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••••