Interconversion Reactions of Amides

Summary

• Amides are the least reactive of the neutral carboxylic acid derivatives.
• The only interconversion reaction that amides undergo is hydrolysis back to the parent carboxylic acid and the amine.
• Reagents : Strong acid (e.g. H₂SO₄) or strong base (e.g. NaOH) / heat.
• More details on the following page.

Hydrolysis of Amides

Summary

• Amides hydrolyze 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 catalyzed mechanism is analogous to the acid catalyzed 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 catalyzed  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 ester. 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.
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.

Reduction of Amides
(for more detail see Chapter 22)

Reactions usually in Et₂O or THF followed by H₃O⁺ work-ups

Summary

• Amides, RCONR'₂, can be reduced to the amine, RCH₂NR'₂ by conversion of the C=O to -CH₂-
• Amides can be reduced by LiAlH₄ but NOT the less reactive  NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followed by aqueous work-up.
• Note that this reaction is different to that of other C=O compounds which reduce to alcohols
• The nature of the amine obtained depends on the substituents present on the original amide.
  look at the N substituents in the following examples (those bonds don't change !)

• R, R' or R" may be either alkyl or aryl substituents.
• In the potential mechanism note that it is an O system that leaves. This is consistent with O systems being better leaving groups that the less electronegative N systems.

REACTION OF LiAlH4 WITH AN AMIDE
Step 1: The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 2: The tetrahedral intermediate collapses and displaces the O as part of a metal alkoxide leaving group, this produces a highly reactive iminium ion an intermediate.
Step 3:   Rapid reduction by the nucleophilic H from the hydride reagent as it adds to the electrophilic C in the iminium system. p electrons from the C=N move to the cationic N neutralizing the charge creating the amine product.