Stereochemistry

What is stereochemistry?
It is the study of the spatial three dimensional arrangement of atoms or groups in molecules.

Importance of Stereochemistry
1) It plays an important role in determining the physical or biological property of molecules.
CHO CHO
Example 1: Example 2: H OH HO H
HO2C CO2H HO2C H HO H H OH
H OH HO H
H H H CO2H H OH HO H
Maleic acid Fumaric acid CH2OH CH2OH
(essential for plants and animals) (toxic to tissue) D-glucose L-glucose
(Naturraly occuring) (not naturally occuring)
Example 3: Among 20 proteogenic (protein synthesizing) amino acids, 19 amino acids
have D- or L- forms, but only the L- form is proteogenic.

2) The biological receptors (enzymes) respond to only one isomer of a ligand/drug.

3) Most of the enzyme catalyzed reactions are stereoisomer specific.

4) More than half of the synthetic agents used in anesthesia practice are chiral drugs.
Representation of 3D structure

i) Fischer projection

ii) Sawhorse projection

iii) Newmann projection

iv) Flying wedge projection

v) Zigzag projection
 Representation of 3D structure
i) Fischer projection
 In this representation, the molecule is so oriented that each chiral carbon is in the
plane of the projection (paper line) and the four bonds are shown by two vertical and
two horizontal lines.
CO2H
H OH
CH3
Lactic acid

 However, the structure can’t be lifted from the plane of paper. It can be
rotated in the plane through 180° or 360°, but not 90° or 270°.

 Fischer projection can be extended to compounds containing more than one

chiral centre. In that case, long chain of carbon should be in vertical line.
CHO CHO
HO H H OH
H OH H OH
CH2OH CH2OH
D-Threose D-Erythrose
 Representation of 3D structure
ii) Sawhorse projection
In this projection, the two key carbon atoms are joined by a diagonal line which is in the
plane of paper and the remaining bonds are shown by small lines projected above or
below the plane.
Example : n-Butane (CH3CH2CH2CH3) can be represented by following Sawhorse projections
CH3
H H
CH3 H H
CH3 CH3

H H
H H
(Staggered) (Eclipsed)

iii) Newmann projection

In this projection, the molecule is viewed along the bond joining the carbon atoms and
these atoms are represented as superimposed circles, only one circle being shown.
Example: n-Butane (CH3CH2CH2CH3) can be represented by following Newmann projections
CH3 CH3
H H CH3

H H H
CH3 H H H
(Staggered) (Eclipsed)
 Representation of 3D structure
iv) Flying wedge projection

In this type of representation, two bonds of the chiral centre are shown in the plane of
paper and in between other two, one is above the plane (by showing like ) and
another is below the plane (by showing like ).
Example: Lactic acid can be drawn by following flying wedge formula.
CO2H CO2H

H3C H H CH3
OH HO
(+)-Lactic acid (-)-Lactic acid

v) Zigzag projection
It is generally used to represent compounds containing two or more chiral centres.

Example : D-Glucose can be represented by following zig-zag projection

OH OH
HOH2C
CHO
OH OH
 Interconversion of projection formulas
Fischer projection to Newmann to Sawhorse and vice-versa
CO2H
CO2H H H OH
H OH H OH OH H OH
H OH
H OH CO2H
CO2H HO H
CO2H CO2H
CO2H
CO2H

H OH H OH
CO2H
CO2H CO2H
H OH

CO2H HO H

Fischer projection to Flying wedge and vice-versa

CO2H
CO2H
H OH H
Left hand side group CH3 Right hand side group CH3
HO
CO2H CO2H
CH3
H H OH H3C Cl Cl H
Ph Ph H
Br H Br
HO
H CH3 CH3
 Classification of isomers
Molecules with same molecular formula
Superposable
Yes No
Homomers Isomers
Same bonding
connectivity
Yes No
Stereoisomers or Constitutional
configurational isomers isomers

Mirror image relationship

Yes No
Enantiomers Diasteromers
 Classification of isomers
Homomers - The molecules which have same molecular formula and superposable on
its mirror image, are called homomers.
CO2H CO2H Me H
Example - H OH
180° HO H Me H
180°
H OH HO H H Me
CO2H CO2H H Me

