‫بسم أهلل الرحمن الرحيم‬

ISOMERISM
Dr. Salih Mahdi Salman

4th lecture in Medical Chemistry

Faculty of Medicine
University of Diyala
ISOMERS

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4th Lecture of Medical Isomerism

INTRODUCTION
Isomerism

Occurs when certain compounds, having the same

molecular formula, exist in different forms each form
called isomer.

Isomers

Compounds having the same molecular formula but

different linkages or spatial arrangements of atoms

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4th Lecture of Medical Isomerism

Classification Isomerism

Two main types of isomerism

1.Structural isomerism
Different linkages of atoms.
Same molecular formula.
Different structural formula.

2.Stereoisomerism
Different spatial arrangements of atoms
Same molecular formula
& structural formulae

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CHAIN ISOMERISM

STRUCTURAL ISOMERISM POSITION ISOMERISM

Same molecular formula
but different structural
formulae FUNCTIONAL GROUP
ISOMERISM
Isomerism

GEOMETRICAL ISOMERISM
Occurs due to the restricted
rotation of C=C double
STEREOISOMERISM bonds... two forms - CIS and
TRANS
Same molecular
formula but atoms
occupy different OPTICAL ISOMERISM
positions in Occurs when molecules
have a chiral centre. Get
space.
two non-superimposable
mirror images.

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4th Lecture of Medical Isomerism

Structural Isomerism

Due to the presence of different carbon skeletons.

1. Chain isomerism C6H14

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4th Lecture of Medical Isomerism

Properties
Different physical properties
e.g : Boiling point
Straight-chain > branched-chain
Because the larger surface area and thus stronger van der
Waals force

>
Butane ( b.p= -0.5 °C) Methylpropane (b.p= -11 °C)

Same Chemical properties

Chain isomers have similar chemical properties because they
have the same functional groups.

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4th Lecture of Medical Isomerism

Position isomerism

e.g. Butan-1-ol and butan-2-ol

(molecular formula: C4H10O)

Butan-1-ol butan-2-ol

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4th Lecture of Medical Isomerism

Functional Group Isomerism

Due to the presence of different functional groups

e.g. C2H6O

Alcohol Ether
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4th Lecture of Medical Isomerism

e.g. C3H6O

Aldehyde Ketone

e.g. C3H6O2

Carboxylic acid Ester

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Metamerism

Occurs when the functional group (-oxy or –carbonyl) interrupts

the main carbon skeleton at different positions.

e.g. Methoxypropane and ethoxyethane

(molecular formula: C4H10O)
CH3-O-CH2-CH2-CH3 CH3-CH2-O-CH2-CH3 Position
Methoxypropane Ethoxyethane Isomers

e.g. Pentan-2-one and pentan-3-one

(molecular formula: C5H10O)

Write the chemical structure?

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Position isomers

Chain isomers C4H10O Chain isomers

Position isomers
OH
OH

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4th Lecture of Medical Isomerism

Position isomers

functional group C4H10O

isomers

Metamers
O O

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Tautomerism

Occurs when functional group isomers are in dynamic

equilibrium with each other.

ethanal ethanol

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Stereoisomerism

Stereoisomerism occurs when compounds having

the same structural formula show different spatial
arrangements of atoms in the space .

Two categories of stereoisomerism:

1.Geometrical isomerism
2.Optical isomerism

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4th Lecture of Medical Isomerism

GEOMETRICAL ISOMERISM

o An example of geometrical isomerism found in some,

but not all, alkenes.
o Occurs due to the restricted rotation of C=C bonds
o Get two forms....

CIS TRANS
Groups/atoms are on the Groups/atoms are on OPPOSITE SIDES
SAME SIDE of the double bond across the double bond

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GEOMETRICAL ISOMERISM

FREE ROTATION OF C-C BONDS

Single covalent bonds can easily rotate.

All these structures are the same because C-C bonds have
free rotation

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4th Lecture of Medical Isomerism

GEOMETRICAL ISOMERISM

RESTRICTED ROTATION OF C=C BONDS

C=C bonds have restricted rotation so the groups on either

end of the bond are ‘frozen’ in one position; it isn’t easy to
flip between the two.

