Nucleophilic substitution reactions are a class of reactions in which an electron rich nucleophile attacks a positively charged electrophile to replace a leaving group. For alginate reactions, the most reactive nucleophile is the C6 carboxylate group

1. NUCLEOPHILIC SUBSTITUTION REACTION
&
ELIMINATION REACTION
PREPARED BY,
Manimegalai.G
M.Pharm-I year
Advanced organic chemistry-I
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 1

2. SUBSTITUTION REACTION
 Substitution reaction are those reaction in which an atom or group of
atoms directly attached to a carbon in the substrate molecule is replaced by
another atom or groups of atoms.
The bromine atom of ethyl bromide is substituted by a hydroxyl group
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 2

3. CONT…
 The carbon-halogen bond in alkyl halides is polar because of
the high electronegativity of the halogen atom and hence it
becomes a good target for attack by nucleophiles.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 3

4. NUCLEOPHILE
 A reagent which can donate an electron pair in a reaction is
called a nucleophile. It means “nucleus-loving” and it indicates
that it attacks the region of low electron density in the substrate
molecule.
For eg.,
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 4
Cl-
, Br-
, I-
, OH-
, CN-
, RCH2
-
, NH3 , RNH2,
H2O, ROH

5. SN1 MECHANISM
 It stands for unimolecular nucleophilic substitution.
 When the rate of reaction depends only on the concentration of
the alkyl halide, the reaction is the first order rate.
 The reaction takes pace in two steps
First step : Breaking of the C-X bond
Second step : Making of the C-Nu bond
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 5

6. CONT…
 A typical example of this process is the hydrolysis of tertiary
butyl bromide in the presence of sodium hydroxide.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 6

7. CONT…
 The first one being the ionization of alkyl halide producing
carbocation. This will obviously be a slow (rate determining) step
as it involves breaking of a covalent bond.
This is followed by the fast (non-rate determining) step which
involves addition of nucleophile to the reactive carbocation.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 7

8. STEREOCHEMISTRY OF SN1 REACTION
 The reaction of alkyl halide in which halogen is bonded to a
chiral carbon leads to the formation of enantiomers: One with
the same relative configuration as the reacting alkyl halide and
other with the inverted configuration.
Formation of enantiomeric pair is due to the formation of
carbocation whose geometry is planar.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 8

9. CONT…
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 9

10. REARRANGEMENT
 If carbocation is primary or secondary having at least three
carbons then rearrangement takes place in carbocation. This
leads to the formation of two or more products, one is normal
and others are rearranged products.
For eg.,
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 10

11. SN2 REACTION
 It stands for bimolecular nucleophilic substitution.
 When the rate of a nucleophilic substitution depends on the
concentration of both the substrate and the nucleophile, the
reaction is second order rate.
[Nucleophile]
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 11

12. CONT…
 The hydrolysis of methyl bromide in the presence of NaOH.
 Kinetic studies have revealed that the reaction rate depends on
the concentration of alkyl halide as well as the concentration of
the nucleophile, both the reactants being involved in the rate
determining step.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 12

13. CONT…
 In this mechanism, formation of carbon-nucleophile bond
cleavage of the carbon-halogen bond occurs simultaneously.
 Therefore, involves a transition state in which the carbon atom
appears to be pentavalent. The three hydrogen acquires a
coplanar geometry.
The nucleophile attacks the carbon from the side just opposite
to that from which halide is leaving.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 13

14. STEREOCHEMISTRY OF SN2 REACTION
 The nucleophile enters as the halide is leaving. If the alkyl
halide is optically active, inversion of configuration will occur.
 The nucleophile is attached to just opposite side of the leaving
group. Thus the substitution product is still optically active but of
the opposite configuration to the alkyl halide.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 14

15. COMPARISON OF SN1 & SN2 REACTION
SN1
 Two step mechanism
 Unimolecular reaction
 Product formation takes place
by carbocation intermediate
 Rearrangement occurs
 Reaction favoured by polar
protic solvents
SN2
 One step mechanism
Bimolecular reaction
 Product formation takes
place by transition state
 No rearrangement
 Reaction is favoured by polar
aprotic solvents
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 15

16. SN1
It follows first order kinetics
Rate of reaction depends upon
the concentration of substrate
only
Reactivity order :
alkyl benzyl>tertiary > secondary
> primary > methyl halide
SN2
It follows second order kinetics
 Rate of reaction depends upon
the concentration of substrate and
nucleophile
 Reactivity order :
methyl halide > primary >
secondary > tertiary halide
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 16

17. ELIMINATION REACTION
 The removal of atoms or groups of atoms from two adjacent
atoms in the substrate molecule to form a multiple bond.
It may be regarded as reverse of addition reaction.
Two sigma bonds are lost and a new pi bond is formed.
Saturated compounds become unsaturated.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 17

18. E2 REACTION
Bimolecular elimination
Rate of reaction depends upon the concentration of a substrate
and nucleophile. It follows second order.
It is a one step process in which the abstraction of the proton
from the beta carbon and the expulsion of the halide ion from the
alpha carbon occurs simultaneously.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 18

19. E1 REACTION
Unimolecular elimination
Rate of reaction depends on the concentration of substrate , it
follows first order.
It is two step process
a) Ionization – Carbon halogen bond breaks to give a
carbocation intermediate
b) Deprotonation – Deprotonation of the carbocation of gives
alkene
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 19

20. MECHANISM
Step- 1 The alkyl halide ionizes to give the carbonium ion
Step-2 A proton is abstracted by the base from the adjacent beta
carbon atom to give the alkene
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 20

21. ORIENTATION IN E2
SAYTZEFF RULE
 It states that hydrogen will be eliminated preferentially from
that beta carbon atom which is attached with least number of
hydrogen atoms. Therefore, that alkene will predominate which
has most alkyl substituent on the double bond carbon.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 21

22. HOFFMANN RULE
 It states that the hydrogen will be eliminated preferentially from
that beta carbon atom which is attached with most number of
hydrogen atoms.
According to the rule , that alkene will predominates which has
least alkyl substituents on the double bond carbon.
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 22

23. REFERENCE
 Morrison, R.T ., Boyd, R.N., Organic Chemistry, 6 – edition,
Pg.no: 460-472
 Dr. Jagdamba Singh., Dr. L.D.S. Yadav., Pharmaceutical
Organic Chemistry, Volume –I ,Pg.no : 272-282
 Arun Bahl., Bahl, B.S., A textbook of Organic Chemistry, 22-
edition, Pg.no: 100-108
5/17/2023 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 23