Stereochemistry

Stereochemistry is a Greek word in which stereo

means solid.

Stereochemistry is the chemistry of space; i.e.

stereochemistry deals with the spatial arrangements
of atoms and groups in a molecule.

Stereochemistry, a sub-discipline of chemistry,

involves the study of the relative spatial
arrangement of atoms and groups within molecules.
Isomers
Isomers are different compounds that have the
same molecular formula (no. and types of atom
present) but different in structural formula.

The compounds that process the same molecular

formula but differ from each other in physical and/or
chemical properties are called isomers.

This phenomena is termed as isomerism (Greek:

isos-equal, meros-part).
Kinds of isomers

Isomer

Structural isomer Stereoisomer

Optical isomer Geometric isomer

Enantiomer Cis-isomer

Diastereoisomer Trans-isomer
Constitutional (structural) isomers
The isomers that have different arrangement of
atoms within the molecule, without any reference to
space, the phenomenon is termed as constitutional
(structural) isomerism and the isomers are called
constitutional (structural) isomers.

Constitutional isomers have (Properties)-

- Different IUPAC (International Union of Pure
and Applied Chemistry) names
- Same or different functional groups
- Different physical properties and
- Different chemical properties
Constitutional isomers
Stereoisomer
Stereoisomers are isomers with the same molecular
formula and same connectivity of atoms but
different arrangement of atoms in space.
In stereoisomers the atoms and/or groups are
attached to the molecule in the same order, but
they have a different orientation in space.

Properties:
- Stereoisomers differ only in the way the
atoms are oriented in space
- They have identical IUPAC names (except for
a prefix like cis or trans and R or S)
- They always have the same functional group
Stereoisomers are of two types:
Optical isomers
Geometric isomers

a) Optical isomers
Optical isomers are characterized by compounds
having the same structure but different
configurations, and because of their molecular
asymmetry these compounds can rotate the plane of
polarized light.
Optical isomer has similar physical and/or chemical
properties. The most marked different between them
is there action on polarized light. Example-
 CHO CHO
H OH OH H

CH2OH CH2OH
(-) Glyceraldehyde (+) Glyceraldehyde

It has been found that only those structures;

crystalline or molecular, which are not
superimposable on their mirror images are optically
active.
Optical isomer has classified into two groups,
there are-
Enantiomer
Diastereoisomer
Enantiomer
Enantiomers are optical isomers that rotate the plane
of polarized light equal and opposite amounts and
differ in structure only in the left and right-
handedness of their orientation.
Enantiomers are that isomers, which are, mirror
image of each other; i.e. that are not superimposable
of mirror images.

//////////////////////////////////////////////

Fig: Enantiomer
Properties:

Enantiomers have identical physical and chemical

properties (same boiling point, melting point, density,
refractive index), except in two important respects-
# They rotate the plane of polarized light in opposite
direction, though in equal amounts.
The isomer which rotates the plane to the left
(counterclockwise) is called the levo isomer and
designated as (-), while the one which rotates the
plane to the right (clockwise) is called dextro isomer
and is designated as (+).
# Though chemically they are identical but their rate
of reaction with other optically active compounds
(chiral compounds) are usually different. This is the
reason that many compounds are biologically active
while theirs enantiomers are not.
Enantiomers react at the same rate with achiral
compounds. (+) nicotine- less
poisonous
(-) nicotine- more
poisonous
(+) histidine- sweet

(-) histidine- tasteless

Diastereomers
These are the optical isomers rotate the plane of
polarization by different amount.
Stereoisomers that are not mirror images of each other
are called diastereomers.
Enantiomers are mirror image isomers. All other
stereoisomers are called diastereomers. Alternatively,
diastereomers are stereoisomers that are not mirror
images.
Most diastereomers are either geometric isomers, or
compounds with two or more chiral atoms.
Propertie
s:
# Diastereomers have different physical properties
(like solubility will differ)
# Diastereomers have similar chemical properties
# Diastereomers differ in specific rotation; they may
have the same or opposite signs of rotation or some
may be inactive
 For example in 2,3 dichloropentane there are 2-
chiral center present, so the no. of isomer will be 4.
* *
CH3 CH2 CH CH CH3

