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ALIPHATIC NUCLEOPHILIC SUBSTITUTION

REACTIONS

Dr. Pandeeswar Makam

Assistant Professor
Department of Chemistry
Indian Institute of Technology (BHU) –Varanasi
Uttar Pradesh, India-221005
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Nucleophilic substitution reactions

A reaction in which a nucleophile displaces a leaving group and
takes its position is called a nucleophilic substitution reaction.

In this reaction nucleophile selectively attacks the electrophile to

make a new bond.

Solvent
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Major Factors Involved in the NS Reaction

R + R
− Solvent
R C LG + Nu R C Nu + LG
R R

• Substrate (R-X)
• Nucleophile -
(Nu )
• Leaving group (LG)
• Solvent (Polar/Nonpolar)
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Substrates for Nucleophilic Substitution

Reactions
❖ In general Alkyl halides are the best substrates for NS reactions
° ° °
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Nucleophiles:
A nucleophile is a chemical species that donates an electron pair to
an electrophile. Nucleophiles can be negatively charged molecules or neutral
molecules
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Leaving groups
A molecular fragment that leaves with a pair of electrons in heterolytic bond cleavage

1. Leaving groups are also nucleophiles and consider to be weak Lewis bases

2. Leaving groups can be negatively charged molecules or neutral molecules

Halogen leaving groups Sulfonate Leaving groups Neutral leaving groups

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Solvents: A medium used for dissolving

the reactants

❖ Non-polar solvents are not suitable of NS reaction e.g.

Hexane
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Types of Nucleophilic substitution reactions

R + R
−
R C LG + Nu R C Nu + LG
R R

Substrate = comfy chair; LG = Cat #2, Nu- = Cat #1

#1 SN1

#2 SN2
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Types of Nucleophilic substitution reactions

R + R
−
R C LG + Nu R C Nu + LG
R R

Nucleophilic substitution can occur under different

mechanistic pathways (Majority of them are one of the
following…)

• SN1 (Substitution nucleophilic unimolecular reaction)

• SN2 (Substitution nucleophilic bimolecular reaction)
• SNi (Substitution nucleophilic internal reaction)
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Types of nucleophilic substitution

1) SN1 (Substitution nucleophilic unimolecular reaction)

This implies that the rate determining step of the mechanism

depends on the decomposition of a single molecular
species.

Best Example for SN1 reaction: Solvolysis of tert-alkyl halides

HBr
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SN1 Mechanism : Multi-steps reaction (at least two steps)

It is a unimolecular reaction
because, Reaction rate only
depends on a formation of
carbocation which is a slow
process.

Rate = k[Substrate]

For the particular reaction

Rate = k[(CH3)3CBr]
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A modified hourglass that serves as an analogy for a

multistep reaction
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❖ Energy profile Diagram

Multi-step reactions
have intermediates
and a several
transition states
(TS). In an SN1 there
is loss of the leaving
group generates an
intermediate
carbocation which is
then undergoes a
rapid reaction with the
nucleophile..
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Examples for SN1 reaction

CH3

CH3

CH3
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Stereochemistry
Ideally SN1 reaction
provides Racemic
Mixture

Path A Retention Path B Inversion

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That’s the reason for 49% product with retention and 51% with inversion.
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Types of nucleophilic substitution

2) SN2 (Substitution nucleophilic bimolecular reaction)
Rate of the reaction depends on two substrates.

Example:

Kinetic data show that the rate of reaction depends on the concentration of both
reactants, which suggests a bimolecular reaction with a one-step mechanism. This
is an example of an SN2 (substitution nucleophilic bimolecular) mechanism.
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SN2 Mechanism : Single step reaction

One step reaction: nucleophilic attack and dismiss of a leaving group takes
place simultaneously .

Examples of SN2 reactions

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Stereochemistry of the SN2 reaction

• All SN2 reactions proceed with backside attack of the

nucleophile, resulting in inversion of configuration at a
stereogenic center.
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examples of SN2 inversion of configuration: The Walden

Inversion.
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Energy profile diagram

+
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SN1 SN2

Rate = k[Substrate] [Nucleophile]

Rate = k[Substrate]

Product: Inversion of configuration

Product: Racemic mixture

Carbocation stability Less steric hindrance

 Factors affecting SN1 and SN2
Nucleophilic reactions are mainly depended on the following
factors

• Substrate (Type of Carbon)

• Nucleophile (strong Vs week)

• Leaving group

• Solvent (Aprotic Vs protic)

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Substrates Play Important Role in Deciding

Mechanism of the NS reaction
Increasing stability of carbocation more number of
hyperconjugation and Inductive effect

Decreasing steric hindrance favors backside attack of Nu-

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SN1 Reaction Rate

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SN2 Rate of the reaction

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Nucleophile

Prefers SN2 Mechanism Prefers SN1 Mechanism

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Nucleophile in predicting SN1 vs SN2

mechanisms:
• The strong nucleophile favors an SN2 mechanism.

