Stereochemistry

Stereoisomers – compounds with the

same connectivity, different
arrangement in space
Enantiomers – stereoisomers that are non-
superimposible mirror images; only properties that
differ are direction (+ or -) of optical rotation
Diastereomers – stereoisomers that are not mirror
images; different compounds with different physical
properties
Asymmetric center – sp3 carbon with 4 different groups
attached

Optical Activity – the ability to rotate the plane of plane

–polarized light

Chiral Compound – a compound that is optically active

(achiral compound will not rotate light)

Polarimeter – device that measures the optical rotation of

the chiral compound
Chirality

 Handedness: Right
hand glove does not fit
the left hand
 An object is chiral if its
mirror image is
different from the
original object
 Chiral Carbon Atom

 Also called asymmetric

carbon atom.
 Carbon atom that is bonded
to four different groups is
chiral.
 Its mirror image will be a
different compound
(enantiomer).
 Stereocenters
An asymmetric carbon atom is the most
common example of a chirality center.
Chirality centers belong to an even broader
group called stereocenters. A stereocenter (or
stereogenic atom) is any atom at which the
interchange of two groups gives a stereoisomer.
Asymmetric carbons and the double-bonded
carbon atoms in cis-trans isomers are the most
common types of stereocenters
 Stereochemistry
Stereoisomers: isomers that have same formula and connectivity but
differ in the position of the atoms in space. They possess one or
more stereocenters.
Stereocenter: a carbon atom bearing 4 different atoms or group of
atoms.
Chiral: any molecule that is nonsuperposable with its mirror image.
Enantiomers: stereoisomers that are non superposable mirror
images.
Racemic mixture: a 1:1 (equimolar) mixture of two enantiomers.
Optically Active: the ability of some compounds to rotate plane
polarized light.
 Cahn-Ingold-Prelog (CIP) rule

1. Assign the priorities to the groups attached 4

to the stereocenter. Priority is based on the
atomic number, 1
3 4 3

2
2. Orient the molecule so that the group
1 of priority four (lowest priority) points
2 away from the observer.

3. Draw a circular arrow from the group of first priority to the

group of second priority up to third priority.
4. If this circular motion is clockwise, the enantiomer is the R
enantiomer. If it is counterclockwise, it is the S enantiomer. These
are known as absolute configuration
 Absolute Configuration
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 or S
If chiral center is attached to more than one carbon atom

3 CH3
CO2H CO2H switch the 2 clockwise=R
2 3 HO C switch the H and OH H C
H OH
CH3 and CO2H HC 1
HO2C
OH
H3C H3C 2
inverts the inverts the
stereochemistry
1 stereochemistry

switch the
CH3
C OH
switch the H and CH3
H
C OH
OH and CO2H 4HC 2 left hand =S
CO H
HO2C HO2C HO 2
H CH3 1 3 CH

4 1 inverts the
stereochemistry
3
inverts the
3 stereochemistry

2 1

3
 Geometrical Isomers
 Stereoisomerism ascribed to different directional arrangements of
specifically located groups in the molecule and usually considered to be
caused by prevention of free rotation in parts of the molecule (as by a
double bond or a ring).
 This type of isomerism most frequently involves in compounds containing
carbon-carbon double bonds with suitable substituents. Rotation of these
bonds is restricted, compared to single bonds, which can rotate freely.
 This means that, if there are two different atoms, or groups of atoms,
attached to each carbon of the carbon-carbon double bond, they can be
arranged in different ways to give different molecules.
 Example of geometrical isomerism:

a. 1,2 dichlorto cyclopropane

b. 1,2 dimethyle cyclohexane

c. 1,2 dichlorto cyclopropane

Enantiomers will rotate the plane of polarization in exactly equal amounts
(same magnitude) but in opposite directions.
Dextrorotary designated as d or (+), clockwise rotation (to the right)
Levorotary designated as l or (-), anti-clockwise rotation (to the left)

If only one enantiomer is present a sample is considered to be optically pure.

