Organic Pharmacy (Pharm 1209)

Chapter 1

Isomerism

Introduction
• Isomerism is a very common phenomenon
in organic chemistry.
• A large number of organic molecules show
isomerism. In contrast, inorganic molecules
rarely show isomerism (mostly confined to
coordination compounds).
• The biomolecules also show isomerism and
this isomerism is very important to the
living organisms (including humans).
 Concept
• In organic molecules, it is frequently
possible for a molecular formula to exist as
different structures.
• For example, the molecular formula C4H10O
can exist as any of the following structures.
OH
H2 H2 H2 H2
H3C C C C OH H3C C C CH3
H

H2 H2 H2 H2
H3C C O C CH3 H3C O C C CH3

Concept Contd.
• Again, it is possible that two molecules have the
same molecular formula and the same structural
formula, but the atoms are at different position in
space.
• For example, the atoms can occupy space in two
ways in the following structure:
HO HO
H H

C2H5 H3C
CH3 C2H5
 Concept Contd.
• Two molecules who have the same molecular
formula but different structures will show
differences in some physical and chemical
properties.
• Similarly, two molecules who have the same
molecular formula but different arrangement in
space will also show differences in physical and
chemical properties.
• Hence two such molecules can’t be considered
the same.
• Such molecules are called isomers of each other.

Concept Contd. [Definitions]

• So, when two or more molecules have the same
molecular formula but have different physical
and/or chemical properties due to having
different structures or different arrangement
of atoms in space, they are called isomers [Isos
= same, equal, identical; Meros = part, a share].
• Simply, when two or more different compounds
have the same molecular formula, they are called
isomers.
• This phenomenon of one molecular formula
existing as different compounds is called
isomerism.
 Types of Isomerism in
Organic Molecules
• As we have stated in the previous slides, isomerism
can arise from two conditions:
1. The atoms are connected differently to each other.
2. The atoms are connected the same, however
occupy different position in space.
• In keeping with that, broadly isomerism is of two
types as shown below:
Isomerism
• These two types can be
further divided into
other types.
Structural Stereo-
isomerism isomerism

8
 Types of Isomerism in
Organic Molecules Contd.
A more intensive classification is shown below:

Isomerism

Structural Stereo-
isomerism isomerism

Chain Positional Functional Geometric Optical

isomerism isomerism group isomerism isomerism
isomerism

cis/trans E/Z D/L R/S

isomers isomers isomers isomers

Structural Isomerism
Definition
• Structural isomerism can be defined as the isomerism
that occurs when two or more molecules have the same
molecular formula but have different structures.
• In another words, atoms are connected differently in
structural isomers.
• Structural isomerism is also referred to as
constitutional isomerism.
Types
• Mainly, structural isomerism can be of 3 types –
– Chain isomerism
– Positional isomerism
– Functional group isomerism
• Some refer to ‘metamerism’ and ‘tautomerism’ as types
of structural isomerism as well.
 Structural Isomerism Contd.
Chain isomerism
• It is also known as nuclear isomerism or skeletal
isomerism.
• Chain isomers are those in which the (carbon)
chain lengths are different.
• So, we can say that chain isomerism is a
phenomenon where two or more molecules have
the same molecular formula, but their structures
are different due to different chain length.
• We can get one straight-chain and one or more
branched-chain isomers due to chain isomerism.

Structural Isomerism Contd.

Examples of chain isomerism:
H2 H2 H2 CH3
H3C C C C CH3 H2 H2
Pentane H3C C C OH H3C C OH
H
Chain length = 5 carbon Propan-1-ol
Propan-2-ol
(Propanol-1)
(Propanol-2)
CH3 CH3
H2
H3C C C CH3 H3C C CH3
H
2-Methyl-butane CH3
(iso-pentane)
2,2-Dimethyl-propane
Chain length = 4 carbon
(neo-pentane)
Chain length = 3 carbon
 Structural Isomerism Contd.
Positional isomerism
• It is also known as regioisomerism.
• In case of positional isomers (or position isomers),
the chain length doesn’t change rather the position
of the functional group changes.
• So in positional isomerism:
– The molecular formula is same.
– The chain length is same.
– The functional group is same.
– But the position of the functional group is
different.

Structural Isomerism Contd.

Examples of positional isomerism:
H2 H2 H2 H2
H3 C C C C C OH
Pentan-1-ol
(Pentanol-1)

OH
H2 H2
H3 C C C C CH3
H
Pentan-2-ol
(Pentanol-2)

OH
H2 H2
H3 C C C C CH3
H
Pentan-3-ol
(Pentanol-3)
 Structural Isomerism Contd.
Functional group isomerism
• It is also known as functional isomerism.
• In functional group isomerism:
– The molecular formula is the same.
– The functional groups are different.
• So, when two or more molecules have the same
molecular formula but different functional groups,
they are called functional group isomers and the
phenomenon is called functional group isomerism.

Structural Isomerism Contd.

