OPTICAL ISOMERISM Prepared By:

Unit-1 (BP401TT) Mr. Nadim Chhipa,

Assistant
Professor,
ASP & BRI
CONTENTS

▸ Optical activity, enantiomerism, diastereoisomerism, meso compounds

▸ Elements of symmetry, chiral and achiral molecules
▸ DL system of nomenclature of optical isomers, sequence rules,
▸ RS system of nomenclature of optical isomers
▸ Reactions of chiral molecules
▸ Racemic modification and resolution of racemic mixture.
▸ Asymmetric synthesis: partial and absolute
 ISOMERISM

• Compound that have same

molecular formula but
different molecular
structure are called
isomers and this
phenomenon is known as
Isomerism.
• The word “isomer” is
derived from the Greek
words “isos” and “meros”,
which mean “equal parts”.
This term was coined by
the Swedish chemist
Jacob Berzelius in the year
1830.
Structural Isomerism

• Isomers, which have same molecular formula, but different structural formula are called structural
isomers.
• Different Structural formula means:
• Different bond pattern or
• Different arrangement of s bonds or
• Different connectivity of atoms.
1. Chain Isomers: Isomers which have same functional groups but different arrangement of carbon
skeleton in principal chain or side chains are chain isomers.
▸ Examples are: n-butane and iso-butane
Structural Isomerism

2. Positional Isomers: Isomers which have same functional groups, same arrangement of carbon
skeleton but different position of functional groups or substituents.
▸ Examples are-

3. Functional isomers: Functional isomers have same molecular formula but differ in functional
groups.
▸ For example: Ethyl alcohol and Dimethyl ether
Structural Isomerism

4. Ring-Chain Isomers: The same molecular formula represents two or more compounds.
• It differs in the mode of linkage of carbon atoms.
• The isomers have either open chain or closed chain.
• Example, Propene and cyclopropane are ring chain isomers.
Structural Isomerism

5. Metamers: This type of isomerism is due to unequal distribution of carbon atoms on either side of
the functional group
• Such compounds are members of homologous series
• Example: Diethyl ether and Methyl propyl ether
Structural Isomerism

6. Tautomers: A type of functional Isomers which exist in rapid equilibrium in solution are called
Tautomers.
• Tautomers are interconvertable in solution
• Tautomers usually differs in position of H atom at a carbon.
• Interconversion of tautomers can be catalysed.
• Tautomers can’t be seperated in solution at normal temperature.
• The more stable form dominates in equillibrium.
• Examples are:
Stereochemistry

Definition:

▸ The branch of chemistry which is concerned with the three-dimensional

arrangement of atoms and molecules and the effect of on chemical reaction is
called as Stereochemistry.
▸ The science of organic chemistry is based on the relationship between
molecular structure and properties. That part of the science which deals with
structure in three dimensions is called as stereochemistry.
▸ It is sub discipline of chemistry, involve the study of the relative spatial
arrangement of atom that from the structure of molecules and their manipulation.
Stereoisomerism

▸ The compounds with same qualitative and quantitative composition of elements

therefore their relative molecule weight, general formula are identical, but their
structure are including 3D arrangement – difference is called as Stereoisomer.
Optical activity

▸ Light possesses certain properties that are best understood by considering it to be a

wave phenomenon in which the vibrations occur at right angles to the direction in
which the light travels. There are an infinite number of planes passing through the
line of propagation, and ordinary light is vibrating in all these planes.
Polarimeter
▸ The optically activity is measured in the laboratory by polarimeter.
▸ A polarimeter consists of a light source(usually D- line of sodium), two
polaroid lenses(one polarizer and one analyser), and a sample tube placed
between polarizer and analyser lenses.
Polarimeter
Polarimeter
Polarimeter
▸ Plane-polarized light is light whose vibrations take place in only one of
these possible planes.
▸ Ordinary light is turned into plane-polarized light by passing it through a
lens made of the material known as Polaroid.
▸ If the sample tube is empty and polarizing axes of two lenses are parallel,
the intensity of light reaching the observer is ‘maximum’.
▸ Once the solution of the sample is placed in the tube, the emerging light is
observed from the analyzing lens.
▸ If there is no change in the intensity of light, the sample is said to be
optically inactive.
Polarimeter
▸ If the sample rotates the plane of polarization, the intensity of light observed through analyzer
lens is found to decrease and the sample is said to be optically active.
▸ The analyzer lens is then rotated to observe the maximum intensity of light.
▸ If the substance does not affect the plane of polarization, light transmission is still at a maximum
and the substance is said to be optically inactive.
▸ If the substance rotates the plane of polarization, then the lens nearer our eye must be rotated to
conform with this new plane if light transmission is again to be a maximum, and the substance is
said to be optically active.
▸ If the rotation of the plane, and hence our rotation of the lens, is to the right (clockwise), the
substance is Dextrorotatory (Latin: dexter, right)
▸ if the rotation is to the left (anti-clockwise), the substance is Levorotatory (Latin: laevus. left).
Optical Activity
The optical activity of a compound was found to be proportional to
▸ The concentration of the compound in solution (c)
▸ The length through light traverses through the solution (l)
▸ The wavelength used for the measurement (λ) and the temperature at
which the measurement is made (t). Usually, the sodium D-line is used for
polarimetric measurement.

