Reactions

Ionic reactions: Radical reactions:

Bond breaking and bond Bond breaking and bond making

making take place in a take place in a
heterolytic fashion homolytic fashion

- R. X.
R X R+ + X R X +
Ionic Reactions :

1) substitution :
Y + R X R Y + X

R = aliphatic as well as aromatic

2) elimination :

3) addition :
R1
R1 X H R1 XH
X + Y
R2 Y R2 Y
R2

X = O , NH
Nucleophilic Substitution
 Nucleophilic Substitution

Y + R X R Y + X

R = aliphatic as well as aromatic

Nucleophile + Substrate Product + Leaving group

 Nucleophilic Substitution

SN1 SN2

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

leaving group goes first and nucleophile comes later

Y + C X C+ C Y + X

nucleophile attacks and leaving group goes simultaneously

Y + C X C Y + X
 SN2

 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:

9
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

12
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

=>
THE INVERSION sp2
R 2p
HO C B
PROCESS
partial bonding
HO C Br
activated complex
CH3 H is trigonal planar (sp2 )

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

 Should stabilize the

transition state
SN2 Reaction: substrate structure
KI in Acetone at 25°
krel

CH3 Br 150

CH3 CH2 Br 1

CH3 CH Br 0.008
CH3

CH3
unreactive!
CH3 C Br

CH3
Relative rates of SN2 reactions of alkyl chlorides with the iodide ion

The rates are

given with
respect to
Alkyl chloride relative rate n-BuCl

Me Cl 200

0.02
Cl

Me 920
O Cl

Cl
1,00,000
 O
Cl 1:500
Me Cl

 * of of the C-Cl +
+
* of the C=O Cl * of Cl
H the C=O H
H H

Nu Nu

C=O group stabilizes the T.S. by Overlap of its * 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-

 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

31
The Leaving Group
Sulfonate Leaving Groups
O

R O S CH3 R OTs
O
para-Toluenesulfonate Tosylate

R O S Br R OBs

O
para-Bromobenzenesulfonate Brosylate
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:

O O
CH3 C N C CH3 C
acetonitrile H N H3C CH3 =>
CH3 acetone
dimethylformamide
(DMF)
Marked effect on the rate of SN2 reaction, when that transferred from
polar protic solvent to polar aprotic solvent.

solvent
Me I + N3-Na+ Me N3 + NaI

Rate in MeOH ( 33) 1

DMF ( 37) 4.5X104 DMF: HCONMe2

DMSO ( 46) 1X109 DMSO: Me2SO

•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
 SN1
 reaction and mechanism
 kinetics

 stereochemistry

 substrate structure
 nucleophiles

 leaving groups

 solvents
SN1: reaction and mechanism
 Solvolysis of tert-Butyl Bromide

CH3 CH3
acetone
CH3 C CH3 + H 2O CH3 C CH3 + H Br

Br OH
+ other products
SN1: Mechanism

carbocation

1935: Hughes & Ingold

SN1 reaction : Kinetics
 SN1 Reaction: kinetics

 Thereactions follows first

order (unimolecular) kinetics

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

Me
HO Me
fast
Me
Me Me -
slow OH
Me Cl +
fast
Me Me - Me
Me OH
3 2 Me OH
sp sp Me

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.
SN1 reaction : substrate
structure
 Stability of carbocation
 CH3

CH3 C Br > CH3 CH Br > CH3-CH2-Br > CH3-Br

CH3
CH3

tertiary secondary primary

CH3
+ + +
CH3 CH CH3 CH 2 CH3
CH3 C+
CH3
CH3

tertiary secondary primary very unstable

carbocation carbocation carboc
carbocation carbocation
(very stable) (unstable)

three methyl two methyl one methyl no methyl

groups groups group groups
 SN1 Reaction: substrate
structure
krel
CH3 Br no reaction

CH3 CH2 Br 1.00

CH3 CH Br
11.6
CH3

CH3
6
CH3 C Br
1.2 x 10
CH3

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:
Water O
H H
abbreviations
O HOMe
Methanol H CH3

Ethanol O CH3 HOEt

H CH2

Acetic acid O HOAc

H C CH3
O

Formic acid O
H C H
O
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

Dielectric constant (, at 25 C): H2O 79

EtOH 25
 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
=>
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?

