Stereochemistry

Branch of science or chemistry which deals with the study of properties of

molecules on the basis of three dimensional structure

Concept of stereochemistry is based on the Vant Hoff and Le Bels theory,

the four valencies of a carbon are directed towards the four corner of regular
tetrahedron constructed around the carbon atom as the center.
Stereochemistry deals with isomerism of compounds having same molecular
formula (structural formula) but different arrangement of atoms or group of
atoms in space

[Cr(H2O)6]3+

CHF2Cl

CF4

Stereochemistry

Isomerism

Structural

Chain

Functional

Stereoisomerism

Conformational

Configurational

Positional
Eclipsed

Staggered
Gauche

Optical

Geomet
rical

Isomers different compounds with the same molecular formula.

Constitutional isomers (also known as structural isomers) have the same molecular
formula but differ in the sequence in which the individual atoms are bonded
(connectivity).
Functional isomers: - compounds of identical molecular formula but which have
different functional groups.
Stereoisomers have the same atomic connectivity but differ in the spatial
arrangement of the constituent atoms

Optical Activity and Chirality

Any compound which rotates the plane polarized light is said to be optically active

COOH

COOH
HO
H3C

OH
CH3
d-lactic acid

l-lactic acid

The light which can be vibrate in only one plane.

A carbon atom or center containing four different substituents is called as chiral carbon/
chiral center.
R

R
+

R
2

R
Chiral compound

R
2

R
Chiral compound

R1

R2

R4

R3

R5
Chiral compound

Center of symmetry

Plane of symmetry

CH3

COOH

b
a

d
b

COOH

Elements of
symmetries

Ph

Ha

Hd
Hb

Hd

Hb
Ha

H
CH3

Alternative axis of
symmetry

Axis of symmetry

plane of symmetry

Hb

Ha
Hd

COOH

COOH

H
Ph

Center of symmetry

(a)

H
COOH Ph

Ph
H

Ph

COOH

Plane refle
ction
COOH

COOH

H
Ph

(a)

Enantiomers
S

NH

OH

NH

Disteriomers

OH

S - isomer,
beta -blocker

R - isomer,
Contraceptive

Optical Active
compounds

Epimers

COOH
CHO

OH

HO

* H

OH

HO

* H
* OH

CHO
H

* OH

HO

* H
* OH

CH2OH

Epimers

CH2OH

COOH

plane of symmetry

Same physical and

chemical properties

Enantiomers

Rotate plane polarized light in opposite directions (optical antipodes)

Reacts with different rates with other chiral compounds.
e.g. 1. One isomer is biologically active while other does not.
2. Both enantiomers are reacts different rates with chiral reagents or in presence of chiral
catalyst.
3. Having different solubility in optical active solvents.
O

NH

R
O

OH

OH

Et

NH
H

OH

NH
NH

Et
H

OH

S - isomer,
beta -blocker

Isomer rotate plane polarized

light to left (anticlockwise) is
leavo isomer (-) or l

NH

NH
Et
H

OH

(S,S) -isomer
Tuberculostatic
R - isomer,
Contraceptive

OH

Et

(R,R)-isomer
Cause blindness
Ethambutol

Isomer rotate plane polarized

light towards right (clockwise)
is dextro isomer (+) or d

The mixtures of equal amounts of enantiomers (d and l form) are optically inactive are
called as racemic mixtures (dl)

They are differ in

their specific
reaction and specific
rotation may have
same or opposite
side
Disteriomers having
different physical
properties such as
m.p., b.p.,
solubility, density,
refractive index, etc

Many of the
chemical
reactions are
similar but few of
them are different
They may have
different energy of
activation,
resulting the
different reaction
rates

Disteriomers

The stereoisomers which are not mirror images of each others are called as
disteriomers
H
HO

OH

HO

H
COOH
(I)
Enantiomers

COOH

COOH

COOH

COOH

OH

HO

OH

OH

HO

COOH
(II)