Examples of functional group isomerism:
H2 H2 H2 H2 H2 H2
H3C C C C OH H3C C C C COOH
Butan-1-ol Pentanoic acid
(Butanol-1)

H2 H2 H2 H2
H3C C O C CH3 H3C C COO C CH3
Ethoxy ethane Ethyl propyl ester

O O
H2
H3C C CH3 C2H5 C H H2C C C OH
H
Propan-2-one Propionaldehyde
Prop-2-en-1-ol
(2-propen-1-ol)
[Propenol-2]
 Structural Isomerism Contd.
Tautomerism
• When two compounds which have different structures and
different functional groups but same molecular formula are
interconverted between each other, it is called tautomerism.
• Two such compounds are tautomers of each other. These
tautomers are at a dynamic equilibrium with each other.
• Tautomerism is also known as desmotropism,
• The most prominent example is the interconversion between
ketone and enol.

O OH
H2
H3 C C C CH3 H3 C C C CH3
H
Butanone
But-2-en-2-ol
• This is a kind of functional group isomerism.

Structural Isomerism Contd.

Metamerism
• If the alkyl groups attached to the functional group differs in
two compounds with same molecular formula, this is known
as metamerism.
• In another words, if the number of carbons at different side of
the functional group differs in two or more compounds, then
they are metameric isomers (metamers).
• This is seen when the functional groups are:
H O
O N C
Examples:
C3H7 O CH3 C2H5 O C2H5
Methyl propyl ether Diethyl ether
• So, basically it is a type of positional isomerism.
 Stereoisomerism
Stereochemistry
• The branch of chemistry which discusses the molecular
structure and reactivity of molecules in three
dimensions (3D) is called stereochemistry.
Definition of stereoisomerism
• Stereoisomerism can be defined as the isomerism which
occurs when two or more molecules have the same
molecular formula and structural formula, but there is
a difference of properties due to difference in position of
the atoms in space.
• In another words, the atoms are positioned differently
in stereoisomerism.
• It can also be said that the isomerism that results from
difference of spatial arrangement of atoms is called
stereoisomerism.
Types of stereoisomerism
• Broadly, stereoisomerism can be divided into two types:
– Geometric isomerism
– Optical isomerism

Geometric Isomerism
Definition
• The isomerism which occurs due to difference in the
positions of the substituents about a double bond or a
ring is called geometric isomerism.
• It is also known as cis-trans isomerism.
• Conditions for geometric isomerism
• There must be a carbon-carbon double bond in the
compounds.
• Each of the carbon of the double bond must be
attached to two different substituents.
• Now…… Are these compounds below geometric
isomers?
H3C H C2H5 H
H3C H H3C C2H5

H C C C2H5
C C C C
H C C H

C2H5 CH3 C2H5 CH3 C2H5 H H3C H

Geometric Isomerism Contd.
Why does geometric isomerism occur?
• Geometric isomerism occurs because there is no possibility of
free rotation about a double bond or a ring.
• As a result, the substituents are fixed in position. They can’t
change position without breaking bond.
H H H3C H
can't rotate about
C C
the double bond into C C

H3C CH3 H CH3

• So, the two structures above are separate compounds, and
therefore isomers.
Types of geometric isomers
• There are two methods to denote geometric isomers.
According to these two methods there are:

Cis or Trans isomers E or Z isomers

Geometric Isomerism Contd.

Cis/trans isomerism
• This method of denoting geometric isomerism works best
when the alkene is disubstituted. In fact, it will always work
when the alkene is disubstituted (and other conditions are
fulfilled).
• But this method can fail with trisubstituted or
tetrasubstituted alkenes.
Cis isomer
• The geometric isomer in which the identical groups on the
two carbons of the double bond are on the same side of the
double bond is called the cis isomer.
Trans isomer
• The geometric isomer in which the identical groups on the
two carbons of the double bond are on the opposite sides of
the double bond is called the trans isomer.
• In cases of ring compounds, if the groups are on the same
side of the ring then it is cis and if on the opposite sides then
it is trans.
Geometric Isomerism Contd.
• For this cis/trans method of denoting to work,
there must be at least one identical group on each
carbon of the double bond. For example:
H3C CH3 C2H5 CH3 C2H5 C2H5

C C C C C C

H H H H H3C H

Disubstituted Disubstituted Trisubstituted

C2H5 CH3 C2H5 C3H7 C2H5 C4H9

C C C C C C

H3C C2H5 H3C H H3C C3H7

Tetrasubstituted Trisubstituted Tetrasubstituted

Geometric Isomerism Contd.

Cis isomer is less stable than trans isomer
• In cis isomer, two large groups on the separate carbons are
always on the same side. Thus, these two groups are closer to
each other and repel each other. This is called steric strain.
• On the other hand, in trans isomer the two large groups are
on the opposite sides. So they are far apart. Hence they don’t
repel each other. So, the steric strain is far less.
large groups are close large groups are far

C2H5 CH3 C2H5 H

C C C C

H H H CH3
cis-pentene-2
trans-pentene-2
• This is why cis isomer is less stable than trans isomer.
Geometric Isomerism Contd.
E/Z isomerism
• E/Z method of denoting geometric isomers is universal.
• This method will not fail even when cis/trans method
has failed.
• While this method can work on all compounds that
have geometric isomers, it is used for those compounds
where cis/trans method fails.
• According to this method, the groups attached to each
carbon of the double bond are analyzed and then given
priorities according to Cahn-Ingold-Prelog (CIP) rules.
• If the group of highest priority on both carbon are on
the same side, then it is Z (Z = Zusammen = Together)
isomer, if they are on opposite sides, then it is E (E =
Entgegen = Opposite) isomer.

