Organic Chemistry

Section 24.7 Intramolecular Catalysis 1013

3-D Molecules:

cis-2-Thiophenyl-

chlorocyclohexane;

trans-2-Thiophenyl-

chlorocyclohexane

A 2-thio-substituted chlorocyclohexane undergoes the same reaction. However, the
rate of the reaction depends on whether the thio substituent is cis or trans to the chloro
substituent. If it is trans, the 2-thio-substituted compound reacts about 70,000 times
faster than the unsubstituted compound. But if it is cis, the 2-thio-substituted com-
pound reacts a little more slowly than the unsubstituted compound.

What accounts for the much faster reaction of the trans-substituted compound? In
this reaction, the thio substituent is an intramolecular nucleophilic catalyst. It
displaces the chloro substituent by attacking the back side of the carbon to which the
chloro substituent is attached. Back-side attack requires both substituents to be in axial
positions, and only the trans isomer can have both of its substituents in axial positions
(Section 2.14). Subsequent attack by water or ethanol on the sulfonium ion is rapid
because the positively charged sulfur is an excellent leaving group and breaking the
three-membered ring releases strain.

PROBLEM 11

Show all the products, and their configurations, that would be obtained from solvolysis of

the trans-substituted compound illustrated in the preceding diagram.

The rate of hydrolysis of phenyl acetate is increased about 150-fold at neutral
pH by the presence of a carboxylate ion in the ortho position. The ortho-carboxyl-
substituted ester is commonly known as aspirin (Section 19.9). In the following
reactions, the reactants and products are shown in the form that predominates at
physiological pH (7.3).

The ortho-carboxylate group is an intramolecular general-base catalyst that increases
the nucleophilicity of water, thereby increasing the rate of formation of the tetrahedral
intermediate.

CH 3 CO

OO

C

O

−

HH

O

relative rate = 1

CH 3 CO +

O

H 2 O CH 3 CO− + HO

O

relative rate ∼ 150

CH 3 CO +

O

H 2 O

−OOC −OOC

CH 3 CO− + HO

O

SC 6 H 5

++HCl

SC 6 H 5 SC 6 H 5

Cl OH OCH 2 CH 3

CH 3 CH 2 OH

H 2 O

3-D Molecule:

Aspirin

C 6 H 5

S

Cl HO

H +

C 6 H 5

S

C 6 H 5

S

OH

Cl− H

+

+

C 6 H 5

S

OH

+ H+

AU: OK as changed?