Introduction:

Stereoisomerism is arising due to the difference in arrangement (configuration)

of atoms or groups in space.
When two or more than two isomers have the same structural formulae but
having difference in the arrangement (configuration) of atoms in space are
called stereo isomer and the phenomenon is called stereo isomerism.
Stereo isomerism can be further classified as
i. Geometrical or cis-trans isomerism
ii. Optical isomerism
Optical isomerism
An optically active compounds exists in two isomeric forms that rotate the plane
polarized light in opposite directions. They are called optical isomers and the
phenomena is called optical isomerism.
Optical isomerism in Lactic acid:

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Optical Activity:
Optical isomers have the ability to rotate the plane polarized light. This property
is often referred as Optical Activity.
Sir Christiaan Huygens (1629-1695). Dutch astronomer, mathematician, and
physicist. He discovers plane polarized light.
What is plane-polarized light?
A beam of ordinary light consists of electromagnetic waves that oscillate in an
infinite number of planes at right angles to the direction of light travel. When a
beam of ordinary light is passed through a device called a polarizer, or a Nicol
prism (made of calcite or CaCO3), light is found to vibrate in only one plane and
is said to be plane-polarized. Light waves in all other planes are blocked out.

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 Light waves oscillate in all planes. Light waves oscillate in a single plane.
A POLARIMETER is an instrument that allows plane-polarized light to travel
through a sample tube containing an organic compound. After the light exits the
sample tube, an analyzer slit is rotated to determine the direction of the plane
of the polarized light exiting the sample tube. There are two possible results.
With achiral compounds, the light exits the sample tube unchanged, and the
plane of the polarized light is in the same position it was before entering the
sample tube. A compound that does not change the plane of polarized light is
said to be optically inactive.

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Optically Active Compounds
When a beam of plane polarized light passes through a solution of certain
organic molecules, such as sugar or camphor, the plane of polarization is rotated
through an angle α. Not all organic substances exhibit this property, but those
that do are said to be optically active.
The angle of rotation can be measured with an instrument called a polarimeter.
When a solution of known concentration of an optically active material is placed
in the polarimeter, the beam of light is rotated either to the right (clockwise) or
to the left (anti-clockwise). So, the compounds which rotate the plane polarized
light (PPL) to the right (clockwise) is said to be Dextrorotatory, and those which
rotate the PPL to the left is said to be Levorotatory. Dextrorotatory is indicated

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by + sign, while Levorotatory by a minus sign (─).
(─)-Morphine, for example, is levorotatory, and (+)-sucrose is dextrorotatory.
SPECIFIC ROTATION
The observed rotation depends on the number of chiral molecules that interact
with polarized light. This in turn depends on the concentration of the sample
and the length of the sample tube.

To standardize optical rotation data, the quantity specific rotation ( αD) is

defined using a specific sample tube length (usually 1 dm), concentration,

temperature (25 °C), and wavelength (589 nm, the D line emitted by a sodium
lamp). Specific rotations are physical constants just like melting points or boiling
points, and are reported in chemical reference books for a wide variety of
compounds.

CONDITIONS FOR OPTICAL ACTIVITY

1) To exhibit optical activity molecule must possess asymmetric carbon:
Asymmetric carbon compounds are optically active. But, presence of
asymmetric is not only the requirement.

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2) To exhibit optical activity molecule must not have the symmetry elements, (a)
plane of symmetry (b) centre of symmetry (c) n-fold alternating access of
symmetry. If these three are absent then only the compounds exhibit optical
activity.
(a) Plane of symmetry:
A plane which bisects the molecules into two mirror images are called plane of
symmetry. If the plane of symmetry is present then the molecule is optically
inactive, if absent then optically active.

(b) Centre of symmetry: If all the lines two identical groups pass through a single
point or a central point is called centre of symmetry.