COOH
COOH
(IV)
(III)
mesoform (inactive)

I and III, I and IV, II and III, II and IV are disteriomers of each others

Epimers

Disteriomers which differs in the configuration at only one

asymmetric carbon atom are called as epimers
CHO

CHO
H

* OH

HO

* H
* OH

CH2OH

Epimers

HO

* H

HO

* H
* OH

CH2OH

Some compounds possesses chiral carbon atoms can show optical inactivity

Reasons
1. Due to internal compensation:
In meso form of the molecule, one half of the
molecule is the mirror image of the other
half; thus if one half of the molecule rotates
the light towards the right, the other half
would rotates it to the same extent towards
the left. Therefore no deflection of the light
is observed due to intrinsic property of the
molecule
COOH
H

OH

OH
COOH

plane of symmetry

2. Due to external compensation:

The external compensation is observed
when the two enantiomers are present in
equal quantities. This mixture is term as
racemic mixture

Absolute configuration of chiral compounds

dl Nomenclature
(obtained by comparing
with glyceraldehyde

Erythro & threo

nomenclature

Absolute or RS
nomenclature

2
1

R (Rectus means
right handed)

Sequence rule

4
R
Clockwise rotation
2
3

4
S
Anticlockwise rotation

S (Sinister means
left handed)

Priority
rule/Sequence rule
Rules used to decide the priority order of the groups of atoms or atoms attached to chiral center
X

Chiral Molecule

1. The atom having highest atomic number (atomic mass) was given highest priority and
the atom with the lowest atomic number has lowest priority.
1-Chloroethanol. The four atoms/groups attached to chiral carbon are Cl, OH, CH3, and H.
The priority order of substituents according to the atomic number are Cl>O>C>H. Therefore
the priority order of the four atoms/groups is Cl > OH > CH3 > H.
CH3
HO

Cl

Priority rule/Sequence rule

3. The groups having double or triple bonds, instead of considering presence of a single
double bond or a single triple bond, each bond is dublicated in case of a double bond and
triplicated for a triple bond.
2

CH

C C
1

C C

C C
Triple bond replaced by-

CH CH2

H2
CH C
2

C C
double bond replaced by-

In a compound 3-methyl-pent-1-en-4-yne. The group attached to the chiral carbon atom

are -CCH, -CH=CH2, -CH3 and H. The hydrogen is the lowest priority group. The
acetylenic group, the second atoms attached are three carbon whereas in the ethylenic
group the second atoms attached are two carbons and methyl group has three hydrogens
attached as second atoms. Therefore the priority order of the four atoms/groups is CCH >
CH=CH2 > CH3 > H.
According to the rule suggested above the priority order of some groups with unsaturated
bonds can be arranged as follows.
-COOH > -CO- > -COH > -CN > -C=N- > -CC- > -C=C-

4. In case the molecules have two isotopes of the same element attached
to the chiral carbon atom, higher priority is given to the heavier isotope.
For example deuterium would get priority over hydrogen and C-13 would
set priority over C-12.

To determine the configuration of given

compounds, the molecule is viewed in manner
so that the lowest priority group is placed
furthest (putting behind) from the eye and the
rest three groups (putting in front) are
placed facing the eyes.

CHO
CHO
H

OH

converted to

CH2OH
H

OH
(II)
(Tetrahedral form)

CH2OH
(I)
(Planar structure)

Determination of
R/S configuration
The plane projection diagram of glyceraldehydes
molecule I is converted to the tetrahedral form structure II
places the CH2OH furthest away from the eye. To
determine the R and S configuration of the molecule, the
lowest priority group should occupy the position, furthest
from the eye. Therefore to determine configuration, the
hydrogen atom should be occupy the position occupied
by CH2OH group and hence interchange of the
positions of the groups are required

