Problems with Aniline
A.
Bromination Amine substituents are so strongly activating that halogenation is carried out
without the Lewis acid catalyst (FeBr3 or FeCl3). Even at low temperature without a catalyst,
multiple halogenation is observed.
NH2
NH2
Br2
Br
Br
0°C
Br
Solution: Acylate the amine. This turns the ring from strongly activated to moderately
activated and allows monohalogenation:
NH2
hydrolysis of amide
(chapter 22)
O
O
NHCCH3
NHCCH3
NH3
NH2
O
Br2
CH3CCl
pyridine
FeBr3
H3O+
H2O
NaOH
Br
Br
* about 95% para b/c
+ CH3CO2H
acetanilide is so hindered
Q. What if I want the ortho product?
A. Block the para position with a sulfonyl group.
NH2
Br
hydrolysis of amide
+ removal of -SO3H
O
O
O
NHCCH3
NHCCH3
NHCCH3
O
CH3CCl
pyridine
Br
H3O+
Br2
SO3
H2SO4 (conc.)
H2O
FeBr3
SO3H
SO3H
NH2
NH3
Br
NaOH
Br
B. Friedel-Crafts Alkylation & Acylation. The amino groups -NH2, -NHR, and NR2 are
changed into powerful deactivating groups by the Lewis acids used to catalyze FriedelCrafts reactions. Deactivated, meta directing benzene derivatives do not do Friedel-Crafts
reactions.
H
NH2
H N AlCl3
O
CH3CCl
no Friedel-Crafts reactions
AlCl3
Solution: Acylate the amine. This turns the ring from strongly activated to moderately
activated and allows Friedel-Crafts reactions to take place:
NH2
O
hydrolysis of amide
(chapter 22)
O
O
NHCCH3
NHCCH3
NH3
NH3
O
CH3CCl
CH3CCl
pyridine
AlCl3
H3O+
H2O
NaOH
O
C
CH3
* about 95% para b/c
acetanilide is so hindered
C
O
CH3
+ CH3CO2H
O
C
CH3
For ortho product, block para position with a sulfonyl group, like in a. Even
though a sulfonyl group is deactivating, this effect is counteracted by the
acetanilide group, so Friedel-Crafts acylation will work
C. Nitration of Aniline Derivatives. Aniline derivatives cannot be nitrated because nitric acid
is an oxidizing agent and primary amines are easily oxidized (nitric acid and aniline can be
explosive). Only tertiary aromatic amines and acetamide derivatives can be nitrated.
NH2
N(CH3)2
HNO3
H2SO4
Tar or explosion
1° not safe or effective
NH(CH3)2
HNO3
H2SO4
NO2
2°, 3° okay, but nitrogen will be pronated
in strong acid, becoming a meta director.
Solution for 1° Amines: Acylate
NH2
hydrolysis of amide
(chapter 22)
O
O
NHCCH3
NHCCH3
NH3
NH2
O
CH3CCl
HNO3
pyridine
H2SO4
H3O+
H2O
NaOH
O
N
O
* about 95% para b/c
acetanilide is so hindered
NO2
+ CH3CO2H
For ortho product, block para position with a sulfonyl group, like in a.
NO2