S.SEETARAM SWAMY, M.Pharm.

,
Asst. professor,
Dept. of Pharmaceutical Chemistry,
Chilkur Balaji College of Pharmacy.
E-mail:[email protected]

1
 STEREOCHEMISTRY

• 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.
A comparison of consitutional isomers and stereoisomers…..
Classification of Isomers:
 Constitutional Isomers
Constitutional isomers are isomers which have the same molecular formula but differ
in the way their atoms are connected.
 GEOMETRICAL ISOMERS

The π-bond in an alkene does not permit rotation, thus all of the atoms attached
directly to the alkene lie in a plane.
Groups attached to the alkene could be positioned on the same side of the alkene
(or) on opposite sides of the alkene. Such compounds are different in chemical and
physical properties as well as in their geometry, and are called geometrical
isomers.
Ex:
In 2-butene the methyl groups can be located on the same side or on the opposite
side of the double bond, giving rise to two geometrical isomers.

cis-2-butene trans-2-butene

The isomer with the groups on the same side is called the Cis isomer, while the
isomer with the groups located on opposite sides is called the Trans isomer.
Trans isomers of compounds are usually more stable than Cis isomers.
 Geometric (Cis and Trans or E & Z) Isomers

Geometric (Cis and Trans) Isomers result from restriction rotation.

Compounds with double bonds:
Cis isomer – have same substituents on the same side of the double bond (Z-
zusammen (together) with more complex molecules having high priority
groups on the same side).
Trans isomer – have the same substituents on the opposite side of the double
bond (E - entgegen (opposite) with more complex molecules having high
priority groups on opposite sides).
Compounds with bonds in a ring:
Cis isomer – have the same substituents on the same side of the ring.
Trans isomer - have the same substituents on the opposite side of the ring.
 Cis-trans (Geometric) isomerism in Alkenes

cis-1,2-dichloroethene trans-1,2-dichloroethene

(Z)-1,2-dichloroethene (E)-1,2-dichloroethene
*If one of the two carbon atoms of the double bond has two identical substituents,
there are no cis-trans isomers for that molecule

1-pentene 3-ethyl-3-hexene

1,1-dichloroethene
 Identifying cis and trans isomers of Alkenes

Example:
Name the following geometric isomers.

trans-3,4-dichloro-3-heptene cis-3,4-dimethyl-3-octene
 Identifying Geometric Isomers

Example:3
Determine whether each of the following molecules can exist as cis-trans isomers:
(1) 3-methyl-2-pentene

cis-3-methyl-2-pentene trans-3-methyl-2-pentene
 Cis-trans (Geometric) isomerism in Cycloalkanes

Cis-trans isomers are molecules having the same arrangement of atoms but differ in the
spatial orientation of their substituents.

cis-1,2-dichlorocyclohexane trans-1,2-dichlorocyclohexane
 Naming cis-trans Isomers of Substituted Cycloalkanes

Example:3
Determine whether the following susbstituted cycloalkanes are cis or trans isomers.

trans-1,2-dimethylcyclopentane cis-1,2-dimethylcyclopentane
OPTICAL ACTIVITY:
Optical activity is the ability of a Chiral molecule to rotate the plane of plane-
polairsed light, measured using a polarimeter.
PLANE POLARIZED LIGHT:
light that has been passed through a nicol prism or other polarizing medium
so that all of the vibrations are in the same plane.

non-polarized polarized
Polarimeter – an instrument used to measure optical activity.
A simple polarimeter consists of a light source, polarizing lens, sample tube and
analyzing lens.

polarizer analyzer

light source sample tube

Dextrorotatory (+):
An optically active compound that rotates plane polarized light in a clockwise
direction.
(+) or (d) do not confuse with D
Levorotatory (-):
An optically active compound that rotates plane polarized light in a counterclockwise
direction.
(-) or (l) do not confuse with L
The angle of rotation of plane polarized light by an optically active substance is
proportional to the number of atoms in the path of the light.
COOH COOH