Geometric Isomerism Contd.

CIP rules for E/Z naming convention
• Substituents on any one of the two double-bonded
carbon atom is looked at.
• First, the atom which is directly attached to the
double bond carbon is looked at. This is the first
atom. The group where first atom has higher
atomic number has higher priority.
Geometric Isomerism Contd.
• If, both groups are attached by the same first atom,
then the atomic number of the second atom (atom
attached to the first atom) is looked at.

• Similarly, if the second atoms are also the same,

third atoms are looked at.

Geometric Isomerism Contd.

• If the first atoms of two groups have the same

higher atomic number substituents, one with more
such substituent is given higher priority.
Geometric Isomerism Contd.
• If there is any double bond or triple bond within the group, it
is considered at two or three single bonds respectively. So:
O O O

C H means C H

• Exemplary:
first atom is attached to one O and two H

HO
Priority 2
CH2 C2H5 HOH2C C2H5

C C Two gets C C
priority so
C H OHC H

O H Priority 1

First atom is attached to two O and one H

• If there is a phenyl group attached to first atom, then it is

thought that First atom is attached to three carbons.

Geometric Isomerism Contd.

• Example of E and Z isomers:
Priority 1 Priority 1 Priority 1 Priority 2
C2H5 C2H5 C2H5 H

C C C C

H3C H H3C C2H5

Priority 2 Priority 2 Priority 2 Priority 1

Z-3-methylhexene-3 E-3-methylhexene-3

• Z isomer is not always cis and E isomer is not

always trans
Priority 2 Priority 1 Priority 2 Priority 2
C2H5 C2H5 C2H5 H

C C C C

Br H Br C2H5
Priority 1 Priority 2 Priority 1 Priority 1

E-3-bromohexene-3 Z-3-bromohexene-3
[cis-bromohexene-3] [trans-bromohexene-3]
 Optical Isomerism
Definition
• When two molecules only differ by the three-
dimensional position of the substituents around
one or more atoms, they are called optical isomers
and this phenomenon is called optical isomerism.
Br Br

H *C H
*C
Cl H3C
CH3 Cl
Cl
Br
H
H *1C
The positions of Cl and CH3 around the *C1
Br CH3
carbon differs in the two molecules Cl F
*2 C
*2 C F
H3C
H
H

The positions of Cl and Br differ around carbon 1

and the positions of CH3 and F differ around
carbon 2 in the two molecules

Optical Isomerism Contd.

Chirality
• The term ‘Chiral’ and therefore the term ‘Chirality’
comes from a Greek word Kheir which means hands.
• An object is called chiral when its mirror image is non-
superimposable on the original and this phenomenon is
called chirality.
• If the mirror image is superimposable then the object is
called achiral.
 Optical Isomerism Contd.
Chiral center
• In chemistry, an atom which is attached to non-
identical substituents and the mirror image is non-
superimposable is called a chiral center.
Br C2H5 H
N
H is this a chiral center?
*C CH3
Cl
CH3 C3H7 C6H5
P
Technically, for an atom attached to non- is this a chiral center?
identical substituents, the mirror image CH
3
should be non-superimposable.
But if the mirror image is not stable
enough, then practically that atom will
not be considered as a chiral center.

Optical Isomerism Contd.

Tetrahedral center
• In chemistry, an atom which is attached to four
substituents is called a tetrahedral center.
• Most commonly, carbon shows tetrahedral centers.
Chiral carbon
• A carbon which is attached to four different
substituents is called a chiral carbon.
Br Br

Cl C H Cl C H

H CH3
a tetrahedral carbon a tetrahedral carbon
but not a chiral carbon and a chiral carbon
 Optical Isomerism Contd.
Elements of symmetry
• Any point, line or plane which divides an object into two
equal parts is referred to as an element of symmetry.
Plane of symmetry
• The imaginary plane which divides an object into two
equal parts is called a plane of symmetry.
• In chemistry, the plane of symmetry is an imaginary
plane which divides a molecule into two parts which are
mirror image of each other.
COOH

HO H
Plane of symmetry
HO H

COOH

Optical Isomerism Contd.

Conditions for optical isomerism
• Following conditions must be met if a molecule is
to have optical isomers:
– The molecule must have at least one chiral carbon.
– There should not be any elements of symmetry
(specifically plane of symmetry).
– The mirror image of the molecule must not be
suporimposable on the original.
• So, what about the following structures….
Cl Cl

H3C C C2H5 H3C C CH3

Br Br OH Cl
 Optical Isomerism Contd.
HO OH
HO OH H Cl H

H3C C C C CH3

OH Br OH

OH Cl H COOH COOH

H3C C C C CH3 HO C H H C OH

H Br OH HO C H HO C H
COOH
COOH
COOH COOH
H C OH
HO C H

H C OH H C OH

COOH COOH

Optical Isomerism Contd.

