Lecture 3

Problems :
SN2 reaction by EtO- in EtOH:
CH3CH2 Br
relative rate

CH3CH2CH2 Br

Me2HCCH2 Br

Me3CCH2 Br

3.0X10-2

24.2X10-6

2.8X10-1

Explain ?

Rate of solvolysis in EtOH :

Br

Br

Br

Explain?
1
Br

10-6

10-14

Br

Explain ?
1

10-23

Relative Rates of Reaction of Alkyl

Bromides with Lithium Iodide in Acetone
Alkyl group

Relative Rate

Isopropyl

1.0

Cyclopropyl

no reaction detected

Cyclobutyl

0.008

Cyclopentyl

1.6

Cyclohexyl

0.01

Cycloheptyl

1.0

Q. Relative rate of solvolysis under SN1 condition

Me

Me
HC

C
Me
1.0

Explain

Cl

H2C

C
H

C
Me
10,000

Cl

Q. Compare the relative rates of solvolysis of

t

CH3
H3C
H3C

Bu

Cl

Which reaction is faster?

&

But t
Bu

Cl

Solvent
effect
Me
Rate solvolysis of

Me
Me

in EtOH
1
in EtOH-H2O (1:1) 3X104

Br

Dielectric constant (, at 25 C): H2O

EtOH

79
25

Increase in dielectric constant and/or ion-solvating ability

result in a marked increase in reaction rate
R

Hal

Hal

R+ Hal-

The energy required for this process decreases as dielectric constant

increases
The process is also facilitated by increasing solvation and consequent
stabilization of the ion-pair

For SN2: Increasing dielectric constant has much less

effect.
Nu- + R

Hal

Nu

Hal

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.
Me

I +

N3-Na+

solvent

Rate in MeOH ( 33)

DMF

( 37)

DMSO ( 46)

Me N3

1
4.5X104

1X109

+ NaI

DMF: HCONMe2

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

When an alkyl halide undergoes both SN1 and SN2 reactions, the SN2 reaction
will be
favored by a high concentration of a good (negatively charged) neocleophile
in a polar aprotic solvent, whereas the SN1 reaction will be favoured by a
poor (neutral) nucleophile in a polar protic solvent
H3C

O
H

CH3

C N
DMF

S
CH3

O
H3C

O
H3C

H3C

H3C

Me

polar protic solvent: H2O , MeOH, EtOH

Me

..

O
..

CH3

H
O

Na
..
O
..

Me
H

CH3

O
H

Me

..
..

..
..

CH3

polar aprotic solvent

DMSO

Me

Na

CH3

CH3

O
Me

N3

Me
H

H
O

Me

Increase in solvent polarity & ion-solvating ability may change the reaction mode from
SN2SN1
Transfer from polar, protic to polar, aprotic solvents can change the reaction mode from

Q. Which reaction will take place more rapidly?

CH3Br +

NH3

CH3Br +

NH3

Et2O
EtOH

CH3NH3

Br

CH3NH3

Br

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

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
CH3O

CH3OH

+
+

rapid
H3C

very
H3C

Nucleophilicity of CH O
3

slow

>

Stronger base
better nucleophile

CH3OH

CH3OCH3

HI

A negatively charged nucleophile is

always stronger than its conjugate acid.

weaker base
poorer nucleophile

HO

>

H2O

CH3O

>
>

CH3OH

H2N

CH3OCH3

NH3

The direct relationship between basicity and nucleophilicity

is maintained if the reaction occurs in the gas phase

increasing
size

increasing
nucleophilicity
in a protic solvent

FClBrI-

increasing
basicity

increasing
nucleophilicity
in gas phase

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:

Effectiveness of different nucleophiles in SN2 reaction

Relative rates of reaction with MeBr in EtOH
Nucleophile

pKa of HX

Relative rate

HO

15.7

1.2 x 104

PhO

10.0

2.0 x 103

AcO

4.8

19.0 x 102

H2O

-1.7

1.0

Relative rates of reaction with MeBr in EtOH

Nucleophile

pKa of HX

Relative rate

PhS

6.4

5.0 x 107

PhO

10.0

2.0 x 103

Relative nucleophilicity toward CH3I in MeOH

RSICN
CH3OBrNH3
ClFCH3OH

increasing
nucleophilicity

O
S

S
R

Br

X
O

S
S

So, sulfur is a better nucleophile than is oxygen for saturated carbon. Why should this be ?

There are two main factors controlling bimolecular reaction:

i) Electrostatic attraction (simple attraction of opposite charges)
ii) Productive interaction between the HOMO of the nucleophile and the LUMO of the electrophile
R1
X

R1

R2

R1

XH

R2

Heavily influenced by electrostatic attarction

(as well as by HOMO-LUMO interaction).

X = O , NH

Electrostatic attarction is unimportant in SN2 reactions,

only HOMO-LUMO interaction matter
_

Hard nucleophiles, soft nucleophiles

Hard nucleophiles

Soft nucleophiles

small

large

charged

neutral

basic ( HX weak acid )

low-energy HOMO
like to attack C=O
such as RO, NH2, R, F, Cl

not basic ( HY strong acid )

high-energy HOMO
like to attack satd. carbon
such as RS, I, R3P, RSH

Broder line: N3, CN, Br, RNH2

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

N + CH3I

CH3 +

Explain the relative rate

Me

1.00

2.27

Me

N
0.47

Me

N
0.042

Me

Proble
m

Ph

Relative rate of reaction of nucleophiles PhCH

with2S
Ph

Nucleophile AcO Cl PhO HO PhS

rate
3.9
4.0 3.8 74 107

Relative rate of reaction of nucleophiles with

MeBr

Nucleophile AcO
rate
900
Explain

Cl PhO
1100 2000

PhS
HO
1.2x104 5x107

Ambident nucleophile: Nucleophiles which have more than one

(generally two) suitable atoms through which they can attack the substrate.

