Department of Pharmacy

Assignment on Reaction
Mechanism
Course title: Organic
Pharmacy
Course code: Pharm-1103
Submitted to:
Mohammad Shoriful Islam
Course teacher, Organic Pharmacy
Department of Pharmacy
Islamic University, Kushtia
Submitted by:
Md. Abul Bashar
Roll no: 1930006
Session: 2019-2020
Homolytic and Heterolytic fission:
Every reaction of organic compounds involves the breaking(fission) of at least one bond
and the making of another bond. To break a bond, in fact, we are breaking down a
molecular orbital to give atomic orbitals. We know that molecular orbitals are at a lower
energy(more stable) than atomic orbitals. therefore, energy has to be supplied to break a
bond. Assuming that sufficient energy is available, a covalent bond(sigma bond) can
undergo fission in two ways:

(1) By Homolytic fission or Homolysis,

(2) By Heterolytic fission OR Heterolysis

Homolytic Fission:
In this process each of the atoms acquires one of the bonding electrons.
. .
A B or A:B A + B
. .
The products, A and B are called Free Radicals.

Heterolytic Fission:
In this process one of the atoms acquires both of the bonding electrons when the bond is
broken.

+ -
A B A + B (1)
A B A
- + B (2)
+

In example(1), B is more electronegative than A which thereby acquires both the bonding
electrons and becomes negatively charged. The arrow indicates that the sigma electrons
that form the A-B bond are leaving A and becoming the exclusive property of B. In
example(2), A is shown to be more electronegative than B.

Reaction intermediates:
Carbonium Ions(Carbocations): Organic ions which contain a positively charged
carbon atom are called carbonium ions. They are formed by heterolytic fission.
 C:Z C+ + :Z -

Carbonium Ion

Where Z is more electronegative than carbon.

Carbanions: Organic ions which contain a negatively Charged carbon atom are called
carbanions. They are formed by heterolytic bond fission.

C:Z C:- + Z+

Carbanion

Free Radicals: In contrast to carbonium ions and carbanions, these have no charge.
They are formed by homolytic bond fission.

C:Z C. + .
Z

Carbon free radical

Here Z and carbon atom have similar electronegativities.

Electrophiles: A reagent which can accept an electron pair in a reaction is called

an electrophile. Example:
H+, Cl+, Br+, I+, NO2+, R3C+, +SO3H, AlCl3, BF3
An electrophile can be represented by the general symbol E +.

Nucleophiles: A reagent which can donate an electron pair in a reaction is called

a nucleophile. Example:
 Cl-, Br-, I-,CN-, OH-, RCH-2, NH3, RNH2, H2O, ROH
A nucleophile can be represented by a general symbol Nu: - .

Types of Organic Reactions

The reactions of organic compounds can be classified into four main
types:
1. Substitution Reactions
2. Addition Reactions
3. Elimination Reactions
4. Rearrangement Reactions

Mechanism of Substitution reactions:

Reaction which involve the replacement or substitution of one or more atoms or groups of
a compound by other atoms or groups are known as substitution reactions. These
reactions may be initiated by a nucleophile, electrophile, or free radical.

Free-Radical Substitution Reactions: These reactions are initiated by free

radical. The chlorination of methane in the presence of ultraviolet light is an example of
free radical substitutions.
UV
CH4 + Cl2 CH3Cl + HCl
Methane light Methyl chloride

This mechanism of the above reaction involves the following steps:

(1) Initiation steps. A chlorine molecule undergoes homolytic fission in the presence of
ultraviolet light to give chlorine free radicals.

Cl Cl
UV
Cl + Cl
. .
light
(2) Propagation steps. A chlorine atom attacks the methane molecule to give methyl
free radicals and hydrogen chloride.
. .
 Cl + CH4 CH3 + HCl
The methyl free radical attacks a chlorine molecule to yield methyl chloride and chlorine
atom.

CH3 + Cl
.
Cl CH3 Cl + Cl
.

(3) Termination steps. These involve the formation of stable molecules by combination
of free radicals.

Cl + Cl . . Cl Cl
. .
CH3 + Cl CH3 Cl
CH3 + CH3
. . CH CH3
3

Electrophilic Substitution Reactions: When a substitution raction

involves the attack by an electrophile, the reaction is referred to as electrophilic
substitution. The bromination of benzene in the presence of FeBr 3 is an example of
electrophilic substitution.

+ Br2

Bromobenzene
Benzene

The mechanism of the above reaction involves the following steps:

Step 1. Formation of electrophile.

Br Br + FeBr3 Br+ + FeBr4-

Step 2. The electrophile (Br+) attacks the benzene ring to from resonance stabilized
carbonium ion.

+
H H
+
+ Br Br
Br
+

H
H
Br
+ +
Br
Step 3. Elimination of proton toResonance hybrid
give the substitution product.