This produces two possibilities.. The two structures cannot

interchange easily so the atoms in the two molecules occupy
different positions in space.
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4th Lecture of Medical Isomerism

GEOMETRICAL ISOMERISM
Isomerism in butane
There are 3 structural isomers of C4H8 that are alkenes*. Of these
ONLY ONE exhibits geometrical isomerism

BUT-1-ENE cis BUT-2-ENE trans BUT-2-ENE 2-METHYLPROPEN

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4th Lecture of Medical Isomerism

Properties of Geometrical Isomers

Have similar chemical properties - in most cases

They have significantly different physical properties

m.p. 80C 50C

b.p. 60C 48C

b.p. depends on van der Waals’ forces ONLY

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Zero net
dipole moment

van der Waals’ forces : cis > trans

 b.p. : cis > trans

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Stereoisomers

Isomers with same connectivity but differ in the

arrangement of atoms in space

stereoisomers subdivided into:

1. Enantiomers non superposable mirror images
2. Diasteromers non mirror images

Geometric isomers cis/trans-isomers are

diastereomers

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Enantiomers ( Optical Isomers)

o Enantiomers occur when compounds have non-superimposable

mirror images

o The two different forms are known as optical isomers or , Chiral

molecules enantiomer

o They occur when molecules have a chiral centre

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A chiral centre contains an asymmetric carbon atom

An asymmetric carbon has four different atoms (or

groups) arranged tetrahedrally around it.

A chiral ≠ Achiral
Asymmetric ≠ symmetric

Achiral (not chiral) if

object and its mirror
image are identical
(symmetry element)

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Optical activity arises from asymmetry or chirality

Any molecule with an sp3 carbon atom bonded to FOUR
different groups arranged tetrahedrally show optical activity

*
*

There are four different 2-chlorobutane exhibits optical

colours arranged isomerism because the second
tetrahedrally about the carbon atom has four different
carbon atom atoms/groups attached

In compounds with n chiral centers, the maximum number of

stereoisomers is 2n.
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4th Lecture of Medical Isomerism

(R) And (S) Nomenclature

Assign a numerical priority to each group bonded to the asymmetric

carbon:
group 1 = highest priority I I 1
group 4 = lowest priority rotate
Cl F 4 H Cl 2
H F3

C Y
Y focus down C-4 bond
C Y C
Atoms with higher atomic numbers Y have
C higher priority
I > Br > Cl > S > FY > O > N > 13C > 12C > 3H > 2H > 1H
C Y C Y
CH(CH3)2 > CH2CCHY2BrC > CH3CH2
Y C
Y
C Y Y
C Y C Y C Y C Y C
C Y C
Y C Y C
Y C
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C Y C Y
4th Lecture of Medical Isomerism

Draw an arrow from the 1st priority group to the 2nd group to the 3rd group.
Clockwise arrow (R) configuration
Counterclockwise arrow (S) configuration

CO2H CO2H

C C
H H
H3C CH3
NH2 H2N
(S)-alanine (R)-alanine

When naming compounds containing multiple chiral atoms, you must give
the configuration around each chiral atom:

H Br H 1 1
Cl 4
OH OH
4
H CH3 CH3 H
H3C CH3 HO2C
3 3
CO2H
2 2
(2S, 3S)-2-bromo-3-chlorobutane
(S) (R)
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Fischer Projections
OH OH OH
H CO2H H CO2H
H CH3
HO2C CH3 CH3

Horizontal bonds approach you (wedge bonds)

Vertical bonds move away (dashed bonds)

OH OH OH
H CO2H H CO2H
H CH3
HO2C CH3 CH3
rotate
(S) (S) (S)

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 H OH H OH
3 3
2 2
CO 2H CO 2H
H Br Br H
(2S,3S) (2S,3R)
same stereochemistry at C2 (S)
opposite stereochemistry at C3
CO 2H CO 2H
2 2
H OH H OH

3 3
Br H H Br

CH3 CH3
(2S,3S) (2S,3R)
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4th Lecture of Medical Isomerism

Chirality in the Biological World

1. An enzyme distinguishes between a molecule and its enantiomer
A schematic diagram of an enzyme surface capable of binding with (R)-
glyceraldehyde but not with (S)-glyceraldehyde.

All three
substituents
If two are
match up
with sites matched
on the up then
enzyme. the third
will fai!

