Revolutionising B.

Tech
 Module 4
Stereochemistry, Organic Reactions and
the Synthesis of Drug Molecules
Table of Content

• Aim
• Introduction
• Objective
• Sections/Topics
• Summary
• Terminal Questions
• Reference Links*
• Thank You
Aim

To equip students in the fundamentals and understanding the importance of

fundamental aspects of organic chemistry
To understand the concepts of drugs and stereochemistry
 a. Classification of stereoisomers

b. Recognize a stereogenic (chiral) center in a molecular structure

c. Various representation of three dimentional molecules

d. To be able to predict, identify and distinguish between enantiomers

and diastereomers.
Objectiv
e
Syllabus
Introduction to reactions involving substitution, addition,
elimination, oxidation, reduction, cyclization and ring
openings. Synthesis of commonly used drug molecules
(Aspirin, Paracetamol, Phenacetin).

Structural isomers and stereoisomers, configurations and

symmetry and chirality, enantiomers, diastereomers, optical
activity, absolute configurations, conformational analysis of
alkanes and cycloalkanes.
Organic
reactions
Organic reactions are chemical reactions involving organic
molecules. Organic reactions can be classified into many
categories, some of which are:

● Substitution reactions
● Addition reactions
● Elimination reactions
● Oxidation and reduction reactions
● Cyclization and ring opening reactions
Substitution
reactions
A substitution reaction is the one in which an atom or a
functional group in a molecule is replaced by another atom or
functional group.

Chlorination of
methane
Substitution reactions can be further classified as:

● Nucleophilic substitution reactions

● Electrophilic substitution reactions
Nucleophilic substitution
reactions
A substitution reaction in which the attacking reagent is a
nucleophile (an electron-rich group) is called a nucleophilic
substitution reactions. In these reactions, a stronger
nucleophile replaces a weaker nucleophile.
In alkyl halides (R-X), the greater electronegativity of halogen (X) makes
the carbon-halogen bond polar. This causes a partial positive charge on
the carbon atom and facilitates the attack by a strong nucleophile. The
attacking nucleophile will eventually replace the halide atom.
Types of nucleophilic substitution
reactions
Based on the kinetics and the reaction mechanism, nucleophilic
substitution reactions are classified as:
●Unimolecular nucleophilic substitution reactions (SN1
reactions).
●Bimolecular nucleophilic substitution reactions (SN2
reactions).
Bimolecular nucleophilic substitution
reactions
(S N2 reactions)
A nucleophilic substitution reaction which is kinetically second
order is known as bimolecular nucleophilic substitution reaction or
SN2 reaction.
Kinetics of SN2 reactions
Two molecules (the nucleophile and the substrate) are involved in the
rate determining step of the reaction and so the rate of a SN2 reaction
depends on the concentration of both the substrate and the nucleophile.
The rate can be given by
rate = k[substrate][nucleophile]
where k is the rate constant of the reaction.
Example: The reaction between methyl bromide and hydroxide ion to
yield methanol.
Mechanism of SN2 reactions
The mechanism of SN2 reactions occurs in a single step
(concerted mechanism) without the formation of an
intermediate.

1. The nucleophile, OH– attacks the carbon from the sterically favourable
rear side, ie. the side opposite to the leaving group.
2. The reaction proceeds through a transition state in which carbon is
partially bonded to both OH and Br. The three hydrogens and the carbon
atom lie in the same plane with bond angles 120°. The OH and Br lie as
far apart as possible on either side of this plane and perpendicular to it.
3. The bond between C and Br is completely broken and that between
C and OH is formed to yield the product with tetrahedral carbon.
Unimolecular nucleophilic
substitution reactions (SN1 reactions)
A nucleophilic substitution reaction which is kinetically of the first order
is known as a unimolecular nucleophilic substitution reaction or SN1
reaction.

The rate of an SN1 reaction depends on the substrate concentration and

is independent of the nucleophilic concentration.
Mechanism of SN1 reactions
The SN1 mechanism involves two steps. Consider the following reaction.

1. The leaving group (Br–) breaks 2. The carbocation reacts with the
away by the nucleophile to yield the product.
heterolytic fission of the carbon-
bromine bond producing a carbocation
(tert-butyl cation). This step is the slow
and rate-determining step.
Kinetics of SN1 reactions
The kinetics of SN1 reactions can be explained on the basis of the
mechanism of the reaction.