H
 B
+ Br r
FeB
+HBr +
r3
Bromobenzene

Nucleophilic Substitution Reactions: When a substitution reaction

involves the attack by a nucleophile, the reaction is referred to as S N (S stands for
substitution and N for a nucleophile). The hydrolysis of alkyl halides by aqueous NaOH is
an example of nucleophilic substitution.

R X + -OH R OH + X-
Nucleophile Leaving group
The nucleophilic substitution reactions are divided into two classes:
(1) SN2 Reactions
(2) SN1 Reactions

SN2 Reactions. S 2 stands for bimolecular nucleophilic substitution. When the rate
N

of a nucleophilic substitution reaction depends on the concentration of both the substrate

and the nucleophile, the reaction is of second order and is represented as S N2.
Rate Substrate Nucleophile
Evidently, the rate-determining step involves the participation of both the substrate and
the nucleophile.

H H H H
-
HO : C Br
HO C Br HO C + : -Br
H
H H H H
Methyl bromide Transition slate Methyl alcohol

Fig : Nucleophilic substitution by SN2 mechanism.

SN1 Reactions. S 1 stands for unimolecular nucleophilic substitution. When the

N

rate of a nucleophilic substitution reaction depends only on the concentration of the alkyl
halide, the reaction is of first order and is represented as S N1.

Rate Substrate
Consider the hydrolysis of t-butyl bromide. The reaction consist of two steps :
Step 1. The alkyl halide ionizes to give the carbonium ion. This is rate determining step.

CH3 CH3 CH3

C Br C+ + :-Br
CH3 CH3
CH3

The carbonium ion is polar. This is because the central positively charged carbon atom is
sp3 hybridized.
STEP 2. The nucleophile can attack the planar carbonium ion from either slide to give t-
butyl alcohol.
CH3 CH3 CH3

C+ C OH

CH3 CH3
CH3
O- tert- butyl
H
alcohol

Remember that the primary alkyl halides undergo hydrolysis by S N2 mechanism.

The tertiary alkyl halides undergo hydrolysis by S N1 mechanism. This is because the
attack of the hydroxide ion on the crowded tertiary alkyl halides is quite difficult.
Secondary alkyl halides may undergo hydrolysis by either S N1 or SN2 mechanism.

MECHANISM OF ELIMINATION REACTIONS

Elimination reactions are reverse of addition reactions. Here two or four
atoms or groups attached to the adjacent carbon atoms in the substrate molecule
are eliminated to form a multiple bond. The dehydrohalogenation of alkyl halides
with alcoholic alkalis is an example of elimination.

R CH2 CH2 X R CH CH2 +H2O + -X

These reactions like substitution reactions are also divided into two classes:
(1) E2 Reactions
(2) E1 Reactions
E2 Reactions. E2 stands for bimolecular elimination. When the rate of an
elimination reaction depends upon the concentrations of a substrate and the
nucleophile, the reaction is of second order and is represented as E2.
H

HO-R: + CH CH2 X R CH=CH2 +H2O+X-:

bita alpha

Fig : Elimination by E2 mechanism.

E1 Reactions. E1 stands for unimolecular elimination. When the rate of an

elimination reaction depends only on the concentrations of the substrate, The
reaction is of first order and is designated as E1. E1 like S N1 reactions are also two
step procedures.

Step 1. The alkyl halide ionizes to give the carbonium ion.

CH3 CH3 CH3
C Br C+ + :-Br
CH3
CH3
CH3
tert-butyl alcohol
Carbonium ion

Step 2. A proton is abstracted by the base form the adjacent bita-Carbon atom
to give the alkene.

HO-

CHCH
2 H CH3 CH2

C+ 2 C + H2O

CH2 CH3
Carbonium ion 2-
Methylpropen
e

MECHANISM OF ADDITION REACTIONS

Addition reactions are those in which atoms or groups of atoms are simply added
to a double or triple bond without the elimination of any atoms or other
molecules. These reactions may be initiated by electrophiles, nucleophiles, or free
radicals.
Electrophilic Addition Reaction:
When an addition reaction involves the initial attack by an electrophile, the
reaction referred to as electrophilic addition. Compounds containing carbon
double and triple bonds undergo reaction.
H Br
CH2=CH2 + HBr CH2-CH2

The mechanism of the above reaction involves the following steps:

Step 1. Hydrogen bromide gives a proton (H+) and bromide ion (Br:-),
H-Br H+ + Br-
Electrophile Nucleophile
Step 2. The proton (Electrophile) attacks the bond of ethylene to give a carbonium
ion.