▸ Mathematically, α=[α]Dlc
▸ Where, [α]D = Specific Rotation
Specific rotation
▸ The specific rotation of plane polarization is measured in degrees and is known as
observed optical rotation (α).
▸ Specific rotation is the number of degrees of rotation observed if a 1-decimeter tube is
used, and the compound being examined is present to the extent of 1g cc.
▸ This is usually calculated from observations with tubes of other lengths and at different
concentrations by means of equation.
▸ Where d represents density of pure liquid or concentrations.
Optical Purity
▸ Whether a particular sample consists of a single enantiomer or a mixture of
enantiomers can be determined by its observed specific rotation.
▸ From the observed specific rotation, we can calculate the optical purity of
the mixture.

For example, if a sample of 2-bromobutane has an observed specific

rotation of +9.2°, an enantiomerically pure sample-meaning only one
enantiomer is present-of (S)-(+)-2-bromobutane will have an observed
specific rotation of +23.1°
Optical Purity
▸ Enantiomeric Excess (ee)
▸ Because the observed specific rotation is positive, we know that the
solution contains excess (S)-(+)-2-bromobutane. The enantiomeric
excess (ee) tells us how much excess (S)-(+)-2-bromobutane is in the
mixture. As long as the compound is chemically pure, enantiomeric excess
and optical purity will be the same.

What is the ee of a mixture containing 12.8 mol (R)-2-bromobutane and 3.2

mol (S)-2-bromobutane?
Enantiomerism
▸ There are two stereoisomers of which are different from each other like a
scheme and its mirror image, like right hand is different from left hand.
These two compounds are called as chiral, these are enantiomers of each
other, while this special case of stereoisomerism is called as
Enantiomerism.
Enantiomerism
▸ Enantiomers have identical physical properties, except for the direction
of rotation of the plane of polarized light.
▸ For example, have identical melting points, boiling points, densities,
refractive indexes, and any other physical constant one might measure,
except for this: one rotates plane polarized light to the right, the other to tire
left.
▸ Enantiomers have identical chemical properties except toward optically
active reagents.
Chirality
▸ Molecules that are not superimposable on their mirror images are chiral.
▸ Chirality is the necessary and sufficient condition for the existence of
enantiomers.
▸ a compound whose molecules are chiral can exist as enantiomers.
▸ a compound whose molecules are achiral (without chirality) cannot exist as
enantiomers.
Chiral center
▸ A carbon atom to which four different groups are attached is a chiral center
or it is called chiral carbon.
Diasteromerism
▸ Diasteromerism occurs when two or more stereoisomers of compound have
different configurations at one or more of the equivalent stereoisomers and
are not mirror images of each other.
▸ Diastereomers are different geometrical entities. But enantiomers are
identical geometrical entities.
Diasteromerism
▸ Diastereomers have similar chemical properties.
▸ Diastereomers have different physical properties: different melting points,
boiling points, solubilities in a given solvent, densities, refractive indexes.
▸ Diaslereomers differ in specific rotation; they may have the same or
opposite signs of rotation, or some may be inactive.
Enantiomers v/s Distereomers
Meso Compounds
▸ An optically inactive compound whose molecule is superimposable on its
mirror image inspite of the presence of chiral carbon atoms is called a meso
compound.
▸ If a molecule has two or more chiral centers, it is usually chiral. The
exceptions are meso‐molecules, which are not chiral. These are molecules
that due to symmetry have chiral centers that ‘cancel’ each other out.
▸ Has two or more chiral centers
▸ Has a plane of symmetry.
Meso Compounds
Calculation of number of optical isomers in
compounds (containing ‘n’ chiral atoms)
Compounds Number of Number of Number of Total number
optical active meso Racemic of optical
forms (a) Forms (m) mixture (a/2) isomers

The molecule 2n 0 2n-1 a+m

has
no symmetry
Calculation of number of optical isomers in
compounds (containing ‘n’ chiral atoms)
Compounds Number of Number of meso Number of Total number
optical Forms (m) Racemic mixture of optical
active (a/2) isomers
forms (a)

The molecule has symmetry:- 2n-1 2n/2-1 2n-1/2 a+m

Case 1:
When compound has even
number of chiral carbon atom
Calculation of number of optical isomers in
compounds (containing ‘n’ chiral atoms)
Compounds Number of Number of meso Number of Total number
optical Forms (m) Racemic mixture of optical
active (a/2) isomers
forms (a)

The molecule has symmetry:- 2n-1-2(n-1)/2 2n-1/2 a/2 2n-1

Case 2:
When compound has odd
number of chiral carbon atom
Elements of Symmetry

Plane of symmetry
Center of symmetry

1. Plane of symmetry:
plane of symmetry (internal mirror plane ) is a mirror plane that cuts the
molecule into two halves, so that one half of the molecule is a reflection
of the other half.
The plane may pass through atoms, between atoms, or both
Plane of Symmetry

▸ Has plane of symmetry, •Has no plane of symmetry,

Achiral molecule chiral molecule
▸ Molecule has two identical •Molecule has not two identical
halves halves
Plane of Symmetry

Example
(a)2-Chloropropane has a plane of symmetry and is achiral.
(b)2-Chlorobutane does not possess a plane of symmetry and is chiral.