• The weak nucleophile favors an SN1 mechanism.

H2O
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The Nucleophile: Size effect

• Nucleophilicity does not parallel basicity when steric
hindrance becomes important.
• Steric hindrance is a decrease in reactivity resulting from the
presence of bulky groups at the site of a reaction.
• Steric hindrance decreases nucleophilicity but not basicity.
• Sterically hindered bases that are poor nucleophiles.
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Leaving Group in predicting SN1 vs SN2

mechanisms:
• The leaving group is the third factor. A better leaving group
increases the rate of both SN1 and SN2 reactions.
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Solvent effect: Polar protic solvent

Polar protic solvent has a hydrogen atom attached to a strongly
electronegative element (e.g. oxygen) that forms hydrogen
bonds.

-Polar protic solvent solvate cations and anions effectively

while aprotic solvents do not solvate anions to any appreciable
extend.

-Polar protic solvents are more suitable for SN1 reactions, while
aprotic solvents are used for SN2 reactions

Example of polar protic solvents

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Polar Protic solvent in SN1 reaction

Polarization Stabilization
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Polar Protic solvent in SN2 reaction

For SN2 reaction: We need Strong Nucleophile e.g. NaOMe

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Solvent effect: Polar Aprotic solvents

• Polar aprotic solvents are those solvents whose molecules do
not have a hydrogen atom that's attached to an atom of an
electronegative element.
Polar aprotic solvents also exhibit dipole—dipole interactions,
but they have no O—H or N—H bonds. Thus, they are incapable
of hydrogen bonding.
Examples of polar aprotic solvents
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Polar aprotic solvent in SN2 reaction

Polar aprotic solvent increases the reactivity of SN2 reaction

Strong “free” Nu
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Solvent Vs halogen Nucleophile

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Summary of SN1 and SN2 reactions

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Substrate effects on NS reactions

➢ Rearrangements to form more stable C+

(Hydride/alkyl)

➢ Presence of allylic Carbon

➢ Neighbouring group participation

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Rearrangements in SN1 reactions

H H
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examples
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✓ H vs alkyl Shift
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C3-O
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Nucleophilic substitution at allylic Carbon

What is allylic Carbon?

An allylic carbon is a
carbon that attached
immediate next to the
double bond

allylic halides readily

under go NS reactions
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Reactivity of Allylic carbon in NS rxn

Solvolysis of allyl halides are >100 Times Faster than

simple alkyl halides
Allyl carbocations are stabilized by resonance
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SN1 or SN2 reactions in Allyl substrate

Allylic Substrates can undergo either

SN1 or SN2 depends on substrate,
nucleophile
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Simple example

Products cannot be distinguished

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SN1 vs SN1 Prime (SN1') Reactions

SN1 SN1'

--------SN1

Allylic rearrangement
------- SN1'

Prime Reaction
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SN1 vs SN1 Prime (SN1') Reactions

SN1' SN1

--------SN1

Allylic rearrangement
------- SN1'

Prime Reaction
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SN2 Vs SN2 prime (SN'2) Reactions

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SN2 Vs SN2 prime (SN'2) Reactions

SN2’ SN2
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Neighbouring group participation

The role of the nucleophilic atom in the substrate in the overall reaction is known as
neighbouring group participation or anchimeric assistance.

1. Slow reaction

2. Fast reaction

The electron density will accelerate the rate for departure of the leaving group
The second reaction is very fast, Because sulfur participate in the reaction as shown
in the mechanism

No Neighbouring group
effect. Slow Rxn Neighbouring group effect. Fast Rxn
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Over all mechanism

Two SN2 reactions taking place.

✓ N.G. should have its lone pair of e-

✓ N.G. and L.G. must be antiperiplanar to each other.
✓ Retention of configuration
✓ First order kinetics
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Some examples…
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Stereochemistry in NGP

Silver ion here act as electrophilic catalyst & ease the removal of bromine

Retention of configuration

More Important: low concentrated nucleophile will be used to occur N.G.P

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Simple SN2
When nucleophile concentration will be higher in reaction medium then normal
SN2 reaction will undergo & product will be with inversion of configuration
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SN i
( Substitution Nucleophilic Internal)
SNi reaction is a reaction in which substitution of a nucleophile takes place internally

✓ Internal Transfer of nucleophile

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SNi: stereochemistry

✓ Retention of configuration
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SNi reaction

Chlorosulphite ester
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SNi with pyridine

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Thank you