H+ + CH2=CH2 CH3 +
CH2
Carbonium
ion
Step 3. The bromide ion (nucleophile) attacks the carbonium ion to give the
addition product.
+
CH3 CH2 + Br-: CH3 CH2 Br
Carbonium ion Ethyl bromide

Other reagents like HCl, HOCl, H2SO4, H2O, Br2, Cl2. Etc., add to alkenes similarly.
When an alkene is symmetrical about the double bond, as ethylene is, the product
formed in addition reaction is the same no matter which way the same no matter
which way the reagent becomes attached to the alkene.

CH2=CH2 + HBr CH3 CH2Br

CH2=CH2 + HBr BrCH2 CH3
If, however, both the alkene and the adding reagent are unsymmetrical, two
alternatives are possible:
 Br
CH
CH 3 CH3
Isopropyl bromide
CH3 CH=CH2 + HBr
CH3 CH2 CH2Br
Propene
n-propyl bromide

Experimentally it has been found that isopropyl bromide is the major product.

Valdimir Markovnikov Rule:

‘’ When an unsymmetrical reagent adds to an unsymmetrical double bond, the positive
part of the reagent becomes attached to the double-bonded carbon atom which bears the
greatest number of hydrogen atoms. ‘’
Markovnikov Rule can be rationalized in terms of modern mechanistic theory. Consider
the addition of HBr to propene. The mechanism of this reaction involves the following
steps:

Step 1. Hydrogen bromide gives a proton(H+) and a bromide ion (Br-:)

H-Br H+ + Br-:
Step 2. The proton (electrophile) attacks the pi bond of propene to give a more stable
carbonium ion.
+
CH3-CH-CH3
o
+ 2 (more stable)
CH3-CH=CH2 + H
+
CH3-CH2-CH2
o
Propene 1 (less stable)

Remember: The tertiary carbonium ions are more stable than secondary carbonium
ions. Secondary carbonium ions in turn are more stable than primary carbonium ions.

Step 3. The bromide ion (nucleophile) combines with the more stable secondary
carbonium ion to give the major product.

Br
+
CH3-CH-CH3 + Br-: CH3-CH-CH3
o
2 carbonium ion Isopropyl bromide
Markovnikov rule may now be restated : Addition of an unsymmetrical reagent to an
unsymmetrical double bond proceeds in such a way as to involve the most stable
carbonium ion.

Nucleophilic Addition Reactions: When an addition reaction involves

the initial attack by a nucleophile, the reaction is referred to as nucleophilic addition.
Aldehydes and ketones which contain carbon-oxygen double bonds undergo such
reactions.
The carbon-oxygen double bond (carbonyl group), as we have recently learned, is highly
polar in character. This is because of higher electronegativity of Oxygen as compared to
carbon.
The addition of HCN to acetone is an example of nucleophilic addition.

o
OH
CH3-C-CH3 + HCN CH3-C-CH3
Acetone CN
Acetone
cyanoh
ydrin
The mechanism of the above reaction involves the following steps:
Step 1. Hydrogen cyanide gives a proton and cyanide ion (CN -:).

H-CN H+ + CN-:
Step 2. The cyanide ion (nucleophile) attacks the positively charged carbonyl carbon to
give the corresponding anion.

H3C CH3

CN-: C=O C O-

H3C CH3
CH3
Acetone

Step 3. The proton(electrophile) combines with the anion to from the addition product.

CH3 CH3
 C O - + H+ C OH
CH3 CH3 CH3
CH3
Acetone cyanohydrin

Mechanism of Rearrangement reactions:

A rearrangement reaction is a broad of organic reactions where the carbon skeleton of a
molecule is rearranged to give a structural isomer of the original molecule. Often a
substituent moves from one atom to another atom in the same molecule. In the example
below the substituent R moves from carbon atom 1 to carbon atom 2:

-C-C-C- -C-C-C-
R R

Hofmann Rearrangement Reaction: The Hofmann rearrangement is the

organic reaction of a primary amide to a primary amine with one fewer carbon atom.
The reaction of bromine with sodium hydroxide forms sodium hypobromite, which
transforms the primary amide into an intermediate isocyanate. The formation of an
intermediate nitrene is not possible because it implies also the formation of a hydroxamic
acid as a byproduct, which has never been observed. The intermediate isocyanate is
hydrolysed to a primary amine, giving off carbon dioxide.

Fig: Mechanism of
Hofmann
rearrangement
1. Base abstracts an acidic N-H proton, yielding an anion.
2. The anion reacts with bromine in a alpha-substitution reaction to give an N-
bromoamide.
3. Base abstraction of the remaining amide proton gives a bromoamide anion.
4. The bromoamide anion rearranges as the R group attached to the carbonyl carbon
migrates to nitrogen at the same time the bromide ion leaves, giving an isocyanate.
5.The isocyanate adds water in a nucleophilic addition step to yield a carbamic acid.
6. The carbamic acid spontaneously loses CO2, yielding the amide product.