
heteroatom and their derivatives with
condensed ring systems
I/ Furan and its derivatives
Nomenclature
CH
O O O O O C
Preparation
NH3 P2S5
R R ((NH4)2CO3) R OO R R S R
N
H
R NH2 P2O5
160 oC
R N R R O R
R
Its mechanism: E P2O5, H
H
+E
R R R R R R
OO O O O O
E E
E
H
H H 2O
R R E R R
O O
O
H E
2/ From polyhydroxy oxocompound
HO OH 4 3
H H O
O
Found in wheat germ, 5
H OH HO C H 3H2O
O
2 C
corn germ 1 H
HO OH
H H HCl
HO OH HO OH
OHHO O
O O O O
OH
O - CO2 O
O
5/ By ring synthesis from β-oxoester and from α-chloroketone
ROOC H Cl
NaOEt
- EtOH
- NaCl
O O
ROOC ROOC
O O O
Feist-Benary
aldol
EtOOC H R1 EtOOC R1
+ O
R2 O SN i Cl R2 O
O-alkylation
This can be the side reaction of Hantzsch reaction
EtOOC H Cl EtOOC
+
R2 O O R1 R2 O R1
C-alkylation
EtOOC EtOOC H EtOOC
3
R -NH2
R2 O R2 N R2 NH
R3 R3
Hantzsch
EtOOC Cl EtOOC
+
R2 NH O R1 R2 N R1
C-alkylation
R3 R3
EtOOC R1 EtOOC R1
O
+
R2 NH Cl R2 N
R3 N-alkylation R3
Physical properties
The parent compounds (furan, pyrrole, thiophene) are poorly soluble in water,
but imidazole and pyrazole are water-soluble due to hydrogene bridges
1H NMR spectra: the signal of α H appears at lower δ value (more shielded), compared to the
signal of β H (each within the usual aromatic range)
There are usual couplings typical for aromatic compounds.
Chemical properties
O O O O O O
E H H H
α
O O E O E O E
E
β E E
H H
O O
α > β σ−complex is more stable, since more mesomeric structures can be written for it.
Friedel-Crafts alkylation
R Cl
AlCl3
O R O
Nitration
O
O
acetic anhydride
CH3C O NO2 anhydride
HNO3 anhydrous
acetyl nitrate
1,4-addition
1. H2 Ni
2. H3O
H Br
O
O O
Diels-Alder reaction
O H H O
O O O O
maleic anhydride
H O
O H
3/ Other reactions
Cannizzaro reaction
1. cc. KOH
2 + OH
H 2. H 3O
O O CH2OH O
O O
furfural furfurylalcohol furan-2-carboxylic acid
(furfurol)
Acyloin condensation
KCN
H KOH
O CH C
O O
O OH O
furoin
(similar to benzoin)
C C
O O
O O
furyl (similar to benzyl)
Polymerisation
n H
O O O O
n
1,4-addition
addition polymerisation
O O
Reduction
H2 Ni
o butan-1,4-diol
150 C 100 atm (for preparation of diolefins by Reppe synthesis)
O
O
THF
tetrahydrofuran
More important derivatives
H
H2O, 400 oC
H2/Ni
cat.
80 atm H - H2, - CO2
O CH2OH O O
O
Al2O3 350 oC furfurol, the cheapest
-H O aromatic aldehyde H2 /cat.
2
4
3 5 ROH/H
2 6 O
H3O
O O OR
1 - ROH
butadiene polymer,
BUNA or copolymer
O OH OH OH O OO OR
H H
- H2O
cc. HCl
O Cl Cl O OR
cc. HCl 2 KCN
HCN
O O Cl Cl N C C N
O
N 1,4-dichlorobutane
red.
NaCN
1. H3O H2/cat.
c
2.. c. H
Na Cl
O CN
O
N C C N NH2
pimelic acid dinitrile HO HN
OH
H2/cat O H
H3O
adipic acid butan-1,6-diamine
6C 6C
HO OH hexamethylene diamine
C C
O O
NH2 NH2 O
HO NH2
pimelic acid butan-1,7-diamine N
7C 7C H
O 6C 6C
polymerisation
HO OH Nylon 66
HN NH2
O O H
- H2O
H
HO N NH2
polimerisation
O O
7C 7C
Nylon77
2 2CO Na ε-caprolactam + ε-aminocaproic acid
2 2NaCN H2
2 O
O
O O O -H2O O
N
ε γ ε-amino- NH
H2O α OH caproic acid H2N OH
2 H2N
O δ β
N 6C 6C
H O O
Nylon 6
ε-caprolactam
Nylon 6
OH
H +CH2O
CH3 CH2 N(CH3)3 H
OH O polymer plastics
O
H H O
OH OH HO OH OH
H2
(+)-2S,3R,5S HO
Muscarin
(H H ) C CH CH2OH
alkaloid of O
-H2O O
Amanita muscaria C
H H
−δ O OH polymerisation chances
H
R C H OH
+δ R CH
OH
II/ Furan derivatives with condensed rings
Nomenclature
4 4
5 3
5 3
6 2 O
6 2
O O
7 1
1
H H OH
C O O Perkin
H2C C synthesis CH Br2
+ CH H
O
H3C C NaOAc C O O
OH OH OH O O
O O HO
coumarin
C O
H3C
Br
Br +KOH Br
H
-KBr OH
O O -H2O OO O O O
HH O
3,4-dibromocoumarin coumarilic acid coumarone
HO ZnCl 2
Cl - HCl -H2O
OH O OO O
coumarone HH
dibenzofuran
R
CH2 R CH2 R'
C
+ O C
R' N
O NH2 O
O-phenylhydroxylamine O-phenyloxime
R R
CH R'
C C R'
C
NH
O OH NH2
R
according to Fischer’s indol synthesis
O R'
CH2 R R
+ O C
NH2 R' R'
N N
H H
III/ Thiophene and its derivatives
Nomenclature
β' β
O
α' α
S S S S CH2 S CH S C
Preparations
1/ By Paal-Knorr synthesis from dioxo compounds
NH3 P2S5
R R ((NH4)2CO3) R OO R R S R
N
H
R NH2 P2O5
160 °C
R N R R O R
R
2/ From acetylene
CH CH
HC CH
S S
-2 H2S 2S 2S -H2S
4/ According to Hinsberg
R R R
R
C CH3ONa
C
O O 20 oC
ROOC S COOR
Chemical properties
1/ By halogenation
SO2Cl 2 SO2Cl 2
sulfuryl
chloride Cl Cl Cl
S S S
2/ By chloromethylation
CH2OH, HCl
CH2O CH2O
NH4Cl
CH2 NH2 HCl CH2
S S S
HN
Cl CH2
4/ By Vilsmeier formylation
N CH3
C H
O
H
POCl3
S S
O
5/ By Friedel-Crafts acylation
O
Wolff-Kishner
CH3C Cl red.
AlCl3
CH3
S S C S CH2CH3
O
6/ Transformation to mercury derivatives
HgCl2
ClHg S HgCl
HgCl2
CO2
S S HgCl
NaSCN
O OH
R C S
Cl O
NaI Br2
S SCN R
S
O
Mg
S I S Br S MgBr
7/ By Diels-Alder (addition) reaction
F F
S
F F
F S F
F F
8/ By polymerisation
S S S
n
9/ By hydrogenation
Raney Ni H2
R CH2 C OH EtOH R CH2 C OH CH2 C OH
S S
O O R O + H 2S
10/ By indophenin reaction
O O
S S
N O O N
H H
isatin
HCl
S S compound with
blue colour
N O O N
H H
indophenin
IV/ Thiophene derivatives with condensed ring system
Nomenclature
4 4
5 3 5 3
6 2 6 S2
S S
7 1 7 1
thionaphthene iso-benzothiophene dibenzothiophene
benzo[b]thiophene benzo[c]thiophene
isonaphthene
Preparations
O O
K3 FeIII(CN)6
OH H2O / OH OH O H -H
C
-H O - CO2
SH S S S
oxid.
mercaptocinnamic acid
white-hot
iron
S S
O O
S K3 FeIII(CN)6 S
S oxidation S
O O
thioindoxil
trans thioindigo
red precipitation
O O
S S
cis thioindigo
Chemical properties
Y
S
C 2 H H
S Y S Y
the aromatic system is
decomposed
disadvantageous
H H H
S Y S Y S Y
V/ Pyrrole and its derivatives
Nomenclature
N N N N
H H H H O
pyrrole α-pyrryl- β-pyrryl- α-pyrroyl-
Preparations
NH3 P2S5
R R ((NH4)2CO3) R OO R R S R
N
H
R NH2 P2O5
160 °C
R N R R O R
R
2/ By Hantzsch synthesis
CH2 Cl
ROOC ROOC ROOC C
CH2 R NH2 CH2 CH2 O R
C R = alkyl, C C
H3C O aralkyl H 3C N H3C NH
R R
ROOC ROOC
CH CH2
C C R
Cl H3C NH O H 3C N R
R R
3/ By Knorr synthesis
H3C C5H11ONO H3C
C O (isopentyl nitrite) C O Zn / CH3COOH
CH2 or C
ROOC NaNO2 CH3COOH ROOC N OH
R = Et
R 2
O R2 N R2 NH
R3 R3
Hantzsch
EtOOC Cl EtOOC
+
R2 NH O R1 R2 N R1
C-alkylation
R3 R3
EtOOC R1 EtOOC R1
O
+
R2 NH Cl R2 N
R3 N-alkylation R3
4/ By pyrolysis of ammonium mucoate
HO OH
NH3
HO OH HO OH
OO N - 2 CO2 N
O HH O O H O H
main product
NH2
N
H O side product
NH3 450 °C
OH
O - CO2 O Al2O3 N
O H
6/ According to Reppe, from butyn-1,4-diol
NH3,
HO CH2 C C CH2 OH
Al2O3 - ThO N
H
H2CO CH2O
H C C H
1/ Acid-base properties
H
N N
H
pKa ~ 15
(pKa water = 15.6)
2/ Tautomerism
Tautomerism of hydroxy- and amino-derivatives
The hydroxy compounds exist mostly in oxo forms, the amino compounds in amino forms (→ can be diazotised)
tautomers tautomers
N α OH N OH N α NH2 N NH
N O H H H
H H
lactam amino form imino form
cyclic amide (stable)
mesomers
NH
NH2
β
N O N N
H H H
OH tautomers O tautomers
OH
β
N N N
H H vinylogous
lactam
mesomers
O
N
H
3/ SEAr reactions
Take place in two steps, with much greater reaction rate, compared to of benzene
E H H H
α
N N E N E E
N
H H H H
E
β E E
H H
N N
H H
α > β σ−complex is more stable, since more mesomeric structures can be written for it.
