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Isomerism in Organic Chemistry

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Isomerism in Organic Chemistry

Prof. Vajira P.Bulugahapitiya

Professor in Chemistry
Department of Chemistry
Faculty of Science
University of Ruhuna
10th May 2020
 CONTENT
Title Page No.

1. Isomerism in Organic Chemistry

1.1 Constitutional isomers……………………………………………………………………01
1.1.1Chain isomerism………………………………………………………………..02
1.1.2 Position isomers………………………………………………………………..02
1.1.3Functional group isomers…………………………………………………..03
1.2 Stereoisomerism ……………………………………………………………………………04
1.2.1 Geometrical Isomerism…………………………………………………..…05
1.2.1.1 What is requirement to show
geometrical isomerism?..........................................06
1.2.1.2 Rules for determining priorities……………………………07
1.2.1.3 Cis / Trans Isomerism in cyclic compounds……………09
1.2.2Optical Isomerism (Enatiomerism)…………………………………....09
1.2.2.1 Chiral molecule……………………………………………………09
1.2.2.2 Chiral atom/ asymmetric atom…………………………….10
1.2.2.3 Optical active molecules………………………………………10
1.2.2.4 Non-Superimposable Mirror Images……………………11
1.2.2.5 Enantiomers………………………………………………………..11
1.2.2.6 Racemic mixture………………………………………………….11
1.2.2.7 Plane polarized light…………………………………………….12
1.2.2.8 Specific Rotation………………………………………………….13
1.2.2.9 Absolute and Relative Configuration……………………14
1.2.2.10Representing chiral molecule………………………………14
1.2.2.11Determination of Absolute Configuration……………15
1.2.2.12 Notation of enantiomers by the
Cahn-Ingold-Prelog (CIP) notation system……………15
1.2.2.13 R and S notation using Fisher Projection
Formula..17
1.2.2.14 Molecule with more than chiral centres ……………..20
1.2.2.1 Meso Compounds……………………………………………….22
Further reading ………………………………………… .23
1. Isomerism in Organic Chemistry
Isomers are the compounds with the same qualitative and quantitative
composition of elements; therefore, their relative molecular weights and
general formulas are identical, but their structures such as sequence of bonding
and or arrangement of the atoms or groups in the space are different.
This variation of the structures i.e., different structural formulae or three-
dimensional arrangement of atoms can lead to possess different physical and
chemical properties and hence these compounds behave as different
compounds with same molecular formular.

The isomers can be subdivided into two main categories that are constitutional
isomers and stereoisomers. Constitutional isomers can be different in different
ways of connectivity and stereoisomers are also can have geometrical isomers
and optical isomers (enantioisomerism). Other category of isomers named as
conformational isomers which are formed due to rotation of single bonds. As
those are not always separable and show some differences, it is not discussed
under the normal isomerism.

The following flow chart show the different isomers categories

Isomerism

Constitutional
Stereoisomerism
Isomerism

Functional
Chain Position Optical Geometrical
group
isomerism isomerism isomerism isomerism
isomerism

1
1.1 Constitutional isomers
Isomers that differ from the order in which the constituent atoms are connected
to each other are called constitutional isomers. Some examples for
constitutional isomers are given in the table 1.

Table - 1
Molecular Formula Constitutional Isomers
CH3 CH3
C5H12 CH3CH2CH2CH2CH3 CH3CHCH2CH3 CH3CCH3
CH3
CH3
C3H8O CH3CH2CH2OH CH3CHOH CH3CH2OCH3
H CH3 CH3
C4H8O CH3CH2CH2C=O CH3CHC=O CH3CH2C=O
H

Different structural isomers are assigned different IUPAC names.

Constitutional isomers (structural isomers) can be different in their chain

structures, functional groups due to different connectivity of atoms within the
molecule. Different structural isomers are assigned different IUPAC names.
Therefore, constitutional isomers can be subcategorized into Chain isomers,
position isomers and functional group isomers.

1.1.1 Chain isomerism

When two or more compounds have similar molecular formula but different
carbon skeletons, these are referred to as chain isomers and the phenomenon
is termed as chain isomerism.
For example,
a) C4H10 represents three compounds

2
 b) C5H12O shows three compounds,

1.1.2 Position isomers

When two or more compounds differ in the position of substituent atom or
functional group on the carbon skeleton, they are called position isomers and
this phenomenon is termed as position isomerism.

CH3CH2C CH CH3C CCH3

1-butyne 2-butyne

Position isomers for the molecular formula C4H6

OH
CH3CH2CH2OH CH3CHCH3
1-propanol 2-propanol
Position isomers for the molecular formula C3H8O

1.1.3 Functional group isomers

Two or more compounds having the same molecular formula but different
functional groups are called functional isomers and this phenomenon is termed
as functional group isomerism.

