Chapter Four

Substitution Reaction

Introduction
Structures of Organic compounds highly determine the reactivity
nature and ways of reactions of compounds.
 Reactivity of compounds – the rate of chemical reactions that
reactants exhibit during organic reactions.
 Mechanism – possible ways of reactions which the reactants may
follow to give the desired products.

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 Nucleophilic Substitution Reactions
 Nucleophiles - electron rich species
 Electrophiles - electron poor sites
 Leaving group - is a fragment that departs with a pair of
electrons in heterolytic bond cleavage. Leaving groups can be
anions or neutral molecules.
Any reaction in which the atom group is replaced by another atom is
called substitution reaction.

Types of substitution reactions;

1) Free radical substitution reactions

2) Electrophilic aromatic substitution reactions

3) Nucleophilic substitution reactions

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1) Free radical substitution reactions
Example; Chlorination of alkanes
Initiation step

Cl2 light
2 Cl
.
Propagation step
R-CH3 + Cl
. .
R-CH 2 + HCl

R-CH
. .
2 + Cl-Cl R-CH2Cl + Cl
Termination
.
R-CH +
.
2 Cl R-CH2Cl

R-CH
. .
2 + R-CH 2 R-CH2-CH2-R

Cl
. .
+ Cl Cl-Cl
3
 2) Electrophilic aromatic substitution reactions
Step 1: Generation of electrophile group
+
Electrophile source E
Step 2: Electrophile – aromatic ring reaction
 This generates a carbocation which is resonance stabilized (but not
aromatic)

Step 3: Rearomatization

When a reaction proceeds this way, it is called electrophilic

aromatic substitution. 4
 Example; Electrophilic aromatic bromination
Br
FeBr3
+ Br2

Mechanism

5
 3) Nucleophilic substitution reactions
Any reaction in which the leaving group is replaced by
nucleophile group is called nucleophilic substitution reaction.
Mechanism of Nucleophilic Substitution
i) SN2 Mechanism
S = substitution
N (subscript) = nucleophilic
2 = both nucleophile and substrate in characteristic step
(bimolecular)

It is a single step or concerted reaction.

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Example;
Leaving Group

Nucleophile Electrophile Substituted product

SN2 reaction is a back side attack reaction and causes inversion of

configuration. Examples;

a)

b)

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Energy Diagram of the SN2 reaction

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Order of Reactivity in SN2
 The more alkyl groups connected to the reacting carbon, the
slower the reaction.

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10
 ii) SN1 mechanism
 SN1 reaction occurs in two distinct steps and it is a step-wise reaction
Step 1: Ionization process (slow step)- the rate determining step
- Leaving group leaves the bond
-Planar (sp2) carbocation is formed

Step 2: Nucleophile – carbocation reaction (fast step)

-Nucleophile group has equal chances (50% / 50%) to attack the
planar carbocation carbon center from top and bottom sides and it
forms racemic mixture.

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 3 Alkyl halides are essentially inert to substitution by the SN2
mechanism because of steric hindrance at the back side of the α-
carbon.
 3 Alkyl halides do undergo nucleophilic substitution reactions
quite rapidly by SN1 mechanism.
 The order of reactivity of substrates for SN1 reactions is the
reverse of SN2.
R H H H
R C X > R C X > R C X > H C X
R R H H
3 alkyl halide 2 alkyl halide 1 alkyl halide Methyl halide

Increasing relative reactivity of alkyl halide in an SN1 reactions

12
Energy Diagram of SN1 reaction

13
Example;

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 Factors affecting SN2 and SN1 reactions
 The rate of an SN2 reaction depends upon 4 factors:
1) The nature of the substrate (the alkyl halide)
2) The power of the nucleophile
3) The ability of the leaving group to leave
4) The nature of the solvent
1) The nature of the substrates
Unhindered alkyl halides, those in which the back side of the α-
carbon is not blocked, it will react faster in SN2 reactions. i.e.,
Methyl >> 1° >> 2° >> 3°
Methyl halides react quickly in SN2 reactions, but 3° alkyl halides
does not react.
The back side of an α-carbon in a 3° alkyl halides is sterically
hindered and that decreases the rate of substitution.
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 2) Effect of the nucleophile on rate of SN2 reactions

 The better the nucleophile, the faster the rate of SN2 reactions.
 The best nucleophiles are the best electron donors.

