Concepts to be covered

⮚ Enantiomers

⮚ Optical activity

⮚ R &S nomenclature

⮚ Diastereomers

⮚ Meso compounds

⮚ Cis-trans stereoisomerism

⮚ Conformational analysis of cycloalkanes

⮚ Steric and angle strain

⮚ Cyclohexane, axial and equatorial substituents

 ISOMERISM
Isomerism is the phenomenon in which more than one
compounds have the same chemical formula but different
chemical structures.
Chain isomer

Position isomer

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Functional isomer

As the name suggests, it refers to the compounds that have the same chemical formula
but different functional groups attached to them.

Metamerism

This type of isomerism arises due to the presence of different alkyl chains on each side
of the functional group.

● Example: C4H10O can be represented as ethoxyethane (C2H5OC2H5)

and methoxy-propane (CH3OC3H7).
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Tautomerism

• A tautomer of a compound refers to the isomer of the compound which only differs
in the position of protons and electrons.
• Typically, the tautomers of a compound exist together in equilibrium and easily
interchange.
• It occurs via an intramolecular proton transfer.
• An important example of this phenomenon is Keto-enol tautomerism.
Ring-Chain Isomerism

• In ring-chain isomerism, one of the isomers has an open-chain structure whereas the
other has a ring structure.
• They generally contain a different number of pi bonds.
• A great example of this type of isomerism can be observed in C 3H6. Propene and
cyclopropane are the resulting isomers, as illustrated below.
 Stereoisomers

Isomers having same constituents but different spatial arrangement

of their atoms or groups are known as stereoisomers

i) Configurational stereoisomers
ii) Conformational stereoisomers

The different spatial arrangement of atoms in a molecule which are readily

interconvertible by rotation about single bonds are called conformation

The different spatial arrangement of atoms in a molecule which are not

interconvertible without breaking of bond and formation of bonds are called
configurations.

A molecule can have only one configuration. Different configuration is a different

molecule, whereas a molecule could have an infinite number of conformations.
● The vast majority of biological molecules contain chiral centers and/or
stereogenic alkene groups.

● Most importantly, proteins are chiral, which of course includes all of

the the enzymes which catalyze the chemical reactions of a cell, the
receptors which transmit information within or between cells, and the
antibodies which bind specifically to potentially harmful invaders.

● Because they are chiral molecules, proteins are very sensitive to the
stereochemistry of their ligands: a protein may bind specifically to (R)-
glyceraldehyde, for example, but not bind to (S)-glyceraldehyde

● The over-the-counter painkiller ibuprofen is currently sold as a

racemic mixture, but only the S enantiomer is effective, due to the
specific way it is able to bind to and inhibit the action of prostaglandin
H2 synthase, an enzyme in the body's inflammation response process.

[Link]
%3A_Essential_Organic_Chemistry_(Bruice)/06%3A_Isomers_and_Stereochemistry/5.20%3A_The_Stereochem
Configurational Stereoisomerism

⮚ Optical Isomerism

⮚ Geometric Isomerism

Optical Isomerism

• When an sp3 hybridized tetrahedral carbon is attached to four different groups,

the molecule cannot be superimposed on its mirror image, hence called chiral
molecule.

• Chirality then is the property of handedness, and the adjective ‘chiral’ refers to
the molecule as a whole, rather than to a particular atom. Molecules such as
CCl4, and CH3Cl, that can be superimposed on their mirror images are said to be
‘achiral’

• Enantiomers are defined as a pair of molecules related as non-superimposable

mirror images
• Each enantiomer of a pair has the same physical properties (e.g. m.p.,
b.p. and solubility) with one exception, its behaviour towards plane
polarized light

• when a beam of plane polarized light is passed through a solution of

certain naturally occurring organic compounds, the plane of polarized
light is rotated either to the left or to the right. Molecules that induce
this rotation are said to be optically active.
Enantiomers that rotate the plane to the right, i.e.
clockwise, are called Dextrorotatory and are sometimes
given the symbol ‘d’; those that rotate to the left, anti-
clockwise, are correspondingly called with Laevorotatory
the symbol ‘I’.