3
 O O
CH3CH2CH CH3CCH3
propanal propanone

Functional group isomers for the molecular formula C3H6O

O O
CH3CH2CH CH3CCH3
propanal propanone
Functional group isomers for the molecular formula C3H6O

CH3CH2CH2OH CH3CH2OCH3
1-propanol ethylmethylether
Functional group isomers for the molecular formula C3H8O

1.2 Stereoisomerism
Stereoisomerism is the existence of compounds whose structures differ from
each other only in the orientation of bonds in three-dimensional space.
Stereoisomers have the same structural formulae. They have the same
connectivity: their constituent atoms are connected in the same order but differ
in the manner in which atoms or groups are arranged in three-dimensional
space. Therefore, their structures cannot be superimposed on each other even
though they have the same molecular and structural formulae.

Those can be classified as geometrical and optical isomerism.

4
1.2.1 Geometrical Isomerism
A C=C double bond consist of a σ-bond and a π-bond. Due to the π bond the two
carbon atoms cannot freely rotate about the σ-bond. Both alkene carbon atoms
and the four atoms attached to them are all in one plane. For geometrical
isomers to exist, the two groups attached to each carbon atom of the double
bond should not be identical. In such an instance it is possible to have two
compounds which differ from each other in the spatial arrangements of the
groups joined to the two carbon atoms. These two compounds cannot be
superimposed on each other and cannot interconvert by rotation around
carbon-carbon bond axis (due to the π-bond). Such compounds are known as
geometric isomers.

Examples
2-butene show geometrical isomerism as shown below;

H3C H
H H
C C
C C
H CH3
H3C CH3

cis-but-2-ene trans-but-2-ene

When two identical groups/ atoms are same side of the double bond, it is cis
isomer whereas two identical groups/ atoms are opposite side of the double, it
is trans isomer. Two isomers are not interconvertible as C=C bond rotation is
restricted. Bonds would have to be broken and reformed. About +270 kJ mol -1
energy needed to break this bond, and insufficient energy available at room
temperature.

These two compounds above cannot be superimposed on each other hence they
are diastereoisomers. Geometrical isomers show different physical properties
and also some instances they show different chemical properties. Trans isomers
are more stable than cis isomers.

5
1.2.1.1 What is requirement to show geometrical isomerism?
Two atoms/ groups attached to each carbon of the double bond should be
different. For example, following compounds do not form geometrical
isomerism
H H
C C
CH3
H
propene

The two compounds of above are superimposable on each other. Therefore,

no geometrical isomers.

H CH3
H H
C C
C C
H H
CH3
H

Cis and trans notation are not possible when there are no identical groups
connected to the double bonded carbon. Then, new set of stereochemical
symbols are used, it is E and Z notations.

Cahn – Ingold – Prelog priority sequence is applied to getting E & Z symbols. The
group of highest priority, on both the double bonded carbon atom is first
chosen. If the two group of highest priority are on the opposite side of the
double bond. The alphabet E (from the German word Entagagen meaning
opposite) is used for the structure and if the groups of highest priority are on
the same side the alphabet Z (from German word, Zussamen meaning together)
is used. Thus, E stands for opposite side and Z for the same side

6
For example, bromine get higher priority over chlorine and iodine get higher
priority over hydrogen.

1.2.1.2 Rules for determining priorities

It is known as, rules with the names of people who develop the system.

(1) The atom which has the higher atomic number is given the higher priority

Cl Br
Cl I
C C
C C
F I
Br
F
E
Z
Cl is higher priority over F & I is higher priority over Br

(2) When two atoms are identical, compare the atoms attached to them on the
basis of their atomic numbers. Precedence is established at the first point of
difference

7
(3) Work outward from the point of attachment, comparing all the atoms
attached to a particular atom before proceeding further along the chain. Always
first point of difference needs to be considered

(4) Evaluate substituents one by one. Don't add atomic numbers within groups

(5) When one atom is multiply bonded to another atom, it is considered as

replicated of the substituent on that atom
-HC=O considered as C, O, O, H
-CH2OH considered as C, O, H, H

higher priority
Br CHO higher priority

C C

Cl CH2OH
Z

6) Substituent double bond is considered as 2 C connected & substituent triple

bond is considered as 3C are connected.

8
See the example below;
Br CH Highest priority

Cl CH2 Lowest priority

1.2.1.3 Cis / Trans Isomerism in cyclic compounds

In ring structures, groups are unable to rotate about any of the ring carbon–
carbon bonds. Therefore, cis / trans nomenclature is frequently used for naming
cyclic compounds and describes the relative position of two substituents with
respect to the ring. If a selected pair of groups are on the same side of a
reference plane common to both isomers (the ring of a cyclic compound), the
groups are said to be cis. If the groups are on opposite sides of the common
reference plane, they are said to be trans
Example: 1,2 dimethylcyclopropane has two geometrical isomers

1.2.2 Optical Isomerism (Enatiomerism)

• Only chiral molecule shows optical isomerism.