Enantiomers and diastereomers - The stereoisomers having mirror image relationship

with each other are called enantiomers and not having mirror image relationship are
called diastereomers.
CH3 CH3 CH3 CH3
Example - H OH
&
HO H H OH
&
HO H
H OH HO H HO H HO H
CO2H CO2H CO2H CO2H
Enantiomers Diastereomers

Constitutional isomers
Isomers having different bonding connectivity are called constitutional isomers
CH3 CH3
Example - H OH H Br
&
H Br H OH
CO2H CO2H
Constitutional isomers
 Examples of different isomers
CO2H CO2H CO2H CO2H CO2H CO2H
H OH HO H HO H H OH H OH HO H
H OH H OH HO H H OH HO H HO H
H OH H OH H OH HO H HO H HO H
CO2H CO2H CO2H CO2H CO2H CO2H
I II III IV V VI

I and II Diastereomer II and V Enantiomer

I and III Diastereomer II and VI Diastereomer

I and IV Diastereomer III and IV Enantiomer

I and V Diastereomer III and V Enantiomer

I and VI Homomer III and VI Diastereomer

II and III Homomer IV and V Homomer

II and IV Enantiomer IV and VI Diastereomer

V and VI Diastereomer
 Symmetry operation
A symmetry operation is an arrangement of atoms such that the molecule is transformed
into a indistinguishable from the original one.
There are generally four types of symmetry operations.
1) Simple axis of symmetry (Cn)
2) Plane of symmetry (σ)
3) Centre of symmetry (i)
4) Alternating axis of symmetry (Sn)

1) Simple axis of symmetry (Cn)

If a molecule is rotated around an appropriate imaginary axis by an angle of 360°/n and
indistinguishable arrangement with the original is achieved, then the molecule is said to
possess n fold axis of symmetry i.e. Cn.
Example :
H

O C
H H Cl Cl
C2 Cl
C3
180° rotation 120° rotation
H2O has C2 axis of symmetry CHCl3 has C3 axis of symmetry
 Symmetry operation
2) Plane of symmetry (σ)
If a molecule is bisected through an imaginary plane in such a way that one part is the
mirror image of the other part, then the molecule is said to posses plane of symmetry (σ).

Example:

H2O has two σ (2σv) CHCl3 has three σ (3σv) benzene has seven σ (6σv + 1σh)
 Symmetry operation
3) Centre of symmetry (i)
It is an imaginary centre such that if a line is drawn from a point or group or an atom
through this centre and then is extended to equal distance but opposite direction of the
plane and equivalent point or group or atom results, then the molecule is said to
possess a centre of symmetry (i).
Example: Ph CO2H

H H
H H

CO2H Ph

4) Alternating axis of symmetry (Sn)

It is also an imaginary axis such that a rotation of 360°/n around it followed by reflection
in a plane perpendicular to the axis generates a structure which is indistinguishable with
the original, then then the molecule is said to possess an alternating axis of symmetry (S n)
Example:
Ph CO2H CO2H Ph Ph CO2H
180°
H H H H H H
H H H H H H
CO2H Ph Ph CO2H CO2H Ph
 Chirality
It is a property of a molecule which is not superposable on its mirror image having no plane or
centre of symmetry. The corresponding molecule is known as chiral molecule.
There are two types of chirality
1) Asymmetry
2) Dissymmetry

1) Asymmetry - If a carbon atom is joined with four different groups or atoms, then the
carbon atom is called asymmetric carbon atom (or chiral carbon) and is said to posses
asymmetry or chirality.
CH3
Example:
H OH
CO2H
Lactic acid

2) Dissymmetry - The molecule which has no chiral centre and optically active, is said to posses
dissymmetry. This property is also known as axial chirality.
Example: Me Me
C
H H
Penta-2,3-diene
 Meso compound, Erythro and Threo isomers
Meso compound - The compound having more than one chiral centre and having plane
of symmetry, is known as meso compound. This must be optically inactive.

Example : CO2H
H OH
H OH
CO2H
meso-tartaric acid

Erythro and threo isomer - In Fischer projection, erythro isomer is the diastereomer, in
which two similar groups or atoms are in the same side of vertical chain of carbons.
Whereas, in threo isomer, two similar groups are in opposite side.

