20.13 Preparation of Amides Preparation of Amides Amides

20.13 Preparation of Amides Preparation of Amides Amides

20.13 Preparation of Amides Preparation of Amides Amides are prepared from amines by acylation with: acyl chlorides (Table 20.2) anhydrides (Table 20.3) esters (Table 20.6) Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). O O +

+ R'NH3 RCO RCOH + R'NH2 If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating. Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). O O + + R'NH3 RCO RCOH + R'NH2

heat O RCNHR' + H2O Example O COH + H2N 225C O + H2O CNH (80-84%) 20.14

Lactams Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. N O -Caprolactam*: used to

prepare a type of nylon H *Caproic acid is the common name for hexanoic acid. Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. O C6H5CH2CNH N O S

CH3 CH3 CO2H Penicillin G: a -lactam antibiotic 20.15 Imides Imides Imides have 2 acyl groups attached to the nitrogen. O O RCNCR R' Imides

The most common examples are cyclic imides. O NH O Succinimide O NH O Phthalimide Preparation of Imides Cyclic imides are prepared by heating the ammonium salts of dicarboxylic acids. O O

O NH3 HOCCH2CH2COH O NH O O OCCH2CH2CO + +

NH4 NH4 heat 20.16 Hydrolysis of Amides Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. O O + + RCNHR' + H2O + H RCOH + R'NH3

Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. O RCNHR' O + HO RCO + R'NH2 Example: Acid Hydrolysis O

O CH3CH2CHCNH2 CH3CH2CHCOH H2O H2SO4 heat + + NH4 HSO4 (88-90%) Example: Basic Hydrolysis O CH3CNH O

KOH H2O NH2 CH3COK + heat Br Br (95%) Mechanism of Acid-Catalyzed Amide Hydrolysis Acid-catalyzed amide hydrolysis proceeds via the customary two stages: 1) formation of tetrahedral intermediate

2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate O RCNH2 + H2O H+ OH RC OH NH2 water adds to the carbonyl group of the amide this stage is analogous to the acidcatalyzed addition of water to a ketone

Second stage: cleavage of tetrahedral intermediate O RCOH + + NH4 H+ OH RC OH NH2 Mechanism of formation of

tetrahedral intermediate Step 1 O RC NH2 H H O + H Step 1

H O H RC O + H NH2

+O RC NH2 H H O H Step 1 O

H RC + NH2 +O RC NH2 H carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization

(resonance) Step 2 +O RC NH2 H H O H

Step 2 OH + RC O NH2 +O RC NH2 H H H

H O H Step 3 OH + RC O NH2 H H H

O H Step 3 OH + RC O O H

OH NH2 H H NH2 RC H H O

+ H O H H Cleavage of tetrahedral intermediate Step 4 OH RC H2N H

O H H O + H Step 4 OH

H RC OH H2N + H OH RC H2N O H H

O H H O + H Step 5 OH

RC OH H2N + H Step 5 OH RC OH H2N + H OH

RC + OH + NH 3 Step 6 OH RC OH H2N +

H + NH4 OH RC + OH + H3O + NH 3

Step 6 OH RC + OH + OH RC OH

Step 6 H O RC O+ H H H

O OH +O RC

H OH H Mechanism of Amide Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate O RCNH2 + H2O HO OH

RC OH NH2 water adds to the carbonyl group of the amide this stage is analogous to the base-catalyzed addition of water to a ketone Second stage: cleavage of tetrahedral intermediate O RCO

+ NH3 HO OH RC OH NH2 Mechanism of formation of tetrahedral intermediate Step 1 O

RC NH2 H O Step 1 O H O RC

NH2 O RC NH2 H O Step 2 O H

H O RC NH2 H O Step 2 O H

O H O H H O RC NH2

H O RC NH2 H O Dissociation of tetrahedral intermediate Step 3

OH RC H2N H O H H O Step 3

OH H RC OH H2N + H OH RC H2N O

H O H H O Step 4 O

H H O RC H3N + OH Step 4

O H O H O H

RC OH H3N + H O RC O

H NH3 Step 5 O RC O HO O

RC O H NH3

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