1.2.2.1 Chiral molecule: A carbon atom must have four different atoms or
groups bonded to it in order to be chiral. If two or more of the groups or atoms
on a tetrahedral C are identical, the C cannot be chiral and it is described as
achiral. While CHBrClF has a chiral C, the compound CH2BrCl is achiral because
it has a tetrahedral C on which two of the bonded atoms are the same (the two
H's). The chiral molecule shows enatiomerism / optical isomerism.

9
See molecule shown below;

1.2.2.2 Chiral atom/ asymmetric atom: The carbon atom that connected
to four different groups or atom is the chiral atom/ chiral carbon. The chiral
atom is also named as chiral centre of asymmetric centre.

1.2.2.3 Optical active molecules: Chiral molecules are optically active and
achiral molecules are optically inactive.

For example: 2-propanol is optically inactive

CH3 CH CH3

OH

Example: 2-chlorobutane is optically active

CH3 CH CH2 CH3

Cl

10
1.2.2.4 Non-Superimposable Mirror Images
Chiral molecules and its mirror image are not superimposable each other. See
the example given below for lactic acid, which is a chiral molecule.

1.2.2.5 Enantiomers
The chiral molecule and its non-superimposable mirror image are enantiomers.
The enantiomers are noted as (+) / (-) or R/S configurations. These enantiomers
are optical isomers and they show different physical properties mainly they can
rotate plane polarized light to opposite directions. They may show different
chemical reactivities, especially they act different way in a chiral environment.
Most of the biological molecules are chiral. Example: amino acids, glucose. Many
medicines are chiral molecules and hence its activity is influenced in the
biological systems/ body. Enantiomers can show different biological activities.
For example, one enantiomer of a chiral molecule can be the active drug and the
other enantiomer can be fatal or mutant.

1.2.2.6 Racemic mixture

The mixture of enantiomers which contain 50:50 ratio of both enantiomers is
racemic mixture or racemate. Racemic mixtures are optically inactive as they
cancel off the optical rotation of opposite directions.

1.2.2.7 Plane polarized light

11
Normal light and plane polarized light are indicated below.

normal light plane-polarised light plane-polarised light after

(waves vibrate in all directions) (vibrates in only one direction) clockwise rotation

Enantiomers rotate the plane polarized light to opposite directions and

racemate dose not rotate it as shown below.

(-)-enantiomer (+)-enantiomer (±)-racemate

(anticlockwise rotation) (clockwise rotation) (no overall effect)

Polarimeter can be used to observe the rotation of plane polarized light as

shown below.

Figure: polarimeter observation of rotation of the direction of

plane polarized light by chiral molecule

Enantiomers will rotate plane polarized light the same magnitude () but in
opposite directions (+ or -)
90% (+) + 10% (-) will rotate light 80% of pure (+)
75% (+) + 25% (-) will rotate light 50% of pure (+)
50% (+) + 50% (-) will be optically inactive

12
1.2.2.8 Specific Rotation []D

This is the standardized value for the optical rotation

 = optical rotation in degrees
l = path length in dm
c = concentration of sample in g/100 mL
T = temperature in °C
 = wavelength of light, usually D for the
D-line of a sodium lamp (589 nm)

The specific rotation is a physical constant of a chiral molecule. The []D may
also depend upon solvent; therefore, the solvent is usually specified.
Some examples:

13
1.2.2.9 Absolute and Relative Configuration
Absolute configuration is the precise three-dimensional arrangement of atoms
in space Relative configuration compares the three-dimensional arrangement of
atoms in space of one compound with those of another compound

1.2.2.10 Representing chiral molecule

Chiral molecules are shown in different ways

• Wedge-dash diagrams
• Sawhorse formula
• Fischer projection

Wedge-dash diagrams

Sawhorse formula

14
 Fischer projection

Fischer Projection

1.2.2.11 Determination of Absolute Configuration

There is notation of (+) or “d” and (-) or “l” for enantiomers. (+) of “d” denotes
dextrorotatory, means plane polarized light turn right or clockwise, similarly (-)
or “l” denotes levorotatory means plane polarized light turn left or counter
clockwise.
In systematic nomenclature, R & S notation is applied to show the absolute
configuration of chiral centres, this is based on precedence of the groups or
atoms connected to chiral centre determined by the Cahn-Ingold-Prelog (CIP)
notation system.

1.2.2.12 Notation of enantiomers by the Cahn-Ingold-Prelog (CIP)

notation system
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 counterclockwise
manner, then assign the chiral center a S (“sinister” or left)
(how to determine the priority using CIP discussed under E & Z
nomenclature.