In order to characterize the extent of rotation, an index

called specific rotation [α]D is used
 VIBGYOR

λ = 589 nm

• Optical rotation is measured with an instrument called a polarimeter

⮚ When interchange of two ligands bonded to an atom results in a new

stereoisomer, the atom is termed a stereogenic centre.

⮚ In case the new stereoisomer is an enantiomer, the stereogenic centre is a

chiral centre.

⮚ All chiral centres are stereogenic centres but all stereogenic centres are not
chiral centre.
Example of chiral centre and stereogenic centre

Stereogenic centre

Exchange the groups of C2

Cis–2-butene

trans–2-butene
 Stereogenic centre or not?
Find out stereogenic centre Chiral or Not?
 1. 3,4-dimethylpent-1-ene

2. cis-1,2-Dimethylcyclobutane

3. trans-1,2-Dimethylcyclobutane
Representation of Three dimensional molecule

Flying Wedge Representation

 Absolute Configuration: R-S Sequence Rules (Cahn-Ingold-Prelog rules)

S ("Sinister" → Latin= "left")

R ("Rectus" → Latin= "right")

• A substituent with a higher atomic number takes precedence over a

substituent with a lower atomic number.

• When dealing with isotopes, the atom with the higher atomic mass receives
higher priority.

• When visualizing the molecule, the lowest priority substituent should

always point away from the viewer (a dashed line indicates this)

• Then, draw an arrow from the highest priority atom to the 2nd highest
priority atom to the 3rd highest priority atom. Because the 4th highest
priority atom is placed in the back, the arrow should appear like it is
going across the face of a clock. If it is going clockwise, then it is an R-
enantiomer; If it is going counterclockwise, it is an S-enantiomer.
 2
a.n.: 35
a.n.: 16
4
a.n.: 1
3
a.n.: 9

a.n.: 53
1
Rule 2:if two or more of the atoms directly bonded to the chiral carbon are
identical, the atomic number of the next atoms are used for priority assignment.

• First, determine which of the chains has the first connection to an atom with the
highest priority (the highest atomic number). That chain has the higher priority.
• If the chains are similar, proceed down the chain, until a point of difference.

-CH (CH3)2

-CH2 CH3

H
-CH3
If the group of lowest priority is not bonded by dashed line then If rotates
clockwise then the configuration is S and if anticlockwise, the configuration is R

C
C≡CH = C C
C

O
‖
C - OH
 Fischer Projection Formula
This is also called Fischer projection in which all bonds are drawn as solid lines
with the understanding that horizontal bonds (both left and right) point toward
the observer (above the plane of the paper) and vertical bonds point away from
the observer (below the plane of the paper).

Drawing mirror images of Fischer projection:

Method to know whether mirror image is the same or different:
If the mirror image cannot be made to look the same as the original structure (Fischer
projection) with a 1800 rotation, the mirror image is different from the original
structure. In this case the mirror image and the original structure are not
superimposable and are enantiomers.

mirror image is the same or different?

Simple Method for Converting Wedge Formula into Fischer
Projection Formula

• The group which is below the plane of the paper (i.e., connected by --- ) is kept at
bottom in the Fischer projection formula

• the remaining three groups are attached in the same sequer (i.e., clockwise or
anticlockwise) as they appear in the flying wedge formula.

Example
Answer this
Simple Method for Converting Fischer Projection Formula into
Wedge Formula
• The group which is at the bottom of the Fischer projection formula is kept
below the plane of the paper in the flying wedge formula (i.e., connected
by ..., and the remaining three groups are attached in the same sequence
(i.e., clockwise or anticlockwise) as they appear in the flying wedge formula.

• One of the horizontal line groups is kept above the plane of the paper in the
flying wedge formula. Thus, the sequence of all the four groups in both the
formulae should be the same.
1.

Cl

2.

3.
Sawhorse Formula

• The sawhorse formula indicates the spatial arrangement of all the atoms or
groups on two adjacent carbon atoms.

• The bond between the adjacent carbon atoms is represented by a diagonal

line, usually from lower left to upper right, the left hand bottom end
representing the atom nearest to the observer and the right hand top end the
atom that is farther away.
 Newman Projection

• Newman projection represents the spatial arrangement of all the atoms or

groups on two adjacent carbon atoms.