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(c) n-Fold alternating access of symmetry: If a rotation by 360º/n degrees (n = 1,
2, 3, …) followed by reflection in plane perpendicular to the access taken results
in identical molecule the compound said to be possess n-fold alternating access
of symmetry. If plane of symmetry or centre of symmetry is present then n-fold
alternative access of symmetry is present. If plane of symmetry or centers of
symmetry are absent then n-fold alternating access of symmetry will be absent.
If the n-fold alternating access of symmetry present then the molecule is
optically inactive, if absent then optically active.

Enantiomerism:
Optically active chiral compounds that are non-super imposable mirror image of
each other are called enantiomers.
Properties of enantiomers:
The main properties of enantiomers are given as follow
❖ Enantiomers always exist in pair
❖ Enantiomers are non-super imposable mirror image to each other.
❖ Enantiomers have same physical properties (like boiling point, melting point,
solubility, density, viscosity, refractive index etc.) and chemical properties in
achiral environment.
❖ Each enantiomers have opposite behavior with respect to plane polarized
light, if one of them will rotate the plane polarized light towards right hand
direction then definitely the other will rotate the plane polarized light
towards left hand direction.

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❖ Each enantiomers shows the same chemical reactivity with achiral reagent;
however, they have different reactivity with chiral reagent.
Ex., Glyceraldehyde molecule is a chiral molecule. It has a pair of enantiomers
with same physical properties except their behavior towards plane polarized
light.

Diastereoisomerism:
❖ Stereoisomerism other than enantiomerism.
❖ Diastereoisomers (or diastereomers) are stereoisomers not related as mirror
images.
❖ Diastereoisomers are characterized by differences in physical properties, and
by some differences in chemical behavior towards achiral as well as chiral
reagents.

❖ If two molecules are mirror images, then their configurations are exactly
opposite and they are enantiomers. For example, D and L erythroses are

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❖ mirror images, so they are enantiomers, same way D and L threoses are
enantiomers.
❖ If two molecules are not mirror images, but still, they are stereoisomers they
are diastereomers, D-erythrose and D-threose are not mirror images so they
are diastereomers, same way D-erythrose and L-threoses; L-erythrose and D-
threose; L-erythrose and L-threoses are diastereomeric pairs.
❖ Diastereomers are different geometrical entities. But enantiomers are
identical geometrical entities.
❖ For the diastereomeric relationship chirality is not essentiality. For example,
cis- and trans-isomers are diastereomers.

Single asymmetric centre cannot show diastereoisomerism.

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Enantiomers & Diastereomers:
Enantiomers Diastereomers
An enantiomer is one of two Diastereomers (or diastereoisomers)
stereoisomers that are non - are stereoisomers that are not
superimposable complete mirror enantiomers (non-superimposable
images of each other. mirror images of each other).
Molecules must contain at least one Molecules must contain more than one
chiral center. chiral center.
Enantiomers have, when present in a Diastereomers can have different
symmetric environment, identical physical properties and different
chemical and physical properties reactivity. In another definition
except for their ability to rotate diastereomers are pairs of isomers that
plane have opposite configurations at one or
polarized light by equal amounts but more of the chiral centers but are not
in opposite directions. mirror images of each other.
A mixture of equal parts of an Racemic mixture is not possible.
optically active isomer and its
enantiomer is termed Racemic and
has a net rotation of plane polarized
light of zero.

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Meso Compound
❖ An optically inactive compound whose molecule is superimposable on its
mirror image in spite 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.
Example., 2,3-dibromobutane have two stereocenters, but the molecule has
two symmetric ends therefore it can be divided in to two equal halves. In other
words, the molecule has plane of symmetry.

Another example of meso compound is one of the stereo isomeric forms of

Tartaric acid (2, 3-dihydroxysuccinic acid). The molecule is optically inactive
because it has internal plane of symmetry.

