SYNTHETIC APPLICATION

IN THE SUBSTITUTION REACTION OF

AROMATIC RINGS
Electrophilic Aromatic Substitution Reaction
X
X2, FeX3
Halogenation
(X = Cl, Br)

NO2
HONO2 Nitration

H2SO4

SO3 SO3H
Sulfonation
H2SO4

RCl, AlCl3 R
Friedel- Crafts Alkilation
(R can rearrange)

O O
R C Cl, AlCl3 C R
Friedel-Crafts Acylation
 The Clemmensen Reduction
Rearrangements of the carbon chain do not occur
in Friedel-Crafts acylation, because acylium ion is
more stable than most other carbocations.

Friedel-Crafts acylations followed by reduction of

the carbonyl group to a CH2 group often give us
much better routes to unbranched alkylbenzenes
than do Friedel-Crafts alkylations.
 H3C CH3
CH CH2CH2CH3
AlCl3
+ CH3CH2CH2Br + + HBr

isopropyl benzene propyl benzene

mayor product minor product

O
O
C
AlCl3 CH2CH3
+ CH3CH2CCl + HCl

propanoyl chloride ethyl phenyl ketone

(90%)

This ketone can be reduced to propylbenzene by the

Clemmensen reduction (consist of refluxing the ketone with
hydrochloric acid containing amalgamated zinc).
 O CH2CH2CH3
C
CH2CH3
Zn (Hg)

HCl, reflux
ethyl phenyl ketone
(90%) propyl benzene
(80%)

Exercise:
Starting with benzene and the appropriate acyl
chloride out line the synthesis of each of the following:
a. butyl benzene
b. (CH3)2CHCH2CH2C6H5
c. benzophenone (C6 H5COC 6H5)
 The substitution reaction of the aromatic rings
and the reaction of the side chains of alkyl- and
alkenyl benzenes, offer us a powerful set of
reaction for organic synthesis.
We shall be able to synthesize a large number of
benzene derivatives.
Part of the skill in planning a synthesis is in the
deciding in which reactions should be carried out.
Example: If we want to synthesize
o-bromonitrobenzene we should introduce the
bromine into the ring first because it is an ortho-
para director.
 Br Br Br
Br2 HNO3 NO2
+
FeBr3 H2SO4

o-bromonitrobenzene NO2

p-bromonitrobenzene

The ortho- dan para compounds can be separated by

various methods.
However, had we introduced the nitro group first, we
would have obtained m-bromonitro- benzene as the
major product.
Summary of Substituen Effects on Orientation
o- and p- director m-director
strongly
activating
H2N RHN R2N RC
O
HO RO2C
RO HO3S
RC HN HC
O O
HO2C

N C
R O2N
X +
R3N
strongly
deactivating
Reaction of the side chain of alkyl benzenes
Halogenation
CH3 CH2Cl CHCl2 CCl3
Cl2 Cl2 Cl2
h h h

Oxidation
(1)KMnO4, OH-,heat
CH3 CO2H
(2) H3O+
Exercises:
Starting with benzene, outline a synthesis of
(a) m-chlorotoluene
(b) m-chloroethylbenzene
(c) m-nitrobenzoic acid
 REPLACEMENT REACTION
OF ARENEDIAZONIUM SALTS
 Diazonium salts are highly useful intermediates in
the synthesis of aromatic compounds, because
the azonium group can be replaced by any one of
a number of other atoms or group, including F, -
Cl, -Br, -I, -CN, -OH, and
-H
Diazonium salts are almost always prepared by
diazotizing primary aromatic amines. Primary
arylamines can be synthesized through reduction
of nitro compounds that are readily available
throught direct nitration reaction.
 Most arenediazonium unstable at
temperatures above 5-10o C, and many
explode when dry.

Fortunately, most of the replacement reaction

of diazonium salts do not require their
solution.