15
Examples: Rank the groups bonded to the asymmetric carbon
1

2 4

If the group (or atom) with the lowest priority is bonded by hatched wedge, it
means it is behind the plane, then configuration can be directly applied.

See two situations below;

It is not possible to draw 1-2 without passing 3

Example below;

16
If Lowest priority is not bonded by hatched wedge, then molecule needs to be
rotated till lowest priority group cannot be seen (behind the plane). This rotation
can be done, holding one bond and rotate other bonds and then check the
descending of the priorities whether “clockwise” or “counterclockwise”?

In the given example below, the molecule is rotated by 120 degrees, holding one
bond which is connected to -OH
1 1
OH OH
2 orient low est p riority H
4 H CO2H
grou p aw ay H3C CO2H 2
CH3
3
3

clockw ise = R
Similarly see the example given below;
1 1
OH
3 orient low est p riority OH
4 H CH3 H
group aw ay
CO2H HO2C CH3 3
2 2

counter clockw ise = S

1.2.2.13 R and S notation using Fisher Projection Formula

As given above, optical isomers can be represented using Fisher formula. The
process is called as projection of the spatial structure to a plane. Carbon atom
of the centre of chirality is seldom drawn, but imagine into the point of
intersection of the bonds. The vertical bonds would have to be drawn by dotted
lines according to this arrangement, while the horizontal bonds would have to
be drawn by bold lines, but each bond is drawn by identical width.

17
Example:

The projected formula and the Fischer's notation rule of projecting:

a) the group on the highest oxidation level is found on the top
b) the longest chain is down
c) both previous groups are behind the plane of the vertical plane
d) the other two groups are located horizontally, in front of the plane of the
vertical plane

How to assign R & S configuration in Fisher Projection Formular

1) Assign priorities to the four substituents using CIP rules
2) The group of the lowest priority has to be at the top.
3) Determine the direction of rotation in going from priority 1 to 2 to 3, and
assign R or S configuration.
4) If the group with the lowest priority (4) is not at the top, switch two groups
to make it on the top and switch again for any two groups without switching
the lowest priority (4).

Example - 1

18
Example - 2

If the lowest priority group is not placed at the top, switch two groups to make
it on the top and switch again for any two groups without switching the lowest
priority. The reason;
Applying replacement of groups by even number, we get the original
configuration, but with different arrangement. The projected formula can be
rotated by 180 in the sheet of paper, but not by 90 or 270, since the latter
rotations would result in centre of chirality of the opposite configuration,
according to the rules of projection.
Rotating 180 degrees is similar to switching two groups twice;

See the example below;

At first H and -COOH groups are switched, this resulted lowest priority group
placed at the top. Then, again -COOH and -NH2 are switched without touching H
at the top.

2 place at
CO2H the top 4
H
1 H2N H 4 2 HO2C NH2 1
hold steady CH3 CH3
rotate other 3 3
three groups
counterclockwise
1-2-3 counterclockwise = S

19
Example - 2

2
4 2
CO2H
H CO2H
4 H 1 2
NH2 1 H2N
H2N CO2H CH3
CH3 1 3
CH3 H
3 4
3

1-2-3 clockwise = R

1.2.2.14 Molecule with more than chiral centres

When compounds is having more than one chiral centres , the number of
stereoisomers possible can be calculated as below;

Maximum number of stereoisomers = 2n

where n = number of chiral centers

For example: The compound shown below has two chiral centers (stereogenic
centers).

How many stereoisomers are possible?

There are four stereoisomers are possible for the above molecules. Chiral
centres of these four isomers can be assigned to R / S configuration using CIP
rule.

20
 2S, 3S 2R, 3R 2S, 3R 2R, 3S

Out of four stereoisomers drawn, two sets of enantiomers exist.

Example:
• 2S, 3S & 2R,3R are mirror images of each other but they are non-
superimposable
• 2S,3R & 2R,3S are mirror images of each other but they are non-
superimposable
Therefore, those are enantiomers.

But, if 2S, 3S & 2R,3S are considered, they are not mirror images of each other,
hence they are diastereoisomers. Similarly, 2R,3R & 2S,3R are diastereoisomers.

In the following example, this is more explained;

21
Diastereosiomers show different physical and chemical properties, therefore
they are separable using normal separation techniques, in contrast enantiomers
are non-separable using normal separation techniques as they do not show
difference in many of the physical properties and chemical properties.

1.2.2.15 Meso Compounds

In general, 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 there is 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.

Some examples;

22
Further Readings

Isomerism in Organic Compounds 1st Edition by S Kalaivani

Structure, Isomerism, and Stereochemistry by Claude H. Yoder , Phyllis A. Leber , Marcus

W. Thomsen ( Willey Online Library)

Basic Principles of Organic Chemistry by John D.Roberts and Marjorie C Caserio

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