• Here a molecule is viewed along the axis of a carbon-carbon bond. The carbon
atom toward the front is represented by a dot and the carbon atom toward the
rear by a circle.

• The atoms or groups on the carbon atoms are shown as being bonded to the
dot or circle.
ELEMENTS OF SYMMETRY

When a molecule has a plane of symmetry or a centre of symmetry,

it is superimposable on its mirror image and is achiral (optically
inactive).

Plane of Symmetry

The plane which divides a molecule into two equal halves which are
related as object and mirror image is known as plane of symmetry

The molecules having a plane of symmetry are achiral (optically

inactive).
• meso-tartaric acid is optically inactive because the molecule has
a plane of symmetry and thus is achiral.

Centre of Symmetry

The centre of symmetry is a point in a molecule from which if lines

are drawn on one side and extended an equal distance on the other
side, will meet the same atoms or groups.
When a molecule contains two chiral centres, each chiral centre is
assigned an R or S configuration according to the sequence and
conversion rules.

How many chiral carbon atoms are there?

Define R, S nomenclature for all chiral carbons.
 Erythro and Threo Nomenclature
This system of nomenclature is used only in those compounds which have :
(i) only two chiral carbons, and
(ii) the following general structure

R-Cab-Cab-R' or R-Cab-Cbc-R‘

Erythro and threo nomenclature is based on aldotetroses, erythrose and

threose which exist as two enantiomeric pairs.
When two similar groups at two adjacent (nonidentical) chiral carbons are on
the same side of the vertical line of the Fischer projection, the isomer is called
erythro isomer; if the groups are on the opposite sides, the isomer is called
threo isomer.

(-)-Erythrose (+)-Erythrose
Enantiomeric pair
One pair of enantiomers either can be named as erythro-2, 3-dihydroxybutanoic
acid, and these enantiomers called erythro enantiomers.

(+)-Threose (-)-Threose
MOLECULES WITH ONE CHIRAL (STEREOGENIC) CENTRE
If a molecule contains only one chiral carbon, it must be chiral and will exist in
two optically active forms, i.e., as two enantiomers.

Properties of Enantiomers

1. Enantiomers have identical physical properties (such as mp, bp, density and
refractive index) except their optical rotations which are of equal magnitude
but opposite sign. Enantiomers may also have different odours, e.g., (+)-
limonene has smell of oranges and (-)-limonene smells like lemons.

2. Enantiomers have identical chemical properties except in the presence of chiral

reagents and chiral solvents, when their rate of reactions are different.
 Enantiomers may also be different physiologically, e.g., (-)-nicotine is more
poisonous than (+)-nicotine; (+)-histidine is sweet but (-)-histidine is tasteless; L-
(+)-ascorbic acid (vitamin C) is more efficient than D-( - )-ascorbic acid. In many
cases one enantiomer of a drug molecule is more efficient and safe than the
other.

Racemic Modification
⮚ An equimolar mixture of a pair of enantiomers is known as racemic
modification.

⮚ Racemic modifications are optically inactive due to external compensation of the

two components. Racemic modifications are designated by the prefix (±)- or RS
or rac-.

⮚ Thus, a compound containing only one chiral carbon can exist in three forms,
viz., (+), (-) and (±).
MOLECULES WITH TWO CHIRAL (STEREOGENIC) CENTRES

⮚ In the case of an acyclic molecule with n dissimilar (nonidentical) chiral

carbons, the number of stereoisomers will be 2n (all optically active forms).
There will be 2(n - 1) pairs of enantiomers and the same number, 2 (n - 1) of racemic
modifications.

⮚ Any molecule with more than one chiral centre must have diastereomers.

3-chloro-2-butanol contains two chiral carbons. Number of stereoisomers will be ?

 Total number of stereoisomers:

• 2 pairs of enantiomers I and II ; III and IV

• Equimolar mixtures of enantiomers I and II; and III and IV constitute two
different racemic modifications.

• Thus, we can say that such compounds exist in six different forms; two
enantiomeric pairs and two racemic modifications.

