Chemistry Reference
In-Depth Information
Acyl halides
and
anhydrides
are the most reactive
class of carboxylic acid derivatives, and readily react
with amines to give amides. It should be noted that in
both cases the leaving group is a conjugate base that,
upon protonation during the reaction, will become an
acid. Consequently, this acid forms a salt with the
amine reagent, and the reaction will tend to stop.
For success, the reaction thus requires the use of
2 mol of amine, or some alternative base must be
added.
RCOCl
+
NHR
′
2
RCONR
′
2
need extra mole of amine
or base to take up HCl
+
HCl
secondary
amine
tertiary amide
O
O
O
O
acyl halide
Cl
R
Cl
R
Cl
R
Cl
R
NR′
2
N
forms salt
with amine
N
R′
R′
R
′
H
NHR
′
2
R′
NHR′
2
Cl
NH
2
R′
2
O
O
O
O
O
O
O
O
anhydride
O
R
R
O
R
R
O
R
R
NHR′
R
O
R
N
N
forms salt
with amine
R′
H
R′
H
NH
2
R′
H
RCO
2
NH
2
R
′
NH
2
R
′
Esters
also react smoothly with amines, which is
a useful reaction if the corresponding acyl halides
or anhydrides are not easily available. The reaction
proceeds through the anticipated tetrahedral anionic
intermediate. There are two possible leaving groups
in this tetrahedral intermediate: alkoxide anion or
amide anion. Since ammonia is a considerably weaker
acid than an alcohol, the preferred leaving group is
the weaker base alkoxide.
+
+
RCO
2
Et
NH
3
RCONH
2
EtOH
primary amide
O
O
O
O
p
K
a
EtOH 16
OEt
R
OEt
R
OEt
R
OEt
R
NH
2
N
N
H
H
H
H
NH
3
H
O
O
p
K
a
NH
3
38
NH
2
R
OEt
R
OEt
N
H
amide is a poorer
leaving group
H
The consequence of this is that an ester can react
with ammonia to give an amide, but the reverse
reaction does not occur; simply treating amides with
alcohols does not produce esters. Production of esters
from amides requires acid or base catalysis. It should
also be noted that amines are better nucleophiles