Meso compounds
• The compounds which have the following criteria
are called meso compounds:
– They have two or more chiral carbons.
– There is a plane of symmetry.
– The mirror image of the molecule is superimposable on
the original.
COOH COOH COOH

HO H H OH HO H

HO H H OH HO H

COOH COOH COOH

A meso compound The mirror image 180o rotated mirror
molecule
image molecule
 Optical Isomerism Contd.
Wedge and dash representation
• Wedge and dash projection is a method to represent the
three-dimensional (3D) structure of a molecule.
• In this method, three types of lines are used to denote bonds:
– Solid lines: Represent atoms/groups in the same plane (the
paper).
– Wedged lines: Represent atoms/groups which are coming out of
the plane, towards the viewer.
– Dashed lines: Represent atoms/groups which are extending
away from the plane, away from the viewer.
CH3
H

CH3
Cl Br
H

Br Cl

Optical Isomerism Contd.

Fischer projection
• Fischer projection is an attempt to depict three-
dimensional molecules in two-dimensional paper.
• According to this method, the groups bonded by
horizontal bonds are coming towards the viewer and
the grops bonded by vertical bonds are going away
from the viewer.
Br Br
Br
F
H C F H C F
H3C
CH3 CH3 H

• In this projection, the longest chain is drawn

vertically with C1 at the top.
 Optical Isomerism Contd.
• Types of optical isomerism

Optical isomers

Enantiomer Diastereomers

Dextrorotatory Levorotatory Erythro Threo

Optical Isomerism Contd.

Enantiomer
• Enantiomers are those optical isomers which are
mirror images of each other.
• Since there can only be one mirror image, there
will always be two and only two molecules which
are enantiomers of each other.
• These two enantiomers differ in one property -
optical activity. Based on optical activity, the
enantiomers are divided into:
– Dextrorotatory enantiomer: This is the enantiomer which
rotates the plane of plane-polarized light to the right.
– Levorotatory enantiomer: This is the enantiomer which
rotates the plane of plane-polarized light to the left.
 Optical Isomerism Contd.
CH3 CH3
CH3 CH3
Br H H Br
Br H H Br

H C Br H C Br
Cl Cl

• These two compounds F F

fullfill the conditions for
• So… What about these two
optical isomerism.
structures?
• They are also mirror images
• Are they optical isomers?
of each other.
• Are they enantiomers?
• Hence they are
enantiomers.

• So, can you tell me among the two structures on the left
side, which is dextrorotatory and which is levorotatory?
• Can you tell me, which is R isomer and which is S isomer?

Optical Isomerism Contd.

Diastereomers
• Optical isomers which are not enantiomers are
diastereomers.
• Meaning, two optical isomers which are not mirror
images of each other are diastereomers.
• For diastereomers to exist, there must be at least
two chiral carbons in the structure.
• In diastereomers, the configuration of at least one
chiral carbon will be same.
• Diastereomers differ in many physical and
chemical properties.
• Two terms ‘erythro’ and ‘threo’ are associated with
diastereomers. Another two terms commonly used
are ‘syn’ and ‘anti’.
 Optical Isomerism Contd.
CH3 CH3 • Erythro: When the identical
groups on adjacent chiral
Br C H H C Br
carbons are on the same side,
H C Br H C Br the diastereomer is called
ERYTHRO.
F F • Threo: When the identical
• These two compounds groups on adjacent chiral
fullfill the conditions for carbons are on the opposite
optical isomerism. sides, the diastereomer is
• But they are not mirror called THREO.
images of each other. CH3 CH3
• Hence they are not
enantiomers, they are Br C H H C Br
diastereomers.
H C Br H C Br

F F

Optical Isomerism Contd.

Racemic mixture
• A racemic mixture is one in which two enantiomers are
present in the same amount.
• Since each enantiomer rotates the plane of the plane-
polarized light by the same degree but in opposite direction,
there is no net rotation in racemic mixture.
• Many optically active compounds exist as racemic mixture.
e.g. thalidomide, tartaric acid etcetera.
• Racemic mixtures are denoted by symbols like (±) or dl-. e.g.
(± tartaric acid).
COOH COOH

H C OH HO C H

HO C H H C OH

COOH COOH
L-Tartaric acid D-Tartaric acid
(50%) (50%)
 Optical Isomerism Contd.
• Physical properties of meso compounds,
racemic mixture and enantiomers
• The chemical properties of enantiomers, meso
compounds and racemic mixtures do not vary at
all. However the physical properties can vary.
• This is shown with tartaric acid below:
Optical Solubility at
rotation Density 20 °C (g/100
Compound Melting point (°C) mL H2O)
[α]D (g/mL)
(degree)
(+)-Tartaric acid 168 - 170 +12 1.7598 139.0
(-)-Tartaric acid 168 - 170 -12 1.7598 139.0
meso-Tartaric acid 146 - 148 0 1.6660 125.0
Racemate of tartaric
206 0 1.7880 20.6
acid

Optical Isomerism Contd.