CHO

HOH 2C

Backside
position

H
OH

Determination of R/S configuration

Fischer suggested some rules to be followed for the interchanging the
groups. The rules are1. One interchange of a pair of substituent group will result in the
change of configuration of the molecule i.e. one enantiomeric form
would get converted to the other enantiomeric form of the molecule by
one interchange of a pair of substituent group.
2. Two interchange of two pairs of substituent groups result in no change
in the enantiomeric form. The configuration of the molecule is retained.
e.g. Glyceraldehyde (I) molecule. The structure (I) can be changed such
that H atom occupies the position farthest from the eye i.e. it should be
occupied the position of CH2OH group. Two interchanges of two pairs of
substituent groups would be required to retain the configuration.
OH

CHO

1st interchnage
H
OH
HOCH2
between H
CH2 OH and CH2OH
(I)

CHO
OH
H

OH

2nd interchange
between OH
and CHO

HOCH2

CHO
H

H
HOCH2

CHO
'R'

To assign the configuration of the molecule, arrow is to be drawn starting

from the highest priority order group OH, going to the next CHO, and
then to the next i.e. to CH2OH. Thus the configuration of glyceraldehyde
molecule is R.

Fischers Plane Projection Diagram

Tetrahydral molecule can be represented with the help of a dashed wedge
line formula. Out of the four bonds, one bond projected towards the viewer,
the other away from viewer and rest two are lie on the plane of the paper.
The heavy wedged bond is drawn to represent the bond towards the
viewer, a dashed bond projected away from the viewer and normal bonds
lying on the plane of paper.
plane containing chiral carbon

above the plane

CHO
H
HO

CH2OH

tetrahedral form

title as suggested
by Fischer
away to viewer

H
OHC

OH
CH2OH towards viewer

below the plane

title form

CHO
H

vertical line

OH
CH2OH

horizontal line

planar structure

Fischer suggested the tilting of the tetrahedral form of the molecule in a

manner that if the chiral carbon atom is held on a line drawn on the paper,
two groups are lie above the plane of paper and the other two groups would
lie below the plane of paper. Fischer then represented the title form of
molecule on a cross with the groups above the plane of paper represented
on horizontal line of the cross and the group lying below the plane of
paper in the title form is represented on the vertical line of the cross.
Out of the two groups present below the plane of paper in title form, the
group away from the viewer is placed at the upper end of the vertical line
and the group towards the viewer on the lower end of the vertical line.

Determination of R/S configuration

The configuration of the molecule does not change by
rotating it through 1800 within the plane of the paper
about an axis perpendicular to the paper.
But rotation of the same molecule by 900 or 2700 will leads
to an enantiomeric mirror image form.
Br
Br
H3C

C2 H5

CH3

H
180

CH3
Br

'R'

Rotation

H
C2 H5

C2 H5

C2 H5

1st interchange
H
of H and Et

CH3
Br

C2 H5
C2 H5

2nd interchange
of H and Br

Br

CH3

H
Br

CH3

H
'R'

Determination of R/S configuration

Rotation by 90/270 degree:
Br
Br
H3 C

C2 H5

CH3

H
90

'R'

Rotation

CH3
H

C2 H5

Br
C2 H5

CH3

1st interchange
of H and Et

C2 H5

Br
H

C2 H5
C2 H5

2nd interchange
of Me and Et

H3C

Br

H
CH3

Br

H
'S'

Molecules with more than one chiral atom

The total number of optical isomers containing n number of chiral
carbon atoms is 2n.
Fischers projection diagram of a molecule with more than one
chiral carbon atom always represented in eclipsed conformational
form of the molecule.
e.g. erythreose molecule.
CHO
H

OH

OH
CH2OH

Fischer plane projection dia.