The compound have plane of symmetry is: Optically inactive and called Meso
compound
Plane of Symmetry
cis-1,2-dimethylcyclohexane
This molecule has a plane of symmetry cutting the molecule in half.
Everything on the left side of the plane is mirrored by everything on the
right side. Classify each of the following
pairs as chiral or achiral

Achiral: the molecule has plane of

symmetry, Not has chiral carbon

Achiral: the molecule has plane of

symmetry
Centre of symmetry

It is the point in the center of molecule to which a line can be drawn from any
atom such that when extended an equal distance past the center, the line
meets another atom of the same kind

Center of symmetry

▸ So, for any compound to be optically active it must not possess any
element of symmetry.
Chiral and Achiral Molecules

Chiral compounds:
• Has chiral center
• Has no element of symmetry
• The compound and its mirror image are Non superimposable.
• N.B. The compound and its mirror image called Enantiomers
Chiral and Achiral Molecules

Chiral compounds:
Chiral and Achiral Molecules

Achiral compounds:
• Has No chiral center
• May contain chiral center but the compound and its mirror image are
Superimposable
• Has element of symmetry (Plane of symmetry or center of symmetry)
• N.B: Achiral compound is optically inactive

Achiral compound, not Achiral compound, has Plane

contain chiral center of symmetry, superimposable
Chiral and Achiral Molecules
Chiral and Achiral Molecules

1 2 3 4
Chiral and Achiral Molecules

The glass and its mirror This mug is chiral.

images are superposable.
Configuration

 The arrangement of atoms that characterizes a particular stereoisomer

is called its configuration.
 two stereoisomeric sec-butyl chlorides; their configurations are I and II.
 one rotates the plane of polarized light to the right, and the other to the
left; one (+)sec-butyl chloride and the other (-)sec-butyl chloride
respectively.
Representation of three dimensional molecules
Fischer Projection

 Fischer Projections are abbreviated structural forms that allow one to

convey valuable stereo chemical information.
 The definition is that every carbon is specified completely by a cross
designating the carbon (at the center) and the four bonds to that
carbon.
 The stereochemistry of the bonds is defined (now) as the horizontal
bonds are in front of the plane (coming toward you, the viewer); the
vertical bonds are behind the plane (going away from you).
Fischer Projection

A Fischer projection or Fischer

projection formula is a
convention used to depict a stereo-
formula in two dimensions without
destroying the Stereochemical
information, i.e., absolute
configuration, at chiral centers.
Fischer Projection

To convert this stereoformula into a Fischer projection use the following

procedure [Fischer Projection of (R)-Lactic acid]
Step 1: Hold the molecule so that
(i) The chiral center is on the plane of the paper,
(ii) Two bonds are coming out of the plane of the paper and are on a
horizontal plane,
(iii) The two remaining bonds are going into the plane of the paper and are on
a vertical plane.
Fischer Projection

Step 2: Push the two bonds coming out of the plane of the paper onto the
plane of the paper.
Fischer Projection

Step 3: Pull the two bonds going into the plane of the paper onto the plane of
the paper.
Fischer Projection

Step 4: Omit the chiral atom symbol for convenience.

Nomenclature

 A racemic mixture is denoted by the prefix (±)- or dl- , indicating an

equal (1:1) mixture of dextro and levo isomers. Also the prefix rac- (or
racem-) or the symbols RS and SR (all in italic letters) are used.
 If the ratio is not 1:1 (or is not known), the prefix (+)/(−), D/L- or
d/l- (with a slash) is used instead.
DL system of nomenclature

 The system that is used to designate the configurations of chiral carbons of naturally
occurring compounds is called the D and L convention or system.
 This descriptor (D and L) represent an older system for distinguishing enantiomers of
Carbohydrates and Amino acids.
 The arrangement of atoms in an optically active molecule, based on chemical
interconversion from or to a known compound, is a Relative configuration.
 D- & L - Glyceraldehyde are used as standard references for D-L system of
configuration of carbohydrates.
 D- & L - Alanine are used as standard reference for alpha amino acid with D-L system
of configuration.
 D-L system is also called as Fischer-Rosanoff convention.
DL system of nomenclature

 Fischer projections were originally proposed for the depiction of carbohydrates and used by
chemists, particularly inorganic chemistry and biochemistry.
 The L and D forms of the sugar depends on the orientation of the -H and -OH groups around
the carbon atom adjacent to the terminal primary alcohol carbon (carbon 5 in glucose)
determines whether the sugar belongs to the D or L series.
 Most of the monosaccharide occurring in mammals is D sugars, and the enzymes responsible
for their metabolism are specific for this configuration. In solution, glucose is dextrorotatory-
hence the alternative name dextrose.
 The direction of rotation is independent of the stereochemistry of the sugar, so it may be
designated D (-), D (+), L (-), or L (+). For example, the naturally occurring form of fructose is the
D (-) isomer.
DL system of nomenclature

To determine whether a given enantiomer of a chiral monosaccharide is D or L, use the following

procedure.