3) The nature of the leaving group

 The leaving group usually has a negative charge
 Groups which best stabilize a negative charge are the best leaving
groups, i.e., the weakest bases are stable as anions and are the best
leaving groups.

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 pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7 pKb = -2 pKb = -21
I- Br - Cl- F- HO- RO- H2N-
30,000 10,000 200 1 0 0 0

Increasing leaving ability

 Iodine (-I) is a good leaving group because iodide (I-) is weak base.
 The hydroxyl group (-OH) is a poor leaving group because hydroxide
(OH-) is a strong base.

4) The nature of the solvent

There are 3 classes of organic solvents;
 Protic solvents, which contain –OH or –NH2 groups. Protic
solvents slow down SN2 reactions.

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 Polar aprotic solvents like acetone, which contain strong dipoles
but no –OH or –NH2 groups. Polar aprotic solvents speed up SN2
reactions.

 Non polar solvents, e.g., hydrocarbons. SN2 reactions are

relatively slow in non polar solvents.

Protic solvents (e.g., H2O, MeOH, EtOH, CH3COOH, etc.) cluster

around the Nu:- (solvate it) and lower its energy (stabilize it) and reduce
its reactivity via H-bonding.
+ -
 
H OR
+ -
 A solvated anion (Nu:-) has reduced nucleophilicity,
RO H X:- H OR reduced reactivity and increased stability
- +
 
H OR
+ -
 

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 Polar aprotic solvents solvate the cation counterion of the
nucleophile but not the nucleophile.
- +
 
Polar aprotic solvents solvate metal cations N C CH3
..
leaving the anion counterion (Nu: -) bare and
thus more reactive + - :O:
 
+ .. _
:O: H3C C N: Na : N C CH3 + CH3C O
..
:
- +
.. _ CH3CN :  
CH3C O : +
.. Na ..
N C CH3
- +
 

 Non polar solvents (benzene, carbon tetrachloride, hexane, etc.) do not

solvate or stabilize nucleophiles. Cl

C CH3CH2CH2CH2CH2CH3
Cl Cl
Cl
n-hexane
benzene carbon
tetrachloride

 SN2 reactions are relatively slow in non polar solvents similar to that in
protic solvents. 19
 The rate of an SN1 reaction depends upon 3 factors:
1) The nature of the substrate (the alkyl halide)
2) The ability of the leaving group to leave
3) The nature of the solvent
Note: The SN1 rate is independent of the power of the nucleophile.
1) The nature of the substrate
 Highly substituted alkyl halides (substrates) form a more stable
Carbocation.
more less
stable stable
CH3 CH3 CH3 H

H3C C+ H3C C+ H C+ H C+

CH3 H H H
tertiary > secondary > primary > methyl
3º 2º 1º

Increasing relative carbocation formation in an SN1 reactions 20

2) The nature of the leaving group
 The nature of the leaving group has the same effect on both SN1
and SN2 reactions.
 The better the leaving group, the faster a Carbocation can form and
hence the faster will be the SN1 reaction.
 Groups which best stabilize a negative charge are the best leaving
groups.
 The weakest bases are stable as anions and are the best leaving
groups.

pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7 pKb = -2 pKb = -21

I- Br - Cl- F- HO- RO- H2N-
30,000 10,000 200 1 0 0 0

Increasing leaving ability

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3) The nature of the solvent
 For SN1 reactions, the solvent affects the rate only if it influences
the stability of the charged transition state, i.e., the Carbocation.
 The Nu:- is not involved in the rate determining step so solvent
effects on the Nu:- do not affect the rate of SN1 reactions.
 Polar solvents, both protic and aprotic, will solvate and stabilize
the charged transition state (Carbocation intermediate), lowering
the activation energy and accelerating SN1 reactions.
 Nonpolar solvents do not lower the activation energy and thus
make SN1 reactions relatively slower.
H2O 20% EtOH (aq) 40% EtOH (aq) EtOH
100,000 14,000 100 1
Reaction rate increases with polarity of solvent

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23
Applications of Substitution Reactions

an alcohol

a thiol

an ether

a thioether

an amine

an alkyne

a nitrile

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