The configurations I and III; I and IV; II and III; and II and IV are not mirror images of
each other. Such stereoisomers which are not mirror images of each other are
known as diastereomers, i.e., the stereoisomers which are not enantiomers are
diastereomers.
Properties of Diastereoisomers
1. Diastereomers have different physical properties such as m.p., b.p., density,
solubility, refractive index, etc.

2. They may or may not be optically active, e.g., achiral stereoisomers like meso
forms and geometrical isomers are optically inactive.

3. Diastereomers have similar but not identical chemical properties. Their rate of
reactions differs with chiral as well as achiral reagents and solvents.

4. Due to difference in their physical properties, diastereomers can easily be

separated through techniques like fractional crystallisation, fractional distillation,
chromatography, etc.
Molecules with Two Similar (Identical) Chiral Centres

E.g. Tartaric acid

• Identically substituted chiral carbons are called as similar (identical) chiral carbons.

• The number of stereoisomers in a compound containing n number of similar chiral

carbons is always less than 2n.

Molecule III has a plane of symmetry, therefore the molecule as a whole is achiral and is
optically inactive. Such a stereoisomer that contains chiral carbons but is achiral and
optically inactive is called a meso form.
• Because of the plane of symmetry in meso-tartaric acid, there are only three
stereoisomers for tartaric i) a pair of enantiomers (I and II), ii) the meso form
(III or IV).

• The stereoisomers I and III; and II and III are not mirror images of each other,
hence these are diastereomers.

• It should be noted that tartaric acid will also exist as a racemic form (racemic
modification) besides a pair of enantiomers and a meso form. The racemic
modification is not a stereoisomeric form; actually it is an equimolar mixture
of two enantiomeric forms (I and II).

The racemic modification is optically inactive because of external compensation,

whereas the meso form is optically inactive because of internal compensation
caused by the presence of a plane of symmetry in the molecule.
GEOMETRICAL (CIS-TRANS) ISOMERISM

The isomerism which arises due to restricted (frozen) rotation about

a bond in a molecule is known as geometrical or cis-trans
isomerism. The rotation either about a double bond or about a
single bond incorporated in a ring is restricted.
Geometrical (cis-trans) isomerism is exhibited by a variety of compounds which
may be classified as follows :

(i) Compounds containing a double bond; C=C, C=N, N=N.

(ii) Compounds containing cyclic structure; homocyclic, heterocyclic and fused-

ring, ring systems.

(iii) Compounds having restricted rotation about a single bond due to steric
hindrance; some biphenyls.

No stereoisomerism can result from triply bonded tetravalent or trivalent atoms because
such systems display cylindrical symmetry.
Geometrical isomers are not related as object and mirror image, hence they are
diastereomers (according to the definition: stereoisomers which are not mirror
images of each other are called diastereomers).

✔ The energy barrier for rotation about bond in simple alkenes is

about 62-65 kcal/mole.

✔ If the rotation barrier values are down to about 10 kcal/mole then these result
in conformers but not geometrical isomers.

✔ Compounds containing bond with frozen rotation exhibit

geometrical isomerism if they are suitably substituted, i.e., the ligands
attached to the same double bonded carbon are different.
Nomenclature of Geometrical Isomers

1. cis-trans nomenclature: Compounds of the type abC=Cab can exist in the

following two forms due to frozen rotation about carbon-carbon double bond.

The isomer in which the identical groups are on the same side of the double
bond is called cis and the isomer in which the identical groups are on the
opposite sides is called trans.

cis-trans nomenclature can be used only in those compounds in which only two
or three types of ligands are attached to both the double bonded carbons.
2. When all the four ligands are different, this nomenclature cannot be used, then E
- Z system of nomenclature will be applied.
1
E.g:

1 2
1

In the E - Z system the group of highest priority on each carbon atom is

identified by using the sequence rules. If the highest priority groups are on the
same side of the double bond, the configuration is Z (German : zusammen =
together), and if they are on the opposite sides, the configuration is E (German:
entgegen = opposite).
If geometrical isomers contain two or more double bonds, the compound is
considered as a derivative of the longest chain which contains the maximum
number of double bonds and the prefixes Z and E are placed before the numbers
indicating the positions of the double bonds in the main chain.