H C OH OH C H

CH3 CH3
(+)/d - Lactic Acid (-)/l - Lactic Acid
SPECIFIC ROTATION:
The angle of rotation of plane polarized light by a 1.00 gram per cm-3
sample in a 1 dm tube.
[α ]D (D = sodium lamp, λ = 589 mμ).
α
[ α ]D =
l×d
where α = observed rotation
l = length (dm)
d = concentration (g/cc)
(+)-alanine [ α ]D = +8.5
(-)-lactic acid [α ]D = -3.8

Specific Rotation depends on the nature of substance, wavelength of light used, concentration
of the solution, thickness of the layer, nature of the solvent and temperature at which
experiment is conducted.
 Assymetric Center
Chirality is not reserved just for objects - molecules can be chiral
Chiral molecules - generally molecules containing an asymmetric center
Asymmetric (chiral) center - tetrahedral atom bonded to four different groups -
indicated with an asterisk (*)
 Chirality

Chiral objects are objects with left-handed and right-handed forms

Achiral objects - objects that have superimposable mirror images
Nonsuperimposable mirror images - a mirror image that is not the same as the
image itself - chiral objects have nonsuperimposable mirror images
 CHIRAL CENTERS
•A point in a molecule where four different groups (or atoms) are attached to carbon
is called a Chiral center.
•If two groups are the same, then there is only one way
•A Chiral molecule usually has at least one Chiral center.
Label the stereogenic centers in each molecule and decide if it is chiral….?
H CH3
H OH

H Cl
How many stereogenic centers does each molecule have?

Br

A)
Br

B)

CO2H O

H
N OH
C) H2N N
H

O O
SH
 CONFIGURATION

The arrangement of atoms that characterizes a particular stereoisomer is called

its Configuration.
The following methods are used to assign configuration.

A. Absolute configuration [R and S system]

B. Relative configuration [D and L system]

 Fischer Projections and the D/L Notation:

 The first system for doing this was developed by Fischer and Rosanoff around
1900.
 Fischer first developed a method for drawing carbohydrates in two-dimensions,
and a convention with respect to orientation, so as to indicate their three
dimensional structures, so-called Fischer projections.
 Fischer and Rosanoff then devised a notation for designating the configurations
of stereogenic centres, depicted in Fischer projections, as either D or L.

The symbols D and L DO NOT relate to the sign of rotation of an optically active
molecule which is designated (+)- (or d) and (-)- (or l).
Example: D (+)-glyceraldehyde was defined as being D because the OH group attached to
the C-2 is on the right hand side (RHS) of the molecules when drawn in its correct Fischer
projection (in which the CHO group appears at the top).
Its enantiomer L (-)-glyceraldehyde was defined as L because the OH group is on the left
hand side (LHS).
In carbohydrates, in general, the OH group attached to the penultimate carbon atom
in the chain determines the assignment of D or L. Thus (+)-glucose has the D-
configuration and (+)-ribose has the L-configuration.
The notation was extended to a-amino acids : L enantiomers are those in which the
NH2 group is on the LHS of the Fischer projection in which the carboxyl group
appears at the top. Conversely, the D enantiomers are those in which the NH2
group is on the RHS. Thus (+)-alanine and (-)-serine are L-amino acids.
Cahn-Ingold-Prelog sequence rules /R-S Notational System(R/S)

Assigning the Absolute Configuration

1. Use the Cahn-Ingold-Prelog priority rules to assign priority (one through four) to the
four groups on the “chiral” atom.
2. Orient the molecule so that the lowest priority atom is in the back (away from you).
Look at the remaining three groups of priority 1-3. If the remaining three groups are
arranged so that the priorities 123 are in a clockwise fashion, then assign the chiral
center as R (“rectus” or right). If the remaining three groups are arranged 123 in
a anti-clockwise manner, then assign the chiral center as S (“sinister” or left).