Step 1: Make sure the acyclic form of the molecule is drawn as a Fischer projection. If the
monosaccharide is an aldose, the aldehyde group must be on top; if it is a ketose, the carbonyl
carbon must be the second carbon from the top.
DL system of nomenclature

Step 2: Number the carbon atoms starting at the top.

DL system of nomenclature

Step 2: Number the carbon atoms starting at the top.

DL system of nomenclature

Step 3: Locate the carbon atom that bears the second highest number, which is known
as the penultimate carbon. If the hydroxy group on the penultimate carbon is on the
right of the carbon chain, assign the label D to the compound; if it is on the left of the
carbon chain, assign the label L.
DL system of nomenclature

The enantiomer of a given chiral monosaccharide, simply draw its mirror image.
DL system of nomenclature

The D- & L- system has the disadvantage of specifying configuration of only one stereocenter.
DL system of nomenclature

- Penultimate means next to last.

- The penultimate (second to last carbon) carbon is the last chiral carbon of the
chain.
DL system of nomenclature

To determine whether a given enantiomer of a chiral alpha-amino acid is D or

L, use the following procedure.

Step 1: Make sure that the molecule is drawn as the Fischer projection in
which the carboxylic acid group is on top and the side chain on bottom.
DL system of nomenclature

Step 2: If the amine group is on the right of the carbon chain, assign the label
D to the compound; if it is on the left of the carbon chain, assign the label L.
DL system of nomenclature
Threo and Erythro system of nomenclature

 A molecule with two adjacent stereocenters and with

two groups are common to each carbon while third
group is different i.e. Cabx-Caby gives rise to threo and
erythro diastereomers.
 When similar groups are on the same side = Erythro
 When similar groups are on the opposite side = Threo
 The term erythro and threo are generally applied only to
those molecules which do not have symmetric ends.
Instead Meso or (d, l) will be used.
RS system of nomenclature

 The precise arrangement of substituents at a stereogenic centre is known

as the Absolute configuration of the molecule and its Stereo chemical
description e.g. R (Rectus) or S (Sinister).
 This system, adopted by IUPAC, is called the RS convention or the
sequence rule system.
 R and S notations are used only to describe asymmetric molecules
following Cahn-Ingold-Prelog (CIP) sequence rules.
 Four substituents on an asymmetric carbon may be assigned priorities 1, 2,
3 or 4
RS system of nomenclature

Rule I: first we assign the priority numbers to the four atoms/groups attached to chiral
center according to CIP rules. For example in the case of CHClBrI, the four atoms
attached to the chiral center are all different and priority will be given based on atomic
weight, thus the priority follows as I, Br, Cl, H.
RS system of nomenclature

Rule I: If two atoms are isotopes of same element, the atom of higher mass number
has the higher priority.
RS system of nomenclature

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.
RS system of nomenclature

Rule 2:
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.
RS system of nomenclature

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.
RS system of nomenclature

Rule 4: In Fischer projection representations orient the molecule so that the least priority
group must be on lower end of vertical line. If the lower priority group on horizontal line or
upper side on vertical line, then to bring the group on to vertical line do two mutual
exchanges of groups so that the least priority group come to lower end of vertical line.
RS system of nomenclature

Rule 4: In Fischer projection representations orient the molecule so that the least priority
group must be on lower end of vertical line. If the lower priority group on horizontal line or
upper side on vertical line, then to bring the group on to vertical line do two mutual
exchanges of groups so that the least priority group come to lower end of vertical line.
RS system of nomenclature

Rule 5: After giving priority order for the groups at asymmetric center, if priority direction
is clockwise the configuration is specified ‘R’ (Latin: rectus, right); if anticlockwise the
configuration is specified ‘S’ (Latin: sinister, left).
RS system of nomenclature

 To assign R and S configuration to the chiral molecule, the least priority group should be
vertically downward in the Fischer projection.
 If it is not so, then interchanges in the positions are carried out to bring it to that position
but care needs to be taken so that the interchanges do not change the actual
configuration of the molecule.
 This is done by following two rules which state—

1. The interchange is to be carried out only between adjacent positions in the Fischer
projection.
RS system of nomenclature

2. An even number of interchanges must be carried out, as it does not change the actual
configuration of the molecule. It is to be noted that an odd number of interchanges cause a
change in the configuration of the molecule.
RS system of nomenclature
RS system of nomenclature

Rule 6: 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.
RS system of nomenclature

Assign R or S configuration to following molecules:

RS system of nomenclature

Assign R or S configuration to following molecules:

RS system of nomenclature

Assign R or S configuration to following molecules:

RS system of nomenclature

Assign R or S configuration to following molecules:

RS system of nomenclature
RS system of nomenclature
Reaction of Chiral Molecules

Chemical reactions Involved Chiral Molecules are:

a) the conversion of an achiral molecule into a chiral molecule, with the
generation of a chiral center;
b) reactions of chiral molecules in which bonds to the chiral center are not
broken, and see how such reactions can be used to relate the configuration
of one compound to that of another;
c) reactions of the kind in (b) in which a second chiral center is generated;
d) reactions of chiral compounds with optically active reagents.
Reaction of Chiral Molecules

a) The conversion of an achiral molecule into a chiral molecule, with the generation
of a chiral center
 One of the products of chlorination of n-butane is the chiral compound, sec-butyl
chloride.
Reaction of Chiral Molecules

a) The conversion of an achiral molecule into a

chiral molecule, with the generation of a chiral
center
 Each enantiomer should, of course, be optically
active. Now, if we were to put the sec-butyl
chloride actually prepared by the chlorination of w-
butane into a polarimeter, would it rotate the plane
of polarized light? The answer is no,
Reaction of Chiral Molecules

b) Reactions of chiral molecules: Bond breaking

A number of isomeric dichlorobutanes are formed, on free radical chlorination of sec-
butyl chloride, corresponding to attack at various positions in the molecule.
Reaction of Chiral Molecules

b) Reactions of chiral molecules: Bond breaking

Following the familiar steps of the mechanism, we remove an H from CH3 and replace
it with a Cl.
Since we break no bond to the chiral center in either step, the model we arrive at
necessarily has configuration II, in which the spatial arrangement about the chiral
center is unchanged or, as we say, configuration is retained.
Reaction of Chiral Molecules

b) Reactions of chiral molecules: Bond breaking

 It is an axiom of stereochemistry that molecules, too, behave in just this way,

and that a reaction that does not involve the breaking of a bond to a chiral

center proceeds with retention of configuration about that chiral center.

Reaction of Chiral Molecules

b) Reactions of chiral molecules: Relating Configuration

the configurational relationship between two optically active compounds can be
determined by converting one into the other by reactions that do not involve breaking
of a bond to a chiral center,

No bond to the chiral center is broken, and therefore configuration is retained

Reaction of Chiral Molecules

b) Reactions of chiral molecules: Relating Configuration

No bond to the chiral center is broken, and therefore configuration is retained

Reaction of Chiral Molecules

c) Reactions of chiral molecules. Generation of a second chiral center

free –radical chlorination of sec-butyl chloride, in which a second chiral center is
generated: 2,3 dichlorobutane.
This compound exists as three stereoisomers, meso and a pair of enantiomers.
Reaction of Chiral Molecules

c) Reactions of chiral molecules. Generation of a second

chiral center
 products from (S)-sec butyl chloride show an
S,S:meso ratio of 29:71
 products from (R)-sec butyl chloride show an
R,R:meso ratio of 29:71
 Since there are exactly equal quantities of (S)-and
(R)-reactants, the two sets of products would exactly
balance each other, and we would obtain racemic and
meso products in the ration of 29:71.
Reaction of Chiral Molecules

d) Reactions of chiral molecules with optically active reagents. Resolution

 resolution of a racemic modification, that is, the separation of a racemic modification
into enantiomers.
 such resolutions are accomplished through the use of reagents that are themselves
optically active; these reagents are generally obtained from natural sources.
 resolutions that have been carried out depend upon the reaction of organic bases
with organic acids to yield salts.
 we have prepared the racemic acid, (±)-HA. Now, there are isolated from various
plants very complicated bases called alkaloids (that is, alkali-like), among which are
cocaine, morphine, strychnine, and quinine.
Reaction of Chiral Molecules

d) Reactions of chiral molecules with optically active reagents. Resolution

 The salts are stereoisomers that are not enantiomers, and therefore are
diastereomers.
 a racemic modification is converted by an optically active reagent into a mixture of
diastereomers which can then be separated.
Reaction of Chiral Molecules

Reactions of chiral molecules. Mechanism of free-radical chlorination

What is the stereochemistry of reactions in which the bonds to the chiral center are
broken? The answer is: It depends on the mechanism of the reaction that is taking
place.
photochemical halogenation of optically active S-(+)-1-chloro-2-methylbutane.
A number of isomeric products were, of course, formed, corresponding to attack at
various positions in the molecule.
attention on just one of these products: 1,2-dichloro-2-mcthylbutane, resulting from
substitution at the chiral center
Reaction of Chiral Molecules

Reactions of chiral molecules. Mechanism of free-

radical chlorination
 from (S)-sec-butyl-chloride shown an
S,S:meso ratio of 29:71
 from (R)-sec-butyl-chloride shown an
R,R:meso ratio of 29:71
 Since there are exactly equal quantities of (S)-
and (R)-reactants,
 the two sets of products would exactly balance
each other, and we would obtain racemic and
meso product products rn the ratio of 29: 71.
Racemic modification

 A mixture of equal part of enantiomers is called a racemic modification.

 A racemic modification 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.
 The prefix ± is used to specify the racemic nature of the particular sample.
 For example, (±) lactic acid or (±) 2-methyl-l-butanol.
 It is useful to compare a racemic modification with a compound whose molecules are
superimposable on their mirror images, that is, with an achiral compound. They are
both optically inactive.
Racemic modification

 Equal quantities of d- and l-enantiomers.

 Notation: (d,l) or (±) No optical activity.