It should be noted that there is no relation between cis, trans and E, Z

configurations, i.e., all the cis compounds may not be Z and all the trans may not
be E.
 Nitrogen compounds containing as well as bond exhibit
geometrical isomerism. The important classes of compounds exhibiting
geometrical isomerism due to C=N- bond are : (i) oximes (ii) nitrones (iii)
hydrazones and (iv) semicarbazones.

.. ..

The prefixes syn and anti are used instead of cis and trans. In the syn oxime the hydroxyl
group on nitrogen, and hydrogen or the first-named of the two groups on the carbon are on
the same side, while in the anti-isomer they are on the opposite sides. The E - Z system of
nomenclature is also applied to oximes and it is more convenient. If the group with greater
priority and the hydroxyl group are on the same side of the double bond, the configuration
is Z, if on the opposite sides it is E. For example:
 .. ..

..
GEOMETRICAL ISOMERISM OF ALICYCLIC COMPOUNDS
CONFORMATIONAL ANALYSIS

The different spatial arrangements of atoms in a molecule which are readily inter
convertible by rotation about single bonds are called conformations;
Conformations represent conformers which are readily interconvertible and thus
nonseparable. The terms conformational isomers and rotamers are also used for
conformers.
The study of the existence of preferred conformations in molecules, and the relating of
physical and chemical properties of a molecule to its preferred conformation is known as
conformational analysis.
The terms conformation and configuration are related to energy barrier for
interconversions of different spatial arrangements of atoms in a molecule.

Conformations of Acyclic Systems

Conformations of ethane:

⮚ When an ethane molecule rotates about its carbon-carbon single bond, two
extreme conformations can result : the staggered conformation and the
eclipsed conformation.

⮚ An infinite number of conformations between these two extreme

conformations is also possible. These are called skew conformations.
 Staggered conformation: A conformation with a 60° dihedral (torsional) angle is
known as staggered conformation. The angle between the atoms attached to
the front and the rear carbon atoms is called the torsional angle.

Eclipsed conformation: A conformation with a 0° torsional angle is known as

eclipsed conformation.

⮚ The electrons in a carbon-hydrogen

bond will repel the electrons in
another carbon-hydrogen bond if the
bonds get too close to each other. This
is called torsional or bond opposition
strain or eclipse strain.

⮚ The staggered conformation is the most

stable conformation because the
carbon-hydrogen bonds are as far away
from each other as possible, i.e., it has
least torsional strain.
⮚ The eclipsed conformation is the least stable conformation because the
carbon hydrogen bonds are closest.

⮚ In staggered conformation the distance between the hydrogen nuclei is 2.55

A0, but they are only 2.29 A0 apart in the eclipsed conformation. The rotational
energy barrier in ethane is 2.9 kcal/mole.

Conformations of n-butane:

• If the rotation will be about C2 and C3 bond, then conformations will be

symmetrical.

• For conformational analysis butane may be treated as the derivative of ethane

where one hydrogen on each carbon is replaced by a methyl group.
Different conformations of butane can be obtained by rotation about its middle carbon-
carbon bond (i.e., between C2 and C3 bond)
⮚ Butane has three staggered conformers (I, III and V). Conformer III, in which
the two methyl groups are as far apart as possible is more stable than the
other two staggered conformers I and V. The most stable of the staggered
conformers (III) is called the anti conformer and the other two staggered
conformers (I and V) are called gauche conformers (anti is Greek for
"opposite of', gauche is French for "left.")

⮚ In the anti conformer the largest substituents are opposite to each other; in
the gauche conformer, they are adjacent. The two gauche conformers have
the same energy but each is 0.9 kcal/mole less stable than the anti
conformer.

⮚ Anti and gauche conformers do not have the same energy because of the
steric strain. Steric strain or steric hindrance is the strain put on a molecule
when its atoms ,or groups are large in size and due to this they are too
close to each other, which causes repulsion between the electrons of atoms
or groups.

⮚ There is more steric strain in the gauche conformer than in the anti because
the two methyl groups are closer together in the gauche conformer. Steric
strain in gauche conformer is called gauche interaction.
⮚ The eclipsed conformer in which
the two methyl groups are
closest to each other (VI) is less
stable than the other eclipsed
conformers (II and IV).

⮚ All these eclipsed conformers

have both torsional and steric
strain.