..

N
O

Br + AgCN

Br + NaCN

slow

AgBr + R + [CN]
NC

fast

R
R

Br

N
C

SN1

SN2

TS

Br + AgNO2

Br + NaNO2

slow

AgBr + R + [NO2]
O2N

fast

SN1

O-N=O

SN2

RNO2

Br

TS

O
H3C

H3C

CH2

CH3I

CH2

Me3SiCl

O
OSiMe3
H3C

CH2CH3

H3C

OH

RCHO

CH2

The leaving group:

X +

RCH2
X:
Relative rate

HO

I
30,000

RCH2
Br
10,000

Cl
2,00

OH + X
F
1

The weaker the basicity of a group, the better is the leaving ability.
Relative acidity

HI > HBr > HCl > HF (also from C-X bond energy)

Size is more important than the electronegativity

a)
b)
c)
d)

The strength of R-X bond

The polarisability of the bond
The stability of X(-)
The degree of stabilisation through solvation of X (-)

For halides (a) & (b) are more imporatnt

O
O
S
O

Me
tosylate

O
O
F3C S
O
triflate

(c) & (d) are more imporatnt

Nucleophilic catalysis
H2O: + R Cl

slow

R OH +

H Cl

I trace amt. (cat.)

H2O: + R Cl

+ R Cl

fast

fast
I R
fast

R OH

H2O:

+ R OH

+ Cl

Br

+ R OH

Br R + HO

Br

Br R + H2O

+ R O H
H

Me
Me
Me

OH

shake 20 min.
rt
OH

HO

Me

conc. HCl

Br

conc. (48%) HBr

OH

conc. (48%) HBr

H2SO4

SN1

Cl

Me
Me

Br

SN2 & SN1

Br

R is also
important

SN2

Stronger base
better nucleophile

HO

poorer
leaving group

weaker base
poorer nucleophile

H2O
better
leaving group

OH

PBr3

Br

Br

P Br

Br
-H
Br
O

PBr2

Cl

solvolysis

OEt

solvolysis

OEt

Cl

EtOH

EtOH

SN1 solvolysis

Cl

In presence of high concentration of EtOR

EtO

EtO

SN2'

Tends to occur when R is bulky enough to reduce markedly the rate of direct SN2 displacement.

A modern SN2 reaction: Mitsunobu reaction

O

+ NuH

OH

Ph3P, DEAD

OH

Et

Et

O
Diethyl azo dicarboxylate (DEAD)

Ph3P, DEAD

Nu

R
O
Ph
100% inversion

PhCO2H

Mechanism
Ph3P:
EtO2C

CO2Et

Ph3P
N
CO2Et
EtO2C
N
H

Ph3P
EtO2C
O

N
H

CO2Et

Nu

SN2

Ph3P

H Nu

Nu
100%

EtO2C

N
H

CO2Et

EtO2C

H
N

N
H

CO2Et

Problem:
O
HO

Ph3P, DEAD
Mitsunobu PhCO2H
reaction
O
O
PhCO

O
HO

hydrolysis

SN2: Inversion of configuaration

SN1: ideally Racemization
Retention of configuaration :

SNi ( substitution nucleophilic internal)

Me

Me
OH

Ph

SOCl2

Cl

Ph

SO2

HCl

S N2

Rate = K [ROH] [ SOCl2]

However, it cant be a simple SN2.

OH

Ph

SOCl2

O
OSCl

Ph
H

Ph

Cl + HCl

SNi

Me

Me

Me

Me

Me

Slow
OS

Ph

Cl

Cl

Ph
H

ion pair

Me
Ph

Cl

H
Cl attacks from the
same side with
retention configuration

Problem:
Me

Me
OH

Ph

SOCl2
Py

Cl

Ph
H

Inversion

Neighbouring Group Participation (Anchimeric asssitance)

Hydrolysis of EtSCH2CH2 Cl is 104 times faster than that of EtOCH2CH2Cl. Why?

..

slow

EtS

Cl

fast

EtS

Cl

..

EtS

OH

..
OH2

Neighbouring Group Participation : Retention

Br

Br
OH

conc. NaOH

O
(S)-2-bromo propanoic acid

SN2

H3O

OH
O
(R)-lactic acid

HO
Ag
Br
H

H3O

O
HO

OH
O

OH

Ag2O, H2O
HO

OH

of configuration

NGP
1st inversion

H
O

2nd inversion

(S)-lactic acid

Double inversion = Retention of configuration

Q. The chemistry shown here is the first step in the manufacture of

Pfizers doxasolin (Cardura), a drug for hypertension. Draw the
mechanism of the reaction involved and comment on the bases used

OH
+

OH

Br

KOH

CO2Me
K2CO3, acetone

Br

H2O

CO2H

Q. Draw mechanism for the reactions and describe the stereochemistry

of the product
OR
O

Br

H 2N

Cl
CO2Et
1. PhNMe2, CH2Cl2
2. NaH, DMF

N
CO2Et

OR

Q. Predict the stereochemistry of these products. Are they single

diastereomers, enantiomerically pure, or racemic, or something else ?
OH
O

(a)

N
H

Ph

OTs
(b)

OTs

Ph

KOH
H2S

Q. Describe the stereochemistry of the products of these reactions.

Cl

LiAlH4

(a)

S
_)
(+

OH
O
(b)

HS
enantiomerically pure

base

State with reasons whether these reactions will be either S N1 or SN2.

O
(a)

Br

O
N3

N3

O
O

O
n-PrOH

(b)

OH

H
( _+ )

OH

O
n-PrO

(c)
( _+ )

OPr
( _+ )