Representation of optical isomerism
• In general optical isomerism is represented
based on two criteria:
• Based on optical activity
– d/l method (old).
– (+)/(-) method (modern).
• Based on configuration around chiral
carbon.
– D/L method (limited use).
– R/S method (universal).
 Optical Isomerism Contd.
Optical isomers based on optical activity
• Based on the ability to rotate the plane of the
plane-polarized light, optical isomers are divided
into two types.
– Dextrorotatory: Rotates the plane to the right. It is
denoted by d- or (+).
– Levorotatory: Rotates the plane to the left. It is denoted by
l- or (-).

Optical Isomerism Contd.

d/l or (+)/(-) denotation is placed on a compound after its optical
rotation is measured with a polarimeter. D/L or R/S denotion has
nothing to do with it.

This compound is denoted This compound is denoted

(−)-tartaric acid because it's (+)-tartaric acid because it's
specific optical rotation is −12o specific optical rotation is +12o

COOH
COOH

H C OH
HO C H

HO C H
H C OH

COOH
COOH

On the other hand, it is denoted On the other hand, it is denoted

L-tartaric acid because the OH group D-tartaric acid because the OH group
on the carbon before terminal is on the left, on the carbon before terminal is on the right,
it has nothing to do with optical rotation it has nothing to do with optical rotation
 Optical Isomerism Contd.
D/L configuration
• Dand L method is used to describe the position of the
atoms/groups around the chiral carbon. It doesn’t tell
whether the compound is dextrorotatory or levorotatory.
• This method was proposed by Rosanoff in 1906.
• This method uses the two enantiomers of Glyceraldehyde as
reference molecules.

• Any compound which looks like or degrades to D-

glyceraldehyde would be denoted by D- and any compound
which looks like or degrades to L-glceraldehyde would be
denoted by L-.

Optical Isomerism Contd.

D/L naming method
• It can be applied to compounds which are similar
to glyceraldehyde or degrades to glyceraldehyde.
• This method is applied to:
– Carbohydrates
– Derivative of carbohydrates (e.g. some carboxylic acids,
aldehydes)
– Amino acids
• For this method, first Fischer projection of the
compound must be drawn.
• For carbohydrates and its derivatives, the
position of the OH group on the highest
numbered chiral carbon is looked at. If the OH
group is on the left it is termed L- and if it on
the right then it is termed D-.
 Optical Isomerism Contd.
1 CH OH 1 CH OH
1 CHO 1 CHO 2 2

2 2
2 2 HO C H H C OH
HO C H H C OH

3 3 3 3
H C OH HO C H H C OH HO C H

4 4 4 4
HO C H H C OH HO C H H C OH

5 5 5 5
HO C H H C OH HO C H H C OH

6 6 6 6
CH2OH CH2OH CH2OH CH2OH
L-glucose D-glucose L-sorbitol D-sorbitol

1 CH OH 1
2 CH2OH

2 2
CHO HO C H H C OH
CHO
3 3
H C OH HO C H
HO C H H C OH
4 4
HO C H H C OH

CH2OH CH2OH HO C
5
H H C
5
OH
L-glyceraldehyde D-glyceraldehyde 6 6
COOH COOH

L-glucoronic acid D-glucoronic acid

Optical Isomerism Contd.

CHO CHO
CH3 CH3
H C OH HO C H
HO C H H C OH
H C OH HO C H
COOH COOH
CH2OH CH2OH
L-lactic acid D-lactic acid
L-erythrose D-erythrose

CHO CHO

HO C H H C OH

HO C H H C OH

H C OH HO C H

HO C H H C OH

HO C H H C OH

CH2OH CH2OH
L-heptoglucose D-heptoglucose
 Optical Isomerism Contd.
R/S configuration
• D/L method of expressing chiral carbon
configuration works on only a few types of
compounds.
• To express the configuration of chiral carbons in
other compounds, we need another method.
• This other method is the R/S method. This method
is universal, meaning that this method works on
any compound.
• In R/S method, the configuration of each chiral
carbon of the compound is described.

Optical Isomerism Contd.

R/S naming method
• First, every chiral carbons in the molecule are
identified.
• Then the configuration in each chiral carbon is
determined.
• To determine the configuration, the groups attached
to the chiral carbons are assigned priority 1, 2, 3, and
4 according to Cahn-Ingold-Prelog (CIP) rules.
• The group with priority 4 (lowest priority) is sent to
the back. Then it is identified which direction is
followed if one goes from 1 → 2 → 3.
• If the direction is right (clockwise), the chiral carbon
is at R (R = rectus, meaning right) configuration.
• If the direction is left (anticlockwise), the chiral
carbon is at S (S = sinister, meaning left)
configuration.
 Optical Isomerism Contd.
• It is important to note however that Fischer projection
is not always reliable, and one should convert the
Fischer projection into wedge and dash projection.

Optical Isomerism Contd.