We simply add another reagent (CuCl, CuBr,

KI, etc.) to the mixture, gently warm solution,
and the replacement takes place.
Preparing a primary amine from an alkyl halide
The Gabriel Synthesis
 Exercises
Outline a preparation of benzylamine using
the Gabriel Synthesis.
 Preparation of Aromatic Amines
through Reduction of Nitro Compound
Syntheses Using Diazonium Salts
The Sandmeyer Reaction: Replacement of
The Diazonium Group by: -Cl, -Br, or -CN
Replacement by -I
 Replacement by -F
CH3 CH3 CH3
(1) HONO, H+ heat
+ N2 + BF3
(2) HBF4
NH2 N2+ BF4- F
m-toluidine m-toluenediazonium m-fluorotoluene
fluoroborate (79%) (69%)

Replacement by -OH
Cu2O
H3C N2+HSO4- H3C OH
2+
Cu , H2O
p-toluenediazonium p-cresol
hydrogen sulfate (93%)
The Sulfa Drugs

In 1936, Ernest Fourneau of the Pasteur Institute

in Paris demonstrated that prontonsil break
down in the human body to produce
sulfanilamide, and that sulfanilamide is the
actual active agent against streptococci.
The best theurapic results were obtained from
compounds in which one hydrogen of the
SO2NH2 group was replaced by some other
group, usually a heterocyclic ring.
 NH2
O O
H2N N N S NH2 H2N S NH2
O O
protonsil sulfanilamide

NH2 NH2 NH2

SO2NH SO2NH SO2NHCCH3

O
N N
O CH3
sulfapyridine sulfamethoxazole sulfacetamide
(for pneumonia) (for typhoid, etc.) (for urinary track infection)
 Synthesis of Sulfa Drugs
O O
NH2 NHCCH3 NHCCH3
O
(CH3C)2O 2HOSO2Cl

(-CH3CO2H) 80oC,-H2O

acetanilide SO2Cl
aniline
p-acetamidobenzene-
sulfonyl chloride

O
NH2 NHCCH3 (-HCl)
1. dilute HCl, heat H2N-R

2. HCO3
SO2NHR SO2NHR
sulfanilamide
Exercise:

1. Show how you convert aniline into each of the

following compounds:
a. p-nitroaniline
b. klorobenzene
c. phenol
d. benzonitrile
e. iodobenzene
f. fluorobenzene
Use of Protecting and Blocking Groups
Very powerful activating groups such as amino
and hydroxyl groups cause the benzene ring to be
so reactive that undesirable reactions may take
place.
Some reagents use for electrophilic substitution
reaction, such as nitric acid, are also strong
oxidizing agents.
Amino and hydroxyl groups not only activate the
ring, they also activate it toward oxidation.
Example: direct nitration of aniline results in
considerable destrucion of the benzene ring
because it is oxidized by nitric acid.
 Treating aniline with acetyl chloride (CH3COCl), or acetic
anhydride , (CH3CO)2O converts aniline to acetanilide
(acetamido groups). The acetamido is only moderately
activating and one that does not make the ring highly
susceptible to oxidation. With acetanilide, direct nitration
becomes possible. O
O O
NH2 NHCCH3 NHCCH3 NHCCH3
CH3COCl HNO3 NO2
heat +
H2SO4

aniline acetanilide NO2

p-nitroacetanilide, o-nitroacetanilide,
(90%) (trace)

NH2
O
(1) H2O, H2SO4,heat
CH3CO- +
(2) OH-

NO2 p-nitroaniline
 Synthesize o-nitroaniline

O O O
NH2 NHCCH3 NHCCH3
NHCCH3
CH3COCl H2SO4 conc. HNO3 NO2
heat

aniline acetanilide SO3H SO3H

NH2
NO2 (1) H2O, H2SO4,heat
(2) OH-
Exercises:
Starting with aniline, outline a synthesis of :
a. p-nitroaniline
b. 4-bromo-2-nitroaniline