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Calculation for determination of optical isomers:

Number of optically active forms: a = 2n= 23= 8

Number of Racemic mixtures: (a/2) = 2n-1= 23-1= 4
Total number of optical isomers: a+m = 8+0 = 8
ELEMENTS OF SYMMETRY:
Elements of symmetry are a simple tool to identify whether a molecule is chiral
or not. The necessary condition for optically active molecule to be chiral is that,
the molecule should not possess any kind of symmetry elements. The elements
of symmetry are generally categorized as follows:
(i) Simple axis of symmetry (Cn)
(ii) Plane of symmetry (σ)
(iii) Centre of symmetry (Ci)
(iv) Alternating axis of symmetry (Sn)
(i) Simple axis of symmetry (Cn):
When a rotation of 360°/n (where n is any integer like 1,2,3…etc.) around the
axis of a molecule or object is applied, and the rotated form thus obtained is
non-differentiable from the original, then the molecule/object is known to have
a simple axis of symmetry. It is represented by Cn.
Example., Water molecule has C2 (two-fold axis of symmetry) whereas
chloroform has C3 axis of symmetry.

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From above example you can easily understand that if you rotate the water
molecule by 180° (i.e., 360°/2=180°) along its molecular axis you will get the
identical (non-differentiable) form of water molecule, hence water molecule has
two-fold of symmetry. Similarly, if you rotate the chloroform molecule by 120°
(i.e., 360°/3=120°) along its molecular axis you will get the identical (non-
differentiable) form of chloroform molecule, hence chloroform molecule has
three-fold of symmetry.
(ii) Plane of symmetry (σ):
It is defined as ‘when a plane that devised a molecule or object in to two equal
halves which are related to object and mirror image is known as plane of
symmetry. It is represented by σ.
Example., Plane of symmetry in Tartaric acid

From above example you can easily understand that if we put a mirror
plane/reflection plane exactly at the centre axis of the molecule/object; you will
find that the mirror image thus obtained is the complementary of the original
and both will give us the appearance of complete molecule/object.

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(iii) Centre of symmetry (Ci):
A molecule has a centre of symmetry when, for any atom in the molecule, an
identical atom exists diametrically (diagonally) opposite to this centre and at
equal distance from it.
Example., An isomer of 1,3-dichloro-2,4-dibromocyclobutane has a centre of
symmetry.

From above example you may understand that all the identical atoms are
situated diagonally and at equal distance from the centre. This is called centre
of symmetry.
(iv) Alternating axis of symmetry (Sn):
An alternate axis of symmetry is defined as, when a molecule is rotated by
360°/n degrees about its axis and then a reflection plane is placed exactly at
perpendicular to the axis, and the reflection of the molecule thus obtained is
identical to the original. It is represented by Sn.
Example., An isomer of 1,3-dichloro-2,4-dibromocyclobutane has a 2-fold
alternate axis of symmetry.

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CHIRAL AND ACHIRAL MOLECULES:
❖ A molecule (or an object) is said to be chiral or dissymmetric, if it is not
superimposable on its mirror image and the property of non-
superimposability is called chirality.
❖ On the other hand, a molecule (or an object) which is superimposable on its
mirror image is called achiral (non-dissymmetric or unsymmetrical).
❖ Chiral carbon atom (chiral centre/stereo centre). Carbon atom bonded to
four different atoms or groups is called an asymmetric carbon atom or a
chiral atom. A chiral atom is indicated by an asterisk (*).
Note: Isotopes of a particular atom behave as different groups in
stereoisomerism.

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➢ If a molecule contains only one chiral centre/atom, then the molecule has to
be optically active (i.e., non superimposable on its mirror image) as it will not
contain any element of symmetry.
➢ Molecules containing two or more chiral centers may or may not be chiral
(optically active).
➢ It is necessary to distinguish chiral and chiral centre. The word chiral is used
for molecule as a whole which is optically active, whereas chiral centre is for
an atom which is attached to form different atoms/groups.

