Nucleophilic Substitution

1
 Topics

General Reactions

Representing mechanisms through curly arrows

SN1 & SN2:

Mecahanisms, Reaction profiles

Various Effects on SN1 and SN2 reactions

Substrate, Solvent, Nucleophile, Leaving groups

Stereo chemical implications

2
 Nucleophilic Substitution at a saturated carbon
Nucleophile? “Nucleophilic substitution" ?
It is an electron rich species
reacts with an electron poor species one nucleophile replaces another nucleophile.
It occurs when an electron rich species, the nucleophile, reacts with an
electrophilic saturated C atom which is attached to an electronegative
group (important), the leaving group.

Y + C X C Y + X

nucleophile add first & leaving gr. go later

Y + C X Y C X C Y + X
X
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
3
 Two types of discrete mechanisms

SN1 SN2
S: Substitution S: Substitution
N: Nucleophilic N: Nucleophilic
1: Unimolecular 2: Bimolecular

SN1 :
SN2:
slow
R X R + X
Y + R X Y R + X
fast Y
Rate = K[R__X ] [Y]
Rate = K[RX]
R Y

4
 S N2 SN2
Hydrolysis of bromomethane in aqueous base proceeds according to

Rate = k2[CH3Br] [-OH]

H H H
- Br
HO + H HO Br HO H
H H H
H
trasition state

Both alkyl bromide and -OH are participating in the rate-

limiting (slowest) step of the reaction.
-OH becomes partially attached to carbon before Br- is

fully detached.
Energy necessary for breaking C-Br bond is supplied by
that produced in forming HO-C bond.
Quantum mechanical calculation shows that an approach
by -OH along the line of centers of the C & Br is that of
lowest
5
 Pictures of bonding and antibonding Orbitals
HOMO of nucleophile
antibonding sigma * * Cl
interacts with LUMO of
high
electrophile
Unoccupied
antibonding pi *
Best electrophiles should
have low-energy UMO
Pi* & sigma*
nonbonding () N
Lone pairs
Best nucleophiles should
Relative have high-energy OMO
energy
(non-bonding or pi)
Occupied
bonding pi 

low bonding sigma () H

LUMO: lowest unoccupied molecular orbital

HOMO: highest occupied molecular orbital
6
 New  bond old  bond
being formed being broken
H
H

Nu- X
Nu- X-
Filled orbital H
H H
of Nu- H
Empty*
P orbital of C-atom
orbital of C-X

H
H

X Nu
H H
H Bonding orbital H

7
 T.S. for SN2

_ _

C X   Y C
Y Y C X

_ _

Inversion of configuration (Walden inversion)

8
Stereochemistry of SN2
Walden inversion

=>

9
 Important Point to Remember :

Inversion of configuration does not mean R going to S or vice versa.

It means that bond formation takes place opposite to that of bond
breaking….…..which leads to the inversion.
it is like inversion of umbrella in a storm.

C6H13 C6H13
Q.
I*
C I I* C
Me Me
H _
( )
H

(+)

Rate of racemization = twice the rate of inversion or incorporations

10
Reaction profile for SN2 reaction:

11
 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.
12
 SN1 Reaction
◼ Unimolecular nucleophilic substitution.
◼ Two step reaction with carbocation
intermediate.
◼ Rate is first order in the alkyl halide,
zero order in the nucleophile.
◼ Racemization occurs.

=>
13
 SN1 Mechanism (1)
Formation of carbocation (slow)
+ -
(CH3)3C Br (CH3)3C + Br

=>
14
Stereochemistry of SN1
Racemization:
inversion and retention

=>
15
 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.

=> 16
 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

17
 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
18
 SN2 or SN1?
◼ Primary or methyl ◼ Tertiary
◼ Strong nucleophile ◼ Weak nucleophile
◼ Polar aprotic (may also be solvent)
solvent ◼ Polar protic solvent,
◼ Rate = silver salts
k[halide][Nuc]
◼ Rate = k[halide]
◼ Inversion at chiral
◼ Racemization of
carbon optically active
◼ No rearrangements compound
◼ Rearranged products
=> 19
 For SN1 :

R1 R1 R2 R1 R1

R2 Nu R2 R2
C X C Nu + Nu C

R3 R3 R3 R3

Racemization is expected
Extent of inversion = extent of retention
However, due to ion pair formation, more inversion than retention.

Ion pair mechanism :

R1 R1 R2
R2
C X X

R3 R3

20
More inversion than retention.
Reaction profile for SN1 reaction

slow fast
R LG LG + R R Nu
Nu
Rate = K[R-LG]

21
Factors Affecting the Rates of SN1 and SN2 reactions :

1) The structure of the substrate

2) Concentration and Reactivity of Nucleophile

(for bimolecular reactions only)

3) The effect of solvent.