Protonation
H
protomers
H
addition N
N N
H H
H H
By bromination
Br - Br H H - HBr
1,4-addition Br elimination Br
N Br N N
H H
By chlorination
Cl Cl
Cl2 SO2Cl2
sulfonyl
Cl N Cl N chloride N Cl
H H H
By nitration, sulfonation
O
equimolar HNO3
O S O
N
S N (CH3CO)2O NO2
N OH O N
H H explosive mixture H
O o
the reaction runs at low (20 C) temperature
O
HO O
N SO3 N O
CH3 C O
HO C CH3 N
O O
O
acetyl nitrate
By Friedel-Crafts acylation
pyrrole > benzene (SnCl4 < AlCl3 both are
(CH3CO)2O electrophilic catalyst, but the latter is much
SnCl4 CH3
more powerful, therefore the latter is not
N N
H H used for the acylation of pyrrole, since the
O reaction would be too vigorous
By Reimer-Thiemann reaction
CHCl3 Cl hydrolysis (
OH
cc. base CH CH
N N N
H H Cl H (OH
Cl
Cl CH
δ δ Cl
H
-H2O pyrrole > benzene (reacts more easily)
N
H
O
KOH
At first, N-potassium salt is formed due to cc. KOH
N N
H
K
Formation of dipyrrylmethane
H
C O H N
H
H
N N CH2 OH -H2O
H H
conjugate acid
(many mesomeric N C of dipyrrylmethene
N
structures can be written) H H
O CH3
C N CH3
H CH3 HCI CH N
N N
H H
CH3
Ehrlich reagent
(dimethylaminobenzaldehyde)
mesomers
CH3
N CH N
CH3
red colour
By Fischer-Bartholomäus reaction
N N Cl N N Cl
N N N N
H H
4 3
5
N N N1 2 N N
H
2,5-bis(phenylazo)pyrrole
4/ Transformation to heteroalkene-, or heteroalkane derivatives
By reduction reactions
4 3
Zn / H Pt / H2
5 2
N1 HCl N N
H H H
3 tetrahydropyrrole
- pyrroline
3 - pyrroline Ph-Al2O3 (pyrrolidine)
H2
Zn: electrondonor
water: protondonor
4 3 4 3
5 2 5 2
N1 N1
H H
2 1
- pyrroline - pyrroline
2 - pyrroline 1 - pyrroline
LiAlH4 or
O N O Na metallic / pentan-1-ol N
H H
By oxidation reaction
CrO3
N glacial O N O
H acetic acid H
maleic acid imide
By Diels-Alder reaction
F F
F
F F F
+ NH
N
H F F F F
F
F
there is no reaction with pyrrole, but there is formation of adduct with hexafluoro-Dewar-benzene
By polymerisation
H
N N N N
H H H H
5/ Amphotheric properties of pyrrole
CH3MgI R I
N - CH4 N - MgI2 N N R
H H
O MgI R
H5C2O C Cl
ethyl chloroformate
O
O R C Cl
C OC2H5 R
N N N
H H O
C
O R
Pyrrole does not react by nucleophilic substitution reactions
H The H at α-metil group is not active (the C-H bond is stable due to π electron excess)
N C H
H H
X O X = H proline
C = OH hydroxyproline
OH N N O
N CH3 H H
H pyrrolidine pyrrolidone
HO OH 200 °C
OH cc. NH3 HC CH
HO
O O N O
O H
butyric acid butyrolactone
N O N O
N N N N
H tautomers H H
H 4 tautomers
N N are possible N N
N N N N
H mesomers H
H there are 12 H
N N mesomers N N
totally
Nomenclature
H
N
N N CH3
H
3H-indole N-methylisoindole
1H-indole
benzo[b]pyrrole benzo[b]pyrrole (isoindole does not exist)
(indolenine) benzo[c]pyrrole
O O
N N O N N O
H H H H
indoline oxindole indoxil isatin
HO OH
NH2 NH2 O
N N N
H H H
tryptamine serotonine 3-indolylacetic acid
5-hydroxytryptamine heteroauxin
takes place in the
important for brain work plant growing
biosynthesis of indolealkaloids
hormone
Preparations
1/ Preparation of indole
H3C COOH
H3C COOH COOH
O ZnCl2 250oC
+
N -CO2
NH NH2 N N N
H H
H
CH3 KOC(CH3)3
O
-H2O
NH CH N
H
R2 R2 R2
+ CH2 ZnCl2 or
CH2
NH2 C polyphosphoric acid
C 1
N O 1 N N R -H2O, -NH3 N R1
R H H
H
N O
N OH cc. H2SO4 C H 2O
O
-NH3
N O N O N
H H isatin H
Zn/HCl
OH red. oxidation
Na/Hg
O O O H
red.
N N N
H H
oxindole
N
H O
indigo
b/ Heumann’s indigo synthesis
H
HO O
HO C NaNH2
+ Cl CH2 COOH
-HCl CH2 -H2O
NH2 N
H
O H
ONa
O2 N
Fe3+ N cis
N
H H O
Na2S2O4/NaOH
reduction O2 deep blue, insoluble in water
trans indigo
oxidation
it is reduced at first,
Na
then is oxidised O H
Indigofera tinctoria
N
colourless, water soluble
N leucoindigo
it is adsorbed and H O
keeps its colour Na
O O O
ONa NaOBr OH
NaOH
NH HCl CO2
NH2
NH2
O O
anthranilic acid
O O
O
OH ClCH2COOH OH KOH
CH2 melting
NH2 NH COOH N COOH
H
-CO2
O
H
N O
oxidation
N
H
O N
H
indigo
O O
OH HO OH O
+ Cl CH2 COOH
-HCl CH2 C OH
NH2 N
H
O O
KOH O2
melting OH -CO2 Fe3+
N N
H H
O
indoxil
indoxil-2-carboxylic acid
O H
O
N oxidation
N N O
H H
O
isatin
indigo
Chemical properties
1/ SEAr reactions
halogenation
goes to nitration
β position mainly sulfonation
N
H alkylation
acylation
2/ Other reactions
O
CHCl3 H
KOH
N N
H H
N N Cl N N
N
H
CH3
CH2N(CH 3)3
(CH3)2NH CH2N CH3I I
CH3
N HCH
H N gramine N
O H H
COOR KCN
H C NHCOCH3 CH2CH2NH2 CH2CN
COOR red.
KOH
- NH(CH3)2 N tryptamine N
H H
indole alkaloids
COOR
CH2 C NHCOCH3 hydrolysis,
COOR decarboxylation
N
H
H2/cat. H2/CuCrO 4
N N N
H H H
octahydroindole indoline
O
OR
CH3MgI ClCH2COOR
-CH4 N
N N
H H
Na MgI
K N NH2
-1/2 H2
-1/2 H2 H
N
N H
CO2
Na O
OH
N
K R X
N
H
N
R R
R: alkyl, acyl
N
H
Benzocondensed systems with five-membered heterocycle
SEAr
4 X: NH 1H-indole β (α)
5 3 (β)
O coumarone α
6 2 (α)
X S thiocoumarone β (α)
7 1
β
E alkylation (β)
E
acylation (β)
NH alkylation N rearrangement NH α sulfonation (α)
acylation
E
sulfonation
E : R
O
R C
SO2OH
H
O E coumarone
advantageous
E E
H H
E O O
disadvantageous
E
N N N
H H H
aromatic
1H-indole and nonaromatic
advantageous
thiocoumarone disadvantageous
E
E
S S S
Five-membered heterocycles with two
or more heteroatoms and their deri-
vatives with condensed ring systems
Compounds with two heteroatoms
Nomenclature
4 3 4 N3 4 3 4 N3 4 3 4 N3
5 N2 5 2 5 N2 5 2 5 N2 5 2
O1 O1 S1 S1 N N
H1 H1
isoxazole oxazole isothiazole thiazole pyrazole imidazole
1,2-oxazole 1,3-oxazole 1,2-thiazole 1,3-thiazole 1,2-diazole 1,3-diazole
Introduction of another nitrogen → the pyrrole-like properties are shifted to the pyridine-like properties,
e.g., at basicity, water solubility.
I/ Isoxazole and its derivatives
Preparations
nitrile oxide
1,3 - dipolar
one of the components (nitrile oxide)
is dipolar
C6H5 C 6H 5
C mesomers C1
the charged atoms (C, O)
N N are in 1,3 positions
O O
3
By 1,3-dipolar cycloaddition
1 1
R 1 R
a R a
a a
2 b
b+ + + b+ 2 b
R c 2 c R
c - R - c
E-olefin
dipól dipól
(dipolarofíl)
1 1
R 1 R
a R a
a a
2 b b+ + + b+ 2 b
R c 2 c R
c - R - c
1 1 1
R R R
a a
a a
2 b b+ + + b+ 2 b
R c c R
c - 2 - c
R
a a+ a b c a b c
a a+
C N N N N C
b b C N N N N N b b
+ +
c c C N O N N O c c
- - - -
H CH3 R R R
H2N OH
H3C N N N O
O - H2O O Cl - H2O Cl
OH HO
R=H
CH3
H2C C
H3C C N R = CH3
O HO
Chemical properties
E
2/ SEAr reactions
N N
R O R
O
R=H
N N
N NH
N S N O
H H
N O
OH OH
OH NH
H 3C H3C
1. 1.