⮚ Torsional strain is due to bond-

bond repulsion and steric strain
is due to the closeness of the
eclipsing groups. In general,
steric strain in the molecule is
directly proportional to the size
of the eclipsing groups.

⮚ Eclipsed conformer VI s called the fully eclipsed conformer, while II and IV are called
eclipsed conformers.
Thus, the relative stabilities of the six conformers of n-butane in decreasing order is as
follows:

Molecules with carbon-carbon single bonds have many interconvertible conformers.

Conformers cannot be separated because they rapidly interconvert.

Structure of cycloalkanes

• Angle strain
• Torsional Strain

Conformation of Cyclohexane

Two possible forms of cyclohexane are chair and boat conformations of

cyclohexane which are free from angle strain (The angle between the carbon-
carbon bonds are all 111 ° which is very close to tetrahedral angle 109·5°. Both
forms are interconvertible into each other.
Because of differences in the steric strain and bond opposition strain, the two
forms differ in energy content.

In the chair form all the C-H bonds on adjacent carbons are in the gauche position. On the
other hand, in the boat conformation there are four skew interactions (2, 3; 3, 4; 5, 6 and
6, 1) and two eclipsed interactions (1, 2 and 4, 5)

Flagpole Hydrogen in boat conformation

1. This boat structure still has two eclipsed bonds and severe steric crowding of
two hydrogen atoms on the "bow" and "stern" of the boat. This steric crowding is
often called steric hindrance.
 2. It is the repulsion between hydrogen atoms which are at the top of the boat.
These hydrogens are known as flagpole hydrogens. The distance between their
centres is only 1.83 A0 while the sum of the van der Waals radii of the two
hydrogen atoms is 2.5 A0. This repulsion is called bow-sprint repulsion that
contributes to increase the energy of the boat form

Chair conformation

• By lifting one carbon above the ring plane and the other below the plane, a
relatively strain-free 'chair' conformer is formed. This is the predominant
structure adopted by molecules of cyclohexane.

• On careful examination of a chair conformation of cyclohexane, we find that

the twelve hydrogens are not structurally equivalent. Six of them are located
about the periphery of the carbon ring, and are termed equatorial. The other
six are oriented above and below the approximate plane of the ring (three in
each location), and are termed axial because they are aligned parallel to the
symmetry axis of the ring.
• Thus the total strain in the boat conformation is larger than that in the chair conformation

• The carbon atoms of the chair form of cycIohexane roughly form a plane

a = axial hydrogen
e = equatorial hydrogen

The rigid cyclohexane ring can change its conformation by flipping to another chair
conformation

In this transformation the axial bonds of one chair conformation become equatorial and
the equatorial bonds become axial in the other conformation.
Note: (i) 1, 2- or 1, 4-diaxial and 1, 2- or 1, 4-diequatorial bonds of cyclohexane are always
trans to each other.

(ii) Similarly, 1, 3,- or 1, 5-diaxial and 1,3- or 1, 5-diequatorial bonds of cyclohexane are
always cis to each other.
Conformations of Monosubstituted Cyclohexanes
The two chair conformers of a monosubstituted cyclohexane such as
methylcyclohexane are not identical.

A substituent In the equatorial position in one chair conformation and in the axial position
in the other chair conformation. The conformation with the substituent in the equatorial
position is more stable.

• When the methyl group is in the axial position, it is gauche to both the C-3 and C-5
carbons

• There is one more factor which makes axial methyl cyclohexane less stable. This is
called 1,3-diaxial interaction.
 • When the methyl group (or any other larger group at C-1 is in axial position it faces
repulsion from the other two axial hydrogens (or other substituents) on C-3 and C-5
due to steric problem.

• The repulsion results from the distance between them because the distance between
them is less than the van der Waals radii of the two hydrogen atoms.

• 1, 3-diaxial repulsion increases strain of the conformer. The strain due to the 1, 3-
diaxial repulsion is known as transannular strain.

1, 3-diaxial Interaction

Thus conformer with equatorial methyl dominates because it has less energy. An axial
substituent has a less favourable spacial orientation than its equatorial mate because it is
more crowded-a fact attributed to either
(i) 1, 3-interaction and
(ii) Gauche interaction.