CHO CHO
Example :
H OH H OH
H OH HO H
CH2OH CH2OH
Erythro Threo
 Optical activity
Optical activity is the property of chiral molecule to rotate the plane of plane polarised light
in a polarimeter.
A simple polarimeter consists of a light source, polarizing lens, sample tube and analyzing
lens.
The optical acivity of a chiral molecule can be measured by specific rotation.

Specific rotation: The specific rotation may be defined as the rotation in degrees brought
about by a pure solution containing 1 gm of an optically active substance per ml of solution,
placed in 1 decimeter polarimeter tube.
It is measured by the following equation
Where t = Experimental temperature
α = Observed angle of rotation
l = Length of polarimeter tube in dm
c = Concentration of solution in gm/100 ml
λ = Wave length of polarised light
 Optical activity
Dextrorotatory (d or +) and Laevorotatory (l or -):
If an enantiomer rotates the plane of polarized light in a clockwise direction, then the molecule
is called dextrorotatory (d or +) and the rotation in an anti- clockwise direction results
laevorotatory ( l or -) enantiomer.
Example: [α]D21 = +2.6° for (+)-lactic acid and -2.6° for (-)-lactic acid

Racemic modification or racemic mixture:

When equimolar quantities of two enantiomers of a chiral molecule are mixed together or
formed in a reaction, the resultant mixture is called a racemic modification or racemic mixture
or (±) pair.

Optical purity:
Optical purity of an enantiomeric mixture means the excess of one enantiomer over the
racemic mixture. It is expressed as % optical purity, which is given by,

It is also expressed as enantiomeric excess (ee), which is given by

Where [d] and [l] are the mole fractions of the individual
enantiomers d and l.
 Necessary and sufficient conditions for optical activity
1) If a carbon atom in a molecule is joined to four different groups or atoms and having
non-superposable mirror image, then the molecule will show optical activity.
CH3
Example: H OH
CO2H

2) If the molecule posses more than one chiral centre, then the molecule will be optically
active if it does not posses σ, i or Sn.
CHO
Example: H OH
H OH
CH2OH

3) The dissymmetric molecule which does not posses any chiral centre and has no σ, i or S n
symmetry but has a C2 axis, also shows optical activity.
H3C H
Example: C
H CH3
 Number of possible stereoisomers

Type Optically Optically Total Examples

active inactive
1) n different chiral centres 2n None 2n OH
and the molecule cannot be H3C
CH3
divided into two equal halves Br
3-Bromo-2-butanol
No of total stereoisomers = 4
2) n chiral centres ( n= even) 2n-1 2(n-2)/2 2n-1 + 2(n-2)/2 OH
and can be divided into two H3C
CH3
equal halves OH
Butane-2,3-diol
No of total stereoisomers = 3

3) n chiral centres ( n= odd) 2n-1 – 2(n-1)/2 2(n-1)/2 2n-1 OH OH

and can be divided into two HO2C CO2H
equal halves OH
2,3,4-trihydroxyglutaric acid
No of total stereoisomers = 4
 Number of possible stereoisomers
1) n different chiral centres and the molecule cannot be divided into two equal halves
CH3 CH3 CH3 CH3
Example H OH HO H H OH HO H
H Br Br H Br H H Br (n = 2)
CH3 CH3 CH3 CH3

Optically active Optically active

3-Bromo-2-butanol

2) n chiral centres ( n = even) and can be divided into two equal halves
CH3 CH3 CH3
Example H OH H OH HO H
H OH HO H H OH (n = 2)
CH3 CH3 CH3

Optically inactive Optically active

Butane-2,3-diol

3) n chiral centres ( n = odd) and can be divided into two equal halves
Example CO2H CO2H CO2H CO2H
H OH H OH HO H H OH
H OH H OH HO H HO H
H OH HO H H OH H OH
(n = 3)
CO2H CO2H CO2H CO2H

Optically inactive Optically active Optically inactive

2,3,4-Trihydroxyglutaric acid
 Selection of highest priority group
Determination of configurations depends on selection of highest priority group. The selection
of highest priority group depends on the following rules.
1) Higher atomic number precedes lower. e.g. S > F > O > N > C > H
2) Higher atomic mass precedes lower. e.g. T > D > H
3) ‘Cis’ precedes over ‘trans‘ and ‘Z’ precedes over ‘E’.
The elaboration of rule 1 is given below.

