Lecture 9

Substitution Reactions

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 SUBSTITUTION REACTIONS

One group takes the place of another.

Y + R X R Y + X

Y takes the place of X ( Substitution )

Y “displaces” X

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Alkyl Halides and Substitution reaction
Halogens are more electronegative than
carbon
Carbon-halogen bond is polar, so carbon
has partial positive charge.
Electrostatic potential maps of alkyl
halides illustrate this point.

3
 Substitution Reactions

• The halogen atom on the alkyl halide is

replaced by another group.
• Since the halogen is more electronegative
than carbon, the C-X bond breaks
heterolytically and X- leaves.
• The group replacing X- is a nucleophile. 4
 Elimination Reactions

• The alkyl halide loses halogen as a halide

ion, and also loses H+ on the adjacent
carbon to a base.
• A π bond is formed and the product is
alkene.
• Also called dehydrohalogenation (-HX).
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NUCLEOPHILIC SUBSTITUTION REACTION
They are ionic reactions, which means
they involve heterolytic bond breaking.
Consider a general reaction :
R – X + OH- → R – OH + X-
The reaction is carried out in a solvent that
dissolves both reactants.
Carbon to halogen bond in RX is broken
Carbon to oxygen ( of OH- ) bond is formed
X leaves RX as X- .
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NUCLEOPHILIC SUBSTITUTION REACTION
RX is called the substrate
OH- the nucleophile (because it attacks the
carbon in R to which X is bonded)
X- the leaving group (because it leaves R).
This is a substitution reaction since the –
OH group is substituted for the X.
The carbon looses the electron pair it
was sharing with the departing halide ion, but
gains it, by sharing the electron pair of OH-. 7
NUCLEOPHILIC SUBSTITUTION REACTION

Why nucleophilic substitution is

characteristic of alkyl halides?
It is because, halide ion is an
extremely weak base.
Why X - is a weak base ?
Because, hydrogen halides, are strong
acids. HX can readily release a proton to
other bases.
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NUCLEOPHILIC SUBSTITUTION REACTION
In an alkyl halide, halogen is attached
to carbon; and just as HX (hydrogen halide)
readily releases a proton , it also releases
the carbon readily to other bases when
bases attack the carbon bonded to halogen.
The attacking bases posses an
unshared pair of electrons hence seek a
relatively positive center, with which to share
their electron pair.
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NUCLEOPHILIC SUBSTITUTION REACTION
As a synthetic tool, nucleophilic substitution
is one of the most useful classes of organic
reactions.
The synthesis of aliphatic compounds, most
often starts with alcohols.
But –OH group being a very poor leaving
group, it is only conversion of alcohols into alkyl
halides - or other compounds with good leaving
groups - that opens the door to nucleophilic
substitution. 10
NUCLEOPHILIC SUBSTITUTION REACTION

Components required for nucleophilic

substitution reactions are:
Substrate
Nucleophile
Leaving group
Solvent
The substrate consists of two parts
Alkyl group and the leaving group.
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NUCLEOPHILIC SUBSTITUTION REACTION

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 THESE REACTIONS HAVE A
WIDE RANGE OF SUBSTRATES

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 COMMON SUBSTRATES
( Leaving group varies )
alkyl halides alcohols
+
R Cl R OH R O H

R Br H
Alcohols require acid
R I and then H2O leaves

tosylates ABBREVIATION
O R O Ts
R O S CH 3
O
alkyl p-toluenesulfonate 14
 The Leaving group
The C—X bond is heterolytically cleaved,
and the leaving group departs with the
electron pair forming X:¯. The more stable the
leaving group X:¯, the better able it is to
accept an electron pair.
In comparing two leaving groups the
better leaving group is the weaker base.
For example, H2O is a better leaving
group than HO¯ because H2O is a weaker
base.
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 The Leaving group

There are periodic trends in leaving group

ability:
Left to right across a row, basicity
decreases so leaving group ability increases.

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 The Leaving group

Down a column of the periodic table,

basicity decreases so leaving group ability
increases.

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 The Leaving group

Conjugate Bases of Strong Acids are Good

leaving groups

Good leaving groups 18

 The Leaving group
Conjugate Bases of Weak Acids are
Poor leaving groups

Poor Leaving Group 19

 THERE IS ALSO A
WIDE RANGE OF NUCLEOPHILES

A WIDE VARIETY OF COMPOUNDS CAN BE MADE

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 The Nucleophile
A nucleophile may be any molecule with
an unshared electron pair.
Nucleophiles in general are anions
( -CN-,- I-, -SH- etc.)or neutral molecules
(H2O,ROH, NH3 etc.)

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 NUCLEOPHILES

Nucleophile Product Class

- - -
Cl ,Br ,I R X alkyl halides
-
OH R OH alcohols
‘
RO
-
R O R‘ ethers
C N -
R C N nitriles
O O
esters
R' C R' C
O- O R 22
 NUCLEOPHILES

Nucleophile Product Class

-
R' C C: R' C C R alkynes

SH - R SH thiols
H O H R O H alcohols
R‘ O H R‘ O R ethers

NH 3 R NH2 amines

R' NH 2 R' NH R amines 23

 The Nucleophile
Nucleophiles and bases are structurally
similar: both have a lone pair or a π bond.
They differ in what they attack.
Bases attack protons.
Nucleophiles attack electron deficient atoms
(usually carbons)

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 The Nucleophile

Although nucleophilicity and basicity are

interrelated, they are fundamentally different.
Basicity is a measure of how readily an
atom donates its electron pair to a proton.
It is characterized by an equilibrium
constant, Ka in an acid-base reaction,
making it a thermodynamic property.