Relationships between Chiral Centers and Chiral Molecules:

➢ The term chiral center refers to an atom in the molecular structure. The term
chiral molecule refers to the entire molecule.
➢ The presence of one chiral center renders the entire molecule chiral. The
presence of two or more chiral centers may or may not result in the molecule
being chiral. In the examples given below the chiral centers are indicated with
an asterisk. The vertical broken line represents a plane of symmetry.

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What is Chirality?
The property of non-superimposability of an object on its mirror image is called
chirality. Such molecule has no symmetry elements of the second kind. If the
molecule is superposable on its mirror image, it is ACHIRAL.
RELATIVE AND ABSOLUTE CONFIGURATION:
Relative and absolute configuration of a compound discusses about the spatial
arrangement of atoms/groups around the centre chiral atom. Relative
configuration is a comparison of the spatial arrangement of attached
atoms/groups of two different chiral centers.
Relative configuration is a geometrical property which do not changes on
reflection; whereas, the absolute configuration is the precise arrangement of
atoms in three-dimensional space. The D/L system is usually known as relative
configuration whereas, the R/S stereo descriptor or nomenclature system for
chiral molecules is known as absolute configuration. The absolute configuration
is a topographic property which changes on reflection.
D & L-System of nomenclature of optical isomers:
The D & L convention, not to be confused with the d (dextro) and l (levo)
descriptors used to designate the direction of specific rotation of chiral
compounds, is a convention used to distinguish between enantiomers of chiral
monosaccharides and chiral alpha-amino acids, based on the molecule drawn as

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a Fischer projection in a specific orientation.
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.
The D- and L- notation is based on glyceraldehyde.
When the -OH group on this carbon is on the right, then sugar is the D-isomer;
when it is on the left, then it is the L-isomer.

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 presence of asymmetric carbon atoms also confers optical activity on the
compound. When a beam of plane-polarized light is passed through a solution
of an optical isomer, it will be rotated either to the right, dextrorotatory (+); or
to the left, levorotatory (-). 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.

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Application of D, L convention to monosaccharides:
One enantiomer of a chiral monosaccharide is labeled D and the other L. 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.

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

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.

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

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Application of D, L convention to alpha-amino acids:
One enantiomer of a chiral alpha-amino acid is labeled D and the other L. 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.

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.

To draw the enantiomer of a given chiral alpha-amino acid, simply draw its
mirror image.

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What is the PENULTIMATE CARBON?
Penultimate means next to last. The penultimate (second to last carbon) carbon
is the last chiral carbon of the chain.

Sequence Rules:
What is C. I. P. system or CIP priority and what are their rules?
❖ It is a short form for Cahn-Ingold-Prelog (CIP) priority rules system. CIP
system or CIP conventions are a set of rules used to name the stereoisomers
of a molecule.
❖ A molecule may contain any number of stereocenter and any number of
double bonds and each gives rise to two possible configurations.
❖ The purpose of the CIP system is to assign ‘R’ (Rectus means clock wise) and
‘S’ (Sinister means anti-clock wise) descriptor to each stereocenter and an ‘E’
or ‘Z’ descriptor to each double bond so that the configuration of the entire
molecule can be specified uniquely by including the descriptors in its
systematic name.

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The CIP sequence rules are:
1) Rule 1: Give priority (numbering) to the groups at the asymmetric centre
based on the atomic weight of an atom which is directly attached to the
asymmetric centre, i.e., more atomic weight atoms are given first priority.

2) Step 2: If two or more atoms attached to the chiral centre have same atomic
number, the priorities are assigned by comparing the atomic numbers of the
next atoms attached to each group/atom.

Rule 3: If multiple bonded groups attached to asymmetric centre do the

duplication and triplication of the group.

Rule 4: If asymmetric centre attached ‘R’ and ‘S’ configuration groups, then the
carbon having ‘R’ configuration should be given priority over ‘S’.