When a sample consists of a mixture of enantiomers, the effect of each
enantiomer cancels out, molecule for molecule.
 Problem on optical activity
Optical Activity in depth: Consider that (S)-bromobutane has a
specific rotation of +23.1o and (R)-bromobutane has a specific rotation
of -23.1o
Question: Determine the optical purity of a racemic mixture.
Answer: The specific rotation, [a], of the racemate is expected to be 0, since the effect of
one enantiomer cancel the other out, molecule for molecule.
Optical purity, % = 100 [a]mixture / [a]pure sample
= 100 (0) / +23.1o
= 0%

Question: Determine the enantiomeric excess of the racemic mixture.

Answer: You would expect [R] = [S] = 50%.
ee% = 100 ([R]-[S]) / ([R]+[S])
= 100 (50-50) / (50+50)
= 0%

Question: Which isomer is dominant and what is the optical purity of a mixture, of (R)-
and (S)-bromobutane, whose specific rotation was found to be -9.2 o?
Answer: The negative sign tells indicates that the R enantiomer is the dominant one.
Optical purity, % = 100 [a]mixture / [a]pure sample
= 100 (-9.2) / -23.1o
= 40% this indicates a 40% excess of R over S!
 Optical isomer without chiral carbon

• Atropisomerism

• Allenes

• Spiranes
 1. Atropisomerism
Atropisomers are Stereoisomers obtained due to the
restricted rotation about carbon-carbon single bond are
called atropisomers and the phenomenon is called
atropisomerism. Such compounds also have the chirality
due to the axis.

Examples of Atropisomerism:
Derivative of biphenyls: Biphenyl shows the
enantiomerism when the molecule has the following
properties
Biphenyl shows the enantiomerism when the molecule has
the following properties

 Each ring must be unsymmetrically substituted. Each of

the rings should not contain any kind of symmetry
element

 Suitable substitution (at least one substitution) at

ortho- position must be there at each rings.

 othro- substituents must be larger in size (-Cl, -Br, -I, -

COOH, -NO2, -NHCOCH3, - SO3H, -R groups etc.).
 Optical isomers without chiral center
BIPHENYL DERIVATIVES

c
 Optical Isomerism in achiral Spiro Compounds
Example
4 3
1
2

4 2 1
3
View
1
3 2 4 R

3
4 1
2
1 2
3 4
View
1 4
S
2
3
 Optical Isomerism in achiral Spiro Compounds
Example
3 1
2
4 3

View
4 1
2 R

3 1
2
4 3

View
R
4 1 2
Optical isomerism in allenes
• Allenes are compounds with two double bonds side-
by-side. Such bonds are called cumulated double
bonds.
• The central carbon of allene forms two sigma bonds
and two pi bonds.

• The central carbon is sp-hybridized and the two

terminal carbons are sp2 -hybridized.
• The two π-bonds attached to the central carbon are
perpendicular to each other.
Allene exhibit enantiomorphism, if each of the terminal sp2 carbon
atoms contain non-identical substituent.

Allenes cannot exhibit optical isomerism.

Example
Cumulene exhibiting optical isomerism

Cumulene analogous to Allene: it having cumulative even number

of double bond exhibit optical isomerism
The alternate π-bonds
attached to the carbon
are perpendicular to
each other.
This result in the
group attached to
terminal carbon are not
in one plane. Hence
molecule have chiral
plane.
Thus they exhibit
optical isomerism (R- S
configuration).
Cumulene exhibiting geometrical isomerism
Cumulene analogous to Alkene: it having cumulative odd number of
double bond and exhibit geometrical isomerism

Since the alternate π-bonds attached to the carbon are

perpendicular to each other.
This result in the group attached to terminal carbon are in one
plane.
Thus they exhibit geometrical isomerism (E-Z isomers)
 CHIRAL DRUGS
Chemical compounds that come as mirror-image pairs are referred to by chemists
as chiral or handed molecules.
Each twin is called an enantiomer. Drugs that exhibit handedness are referred to
as chiral drugs.
Chiral drugs that are equimolar (1:1) mixture of enantiomers are called racemic
drugs and these are obviously devoid of optical rotation.

Few examples of chiral drugs whose enantiomers have vastly different properties

The R-enantiomer is an effective sedative withn a soothing effect that

relieves anxiety whereas S-enantiomer causes teratogenic birth defects.
 These two smells differently. R-
carvone smells like spearmint
whereas s- carvone smells like
caraway seed.

S-ibuprofen is a pain killer drug whereas r-ibuprofen is inactive.