Chandigarh College of pharmacy

ASBASJSM COLLEGE OF PHARMACY

Name of Unit Stereoisomerism
Subject /Course Name Pharmaceutical Organic Chemistry-III
Subject/Course ID BP401T
Class: B.Pharm. Semester IV
Subject teacher Dr Neetu Chopra

Learning Outcome of Module 01

LO Learning Outcome
LO1 To understand about Stereoisomerism and its types.
LO2 To understand about Optical Isomerism, Optical Activity and Chirality.
LO3 To understand how to assign configuration of optical isomers.
LO4 To understand about Racemization and methods of resolution of racemic
mixture.
LO5 To understand about Asymmetric synthesis.
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Content Table

Topic

 Isomerism
 Stereoisomerism
 Optical Isomerism
 Optical Activity
 Elements of Symmetry
 Enantiomerism
 Diastereoisomerism
 Meso compounds
 Racemization
 Resolution of racemic mixture
 Configuration
 DL System
 RS System
 Reactions of Chiral molecules
 Asymmetric Synthesis

INTRODUCTION OF ISOMERISM
ISOMERS: Isomers are different compounds having the same molecular formula but different
physicaland chemical properties. These compounds are known as isomers and this property is
known as Isomerism.
The two major classes of Isomerism are:

1. Constitutional/Structural Isomerism
2. Stereoisomerism
Constitutional/Structural Isomerism: These have same molecular formula but different
structure and have different properties. This is further types which given below:
 Chain Isomerism
 Position Isomerism
 Functional Isomerism
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 Metamerism
 Tautomerism
 Ring Chain Isomerism
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STEREOISOMERISM

Stereoisomers have same molecular and structure formula, same bonding sequence but differ
only in the way the atoms are oriented in space. Stereoisomers differ in configuration. This
phenomenon is called Stereoisomerism.

Stereoisomerisms are two types.

Conformational Isomerism
Configurational Isomerism
Conformational Isomerism: It is a form of stereoisomerism in which the isomers can be
interconverted just by rotations about single bonds. While any two arrangements of atoms in
a molecule that differ by rotation about single bonds can be referred to as different
conformations.

Configurational Isomerism: It is a form of stereoisomerism in which the isomers can be

interconverted only by breaking and remaking of covalent bonds. These cannot be
interconverted by simple rotation boutas i n g l e bonds.

It has two types:

Optical Isomerism
Geometrical Isomerism
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Optical Isomerism:
 Isomers which differ only in their behavior towards plane polarized light.
 Rotates plane of polarized light towards right or left to the same extent and this phenomenon
is called optical activity.
 The chemical and physical properties of two enantiomers are identical except in their
interaction with chiral substances and plane polarized light.
In order to understand the phenomenon of optical isomerism and optical activity, we must
know the following terms:

Plane Polarized Light: If by filtering the beam with specialized materials, the electric field
vectors are limited to a single plane, then the light is referred to as plane or linearly polarized
with respect to the propagation direction. All waves vibrating in a single plane are referred
to as plane parallel or plane-polarized.

Optical Activity: Optical activity was first observed by the French physicist Jean-Baptiste
Biot. He concluded that the change in direction of plane-polarized light when it passed through
certain substances was actually a rotation of light, and that it had a molecular basis. His work
was supported by the experimentation of Louis Pasteur.
Pasteur observed the existence of two crystals that were mirror images in tartaric acid, an acid
found in wine. Through meticulous experimentation, he found that one set of molecules
rotated polarized light clockwise while the other rotated light counterclockwise to the same
extent. He also observed that a mixture of both, a racemic mixture (or racemic modification),
did not rotate light because the optical activity of one molecule canceled the effects of the other
molecule. Pasteur was the first to show the existence of chiral molecule.
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Optical active compound: A chiral compound that rotates the plane of polarized light is said to
be optically active.