 The mixture may have different boiling point (b. p.) and melting point (m. p.)
from the enantiomers!
 If optically inactive reagents combine to form a chiral molecule, a racemic
mixture is formed.
Racemic modification
Racemic modification

Conglomerate
If the molecules of the substance have a greater affinity for the same enantiomer
than for the opposite one, a mechanical mixture of enantiomerically pure crystals will
result.
The melting point of the racemic conglomerate is always lower than that of the pure
enantiomer. Addition of a small amount of one enantiomer to the conglomerate
increases the melting point.
Racemic modification

Pseudoracemate (sometimes racemic solid solution)

When there is no big difference in affinity between the same and opposite
enantiomers, then in contrast to the racemic compound and the conglomerate,
the two enantiomers will coexist in an unordered manner in the crystal lattice.
Addition of a small amount of one enantiomer changes the melting point just
little bit or not at all.
Formation of Racemic modification

1. By Mixing:
Racemic modification is by intimate mixing of exactly equal amounts of
dextorotatory (+) and levorotatory (-) isomers. This process is associated
with an entropy mixing, since the racemic modification represents a more
random state of affairs than the separate enantiomers.
Formation of Racemic modification

2. By synthesis:
Any synthesis of dissymmetric molecules, starting from either symmetric
molecules or a racemic modification and using active reagent or
catalysts and no asymmetric physical influence always produces a
racemic modification.
The first method is exemplified by the bromination of propionic acid to
alpha bromopropionic ace by the Hell- Volhard-Zelinsky (H-V-Z) Method.
two alpha hydrogen bears the same relationship to the other and to the rest
of the molecule each is replaced at the only chiral centre.
Formation of Racemic modification

2. By synthesis:
 Rate as the other and equal numbers of (+) and (-) molecule of alpha
bromopropionic acid result.
 Bromination of propionic acid
Formation of Racemic modification

3. Epimerization, and Mutarotation.

a) Epimerization :- Change in configuration (arrangement of the group) at
one asymmetric atom in a compound having more than one such atom.
Epimerization of an optically active compound does not involve
racemization.

Epimers
- Those stereoisomers which are differing in its configuration at only one chiral
carbon atom are called as Epimers.
- Epimers are diastereomers that contain more than one chiral center but differ
from each other in the absolute configuration at only one chiral center.
Formation of Racemic modification
Formation of Racemic modification

 In epimers the chiral carbon atoms whose absolute configuration

makes the two compounds different are called the epimeric carbons.
 EPIMERISATION
 The chemical conversion of one epimer to another is called
epimerization.
 If this interconversion is catalyzed by an enzyme, the enzyme is an
epimerase
Formation of Racemic modification

a) Enolate Mechanism:
Formation of Racemic modification

a) Enediol Mechanism:
Formation of Racemic modification

b) Mutarotation and first-order asymmetric Transformation :-

In 1846 Dubrunfaut discovered that, When glucose is dissolved in
water and the optical activity of the solution observed, there is a
gradual change in roatation from an initial value corresponding to
[a]20 D of +1110 to an equilibrium value of [a]20 D +52.50
Formation of Racemic modification

 In the case of (+) glucose mutarotation involves a change of configuration

at the No. 1 carbon ( called anomeric center) owing to an opening and
reclosing of the hemiacetal ring.
 The intermediate open-chain aldehyde form is present in negligibly small
concentration. Equilibrium corresponds to 38% of the alpha and 62% of
the beta form.
Properties of Racemic modification

Physical properties

Racemate may have different physical properties from either of the pure
enantiomers because of the differential intermolecular interactions . The
change from a pure enantiomer to a racemate can change its density,
melting point, solubility, heat of fusion, refractive index, and its various
spectra. Crystallization of a racemate can result in separate (+) and (−)
forms, or a single racemic compound.
Properties of Racemic modification

Racemic Mixture :- In a crystal each enatatiomers has a greater affinity for

molecule of the same kind than for molecule of the other enantiomer. In
that case once molecule of the (+) form is laid down in the crystal, only
(+) molecule will grow on it. And similarly (-).

eg. Solubility and Melting Point of racemic mixture.

Resolution of Racemic Mixture

 The separation of a racemic mixture into the individual enantiomerically pure

enantiomers is called resolution.
 Since enantiomers have identical physical properties, such as solubility, boiling
point and melting point, they cannot be resolved by common physical techniques
such as direct crystallization, distillation or basic chromatography.
 The main difficulty in a process of resolution is that d or (+) and l or (–) forms
have identical physical and chemical properties, so they cannot be separated by
ordinary methods. However, the following methods can be used for this purpose.
Resolution of Racemic Mixture
Resolution of Racemic Mixture

1. Mechanical Method:
 It was the first method used by Pasteur (1884) for the resolution
of sodium ammonium tartarate which crystallizes out in the form
of racemic mixtures below 270C.
 Since the crystals too are nonsuperimposable, their appearance
is not identical. They can be separated with the help of
magnifying lens and a pair of tweezers. This method is
laborious and is applicable to only those isomers having different
crystal.
Resolution of Racemic Mixture