HC NH2 Cl HC NH 1. PCl5
2. C C 3. 2. C C 3.
O - HCl H5C6 R 2. NaOH
H5C6 O R O O
H3C H 3C
N N
3.
3.
H 5C 6 R - H 2O H5C6 R
OO O
HH
1.
H2C NH2 Cl HC NH 4
1.
1. N3
HC C 3. CH C 1. 3.
- HCl
H3C OH O R H3C OH O R H 3C 5
O1 2 R
H 2-oxazoline derivative
.
C2
O R
1.
CH2 NH 1. NH
1.
HC 1. 2.
CH
H3C OH H3C O R
HO R
oxazolidine
derivative
More generally:
1 H
1 R 1
R NH2 Cl N R= CH3
C6H5
C 3 2
2 O R 3
O R O R
R
2
R = -H,-CH3,-C6H5
3
R = -CH3,-C6H5
a. a.
Cl H2N it is difficult to alkylate the amide nitrogen
N b. Cl HN C
O
O a. O
OH HO
N 6 π-electrons NH2 O NH
the nonbonding electron pair of O
takes part in the formation of an aromatic sextet R
O OH H R O
R R R
NH2 Cl N NH3 N
-HCl Ph
Ph O O Ph -H2O Ph O Ph N Ph
H
NH4OCOCH3
CH3COOH
Ph Ph
O H2N N
-HCl
Ph Cl X Ph Ph X Ph
-H2O
X: O, S, NH
Chemical properties
1/ SEAr reactions
4
N E
N N HOH NH CH2 NH
HO CH3 CH3
HO CH2 C CH3
O CH3 O OH O OH
OH O
2,4-oxazolidindione
NH2 Cl EtONa NH
C + HCl + H2O
O Cl O O O
OH O
2,5-oxazolidindione
O
H3C C N H3C C
H3C HCN H3O C OH ROH/H
C C
H3C OH H3C OH
H3C O
aceton-cyanhidrine
O O CH3
O H2N NH N
C OR ( CH3O )2SO2 H3C
H3C H3C
C H2N O )
H3C O O H 3C O O
H3C OH Ptimal
NH CH3 N
C
(CH3CO)2O CH3
O
OH O
O
O
O2N
cc. H2SO4 H Na2S2
H 2
2 cc. HNO3 160 oC EtOH
Cl
Cl
O O O
O2N O2N
HH Br2/CCl4 H
100 oC
S S S
Br
O2N H2N
cc. NH4OH N FeSO4 N ox.
benzene S alcohol S
red.
O O
1. CH3N2 H 2N
HO HO 2. H2NNH2 N
N N
HO -CO2 3. Curtius
S S degrad. S
1. NaNO2 /HCl N
2. H3PO2
S
3. base
isothiazole
SH SnCl2
S
cc. HCl N
NO2
thioanthranil
O rotation NH CONH2
NH3 C C
CO NH
O =
NH3
S NH2
SH SH
CONH2 COOH
H2O2
N 1. OH N 175 oC N
ox. 2. H3O -CO2
S S S
benzisothiazole
IV/ Thiazole and its derivatives
R1 2. H2N
O 3.
NH 3. N
1. S R 2 P2S5 3.
2
Br R1 OO R R1 S R2
R R R
NH2 Cl N NH3 N
-HCl Ph
Ph O O Ph -H2O Ph O Ph N Ph
H
NH4OCOCH3
CH3COOH
Ph Ph
O H2N N
-HCl
Ph Cl X Ph Ph X Ph
-H2O
X: O, S, NH
Chemical properties N N
E
E
1/ SEAr reactions S S
N N
E
E
S XH S XH
X=O, NH
2/ SNAr reactions
H3C H3C
N N
NaNH2 pyridine-like property
S S NH2
N N N N
melting
S NH NH S H2N S NH2
S
N N
NaNO2/HCl
0-5 oC
S S N N Cl
reduction Y = halogene, hydroxy, etc.
(see reactions of (aromatic) diazonium compounds)
N
S Y
3/ By oxidation
N N
ox.
H 3C HO
S S
O
thiazole ring is resistant to oxidation
2-thiazoline derivative
4 3
1. 1.
NH2 NH
O 2. 2.
1. 5 2
C 1.
SH H H S
1
thiazolidine
NH2 N
O 3.
3.
C
HO H S
Cl
benzo[d]thiazole
benzo[d][1,3]thiazole
CH3
NH O C CH3
NH C CH2 N
SH Cl
O S O
SO2 NH S
1.
Ultraseptyl
2. NaOH
NH C CH3 chemotherapeutic agent
O NH2 with antibacterial effect
H O R = H 6-aminopenicillanic acid (6-APA)
HOOC N
β O
H3C α
H3C S NH R R = C6H5 CH2 C
H H
benzylpenicillin
penam skeletone Penicillin G
(condensed ring system of thiazolidine and
R=
azetidine monocycles)
O
C C6H5
N
H3C O
Oxacillin (see at isothiazoles)
Β lactam ring is unstable group, sensitive to acids, to bases, as well as to penicillinase enzyme.
They are inhibitors of synthesis of cell walls. If a microorganism produces penicillinase, then it
will be resistant to the given penicillin derivative other derivative must be prepared.
Previously, penicillin derivatives were prepared from ferment solution, adding phenylacetic acid
to it, generating benzylpenicillin. Benzylpenicillin + enzyme 6-APA +R-COCl many
thousands penicillin derivatives.
Source: Penicillium notatum, P. crysogenum bacteria. Antibiotics are more uniform compounds,
than vitamins.
Antibiotics are natural compounds, produced by some microorganisms against other
microorganisms, blocking the latter. Fleming observed extinction spots, thus he had hard earned
the Nobel Prize.
Currently penicillin derivatives are prepared by semisynthesis methods: 6-APA is made to be
produced by bacteria. This was one of the first trials of biotechnology.
V/ Pyrazole and its derivatives
Preparations
R R
2. 2. 2.
R 2. O N
O NH2 R N
H R = H, alkyl
H2N
R H R
2.
R C C 2.
CH2 2.
2. C C N N
N R R
C N N
N H
R
NH3
N N
O pressure N
H
Chemical properties
1/ Acid-base properties
makes a H-bridge
weak base pKa = 2.5
(pyrrole< pyrazole< imidazole< pyridine)
very weak acid pKa = 14
(it is amphotheric compound)
H
3/ SEAr reactions E E
N N N N
N E N E N N
H H H H
E
advantageous not advantageous not advantageous
4 3
5
substitution on the C-4:
N2
N 1
bromination, nitration, sulfonation
H
O2N H2N
HO-NO2 H2 OH
N N N
N N N
H H H OH
NaNO2 / HCl
0-5 oC
Cl N N
coupling N
N
reaction N
N
H
N N
H
More important derivatives
O NH N
2
acrolein N
H2N H
2-pyrazoline
Br NH
NH2
Br N
H2N H
pyrazolidine
CH3 benzene
O
N
N 20 oC -benzoic acid
N N N
- H2O H
C C
O C 6H 5 O C6H5 indazole
N-benzoyl-N-nitrozotoluidine
CH3
CH3
NH
O N N
H HO N N
O N CH3
pyrazol-3-one
(CH3O)2SO2
tautomerism
antipyrin
CH3 CH3
H CH3 fever- and pain-killer compound
NaOEt CH C
O - H2O NH
O OEt C N tautomerism O
O N
NH2 N
- EtOH NH
norantipyrin
O O OH
tautomerism
NaOEt
OEt NH N
O OEt O N HO N
NH2
H H
H2N
O O O
tautomerism
NaOEt
OEt N N
O O N HO N
OEt
NH
NH
H9C4 O
H9C4 O
NaOEt
NH N
OEt
NH O N
O OEt
Phenylbutazone
inflammatory drug
E (NO, Br )
H C O
H O
H C
Br2
OH
H3C
N CH3
(CH3)2NH H3C Leukart-Wallach's
reductive methylation
N
O N CH3
Amidazophene
CH3
H2N CH3 CH N CH3 CH N CH3
CHO
N N CH3X N
O N CH3 O N CH3 O N CH3
CH3 CH3
HN CH3 O3S CH2 N CH3
HCHO
N HSO3 N
O N CH3 O N CH3
H3O SO2OH
CH2OH
Methamisole
VI/ Imidazole and its derivatives
Preparations
C6H5 1. C6H5
CH NH2 Cl CH NH
2. 3.
C C C C
C6H5 O O R C6H5 O O R
O C 6H 5
CH3C O NH4 N
3.
3.
C 6H 5 N R
H
R R
NH2 Cl N
-HCl
Ph O S R' -H2O Ph S R'
R R R
NH2 Cl N NH3 N
-HCl Ph
Ph O O Ph -H2O Ph O Ph N Ph
H
NH4OCOCH3
CH3COOH
Ph Ph
O H2N N
-HCl
Ph Cl X Ph Ph X Ph
-H2O
X: O, S, NH
R1 O R2
pyridine, water, NaOH
HOOC CH NH C CH NH2 + N C S
pH=9, 40 o C
R1 O R2 R1 R2
CH3NO2 NH
HOOC CH NH C CH NH HOOC CH NH3 Cl +
HCl
C O N S
HN S
thiohydantoin
N H
H pKa 14.5 N NH
real
tautomerism
R N R N
H
as base as acid
H
N tautomers N N N
N N N N
H H
-H +H -H +H mesomers
NH NH
N
mesomers
N N
H H
N
3/ By SEAr reactions
N N 1. 1.
Y NH2 O 3. N
-X C 3.
N X N Y 1. 1.
H H HO R N R
NH2
H
X =Cl, Br
R = H, alkyl 2-imidazoline derivative
1. Ar 1. Ar
N N
H O
1. CH2 1. 2.
NH N
2.
Ar Ar
imidazolidine derivative
H5C6 H 5C 6
1. 1.
H2N H 5C 6 NH diphenylhydantoin
H5C6 C OH
3. 4. 3. 4.
