14.23:
Amides to Carboxylic Acids: Hydrolysis
Amides undergo hydrolysis in aqueous acid or aqueous base to give carboxylic acids. These reactions are slow and require heating.
Acid-catalyzed amide hydrolysis begins with the carbonyl oxygen protonation, followed by the nucleophilic addition of water to the carbonyl carbon, forming a tetrahedral intermediate.
Further, deprotonation of the tetrahedral intermediate and protonation of the nitrogen converts the amino group into a better leaving group.
Next, the carbonyl group is re-formed by eliminating ammonia. Final deprotonation yields a carboxylic acid.
Notably, ammonium ion, a weak acid, is formed as a by-product, driving the equilibrium towards products.
Basic hydrolysis of amides is another nucleophilic acyl substitution involving hydroxide as a nucleophile.
The mechanism begins with the nucleophilic attack of the hydroxide ion at the carbonyl carbon, forming a tetrahedral intermediate.
Subsequently, the carbonyl group is reconstructed with the departure of an amide ion.
Final deprotonation yields a carboxylate ion and ammonia. This step drives the reaction to completion, pushing the equilibrium towards the product.
Acidification of the carboxylate ion gives free acid.
14.23:
Amides to Carboxylic Acids: Hydrolysis
Amides can undergo either acid-catalyzed hydrolysis or base-promoted hydrolysis through a typical nucleophilic acyl substitution. Each hydrolysis requires severe conditions.
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more electrophilic. Next, water acts as a nucleophile and attacks the carbonyl carbon to form a tetrahedral intermediate. Further, deprotonation of the tetrahedral intermediate gives a neutral tetrahedral addition intermediate. Subsequent protonation of the amino nitrogen converts the amino group into a better leaving group. In the next step, the carbonyl group is re-formed with the departure of ammonia as a leaving group. A final deprotonation step yields a carboxylic acid.
The formation of ammonium ion drives the equilibrium favoring the product formation.
Base-promoted hydrolysis:
Base-promoted hydrolysis is another nucleophilic acyl substitution reaction, where hydroxide acts as a nucleophile. Amides undergo hydrolysis when heated under basic aqueous solutions to produce carboxylic acid.
The base-promoted mechanism involves a nucleophilic attack by the hydroxide ion at the amide carbonyl carbon to form a tetrahedral intermediate. In the second step, the carbonyl group is reconstructed with the departure of an amide ion as a leaving group. Next, deprotonation yields a carboxylate ion and ammonia. This step drives the reaction to completion, which pushes the equilibrium towards the product. A final step involves acidification of the carboxylate ion to give free acid.
