Chapter 20: Carboxylic Acid Derivatives. Nucleophilic Acyl Substitution

Reduction of Amides
(for more detail see Chapter 22)

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

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

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 followedby aqueous work-up.
• Note that this reaction is different to that of other C=Ocompounds 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 than the less electronegative N systems.

MECHANISM OF THE 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 the tetrahedral intermediate, a 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. π electrons from the C=N move to the cationic N neutralising the charge creating the amine product.

© Dr. Ian Hunt, Department of Chemistry