H
H

OH
OH
CHO
CH2OH

Eclipsed conformation

Molecules with more than one chiral atom

The configuration of each chiral carbon atom is worked out separately. First working
out the configuration of carbon atom C2, the steps adopted are as follows.
CHO
H

OH

OH

CHO

CHO
H

R
H

CH2 OH
Erythreose

OH
of H and R

OH

CHO

1st interchange
R

CHO

2nd interchange

OH

of R and OH

HO

R = -CHOH-CH2OH

R
H

CHO
H
HO

R
'R'

Working out the configuration of carbon atom C3, the steps adopted are as follows.
CHO
H

OH

OH
CH2 OH

Erythreose

R
H

CH2 OH
H

OH

OH

1st interchange

CH2 OH

HOCH2
of H and CH2OH

R
H

2nd interchange
HO
OH
of CH2OH and OH

R = -CHOH-CHO

R
CH2OH
H

R
H
HO

The configuration of carbons C2 and C3 are R respectively.

CH2 OH
'R'

Other Optical active compounds

Compounds with tetravalent chiral atoms (other than carbon):
Atoms with pyramidal geometry or bonding mild be gives optical activity if three
different atoms or groups are present and lone pair is serves as fourth groups. But it is
optically inactive because of pyramidal inversion which is rapid oscillation of the
unshared pair of electrons from one side of X, Y and Z plane to other i.e. 2 x 1011
inversion per second.
Y

X
N
X

z
(Pyramidal inversion)

z
Y

The inversion is less in substituted amines and amides. Two types of nitrogen atom
invert slowly as nitrogen in three membered ring and nitrogen connected to another
atom bearing lone pair of electrons. In some molecules in which nitrogen atom is at a
mirror
bridgehead, pyramidal inversion is prevented.
Cl

Cl

N
CH3

H3C

CH3

N
CH3

Cl

Cl

CH3

H3C

(cis)

(trans)

The phosphorous, arsenic and antimony resolved slowly. Sulfur exists in pyramidal
geometry in sulfoxides, sulfinic esters, sulfonium, sulfonium salts and sulfites.
O

O
CH3

As
H3C

Ph

Et
Me

R
RO

S
O
S

R'
OR'

OR'
R''
S+ X
R'
R

Optical activity of other compounds

Restricted rotation giving rise to perpendicular dissymmetric
planes:
There are certain compounds which are optically active
without containing any asymmetric center because of its
structure in which two perpendicular planes neither of which
can be bisected by a plane of symmetry. The geometry or
structure of molecule is as follow.
This chirality is called as molecular chirality.

A
B

A
B

e.g. Biphenyls, allenes, spiranes, etc.

Stereochemistry of Biphenyls
The biphenyls containing three or four large bulkier substituents in the ortho positions can
not freely rotated about the central bond because of steric hindrance in planar structure.
The two benzene rings are not coplanar because of the steric interactions between the two
different ortho or meta substituents (one may be hydrogen).
The compounds with three or even two large bulky groups are sufficient to prevent the
rotation around C-C bond. Both the rings must have unsymmetrical substitution with
respect to the axis of the bond connecting the two rings.
The isomers are get separated only because of rotation about single bonds prevented or very
slowed are called as atropisomer.
COOH

COOH
F

Cl
Cl
H3 C

HOOC

HOOC
F

CH3

R/S Nomenclature
COOH

B
HOOC

Select the ring which is perpendicular to the plane of paper (to other ring present in
plane or parallel to plane of paper).

The ortho groups attached to ring A are transferred on the horizontal line.
The ortho group of ring B which is pointed towards the viewer (it is on thick
portion of the ring B) is put on the top of the vertical line whereas the group which
is directed away is goes to the bottom of the vertical line.
The two ortho-substituents are identical in one of the ring thus priorities are
given by considering meta substituents in the same ring.
The first rotation of the molecule to put the ring perpendicular to the other at the
bottom, viewing from the bottom and transferring the priorities on the cross. In case
of asymmetric substitution (one side ortho and another is meta) then consider ortho
substitution for deciding priorities.

Here is an example, a biphenyl and its enantiomer.