Rotation of light: The optical active compounds can that rotates plane-polarized light in the
positive direction, or clockwise, is called dextrorotary [(+), or d-], while the compounds that
rotates the light in the negative direction, or counterclockwise, is called levorotary [(-), or l-].
When both d- and l- isomers are present in equal amounts, the mixture is called a racemic
mixture.

Optical Inactive Compound: A achiral compound that does not change the plane of polarized
light is said to be optically inactive.

Measuring Optical Activity (Angle of Rotation): Optical activity is measured by a

polarimeter, and is dependent on several factors:
1. concentration of the sample,
2. temperature,
3. length of the sample tube or cell, and
4 wavelength of the light passing through the sample.
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Rotation is given in +/- degrees, depending on whether the sample has d- (positive) or l-
(negative) enantiomers. The standard measurement for rotation for a specific chemical
compound is called the specific rotation, defined as an angle measured at a path length of
decimeter and a concentration of 1g/ml.
The specific rotation of a pure substance is an intrinsic
property. In solution, the formula for specific rotation is:

where

[α] is the specific rotation in degrees cm3 dm-1 g-1.

λ is the wavelength in nanometers
α is the measured angle of rotation of a substance,
T is the temperature in degrees,
l is the path length in decimeters
c is the concentration in g/ml

Chiral and Achiral Molecules: Chiral molecules are non-superimposable mirror images of
each other. Chiral molecules are superimposable mirror images of each other. Chiral molecules
are asymmetric at one or more centres. Achiral molecules are symmetric at all the centres.
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Chiral or Asymmetric Carbon: An asymmetric carbon atom (chiral carbon) is a carbon atom
that is attached to four different types of atoms or groups of atoms.
Knowing the number of asymmetric carbon atoms, one can calculate the maximum possible
number of stereoisomers for any given molecule as follows:
If n is the number of asymmetric carbon atoms then the maximum number of isomers = 2n

The mirror image of such carbon is non-superimposable as shown below:

Elements of Symmetry: There are three elements of symmetry which helps in identifying the
superimpossibility of a molecule or an object and its mirror image.
Chiral objects do not have an elements of symmetry while achiral objects have one or
more elements of symmetry. The three elements of symmetry.
Plane of Symmetry
Centre of Symmetry
Axis of Symmetry
Plane of Symmetry: A plane of symmetry is an imaginary plane that bisects a molecule into
halves that are mirror images of each other. So, Compound having plane of symmetry are
optically inactive. For Examples, plane of symmetry
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Centre of Symmetry: A centre of symmetry exists in a crystal if an imaginary line can be

extended from any point on its surface through its centre and a similar point is present along
the line equidistant from the centre. This is equivalent to 1, or inversion. For Examples

Centre of symmetry

Axis of symmetry: A molecule can have more than one symmetry axis; the one with the
highest n is called the principal axis, and by convention is aligned with the z-axis in a Cartesian
coordinate system. Plane of symmetry: a plane of reflection through which an identical copy of
the original molecule is generated. For examples,

Optical Isomerism The stereoisomers which resemble each other in their chemical properties
and most of the physical properties but differ only in their behaviour towards plane polarized
light are called optical isomers and this phenomenon is called optical isomerism. It is further
subdivided into three types:-
1.Enantiomerism
2.Diastereoisomerism
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3.Meso compounds
Enantiomerism: Enantiomers are a pair of molecules that exist in two forms that are mirror
images of one another but cannot be superimposed one upon the other. Enantiomers are in every
other respect chemically identical. A pair of enantiomers is distinguished by the direction in
which when dissolved in solution they rotate polarized light, either dextro (d or +) or levo (l or
-) rotatory; hence the term optical isomers. For Examples,

Enantiomers of Lactic Acid

Properties of Enantiomers:

1. Enantiomers generally have identical physical properties such as melting point, boiling
point, infrared absorptions and NMR spectra.
2. It is important to realize that the melting point of one Enantiomer will be identical to that of
the other Enantiomer, the melting point of a mixture of the two Enantiomers may be different.