C phenytoin
N O O N O
O OH H Diphedan
H2
diphenylglycolic acid
O O H
C NH 4. 1. N 4.
3. C OH H2N 4. 3.
C O red.
C O O
3. C OH 3. 3.
H 2N C NH
O N hydantoin
O O H
parabanic acid
H 1. H
1. NH3 Cl N N N 4.
4. HgO
S S O
C
3. S K N 3.
N N N
O OR O O H2 O H O H
R
O CH2 COOH O
CH C C CH2 CH COOH
N H HN N H2 N
C O N O NH2
hydrolysis
C
N N N
H H H histidine
azlactone essential amino acid
CH2 CH2
N histamine
NH2 biogenic amine
-CO2 generated in allergic reactions
N
H
2
R
2 2 NH2 2 NH COOH R
KCN, (NH4)2CO3 R R 3
R NH
C O C C
3 CO2, pressure 3 3
R R C R C HN O
O
N N
2 2
R R
H2O R
3
NH R1 X R
3
NH
O OH O
O N O N
H
1
R
R1 R2 R3
Phenytoin H
Diphedan antiepilepticum
Sacerno antiepilepticum
NH H 2N X NH2 X NH2
R NH C + R NH C R NH C
S CH3 H 2N S CH3 S CH3
- CH3SH R1
- CH3SH
- NH3 NH
- HX
R2
N
R NH C NH
N R NH C
H N R1
R2
C2H5OH NH
CH2 CN CH2 C
HCl OC2H5
CH2 CH2
200oC H2N
NH2 NH2.HCl
N H2N
CH2
N
H
tolazoline sympatholytic
CH3 CH2 Br CH2CN
N
CH2CN CH2
N
H2N CH2 CH2 NH2 / HCl H
melting
Naphazoline
X' H H
O N N
S
Cl2 / H2O, H2SO4
R: Cl
N N N
X" H
Ph
N N
R NH2 + R NH
Cl N X N
H H
NH2 POCl3 X
1) PhSCN R N X
2) CH3SO2Cl NH NH2
C
Cl NH2 X
R'
NH POCl3
R' NH2
R N C N Ph R NH C N Ph
1
NH2
OH NH
+
2
NH2 O H N
3
Br C N benzimidazole
- HBr
NH
C N NH NH
NH NH NH N NH2
H benzimidazol-2-amine
Monocyclic compounds with more
than two heteroatoms
I/ Triazoles and its derivatives
4 3 4 3 4 3
N N NH2
HO 5 N
2 2 2
5 5 N N
N N 6
N1 N 1
NH2 O N1
H H H
1,2,3-triazole 1,2,4-triazole 1,2,3-benzotriazole
R R R
NH
NH N
N
N N N
R R N R N
H H
acetylene azoimide
derivative
H
ROOC ROOC N stereospecific reaction
H N geometry of the starting material and
H
N N of the final product are identical
ROOC
N Huisgen
ROOC H N for 1,2,3-triazoles
R alkylazide R
dialkyl maleate
R R
H3N O N
O
NH N
R N R N
H H
1,2,4-triazoles
II/ Tetrazole and its derivatives
4 3 4 3
N N N N N N N N
5 N 2 NH C N N
2
N1 N1 H N N
H H
H
1H-tetrazole 2H-tetrazole
H N N N
O
hydrogen azide
O
(azoimide)
- N2 NH
H N N N
mesomers
N
Pentetrazol N
analeptic agent N N
1,5-pentamethylenetetrazole
III/ Thiadiazole and its derivatives
4 3 4 3
4 3 4 3
N N N N
5 N 5 N 5 N N 5 2
2 2 2
S S S S
1 1 1 1
NH NH2 N N (CH3CO)2O N N
C C
S S H2N S SH HN S SH
H2N S
C
thiosemicarbazide O CH3
N N N N
O NH3 O
HN S S Cl HN S S NH2
C O C O
O CH3 O CH3
Fonurit
Diamox
diuretic compound
with carboanhydrase blocking effect
IV/ Oxadiazole and its derivatives
4 3 4 3 4 3
3 4
N N N N
5 N2 5 N2 5 N N2 5
2
O O O O
1 1 1 1
1,2,3-oxadiazole 1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole
(azoxime) (furazane)
H3C CH3
H3C CH3 H 3C CH3
C C C C
N N - H2O N N
O O
O
OH HO
+ 2 H2N OH
dimethyl glyoxime
N N
HN NH
symmetric diacyl
hydrazine
Prenoxdiazine
H2NOH.HCl
H2N
N C Na2CO3
HO N
N Cl
N N O
O N
Libexin
O HN
2
N
O N
Less frequent heterocyclic rings and
ring systems
I/ Dioxolanes and dithiolanes
3 4 3 4 3 4 3
4
O S
5 2
5 O2 5 2 5 S 2
O O S S
1 1 1 1
OH O
tosylic acid
O CaCl2
CH2
OH O
Br Na2S S
Br S
II/ Crown ethers and cryptands
O O O
O O O O
Na
Li O O K
O O O O
O O
H 2C C CH2
NH3/ H2
O CH2 O CH2 70 atm,70 oC
C HO C NH2 -2 H2O N
OH HO
OH
O O O O O
8 1
7
LiAlH4
6 N 2
4
5 3
pyrrolizidine
(in alkaloids)
Six-membered heterocyclic compounds
with one heteroatom and their
derivatives with condensed ring system
I/ Pyrane and its derivatives
Nomenclature
H
4 4 4
5 3 5 3 5 3
6 6 6 X
O 2 H O 2 O 2
1 1 1
2H-pyrane 4H-pyrane pyrilium salt
α-pyrane γ-pyrane the benzopyrilium salts
these are not stable compounds are stable compounds
Preparations
C6H5 C6H5
C6H5
C
O H H5C6 OH O C6H5
H5C6 OO C6H5 H
H3C H3C
H5C6 O O C6H5
C6H5 C6H5
H3O oxidation
pyrilium salt
O acetone O O
H3O
C
CH2 CH2 R-ONa H aqueous acid
H H - 2ROH anhydrous
ROOC OO COOR acid ROOC O COOR
OR OR
ROOC O O COOR
dialkyl oxalate
O O O OH
tautom.
NH3
-2CO2
HOOC O COOH HOOC N COOH N N
H H
Cu
γ-pyrone derivative γ-pyridone derivative γ-pyridone 4-hydroxypyridine
( chelidonic acid)
O O O
-2CO2 O
O NH
O N acid amide
O H ester
vinylogous
ester
O acid amide
γ-pyrone
O
C
H 2C CH2
NaOEt/EtOH O
H H anhydrous anhydrous
hydrochloric acid
OEt OEt heating
EtOOC COOEt
EtOOC O O COOEt O O
O O
aqueous
hydrochloric acid NH3
O O OH
heating
HOOC N COOH N N
H H
OH
HOOC H O H
NaOH HOOC H
C
H aqueous medium
H O heating H O
HO O O HO
OH
H
HOOC H HOOC
heating heating
-2H2O -CO2
H O O O
OH OH
CH3NH2 / H2O
pressure, boiling
O O N O
CH3
More important derivatives
O
4
5 3
6 2
O O O O O
1
3,4-dihydro- tetrahydro 2H-pyran--2-one 4H-pyran--4-one
-2H-pyran -pyran α-pyrone γ-pyrone
O O O
α-chromen chroman γ-chromen
2H-chromen (stable) 4H-chromen (unstable)
O O
O O O O O O
2H-chromen-2-one α-chromanone γ-chromanone 4H-chromen-4-one
α-chromone γ-chromone
coumarin
O
O
4
chroman isochroman
5 5 4 5 4
6 3 6 3 6 3
7 2 7 2 7 O 2
O O
8 1 8 1 8 1
2H-chromen 4H-chromen isochromen
O
O O O O
coumarin chromone isocoumarin
O
O O O O
2-chromanone 4-chromanone isochromanone
(dihydrocoumarin) (dihydrochromone) (dihydroisocoumarin)
+
O -
+ X
O
chromilium salt isobenzopyrilium salt
(benzopyrilium salt)
H
Al2O3 H 3O
O CH2 OH 350 oC O
- H 2O O HO
Raney
Ni/H2
H3O ROH
protection of
alcoholic
O
OH
RO O
Br
KOH 1,7-heptandiamine
O O
Nylon 77
(see at tetrahydrofuran)
OH
H
HOOC H HOOC
O -2 H2O - CO2
H O O O O O
aldol
dimeri- α-pyrone
sation HOOC
H OH
enol
R = H α-pyridone
O R = CH3 N-methyl-
H
HOOC H α-pyridone N O
R
C
H O HO O
formylacetic acid
O O
4.08 D measured 22 D
1.75 D calculated
oxo reagents
H2N NH2
O or
H3C O H there is no reaction
HO NH2
1. CH3MgI
2. H2O H
O O stable
it is an ester, O
+HCl it can be Br2
hydrolysed base Br Br
-H2O
by base substitution
(vinylogous (it is not addition)
ester) O O
CH3
O
HO OH
O Cl shifted to the
oxo form
pyrilium salt
O O
aromatic
it can be isolated from
wheat germ oil
Vitamin E it participates in
α-Tocopherol keeping pregnancy
CH3
(tokos: birth, ferein: carry)
HO
* * CH3
*
H3C O
CH3 CH3 CH3 CH3
CH3
OH OH
dicoumarol
an anticoagulant these differ from each
(its antidote is Vitamin K) other in the position of a
O OO O
tautomers H (H anion) and of
a double bond
H
H
(difference lays at oxo-enol taumerism
in differences in mobile H as well as
O O H position of a double bond)
4H-pyran 2H-pyran
-H
oxidation
C6H5
stable aromatic
not existing compound
O H5C6 O C6H5
ClO4
Anthocyanines
These derivatives are compounds with conjugated double bonds (conjugated: 2H-pyran,
or isolated: 4H-pyran) (heterocyclic alkenes). The compounds are reactive ones with high
energy content.
hydrolysis
Anthocyanines are glycosides anthocyanidine (aglycon) + sugar component
Flavinium salts: coloured materials of plants with glycoside type (flower petals, fruits, strawberry,
pelargonium, red poppy, black grape, bluebonnet, chrysanthemum): these might be red, purple,
violet, blue
α-Chromene derivatives are polyhydroxy compounds with 5 hydroxy groups. Its derivatives occur
in the nature only, e.g., methyl ether, acetyl derivative, or with free hydroxy groups.