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Rule 5: if there is a ‘E’ and ‘Z’ configuration groups at asymmetric centre then
the carbon with ‘Z’ should be given more priority over ‘E’.
R, S-System of nomenclature of optical isomers:
An absolute configuration refers to the spatial arrangement of the atoms of a
chiral molecular entity (or group) and its Stereochemical description e.g., R
(Rectus) or S (Sinister).
The arrangement of atoms in an optically active molecule, based on chemical
interconversion from or to a known compound, is a relative configuration.
Relative, because there is no way of knowing just by looking at a structure
whether the assignment of (+) or (-) is correlated to a particular isomer, R or S.
R and S notations are used only to describe asymmetric molecules following
Cahn-Ingold-Prelog (CIP) sequence rules.
(a) Rule I: First we assign the priority numbers to the four atoms/groups
attached to chiral centre 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.

(b) 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.

(c) 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.

(d) 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.

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

(f) 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.

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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:
❖ Reactions where bonds with the chiral center are not broken.
❖ Reactions leading to generation of chiral center.
❖ Reactions of chiral compounds with optically active reagents.
❖ 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
–CH2OH 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

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center. Only relative configuration can be assigned than absolute configuration.
Such reactions are used to get specific rotations of optically pure compounds.
e.g., 2-methyl-1-butanol from fuel oil has a specific rotation of –5.90° and is
optically pure. Upon treatment with hydrogen chloride, 1-chloro 2-methyl
butane has a specific rotation of +1.67°.
So, if a sample has rotation equal to this value, the compound is said to be pure.
If rotation is about + 0.8º, the compound is said to be only 50% optically pure.
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. This is
because the intermediate 3-chloro-2-butyl radical contains a chiral center and it

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lacks symmetry. So, two faces of the molecule for attack are not equal to each
other. Here S isomer would yield the SS and meso compound in the ratio of
29:71.
In some reactions, both configurations may not be generated but probability
exists. Similarly, the R isomer would yield RR and meso compound in the ratio
of 29:71. If the reactant is optically inactive, it yields optically inactive products.
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. Because
enantiomers have similar physical properties (except optical rotation) they
are not separated by usual methods of fractional distillation or crystallization.
❖ 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.

Formed diastereomers have different physical properties and can be easily

separated by fractional distillation or crystallization. Further by the addition of
mineral acid resolved enantiomers can be recovered from the solution.
Alkaloid bases commonly used are (–) brucine, (–) quinine, (–) strychnine, etc.
Similarly, racemic bases can be separated with acid reagents e.g. (–) malic acid.

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Compounds other than acids, bases can also be resolved. Alcohols are weakly
ionized and are not appreciably acidic or basic so their resolution is facilitated
by attaching them with an acidic handle which can be removed later.
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.

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If there is a simultaneous attack of chlorine while the displacement of hydrogen,
only the product from backside attack of chlorine would have been obtained
instead of optically inactive product, so the mechanism involving free alkyl
radicals is correct.
A reaction is stereospecific when reactants exist as stereoisomers and each
isomeric reactant gives a different stereoisomeric product.
A reaction is stereoselective when reactant irrespective of any stereoisomerism
produces predominantly or exclusively one stereoisomeric form of the product
than other possible forms.
RACEMIC MIXTURE
❖ A racemic mixture is a 1:1 mix of two enantiomers (Each of a pair of
molecules that are mirror images of each other).
❖ No matter how many molecules are in a mixture, it is racemic if there are
equal numbers of the two enantiomers.
❖ The racemic mixture produces a net optical rotation - of plane polarized light
- of zero degrees. This is because the mixture contains equal amounts -
equimolar mixture of both enantiomers that have opposite rotations.
❖ A racemic mixture is a solution containing equal amounts of a pair of
enantiomers.

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✓ A solution containing equal amounts of (R)-2-butanol and (S)-2-butanol is a
racemic mixture.
✓ A solution containing an excess of either the (R)-enantiomer or the (S)-
enantiomer would be ENANTIOENRICHED.
✓ A solution containing only the (R)-enantiomer or the (S)-enantiomer will be
ENANTIOMERICALLY PURE.