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4th Lecture of Medical Isomerism

mirror

Enantiomers

R-lipase

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Enzymes are like hands in a handshake the substrate fits into

a binding site on the enzyme surface

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2. The properties of many drugs depends on their stereochemistry

e.g.Thalidomide one mirror image causes birth defects the other

cures morning sickness

(R)(+) Thalidomide (S)(-) Thalidomide

O O H O O H
H N N
H
N O N O

O O
a sedative and hypnotic a teratogen

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4th Lecture of Medical Isomerism

Enantiomers elicit different physiological responses

(S)-ibuprofen is active as a pain and fever reliever, while its
R enantiomer is inactive
S enantiomer of naproxen active as pain reliever, but R
enantiomer is a liver toxin!

HN HN

O O O O
NHCH3 CH
NHCH3NH
3
CH3NH

(S)-ketamine (R)-ketamine
Cl Cl Cl Cl
anesthetic hallucinogen
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NC HO
NH3
O
NMe2 CO2
HO H
Escitalpram L-DOPA
(anti-depressant ) (treatment for Parkinson's)
F
Naproxen
(anti-inflammatory drug)
H CO2H
CH3

MeO

NaO2C
CH3
HO
H S CH3

Cl N
Singulair
(asthma and allergy treatment)
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4th Lecture of Medical Isomerism

Miso Compounds
Compounds with 2 stereocenters do not always have 4 stereoisomers
(22 = 4)
Some stereoisomers are achiral, even though they contain stereocenters
Example: tartaric acid has two stereocenters, but only has 3 stereoisomers
R,R S,S
CO2H CO2H

H OH HO H

HO H H OH R,S S,R
CO2H CO2H
CO2H CO2H
R,S S,R H OH HO H
mirror
CO2H CO2H plane
H OH HO H
H OH HO H
CO2H CO2H
H OH HO H o
rotate 180
CO2H CO2H superimposible
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Internal Plane of Symmetry

Cis-1,2-dichlorocyclopentane contains two asymmetric

carbons but is achiral.
contains an internal mirror plane of symmetry
Both are Meso
CH3 CH3 CH3 CH3
H H

CH3 CH3
Cl Cl
CH3 CH3

Any molecule that has an internal mirror plane of symmetry is

achiral even if it contains asymmetric carbon atoms.

Cis-1,2-dichlorocyclopentane is a meso compound

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4th Lecture of Medical Isomerism

plane-polarized light

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4th Lecture of Medical Isomerism

Optically active substance can rotate the plane of polarization

of plane-polarized light
Measured by a polarimeter.
Dextrorotatory(+) : clockwise (to the right)
Laevorotatory(-): anti-clockwise (to the left

Optically
active

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Properties of enantiomers
o Identical physical properties except their optical activities.

o Identical chemical properties except their reactions with

optically active substances.

Racemic mixture (racemate)

 The racemic mixture (racemate) is a 50:50 mixture of the
two enantiomers.

 The specific rotation is zero.

 The racemic mixture may have different physical properties

(m.p., b.p., etc.) than the enantiomers.
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4th Lecture of Medical Isomerism

Stereoisomerism of Cyclic system

Me H

Me H Me Me

H H
cis-1,4- and trans-1,4-dimethylcyclohexane

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4th Lecture of Medical Isomerism

STEROIDS
Steroids are important “biological regulators” that nearly
always show dramatic physiological effects when they are
administered to living organisms.
Steroids are derivatives of the following ring system
18
12 CH317
11 16
19 13
CH3 C D
1
9 14 15
2
10 8
A B
3 7
5
4 6

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4th Lecture of Medical Isomerism

In most steroids the B, C and C, D ring junctions are trans. The

A, B ring junction may be either cis or trans.
18 18
19 CH3 CH3
11 R 19 11
CH3 13 13
17 R
12 17
CH3 12
2 10 C D 10 C D
1 9 9 8
8 15 1 14 15
B 14 B 16
A 16
6
3 4
5
6
5 H
H 2 A 7
7 H
H
4
all ring junctions are trans 3 A, B ring junctions is cis

When α and β designation are applied to the hydrogen atom at

position 5,the ring system in which the A, B ring junction is
trans become the 5 α series; and the ring system in which the
A, B ring junction is cis becomes the 5 β series.

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4th Lecture of Medical Isomerism

In systematic nomenclature of the R group at position 17

determines the base name of an individual steroid.

R
H3C 18 H
17
19 CH3 H

H H

H
For example:

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Thank you for your attention

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