4) The nature of leaving group (nucleofuge)

5) Stereochemical implications of mechanism

22
 Effect of substrate structure
ready hydrolysis

H3C Br H3CH2C Br Me2HC Br Me3C Br

more resistant
Y
R X RY + X

SN2 SN1
Substituent Compound Relative Rate, k2 Relative Rate, k1

Methyl H3C X 6x103 0.002

1o H3CH2C X 30 0.004

2o (H3C)2HC X 1 1

3o (H3C)3C X 0.00005 4x106

For SN2 methyl > primary > secondary >> tertiary (unreactive)
For SN1 tertiary>> secondary> primary> methyl 23
Rates of Hydrolysis in aq. ethanol NaOH solution

24
 To explain we should consider:
The effect of both electronic and steric factors on T.S.

Increase in Me groups: •Inductive effect increases

•C-Br polarity decreases (minor effect)

Increase in crowding
OH- finds it more difficult to attack at C-Br
H3C Br H3CH2C Br Me2HC Br Me3C Br

SN2 & SN1 SN1

SN2
Steric factors are of more importance
H Me Me
Me
Br Br Me Br
H H Br H
H Me Me
H
5 groups
Me Me Me Me
Me Br X HO Br Me Cl + relief of
Me Me Me Me crowding
Me Me
4 groups trasition state
terribly crowed sp3 sp2 25
 For SN1 : ion pair formation
increasing stability of the carbocation

H Me Me
Me
Br Br Me Br
H H Br H
H Me Me
H

inductive effect
H Me Me Me
+ + + +
H H H H H Me Me Me
no. -hydrogen 0 3 6 9

hyperconjugation H CH2 H+ CH2

+
Me Me Me Me

Stability of carbocation is important for SN1

26
 Br more reactive than Br
True for both SN1 and SN2

For SN1: stabilisation of carbocation by delocalisation

Br Br

For SN2: π* of C=C and σ* of C-Br to have a new stable LUMO, that is
attacked by nucleophile. (-) +
+
+ Br
(-) +
Nu Nu H
H H
Br
H Nu Nu (-)
Br (-)
T.S.
T.S.
X
The benzyl group acts in much the same way:
27
28
 BENZYL AND ALLYL CARBOCATIONS
BENZYL RESONANCE
STABILIZATION
+
+
CH2 CH2 etc

ALLYL +
+
CH2 CH2 etc

Systems that are similar in form to benzyl and allyl are called benzylic and allylic.

+
H3C O CH2
+ + isoelectronic
(benzylic) (allylic)
with allylic 29
 SOLVOLYSIS RATES
80% Ethanol-water at 50°

R C l + H 2O ROH + HCl
( R C l + E tO H ROEt + HC l )
both reactions take place

krel
Ethyl chloride very small good but
Isopropyl chloride 1 not as good
Allyl chloride 74 as tertiary
Benzyl chloride 140
tert-Butyl chloride 12,000

30
WILL NOT REACT - SN1

X
+
Br

cannot become
+ planar

+
“steric rigidity”
31
 WILL NOT REACT - SN2
backside
attack is
difficult

Steric
Hindrance

Br

32
 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 33
34
 O O
Nu- only SN2, no SN1
Hal Nu
R R

R = alkyl, aryl, OR'

Relative rates of SN2 reactions with iodide ion

O
Cl 1:500
Me Cl
C=O group stabilizes the T.S. by
Overlap of its * orbital with full
P-orbital of the C-atom under attack

+
+
* of Cl
the C=O H
H

Nu
35
36
Relative rates of SN2 reactions of alkyl chlorides with the iodide ion
Alkyl chloride relative rate
The rates are
200 given with
Me Cl
respect to
n-BuCl

0.02
Cl

Cl 79

Cl
200

Me 920
O Cl

Cl
1,00,000

37
 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 38
Q. Relative rate of solvolysis under SN1 condition

Me Me

HC C C Cl H 2C C C Cl
H
Me Me

1.0 10,000

Explain?

39
 Triphenylmethyl chloride derivatives (SN1) in SN reaction

Cl
Cl
MeO

Tr-Cl MMTr-Cl

Cl Cl
MeO OMe MeO OMe

TMTr-Cl
DMTr-Cl OMe

40
 Solvent effect
Me
Solvolysis rate of Me Br in EtOH 1
Me in EtOH-H2O (1:1) 3X104

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

EtOH 25

Increase in dielectric constant and/or ion-solvating ability

result in a marked increase in reaction rate

+ -
R Hal R Hal R+ Hal-

The energy required for this process decreases as

dielectric constant increases
The process is facilitated by increasing solvation and
consequent stabilization of the ion-pair
41
 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.

=>

42
 Solvent Effects (2)
◼ Polar aprotic solvents (no O-H or N-H) do
not form hydrogen bonds with nucleophile
◼ Examples:

O
CH3 C N O
C CH3
acetonitrile H N C
CH3 H3C CH3 =>
dimethylformamide acetone
(DMF)
43
 For SN2: Increasing dielectric constant has much less effect.
Results in slight decrease in rate

- -
Nu- + R Hal Nu R Hal R Nu

• New charge is not developed.