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 The Nucleophile

Nucleophilicity is a measure of how

readily an atom donates its electron pair to
other atoms.
It is characterized by a rate
constant, k, making it a kinetic property.
1. For two nucleophiles with the same
nucleophilic atom, nucleophilicity parallels
basicity, i.e. the stronger base is the stronger
nucleophile.
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 The Nucleophile
The relative nucleophilicity of HO¯ and
CH3COO¯, two oxygen nucleophiles, is
determined by comparing the pKa values of their
conjugate acids (H2O = 15.7, and CH3COOH =
4.8). HO¯ is a stronger base and stronger
nucleophile than CH3COO¯.

2. A negatively charged nucleophile is

always a stronger nucleophile than its
conjugate acid.
HO¯ is a stronger base and stronger
nucleophile than H2O. 27
 The Nucleophile

Nucleophilicity does not parallel basicity

when steric hindrance becomes important.
Steric hindrance decreases nucleophilicity
but not basicity.
Sterically hindered bases that are poor
nucleophiles are called non nucleophilic
bases.

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 The Nucleophile

Ethoxide (Stronger nucleophile)

tert. Butoxide (Stronger base)

Three CH3 groups sterically hinder the O atom,

making it a weaker nucleophile 29
Nucleophilic substitution reactions
Nucleophile can be negatively charged or
neutral; the product R:Nu will then be neutral or
positively charged.
The substrate R:L can be neutral or
positively charged; the leaving group will then
be negatively charged or neutral.

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General Features of Nucleophilic Substitution

Negatively charged nucleophiles like HO¯

and HS¯ are used as salts with Li+, Na+, or K+
counterions to balance the charge.
Since the identity of the counterion is
usually inconsequential, it is often omitted
from the chemical equation.

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General Features of Nucleophilic Substitution

When a neutral nucleophile is used, the

substitution product bears a positive charge.

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General Features of Nucleophilic Substitution
Furthermore, when the substitution product
bears a positive charge and also contains a
proton bonded to O or N, the initially formed
substitution product readily loses a proton in a
BrØnsted-Lowry acid-base reaction, forming a
neutral product.

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 COMPARE THESE SUBSTITUTIONS
DISPLACEMENT AT CARBON
- -
Nu: + R X R Nu + :X
substrate
nucleophile product leaving
group

DISPLACEMENT AT HYDROGEN

-
B: + H X B H + :X-
conjugate conjugate
base acid acid base34
 COMPARE THESE SUBSTITUTIONS

Nucleophilic substitution reactions (II)

can be compared to a Brønsted-Lowry
acid-base equilibrium (I)
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NUCLEOPHILIC SUBSTITUTION REACTION

The equilibria of these reactions

generally lies far to the right.
In the Brønsted reaction, hydroxide ion
displaces bromide ion from HBr.
In the organic reaction, hydroxide ion
displaces bromide ion from ethyl bromide.
Thus, by analogy, the equilibrium in
nucleophilic substitution reactions favours the
release of the weaker base.
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NUCLEOPHILIC SUBSTITUTION REACTION
We can now see why the reverse
reaction is not favoured, i.e. bromide ion
does not displace hydroxide ion.
We say that hydroxide ion is a good
nucleophile and bromide ion is a good
leaving group.
Nucleophilicity and leaving group
ability can often be estimated by
comparing pKa values of the species
concerned
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 Kinetics of Nucleophilic substitution

Let us take simplest of the alkyl halide ,

CH3X and react it with OH-.
The rate of the reaction can be determined
experimentally by measuring the rate at which
methyl halide or hydroxide ion disappears from
the solution, or the rate at which methanol or
halide ion appears in the solution.

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 Kinetics of Nucleophilic substitution

We can make any of these measurements

by withdrawing a small sample from the reaction
mixture soon after the reaction begins and
analyzing it for the concentrations.
We perform several such experiments
keeping the temperature constant, but varying the
initial concentrations of the reactants.

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 Kinetics of Nucleophilic substitution

The experiments show that the rate

depends on the concentration of both the
reactants, i.e. doubling the concentration of any
of the reactant doubles the rate. The rate is
therefore expressed as:
rate α [CH3X] [OH-] or
rate= k [CH3X] [OH-] .
This reaction is said to be second order
overall. 40
 Kinetics of Nucleophilic substitution
R – X + OH- → R – OH + X-
This second order reaction is also
bimolecular, meaning that two species are
involved in the rate determining step.
This reaction is said to be SN2
(Substitution Nucleophilic Bimolecular).
S = substitution
N (subscript) = nucleophilic
2 = both nucleophile and substrate in character
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step (bimolecular)
Kinetics of Nucleophilic substitution

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 Kinetics of Nucleophilic substitution
In the case of tertiary alkyl halide substrate
the rate is found to be dependent only upon the
substrate concentration.
The rate expression therefore is,
rate α [(CH3)3CX] or
rate = k [(CH3)3CX] .
This reaction is said to be first order overall.
This reaction is called as SN1 (Substitution
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Nucleophilic Unimolecular).
 Kinetics of Nucleophilic substitution

How the alkyl halides undergo the

nucleophilic substitution reactions?
i.e., What is the step by step description
(mechanism) in the formation of the product from
the reactants?
We say some RX react by SN2 and some by
SN1 or there is duality in mechanism.

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