The kinetics of SN1 reactions can be explained on the basis of the

mechanism of the reaction.
● The first step in the mechanism, the heterolytic cleavage of C-Br
bond is a slow process, while the second step, the attack of the
nucleophile is a fast process.
● In the mechanism of a reaction, the slow step is always the rate
determining step.
● In this case, the first, slow step is the rate determining step and the
rate of reaction depends only on the concentration of the alkyl halide
(the substrate).
Addition
reactions
Addition reactions are the reactions in which two reactants react
together to form a larger molecule (the adduct) with no atoms left
over.

A general addition
reaction

● Addition reactions mostly occur in molecules containing multiple

bonds, such as alkenes, alkynes or molecules with carbon–hetero
atom double bonds, such as carbonyl group (C=O), imine group
(C=N).
Electrophilic addition
reactions
An electrophilic addition reaction takes place
via two steps:

1. The first step is addition of electrophile by

formation of σ bond through donation of π
electrons to the electrophile and
carbocation is formed.

2. The next step is reaction of the positively

charged intermediate (carbocation) with a
species carrying lone pair or negative charge
i.e nucleophiles.
Example of electrophilic addition reaction
Step 1

Step 2
Nucleophilic addition reactions
Nucleophilic addition reaction is an addition reaction where a
chemical compound with an electron-deficient or electrophilic
double or triple bond, a π bond, reacts with electron-rich
reactant, termed a nucleophile, with disappearance of the
double bond and creation of two new single, or σ, bonds.

● Nucleophilic reactions occur in compounds containing polar

functional groups (C=O, C≡N, C=S).
1. In the first step a
nucleophile with its pair
of electrons attacks the
carbon atom of a double
or triple bond, forming a
carbanion.
2. In the second step the
carbanion reacts with a
Example of nucleophilic addition reaction
Addition of HCN to carbonyl group: In this reaction cyanide ion
(CN- ) acts as a nucleophile which attacks the carbon of
carbonyl group, the carbon-oxygen double bond breaks
followed by capture of proton and a cyanohydrins is formed.
Elimination reactions
Elimination reactions involve the loss of elements from the
starting material to form a new π bond in the product.
Alkyl halides (RX) undergo elimination with bronsted bases. The
elements of HX are
lost and alkene are formed.

Classification of elimination reactions

● α-elimination (1,1 elimination)
● β- elimination (1,2 elimination)
● γ- elimination (1,3 elimination)
α-elimination (or 1,1- elimination)
The two groups are eliminated from same carbon, for example
formation of carbene or nitrene.

Example:
β-elimination (or 1,2- elimination)
This is the most common elimination reaction in which the two
groups are eliminated from adjacent carbons.

Example:
Oxidation and reduction reactions
In reference to organic molecules, oxidation is a process by
which a carbon atom gains bonds to more electronegative
elements, most commonly oxygen. Reduction is a process by
which a carbon atom gains bonds to less electronegative
elements, most commonly hydrogen.

Two examples of oxidation-reduction

reactions
Examples of oxidation reactions
Aromatisation
Conversion of cyclohexane to benzene in the presence of a catalyst is a
type of oxidation reaction which proceeds via loss of hydrogen. The most
frequently used catalysts to affect aromatization are hydrogenation
catalysts such as Pt, Pd, Ni etc.
Conversion of alcohol to carbonyl

Primary alcohols are converted to aldehydes and secondary

alcohols are converted to ketones in presence of agents like
CrO3, pyridinium chlorochromate (PCC), pyridinium dichromate
(PDC), DMSO/oxalyl chloride etc.

Cleavage of carbon- carbon bonds

(Ozonolysis)
Fission of carbon-carbon double bond via formation of an intermediate
ozonide.
Examples of reduction reactions
Conversion of carbonyl to alcohol
When aldehydes or ketones are converted to alcohol the hydrogen
content is increased thus it is a reduction reaction.

Meerwein–Ponndorf–Verley reduction
It occurs in the presence of isopropyl alcohol and aluminum
isopropoxide.
Clemmensen Reduction
In the Clemmensen reduction a carbonyl compound is reduced to
alkane using amalgamated zinc and hydrochloric acid reagent.

Conversion of carboxylic ester to alcohol

Lithium hydride often brings out reduction of carboxylic ester by hydride
transfer via formation of aldehyde in first step and further hydride transfer
to the aldehyde leads to formation of alcohol.

Conversion of nitro group to amine group

Conversion of nitro group to amine which involves loss of oxygen and gain
of hydrogen.
Cyclization
reactions
Epoxide formation: Alkenes are capable of reacting with oxygen in
the presence of elemental silver to form a series of cyclic ethers
called epoxides.

