Download - 20.13 Preparation of Amides
20.1320.13
Preparation of AmidesPreparation of Amides
acyl chlorides (Table 20.2)acyl chlorides (Table 20.2)
anhydrides (Table 20.3)anhydrides (Table 20.3)
esters (Table 20.6)esters (Table 20.6)
Preparation of AmidesPreparation of Amides
Amides are prepared from amines by acylationAmides are prepared from amines by acylation
with:with:
Preparation of AmidesPreparation of Amides
Amines do Amines do notnot react with carboxylic acids to give react with carboxylic acids to give
amides. The reaction that occurs is proton-transferamides. The reaction that occurs is proton-transfer
(acid-base).(acid-base).
RCOHRCOH
OO
++ R'R'NNHH22 RCORCO
OO
++ R'R'NNHH33
++––
If no heat-sensitive groups are present, the If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be resulting ammonium carboxylate salts can be converted to amides by heating.converted to amides by heating.
Preparation of AmidesPreparation of Amides
Amines do Amines do notnot react with carboxylic acids to give react with carboxylic acids to give
amides. The reaction that occurs is proton-transferamides. The reaction that occurs is proton-transfer
(acid-base).(acid-base).
RCOHRCOH
OO
++ R'R'NNHH22 RCORCO
OO
++ R'R'NNHH33
++––
heatheat
RCRCNNHR'HR'
OO
++ HH22OO
ExampleExample COHCOH
OO
++
HH22NN
225°C225°C
++ HH22OO
(80-84%)(80-84%)
CNHCNH
OO
20.1420.14
LactamsLactams
LactamsLactams
Lactams are cyclic amides. Some are industrialLactams are cyclic amides. Some are industrial
chemicals, others occur naturally.chemicals, others occur naturally. NN
HH
OO
-Caprolactam*: used to-Caprolactam*: used to
prepare a type of nylonprepare a type of nylon
*Caproic acid is the common name for hexanoic acid.*Caproic acid is the common name for hexanoic acid.
LactamsLactams
Lactams are cyclic amides. Some are industrialLactams are cyclic amides. Some are industrial
chemicals, others occur naturally.chemicals, others occur naturally.
Penicillin G: a Penicillin G: a -lactam antibiotic-lactam antibiotic
CHCH33
CHCH33
SS
COCO22HHOO
NN
CC66HH55CHCH22CNHCNH
OO
20.1520.15
ImidesImides
ImidesImides
Imides have 2 acyl groups attached to theImides have 2 acyl groups attached to the
nitrogen.nitrogen.
RCRCNNCRCR
OO OO
R'R'
ImidesImides
The most common examples are cyclic imides.The most common examples are cyclic imides. NNHH
OO
OO
PhthalimidePhthalimide
NNHH
OO
OO
SuccinimideSuccinimide
Preparation of ImidesPreparation of Imides
Cyclic imides are prepared by heating the Cyclic imides are prepared by heating the
ammonium salts of dicarboxylic acids. ammonium salts of dicarboxylic acids. NNHH
OO
OO
HOCCHHOCCH22CHCH22COHCOH
OO OO
NHNH33 OCCHOCCH22CHCH22COCO
OO OO
––––
NHNH44
++NHNH44
++
heatheat
20.1620.16Hydrolysis of AmidesHydrolysis of Amides
Hydrolysis of AmidesHydrolysis of Amides
Hydrolysis of amides is irreversible. In acid Hydrolysis of amides is irreversible. In acid
solution the amine product is protonated to solution the amine product is protonated to
give an ammonium salt.give an ammonium salt.
++ R'R'NNHH33
++RCOHRCOH
OO
RCRCNNHR'HR'
OO
++ HH22OO HH++++
Hydrolysis of AmidesHydrolysis of Amides
In basic solution the carboxylic acid productIn basic solution the carboxylic acid product
is deprotonated to give a carboxylate ion.is deprotonated to give a carboxylate ion.
RCRCNNHR'HR'
OO
++ R'R'NNHH22
––RCORCO
OO
HOHO++––
Example: Acid HydrolysisExample: Acid Hydrolysis
(88-90%)(88-90%)
CHCH33CHCH22CHCNHCHCNH22
OO CHCH33CHCH22CHCOHCHCOH
OO HH22OO
HH22SOSO44
heatheat
++ NHNH44
++HSOHSO44
––
Example: Basic HydrolysisExample: Basic Hydrolysis
(95%)(95%)
CHCH33COKCOK
OOKOHKOH
HH22OO
heatheat
++
CHCH33CNHCNH
OO BrBr
NHNH22
BrBr
Acid-catalyzed amide hydrolysis proceeds viaAcid-catalyzed amide hydrolysis proceeds viathe customary two stages:the customary two stages:
1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate2)2) dissociation of tetrahedral intermediatedissociation of tetrahedral intermediate
Mechanism of Acid-CatalyzedMechanism of Acid-CatalyzedAmide HydrolysisAmide Hydrolysis
First stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediateFirst stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediate
RCRC
OHOH
OHOH
NNHH22
++ HH22OORCRCNNHH22
OO
HH++
