Sterioisomerism B. Pharmacy Fourth Semester

STERIOISOMERISM
Presented By
Mrs. Snehal B. Fand
(Assistant Professor)
Ithape institute of Pharmacy, Sangamner
email id: snehafand88@gmail.com
UNIT
1

INDEX
 Optical Isomerism ( Optical Activity, Enantiomerism, Diastereoisomerism, Meso Compounds)
 Element of Symmetry
 DL System of Nomenclature of Optical Isomers
 Sequence Rules
 RS system of Nomenclature of Optical Isomers
 Reaction of Chiral Molecules
 Racemic Modification and Resolution of Racemic Mixture

• Isomers are different compounds with the same molecular formula.
• The two major classes of isomers are constitutional isomers and stereoisomers.
• Constitutional/structural isomers have different IUPAC names, the same or different
functional groups, different physical properties and different chemical 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).
• They always have the same functional group(s).
• A particular three-dimensional arrangement is called a configuration.
• Stereoisomers differ in configuration.
INTRODUCTION

Optical Isomerism
 A carbon atom attached to four different atoms or groups is known as
asymmetric or chiral.
 The four groups, arranged tetrahedrally around the carbon atom with bond
angles of 109º5", can be arranged in two different three-dimensional
configurations which are mirror images of each other.
 This is known as optical isomerism.

Optical Isomerism
 Optical isomers are named like this because of their effect on plane polarized
light. Light is a wave motion that contains oscillating electric and magnetic fields.
 However, it is possible to obtain light with an electric field that oscillates in only
one plane. Such light is called as plane polarized light or simply polarized light.

 The light which is coming from ordinary light source is having frequencies in all
directions. But when this normal light passes through Polarizer (Nicol prism), then it
only allows light which have propagation perpendicular to the plane. This is called as
plane polarized light. Now, this plane polarized light is passed through sample tube
containing chiral compound, then the light rotates either in clockwise or in
anticlockwise direction which is analyzed by analyzer.
 If the plane polarized light rotates in clockwise direction, the the compound is said to be
Dextro rotatory and if the plane polarized light rotates in anti clockwise direction, then
the compound is said to be Laevo rotatory.
Optical Isomerism

 Optical isomers will rotate plane polarized light in opposite directions.
a. Dextrorotary (d): A species that rotates plane polarized light to the right (looking
down the beam).
b. Levorotary (I): A species that rotates plane polarized light to the left (looking
down the beam).
c. A racemic mixture (containing equal amounts of both optical isomers) will not
rotate plane polarized light since the optical effects of the two isomers cancel out
each other.
Optical Isomerism

 The property of a compound being able to rotate the plane of polarization of plane-
polarized light is called optical activity, and a compound with such activity is labeled
as optical active. A stereoisomer that is optical active is also called an optical isomer.
 For a pair of enantiomers with the same concentration, under the same conditions, they
rotate the plane of polarization with the same angles but in the opposite direction. One is
clockwise, and the other is counterclockwise.
Optical Activity

 The enantiomer rotates the plane of polarization clockwise and is said to be dextrorotatory (Latin,
which means to the right), and it is labeled with the prefix (d) or (+).
 The enantiomer rotates the plane of polarization counterclockwise and is said to
be levorotatory (Latin, which means to the left), and it is labeled with the prefix (l) or (–).
 The d/l (or +/-) indicates the direction in which an optical active compound rotates the plane of
polarization of plane-polarized light, which has to be determined by an experiment to measure the
optical rotation.
 The rotation degree measured by the polarimeter is called the observed rotation (α), and the
observed rotation depends on the length of the sample tube, the concentration of the sample and
the temperature.
Optical Activity

specific rotation equation
 Examples:
Optical Activity

Chirality
 Chirality is a geometric property of some molecules and ions.
 Because of the tetrahedral geometry of saturated carbon and the associated three-dimensional
properties, molecules can have chirality as one stereochemical feature. Any object is chiral if it is
different (nonsuperimposable) than its mirror image.
 Likewise a molecule is chiral if it is nonsuperimposable on its mirror image. This requirement does
not consider conformational changes (rotations about single bonds) as valid conditions for non-
superimposability.

