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

OH
O

(a)

N
N
H

Ph

OTs

Ph

OTs

KOH

(b)

H2S
HS

SH

SN2

OTs

S
OTs

In presence of high concentration of EtOR

EtO

SN2'

EtO

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

Example:
Cl
D

OCH3
H

NaOMe

OCH3

Cl
D

NaOMe
H3CO

Cl

O
H
O

But

R=Cl2C6H3-

But

H
N

N
+

/
Examples of SNi reaction
Cl
H3CCH

CHCH2OH

SOCl2

H3C

Ether

CH

CH2

(only)
H3 C

H
C

CH

CH2

SOCl2

H3C

Ether

CH

C
H

CH2Cl

(only)

OH

Mechanism
H3C
H3CCH

CHCH2

Cl

..
.Cl.

CH2
O
S
O

H3 C

CH
CH
Cl

CH2

SO2

Payne rearrangement
S
Ph

Ph

Ph
OH

Ph

OH

Ph

O
OH

Ph

S
OH

S
OH

OH
H2O

NaOH

O
Ph

OH

Neighbouring group participation

Q.

HNO2

CO2H

OH H2N

H
O

HO

S
OH

N2
O

CO2H

O
O

H
O

Q.

When I undergoes SN1 solvolysis, it reacts more rapidly than isobutyl chloride II.
Explain.

CH3
H3 C

C
H
I

CH2Cl

H3C

C
H

C Cl
H2

II

phenonium ion

H
H3 C

H
H
Cl

H
H3C

H
Cl
TS

+ Cl
H
H3C

H
Sol

OH

Solvolysis products

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?
S

Cl

H
I

Cl

II

H
OAc

Q. Which compound solvolyses faster in HOAc? (I or II). Give the

structure of the product from I.
OTs

OTs

II

OTs
OAc

HOAc

I
III

Participation of the electrons of the double bond gives the ion III
, which would be stabilized by delocalization of the positive charge

Q. Suggest a mechanism for the following reaction

O

Ph

H2O

Cl

Ph

N
H

CH3CN, heat

Ph

Ph
O

O
O

O
Cl

Ph

Ph

O
N

Ph
O

Ph

Ph

Ph

N
O
OH

O
O
Ph

Ph

N
H
O

Q. Hydrolysis of EtSCH2CHMeCl produces two products:

EtSCH2CH(Me)OH & EtSCHMeCH2OH. Explain.

Q. Hydrolysis of PhSCH2CH2Cl is considerably

slower than that of EtSCH2CH2Cl. Explain.

R X

NaCN

solvent ?

R CN

NaCN, an ionic compound, is soluble only water

RX preferred non-polar organic solvent and those are immiscible.
R X

NaCN

CH2Cl2, H2O

XR

CN

PHASE TRANSFER CATALYST (PTC)

R X

NaCN

R4N HSO4 trace amt. (cat.)

CH2Cl2, H2O

R CN
fast

Phase transfer catalysis

aq. phase
Na+ CN -

aq. phase
+

Na CN
org. phase

+
Q X

Na+ X-

Q + CN

Q + CN
+

add Q + X -

RX

Q+X
+

CH2Cl2
+

QX = R4N X

RCN

RX

such as (CH3CH2CH2 CH2)4 N+ XHere no reaction takes place

because the nucleophile, CN -,
cannot enter the org. phase to
react with RX

org. phase
CH2Cl2

Here the PTC transports the cyanide ion

(as Q + CN -) into the organic phase where
the reaction
CN - + RX

RCN + X -

takes place rapidly

Phase- transfer catalysis of the SN2 reaction between NaCN and an alkyl halide

Example

CH3(CH2)7Cl

(in dioxane)

Bu4 NBr

CH3(CH2)7CN
aq. NaCN, 105 0C
(95 %)

Other types of reactions with PTC

H3C(H2C)5 HC

CH2 (benzene)

R4 N X
0

aq. KMnO4, 35 C

CH3 (CH2)5COOH
99 %

Crown ethers
O

O
O

K+
O

:O

:O

O:

..

