Organic Chemistry

Section 16.8 Designing a Synthesis III: Synthesis of Monosubstituted and Disubstituted Benzenes 643

Which route we choose depends on how easy it is to carry out the required reactions

and also on the expected yield of the target molecule (the desired product). For exam-
ple, the first route shown for the synthesis of 2-phenylethanol is the better procedure.
The second route has more steps; it requires excess benzene to prevent polyalkyla-
tion;it uses a radical reaction that can produce unwanted side products; the yield of the
elimination reaction is not high (because some substitution product is formed as well);
and hydroboration–oxidation is not an easy reaction to carry out.
In designing the synthesis of disubstituted benzenes, you must consider carefully
the order in which the substituents are to be placed on the ring. For example, if you
want to synthesize meta-bromobenzenesulfonic acid, the sulfonic acid group has to be
placed on the ring first because that group will direct the bromo substituent to the
desired meta position.

However, if the desired product is para-bromobenzenesulfonic acid, the order of
the two reactions must be reversed because only the bromo substituent is an ortho–
para director.

Both substituents of meta-nitroacetophenone are meta directors. However, the
Friedel–Crafts acylation reaction must be carried out first because the benzene ring of
nitrobenzene is too deactivated to undergo a Friedel–Crafts reaction (Section 16.7).

It is also important to determine the point in a reaction sequence at which a sub-
stituent should be chemically modified. In the synthesis of para-chlorobenzoic acid
from toluene, the methyl group is oxidized after it directs the chloro substituent to the
para position. (ortho-Chlorobenzoic acid is also formed in this reaction.)

C

CH 3 CH 3

O

O

CH 3 CCl

C

NO 2

O

+

m-nitroacetophenone

1. AlCl 3 HNO 3


2. H 2 O HH 22 SOSO 44

Br Br

SO 3 H

+

p-bromobenzenesulfonic

acid

Br

SO 3 H

o-bromobenzenesulfonic

acid

Br 2 H 2 SO 4

FeBr 3 ∆

SO 3 H SO 3 H

Br

H 2 SO 4 Br 2

m-bromobenzenesulfonic acid

∆ FeBr 3

Tutorial:

Multistep synthesis of

disubstituted benzenes

CH 2 CH 3 CHCH 3

Br

CH CH 2 CH 2 CH 2 OH

CH 3 CH 2 Br

AlCl 3 peroxide

excess

1. BH 3 /THF


2. HO−, H 2 O 2 , H 2 O

NBS, ∆ tert-BuO−

2-phenylethanol

∆