Epoxyethane belongs to heterocyclic compounds. These compounds are

cyclic structures in which one (or more) of the ring atoms is a hetero
atom.
Ring opening reactions
The ring opening reactions takes place by a nucleophiles attack
on the electrophilic C of the C-O bond causing it to break. Ring
opening results reduce the ring strain of epoxides and ends up
with the 2-substituted alcohols as products.

Examples of such nucleophilic systems:

Stronger nucleophiles (anionic e.g.alkoxides, Grignard reagents etc.)
RMgX, RLi, LiAlH4, NaBH4
Weaker nucleophiles (neutral e.g. water) can be made to react with
epoxides in the presence of acid catalysts.
Epoxide ring opening
reactions
In these reactions, an epoxide reacts with a nucleophile to give
an open chain structure.
● An
● An ether epoxide

An epoxide is a cyclic ether with a three

atom ring.

Epoxides are much more reactive than normal ethers due to the higher
amount of ring strain.
Ring opening in presence of a strong
nucleophile

● Examples of strong nuclueophilic systems include RMgX, RLi (R is the

nucleophile in both cases), LiAlH4 and NaBH4 (H– acting as
nucleophile)
● Example for this type of reaction
Ring opening in presence of a weak
nucleophile

Examples of weak nucleophiles are H2O, ROH and R-NH2. An example of

such a reaction is given below.
Synthesis of some drug
molecules
Aspirin
● Effective analgesic (pain reliever), antipyretic (fever reducer)
and anti-inflammatory agent.
● It is irritating to the lining of the mouth, esophagus, and
stomach, and can cause hemorrhaging of the stomach lining.
Synthesis of aspirin
Paracetamol
● It is commonly used for the relief of headaches and pains,
and is a major ingredient in numerous cold and flu remedies.
● It’s chemical name is N-acetyl-para-aminophenol.

Synthesis of
paracetamol
Phenacetin
●It was introduced in 1887 in Elberfeld by German company
Bayer
●It was used principally as an analgesic; it was one of the first
synthetic fever reducers in the market.
●It is also known historically to be one of the first non-opioid
analgesics without anti-inflammatory properties.
Synthesis of
Phenacetin
Isomerism
Isomers are molecules with identical molecular formulae – that
is, same number of atoms of each element – but distinct
arrangements of atoms. This phenomenon is known as
isomerism.

Isomerism can be broadly classified as:

1. Structural isomerism
2. Stereoisomerism
Structural
isomerism
Structural isomerism (constitutional isomerism) is a
phenomenon in which molecules exist with the same
molecular formula but different arrangements of atoms
(different bonding-linkage) within the molecule.

Structural isomerism can be classified into:

1. Chain isomerism
2. Position isomerism
3. Functional group isomerism
4. Metamerism
5. Tautomerism
6. Ring chain isomerism
Chain isomerism
Chain isomerism or nuclear isomerism arises from the
different arrangement of carbon atoms in a carbon chain.

Example:
Isomer-1. CH3-CH2-CH2-CH3 (n-Butane),
Isomer-2... CH3-CH-CH3 (Isobutane).
CH3

Position isomerism
Position isomerism arises from the different position of atoms or groups
in a carbon chain, which remains intact in isomers.

Example:
Functional group isomerism
In functional group isomerism, the isomers have different
functional groups and thus belong to different homologous
series.

Example:

Metamerism
Metamerism is a case of isomerism in which the isomers are formed
when two valencies of a
hetero atom (-O-, -S-, -NH-, etc) are satisfied by different alkyl groups.
The isomers are called
metamers.

Example:
Tautomerism
It is a case of functional isomerism where isomers are co-
existing in equilibrium. It is also known as dynamic isomerism.

Examples:

Ring chain isomerism

Ring chain isomerism arises from the difference in modes of linkages of
carbon atoms to get
straight chain and cyclic isomers.

Example:
Stereoisomeris
mStereochemistry is the branch of chemistry which deals with
spatial arrangement of atoms and groups in molecules.

Isomers having the same structure, but different spatial

arrangement of atoms and groups are called stereoisomers and
this phenomenon is called stereoisomerism.
Stereoisomerism is broadly divided into;
● Configurational isomerism
● Conformational isomerism
Configurational isomerism – refers to the spatial
arrangement of atoms and groups that characterises a
particular stereoisomer.
Configurational isomerism is divided into;
● Optical isomerism
● Geometrical isomerism
Conformational isomerism – Arises due to the free rotation
Optical isomerism
Optical isomerism is the type of stereoisomerism arising from
the chirality of molecules. In optical isomerism the isomers
resemble in most of their properties but differ in their behavior
towards plane polarised light.
Chirality
A molecule non-superimposable on its mirror image is called a chiral
molecule or a dissymetric
molecule. This property is called chirality.