i) Atoms directly attached to the central atom must be sequenced first. If the priority
remains undecided in the first central carbon, then have to pass over to the next central
carbon and so on, until a difference is reached.
H H H H H
Examples CH2OH C O H > CH2NH2 C N H CH2CH3 C C H > CH3 C H
H H H H H H
HOH HNH HCH HHH

H CH3 H H CH3 H
CH2C(CH3)2CH3 C C C H > CH2CH(CH3)CH2OH C C C OH
H CH3 H H H H
HCH CCC HCH CCH

H CH3 H H CH3 H
CH2CH(CH3)CH2Cl C C C Cl > CH2CH(CH3)CH2CH3 C C C CH3
H H H H H H
HCH CCH HClH HCH CCH HCH
 Selection of highest priority group (contd)
ii) When a central atom is a part of a ring system, we have to move along the chain away
from the chiral centre until we find a point of difference.
4 CH3 H CH3 H H H H
2
Examples H C
2
C C > 3
C C C
HO H H H H H H
1 3 HCH CCH HCH HCH

iii) In case of groups with multiple bond, the solution is to expand each multiple bond as a
single bond attached to a ‘phantom atom’.
(C) (C) (C) (C) (O)(C) (N)(C)
C CH2 C C H C CH C C H C O C O C N C N
H
H H (C) (C) H H (N)(C)

(C), (O), (N) are the phantom atoms

Examples
(C) (C) CH3 H (O)(C) (O)(C)
C CH C C H > C(CH3)3 C C H C O
OH
C O
OH
> C O C O
(C) (C) CH3 H H H
CCC CHC CCC HHH OOO OOH

(O)(C) (C) (C) (C) H

H (C)
C O C O > C CH2 C C H 1 2 3
(C) (C)
OR OR
H
H H (C) 6 5
4 H
(C) > C CH
1C 2C H
(C) (C)
OOO CCH (C)
H (C)H
C1 = CCC C2 = CHC C3 = CHC C1 = CCC C2 = CHC
 Configuration
Different arrangement of groups or atoms around an asymmetric (lactic acid) or
dissymmetric (penta-2,3-diene) or rigid part (biphenyl) of the molecule, is known as
configuration.
The different type of configurations are given below.
1) Cis and trans configuration
2) Z and E configuration
3) Syn and anti configuration
4) D and L configuration
5) R and S configuration

1) Cis and trans configuration

If two similar groups are on the same side of olefinic double bond, then the isomer is
called ‘cis’ and on the opposite side of double bond is called ‘trans’.

Example
H3C CH3 H3C H H3C C3H7 H3C H

H H H CH3 H H H C3H7
Cis Trans Cis Trans
 Configuration
2) Z and E configuration
If two higher priority groups are on the same side of olefinic double bond, then the
configuration is called ‘Z’ configuration and on the opposite side of double bond is called
‘E’ configuration.
Example H3C H H3C CO2H H3C H
H3C CH3
Ph H Ph CO2H
H H H CH3

Z (cis) E Z
E (trans)

In some cases, Z and E configurations are trans and cis respectively.

Example Cl Cl Br Cl

Br H Cl H
E (cis) Z (trans)

3) Syn and anti configuration

Syn and anti are identical to Z and E and were often used to describe the geometry
about carbon-nitrogen double bonds. In such cases, the lone pair of electrons is given
the lowest priority.
H3C H3C CH3
Example H3C H3C OH
N N
N N
Ph CH3 Ph
Ph OH Ph
Syn Anti
Syn Anti
 Configuration
4) D and L configuration

D and L configuration nomenclature is applicable in case of carbohydrate compounds in

their Fischer projection formula according to the following conventions.

i) The molecule is written with the longest carbon chain placed vertically.
ii) The most highly oxidized end of the chain is placed at the top (as CHO) by Fischer
convention
iii) If in the projected structure, the OH group at the bottom most chiral centre is on
the right hand side, the molecule is assigned as ‘D’ configuration and if it is on the
left, the molecule is assigned ‘L’ configuration