The glycoside structure is the remnant of molecular phylogenesis, representing its carbohydrate
origine.
Cyanin (greek) – blue
The actual colour depends on pH of cells as well as on depth of layers, since coloured components
do not move freely within the cells, these form layers. Blue colour of bluebonnet and red colour of
red poppy comes from the same molecule.
Colour depends on: 1. pH value
2. number of hydroxy groups
3. the actual form of hydroxy group (free, methyl ether, glycoside)
4. position of glycoside group
OH OH
OH OH
-H
+H
HO O HO O
sp2 OH O
OH O H
cyanidine chloride salt anhydro base
pH = 3 red (red poppy) pH = 8 violet (bluebonnet)
+H2O
+H
- H 2O +H -H
OH OH
OH OH
sp3
HO O HO O
HO
OH O
OH O
pseudobase pH = 11
colourless blue (flower petals)
These differ in the number and positions of hydroxy groups, in quality and
position of the sugar components.
Source of red colour can be carotenoids (red pepper), while other carotenoids
are yellow.
White colour of flower petals come from the colourless air, but from not a
coloured material.
There is sp2 conjugated system in cyanidine chloride, where the pyrilium salt is
the auxochrome component.
Appearence of a sp3 carbon separates the two chromophores, resulting in no
absorbance in the coloured range.
Flavonoids Colour of tulips and other plants by springtime.
There can be 4 types of hydroxy derivatives (free,
Yellow colour of yellow plants (flavus – yellow) methyl ether, acetoxy derivative or glycoside),
γ-chromene derivatives similarly to the anthocyanines.
Ο Ο
5 4
6 3
ΟΗ
7 ∗
Ο 2 Ο Ο
8 1
Ο Ο Ο
Ο Ο
x
Ο
2-phenyl-2H-chromene flavinium salt isoflavone
O O O
CH3 Cl CH3
pyridine
O
OH O C
O
O
KOH glacial acetic acid
pyridine H2SO4 ,
OH O
50 oC -H2O
O
OH OH
H OH
HO HO
O O
O O
O OH Prof. Géza Zemplén
O Technical University at Budapest :
he was a flavonoid
HO O researcher
rutin OH flavanol type
D - glucose L- ramnose
coloured dye of OH
Ruta graveolens rutinose
Vitamine P: discovered by Szent-Györgyi, Rusznyák, Bruchner
It decreases permeability of capillaries, increasing their resistance.
OH O
erythrodicthiol + hesperidin
R=H R = CH3
sugar O O
OR
OH
O O O
Na
Et O
OH O O O OH
C H
H O
- H2O
isoflavone
O
O
O CH3 C
+ O / NaOAc
CH3 C - H2O - CH3COOH
OH O O
O O
H
salicylic aldehyde O CH3
Perkin-synthesis
O O
coumarin
O O H O
1) KOH /EtOH
CH3 H / MeOH
+ or
2) H NaOAc/MeOH
OH O H
hydroxychalcone
OH O
O O
H
flavanone
Anthocyanines: α-chromene derivatives
Flavonoids: γ-chromene derivatives
Anhydrobases: compounds forming salts with acids without generating water (see the
examples on the previous slides)
Pseudobases: some secondary carbons with OH can dissociate to hydroxy, similarly to the
effect of bases pseudobases
- OH
H OH
+ OH
O OH O N OH
R
OH OH
+ OH N
+ OH
O O N R
R
anhydrobase
H
H H
H
O O
OH O H + H2O
OH H O
I II OH
compound II is an anhydrobase, since it contains one water molecule less, than compound I
OH OH O
+ OH
X OH II
- H2O
O does not run O H O
I anhydrobase
xanthydrol
red.
O
O O
8 1
Cl
7 2
6 3
O O O
5 4
xanthene xanthone
CH3
OH
COONa
CH3
O CH3
HO O O tetrahydrocannabinol
fluorescein indicator psychotomimetic agent
Cannabis indica
II/ Thiapyran and its derivatives
O
Structure
S S S
α-thiapyran γ-thiapyran tetrahydrothiapyrone
Preparation Na2S
EtOH
Br Br S
tetrahydrothiapyran
S S O S
α-thiachromene thiacoumarin thiaxanthone
S S S
thiachroman γ-thiachromone thiaxanthene
III/ Pyridine and its derivatives
Structure
X X
N O N
H
picolines: CH3
CH3
N CH3 N N
α β γ
aldehyde
ethyl acetoacetate
O R O O R O
H H atmospheric
OO N N
HH H H
N
3/ From 1,5-dioxo compounds
H 3O
R OO R R OO R R O R
HH
NH3 ox.
R N R R N R
4/ By isosteric exchange
5/ By Chichibabin synthesis
CH3
CH3
C - 3H2O
O H -2H
H 3C CH3 H 3C N CH3
(oxidation)
C C collidine
H3C O O CH3
NH3
Physical properties
Chemical properties
1/ Acid-base properties
The compounds are stable against acids (salt formation), while are somewhat labile to bases
(hydrolysis), except for pyridine. Base sensitivity increases by the number of heteroatoms.
Pyridine is of basic property – introduction a second N decreases basicity.
+Η
Ν pKa = 5.2 Ν
Η
2/ Tautomerism This is function of solvent, of pH, of structure, and of functional group(s)
NH2 NH
tautomerism tautomerism
N NH2 N NH N N
H H
amino amidine amino vinylogous amidine
tautomerism mesomerism
N OH N O N O
H H
lactim lactam
OH O O
tautomerism mesomerism
N N N
H H
vinylogous lactim vinylogous lactam
OH O
protomerism
there is no tauto-
merism
N N
H
N α XH N X N X
H
H
XH X X
N N N
H
gas phase H
in polar solvents
XH X
N N
H
X = O, S, NH in water only;
50% ratio of it
* Sulfur trioxide absorbs the water generated in the reaction. KNO3 is less volatile, than HNO3. HNO3 is generated in the reaction
mixture.
Pyridinium ion withdraw electrons from ring carbons even more.
Pyridine reacts in SEAr reactions with difficulties due to two reasons:
a) electron density is decreased in α- or in γ-positions especially, the least in β-position
b) Protonation of the N atom (NH+) increases electronegativity of N, thus withdrawing electrons from the ring carbons even more.
4/ SNAr reactions It takes place in α- and γ-positions mainly due to the lower electron density in these
positions
NaH is deprotonating the amidine NH2, resulting in H2.
The reaction becomes irreversible, since H− is the leaving group, and it reacts with
α-substitution: the proton source NaH.
acid amidine
system
Na-NH2, liq. NH3
H
N -33 oC N NH2 N NH2
Na
+NaH
H2O
N NH2 N NH
α-pyridinamine Na +H2
RMgX RMgX
150 oC
N N R R N R
Regioselective α- and γ-substitution
N X
CH3
alkyl pyridinium salt
HO M KCN
C N
N C H
K3 FeIII(CN)6
H I2
N O N OH oxidation
N N
CH3 CH3
MX CH3 CH3
+KX
NH2
Cl NH2
KNH2/NH3 liq. + NH3 γ-substitution
- 33 °C +
N - HCl N N N
KCN H α-substitution
- KI - CH3OH
N N CN N CN
I
OCH3 OCH3
Pyridine in nucleophilic reactions
H H H
N NH2 N NH2 N NH2
N N N
H H H
N Br N Br N Br
Br Br Br
Y H H H
N N N N
Y = Br
Br H Br H Br H
N N N
In ground state
There are lower electron densities in α- and γ-positions
In nucleophilic reactions
The ring N causes –Iα>-Iγ, the β carbon does not react. The negative charge in
the intermediate can appear on the N, as well.
In electrophilic reactions
The relatively highest electron density is found on the β ring carbon, since there
is no positive charge on the N, and moreover, there is no positive charge in any
mesomers if β-substitution takes place.
N N N N N
5/ Reactions at a lone pair of electrons
oxidation
H2O2
HX CH3COOH
pyridin-N-oxide
PCl3
N X N N
H X = Cl
O O O
R-I I-I O C
SO3 R C X R
Thus pyridine
X is catalysing
acylation
N
N N N I
I C
R O S O I R
O
O R' OH
+HX
N
Reactions of pyridin-N-oxide
One of the nonbonding orbitals of oxygen can be coplanar (in the same
plane) to the combining p AO-s of the ring atom. Thus, the +M effect of the
oxygen is overcompensating the -I effect of the nitrogen, resulting in
O N electron richness in α- és γ- positions of the ring. One electron is excited to
the LUMO orbital. Size of delocalisation is increased.
NO2 NO2 NH2
Not at 300 oC-on, like for pyridine t = 200 oC the difference in reactivities is 108 times
NO2
H NO2 O
Hg(OCCH3)2
-H the electrophile
N N N N Hg
goes into
O O O α-position O O
σ-complex C
O CH3
control of orbitals are the reasons of α-, or γ-selectivity
control of charges
X NO2
H2SO4
N N N N
O O O OH
X = NH2, Br, Cl, CN
SO2OH SO2OH
MgBr H2SO4
N N N
nucleophilic reaction
OH
SO3
SO2O
N N N
H
O S O
O
6/ Addition reactions
The Diels-Alder reaction has a very complex mechanism with pyridine, the reaction is not concerted
(asynchronous) and the final product is formed by aromatic stabilization of the previous, coloured
intermediate.
