of Amides
O
RCNHR'
2o
=
=
O
RCNH2
1o
Synthesis Amides from Acyl Chlorides
=
O
RCCl +
-
:NH3
-O
OH
+
RC-N-H
H
=
RC-Cl
+
H-N-H
H
:NH3
O
RCNH2
=
=
OH
+
RC-N-H +
H
O
RC-Cl
+
H-N-H
H
+ Cl-
+
NH4+
O
RCNR'R''
3o
=
Amides like amines are classified
according to the structure around
the nitrogen :
Secondary and Tertiary Amides
The reaction of acyl chlorides with primary and secondary amines
yields secondary and tertiary amides, respectively.
+ 2 R'NH2
primary amine
O
RCNHR' +
=
=
O
RCCl
R'NH3+ Cl-
secondary amide
an N-substituted
amide
+ 2 R'R''NH
secondary amine
O
RCNR'R'' +
tertiary amide
=
=
O
RCCl
R'R''NH2+ Cl-
an N,N-disubstituted
amide
Note: Two equivalents of the amine are required
for complete reaction.
Tertiary amines react with acyl chlorides to produce
salts, not stable amide products.
O+
RCNR'3 Cl-
=
=
O
RCCl + R'3N:
an acylammonium chloride
Amides from Carboxylic Acid Anhydrides
Analogous reactions occur between acid anhydrides and
ammonia or amines.
O
O- +
CH3CNH2 + CH3CO NH4
+ 2 NH3
acetic anhydride
acetamide
=
=
=
=
OO
CH3COCCH3
ammonium acetate
by way of
nucleophilic attack at
acyl carbon
OH
+
CH3C-N-H + CH3CO2
H
=
=
=
OO
CH3C-OCCH3 + :NH3
:NH3
=
O
+
+ NH4
CH3CNH2
Cyclic acid anhydrides react in a similar way:
=
O + 2 NH3
H+
H2O
=
phthalic anhydride
ammonium phthalamate
Vigorous heating results in dehydration and formation of the
important compound phthalimide.
=
O
C
=
O
CNH2
NH + H2O
=
C
O
=
COH
O
150-160o C
phthalimide (~100%)
Ka = 5 x 10-9
Imides have the general structure:
C
O
=
=
C
O
N
O
CNH2
COH
O
=
-+
CO NH4
O
warm
=
C
O
H2O
neutralization
=
O
CNH2
=
O
C
phthalamic acid (81%)
Amides from Esters
Esters undergo nucleophilic substitution at the acyl carbon with
nitrogen nucleophiles such as ammonia (ammonolysis) or amines
(amination).
ethyl acetate
H2O
O
CH3CNH2
=
=
ammonolysis
O
CH3COC2H 5 + :NH3
acetamide
+
C2H 5OH
Amides from Carboxylic Acids
Carboxylic acids react with aqueous ammonia to produce
ammonium carboxylates in an acid-base reaction:
O
+
RCO- NH4
=
=
O
RCOH + :NH3
acid
ammonium carboxylate
(salt)
base
Recovery of the ammonium carboxylate and heating of the dry
salt leads to dehydration and formation of the amide.
(solid)
O
RCNH2 +
=
=
O+
RCO- NH4
heat
H2O
amide
This method is generally not used in organic synthesis because
of the vigorous heating required.
Amides by a Condensation Synthesis using
Dicyclohexylcarbodiimide (DCC)
Amides may be prepared from carboxylic acids and amines in an
indirect dehydration synthesis using DCC. This method was
developed synthesizing for the amide bond in biological systems
under very mild conditions.
amide
O
+ C6H 11NHCNHC6H11
=
O
RCNHR'
=
dicyclohexylcarbodiimide
(DCC)
=
N=C=N
O
+ RCOH + R'NH2
N,N'-dicyclohexylurea
Note that the water byproduct ends up hydrating the diimide
function to an urea compound.
A Proposed Mechanism for the DCC Synthesis of Amides
The central carbon of the diimide function is electropositive and
subject to nucleophilic attack.
nucleophilic addition
:
:
=
=
:O:
RC-OH + C6H 11N=C=NC6H11
::
:
C6H11N=C-NC6H11
:O+
R-C-O-H
fast deprotonation and protonation
:
=
:O+
R-C-O-H
H
C6H11N=C-NC6H11
:O:
R-C=O
:
::
:
H+
C6H11N=C-NC6H11
a reactive intermediate
Note modified leaving
group at acyl carbon.
nucleophilic substitution at acyl carbon
O+ C6H11NHC-NC6H 11
::
=
OH
+
RC-N-R'
H
=
=
:
R'NH2 +
O
RC-O-C=NC6H 11
NHC6H 11
a good leaving group
fast proton exchange
+
amide
Note that the DCC reagent is used to modify the nature of the
leaving group at acyl carbon, turning a poor leaving group into a
good leaving group. This synthesis proceeds well under mild
conditions in ether solvents.
O
C6H11NHCNHC6H 11
=
O
RCNHR'
=
O+ C6H11NHC-NC6H 11
::
=
=
OH
+
RC-N-R'
H
dicyclohexylurea
Hydrolysis of Amides
Amides hydrolyze much more slowly than other acyl derivatives of
carboxylic acids such as acyl chlorides, esters or anhydrides. This
observation is consistent with their generally slower rates of
nucleophilic substitution at the acyl carbon. This decreased
reactivity is, at least in part, associated with the greater stability of
the amide functional group compared with the other acyl
derivatives.
:O:
+
R-C=N
:
:O:
R-C-N
:
=
This enhance stability is explained by
resonance theory through the
following contributors to the hybrid:
Amides are neutral compounds despite the presence of the amino-type
nitrogen in the structure. The decreased base strength compared with
amines is also explained by a stabilization of the amide function
(illustrated above by resonance) that is not possible in simple amines.
Much of this resonance stabilization is lost when the nitrogen is
protonated.
Hydrolysis of Amides
The rate of hydrolysis of amides is faster at lower
or higher pH than at pH = 7.
at low pH (electrophilic catalysis)
:
=
+H
:O
+ H2O
RC-NH2
nucleophile
:
=
:
=
:O:
RC-NH2 + H3O+
+H
:O
RC-NH2 + H2O
enhanced
reactivity
RCO2H + NH4+
at high pH (a better nucleophile)
:
=
:O:
RC-NH2
+ HO-
RCO2- + NH3
nucleophile
N-substituted and N,N-disubstituted amides react similarly.
Typical hydrolysis conditions are extensive heating of an
amide in 6 M HCl or 40% aqueous NaOH.