A Simple trick
• If the lowest priority group (priority 4 group) is bonded
by vertical bonds, then we can use the Fischer
projection to determine R/S configuration directly.
• If the lowest priority group is bonded by horizontal
group, then determine the R/S configuration directly.
The correct configuration is the opposite of the
configuration determined.
Lowest priority group is vertically bonded,
just figure out the configuration Lowest priority group is vertically bonded,
figure out the configuration. The opposite of
that configuration is the correct one
F Br

Br C I Cl C F

Cl I
S configuration From Fischer projection: S configuration
Actual: R configuration
 Optical Isomerism Contd.
• Find the configuration of following structures
Cl COOH CH2OH Br

HOOC C CH3 H C OH H3C C C CH3

H CH3 OH Cl
(2S)-2-Chloro-propionic acid (R)-Lactic acid (2R, 3S)-3-Bromo-3-chloro-2-methyl-butane-1,2-diol

CHO CHO

H C OH HO C H

HO C H H C OH

H C OH HO C H

H C OH HO C H

CH2OH CH2OH
(2R, 3S, 4R, 5R)-Pentahydroxyhexanal (2S, 3R, 4S, 5S)-Pentahydroxyhexanal

The stereoisomers of
aldohexoses
• Monosaccharides which contain six carbons and a aldehyde
group are called aldohexoses.
• Aldohexose contains 4 chiral carbons, so a total of 24=16
stereoisomers are there.
CHO CHO CHO CHO CHO CHO CHO CHO

H C OH HO C H H C OH HO C H H C OH HO C H H C OH HO C H

H C OH H C OH HO C H HO C H H C OH H C OH HO C H HO C H

H C OH H C OH H C OH H C OH HO C H HO C H HO C H HO C H

H C OH H C OH H C OH H C OH H C OH H C OH H C OH H C OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

D-allose D-altrose D-glucose D-mannose D-gulose D-iodose D-galactose D-talose
(+14o) (+33o) (+53o) (+14o) (-20o) (+15o) (+80o) (+21o)

CHO CHO CHO CHO CHO CHO CHO CHO

HO C H H C OH HO C H H C OH HO C H H C OH HO C H H C OH

HO C H HO C H H C OH H C OH HO C H HO C H H C OH H C OH

HO C H HO C H HO C H HO C H H C OH H C OH H C OH H C OH

HO C H HO C H HO C H HO C H HO C H HO C H HO C H HO C H

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

L-allose L-altrose L-mannose
L-glucose L-gulose
o L-iodose L-galactose L-talose
(-14 ) (-33o) (-53o) (-14o)
(+20o) (-15o) (-80o) (-21o)
 The stereoisomers of
aldohexoses Contd.
CHO CHO CHO CHO CHO CHO CHO CHO

H C OH HO C H HO C H H C OH H C OH HO C H HO C H H C OH

HO C H H C OH HO C H H C OH H C OH HO C H H C OH HO C H

H C OH HO C H H C OH HO C H H C OH HO C H H C OH HO C H

H C OH HO C H H C OH HO C H H C OH HO C H H C OH HO C H

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

D-glucose L-glucose D-mannose L-mannose D-allose L-allose D-altrose L-altrose
(+53o) (-53o) (+14o) (-14o) (+14o) (-14o) (+33o) (-33o)

CHO CHO CHO CHO CHO CHO CHO CHO

H C OH HO C H HO C H H C OH H C OH HO C H HO C H H C OH

H C OH HO C H H C OH HO C H HO C H H C OH HO C H H C OH

HO C H H C OH HO C H H C OH HO C H H C OH HO C H H C OH

H C OH HO C H H C OH HO C H H C OH HO C H H C OH HO C H

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

D-gulose L-gulose D-iodose L-iodose D-galactose L-galactose D-talose L-talose

(-20o) (+20o) (+15o) (-15o) (+80o) (-80o) (+21o) (-21o)

Epimers & Anomers

Epimers
• Epimers are diastereomers which differ in the configuration
of only one chiral carbon.
• The configuration of the remaining chiral carbons are the
same.
Anomeric carbon
• Anomeric carbon is the carbon which becomes chiral when
cyclization occurs.
• This term is applicable to carbohydrates. The
monosaccharide carbohydrates can exist in both open chain
form and in cyclic form. When they transform into the cyclic
form another carbon becomes chiral (the C1 carbon). This
carbon is the anomeric carbon.
Anomers
• Based on the configuration of the anomeric carbon, two
stereoisomers are obtained which are called anomers of each
other.
• Anomers are not enantiomers, they are epimers.
 Epimers & Anomers Contd.
1 1
1
CHO H C OH 1 HO C H
H C OH
H C OH H C OH H C OH
H C OH
HO C H HO C H HO C H
O O
HO C H O
H C OH H C OH H C OH
H C OH
H C OH H C H C
H C
CH2OH CH2OH CH2OH
CH2OH
D-glucose
Cyclization by hemiacetal formation, -D-glucose
-D-glucose
C1 is now a chiral carbon
The two anomers, Fischer projection
CH2OH CH2OH

O O OH

OH OH

OH OH OH

OH OH

-D-glucose -D-glucose

The two anomers, Haworth projection

Importance of studying
isomerism
Structural isomerism
• Structural isomers differ in many physical and
chemical properties. Hence knowing about them is
important.
• Many reactions yields two or more structural
isomers, but only one of them is desired.
• Among many structural isomers, only one may be
active drug. COOH COOH COOH

OCH3

OCH3
Aspirin meta isomer
(the main drug) OCH3
para isomer
 Importance of studying
isomerism Contd.
Geometric isomerism
• cis and trans isomers can vary in physical and
chemical properties.
• Sometimes one isomer is an active drug while other
is not. For example, cisplatin is active but not
transplatin.
• Again, one isomer may have one function and the
other may have another function. e.g. Retinal. 11-
cis retinal is normally present in eyes and when
light falls on the eye it is converted to all-trans
retinal and only then vision occurs.