2. Preferential crystallization by inoculation (Gernez-1866)

 This method involves the seeding of a saturated solution of the racemic mixture with a pure
crystal of one of the two enantiomers. The solution now becomes supersaturated with
respect to the added enantiomers and after sometimes cooling it begins to crystallize out.
 Example:-
 Harda (1865) obtained total optical resolution of free alpha- amino acids with the aid of ‘/” or
d-isomers of the corresponding amino acid.
 Sometimes seeds with a crystal of optically active form of another molecule re also possible.
Crystal of (-) asparagines crystallizes out (±) sodium ammonium tartarate from solution of
racemic modification.
Resolution of Racemic Mixture

2. Preferential crystallization by inoculation (Gernez-1866)

Resolution of Racemic Mixture

3. Biochemical Separation
 It was introduced by PASTEUR in 1858.
 Biological molecules may react at different rates with the two enantiomers.
 For example, a certain bacterium may digest one enantiomer, but not the other.
 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 modification they
assimilate on one enantiomers rapidly than the others.
Resolution of Racemic Mixture

3. Biochemical Separation
 e.g. The mould penicillin glaucum preferentially destroys the (+) isomers of racemic
ammonium tartarate and thus leaves the (-) ammonium tartarate in solution.
 This method is limited, since it is necessary to find the proper organism and since
one of the enantiomers is destroyed in the process.
 This process has been called chemoenzymatic dynamic kinetic resolution.
 Reduction of ethyl acetoacetate with Baker’s yeast
O O baker's yeast
H OH O HO H O
Et +
Et Et
Me O H 2O, sucrose Me O Me O

Ethyl acetoacetate
(S)-(+)-Ethyl (R)-(-)-Ethyl
3-hydroxybutanoate 3-hydroxybutanoate
>90 % < 10%
Resolution of Racemic Mixture

4. By Diastereomers
 This method converting the eanantiomers of a racemic modification to
diastereomers with the aid of a pure enantiomers of other compound.
 Diastereomers are non- identical, they have different physical properties and hence
easily separated by crystallization and chromatography techniques.
 Since the base used is, say, the (S) form, there will be a mixture of two salts
produced having the configurations (S,S) and (R,S).
 Example: Resolution of lactic acid using brucine
Resolution of Racemic Mixture

4. By Diastereomers
 Example: Resolution of lactic acid using brucine
COOH COO- COOH
+
H3C H H Brucine-H H
OH H3C OH H3C OH
(S)-(+)-form (SS)-form (S)-(+)-form
HCl
+ (S)-Brucine
COOH COOH
COO-
H3C OH + OH
H OH Brucine-H H3C H
H3C H
(R)-(-)-form (R)-(-)-form
(SR)-form

Other examples:
•Resolution of ibuprofen using a-phenethylamine
•Resolution of Duloxetine (=Cymbalta) using mandelic acid
Resolution of Racemic Mixture

4. By Diastereomers
Commonly used resolution reagents are:
Compound Resolution agent
Carboxylic acids brucine, strychnine, ephedrine, cinchonine
Amines camphor-10-sulfonic acid, tartaric acid, mandelic acid

Alcohols phthalic acid, succinic acid (via half ester)

Aldehyde, ketone mentylsemicarbazide, mentylhydrazine
Resolution of Racemic Mixture

5. By Precipitation
 This method is based on
formation of precipitate by
reaction between any reagent
and racemic mixture.
 Example: (+) & (-) narcotine
when dissolved in HCL
,precipitates (+) narcotine.
Resolution of Racemic Mixture

6. Chromatographic Separation
 When a racemic mixture is placed on a chromatographic column, if the
column consists of chiral substances, then in principle the enantiomers
should move along the column at different rates and should be separable
without having to be converted to diastereomers.
 This has been successfully accomplished with paper, column, thin-layer and
gas and liquid chromatography.
 Columns packed with chiral materials are now commercially available and
are capable of separating the enantiomers of certain types of compounds.
Resolution of Racemic Mixture

6. Chromatographic Separation
 These columns are typically silica gel with bonded optically active functionalities, such as
(either d or l) phenyl urea, naphthyl urea, phenyl glycine or leucine.
 cyclodextrins bonded to silica gel also permit the separation of optical isomers, via the
formation of inclusion complexes within the cyclodextrin cavity.
Resolution of Racemic Mixture

7. Kinetic Separation
 Since enantiomers react with chiral
compounds at different rates, it is
sometimes possible to effect a partial
separation by stopping the reaction before
completion.
 A method has been developed to evaluate
the enantiomeric ratio of kinetic resolution
using only the extent of substrate
conversion.
Asymmetric Synthesis

 synthesize a chiral compound in the form of a single enantiomer or diastereomer,

rather than as a mixture of stereoisomers.
 There are two basic ways in which this can be done.
 The first way, which is more common, is to begin with a single stereoisomer, and to
use a synthesis that does not affect the stereogenic center
 the starting material is obtained from Nature, since many compounds, such as amino
acids, sugars, and steroids, are present in Nature in the form of a single enantiomer or
diastereomer. These compounds have been referred to as a chiral pool.
 The other basic method is called asymmetric synthesis.
Asymmetric Synthesis

Asymmetric
Induction

Internal Relayed External

asymmetric asymmetric asymmetric
induction: Chiral induction: chirality induction: chiral
Center bound to the introduced in information at
reaction center used separate step transition state
Chiral Pool
Chiral auxiliaries Chiral catalysts
Synthesis
Asymmetric Synthesis