CH3
CH3
O CH3
O O O CH3
O O
+ O
O CH3 N
O
2 O O
O
O CH N
3
O
O CH3 O
O O CH3
dimethyl acetylene- O O
dicarboxylate CH3
CH3
oxidation by red intermediate
Hg(OCOCH3)2
ring closure
O O CH
3
O CH3 O O CH
3
H O CH3
O
N O O
N O
O CH3
O O CH3
O CH3
O O CH3
colourless product
yellow product
7/ Reduction Ni or Pd
piperidine
H2
N N
H
Reduction is the easiest, if the compound has strong electron absence.
NaBH4
+NaCl
N K3 FeIII(CN)6 N
Cl
CH3 CH3
O O
reduction H H
NH2 +H NH2
N -H N
R oxidation R R = H nicotinic acid amide
8/ Oxidation 9/ Polymerisation
The stronger the electron absence, the more difficult is the It does not run, in the contrary of five-membered
oxidation. heterocycles.
There is no ring opening for pyridine by oxidation.
Formation of N-oxide is possible from pyridine.
There is active H at α- and γ-methyl groups
for heterocycles with π-electron deficiency
-H
R R
N CH2 N CH2
C C
O CH2 H HO CH2
CH2 H CH2
-H
CH2 H CH2
N N
N N CH2 CH2
H
N N N N N
N CH2 N CH2 N CH2
CH2 CH2
N N
N CH2 N CH2 H H H
X=CH3, O X X
10/ Reactions of the active C-H group
O
CH3 C H
O
N CH2 H HO N CH2 CH CH3
H
HO H D (deuterium)
-H2O exchange is possible OH
N CH CH CH3
H
mesomers -H2O
N CH2 N CH2
N CH CH CH3
Na/EtOH
N CH2 CH2 CH3
H
racemic coniin
More important derivatives nicotine: the very poisonous alkaloid of tobacco (Nicotiana tabacum)
O O
H
OH )N cc. HNO3 OH
OH
N N CH3
N N coenzyme complex belonging
O O to the vitamin B group
2-picolinic acid nicotinic acid it is oxidised
at this carbon NH2
O OH
N
isonicotinic acid
O OH O OCH2CH3 O NH NH2
CH3
N CH3
chloropyramine (Synopen) R
an antihistaminic drug pyridoxine -CH2OH
(pyridoxol vitamin B6 ) their phosphate ester is used
in coenzymes of transaminating
pyridoxal C O and of redoxy reactions
H
pyridoxamine CH2 NH2
H2 /cat.
- NH4Cl Cl
N N
H NH2 NH3
piperidine
NaNH2
CN
C CN C O
H H Na Na CN
-2NaCl CH3CH2OH OCH2CH3
compound with
actíve methylene group H2SO4
HH Cl Cl Dolargan, meperidine
OH OO N N (pethidine)
2 SOCl2 CH2 CH2
CH3NH2 CH3 CH3 morphine substitute
CH2 CH2
H
N N
O
O CH3 N
CH3
CH3
nitrogen mustard
O MgBr
C O
H H -H2O then H2O OH
CH2 C CH2 CH2 N
C + C
H CH2 CH2 N
O N
HCl
H Parkan
Mannich reaction an antiparkinson drug
Indolizine, indolizidine
8
7 1
6 N 2 N
4
5 3
indolizine indolizidine
(in alkaloids)
Quinolizine, quinolizidine
COOR 9a
Diels- COOR
COOR Alder 9 H 1
COOR 2
reaction 8
7
+ 4 CO2
N N N 3
COOR 5
COOR 6 4
dialkyl acetylenedicarboxylate
H2
N N
2
1 3
5 4 5 4 8 9 10
1
4
6 3 6 3 7 2 9
7 b c b c
7 2 6 8 5
2 N 3 N
8
N 1 5 N 4 7 6
1 8
10
quinoline isoquinoline acridine phenanthridine
benzo[b]pyridine benzo[c]pyridine benzo[b]quinoline benzo[c]quinoline
9a
9 1 9 1 9 H 1
8 H 2 2
2 8 8
7 3 3 3
N 7 N 7 N N
6 5 6
5 4 5 X
4 6 4
H
2H-quinolizine 4H-quinolizine 9aH-quinolizine dehydroquinolizinium salt
Quinoline
Preparations
1/ By Skraup synthesis
H CH O H glycerol
Michael-type addition
HC OH
H
CH2 OH
NH2 O
cc.H2SO4
aniline O - 2H2O
CH
CH H
CH2
CH
cc.H2SO4 CH2
(it is not formation CH2 N
of Schiff-base) H
acrolein
OH
H NO2
N CH3
Chemical properties
SE SN
These are similar to of pyridine:
5 4
SE reaction takes place at the carbocycle, in
position 5, or 8 bromination
SN reaction takes place at the heterocycle, in nitration SE Ar
position 2, or 4 2 sulfonation
8 N
SN
SE
oxidation: the carbocycle is oxidized in basic medium,
1/ Oxidation while the heterocycle is oxidized in acidic medium
O O
OH KMnO4 KMnO4 HO
OH H HO HO
N N
O O
2/ Reduction Ni/130 oC Pt/acetic acid
the carbons of heterocycle have low
electron density, therefore oxidation of
H H the carbocycle takes place in neutral/
basic medium. Protonation of the N helps
improving acidity of the heterocycle,
trans therefore phthalic acid is prepared in
N cis N
H H acidic medium.
H H
reduction: depends on
catalyst and solvent
3/ Electrophilic reactions
E
5
6
E
+
N N N
8
E
E = SO2OH E
N
kinetic control
H SO 2OH
+
H2SO 4/H
+
N -H N
SO 2OH
H2SO 4
kinetic
+
+H control +
-H thermodynamic N
control +
-H
+
+H
SO 2OH
SO 2OH
thermodynamic
control
N N
H H (see below) H H
N SO 2OH
H H
X X X
X H
H
H
H
N N H N N
A A N N
H H
H H
X X X X
H H
N N H N N A
N N A
H H
A: advantageous
N: not preferred
4/ Nucleophilic reactions KCN
O Cl
Cl
N N CN
C C
Chichibabin reaction O O C6H5
main product
NaNH2 Li H3O
H
N NH2 N N
+ Li
NH2 N COOH
HO CH3I oxidation by
-LiH C
nitrobenzene O C6H5
N UV light
N OH N I
N
PCl5 CH3
+ OH
HO N
OH KCN
O
CN CN
N Cl
N I2
Cl PCl5
N oxidation N
NH3 HO I
CH3 CH3
N
UV light
NH3
O OH
NH2 CN
HO
N NH2 N N N
More important derivatives
O OH
CH3
CrO3 oxidation
cinchonine
oxidation
N CH3 N N
quinaldine lepidine
O OH
Atophen (aciphenoquinoline)
drug against gout and joint diseases
SN (NaNH2)
O SE mainly
9
H (nitration)
dehydration 2
N N
H 4
SE
drugs and dyes with acridine skeletone
Plasmochin (Chloroquin): against malaria. There were many patients infected with malaria during the II.
World War in Japan, due to the tropical climate. There was international cooperation for drugs against malaria:
100 thousand compounds were tested during 3 years, and 11 compounds became drugs.
CH2CH3
H3C CH CH2 CH2 CH2 N
NH CH2CH3
8 1 8 1
7
N 2 N N 2
7
Cl N 6 3 6 3
Plasmochin N5 4 5 4
1,5-naphthiridine 1,8-naphthiridine
8-Hydroxyquinoline (Chinosan) pyrido[3,2-b]pyridine pyrido[2,3-b]pyridine
H Al, Fe
makes insoluble complexes with heavy metals
(see analytical chemistry)
N
O H alkaloids with quinoline skeletone (see alkaloids)
OH OH OH
NH2 CH2 N N
Skraup Cl2 I2 /KI
O CH synthesis SEAr
CH
OH Cl
I N
Cl
Enteroseptol
CH3O CH3O
H2N NH2
N N
O
NH NH
Primaquin
O
O O
CH3CH(CH2)3 Br K N CH3CH(CH2)3 N
Br Br
O O
Phenanthridine
H N N
O NH2 benzalaniline
1. CH3I
2. NaOH
oxidation
N N N
CH3 CH3 CH3
O OH HO
Preparations
1/ Bischler-Napieralski synthesis
(R CO) 2O ZnCl2 or
or O H N polyphosph-
NH2 R C oric acid
O H
Cl
β-phenylethylamine R
may contain
also P2O5
Pd / 160 oC
- H2O N dehydrogenation N
- PdH2
R (palladium hydride) R
2/ By Pictet-Spengler synthesis
Chemical properties
N
1
(8)
SE SN
(minor)
1/ By oxidation The carbons of heterocycle have low electron density, therefore oxidation
of the carbocycle takes place in neutral / basic medium. Protonation of the
N helps improving acidity of the heterocycle, therefore phthalic acid is
prepared in acidic medium.
O O
OH KMnO4 KMnO4 HO
OH H N HO HO N
H H
2/ By reduction
NH NH
H H
cis trans
4 : 1
3/ By electrophilic reactions
E
5
E
+
N N N
8
E
E = SO2OH
4/ By nucleophilic reactions
NaNH2 CH3MgI
N N N
NH2 CH3
CH3I
I KOH oxidation X
N N N CH
CH3 CH3 3
OH OH
More important derivatives
O O
CH3O CH3O
OH
CH3O CH3O
P2O5 / toluene
NH boiling N
CH3O O CH3O
- 2H2O
OCH3 OCH3
papaverine OCH3
OCH3
N
N
N
N N N
pyridazine pyrimidine pyrazine
1,2-diazine 1,3-diazine 1,4-diazine
Similar heteroaromatic compounds with oxygens or sulfur atoms are not important, their partial or
fullly saturated derivatives only. Introduction of the second nitrogen makes the derivative with even
more π-electron deficient.