Importance of studying
isomerism Contd.
Optical isomerism
• Biological systems see different optical isomers differently.
For example: (R)-carvone smells like spearmint leaves while
(S)-carvone smells like caraway seeds.
• Our body prefers certain optical isomers to other optical
isomers. For example, all 19 optically active amino acids in
our body are L-amino acids.
• Activity of many drugs is affected by optical isomerism. For
example, thalidomide. (R)-thalidomide is useful against
morning sickness but (S)-thalidomide causes birth defect.
O O H
O O H
H N
H N
N O
N O

O
O
(R)-Thalidomide (S)-Thalidomide
 Finished

Thank you

Introduction To Common Essential Drugs

 Introduction
• World Health Organization has prepared a list of drugs
which are essential to proper healthcare management
in a society.
• They update this list every 2 years.
• The Government of Bangladesh also has a Essential
Drug list. Very recently (December 19. 2016), the list
has been updated and now contains 285 drugs.
• These drugs are termed ‘essential’ because they are
required in a society to provide proper medical care to
all patients.
• If an essential drug is not available a society, patients’
treatment may be hampered resulting in morbidity and
mortality.
• In this chapter, we will discuss the chemistry of some
commonly known essential drugs having simple
structures.

Some Common Essential Drugs

• Some of commonly known drugs which are essential
to healthcare are listed here:
– Paracetamol
– Aspirin
– Metronidazole Besides these, there are also:
– Chloroquine - Halothane
– Isoniazid - Sevoflurane
– Glyceryl trinitrate - Valproic acid
- Hydralazine
- Sulfa drugs

• We will discuss these drugs one by one here.

 Paracetamol OH

Common name
• Paracetamol, Acetaminophen.
Chemical name
• N-acetyl-para-aminophenol.
• N-(4-hydroxyphenyl)acetamide. NHCOCH3
Medical use Paracetamol
• It is an analgesic, antipyretic drug. It is used for mild to moderate pain and
fever.
Chemical synthesis
• Paracetamol can be prepared by N-acetylation of para-aminophenol by
acetic anhydride. OH
OH O

H3C C

+ O
conc. H2SO4
[3-4 drops]
+ CH3COOH
Acetic acid
H3C C
CH3
HN
NH2 O

p-Aminophenol Acetic anhydride O

Paracetamol

Aspirin COOH
Common name
OCOCH3
• Aspirin
Chemical name
• Acetyl salicylic acid, 2-Acetoxy-benzoic acid
Medical uses Aspirin

• It is an non-steroidal anti-inflammatory drug. It has analgesic, antipyretic

and anti-inflammatory activity. It also has anti-platelet activity. Currently it
is used as an anti-platelet drug in the treatment/management of
myocardial infarction.
Chemical synthesis
• It can be prepared by acetylation of salicylic acid.
COOH COOH
CH3

OH O C O CH3 O
C
Heat
O +
+ conc. H2SO4 C
O H3C OH
O C

CH3
Salicylic acid Aspirin Acetic acid
Acetic anhydride
 Metronidazole N

Common name
• Metronidazole O2N N CH3

H2 C
Chemical name
CH2
• 2-(2-methyl-5-nitro-1H-imidazol-1-yl)-ethanol.
HO
Medical uses Metronidazole
• It is an antibiotic, antiprotozoal and antimalarial drug. It is mainly used to
treat or prevent anaerobic bacterial infection and protozoal infections of
the body. It is commonly used in Bangladesh to treat the infective
disorders of the GIT.
Chemical synthesis
• 2-methylimidazole can be synthesized by various methods, such as Debus-
Radziszewski method. Then following procedure can be followed:
Chloroethanol
H2 N
C OH
N N
Cl C
HNO3, H2SO4 H2 , reflux
O 2N N CH3
Or O
N CH3 O2N N CH3 H2C
H H , HCOOH/H2SO4
2-Methyl-1H- 2-Methyl-5-nitro-1H-imidazole Oxacyclopropane CH2
imidazole
HO
Metronidazole

CH3

Chloroquine HN
N

Common name
• Chloroquine
Cl N
Chemical name Chloroquine

• N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine.
Medical uses
• It is used to treat malaria infection as an antimalerial drug.
Chemical synthesis
• Chloroquine can be synthesized from 4,7-dichloroquinoline and N,N-
diethyl-pentane-1,4-diamine by nucleophilic substitution reaction. 4,7-
dichloroquinoline can be easily synthesized by Conrad-Limpach quinoline
synthesis.
CH3

N
Cl HN
CH3

N
180oC
+ H2N

Cl N Cl N
4,7-dichloroquinoline N,N-diethyl-pentane-1,4-diamine
Chloroquine
 Isoniazid O
C
H
N
NH2
Common name
• Isoniazid
Chemical name
N
• Isonicotinylhydrazide (INH) Isoniazid