Enantiomers
 When a molecule is chiral, then it will have two isomeric forms called enantiomers, each of
which is the non-superimposable mirror image of the other.
 Enantiomers are distinct stereoisomers because they are compounds that have the same
molecular formula and sequence of bonded elements but which differ in the spatial arrangement
of groups in the molecule. If a molecule is chiral, and thus has two enantiomers, it usually (but
not always) contains at least one chiral center. In organic compounds a chiral center usually
corresponds to an asymmetric tetrahedral carbon atom.

Enantiomers
 When trying to distinguish between chiral compounds followings:
A) Achiral molecules contain a plane of symmetry, but chiral molecules do not.
B) A plane of symmetry is a mirror plane that cuts a molecules in half, so that one half of the
molecule is a reflection of the other half.

Diastereomers
 Diastereomers are defined as compounds which have the same molecular formula and sequence
of bonded elements but which are nonsuperimposable, non-mirror images.
 Diastereomers are stereoisomers that are not mirror images.
 Two dissimilar chiral centers are carbons that differ in at least one bonded group.
 Example: 2,3 dihydroxybutaldehyde

Diastereomers
 Characteristics of Diastereomers
a) Diastereomers have different physical properties such as melting points, boiling points, densities,
solubilities, refractive indices, dielectric constants and specific rotations. Enantiomers have similar
physical properties except the opposite sign of specific rotation.
b) Diastereomers other than geometrical isomers may or may not be optically active.
c) Diastereomers show similar, but not identical chemical properties. The rates of reactions of the two
diastereomers with a given reagent provided that reagent is not rapidly active.
d) On account of differences in their physical properties, diastereomers can be separated from one another
through techniques like fractional crystallization, fractional distillation, chromatography etc. The
difference from enantiomers which can’t be separated by these techniques.

 The terms D- and L- are often found in front of the names of sugars and amino acids. Most natural sugars
are D- and most natural amino acids are L- .
 One method for determining whether a molecule is D- or L- by looking at the Fischer projection of a
molecule. If the -OH (-NH2 for amino acids) on the bottom-most chiral center is on the right-hand
side of the Fischer projection, the molecule is “D“. If it is on the left-hand side, the molecule is “L”.
 Examples:
A. B.
D & L System Nomenclature:

R & S System of Nomenclature of Optical Isomers
 Cahn-Ingold-Prelog (IUPAC, International Union of Pure and Applied Chemistry) :The order of
rearrangement of four groups around a chiral carbon is called the absolute configuration around that atom.
 System which indicates absolute configuration was three chemists R.S. Cahn, C.K. Ingold and V.
Prelog. This system is known as (R) and (S) system or the Cahn-Ingold Prelog system. The letter (R)
comes from the Latin rectus (means right) while (S) comes from the Latin sinister (means left).
 Any Chiral carbon atoms have either an (R) configuration or a (S) configuration. Therefore one
enantiomer is (R) and the other is (S). A racemic mixture may be designated as (RS), meaning a mixture
of the two.
 A general method for assigning the configuration to any chiral center. In summary:
1. Assign priorities to the groups attached to the chiral center.

2. Orient the molecule so the group of lowest priority points directly away from your eye.
3. Follow the direction of the remaining groups from the highest to lowest priority. If the procession is
clockwise, the configuration is designated as R; if the procession is counter-clockwise, the configuration is
designated as S.

 A solution to this quandary was proposed by Robert Cahn, Chris Ingold, and Vladimir Prelog in 1966. The resulting
“CIP” protocol works as follows:
Step I: Prioritize the four groups around a chiral center according to atomic number. The highest atomic number is
assigned priority #1, and the lowest atomic number is assigned priority #4.
Step II: Orient the chiral center such that the 4-priority substituent is pointing away from the viewer. For our purposes,
it’s enough for it merely to be attached to a “dashed” bond.
Step III: Trace the path of priorities 1, 2 and 3. (For this part you ignore 4).
1. If the path traced from 1-2-3 is clockwise, the chiral center is assigned (R) (from Latin, rectus)
2. If the path traced is counter clockwise, the chiral center is assigned (S) (from the Latin sinister)
3. Now we have a better way to describe molecules [A] and [B] shown above. Molecule [A] is named (R)-1-bromo-
1-chloroethane, and molecule [B] is named (S)-1-bromo-1-chloroethane:

Step I: Applying Cahn-Ingold-Prelog (CIP) Rules To Determine (R)/(S) on A Chiral Center
1. Rank atoms attached to chiral center according to atomic number:
2. Rotate the molecule such that substituent ranked 4 is in the back (dashed line)
3. With 4 in the back, trace the path of the 1,2, and 3 ranked substituents 1, 2, and 3 trace a
clockwise path, assign the chiral center as R. 1, 2, and 3 trace a counterclockwise path, assign the
chiral center as S.