Example of a chiral
molecule
Optical isomerism (continued)

● Chirality is a necessary condition for optical isomerism. In

most organic compounds chirality is caused by the
presence of one or more chiral carbons.
Chiral carbon
A chiral carbon or an assymetric carbon is the one whose four valencies
are satisfied by four
different atoms or groups.

The chiral carbon is

marked by an asterix in
the three compounds.
Optical activity
The property by which certain substances rotate the plane of
polarization of plane polarised light is known as optical activity
and such substances are said to be optically active.

Substances which rotate the plane of plane polarized light to the right are
called dextrorotatory
and those which rotate to the left are called laevorotatory.
Specific rotation
Optical activity of a substance is measured using a polarimeter and is
reported in terms of specific rotation.

Specific rotation depends on;

● The nature of optically active substance
● Temperature
● Wavelength of the light used
● The number of optically active molecules the light encounters in its
path (concentration of sample and the length of polarimeter tube).
Specific rotation (continued)
Specific rotation of an optically active compound at a specific
temperature and for a specific wavelength of light is defined as
the observed rotation in degrees when the plane polarised light is
passed through one decimeter (10 cm) of the solution of the
substance having a concentration of one gram/litre.

[ɑ]T 𝝀 - rotation observed in degrees

l - length of the path through which light passes through the solution in
decimeter
c - concentration (g/ml)
T - Temperature in Kelvin
λ - rotation observed in degrees
Fischer projection
● Fischer projections are used to represent three-dimensional
structures containing at least one chiral carbon on a two-
dimensional surface.

● The chiral carbon is assumed

to be located at the point
where the two lines cross.
● Horizontal lines represent the
bonds that are directed out of
the plane.
● Vertical lines represent the
bonds that are directed into
the plane.

More than one cross will be there for molecules

containing more than one chiral carbon.
Enantiomers
The stereoisomers which are related to each other as object to
its non-superimposable mirror image and rotate the plane of
plane polarised light to equal extents, but in opposite directions
are called enantiomers or enantiomorphs. The phenomenon is
known as enantiomerism

● The enantiomer which rotates

the plane of plane polarised
light to the right –
dextrorotatory (dextro, d, +).
● The enantiomer which rotates
the plane of plane polarised
light to the left – laevorotatory
(laevo, l, -).
Properties of enantiomers
● Identical physical properties.
● Identical chemical properties.
● Different optical activity. (rotates the plane of plane polarised
light in opposite directions)
● Different biological properties.
● They differ in their crystal shapes and rates of reaction towards
other chiral compounds.
Diastereoisome
rism
The stereoisomers which are not mirror images of each other
are called diastereoisomers or diastereomers. The
phenomenon is known as diastereoisomerism.

Pairs of diastereomers – I & III;

I & IV;
II & III;
II & IV
Properties of diastereomers
● Different physical properties.
● Different chemical properties.
● Different optical activities
● They may or may not be optically active.
Absolute
configurations
The precise arrangement of substituents at a stereogenic center
is known as the absolute configuration of the molecule.

● The most common labeling method uses the descriptors R or

S is based on the Cahn–Ingold–Prelog priority rules.
● R and S refer to Rectus and Sinister, which are Latin for
right and left, respectively.
Assigning R and S
configuration
Before looking at the Cahn-Ingold-Prelog rules, let’s look at the
set of rules about how we can rotate or move Fischer
projections without changing the stereochemical configuration
of the molecule.

Rule 1: A Fischer projection can be rotated by 180° and retain

its stereochemical configuration.

Rule 2: Doing a 90° rotation on a Fischer projection would

change the configuration of molecule and so is considered as a
forbidden rotation.
Assigning R and S configuration
(continuation)
Rule 3: Any three substituents on a Fischer projection can be rotated,
while holding
the fourth substituent constant and retain the configuration of the
structure.