• Pyridine-4-carbohydrazide
Medical uses
• It is an anti-tubercular drug. It is used in combination with other anti-
tubercular drugs for this purpose.
Chemical synthesis
• There are various pathways of synthesizing isoniazid. When 4-
cyanopyridine is hydrolyzed in basic condition, first an amide is formed,
when it is refluxed with hydrazine, isoniazid is obtained.
N
H
O NH2 O OH O N
C C C C NH2

Hydrazine
H2O H2O H2N NH2
NaOH NaOH o
95 C, reflux
N N NH3 N N
4-cyanopyridine Isonicotinamide Isonicotinic acid Isoniazid

Glyceryl Trinitrate
Common name
H2C O NO2
• Nitroglycerin, glyceryl trinitrate
Chemical name HC O NO2
• Propane-1,2,3-triyl trinitrate
• 1,2,3-Tris(nitrooxy)propane H2C O NO2
Medical uses Glyceryl trinitrate
• It is a vasodilator (venodilator). It is used to immediately dilate blood
vessels in angina pectoris, myocardial infarction etcetera.
Chemical synthesis
• It can be synthesized by esterification (or nitration) of glycerol with nitric
acid in presence of sulfuric acid.
• It is highly explosive, so synthesis must only be carried out in controlled
environment.
CH2OH H2C O NO2

CHOH HNO3/H2SO4
HC O NO2 + 3 H2O

CH2OH H2C O NO2

Glycerol Glyceryl trinitrate
 Sulfa Drugs
Definition
• The term ‘sulfa drug’ usually refers to antibacterial drugs
containing the sulfonamide functional group; but it can also
certain anti-diabetic drugs (sulfonylurea), certain diuretics, and
other drugs.
Common examples
• Sulfanilamide (antibacterial)
– 4-aminobenzenesulfonamide
• Sulfadiazine (antibacterial)
– 4-amino-N-pyrimidin- 2-yl-benzenesulfonamide
• Chlorpropamide (anti-diabetic)
– 4-chloro-N-(propylcarbamoyl)benzenesulfonamide
• Hydrochlorothiazide (diuretic)
– 6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-
sulfonamide

Sulfa Drugs
Medical uses
• Different sulfa drugs have different medical uses.
• Some of these drugs have antibacterial properties and used to treat infections (e.g.
sulfamethoxazole, sulfadiazine).
• Chlorpropamide, tolbutamide, gliclazide etcetera enhances secretion of insulin from
pancreas, and used as antidiabetic drugs.
• Furosemide and thiazide diuretics are also sulfa drugs used in cardiovascular diseases.
• Beyond these, there are sulfa drugs which are anti-consvulsants, antiviral, NSAID among
others.
Chemical synthesis of sulfanilamide
• Sulfanilamide can be synthesized from benzene in six steps.
O O O

C C C
NO2 NH2 HN CH3 HN CH3 HN CH3 NH2

HNO3/H2SO4 Sn/HCl (CH3CO)2O HClSO3 NH3 HCl

50oC CH3COOH, Zn

Benzene Nitrobenzene Aniline Acetanilide

O S O O S O O S O

Cl NH2 NH2
4-Acetylamino- N-(4-Sulfamoyl- Sulfanilamide
benzenesulfonyl phenyl)-acetamide
chloride
 Halothane Br
Common name
F3C CH
• Halothane.
Cl
Chemical name
Halothane
• 2-Bromo-2-chloro-1,1,1-trifluoroethane.
Medical uses
• Halogen is used as a general anesthetic to induce or maintain
whole-body anesthesia.
Chemical synthesis
• Halothane is a ethane derivative. But it is synthesized using
trichloroethylene as the starting material.

HF/SbCl3 H2 Br2, 450oC H

Cl2C C Cl F3C C Cl F3C C Cl
H 130oC

Trichloroethylene Br
Halothane

Sevoflurane F3C
Common name
CH O CH2F
• Sevoflurane.
Chemical name F3C
Sevoflurane
• 1,1,1,3,3,3-Hexafluoro-2-(fluoromethoxy)propane
• fluoromethyl hexafluoroisopropyl ether
Medical uses
• Sevoflurane is a modern inhalation-type general anesthetic used to induce
and maintain whole-body anesthesia in patients.
• It is now replacing halothane as it is safer.
Chemical synthesis
• There are mainly three methods of preparing sevoflurane, all of them
involve 1,1,1,3,3,3-hexafluoroisopyl alcohol.
• Here, the three-step method is described.

F3C F3C F3C F3C

(CH3O)2SO2 Cl2 H2 KF H2
CH OH CH O CH3 CH O C Cl CH O C F

F3C F3C F3C F3C

 Valproic Acid
Common name C3H7 COOH
• Valproic acid.
Chemical name
• 2-propylpentanoic acid C3H7
• 2-propylvaleric acid Valproic acid
Medical uses
• It is a commonly used drug to control epilepsy.
Chemical synthesis
• It is synthesized from cyanoacetic ester.
O
O

C CN C2H5ONa CN
+ 2 C3H7 Br C CN COOH
C2H5 C NaOH NaOH
CH CH
H2 Propyl bromide C2H5 C
C3H7 C3H7 C3H7 C3H7
3-Oxo-pentanenitrile C3H7 C3H7

Valproic acid

Finished

Thank you