18 - Crown - 6

K + CN

C6H5 CH2Cl

RCH2X

KF

18-C-6
benzene
CH3CN

18-C-6

K+ X -

C6H5 CH2F +

K+ Cl -

RCH2CN

100 %

O
O

O
Na+

O
[15]-crown-5
cavity diameter = 1.7-2.2 A

ionic diameter of Na+ is 1.80 A

O
O

inclusion compound

O
O

O
Li+

[12]-crown-4

cavity diameter = 1.2-1.5 A

ionic diameter of Li+ is 1.20 A

Crown ethers are named [X]-crown-Y, where X is the total number atoms in the ring
and Y is the number of oxygen atoms in the ring

Host-guest relationship
The hole has diameter 2.7 A
Diameter of K+ = 2.66 A

An ionophorous antibiotic
O
O

O
O

O
Nonactin
an antibiotic

By disrubting carefully maintained electrolyte

balance between inside and outside

An ionophore is a compound that transport metal ions by binding them tightly.

Mustard gas a war gas that produces blisters all over the body surface
..
.S.
Cl

mustard gas

Cl

Cl

Cl
Nu

Cl

Nu

The toxicity of mustard gas is due to nucleophiles of cell

components becoming alkylated

Biological Nucleophilic Substitution

Biological methylation for an organic chemist

..Nu

CH3 I

CH3Nu +

For nucleophile in a cell, MeI cannot be used, because alkyl halides are insoluble
in water
In biological systems, you have got predominantly aqueous environment
Lets take the case of methylation in the cells of plants and animals:

Here it involves the transfer of a methyl group from an amino acid (methionine)
CH3

O2C CHCH2CH2 S CH3

+NH
3

H3C

N+ CH2CH2OH

HO

CH3 choline

HO

CH CH2NH CH3
adrenaline

OH

N
CH3
N

nicotine

Choline : important in the transmission of nerve impulses

Adrenaline : causes blood pressure to increase
Nicotine : makes smoking tobacco addictive

triphosphate group
OH

nucleophile
O 2C

..

CHCH2CH2SCH3
CH2

NH3

O
O

OH
O

OH
O

OH

leaving
group

Adenine

ATP
CH3
O2CCHCH2CH2

OH
CH2

Adenine

H3N

OH
OH

P
O

OH

NH2

Adenine =
N

OH
O

Triphosphate ion

OH

OH

P
O

OH

CH3

..

N
CH3

HO

CH3

O2CCHCH2CH2

CH2
H

H3N

Adenine

O
H

H
OH

S-Adenosylmethionine (SAM)

CH3
H3C

N
CH3

OH

OH

O2CCHCH2CH2

CH2
H

H3N

Adenine

O
H

choline
H

.
.
.

H
OH

Nature makes use of high nucleophilicity of sulfur

Weakly basic group (eg. triphosphate of ATP) functions as LG
Attack at the less hindered CH3- rather at one of the more
hindered -CH2- groups

OH

OTs

OTs

Q.

CH3

CH3

O
I

II

Which compound solvolyses in HOAc faster ?

Predict the stereochemistry in each case
If I is optically active, will the solvolysed product be racemic ?
OTs
O

OAc
HOAc
OAc

AcOH
..
s

OAc

(+)

OAc

OAc

OAc

(+)

AcOH

Q.

O
Relative rate

1.0

0.014

0.14

4.85 x 10 4

Explain
Transannular participation of ether oxygen
O

..

II

III is more favorable than either I or II

Unfavorable polar effect of the C-O bond

III

 SN1 reaction may be substantially retarded by substitution of deuterium

atoms for hydrogen at one or more -carbons
Cl

Cl

(CD3)2CCD2CH3

(CH3)2CCD2CH3

kD
kH

0.43

H
C

0.71

stabilization by hyperconjugation
Stretching of the -C-H bonds in the activated complex
Since -C-D bonds are somewhat tighter bonds than -C-H bonds, substitution for
-hydrogens lower the extent of stabilization by hyperconjugation in the activated
complex, boost the energy of activation and thus retard the reaction.

H
empty p orbital

H 3C

CH3
H

H
H 2C

CH2
CH2
H

extra stabilization from

donation into empty p orbital of
planar carbocation

H3C
H2C

CH3
CH2
CH2
CH3

extra stabilization from

donation into empty p orbital
of planar carbocation

H
H

no stabilization: no electrons
to donate into empty p orbital
The C-H bonds are at 90 to
the empty p orbital and
cannot interact with it

A C-C bond is just as good as the C-H bond in donating electrons into an empty
p orbital and a C-Si bond is even better.

Q.

D
Ph

CH2Cl

D
HCOOH

Product

Me

Me

Cl

HCOOH

Product

Where do you expect D-effect should be considerably less?

Q. Which one reacts with MeI more rapidly ?

..N

..N

II

Q. Which reaction takes place more rapidly (I or 2) ?

Cl

Cl

H2O

H 2O

Steric acceleration

OH

OH

HCl

HCl

(1
)

(2)