.. slow ..
EtS EtS fast
EtS
Cl Cl OH

..
OH2
 Neighboring Group Participation : Retention of configuration
Et2
Et2(HO)C C
NaOH HO
Cl OH Retention
Me Me
H H
Et2
C
-
OH -O
OH
Et2 Et2 Me
-
C C OH H
Inversion 1 Inversion 2
O -
OH
Cl O
Me Me
H H
 a-Bromopropionate Ion

H 3C conc. [OH-] CH3

H C Br 4M
HO C H
C O O C
O- 0.1M O (R)-config
(S)-config
- inversion
dilute
[OH-] H 3C
H C OH SN2

C O
O- (S)-config
retention
Two different results! neither SN1 or SN2
REACTION IN CONCENTRATED BASE
straightforward SN2 displacement

-
H O H 3C CH 3
H C Br conc [OH-] HO C H
C O SN2 O C
inversion
O O
(S)-config (R)-config

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

 REACTION IN DILUTE BASE
neighboring group participation

H3C inversion-1 CH3

H C Br dilute [OH-] O C H
SN2 O H
C O C
O O
(S)-config inversion-2
SN 2
In dilute base H3C
C OH
the internal
displacement
H
has a competing C O Two inversions
rate.
O give a product
with retention.
(S)-config
Q. Which one will undergo SN1 solvolysis faster? Exaplain?

CH3

H3C C CH2Cl H3C C C Cl

I
H H H2
II

phenonium ion

δ
H H + Cl
H
H H H
Cl H
H3C Cl H3C H
TS H3C H
Sol OH

Solvolysis products
Q. Which compound solvolyses faster in HOAc? (I or II). Give the
structure of the product from I.
OTs OTs

I II


OTs
OAc

HOAc
I

III

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
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.

CH2-Br CH2=CH-CH2-Br

benzyl bromide allyl bromide

 +
+
CH2 CH2 etc

+
+
CH2 CH2 etc
Allylic and Benzylic compounds

Allylic and benzylic compounds are especially reactive in

SN2 reactions.
They are more reactive than typical primary compounds!

CH2-Br CH2=CH-CH2-Br

benzyl bromide allyl bromide

For SN2: stabilisation of TS by conjugation with allylic -bond

+ (-) +
+
(-) +
Br
Nu Nu
H
H
Br H
H Nu
Br (-) Nu (-)

T.S. T.S.
 BENZYL ( GOOD FOR SN1 )
IS ALSO A GOOD SN2 SUBSTRATE
primary, but faster
than other primary

CH2 Br + NaI CH2 I + NaBr

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:

79
Vinyl and aryl halides do not undergo SN2 because:

80
Cyclic systems
rigid bicyclic molecule.

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

bridgehead position at a bridgehead position.

X
+
Br

cannot become
+ planar

+
 Problems :

1) SN2 reaction by EtO- in EtOH:

CH3CH2 Br CH3CH2CH2 Br Me2HCCH2 Br Me3CCH2 Br

Explain ?
relative rate 1 2.8X10-1 3.0X10-2
24.2X10-6

2) Rate of solvolysis in EtOH :

Br
Br Explain?
A) Br
cc at bridge head, less
stable, difficult to attain
planarity due to rigidity
1 10-6 10-14

Br Br
B) Explain ?

A) Rigid structure, cation empty

p-orbitals are at right angles
to  orbitals of Ph
1 10-23
1-bromotriptycene
 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
rapid
CH 3O + H3C I CH3OCH 3 + I

very
CH3OH + H3C I CH3OCH 3 + HI
slow
A negatively charged nucleophile is
Nucleophilicity of CH3O
> CH3OH always stronger than its conjugate acid.

Stronger base weaker base

better nucleophile poorer nucleophile

HO > H2O

CH3O > CH3OH

H2N > NH3

The direct relationship between basicity and nucleophilicity

is maintained if the reaction occurs in the gas phase
 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
Br H H
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3

H H
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3

H H Nuc
CH3 C C CH3 Nuc
CH3 C C CH3 =>
H CH3 H CH3
 Methyl Shift
Br CH3 CH3
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3

CH3 CH3
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3

CH3 CH3 Nuc

Nuc
CH3 C C CH3 CH3 C C CH3 =>
H CH3 H CH3