water adds to the water adds to the carbonyl group of the carbonyl group of the amideamide
this stage is this stage is analogous to the acid-analogous to the acid-catalyzed addition of catalyzed addition of water to a ketonewater to a ketone
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
++
HH++
RCOHRCOH
OO
RCRC
OHOH
OHOH
NNHH22
NNHH44
++
Mechanism of formationMechanism of formationofof
tetrahedral intermediatetetrahedral intermediate
Step 1Step 1Step 1Step 1
RCRC
OO
NNHH22
•••• ••••
••••
OO ••••++HH
HH
HH
Step 1Step 1Step 1Step 1
OO ••••++HH
HH
HH
RCRC
OO
NNHH22
••••
••••
++ HH •••• OO ••••
HH
HH
RCRC
OO
NNHH22
•••• ••••
••••
Step 1Step 1Step 1Step 1
carbonyl oxygen is carbonyl oxygen is protonated because protonated because cation produced is cation produced is stabilized by electron stabilized by electron delocalization delocalization (resonance)(resonance)
RCRC
OO
NNHH22
••••••••
++
HH
RCRC
OO
NNHH22
••••
••••
++ HH
Step 2Step 2Step 2Step 2
•••• OO ••••
HH
HH
RCRC
OO
NNHH22
••••
••••
++ HH
Step 2Step 2Step 2Step 2
RCRC
OHOH
NNHH22
••••••••
••••
OO ••••++
HH
HH
•••• OO ••••
HH
HH
RCRC
OO
NNHH22
••••
••••
++ HH
Step 3Step 3Step 3Step 3
•••• OO ••••
HH
HH
RCRC
OHOH
NNHH22
••••••••
••••
OO ••••++
HH
HH
Step 3Step 3Step 3Step 3
•••• OO ••••
HH
HH
OO ••••
HH
HH
HH++
NNHH22
RCRC
OHOH••••••••
••••
OO ••••
HH
••••
RCRC
OHOH
NNHH22
••••••••
••••
OO ••••++
HH
HH
Cleavage of tetrahedralCleavage of tetrahedralintermediateintermediate
Step 4Step 4Step 4Step 4
OO ••••
HH
HH
HH++
HH22NN
RCRC
OHOH••••••••
••••
OO ••••
HH
••••
Step 4Step 4Step 4Step 4
•••• OO ••••
HH
HH
OO ••••
HH
HH
HH++
HH22NN
RCRC
OHOH••••••••
••••
OO ••••
HH
••••
RCRC
OHOH
HH22NN
••••••••
OOHH••••
••••
HH++
Step 5Step 5Step 5Step 5
RCRC
OHOH
HH22NN
••••••••
OOHH••••
••••
HH++
Step 5Step 5Step 5Step 5 ++RCRC
OHOH••••••••
OHOH••••
••••
++
RCRC
OHOH
HH22NN
••••••••
OOHH••••
••••
HH++
NNHH33••••
Step 6Step 6Step 6Step 6 ++RCRC
OHOH••••••••
OHOH••••
••••
++
RCRC
OHOH
HH22NN
••••••••
OOHH••••
••••
HH++
NNHH33••••
HH33OO++
NNHH44++
Step 6Step 6Step 6Step 6
RCRC
OHOH••••
OHOH••••
••••
++
RCRC
OHOH••••••••
OHOH••••
••••
++
Step 6Step 6Step 6Step 6
OO••••
HH HH•••• RCRC
OO••••
OHOH••••
••••
++ HH ++OOHH HH••••
HH
RCRC
OO••••
OHOH••••
••••
••••
Involves two stages: Involves two stages:
1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate2)2) dissociation of tetrahedral intermediatedissociation of tetrahedral intermediate
Mechanism of Amide HydrolysisMechanism of Amide Hydrolysisin Basein Base
First stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediateFirst stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediate
RCRC
OHOH
OHOH
NNHH22
++ HH22OORCRCNNHH22
OO
water adds to the water adds to the carbonyl group of the carbonyl group of the amideamide
this stage is analogous this stage is analogous to the base-catalyzed to the base-catalyzed addition of water to a addition of water to a ketoneketone
HOHO––
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
++RCORCO
OO
RCRC
OHOH
OHOH
NNHH22
NNHH33––
HOHO––
Mechanism of formationMechanism of formationofof
tetrahedral intermediatetetrahedral intermediate
Step 1Step 1Step 1Step 1
RCRC
OO
NNHH22
•••• ••••
••••
OO ••••
HH••••
•••• ––
Step 1Step 1Step 1Step 1 RCRC
OO
NNHH22
••••••••
••••
OO ••••
HH••••
––
••••
OO ••••
HH••••
•••• ––RCRC
OO
NNHH22
•••• ••••
••••
Step 2Step 2Step 2Step 2
••••••••
HHOO
HH
RCRC
OO
NNHH22
••••••••
••••
OO ••••
HH••••
––
••••
Step 2Step 2Step 2Step 2
RCRC
OO
NNHH22
••••
••••
OO ••••
HH••••
••••
HH
••••––••••
••••OO
HH
••••••••
HHOO
HH
RCRC
OO
NNHH22
••••••••
••••
OO ••••
HH••••
––
••••
Dissociation ofDissociation oftetrahedral intermediatetetrahedral intermediate
Step 3Step 3Step 3Step 3
HH22NN
RCRC
OHOH••••••••
••••
OO ••••
HH
••••
OO ••••
HH
HH••••
Step 3Step 3Step 3Step 3
HH22NN
RCRC
OHOH••••••••
••••
OO ••••
HH
••••
RCRC
OHOH
HH22NN
••••••••
OOHH••••
••••
HH++
OO ••••
HH
HH••••
•••• OO ••••
HH
•••• ––
Step 4Step 4Step 4Step 4
RCRC
OO
HH33NN
•••• ••••
OOHH••••
••••
++
HH
••••––••••
••••OO
HH
Step 4Step 4Step 4Step 4
RCRC
OO
HH33NN
•••• ••••
OOHH••••
••••
++
HH
••••––••••
••••OO
HH
••••••••
HHOO
HH
NNHH33••••
RCRC
••••
OO•••• ••••
••••OO HH
Step 5Step 5Step 5Step 5
RCRC
••••
OO•••• ••••
••••OO HH
HOHO––
RCRC
••••
OO•••• ••••
••••OO ••••
––
NNHH33••••