N
N N N
N N
cinnoline phthalazine benzo[c ]cinnoline
Preparations
O O H + + OH + +
-H /+H +H /-H
R R C N R' R C N R' R C N R'
R' -H2O
H2N R'' R' H R' H R'
O
R + R C N NHR'
H2N NHR'
R' R'
hydrazone
Amide structural unit Hydrazide structural unit
O O
Cl Cl
HN HN
N N
Cl Cl
O H R + - O
O -H /-X
R R' N C R
X X NHR'
H
amide
R' NH2
R: alkyl, aryl
R': alkyl, aryl,
O
X: halogen, OC R
O O
R + H2N NHR' R
X NHNHR'
hydrazide
Mechanism
O O O
O Cl
Cl AN Cl E δ+ Cl
HO HO HO
O Cl O -H /-H HO -H2O H2N N
Cl Cl Cl
δ+ H
HO H H N
H H NH2
N
NH2 SNi
OH O
HO O
Cl Cl H
N HN Cl
H N
N N
Cl Cl -H N
Cl
lactim lactam
3 3
R R
R1 R
1
NH2 O N
+
NH2 O 2 N
R 2
R
R4 R
4
O O
1 1
R R
NH2 HO HN
+
NH2 O 2 N
R 2
R
3
R R3
O O
1
R R1
NH2 HO HN
+
NH2 HO 2 N
R R2
O OH
O O
1
R R1
NH2 HN
+ O
NH2 2 N
R 2
R
O
OH
CH3 CH3 CH3
4
CH2 NaNO2 / HCl / H2O CH2 3
0-5oC - HCl N2
NH2 N N Cl N
1
4-methylcinnoline
Ar N N Ar N N
electrophile
O O
CH3 CH3 N
N N N Cl N N
O N O N
CH3 CH3
pyrimido[5,4-c]cinnoline
ring system
O O
NH2 hydrazinolysis NH
O +
NH2 NH
O O
phthalic anhydride phthalic acid hydrazide
NH POCl3 N 2 H2N-NH2 N
NH 150 oC N N
O Cl NH NH2
Nepresor
decreasing blood pressure
Basic strength in aqueous solution
N
N
N
N N N
N
N
N
N N
N H
H H
Pyrimidine and its derivatives
R R
Preparations 1. NH if R = H
O N
+ pyrimidine
-2H2O
R O H2N R
R N R
CH3 CH3 CH3
4
2. O 5 NH N
NH2 -H2O 3
+ 6 2
O OR -EtOH O N1 O HO N OH
H2N O
H
O O Cl
NH2
3. OR NaOEt NH POCl3 N
+
H2N O - ROH
O OR O N O Cl N Cl
H
HI reduction
O O
R1 NH2
R1
R2 OR NaOEt NH N
+ H2N O R2
- ROH
O OR O N O N
H
barbituric acid pyrimidine
derivative
O O
NH2
4. OR NaOEt NH
+ HN O
N H HN N O
H
addition step
O O
OR H 2N NH
5. +
O OR H2N NH O N NH
H
O O
OR H2N NH
6. +
O OR H 2N S O N S
H
R R
H 2N
O NH
7. +
H 2N O
R O R N O
R' R
O H 2N N
8. +
O OR H 2N S HO N SH
R' = CH3
Basethyrin
hyperthyreotic
compound
R1 R2 R3 X
O
R1 R 3 Amobarbital C2H5 CH2 CH2 CH
CH3
H O
2 N CH3
R Dorlotyn (narcotic, with medium length)
}
long
medium
The efficient
period depends
Phenobarbital C 2H 5 H O
short on the excretion
ultrashort Sevenal (narcotic, long, antiepileptic agent)
CH2 CH3
Inactin C2H5 CH H S
CH3
Venobarbital (parapulmonar narcotic agent)
O O O
C OEt C OEt C OEt
1. OEt 1. OEt R1
1 C
C H2 1 R CH 2 2
2. R X 2. R X R
C OEt C OEt C OEt
O O O
R O
H N 1
R
R
1 COOEt C2H5ONa R
C X N
2 C + 2
R COOEt EtOH R
H N
-2EtOH O N X
H H
R = H, CH3 H 3O
X = O, S, NH (X = NH)
R NH O
HN 2 2
1 CN C2H5ONa R R HO R R
R N 3 N
2 C + C X 1 1
R COOEt R (X = NH) R
H 2N
R = H, CH3 O N X O N O
H H
X = O, S, NH barbituric acid
derivative
O O
R CH CH (CH2)n CH2
OEt OEt
+ R CH CH (CH2)n CH2 X
O OEt O OEt
O O
(CH2)n-1
OEt OEt
+ X (CH2)n X H2C
O OEt O OEt
O O O O
EtO OEt EtO OEt
+ X (CH2)n X + (CH2)n
EtO OEt EtO OEt
O O O O
O O O O
EtO OEt EtO OEt
+ O C (CH2)n C O + CH (CH2)n CH
EtO H H OEt EtO OEt
O O O O
NH2 NH2
H2N
H2N X
X: O, S, NH
CH3 CH3
CH3
N N
O
O N O N X
O OEt H H
O O O
OEt NH NH
O OEt O N O N X
H H
NH NH
C N
NH NH
C
N HN N HN N X
H H
Chemical properties
O
4
H
NH 5 N3 NH
H2
6 2
O N O N1 N
H H
pyrimidine 1,3-diazacyclohexane
active H
O R H O
O C
NH R C NH
H
O N O O N O
H H
4. Resists oxidation: the substituents are oxidised only
O OH
CH3
N oxidation N
N KMnO4
N
5. There is tautomerism at hydroxy- and at aminoderivatives, e.g.,
O N O O N O
H H
N N NH
X = O, S, NH
N X N XH N X
H
O H2N O OH
Cl
+
OH HN H NH PCl5
N
N
formamidine
NH2 N N
N
HI red.
O OH
HO N N KMnO4, H2O N
HO KOH ox.
N N N
O quinazoline
S
+ C H
NH2 N S N SH
S
NH2 NH NH
2-aminobenzyl-amine
+ C
Br
N
H
N NH2
NH3
N
(CH3)2SO4/NaOH
S CH3
} dihydro derivatives
N NH
NH2 NH NH NH NH2
NaOEt / EtOH
+ H2N NH2
OH NH N
NH
O O O
Cl S
NH2 NH2 NH S
LiAlH4/THF Cl CH3I
NH2 NH2 Et2O NH EtOH
(anhydrous)
- 2HCl
O
R1
R1
I HN
NH S CH3 N N
R2
R2
NH - CH3SH NH
- HI
More important derivatives
O NH2 O
H 3C
NH NH NH
pyrimidine bases
N O N O N O
H H H
uracil cytosine thymine
RNA RNA DNA
DNA
7H-purine derivatives
7
O R1 R2 R3
1 R
R xanthine H H H
N
N
theophylline CH3 CH3 H in Chinese tea
Each compound can be found in all of these plants, but the main component is characteristic.
They have diuretic effect.
Synthesis of uric acid and of purine
These are compounds isolated in the XVIII. Century (Scheele, 1776). The following synthetic method for purine
was introduced by E. Fischer (1898):
O O O O
C NH C N OH
H2N RO CH2 (CH3CO)2O NaOH HN HO-N=O
) HN
+
C C C N SE
NH2 N O NH2 O N O O N NH
O H H
nitrosation of actíve
methylene group
O Cl
O
NH2 H N
Al, HCl HN H2N N POCl3 N
C O NH Cl
H2N O
O N NH2 N Cl N N
H O N H H
H
exists in tautomeric forms uric acid
I
H
HI/PH4I N Zn N N
N N N
N N N N N
I N H H
purine
Another synthesis of a purine derivative is Traube’s method (1900):
OH O
NH2 N
N H HN
C O
HO
H2N N NH2 H2N N N
H
guanine
O OH
H
NH N N
N
O N N HO N N
H
H
xanthine
Compounds with purine ring system
H3C O O O O
NH CH3 H3C H3C N O
RO C
C + CH2 NaOEt N CH2 N HO - NO N
O NH C
C
CH3 N O NH N O N NH2 O N NH2
CH3 CH3 CH3
O
O O
H3C NH2
red. N HO H3C H3C
+ N NH N NH
H
O N NH2 O
O N NH2 C H O N N
CH3 O
CH3 CH3
theofilline
Synthesis of theobromine (Traube synthesis)
O O
H 2N O
POCl3 / pyridine 1) NaNO2 / acetic acid NH2
C HN HN
O NH + HO
heating 2) (NH4)2 S (reduction)
CH3 C O N NH O N NH2
N CH3 CH3
O O CH3
H
H 2N N (CH3)2SO4 N
HN HN
C H H
O
O N N CH3OH / HO O N N
boiling H2O, 60 o C CH3
CH3
theobromine
2. Cl N N
Cl 3.
SN reactions N N
H
1. Cl
6 H
1 5 N7 N N More important derivatives:
N 8 - guanine
2
N 4 N9 N N9 - adenine
3 H - xanthine
(7H)-9H-imidazo[4,5-d]pirimidin - theofilline
(unusual, biogenetic numbering) - theobromine
Purine - caffeine
9H-purine derivatives purine bases
NH2 O OH
N N N
N N N
N N N N
N H2N N H2N H
H H
H
adenine guanine
RNS RNS
DNS DNS
Cl
CH2 CH3 Eykmann (1896); absence of it may
N N cause disease beri-beri.
It was isolated at first by Funk from rice
H 3C N NH2 S CH2CH2OH bran. Peeled rice may cause beri-beri.
