1) Nucleophilic substitution :

2) elimination :
Nucleophilic Substitution
 HUBLOT

SANE

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Credit: Alexander Hassenstein

1323749854
 Nucleophilic Substitution

Nucleophile + Substrate Product + Leaving group

 Nucleophilic Substitution

S N1 SN2

S: Substitution S: Substitution
N: Nucleophilic N: Nucleophilic
1: unimolecular 2: Bimolecular
 SN 2

■ reaction and mechanism

■ kinetics
■ stereochemistry
■ substrate structure
■ nucleophiles
■ leaving groups
■ solvents
SN2 reaction and mechanism
 Synthetic Utility of the SN2 Reaction
A variety of functional groups can be prepared employing a good
nucleophile and an electrophile with a good leaving group:

8
H H

Br C +
H

H H
SN2 reaction : Kinetics
 The Rate Law of an SN2 Reaction

Obtained experimentally:

Rate law includes both

the alkyl halide and the
nucleophile, a
second-order process

11
SN2 reaction : Stereochemistry
 SN2 MECHANISM
nucleophilic attack

R (R)-config
..
H O : ..
.. C : Br :
..
CH3
R
attacks H
back lobe
..
H O
.. : C

INVERSION CH3
(S)-config
H
Stereochemistry of SN2
Walden inversion

=>
 Nu:+ C-X

Tetrahedral

8
Nu

Planar

Nu-C

Tetrahedral
2007 Thomson Higher Education
 THE 2
sp
R 2p
HO C B
INVERSION
PROCESS partial bonding
HO C Br
activated complex
CH3 H is trigonal planar (sp2 )

sp3 configuration
.. R is inverted
.. :
H O R
sp3
C : Br
Ea HO : C
CH3
H CH3
(R)-configuration
H
(S)-configuration
SN2 reaction : substrate
structure
■ Less bulky

■ Should stabilize the

transition state
SN2 Reaction: substrate structure
KI in Acetone at 25°
(a) (b)
H CH3
C-Br C-Br
H H7
H H

(c) (d)
CH3 CH3
C-Br C-Br
H3C H3C
H CH3

2007 Thomson Higher Education

Relative rates of SN2 reactions of alkyl chlorides with the iodide ion

The rates are

given with
respect to
n-BuCl
 only SN2, no SN1

Relative rates of SN2 reactions with iodide ion

1:500
C=O group stabilizes the T.S. by
Overlap of its π* orbital with full
P-orbital of the C-atom under attack
SN2 reaction : Effect of Nucleophile
■ The nucleophilicity may be correlated
with the availability of the electron
pairs and the ease with which it is
donated
 Trends in Nuc. Strength
■ Increases down Periodic Table, as
size and polarizability increase:
- - - -
I > Br > Cl >F

■ Of a conjugate acid-base pair, the

base is stronger:
- -
OH > H2O, NH2 > NH3
Polarizability and nucleophilicity - increased
polarizability makes for a better nucleophile

I- > Br- > Cl- >F-

 Effect of Nucleophile :
The nucleophilicity may be correlated to its basicity as both involve the
availability of the electron pairs and the ease with which it is donated

A negatively charged nucleophile is

Nucleophilicity of always stronger than its conjugate acid.

The direct relationship between basicity and nucleophilicity

is maintained if the reaction occurs in the gas phase
 SN2: Nucleophilic Strength
■ Stronger nucleophiles react faster.
■ Strong bases are strong nucleophiles, but
not all strong nucleophiles are basic.

=>
SN2 reaction : Effect of leaving group
•A good leaving group needs to be a
Stable anions that are weak bases
which can delocalize charge

30
The Leaving Group
Sulfonate Leaving Groups
SN2 reaction : Effect of Solvent
■ Solvent

Polar Solvent
nonpolar Solvent

Polar protic Solvent Polar aprotic Solvent

SN2 reaction prefers polar aprotic

solvent
 Solvent Effects (1)
Polar protic solvents (O-H or N-H) reduce
the strength of the nucleophile.
Hydrogen bonds must be broken before
nucleophile can attack the carbon.

=>
 Solvent Effects (2)
■ Polar aprotic solvents (no O-H or N-H) do
not form hydrogen bonds with nucleophile
■ Examples:

=>
Marked effect on the rate of SN2 reaction, when that transferred from
polar protic solvent to polar aprotic solvent.

•In MeOH both Na+ and N3- are solvated.

• In DMF only Na+ is solvated, but not N3-.
• So, unsolvated N3- is a much more powerful nucleophile
 SN 1
■ reaction and mechanism
■ kinetics
■ stereochemistry
■ substrate structure
■ nucleophiles
■ leaving groups
■ solvents
SN1: reaction and mechanism
Solvolysis of tert-Butyl Bromide
SN1: Mechanism

carbocation

1935: Hughes & Ingold

SN1 reaction : Kinetics
Reaction profile for SN1 reaction
 SN1 Reaction: kinetics

■ The reactions follows first

order (unimolecular) kinetics

1
■ Rate = k [R-Br]
SN1 reaction : Stereochemistry
 SN1: Hydrolysis of t -butyl chloride by base proceed according to
Rate = k1[t -BuCl] or independent of [OH-]

1. Halide undergoes slow ionization to yield the ion pair R + and Cl-
followed by first attack by –OH or solvent or nuleophile.
2. The energy necessary to effect the initial ionization is largely
recovered from the energy evolved through solvation of the resultant
ion-pair.
 Chiral substrate