Cl Cl

CH3 CH3

Cl C H H C Cl

H C Cl Cl C H

C2H5 C2H5

I II

Enantiomers
 CH3 CH3

H C Cl Cl C H

H C Cl Cl C H

C2H5 C2H5

III IV
Enantiomers

Relationship between-
I and II Enantiomers
III and IV Enantiomers
I and III/IV Diastereomers
II and III/IV Diastereomers
III and I/II Diastereomers
IV and I/II Diastereomers
Geometrical isomerism
Form of stereoisomerism describing the orientation of
functional groups within a molecule
These compounds do not rotate the plane of plane-
polarized light.
They differ in all their physical and in many of their
chemical properties.
In general, such isomers contain double bonds, which
cannot rotate, but they can also arise from ring
structures, where in the rotation of bonds is greatly
restricted.
The configurations are differentiated in their names by
the prefixes cis- and trans- which indicate that the
similar groups lie on the same side (cis-) and when
opposite sides (trans-).
Consequently, this type of isomerism is often called as
cis-trans isomerism or E-Z isomerism.
The cis/trans system for naming isomers is not
effective when there are more than two different
substituents on a double bond. The E/Z notation
should then be used. Z means together and
corresponds to the term cis; E means opposite and
corresponds to the term trans.
(E)- : the higher priority groups are on opposite sides
of the double bond.
(Z)- : the higher priority groups are on the same side
of the double bond.

(Z)- isomer (E)- isomer

Plane polarized light
Light from ordinary electric lamp is composed of
waves vibrating in many different planes. When it
passed through nicol prisom or polarizing filter, light
is found to vibrate in only one plane, and is said to be
plane polarized.
Solution of some organic compounds have the ability
to rotate the plane of polarized light. These
compounds are said to be optically active.
The isomer which rotates the plane to the left
(counterclockwise) is called the levo isomer and
designated as (-), while the one which rotates the
plane to the right (clockwise) is called dextro isomer
and is designated as (+).
Racemic mixture
Racemic mixture is a mixture of equal parts of
enantiomer. Racemic mixtures are optically inactive
since the equal and opposite rotation cancel each
other.
A mixture is said to be racemic when it contains
exactly equal amounts of two enantiomers. Such a
mixture is optically inactive (zero rotation of plane
polarized light).
A mixture of equal parts of enantiomers is called a
racemic mixture. A racemic mixture is optically
inactive: when enantiomers are mixed together, the
rotation caused by a molecule of one isomer is
exactly cancelled by an equal and opposite rotation
caused by a molecule of its enantiomer.
 For example, (+) Lactic acid [a mixture of (+)
-
Lactic acid and (-) Lactic acid]
COOH COOH
H OH OH H

CH3 CH3
D or (+) Lactic L or (-) Lactic
acid acid
his is demonstrated by the hydrogenation of 2-butanone:

Most chemical reactions which produce chiral molecules

produce them in racemic form
 There is no energy difference for the attack from the top or
bottom face, and there is no energy difference in the (R) or (S)
products.
Therefore although chiral products are produced, the
products are formed in equal amounts a racemic mixture.
Chiral carbon/chiral center
A carbon atom to which four different groups
are attached is a chiral center and is usually denoted
with an asterix (*).

A A
B B
D C C D

2-butanol
 If the molecule has no chiral carbon, it is usually
achiral

If the molecule has just one chiral carbon, it is

usually chiral

If it has 2 or more chiral carbons, it may or may

not be chiral.
Chirality
Chirality means handedness.
Every object has a mirror image, but if a molecules
mirror image is different from the molecule, it is said
to be a chiral molecule.
Chiral objects include: hands, feet, gloves, screws,
cork screws
Achiral objects have mirror images that are identical
to the object.
Any molecule which is not superimposable on its
mirror image is said to possess chirality. The term
chirality means having handedness (either left-
handed or right- handed).
When a molecule is superimposable on its mirror
image that molecule does not posses handedness
and is said to be achiral.
Chirality in organic molecules
If a mirror image of a molecule can be placed on top
of the original, and the 3 dimensional arrangement of
every atom is the same, then the two molecules are
superimposable, and the molecule is achiral.
If a molecule has a non superimposable mirror image,
it is chiral.
 H H

* *
I C Cl Cl C I

SO3H SO3H
Not superimposable: Chiral
H H

* *
CH3 C CH3 CH3 C CH3

Cl Cl
Superimposable: Achiral
Your hands are chiral

The mirror image of a left hand is a right hand

Left and right hands are not superimposable

Meso structures
Contain chiral carbon but optically inactive.
A meso compounds is one whose molecules are
superimposable on their mirror images even
through they contain chiral centers.
A meso compound is optically inactive.
Compound C has two chiral
centers but it contains a
plane of symmetry, and is
achiral; C is a meso
compound.

