Reactivity

Amides are the least reactive among all carboxylic acid derivatives because the electrophilicity of the C=O group is heavily reduced by the electron-donor nitrogen. Despite that, there are some interesting reactions...

Acidic or basic hydrolysis

The hydrolysis of an amide is usually a difficult process that requires strong acids or bases and high temperatures. Important: If other functions are present, many of them will not survive the treatment. As it is customary, the addition-elimination mechanism applies.

Mechanism of the acid hydrolysis of an amide to the carboxylic acid and the ammonium salt

Mechanism of the basic hydrolysis of an amide to the carboxylate and the amine

Hydride reduction

Amides can only be reduced with strong hydrides like LiAlH₄ (LAH). NaBH₄ does not react. Important: Beware other groups' competition!

Reduction of amides to amines with LiAlH₄: an amide gives the amine RCH₂NR′₂ and 2-pyrrolidinone gives pyrrolidine

Hofmann rearrangement

The reaction of amiDes ("with D") with bromine in basic medium induces the C=O loss and the formation of an amiNe ("with N").

Important: do not be confused...
with the Hofmann Degradation. Click here to remember it.

Hofmann rearrangement: a primary amide with halogen and NaOH gives the amine with one carbon fewer and CO₂

The mechanism is rather complex but maintains the usual logic. It implies the rearrangement of a carbon towards nitrogen.

Click here to recall another mechanism involving carbon rearrangement:

Baeyer-Villiger oxidation of aldehydes and ketones.

Click here to recall another mechanism involving carbon rearrangement:

Amides from oximes by Beckmann rearrangement.

Mechanism of the Hofmann rearrangement of benzamide with bromine and NaOH: amidate, N-bromoamide, haloamidate, acylnitrene, phenyl isocyanate, carbamic acid and, finally, aniline and CO₂

Remember that amines can hardly be prepared by simple nucleophilic substitution. Hofmann rearrangement is an excellent alternative as it is shown in the following retrosynthetic scheme:

Click here to recall the inconveniences.

Interconversion scheme: R–X gives R–COOH with Mg and CO₂, and R–COOH gives R–NH₂ with SOCl₂, NH₃ and rearrangement; R–X does not give R–NH₂ directly with NH₃

Reaction with nitrous acid

Sodium nitrite is a common food additive. It can react with the HCl from the stomach leading to the highly reactive nitrosyl cation.

Formation of the nitrosyl cation from sodium nitrite and HCl

Nitrosyl cation can react with the amide and amine groups of proteins and enzymes of our body, giving rise to dangerous carcinogenic compounds.

A secondary amide reacts with the nitrosyl cation to give an N-nitrosamide