Substitution Reaction

Amit Pandit
M. Pharmacy II sem

Neucleophile
 As electron pair donors, nucleophiles must
either contain an electron pair that is easily
available because it is nonbonding or they
must contain a bonding electron pair that
can be donated from the bond involved and
thus be made available to the reaction
partner.
 From this it follows that nucleophiles are
usually anions or neutral species but not
cations.

Good and Poor Nucleophiles
 Within a group of nucleophiles that
attack at the electrophile with the same
atom, the nucleophilicity decreases with
decreasing basicity of the nucleophile
 Nucleophilicity is a measure of how
readily a compound (a nucleophile) is
able to attack an electron-deficient atom.

Nucleophilicity of O nucleophiles
with different basicities.

Nucleophilicity of N and O nucleophiles
that are sterically hindered to different
degrees.

Nucleophilicity decreases with
increasing electronegativity of the
attacking atom.
In comparisons of atomic centers
from the same group of the periodic
table.

The nucleophilicity of a given nucleophilic center is
increased by attached heteroatoms that possess
free electron pairs (-effect)

Nucleophilic Aliphatic
substitution
To ensure that reaction occurs in homogeneous solution, solvents are
chosen that dissolve both the alkyl halide and the ionic salt. The alkyl
halide substrates are soluble in organic solvents, but the salts often are
not. Inorganic salts are soluble in water, but alkyl halides are not. Mixed
solvents such as ethanol–water mixtures that can dissolve enough of
both the substrate and the nucleophile to give fairly concentrated
solutions are frequently used. Many salts, as well as most alkyl halides,
possess significant solubility in dimethyl sulfoxide (DMSO), which makes
this a good medium for carrying out nucleophilic substitution reactions.

Type of Nucleophilic Aliphatic
substitution Reaction

The SN2 Mechanism
 a single step process
 Involves no intermediates
 Involves only one transition state, which is of
low polarity
 Follows second order (bimolecular) kinetics.
That is, rate=k[substrate][nucleophile]
 backside attack

Factors Affecting SN2
Reactions
 The Leaving Group
 The Nucleophile
 The Effect of the Solvent
 Steric Effects

Reactions :The Leaving
Group
 The weaker the basicity of a group, the
better is its leaving ability.

Reactions : The Nucleophile
 the stronger bases are the better
nucleophiles

The Effect of the Solvent
 In a protic solvent, is the smallest atom the poorest
nucleophile even though it is the strongest base.
 Protic solvents are hydrogen bond donors.
 The interaction between the ion and the dipole of the
protic solvent is called an ion–dipole interaction.
 Because the solvent shields the nucleophile, at least
one of the ion–dipole interactions must be broken
before the nucleophile can participate in a SN2
reaction.
 Weak bases interact weakly with protic
solvents, whereas strong bases interact more
strongly because they are better at sharing their
electrons.

STERIC EFFECTS IN SN2
REACTIONS

Stereochemistry of SN2
Substitutions

AN ENZYME-CATALYZED
NUCLEOPHILIC SUBSTITUTION
OF AN ALKYL HALIDE
 Enzymes that catalyze these reactions are
known as haloalkane dehalogenases.
 The haloalkane dehydrogenase is believed to
act by using one of its side-chain carboxylates
to displace chloride by an SN2 mechanism

THE SN1 NUCLEOPHILIC
SUBSTITUTION
 Hughes and Ingold observed that the
hydrolysis of tert-butyl bromide, which
occurs readily, is characterized by a
first-order rate law:

Experimental Evidence
 1. The rate law shows that the rate of the reaction
depends only on the concentration of the alkyl halide. This
means that we must be observing a reaction whose rate-
determining step involves only the alkyl halide.
 2. When the methyl groups of tert-butyl bromide are
successively replaced by hydrogens, the rate of the
SN1reaction decreases progressively . This is opposite to
the order of reactivity exhibited by alkyl halides in SN2
reactions.
 3. The reaction of an alkyl halide in which the halogen is
bonded to an asymmetric carbon forms two
stereoisomers: one with the same relative configuration at
the asymmetric carbon as the reacting alkyl halide, the
other with the inverted configuration.

Factors Affecting SN1 Reactions
 The Leaving Group
 The Solvent
 Carbocation Rearrangements

The Leaving Group
 two factors affect the rate of an reaction:
 the ease with which the leaving group
dissociates from the carbon
 the stability of the carbocation that is formed.
 The weaker the base, the less tightly it is
bonded to the carbon and the easier it is to
break the carbon–halogen bond.
 As a result, an alkyl iodide is the most
reactive and an alkyl fluoride is the least
reactive of the alkyl halides

The Solvent
 The major effect of the solvent is on the rate of
nucleophilic substitution, not on what the
products are.
 The higher the dielectric constant of solvent
(polar) , the better the medium is able to
support separated positively and negatively
charged species.
 The rate of solvolysis of tert-butyl chloride
increases dramatically as the dielectric
constant of the solvent increases.
 Aprotic solvents, lack OH groups and do not
solvate anions very strongly, leaving them
much more able to express their nucleophilic
character.

STEREOCHEMISTRY OF SN1
REACTIONS
Stereochemistry
of an SN1
reaction that
takes place via
a contact ion
pair. The
reaction
proceeds with
66% inversion
of configuration
and 34%
racemization.

Representative Nucleophilic
Substitution Reactions

Reference
 Advanced Organic Chemistry Reaction
Mechanisms Elsevier, 2002
 ORGANIC CHEMISTRY Francis A.
Carey University of Virginia
 MARCH’S ADVANCED ORGANIC
CHEMISTRY
REACTIONS, MECHANISMS, AND
STRUCTURE, SIXTH EDITION Michael
B. Smith, Jerry March
 ORGANIC CHEMISTRY , PAULA
YURKANIS BRUICE, 4th edition

Substitution Reaction

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