RESOLUTION OF RACEMIC MIXTURES:

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.
(i) Mechanical separation:
If the d or (+) and l or (–) forms of a substance exits in well-defined crystalline
forms, the separation can be
done by hand picking with the help of magnifying lens and a pair of tweezers.
For example, the d and l forms of sodium ammonium tartarate can be separated
by this method.

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The method has very limited application and applies to only few crystalline
constituents having different shape.

(ii) Biochemical separation:

In this method, the resolution is done by the use of microorganisms.
When certain bacteria or moulds are added to a solution of a racemic mixture,
they decompose one of the optically active forms more rapidly than the other.
For example, when the mould, racemic ammonium tartarate, the mould
completely decomposes the d form white l form is left practically unaffected.
The main drawback of the method is that half of the material is destroyed during
resolution. The process is very slow and only small amounts of the materials can
be separated.
For example: Penicillium glaucum removes Dextro form from the racemic
mixture of ammonium tartrate leaving a levo ammonium tartrate.
(iii) Chemical separation:
This is probably the best method of resolution. The racemic mixture is made to
combine with another optically active compound and the resulting solubility in
various solvents.

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By fractional crystallization from a suitable solvent, they can be separated.
For example, the racemic mixture of lactic acid is allowed to combine with the
optically active base (-) strychnine or (+) brucine.

Selective Adsorption/Chiral chromatography:

Sometimes 'resolution' may be achieved by passing a solution of the racemate
over a column of a finely powdered, optically active adsorbent such as starch,
sugar or quartz.
The surface of the adsorbent adsorbs selectively one enantiomer and thus the
solution emerging at the bottom is richer in the other enantiomer.
Chromatographic methods, whereby the stationary phase is a chiral reagent that

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adsorbs one enantiomer more strongly than the other, have been used to
resolve racemic compounds.

Example of Resolution of Racemic Mixtures

(i) (S)-1-Phenylethylamine combines with a racemic mixture of lactic acid to form
diastereomeric salts. The diastereomers are separated by fractional
crystallization.

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After the separation process, each of the diastereomers is subsequently treated
with a strong acid such as hydrochloric acid to regenerate the corresponding
enantiomer of lactic acid.

✓ Note that the lactic acid would be soluble in the organic layer, while the
ammonium salt would be in the water layer.
✓ Since enantiomerically pure compounds are very expensive, it is usually
necessary to recover and reuse the chiral amine. This is achieved by treating
the (S)-1-phenylethyl ammonium chloride salt with a base such as sodium
hydroxide to regenerate and recover the chiral amine.

RACEMIZATION:
Racemization is the conversion of an enantiomerically pure mixture (one where
only one enantiomer is present) into a mixture where more than one of the
enantiomers are present. (Or) Conversion of an optically active
substance to a raceme.
Optically active carbonyl compounds of the type −CHC=O, in which the alpha
carbon is asymmetric, are racemized by both acids and bases.

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The racemization of an optically active secondary halide with the chiral carbon
carrying the halogen (e.g., 2-chlorobutane) may occur in the solution and,
usually, the more polar and better ionizing the solvent is, the more readily the
substance is racemized. Ionization of the halide by an S N1 process probably is
responsible, and this certainly would be promoted by polar solvents. All
indications are that an alkyl carbocation once dissociated from its accompanying
anion is planar; and, when such an ion recombines with the anion, it has equal
probability of forming the D and L enantiomers:

Asymmetric Synthesis:
Before 1940, the optically active compounds could be obtained in stereo-
isometrically pure form only by isolation of racemic mixture of optically active
compounds from natural products and
their subsequent enzymatic resolution. Since, equimolar number of
enantiomers (racemic mixture) is obtained when a prochiral molecule
undergoes reaction in the absence of chiral environment. As we know the
physical and chemical properties of enantiomers are always same in the absence