Example:
CHO CHO
H OH HO H CHO CHO
HO H H OH H OH HO H
H OH HO H CHO CHO H OH HO H
H OH HO H H OH HO H H OH HO H
CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH
D-Glucose L-Glucose D-Glyceraldehyde L-Glyceraldehyde D-ribose L-ribose
 Configuration
5) R and S configuration

i) For Fischer projection

According to Epling procedure (1982) (also named as very good method), in a Fischer
projection having four priority groups in the order of a>b>c>d, if the lowest priority group
‘d’ is on the vertical line, then clockwise rotation around a→b→c ignoring ‘d’ resulted in ‘R’
configuration, whereas anticlockwise rotation resulted in ‘S’ configuration. But if ‘d’ is on
horizontal line, then opposite configuration resulted in clockwise and anticlockwise
rotation.
c b b c

a b a c a d a d

d d c b
S R S R

Example:
1 1
(b) CO2H CHO
2 2
CHO CO2H H OH HO H
3 3
(d)H OH (a) HOH2C NH2 HO H H OH
4
CH2OH H CO2H H OH
4
(c)
5
CH2OH
R S 2R, 3R 2S, 3R, 4R
 Configuration
5) R and S configuration

i) For Flying wedge projection

In case of flying wedge formula, 4 back (+ve) rule is applied. This implies if the 4 th priority
group (d) is behind the plane, then rotation around a→b→c give +ve result i.e. clockwise
rotation gives ‘R’ configuration and anticlockwise rotation gives ‘S’ configuration. The overall
rule is summarized below. a
clockwise R
4 back +ve ⇒ 4th priority group behind the plane ⇒ anticlockwise S c d
b
R
a
clockwise S
3 back -ve ⇒ 3rd priority group behind the plane ⇒ anticlockwise R b c
d
R
a
clockwise R
2 back +ve ⇒ 2nd priority group behind the plane ⇒ anticlockwise S d b
c
R
b
clockwise S
1 back -ve ⇒ 1st priority group behind the plane ⇒ anticlockwise R
d a
c
S
(b)CO2H H (d)
HO 3 CH3
Examples OHC
CMe3 2 CH2CH3
H (d) C
(c)H3C HC Ph (c) H3C H
OH (a) (b) (a)
S S
2S 3R
 Conformation
Isomers arising out of C-C bond rotation are called conformation. Stable conformations
having least amount of energy are called conformer.

Conformation of ethane, n-propane and 1-methylpropane

360°
H R H R H R or
R R R
H 120° 180° H H 240° 300°H H 0°
60° H (I)
HH H H H HH H H HH H H H
H
H H H H H
H
Eclipsed (I) Staggered (II) Eclipsed (I) Staggered (II) Eclipsed (I) Staggered (II)

Ethane (R = H), n-Propane (R = CH3), 1-methylpropane (R = C2H5)

Energy diagram

As eclipsing interaction is minimized in staggered form, so staggered form is more stable

than eclipsed form due to low energy.
 Conformation
Conformation of n-butane (C2-C3 bond rotation)
CH3 H H 360°
CH3 CH3 CH3 CH3 CH3 or
CH3 H 0°
60° H CH3 120° 180° H H 240° 300° H3C
(I)
HH H H H HH H H H3C H H H H
H
H CH3 CH3 H H
H
Eclipsed (I) P-Gauche (II) Eclipsed (III) Anti (IV) Eclipsed (V) M-Gauche (VI)

Characteristics

n-Butane exhibits maximum energy eclipsed conformation (I) due to CH3-CH3 eclipsing
interaction and two equal higher energy conformations (III) and (V) due to Me-H eclipsing
interaction.
Among three energy minima conformations, the conformers (II) (P-Gauche) and (VI) (M-
Gauche) with torsion angles +60° and -60° respectively are non-superposable mirror images
to each other. The conformer (IV) is most stable due to maximum torsion angles (180°) and
thereby maximum distance between two Me groups.
 Conformation
Conformational analysis of other compounds

In 2,3-dimethylbutane, unlike n-butane, gauche conformer is more stable than anti. This is
because the widening of Me-C-Me angles is not favorable in anti due to Me-Me steric
hindrance, which is not observed in gauche conformer.

H H
Me Me Me H

Me Me Me Me
H Me

(anti) (gauche)

Usually, 2-substituted ethanols of the type X-CH2-CH2-OH, where X = OH, OMe, NH2,
NHMe, NMe2, F, Cl, Br etc., all have the preferred gauche conformations with OH and X
forming intramolecular H-bonding. Usually the dihedral angle is slightly greater than 60°.
H
O
H X

H H
H
(gauche)
X = OH, OMe, NH2, NHMe, NMe2, F, Cl, Br etc.
Thank You