Chapter 20: Carboxylic Acid Derivatives. Nucleophilic Acyl Substitution

Hydrolysis of Amides

Summary

• Amides hydrolyse to the parent carboxylic acid and the appropriate amine.
• The mechanisms are similar to those of esters.
• Reagents : Strong acid (e.g. H₂SO₄) / heat (preferred) or strong base (e.g. NaOH) / heat.

• Hydrolysis of Esters

• Note that the acid catalysed mechanism is analogous to the acid catalysed hydrolysis of esters.
• The mechanism shown below proceeds via protonation of the carbonyl not the amide N (see step 1).
• The mechanism is an example of the less reactive system type.

MECHANISM OF THE ACID CATALYSED  HYDROLYSIS OF AMIDES
Step 1: An acid/base reaction. Since we only have a weak nucleophile and a poor electrophile we need to activate the amide. Protonation of the amide carbonyl makes it more electrophilic.
Step 2: The water O functions as the nucleophile attacking the electrophilic C in the C=O, with the electrons moving towards the oxonium ion, creating the tetrahedral intermediate.
Step 3: An acid/base reaction. Deprotonate the oxygen that came from the water molecule to neutralise the charge.
Step 4: An acid/base reaction. Need to make the -NH2 leave, but need to convert it into a good leaving group first by protonation.
Step 5: Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral ammonia molecule.
Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the carboxylic acid product and regenerates the acid catalyst.