CHIRAL POOL SYNTHESIS

 simplest and oldest approaches for enantioselective synthesis Uses an
enantiomerically pure natural product as a starting material,
 The chiral pool—Nature’s ‘ready-made’ chiral centres :pure natural products, usually
amino acids or sugars, from which pieces containing the required chiral centres can
be taken and incorporated into the product.
 Aspartame from s- phenylanine and s- aspatic acid
Asymmetric Synthesis

MAJOR APPROACHES IN ASYMMETRIC SYNTHESIS

Asymmetric synthesis are of two types
Partial Asymmetric Synthesis: synthesis of a new chiral center from an achiral center
by using optically active reagents .
Absolute Asymetric Synthesis: It is the synthesis of optically active products from
achiral substrate without the use of optically active reagents .
“ ▸ Partial Asymmetric
Synthesis
Asymmetric Synthesis

Active substrate.
• If a new stereogenic center is created in a molecule that is already optically active, the
product will generate diastereomers and the two diastereomers may not (except
fortuitously) be formed in equal amounts.
• certain additions to the carbon–oxygen double bond of ketones containing an
asymmetric α carbon, Cram’s rule predicts which of two diastereomers will
predominate.
 Asymmetric Synthesis

Active substrate.
• If 45 is observed along its axis, it may be
represented as in 48, where S, M, and L
stand for small, medium, and large,
respectively. The oxygen of the carbonyl
orients itself between the small- and the
medium-sized groups.
• The rule requires that the incoming group
preferentially attacks on the side of the
plane containing the small group. By this
rule, it can be predicted that 47 will be
formed in larger amounts than 46.
Asymmetric Synthesis

Chiral Auxillary
possible to convert an achiral
compound to a chiral compound by:
(i) addition of a chiral group;
(ii) Running an asymmetric synthesis,
and
(iii) cleavage of the original chiral group.

The original chiral group is called a

chiral auxiliary, and an example is 53.
An example is conversion of the achiral
pentan-2-one to the chiral 4-methyl-
heptan-3-one, 54.
In this case, >99% of the product was
the (S) enantiomer.
Asymmetric Synthesis

Chiral Auxillary
possible to convert an achiral
compound to a chiral compound by:
(i) addition of a chiral group;
(ii) Running an asymmetric synthesis,
and
(iii) cleavage of the original chiral group.

The original chiral group is called a

chiral auxiliary, and an example is 53.
An example is conversion of the achiral
pentan-2-one to the chiral 4-methyl-
heptan-3-one, 54.
In this case, >99% of the product was
the (S) enantiomer.
Asymmetric Synthesis

Active reagent.
• A pair of enantiomers can be separated by an active reagent that reacts faster with
one of them than it does with the other.(Kinetic Resolution).
• If the absolute configuration of the reagent is known, the configuration of the
enantiomers can often be determined by a knowledge of the mechanism and by
determining which diastereomer is preferentially formed.
• Creation of a new stereogenic center in an inactive molecule can also be
accomplished with an optically active reagent, although it is rare for 100%
selectivity to be observed.
Asymmetric Synthesis

Active reagent.
 Reduction of methyl benzoylformate with optically active Nbenzyl- 3-
(hydroxymethyl)-4-methyl-1,4-dihydropyridine (55) to produce mandelic acid (after
hydrolysis) that contained ~97.5% of the (S)-(+) isomer and 2.5% of the (R)-(−)
isomer (for another example, see 15-11). Note that the other product, 56, is not
chiral. Reactions like this, in which one reagent (in this case 56) gives up its
chirality to another, are called self-immolative.
Asymmetric Synthesis

Active reagent.
Asymmetric Synthesis

Optically active catalyst or solvent

• Reduction of ketones and substituted alkenes to optically active (though not
optically pure) secondary alcohols and substituted alkanes by treatment with
hydrogen and a chiral homogeneous hydrogenation catalyst.
• use of a chiral catalyst or solvent are the conversion of chlorofumaric acid (in the
form of its di-ion) to the (−)-threo isomer of the di-ion of chloromalic acid by
treatment with H2O and the enzyme fumarase, and the preparation of optically
active aldols.
“ ▸ Absolute Asymmetric
Synthesis
Asymmetric Synthesis

ABSOLUTE ASYMMETRIC SYNTHESIS

It is the synthesis of optically active products from achiral substrate without
the use of optically active reagents .
In this type of synthesis a physical presence of chirality is necessary .
Eg: addition of bromine to 2,4,6-trinitrostilbene give a dextrorotatory product.
Here we are using circularly polarized light for the induction of chirality.
Asymmetric Synthesis

Reactions in the presence of circularly polarized light.

 If the light used to initiate a photochemical reaction of achiral reagents is circularly
polarized, then, in theory, a chiral product richer in one enantiomer might be
obtained.
 However, such experiments have not proved fruitful. In certain instances, the use
of left and right circularly polarized light has given products with opposite
rotations176 (showing that the principle is valid), but up to now the extent of
favoritism has always been <1%.
Eg: Light induced cyclisation of 1,2 –diarylethylenes to dihydrophenanthrene
derivatives
Asymmetric Synthesis