4. Chirality centers have double or triple bonds in their groups, we can determine the configuration of the
chirality center. Assigning priorities to atoms with double and triple bonds requires the consideration of
duplicates and triples.

The designations (R) and (S) bear no relationship to whether a molecule rotates plane-polarized light
clockwise (+) or counterclockwise (-). For example, the most common naturally occurring configuration of
the amino acid alanine is (S), but its optical rotation (in aqueous acid solution) is (+).

 Step II: A chirality center cannot be chiral if the groups
attached to it have similar priority rankings. In order to
align molecules in space properly, the lowest priority group
must face away from the viewer, then be situated behind the
chiral center Make a circle from the highest to the lowest
priority group by tracing a curved arrow.
A. A clockwise rotation yields R as the configuration of the
chiral center, from the Latin rectus, which means right.
B. The chiral center of a circle is shaped like an S, based on
the Latin sinister, which means "left".

 Elements of symmetry offer a simple device to decide whether a molecule is chiral or achiral,
Le, whether it is superimposable on its mirror image or not. When a molecule has no plane of
symmetry, no centre of symmetry and no alternating axis of symmetry, it is non
superimposable on its mirror image and is chiral (optically active).
I. Plane of symmetry: The plane which divides a molecule into two equal halves which are
related as object and mirror image is known as plane of symmetry. For example
Element of Chemistry

II. Centre of symmetry is an imaginary point in the molecules such that if a line is drawn from
any group of the molecule to this point and then extended to an equal distance beyond the point, it
meets the mirror images of the original group.
 Centre of symmetry is also called centre of inversion, denoted by Ci .For example, 2,4-
dimethyl cyclobutane-1,3-di-carboxylic acid exhibit centre of symmetry and so it is optically
inactive.
 The cis form of 2,5-dimethyldihydropyrimidine-4,5-
dione has no centre or plane of symmetry, so it
is optically active.
 whereas trans form of 2,5-dimethyldihydropyrimidine-
4,5-dione has a centre of symmetry, hence it is optically
inactive.

 Alternating axis of symmetry (AAs): A molecule possesses
an AAs if, when rotated through an angle of 360°/n about this
axis and then followed by reflection in a plane perpendicular to
axis, the molecule is indistinguishable from the original
molecule.
 It is also called rotation or reflection of symmetry. For
example,1,3,7,8-tetramethyl-5-azaspiro-[4,4] nonan-5-ium
have alternating axis of symmetry.
 This compound possess alternating axis of symmetry and
also has a plane of symmetry, so it is optically inactive.

Racemic Modification
 It has been observed that an equimolecular mixture of a pair of enantiomers is optically inactive. This is
to expected, since enantiomers have equal but opposite rotatory power. Such type of a mixture is said to
be optically inactive by external compensation and is known as a racemic modification.
 It is denoted by (±) . For example, (±)lactic acid.

 Mixing - A racemic modification can be achieved when two equal amounts of Dextro (+) and Levo
(-) isomers are closely mixed together.
 Chemical synthesis - Without chiral catalyst, a chiral starting material will always produce a chiral
racemate as a product of the reaction. A reaction between hydrogen cyanide and acetaldehyde
(chiral) leads to CH3CHOHCN, which contains both forms of acetonitrile in equal amounts.
 Thermal racemization- Heat can cause racemization in optically active materials. This leads to a
temporary break in one of the four stereocenter bonds. A separating atom or group joins back to the
stereocenter to yield another enantiomer, e.g., when the optically active enantiomer of a-phenethyl
chloride is distilled, it is converted into its racemic enantiomer.
Racemic Modification

Resolution of Racemic Mixture
 The separation of a racemic modification into the constituent enantiomers is called
the resolution of the racemic modification.
 The resolution processes can be classified in general into:
A. Mechanical methods
B. Chiral resolution (formation of diastereomers)
C. Enzymatic resolution
D. Kinetic resolution.

 MECHANICAL METHOD OF RESOLUTION:
Louis Pasteur first used this method in 1848 to separate the stereo isomers of crystalline tartaric
acid salt, i.e. (+) dextro and (-) levo components. If the enantiomers are solids, they are separated
based on their differences in shape. The sublimation method is very easy for the separation.
 CHIRAL RESOLUTION:
In a chiral resolution, the interaction of the racemic mixture with
a pure enantiomer forms diastereomers. These are then separated owing to the difference in
their physical properties (the diastereomers have different physical properties).