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of a chiral environment. However, enantiomers have entirely different
reactivities in biological system.
PRINCIPLES OF ASYMMETRIC SYNTHESIS:
There are three principles of asymmetric synthesis
a) The substrate molecule must be prochiral i.e., the substrate must have either
enantiotropic or diastereotropic ligands or faces.
b) There must be presence of chirality in the reaction/asymmetric
transformation for the preferential formation of one stereoisomer over the
other. Either the substrate, or the reagent, or the solvent, or the catalyst must
be enantiomerically pure.
c) The chiral agent must play an important role in the reaction and must involve
in the formation of two diastereomeric transition states.
Definition:
Asymmetric synthesis relates to any synthetic process that introduces one or
more new elements of chirality during a functional group transformation.

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In asymmetric synthesis, the reactions are either highly enantioselective (high
ee) or enantiospecific (100% ee).
Prior to the development of efficient methods of asymmetric synthesis,
resolution was used to access enantiopure molecules. But resolution is not very
efficient as the maximum yield of the desired enantiomer is only 50%.

Importance of Asymmetric Synthesis:

The ability to synthesize single enantiomers of chiral molecules is important
since biological systems, where they are intended for application, are also
chiral.
Different enantiomers often interact with the target biological receptors very
differently and often with different responses.
Example

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Eg: + and – thalidomide has different action with biological receptors.
Thalidomide

O
O

O O
O N O O N O
H H

Causes foetal defects Sedative for morning sickness

Strategies of Asymmetric Synthesis:

We will cover the two main strategies of asymmetric synthesis:
❖ Chiral pool synthesis or Chiron approach
❖ Chiral auxiliary approach
Chiral Pool:
❖ 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.

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Chiron Approach to Asymmetric Synthesis:
❖ 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 centers from the chiral pool substrate to
influence formation of new chiral centers.
❖ The new chiral centers can be generated through substitution or addition
reactions.
Chiral Pool Synthesis:
Functional Group Interconversion:
Chiral pool synthesis of L-glyceraldehyde, the unnatural sugar, from the natural
amino acid L-Serine.

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Chiral Auxiliary:
A chiral auxiliary is a chiral molecular unit that can be temporarily incorporated
in an achiral substrate to guide selective formation of one of a possible pair of
enantiomers.
Chiral auxiliaries are optically active compounds and introduce chirality in
otherwise achiral starting materials.
Examples of chiral auxiliaries used in the alkylation of enolates.
Chiral Auxiliary Approach to Asymmetric Synthesis:

How Does a Chiral Auxiliary Work?

✓ A chiral auxiliary physically blocks one of two possible trajectories of attack
on an achiral substrate, leaving only the desired trajectory open for reaction.
✓ Since the chiral auxiliary is enantiopure, the two trajectories are not
equivalent but diastereomeric.
✓ The temporary stereocenter introduced by the chiral auxiliary directs the
formation of a second stereocenter.
✓ The stereochemistry of the new chiral centre can be rationalized based on
steric considerations.

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Chiral Auxiliary Approach:
Asymmetric Enolate Alkylation
Optically active carboxylic acids can be prepared with high enantiomeric excess
based on the chiral auxiliary approach to asymmetric synthesis.

Asymmetric synthesis is of two types:

A) PARTIAL ASYMMETRIC SYNTHESIS:
Synthesis of a new chiral centre from an achiral centre by using optically active
reagents.
Different methods of partial asymmetric synthesis are:
Use of chiral substrate (first generation method)
It uses nature's ready-made chiral centers as starting materials.
More economical way of making compounds in enantiopure form.

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Absolute
asymmetric synthesis: It involves the synthesis of an asymmetric compound
from a symmetric compound without the presence of an optically active
reagent. In this method, yield obtained is 100%.
Ex:
1. When succinic acid is heated with dilute sulphuric acid under pressure, it gets
converted to optically active malic acid.

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2. Malic acid can also be obtained from Bromo succinic acid.

The malic acid thus obtained exists ad DL. Naturally occurring malic acid is
levorotatory L (-).

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