Not optically active

Superimposable on its
mirror image
Has a plane of symmetry
Sometimes molecules with 2 or more chiral centers will have less than the
maximum amount of stereoisomers. e.g.
How many stereoisomers?
Maximum number of stereoisomers= 2n
[where n= number of structural units capable of
stereochemical variation. Structural units include
chirality centers and cis and/or trans double bonds.]
Number is reduced to less than 2n if meso forms
are possible
Number of pair of enantiomer= 2n-1

O
* * * *
HOCH2CHCHCHCHCH

OH OH OH OH
4 chirality centers 16 stereoisomers 8
enantiomer
Elements of symmetry
If the molecule contains at least one of these
elements of symmetry, the molecule is symmetric; if
none of these elements of symmetry is present the
molecule is asymmetric and optically active.

a. A plane of symmetry
A plane of symmetry divided a molecule in such a
way that the atoms or group 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 formula e.g. the plane formula of
the meso-forms of Cabd -Cabd posses a plane of
symmetry; the other two (+) and (-) do not.
b. A center of symmetry
A center of symmetry is a point from which lines,
when drawn on one side and produce on equal
distance on the other side, will meet identical atoms
or groups in the molecule.
Center of symmetry
Cl H
C C
H Cl
This test may be applied only to 3-D formula,
particularly those of ring system, e.g. 2,4-dimethyl
cyclobutane-1,3 dicarboxylic acid. The form shown
possesses a center of symmetry which is the centre of
the ring. The form is therefore optically inactive.

A center of symmetry

2,4-dimethyl cyclobutane-1,3 dicarboxylic acid

c. Alternating axis of symmetry
A molecule possesses an n-fold alternating axis of
symmetry if, when rotated through an angle of
360/n about this axis and then followed by
reflection in a plane perpendicular to the axis; the
molecule is indistinguishable from the original
molecule.
Cis-1,3-dichlorocyclobutane

Cl

Cl
Cl

180o rotation

Cl
 I II
Let us consider 1,2,3,4-tetramethyl cyclobutane. This
molecule (I) posses four fold alternating axis of
symmetry.
So when it rotates on angle of 90o about this axis AB
which gone through the center of the ring
perpendicular to its plane then it gives the molecule II.
But the reflection of II in the plane of the ring gives I.
The form is therefore optically inactive.
Conformation
The different arrangement of atoms or groups in the
space due to the free rotation of the groups about a
single bond is called conformation.

Conformation is a three dimensional structural

arrangement.

Font Rear
carbo carbo
n n
Conformers of alkanes
Newman projection formula
This is obtained by viewing the molecule along
the bonding line of the two carbon atoms, with the
carbon atom nearer to the eye being designated by
equally spaced radii and the carbon atom further from
the eye by a circle with three equally spaced radial
extensions.
May differ in energy: The lowest-energy conformer
is most prevalent.
Molecules constantly rotate through all the
possible conformations.
Ethane C2H6 conformers
Staggered [or transoid] form
The conformation in which the hydrogen atoms
of the two carbon remain at maximum distance when
viewed from one end along the CC bond axis.

Model
Staggered conformer has lowest
energy
Dihedral angle = 60 degrees
Eclipsed [or cisoid] form
The conformation in which the hydrogen atoms
of two carbon remain nearer to one another when
viewed from one end along the CC bond axis.

Eclipsed conformer has highest

energy
Dihedral angle = 0 degrees
 Torsional strain: resistance to rotation.
For ethane, only 12.6 kJ/mol
Propane Conformers

Note: slight increase in torsional strain due to the more bulky methyl group.
Butane Conformers C2-
C3
Highest energy when methyl groups are eclipsed (cisoid)
Steric hindrance is the major cause
Dihedral angle = 0 degrees

totally eclipsed
Butane Conformers
(2)
Lowest energy when methyl groups are anti (staggered)
Dihedral angle = 180 degrees

anti
Butane Conformers
(3)
Methyl groups eclipsed with hydrogens
Higher energy than staggered conformer
Dihedral angle = 120 degrees

eclipsed
Butane Conformers
(4)
Gauche, staggered conformer
Methyls closer than in anti conformer
Dihedral angle = 60 degrees

gauche
Conformational
analysis
Conformations of
Butane

55
Conformational analysis of ethylene dichloride
The potential energy of ethylene dichloride C2H4Cl2
undergoes changes when one CH2Cl group is rotated
about the C-C bond with the other CH2Cl at rest.
There are two positions of minimum energy, one
corresponding to staggered (transoid or anti) form and
other to the gauche (skew) form, the latter possessing
approximately 4.6 kj more than the former.
 The fully eclipsed (cisoid) form possesses about
18.83 kj more energy than the staggered form.
Thus staggered form is the preferred form for
ethylene dichloride.
What are the internal factors encountered in the
stability of a conformation?
The existence of potential energy barriers
between the various conformations shows that there are
internal forces acting on the molecule.
However, the possible internal forces that
prevents the free rotation about a single bond are-
a. Dipole-dipole forces
b. Steric repulsion
c. Intermolecular hydrogen bonding
d. Repulsion between adjacent pair of electrons