• Existing charge is dispersed in the T.S. compared with the starting material

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 44
 •When RX is capable of undergoing both SN1 and SN2 reactions:
•SN2 reaction will be favored by a high concentration of a good
(negatively charged) nucleophile in a polar aprotic solvent,
• SN1 reaction will be favored by a poor (neutral) nucleophile in a
polar protic solvent H C CH 3 3
S
Polar aprotic solvents: DMF & DMSO
O CH3 O O

H3 C CH3
H C N CH3 H3C S CH3 S O Na O S
H3 C CH3
O
Polar protic solvents: H2O, MeOH, EtOH
S
Me H3C CH3
H .. Me O
O
..
Me H
H Me Increase in solvent polarity
O O
..
..
..
..

Na
O H N3 H O & ion-solvating ability may
H ..
O
Me
Me change the reaction mode
.. H
Me H from SN2→SN1
O
Me
Transfer from polar, protic to polar, aprotic solvents can
change the reaction mode from SN1 → SN2 45
Solvent effects
Rate of a reaction depends on the difference between the energy of the
reactants & the energy of the TS in the r.d.s. of reaction

•Increasing the polarity of the solvent decreases the rate of the reaction if the
reactants in RDS are charged
•Increasing polarity of the solvent increases the rate of the reaction if none of
the reactants in RDS are charged
46
 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
CH3O + H 3C I CH3OCH 3 + I

very
CH3OH + H 3C 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 47
 SN2: Nucleophilic Strength
◼ Stronger nucleophiles react faster.
◼ Strong bases are strong nucleophiles, but
not all strong nucleophiles are basic.

=>

48
 Trends in Nuc. Strength
◼ Of a conjugate acid-base pair, the base is
stronger:
OH- > H2O, NH2- > NH3
◼ Decreases left to right on Periodic Table.
More electronegative atoms less likely to
form new bond:
OH- > F-, NH3 > H2O
◼ Increases down Periodic Table, as size
and polarizability increase:
I- > Br- > Cl-
49
Polarizability Effect

=>

50
 O R Br O

S S N2 S R

X
O R Br O R

S SN 2 S

In alkyl iodides
+
O −
R Br one of the
best electrophiles
considerable very little there is
polarisation polarisation
X virtually no
electrostatic attractions are unimportant in SN2 reactions dipole at all!!51
There are two main factors controlling
bimolecular reactions:
i) Electrostatic attraction (simple attraction of
opposite charges)
ii) Productive interaction between the HOMO of
the nucleophile and the LUMO of the
electrophile

Electrostatic attraction is unimportant

in SN2 reactions, only HOMO-LUMO
interaction matters

52
 Typical arrangement of molecular energy levels

The higher energy (3sp3) lone-pair electrons on sulfur overlap better

with the high-energy * orbital of C-X bond than do the lower-energy
(2sp3) lone-pair electrons on oxygen because the higher energy of the
sulfur electrons brings them closer in energy to the C-X * orbital.

53
 Nucleophilic power towards saturated carbon

In a particular group, nucleophilicity increases as we go down the group

I > Br > Cl > F

RSe > RS > RO

R3P: > R3N:

Relative rates of reaction of nucleophiles with MeBr in EtOH

nucleophile F- H2O Et3N Br- PhO- EtO- I- PhS-

relative rate 0.0 1.0 1400 5000 2.x10 3 6x104 1.2x105 5x107
54
 Hard nucleophiles and Soft nucleophiles

Small with closely held electrons Large & Flabby with diffuse high
with high charge density energy electrons

Only charged Can be neutral

Basic (HX weak acid) Not basic (HY strong acid)

Low energy HOMO High energy HOMO

Like to attack at C=O Like to attack at saturated

carbon

RO-, -NH2, R-, F-, Cl- RS-, I-,R3P, RSH

Reactions are controlled by Reactions are controlled by

Electrostatic interactions HOMO-LUMO interactions

Broder line: N3, CN, Br, RNH2

55
 Soft nucleophiles are rather large and flabby
with diffuse high-energy electrons

Hard nucleophiles are small with closely held

electrons and high charge density

For hard nucleophiles → reactions are dominated

by electrostatic interactions

For soft nucleophiles→ reactions are dominated

by HOMO-LUMO interactions

56
Ambident nucleophile: Nucleophiles which have more than one
(generally two) suitable atoms through which they can attack the substrate.

..
C N C N

O O
X Y X Y
S S

57
 O O OH O
RCHO

H3C CH2 R CH3

H3C CH2

CH3I Me3SiCl
O
OSiMe3
H3C CH2CH3
H3C CH2

The O-Si bond is much stronger (108 kcal/mol) than

C-Si bond (76 kcal/mol)

Trimethylsilyl enol ether, method to trap in enolate

58