20.13 Preparation of Amides 1

Amides are prepared from amines by acylation with: Preparation of Amides Amides are prepared from amines by acylation with: acyl chlorides (Table 20.2) anhydrides (Table 20.3) esters (Table 20.6) 5

Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOH O RCO O + – + R'NH2 + R'NH3 If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating. 5

Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOH O RCO O + – + R'NH2 + R'NH3 heat RCNHR' O + H2O 5

Example COH O H2N + 225°C CNH O + H2O (80-84%) 4

20.14 Lactams 1

e-Caprolactam*: used to prepare a type of nylon e Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. g b N H O d a e-Caprolactam*: used to prepare a type of nylon e *Caproic acid is the common name for hexanoic acid. 5

Penicillin G: a b-lactam antibiotic Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. a b CH3 S CO2H O N C6H5CH2CNH Penicillin G: a b-lactam antibiotic 5

20.15 Imides 1

Imides have 2 acyl groups attached to the nitrogen. RCNCR O R' 5

The most common examples are cyclic imides. NH O O NH O Succinimide Phthalimide 5

Preparation of Imides Cyclic imides are prepared by heating the ammonium salts of dicarboxylic acids. HOCCH2CH2COH O OCCH2CH2CO O – NH3 NH4 + NH4 + NH O heat 5

20.16 Hydrolysis of Amides 10

Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. RCNHR' O RCOH O + + + H2O + H + R'NH3 5

In basic solution the carboxylic acid product Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. RCNHR' O RCO O – – + HO + R'NH2 5

Example: Acid Hydrolysis CH3CH2CHCNH2 O CH3CH2CHCOH O H2O NH4 + HSO4 – + H2SO4 heat (88-90%) 4

Example: Basic Hydrolysis CH3CNH O Br NH2 Br CH3COK O KOH + H2O heat (95%) 4

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 5

First stage: formation of tetrahedral intermediate + H2O RCNH2 O water adds to the carbonyl group of the amide this stage is analogous to the acid-catalyzed addition of water to a ketone H+ RC OH NH2 5

Second stage: cleavage of tetrahedral intermediate RCOH O NH4 + + H+ RC OH NH2 5

Mechanism of formation of tetrahedral intermediate 8

Step 1 O • • + H RC O NH2 •• • • 8

Step 1 O • • + H RC O NH2 •• • • • • O H RC O NH2 •• • • + H 8

Step 1 RC O NH2 •• • • + H carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O NH2 •• • • + H 8

Step 2 RC O NH2 •• • • + H • • O H 8

Step 2 RC OH NH2 •• • • O + H RC O NH2 •• • • + H • • O H 8

Step 3 RC OH NH2 •• • • O + H • • O H 8

Step 3 RC OH NH2 •• • • O + H • • O H NH2 RC OH •• • • O H O • • H + 8

Cleavage of tetrahedral intermediate 8

Step 4 H2N RC OH •• • • O H O • • H + 8

Step 4 RC OH H2N •• • • H + • • O H H2N RC OH •• • • O H O • • H + 8

Step 5 RC OH H2N •• • • H + 8

Step 5 RC OH H2N •• • • H + RC OH •• • • + + NH3 • • 8

Step 6 RC OH H2N •• • • H + + NH4 RC OH •• • • + H3O + + NH3 • • 8

Step 6 RC OH •• + RC OH •• • • + 8

Step 6 + O H •• RC O •• OH • • O •• H RC O •• OH + H 8

Mechanism of Amide Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate 5

First stage: formation of tetrahedral intermediate + H2O RCNH2 O water adds to the carbonyl group of the amide this stage is analogous to the base-catalyzed addition of water to a ketone HO– RC OH NH2 5

Second stage: cleavage of tetrahedral intermediate RCO O – + NH3 HO– RC OH NH2 5

Mechanism of formation of tetrahedral intermediate 8

Step 1 RC O NH2 •• • • O • • H •• – 8

Step 1 RC O NH2 •• • • O • • H •• – RC O NH2 •• • • H – 8

Step 2 RC O NH2 •• • • H – • • •• H O 8

Step 2 H O H – O H RC O NH2 RC O NH2 H – H O •• • • •• • • • • •• • • 8

Dissociation of tetrahedral intermediate 8

Step 3 H2N RC OH •• • • O H O • • H •• 8

Step 3 RC OH H2N H + O H – H2N RC OH O H O H •• • • • • •• •• • • • • 8

Step 4 •• H O • • • • – •• O H •• RC OH •• + H3N 8

Step 4 H O – O H RC OH + H3N H O RC O H NH3 •• • • •• •• • • •• •• •• 8

Step 5 RC • • O •• – RC • • O •• H HO– NH3 • • 8