Cahn Ingold Prelog (CIP) sequence rules:

Sequence rule 1: The atom attached to the chiral center with the highest atomic number = 1,
next = 2, etc.

Sequence rule 2: If the four atoms attached to the chiral center are not all different, the
sequence is determined at the first point of difference.
 1 1 1 1
OH OH OH
2 3 orient lowest priority OH
orient lowest priority H H
CO2H 4 H CH3
4 H group away group away
CH3 H3C CO2H 2 CO2H HO2C CH3 3
3 2 2
3

clockwise = R counter clockwise = S

 1 1

Br OH
2 Cl H 4 4 H CH3 3
F CH2Br
3 2
3
CH2CH3
1 Br CH=CH2 2
H
4

1 2 2 1

3 3

R S
 Naming Enantiomers -R,S System
Assigning Priorities to Groups

1. Oxygen (from CH2OH) = 16

2. Carbon (from CH2CH3) = attached to carbon
3. Carbon (from CH3) = attached to hydrogen
4. Hydrogen = 1
 ENANTIOMERS
 Enantiomers are non-superimposable mirror image isomers.
 Enantiomers are related to each other much like a right hand is related to a left
hand.
 Enantiomers are said to be Chiral.
 sometimes the terms right-handed and left-handed are used describe compounds
with an asymmetric carbon.
 Characteristic features of enantiomers:
 Enantiomers have identical physical properties (bp, mp, density, solubility and
refractive index) but there is a difference in direction of rotation of plane polarized
light.

Property (+)-Lactic acid (-)-Lactic acid

Specific rotation +2.24º -2.24º
Melting Point 26ºC 26ºC

 They have identical chemical properties except in chemical reactions with other
optically active compounds.
 They have different biological properties
E.g. (+)-Dextrose plays an important role in animal metabolism, where as (-)-Dextrose
is not metabolized.
 When equal quantities of enantiomers are mixed an optically inactive compound
racemic mixture is formed.
 DIASTEREOMERS

Stereomers of a substance that are not mirror images of each other are termed as
Diastereomers.

 They have different physical properties like m.p, b.p, solubility, density and
refractive index, etc.
 Diastereomers have different specific rotation but they may have same or
opposite sign of rotation.
 MESO COMPOUND
 A meso compound is a molecule with multiple stereocenters that is
superimposable on its mirror image.
 Meso compounds are achiral compounds that has multiple chiral centers.
 Meso compounds are optically inactive.
 It has an internal symmetry plane that divides the compound in half.
A meso compound should contain two or more identical substituted stereocenters.
Also, it has an internal symmetry plane that divides the compound in half. These
two halves reflect each other by the internal mirror. The stereochemistry of
stereocenters should "cancel out". What it means here is that when we have an
internal plane that splits the compound into two symmetrical sides, the
stereochemistry of both left and right side should be opposite to each other, and
therefore, result in optically inactive.
 RACEMIC MIXTURE
 A mixture having equal amounts of enantiomers is called racemic mixture or
racemic modification.
 A racemic mixture (or) racemate is one that has equal amounts of left- and right-
handed enantiomers of a chiral molecule. The first known racemic mixture
was racemic acid, which Louis Pasteur found to be a mixture of the two
enantiomeric isomers of tartaric acid.
 A racemic mixture is denoted by the prefix (±)- or dl- (for sugars the prefix DL-

may be used), indicating an equal (1:1) mixture of dextro and levo isomers. Also the
prefix symbols RS and SR (all in italic letters) are used.
 RESOLUTION
 The process of separation of racemic form into individual enantiomers is called
resolution.
 The following are various methods used for resolution of racemic mixtures:

1. MECHANICAL METHODS
2. BIOCHEMICAL METHOD
3. CHEMICAL METHOD
4. CHROMATOGRAPHIC METHOD
 EXCERSIZE:
Which isomer is cis isomer and which is trans…..?

A) B)

C)

D)