Dissociation

Nu Nu

Nu Nu

50% inversion of Planar, achiral carbocation 50% retention of

configuration intermediate configuration

©2007 Thomson Higher Education
 OCH2CH3
CH3CH₂OH -H+ ☐
(S)
from the top H3CC
:Br:
(CH3)2CH CH2CH3
retention of configuration
:Br:

H3CC H3CC+-CH2CH3
(CH3)2CH CH2CH3 (CH3)2CH HC CH3CH3
(S) CH3CH,OH -H+
(CH3) CH C

from the bottom

(R)
OCH2CH3
planar carbocation (achiral)
inversion of configuration
SN1 reaction : substrate
structure
■ Stability of carbocation
 CH3

CH Br CH CH—Br CH3-CH2-Br CH3-Br

v
C— > >

CH3
CH3

tertiary secondary primary

CH

CH
CH CH CHCH2 CH3
CH3
CH3
 SN1 Reaction: substrate
structure

Solvolysis in water at 50°C

SN1 reaction : Effect of Nucleophile
 Nucleophiles in SN1

■ Since nucleophilic addition occurs after

formation of carbocation, reaction rate is
not normally affected by nature or
concentration of nucleophile (weak
nucleophile)
A protic solvent acts as both a solvent
and nucleophile in SN1 reactions -
solvolysis:

abbreviations
SN1 reaction : Effect of leaving group
 Leaving groups

■ Leaving groups are the same as in SN2

reactions:
SN1 reaction : Effect of Solvent
 Solvent effect

Increase in dielectric constant and/or ion-solvating ability

result in a marked increase in reaction rate
■ Polar protic solvents favoring the SN1 reaction since it stabilizes
carbocation of the transition state
■ Protic solvents disfavor the SN2 reaction by stabilizing the ground
state

Transfer from polar, protic to polar, aprotic solvents can

change the reaction mode from SN1 SN2
Things to remember
 SN2 or SN1?
■ Primary or methyl ■ Tertiary
■ Strong nucleophile ■ Weak nucleophile
■ Polar aprotic (may also be solvent)
solvent ■ Polar protic solvent,
■ Rate = k [halide] silver salts
[Nuc] ■ Rate = k [halide]
■ Inversion ■ Racemization
■ No rearrangements ■ Rearranged products
=>
■ Competition reaction in SN1
 Rearrangements

■ Carbocations can rearrange to form a

more stable carbocation.
■ Hydride shift: H- on adjacent carbon bonds
with C+.
■ Methyl shift: CH3- moves from adjacent
carbon if no H’s are available.

=>
Hydride Shift

=>
Methyl Shift

=>
Important substrates……..
Allylic and Benzylic compounds
Allylic and Benzylic compounds
Allylic and benzylic compounds are especially reactive in
SN1 reactions.
Even though they are primary substrates, they are more
reactive most other halides! They form resonance
stabilized carbocations.
Allylic and Benzylic compounds

Allylic and benzylic compounds are especially reactive in

SN2 reactions.
They are more reactive than typical primary compounds!
For SN2: stabilisation of TS by conjugation with allylic
π-bond
 BENZYL ( GOOD FOR SN1 )
IS ALSO A GOOD SN2 SUBSTRATE
primary, but faster
than other primary

I overlap in
the activated
H complex
lowers the
activation
energy
H

Br
critical
overlap
Vinyl and aryl halides
Vinyl and aryl halides do not undergo SN1 because:

75
Vinyl and aryl halides do not undergo SN2 because:

76
Cyclic systems
rigid bicyclic molecule.

You can’t have p orbitals on a -- You cannot form a carbocation

bridgehead position at a bridgehead position.

cannot become
+ planar

+
NEIGHBORING GROUP
PARTICIPATION

WHEN YOU NEIGHBOR HELPS OUT

Neighboring Group Participation (Anchimeric asssitance)

Hydrolysis of EtS–CH2CH2 – Cl is 104 times faster than that of EtO–CH2CH2–Cl. Why?

Neighboring Group Participation : Retention of configuration

NaOH
Retention

-
OH

-
OH
Inversion 1 Inversion 2
-
OH
 α-Bromopropionate Ion
Example-1

- -
SN2

-
Two different results! neither SN1 or SN2
REACTION IN CONCENTRATED BASE
straightforward SN2 displacement

SN2 ( rate = k[RBr] [OH] ) is favored by high [OH]

 REACTION IN DILUTE BASE
neighboring group participation

In dilute base
the internal
displacement
has a competing
Two inversions
rate.
give a product
with retention.
Example-2
THE ACETOXY BROSYLATE GIVES 100% TRANS
 INTERMEDIATE ION

Bridged ion,
OAc attacks
+
equally on
+ either side,
but always
anti

- O-Ac

trans diacetate
Example-3

Participation of the π electrons of the double bond gives the ion III, which
would be stabilized by delocalization of the positive charge.
I undergoes 1011 times greater rate than II
Q. Which compound solvolyses faster in HOAc containing NaOAc
(I or II)?

The product is the same from either I or II. What is the structure
of the product?
APPEL REACTION
Mechanism
 A modern SN2 reaction: Mitsunobu reaction

DEAD +Ph3P
+ HNu

PhCOOH

DEAD +Ph3P
100% inversion

Normal ester formation leads with retention

 Mechanism:
First step involves neither the Nu nor the alcohol

Stable anion

Ph3P=O
+

One step process for esters, all four reagents are taken together