HCl
It gives positive thiochrome reaction
Pteridine and its derivatives
O
folic acid COOH
OH C
4 5 NH C H
N N CH2
3
N 6 N CH2
N
2 7 H CH2
N N H2N N N
1 8 COOH
pteridine pterine part p-aminobenzoic acid L-glutaminic acid
pteroyl group
Folic acid is an important vitamin: its N-formyl derivative builts the C1 unit in biosyntheses
O O
e c
f N d N N
N NH NH
g b
N N a N N O N N O
H H
benzo[g]pteridine alloxazine isoalloxazine
HO CH CH2 OH CH2OH
3
CH2 HO C H
8 9 1
H3C N 2 O HO C H
7
HO C H
6 NH
H3C N 3
5 4 CH2OH
10
O
Vitamin B2 ribitol
take place by prosthetic groups of enzymes
(flavoproteide enzymes, e.g., FAD)
Compounds with pyrimido-pyrimidine ring system
COOCH3 H 2C
HN N anhydrous toluene
+ pyrimido-pyrimidine skeletone
S N CH3 N boiling
H
CH3
COOCH3 COOCH3
HN N HN N
stereoisomers
S N N S N N
H CH3 H CH3
CH3 CH3
regioisomers regioisomers
H
NH2 H 3N N
heating
-2 NH4Cl
NH3 H 2N N piperazine
H
N N
SN
Y
N N Y
SE
Y
R NH2 O R' R N R' R N R'
dehydrogenation
O
NH2 O H N N
KMnO4 HO
+
HO
NH2 O H N N
o-phenylene diamine glyoxal quinoxaline O
O
O
N NH2 N
O
dyes
N NH2 N
o-benzoquinone phenanthrene quinone
phenazine
dibenzophenazine
Compounds with two different
heteroatoms
I/ Oxazine and its derivatives
4 4 4
5 3 5 3 5 3
6 NH 6 6
2
N2 N
2
O O O
1 1 1
4 4 4
5 5
N3 N3 5
N3
6 2 6 2 6 2
O O O
1 1 1
4 4
N N 3
5 3 5
Further derivatives: benzocondensed
6 2 6 2 derivatives
O O partially saturated derivatives
1 1
2H-1,4-oxazine 4H-1,4-oxazine
H
NH3Cl H 2N N
+
OH HO O
dibenzo-1,4-oxazine
phenoxazine
CH3O
O
CH3O C
+ Cl
N H CH3O CH3O O
N 3,4,5-trimethoxy-
HCl
benzoyl chloride CH3O C N O
O O O NR3 CH3O
H H morpholine
4-(3,4,5-trimethoxy-
NH3
ClCl benzoyl)-morpholine
NH N
1 2 1
R R R O R
RO OR O
acetals of β-acetyl-
aminoketones
II/ Thiazine and its derivatives
4
4 4 4 H
3 N N 3
5 5 N3 5 3 5
6 6 2 6 2 6 2
NH
S 2 S S S
1 1 1 1
phenothiazine
CH3
Na
H CH2 CH2 CH2 N
N Cl N Cl CH3
N Cl
NaNH2 Cl (CH2)3N(CH3)2
S 120o C
S
S
chloropromazin (Hibernal, Largactil,
Plegomazin)
neuroleptic drug
OCH3
O
O CH3
C CH2 N CH2 CH2 CH2 N N CH2 CH2 O C OCH3
CH3
N N
OCH3
S S
There are phenothiazine dyes (methylen blue), and other benzocondensed derivatives.
Compounds with three heteroatoms
I/ Triazines
4
4 4
5
N 3 3
N3 5 5
N N
6 6 6
N2 N2 2
N N N
1 1 1
N NH
N N
purine
OH O
N N HN NH
3 HO CN
cyanic acid HO N OH O N O
H
cyanuric acid
Cl
N N HO
3 Cl CN
cyanogen chloride Cl N Cl
NH R
3 RNH2
cyanuric chloride
N N
R NH N NH R
H2N C N NH2
addition
Ca N C N H2N C N H2N C NH C N H2N-CN N N
calcium cyanamide cyanamide NH
H2N N NH2
dicyandiamide
melamine
important raw material of plastic industry
HCHO
aminoplast
polymers
Cl
Cl Cl NH
NH O
H2N C NH CN H C OH N N
N
NH2 NH C NH C NH2 Neourofort
diuretic agent
NH NH
prepared by O. Clauder at first
Cl N
3 N
N N H N N triethylenemelamine
against leukaemia, leucosarcoma
Cl N Cl N N N [2,4,6-tris(aziridin-1-yl)]-1,3,5-triazine
II/ Thiadiazines
5 4
H
6
N 3
Cl N
hydrochlorothiazide
O diuretic agent
7 NH NH
S 2 H 2N S S
8 1 O O
O
2H-1,2,4-benzo[e]thiadiazine
H
O
Cl NH2 Cl N O
H 2N C NH2 CH3I
N
H2N O2S SO2 NH2 H 2N O 2 S SO2 H
H
Cl N O Cl NH2
N OH
H2N O2S SO2 CH3 H 2N O 2S SO2 NH CH3
R CHO
H
Cl N R
N
H2N O2S SO2 CH3
Cl NH2 Cl NH CHO Cl N
HCOOH
N
H2N O2S SO2 NH2 H2N O2S SO2 NH2 H2N O2S SO2 H
Cl NH2
HCHO H
H2N O2S SO2 NH2 Cl N
N
H2N O2S SO2 H
Cl N NaBH4
N
H2N O2S SO2 H
Compounds with four heteroatoms
I/ Tetrazines
H2S red. CH
N N N NH N H2N
N N N NH N
H2O2 ox. CH H2N
-2CO2
O O OK O OH
EtOC
CH N
KOH N NH H N N
N N
N NH ox. N N
N CH
COEt
O OK O OH
O
N
N N
sym. tetrazine
Heterocyclic compounds with
seven- and eight-membered
rings and their derivatives
Heterocyclic compounds with seven-
membered rings
Nomenclature, some important derivatives
1 1 1 1 1
1 H 2
O 2 S N 2 O 2 S 2 Y
2
O S NH
3 3 3
H
1 1 1 1 1
1 H 2
O 2 S 2 N 2 N N 2 N
2
3
3 3
H
4 4
5
H
oxepine thiepine 1H-azepine 2H-azepine 3H-azepine 4H-azepine
H H H
1
2 1 2 1 1 2
Y N N 2 N
N N
3
3 3 3
N
5
N4
Y=O 1,2-oxazepine 1H-1,2-diazepine 1H-1,3-diazepine 1H-1,4-diazepine
Y=S 1,2-thiazepine
10 11
R Name
9 1
CH3 imipramin
8 2
(CH2)3N antidepressant
7 N 5 3 CH3
6 4
R
carbamazepine
C
dibenzoazepine antiepileptics
derivatives O NH2
10,11
Benzodiazepine derivatives
Sedatohypnotica
CH2CH3 CH3
1 O
6 5 4 CH3 9 NHCH3 1
7 N N
CH3O 2
8
N3 3
7
CH3O 8 N2 Cl 7
5 N Cl N4
9 1 6 4
O
chlorodiazepoxide diazepam
tofisopam
Elenium Seduxen
Grandaxin OCH3 Librium Valium
OCH3
CH3
1 H O O
1
N N
7 7
NO2 N4 Cl 5 N
O
nitrazepam clobazam
Eunochtin Frisium
Grandaxin: anxiolitics free from sedative side-effects (e.g., it can be administered before driving)
(J. Kőrösi at GYKI, EGYT, 1966. Hungarian patent)
Preparation
CH3O CH3
CrO3
CH3O CH3
CH3COOH / H2O O
CH3O O
OCH3
OCH3
OCH3
diisohomogenol H3CO
1/ H2N NH2 . HX
2/ HO
CH2CH3
CH3
CH3O
CH3O N
tofisopam
Grandaxin
OCH3
H3CO
CH3 CH3 O CH3
NH H N N
N Cl
+
Cl H
Cl Cl H2N O NH
POCl3
P2O5
CH3
Cl N
medazepam
Rudotel
O EtO O H O
NO2 NO2 N
EtO C PCl5 C
Zn/HCl
+ CH2 CH2
Cl NH HO C Cl N C N
O O O
O O NaOCH3
EtO C EtO C CH3Br
PCl5
CH2 CH2
HO C Cl C
CH3
O O O
N
N
O
clobazam
Frisium
O
C Cl H O
NH2 N C
ZnCl2
2 + 2
Cl Cl
H
C N
O
Cl
H OH
N N
N H 3O
Cl O H N Cl
HO
Cl
Cl
NH2 O
O + OH
Cl H 2N
Cl
Cl O
NH2 NH2 C CH2Cl NH C
CH2Cl
H2NOH O
O NOH NOH
Cl - H2O Cl - HCl Cl
- HCl
H CH3
NH
N CH2NHCH3 N Cl
N CH2Cl
+ CH3NH2
N N N
Cl Cl
O - HCl Cl
O - CH3NH2 O
NHCH3
N C
CH2Cl
Cl NOH
CH3
H
H NH N
N N CH3
Cl
Cl N Cl N
O O
Chlordiazepoxide
Br O
H O 4 H O H O
N N Br 4
5 NH2 N 5
3 3
6 6
2 2
7 SH 7
OH CH3 O S
O
1 CH3 1
O R
R H
NH2 + N O OH H2N O N
+
O R Br
SH + S SH S
Br
SH SCH2COOH S
SOCl2
+ ClCH2COOH O
NH2 NH2
NH
O O O
SH SCH2CH2NH2 S
+ BrCH2CH2NH2
O O
N
Ph Ph Ph
O R R
SH S
+
NH2 RO N
O H O
CH3
N
O N
O CH3 C
C
N Cl N NH Cl
+
S N S
H
O POCl3
Cl C Cl
CH3
NH2 Cl clothiapin
N
antipsychoticum
S N
N
Cl
S
H 3C CH3
N
O O
H O
N (CH3)2NCH2CH2Cl N
OH (CH3CO)2O OCCH3
S K2CO3 S
OCH3 OCH3
diltiazem
antihypertensive agent
for treatment of heart disease
and antiarrhythmics
Heterocyclic compounds with eight-
membered rings
Azocane / Diazocane derivatives
Thiocane derivatives
CH2 CN CH2 CH2 NH2
NH N N
Cl CH2 CN LiAlH4
- HCl
azocane NH2
H3C S C HSO4
NH2
- CH3SH
S-methylthiuronium
hydrogensulfate
NH
CH2 CH2 NH C
N NH2
guanethidin
blood pressure reducing
(antihypertensive) agent