If we view the structures from the left, and project them onto a perpendicular plane, we
obtain:
Left side
view

right side view

Note that the application of the near > far rule means that the CO2H on the front ring takes
precedence over the NO2 on the rear ring. Thus, the left hand structure is S, and the right hand,
R. It may seem that this result could be related to our chosing to view the molecules from the
left; not so. Here are the projections obtained if each is viewed from the right.

Stereochemistry of allene
In allenes, the central carbon atom has sp-hybridization (planar geometry) and the
terminal carbon atom is sp2 hybridized.

As rotation across the carbon-carbon double bond is restricted, the substituents remains
in two different planes which makes the molecule as a whole chiral.
The allenes are optically active only if both sides carbons are unsymmetrically substituted
(different substituents).
A

H3C

H3C

H3C

H3C

mirror

inactive

inactive

H
CH3
active

When three, five or any odd number of cumulative double bonds exist, orbital overlap
causes the four groups to occupy one plane (substituents on terminal carbon atom
become coplanar) and cis-trans isomerism is observed but if two, four or even number of
cumulative double bonds exists, the situation is similar to allenes and optical activity is
observed.

R/S Nomenclature

The allene molecule is rotated so that, the groups in the plane of

paper (shown by continuous line) are at the top while the pair of
groups which are perpendicular are at the bottom.
The molecules are always views from the bottom; the groups at the
bottom precede over the other pair and thus assign the priorities to all
the groups.
The groups present on the top of molecule are drawn on the
horizontal line whereas the groups on the bottom are drawn on
vertical line of the cross. The group which is on front (thick line) is
present on the top while the group at the back (dotted line) is placed
at the bottom.
The sequence 123 is on clockwise shows R configuration while
123 is on anticlockwise direction shows S configuration.

Spiranes
The dissymmetric substituted spiranes (bicyclic ring compounds in which two ring has one
common carbon atom) and compounds with exocyclic double bond are optically active.

The spiro compound is optically inactive even if one of the rings has symmetrical substituents
with respect to horizontal axis passing through the spiro carbon atom. It is optically active
only if both the rings have unsymmetrical substituents.
NH2

H2N

H3C

a
b

CH3
active

active
Spirane
a

exocyclic double bonded ring

a
b

Mirror

Following the same nomenclature procedure of biphenyl for the spirane compounds.

Allenes in which the substituents on each terminus are different (the same condition as for
stereoisomerism in alkenes) are chiral; the long axis of the molecule is a chiral axis.

Spiro compounds are another group of molecules in which ligands remote from the spiro
junction can be placed in a stretched tetrahedral arrangement:

Stereoselective and stereospecific reactions

The stereochemistry of reactants or stereochemical pathway of reaction decides which
isomer is formed.

stereochemical
pathway
direction of attack of reagent
reagent may
attacks from same
side or opposite
side or less
hindered side

stereochemistry of intermediate
or transition state
symmetric or
asymmetric or
planar
intermediates

The stereochemistry of product can be decided by two types of reactions

Stereoselective and stereospecific reactions

Stereoselective reactions
Chemical
reactions

The chemical reaction in which the starting materials reacts to gives one or more
stereo isomers in which one is major product
H

Br
EtOH, KOH

+
H

There are two types of stereoselective

reactions
The chemical reaction in which mixture of
enantiomers is formed, if one of them is
formed predominantly, then it is called
enantioselective reaction (ee)

The chemical reaction in which mixture of

diastereomers is formed, if one of them is
formed predominantly, then it is called
diastereoselective reaction (de)

Ph

OH

OH

O
COOMe

1. Zn(BH4)2
2. H3O+

Ph

COOMe

Ph

COOMe

stereospecific reactions
Chemical
reactions
The chemical reaction in which starting material (optical active or inactive) is converted
into a single stereo-isomeric product is called as stereospecific or regiospecific reaction.
Br Me
Me

Ph

Ph H
(S,S -isomer)