[Dipole moment: when the centers of the electrons and nuclei in

a molecule do not coincide, the molecule will posses a permanent
electric dipole moment, , the value of which given by = e x d,
where e is the electronic charge, and d the distance between the
charges (+ve and ve centers) ]
a. Dipole-dipole forces
According to one theory, the hindering of internal
rotation is may be due to dipole-dipole forces.
Calculation of the dipole moment of dichloro
ethane on the assumption of free rotation gave a value
not similar with the experimental value. Thus the
internal rotation in not completely free and there will be
preferred conformations.
In the staggered form, the dipole moment is zero
but as the molecule absorbs the energy, rotation occurs
to produce finally the eclipsed form in which the dipole
moment is maximum.
[Zero dipole moment: H2, O2, CH4 , CCl4 etc.
Large dipole moment: HF, CH3Cl ]
b. Steric repulsion
Steric repulsion is the repulsion between the non-
bonded atoms (of the rotating groups) when they are
brought into close proximity.
c. Intermolecular hydrogen bonding
In a molecule such as ethylene chlorohydrins or
ethylene glycol, intermolecular hydrogen bonding is
possible in the skew form but not the staggered.
This would stabilize the molecule and make the
skew form more stable than the staggered form.
Infra red spectroscopy has shown that the skew
form predominates.
d. Repulsion between adjacent pair of electrons
Pauling in 1958 has proposed that the energy
barrier in ethane (and in similar molecules) results form
the repulsion between the adjacent bonding pairs of
electrons, i.e. the bonding pairs of the CH bonds on one
carbon atom repel those on the other carbon atom.
Thus, the preferred conformation will be the staggered
one.
Element of symmetry
When a molecule and its mirror image are
superimposable, the molecule is known as symmetric.
But in practice, the following tests are applied to
identify any molecule as symmetric-
a. A plane of symmetry
b. A centre of symmetry
c. An alternative axis of symmetry
How can you assign the configuration of a molecule in R &
S system ? Or What is the sequence rule for R & S
configuration?
Let us consider an asymmetric carbon Cabde and
consider the priority of a,b,d,e is 1,2,3,4 gradually,
where a>b>d>e according to priority.
Now by following priority, if eye moves clockwise
direction, then the configuration is R-configuration (Latin
Rectus,-right) and if eye moves anticlockwise direction,
then the configuration will be S-configuration (Latin
Sinistus,-left).
The Cahn Ingold Prelog sequence rules
Cahn, Ingold and Prelog introduced this systematic
notation during the period 1951-1956. The sequence
rules are-
Priority is assigned by considering the
decreasing order of the atomic number of the atom by
which the group is directly attached to asymmetric
carbon. The atom of highest atomic number gets the
highest priority (1). e.g.
Group Atomic no Priority
Br 35 1
Cl 17 2
F 9 3
H 1 4

Memorize order of priority: I > Br > Cl > F > O > N > C > H
 If two atoms on a stereogenic center are the
same, assign priority based on the atomic number of the
atoms bonded to these atoms. One atom of higher
priority determines the higher priority.
 If two isotopes are bonded to the stereogenic
center, assign priorities in order of decreasing mass
number. Thus, in comparing the three isotopes of
hydrogen, the order of priorities is:

If any substitution is done on groups, then higher

substituents containing group will get more priority.
1
CHCl2
4 -CHCl2> -CH2Cl> -CH3

H C CH2Cl
2
3 CH3
 To assign a priority to an atom that is part of a
multiple bond, treat a multiply bonded atom as an
equivalent number of singly bonded atoms. For
example, the C of a C=O is considered to be bonded to
two O atoms.

Other common multiple bonds are drawn below:

Examples Assigning Priorities
R,S System for isomers with more than one chirality
center
When a compound has more than one stereogenic
center, the R and S configuration must be assigned to
each of them.3
CH3
H OH
H Br
CH3
2 (2R,3S)-3-bromo-2-butanol

Enantiomers have exactly opposite R,S designations.

Diastereoisomers have the same R,S designation for at least one chiral
center and the opposite for at least one of the other chiral center.
Meso compounds have the same R,S designations at every chiral center.
 Molecules with more than one chirality center have
mirror image stereoisomers that are enantiomers.
In addition they can have stereoisomeric forms
that are not mirror images, called diastereomers.

2R,3R 2S,3S 2R,3S 2S,3R

The biological importance of chirality
The binding specificity of a chiral receptor site for
a chiral molecule is usually only favorable in one way.

Drug

Receptor
 Draw the structure without stereochemistry,
identify the chiral center and assign priority to the four
groups attached to the chiral center. Then draw a
tetrahedral carbon and put the group with the lowest
priority on the bond pointed away from you. Put the
highest priority group on any bond. Then put the group
2 in the position clockwise from the group 1 if it is the
(R)-enantiomer or in the position counter clockwise from
the group 1 if it is the (S)-enantiomer. Add group 3 on
the remaining position.