Diastereoisomerism: Diastereomers are defined as non-mirror image, non-identical

stereoisomers. Hence, they occur when two or more stereoisomers of a compound have
different configurations at one or more (but not all) of the equivalent
(related) stereocenters and are not mirror images of each other. For example

Properties of Diastereoisomers:

1. Diastereomers have different physical properties such as melting points, boiling points,
densities, solubilities, refractive indices, dielectric constants and specific rotations.
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2. Diastereomers other than geometrical isomers may or may not be optically active.

3. Diastereomers show similar, but not identical chemical properties. The rates of reactions of
the two diastereomers with a given reagent provided the reagent is not rapidly active.

4. On account of differences in their physical properties, diastereomers can be separated from

one another through techniques like fractional crystallization, fractional distillation,
chromatography etc.

Meso Compounds: An achiral compound with chiral centres is known as a meso compound.
Although it has two or more stereocenters, a meso compound has an internal plane of symmetry
that makes it superimposable on its mirror image and is optically inactive. For examples,

I and II are enantiomers (non-superimposable); III and IV are meso form (superimposable).

Racemization: It is a conversion, by heat or by chemical reaction, of an optically active

compound into a racemic (optically inactive) form. Half of the optically active substance
becomes its mirror image (enantiomer) referred as racemic mixtures (i.e.contain equal amount
of (+) and (−) forms).
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A solution containing equal amounts of (R)-2-butanol and (S)-2-butanol is a racemic mixture

Mechanism of Racemization: Mechanism of racemization through the carbanion formation at

the chiral carbon α to a carbonyl group i.e.,in the case of chiral aldehydes, ketones, carboxylic
acids etc. where the chiral carbon α to the carbonyl group. This is because in such cases the
carbanions undergo racemization.

Resolution of Racemic Mixture: The process of splitting a racemate into its enantiomers is
known as resolution.

Various methods used for separation of a racemic mixture are given below:

1. Mechanical Separation:
This involved mechanical separation of the crystalof one enantiomers from the other in racemic
mixture based on difference in their shapes. Being mirror image of each other, Crystal of the
two forms have different shapes. Separated by magnifying lens and forceps.
This method first used by Pasteur (1884) for here solution of sodium ammonium tartarate
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which crystallize out in the form of racemic mixture below 27ᵒc.

This methods is time consuming and ever compound cannot be crystallized at room
temperature

2. Biochemical Method:This method is based on the fact that when certain micro- organisms
(e.g. bacteria yeast, mould, fungi) are grown in dilute solution of racemic mixture, they
assimilate on one enantiomersrapidlythan theothers.
e.g. The mould penicillin glaucum preferentially destroys the (+) isomers of racemic
ammonium tartarate and thus leaves the (-) ammonium tartarate in solution.

This method has certain disadvantages

 Sometimes it is impracticable to find a microorganism (Enzyme) applicable to given
racemic form.
 Sometimes the racemic modification may be toxic for the micro-organism and may destroy
the enzyme or may not be attacked by either rof them.

3. Chromatographic Method: The racemic mixture can be separated bychromatography on an

optically active support. The diastereomeric adsorbates which are formdehave different
stabilities. Thus one enantiomer will be held more tightly than the other and would be eluted
first. Chromatographic methods are developed for direct seperation of enantiomer.
Stereoselective adsorbents prepared in the presence of a suitable reference compound of known
configuration.eg: silica gel in the presence of quinine. Silica gel adsorbs quinine more readily
then its stereoisomer quinidine.
Cinchonidine (configurationally related to quinine) is adsorbed more readily then its
stereoisomer cinchonine (configurationally related to quinidine).