EtOH, KOH

Me

Me

Ph

Ph

(Z- isomer)

If one enantiomer of reactant give one isomer

while another enatiomer gives different product
rather than mixture, then it is called
enantiospecific reaction

Br Me
Ph

Ph

Me H
(R,S - isomer)

EtOH, KOH

Me

Ph

Ph

Me

(E- isomer)

If particular diastereomer of the reactant

gives specific diastereomer rather than
mixture
of
products
is
called
diastereospecific reaction

Topicity
The stereochemical equivalence or non-equivalence of different atoms or groups
(ligands) in a molecule is called topicity.
Topicity gives relationship between the different parts of the same molecule. It
is very important to understanding stereospecific reactions.
The atoms or group of atoms of same or
different carbon atom replaced by another
atom or group of atoms gives identical
products are called as homotopic ligands
(stereochemically equivalent).

The atoms or group of atoms of same or

different carbon atom replaced by another
atom or group of atoms gives different
products (stereoisomers or geometrical
isomers) are called as heterotopic ligands
(stereochemically non-equivalent)

enantiotopic

diastereotopic

Topicity
Homotopic ligands
1,3-Propane diol. If -H hydrogen atom undergoes deuteration in
presence of suitable catalyst forming two identical compound is
optically inactive. The protons at C2 is symmetric are called as
homotopic ligands.
HO

H D

H H
OH

OH

HO

H
OH

HO

replace beta H
replace alpha-H
by D
by D
Optically inactive

C2 substitution

In following example, replacement of one proton at C1 by D produces the chiral

center at C1 as these protons are non-equivalent (isotopes).
HO

OH

pro-R hydrogen
H
D
beta-H substitution

OH

HO
H

HO

OH

C1/C3 substitution
pro-S hydrogen D
H
alpha-H substitution

Topicity
Heterotopic ligands
HO

OH

pro-R hydrogen
H
D
beta-H substitution

OH

HO

HO

OH
C1/C3 substitution

pro-S hydrogen D
H
alpha-H substitution

As substitution either takes place at H or H produces different stereoisomers.

Hence, this proton is known as heterotopic proton or heterotopic ligand.
As they produces enantiomers are known as enatiomeric ligands or if they
produces disteromers are known as disteriotopic ligands.

Thus the C1 and C3 are prochiral centers.

The replacement of H produces S configuration in product so the H is called as
pro-S hydrogen and replacement of H produces the product having R
configuration, H is called as pro-R hydrogen.

Prochiral center

When chiral center is produced after the substitution

reaction in the original center or assembly is known as
prochiral center.
HO

OH

pro-R hydrogen
H D
beta-H substitution

OH

HO

HO

OH
C1/C3 substitution

pro-S hydrogen D
H
alpha-H substitution

Replacement of one proton at C1 by D produces the chiral

center at C1 as these protons are non-equivalent (isotopes).
As substitution either takes place at H or H produces
different stereoisomers.
Thus the C1 and C3 are prochiral centers.

Prochiral faces
In case of planar or partially planar group or molecules, it has two faces (front
side or back side) for the reaction which may be stereochemically equivalent or nonequivalent.
While such addition of atom or group
from either sides results isomeric
products
i.e.
both
faces
are
stereochemically non-equivalent are
said to be heterotopic faces

If the attachment of any atom or group

from either sides or faces result same
product,
then
two
faces
are
stereochemically equivalent, then such
faces are said to be homtopic faces

Reduction of deutarated acetaldehyde generates the new chiral center:

CH3

CH3

O
H2/Si face

HO

H
(1S)-(1-2H1)ethanol

H2/Re face

attack from backside H C

3
2

attack from frontside

(1- H)acetaldehyde

enantiotopic faces

In Si-face, we obtained S configuration in

prochiral carbon

H
D
HO
(1R)-(1-2H1)ethanol

diastereotopic faces

In Re-face, we obtained R configuration in

prochiral carbon