This chemical resolution method is successful because the diastereomers thus formed are
different compounds, have different physical properties, and often can be separated by physical
means (like fractional crystallization or column chromatography) and purified. The final step
in this scheme is the chemical conversion of the separated diastereomers back to the
individual enantiomers.

 ENZYMATIC RESOLUTION:
Enzymes serve as catalysts and are specialized chiral protein molecules. They
exhibit stereospecificity, meaning they exclusively interact with one enantiomer within
a racemic mixture due to their own chirality. The enantiomer that forms a bond with
an enzyme undergoes a chemical reaction, whereas the other enantiomer remains unaffected.
Upon completing this process, one-half of the initial mixture is retained while the other half is
discarded or reused.

 KINETIC RESOLUTION:
In the kinetic resolution, the separation of enantiomers is based on the difference in reaction
rates of enantiomers with a chiral catalyst. Unlike the former, kinetic resolution takes
advantage of the difference in the chemical properties of the starting materials in the racemic
mixture.
 CHROMATOGRAPHY:
Racemic mixtures can be separated into enantiomers using chiral column chromatography or gas
chromatography. A chiral stationary phase will have stronger interactions with one enantiomer,
isolating the other enantiomer from the mixture.

Asymmetric Synthesis
 Asymmetric synthesis relates to any synthetic process that introduces one or more new
elements of chirality during a functional group transformation.
for example, pyruvic acid on reduction yield a dl mixture of lactic acid.
But if it is esterified with some optical active alcohol and then reduced, the resulting ester on
hydrolysis yields and optically active lactic acid.

 Strategies of Asymmetric Synthesis:
We will cover the two main strategies of asymmetric synthesis:
1. Chiral Pool synthesis
2. Chiral auxiliary approach
Chiral Pool Synthesis: Chiral pool refers to a collection of enantiomerically pure molecules available
from nature. Common chiral starting materials derived from nature include amino acids, chiral
carboxylic acids and monosaccharides.
L- Amino Acid L-Serine (S)- Lactic acid D- Ribose

 A chiron approach or chiral pool synthesis refers to a synthetic process that employs a
member of the chiral pool as a starting material (SM) in the synthesis of a target molecule
(TM).
 The chiral centre(s) in the starting material are (but not all are always) preserved in the target molecule
(TM).
 It may use pre-existing chiral centres from the chiral pool substrate to influence formation of new chiral
centres.
 The new chiral centres can be generated through substitution or addition reactions

 CHIRAL AUXILIARY:
A chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into
an organic compound in order to control the stereochemical outcome of the synthesis.
The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent
reactions.
Chiral auxiliary are optically active compounds and introduce chirality in otherwise achiral
starting materials.

Partial Asymmetric Synthesis
Defined as a method for preparing optically active compound from optically inactive substance by
the use of optically active reagent but without the requirement of resolution (without separation).
Principle:
1. For preferential formation of one stereoisomer over the other, the reagent must be in pure
enantiomeric form.
2. The chiral reagent must play active role in the reaction (transition state)
3. Chiral reagent react with enantiomer at different rates.
So chiral reagent involved in asymmetric synthesis should lead to rapid completion to produce
pure stereo isomeric product (pure enantiomer)

Partial Asymmetric Synthesis
 Direct reduction of pyruvic acid yield racemic mixture of lactic acid.
 Here in this reaction neither pyruvic acid nor hydrogen are chiral but the product lactic acid is
chiral. However it is produced in racemic form i.e. equimolar mixture of (+) and (-) enantiomer.
It becomes stereo-selective reaction.

Absolute Asymmetric Synthesis
 Preparation of optically active compound from optically inactive substance without the use of
chiral reagent but just irradiating it by right or left circularly polarised light is called absolute
(total) asymmetric synthesis.
Example: A racemic mixture of (±) azidopropionic acid dimethyl amide when irradiated separately
by right and left circularly polarized light yielded the corresponding un-decomposed products with
corresponding (+) and (-) rotation.
a. Right polarised light b. Left polarized light

Sterioisomerism B. Pharmacy Fourth Semester

Sterioisomerism B. Pharmacy Fourth Semester

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