4. By Diastereomers: This method converting the eanantiomers of a racemic into diastereomers

with the aid of a pure enantiomers of other compound. Diastereomers are non- identical, they
have different physical properties and hence easily be separated its two compounds by fractional
crystallization.
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Configuration: The spatial arrangement of atoms in a molecule in a space which characterize a

particular stereoisomer.
Two terms are quite often used while describing the configuration of different stereoisomers.
1. Absolute configuration
2. Relative configuration
Absolute configuration: Absolute configuration refers to the spatial arrangement of atoms
within a chiral molecular entity (or group) and its resultant stereochemical description.
Relative configuration: The arrangement of atoms or group of atoms that is described relative to
other atoms or group of atoms in the molecule.

D and L conventions
The notations D and L describe the relative configurations of organic compounds. The
notations D and are used to describe the configurations of carbohydrates and amino acids.
Glyceraldehyde has been chosen as arbitrary standard for the D and L notation in sugar
chemistry. Because, this has an asymmetric carbon and can exist as a pair of enantiomers.

In a Fischer projection, the carbonyl group is always placed on the top position for monosaccharide.
From its structure, if the –OH group attached to the bottom-most asymmetric center (the carbon
that is second from the bottom) is on the right, then, the compound is a D sugar. If the –OH
group is on the left, then, the compound is a L-sugar. Almost all sugars found in nature are D-
sugar.
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R and S Configurational Notations: Absolute configuration uses a set of rules to describe the
relative positions of each bond around the chiral center atom. The most common labeling
method uses the descriptors R or S is based on the Cahn–Ingold–Prelog priority rules.
R and S refer to Rectus and Sinister, which are Latin for right and left, respectively.

Consider the first picture: a curved arrow is drawn from the highest priority (1) substituent to
the lowest priority (4) substituent. If the is arrow points in a counterclockwise direction the
configuration at stereocenter considered S ("Sinister" → Latin= "left"). If, however, the
arrow points clockwise, then the stereocenter is labeled R ("Rectus" → Latin= "right")

Sequence Rule:
Rule1. Prioritize the four atoms, or groups of atoms, attached to the chiral center based on the
atomic number of the atom that is bonded directly to the chiral center. The higher the atomic
number, the higher the priority. Number the four atoms, or groups of atoms, such that “1” has
the highest priority and 4” has the lowest priority.

Rule 2. If two or more of the atoms that are bonded directly to the chiral center are the same,
then prioritize these groups based on the next set of atoms (i.e., atoms adjacent to the directly
bonded atoms). Continue until priorities can be assigned. Priority is assigned at the first point of
difference.
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If two atoms have substituents of the same priority, higher priority is assigned to the atom
with more of these substituents.

A larger group (i.e., more atoms) may not necessarily have a higher priority over another
(smaller) group.

Rule 3. Atoms participating in double/triple bonds are considered to be bonded to an equivalent

number of similar “phantom” atoms by single bonds. Note: “phantom” atoms are bonded to no
other atoms.

Rule 4. Orient the molecule in space so that the lowest priority group (#4) is directed away
from you. The three remaining groups then project toward you.

Rule 5. If the three groups projecting toward you are ordered from highest priority (#1) to
lowest priority (#3) clockwise, then the configuration is “R”. If the three groups projecting
toward you are ordered from highest priority (#1) to lowest priority (#3) counterclockwise, then
the configuration is “S”.
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REACTIONS OF CHIRAL MOLECULES: Chiral molecules react with the reagents in a

variety of ways and accordingly, reactions are classified as follows:
1. Reactions where bonds with the chiral center are not broken
2. Reactions leading to generation of chiral center.
3. Reactions of chiral compounds with optically active reagents.
4. Reactions where bonds with the chiral center are broken.
1. Reactions where bonds with the chiral center are not broken: These reactions can be used
to relate the configuration of one compound to that of another. Configuration is retained when
the reaction does not involve the breaking of a bond to a chiral center.

Here is the bond to the chiral center is not broken „S‟ configuration is retained, because „–CH2–
Cl‟ occupies the same relative position as that was occupied by –CH 2OH in the reactant. This
retention of configuration can be utilized to determine the configurational relationship between
two optically active compounds by converting them into each other by reactions that do not
involve the breaking of a bond to a chiral center.
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2. Reactions leading to generation of chiral center: Generation of first chiral center in a

compound usually yields equal amounts of enantiomers (Racemic mixture) but reactions that
form second/new chiral center yield unequal amounts of diastereomers depending on the side of
attack.