Rule 4: Two pairs of substituents can be interchanged within themselves

and retain
the configuration. In the example given below, the substituents X & Y are
inter-
changed and the substituents W & Z are also interchanged.
For the purpose of assigning the R or S configuration to a chiral
carbon using its
Fischer projection, the substituent with the lowest priority (the
one with lowest atomic number) should be brought to the vertical
downward position with the help of the rules mentioned above.
Cahn-Ingold-
Prelog rules
1. Priority is based on the atomic number. Higher the atomic
number, higher the priority.
2. For isotopes (same atomic number), higher the atomic mass,
higher the priority.
3. If priority cannot be assigned based on the first atom of a
group, then look at the next sets of atoms, until a priority can
be assigned.
4. Multiple bonds are treated as separate single bonds.
Cahn-Ingold-Prelog rules
(continued)
Based on the above rules, if we assign the priorities in the below
example, we can
see that Br has the highest priority, Cl has the next highest priority, CH3
has the next
highest and H has the lowest priority.

Go from the substituent with priority 1 through the substituent with

priority 2 to the substituent with priority 3.

Clockwise – R configuration
Anticlockwise – S configuration
R & S configuration in wedge and dash
structures
(2)

(1)
(3)

(2)

The molecule should be rotated in such

a manner that, the atom/group having
(1) (3) the lowest priority is directed away
from us.
Conformational Isomerism
The isomers which are interconvertible merely by rotation about
a single bond are called conformational isomers or conformers or
rotamers. The phenomenon is called conformational isomerism
or rotational isomerism.
Conformations of ethane
In ethane molecule, the free rotation about the C-C σ-bond gives rise to
an infinite number of
conformations. Of these, the two extreme cases are;
1. Staggered conformation
2. Eclipsed conformation
Representation of conformations of
ethane
Sawhorse projection Newman
projection

Relative stabilities of ethane conformations

The staggered conformation of ethane is more stable than the eclipsed
conformation.

Reason – In eclipsed conformation of ethane, the hydrogen atoms on the

two carbons are
close to each other, while in staggered conformation they are as far as
possible. Consequently,
Cyclohexane
● The chemical formula of cyclohexane is C6H12.
● The planar structure of cyclohexane (in which all the six carbon
atoms lie in the same plane) will be highly unstable due to the angle
strain and the torsional strain.

● Two structures of cyclohexane which are more stable than the planar
form are the chair form and the boat form. In both these forms the
internal bond angles are 109.5°.
The chair form

Some features of the chair conformation of cyclohexane.

● Three carbon atoms are puckered up and the other three carbon
atoms are puckered down, alternatively.
● There are two different types of hydrogens, axial hydrogens and
equatorial hydrogens.
Factors that contribute towards the stability of chair
form of cyclohexane.
● The interatomic angles are all 109.5°.
● The hydrogen atoms on adjacent carbon atoms
are staggered to each other.
Flipping of the chair form

During the flipping of a chair conformer, the carbon atoms which are
puckered up get puckered down and vice versa. Similarly the axial
hydrogen atoms get converted to equatorial hydrogen atoms and vice
versa.
The boat form

The boat conformation is less stable than the chair conformation

(unstable by 7 kcal/mol). The reasons for the instability are:
● The steric strain caused by the ‘flagpole interactions’ between the
hydrogen atoms on C1 and C4 .
● Two pairs of hydrogen atoms (on C2 & C3 and on C5 & C6 ) are
eclipsed to each other.
Assessments

Question 1:
Which of the following is an example of oxidation reaction?

• Conversion of alcohol to carbonyl

• Meerwein–Ponndorf–Verley reduction
• Clemensen reduction
• Conversion of carboxylic ester to alcohol
Did You Know?
Summary

Outcomes:

a. Comprehend the fundamental concepts of organic reactions

b. Identify the importance of the drugs
 Terminal Questions

1. What are nucleophilic substitution reactions? Explain the mechanism of the two
types of nucleophilic substitution reactions with the help of examples.
2. What is meant by structural isomerism? Explain the different types structural
isomerism with the help of examples.
References
1) Jain & Jain (2018), Engineering Chemistry, Dhanpath Rai Publishing Company.
2) Yu A., Chabot V. and Zhang, J. (2017), Electrochemical Supercapacitors for Energy Storage and Delivery, CRC
Press.
3) Owens F. J. & Poole C. P., (2003), Introduction to Nanotechnology, Wiley-IEEE.
4) Agarwal S., (2015), Engineering Chemistry (Fundamentals and applications), Cambridge publications.
5) Sellmeyer, D. & Skomski, R. (2003) Advanced Magnetic Nanostructures, Springer.
6) Abdurakhmonov, I. Y. (2016). Bioinformatics: basics, development, and future. Rijeka: InTech.
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