Retention of configuration(s) occurs as there is no bond breaking to the chiral center. For the
new chiral center, depending on side of attack from the same or opposite side, diastereomers are
formed but in unequal amounts.

3. Reactions of chiral compounds with optically active reagents: Such reactions are
commonly used in the resolution or separation of a racemic mixture/modification into individual
enantiomers. So to obtain pure enantiomers from racemic modification, use of optically active
reagents is made. Such optically active reagent is easily obtained from natural sources or
generated from naturally available reagents.
Common reactions are reactions of organic acids and bases to form salts.

T
Alkaloid bases commonly used are (–) brucine, (–) quinine, (–) strychnine, etc.
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4. Reactions where bonds with the chiral center are broken: The stereochemistry of such
reactions depends on the mechanism of the reaction. Hence, stereochemistry can be helpful to
give evidence of a particular mechanism. e.g.

As the product is optically inactive and a racemic mixture, it implies second chlorine can be
attached from either face of the intermediate, which can be a free alkyl radical with loss of
chirality.

ASYMMETRIC SYNTHESIS: De novo synthesis of a chiral substance from an achiral

precursor such that one enantiomer predominates over the other is called asymmetric
synthesis. For reactions where molecules already contain a chiral element and synthesis
introduces a new chiral element, synthesis is referred to as „stereoselective or enantioselective’
synthesis or diastereoselective synthesis.
Decarboxylation of ethyl methylmalonic acid to give α methyl butyric acid is one of the first
recorded asymmetric syntheses.

Generally, chiral reagents are used to carry out the reaction, if they are not available,
chirality is acquired upon chelation, solvation, etc.
Reactants are adsorbed onto chiral surfaces or within chiral crystals.
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Chiral adjuvant or chiral auxiliary is temporarily attached to the achiral substrate which
is cleaved after the synthesis by hydrolysis to recycle the adjuvant.
When a new stereogenic center is created in an achiral molecule we get a racemic mixture
while in diastereoselective synthesis, the formation of any one of the desired diastereomers
is preferred over the other.

Typical Asymmetric Synthesis Include

Asymmetric hydrogenation
Asymmetric epoxidation
Asymmetric dihydroxylation: The partial term was used when optically active compounds are
prepared from achiral compounds by intermediate use of optically active compounds as reagent
without the necessity of resolution, contrary to the „absolute‟ asymmetric synthesis where
physical reagent like circularly polarised light was used.
Asymmetric hydrogenation: It is used for the asymmetric synthesis of the analgesic drug
Naproxen.

The reaction is carried out in presence of a chiral catalyst to hydrogenate a double bond. The
catalyst selects a single enantiotopic face of the double bond and adds hydrogens across it.
BINAP is a chelating diphosphine. Chirality is due to the restricted rotation of the bond joining
two naphthalene ring systems. Along with Ruthenium, it acts as an excellent catalyst for
hydrogenation.

Asymmetric Epoxidation: Oxidation of alkenes by asymmetric epoxidation is one of the

popular Sharpless reactions.
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Catalyst is a transition metal, Titanium tetra isopropoxide with tertiary butyl hydroperoxide.
The ligand is diethyl tartrate which is chiral and imparts selectivity to the reaction.

Asymmetric dihydroxylation: Dihydroxylation of alkenes by osmium tetroxide in catalytic

amount is carried out.

Difference Between Diastereomer and Enantiomers

DIASTEREOMER ENANTIOMERS

Diastereomers are stereoisomers that aren‟t Enantiomers are stereoisomers that are
a mirror image of each other mirror images of each other

Distinct physical properties Have identical physical properties except for

the ability to rotate plane-polarized light
Present in pairs There can be several molecules

Different molecular shape Similar molecular shape

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