Amides: RCONH ₂

Most Electron Withdrawing							Least Electron Withdrawing
Functional Group: X	Halide	Alkanoate		Hydrogen	Alkyl	Alkoxy	Amino
Carbonyl Compound	Acid Halide	Acid Anhydride		Aldehyde	Ketone	Ester	Amide
Most Electrophilic							Least Electrophilic

Amides do not react readily with nucleophilic reagents – this is a direct consequence of the low electrophilicity of the carbonyl carbon centre. This low reactivity arises from the interaction of the carbonyl carbon centre with the adjacent nitrogen atom (this in turn in essentially non-basic for the same reason). The nitrogen centre is sp² hybridised and as a consequence, amides prefer planar conformation because the three p-orbitals of the N, C and O atoms are favourably aligned to facilitate overlap.

If the amide group is incorporated into a strained bicyclic system (such as that shown below), then conjugation between the nitrogen and carbonyl group cannot occur – in this case the amides’ carbonyl group possesses a reactivity comparable to the that of ketone systems.

The hydrolysis of amides requires much more vigorous conditions in comparison to acid chlorides, acid anhydrides and esters – commonly prolonged heating in acidic or basic media is necessary to achieve effective conversion. Amides can be reduced using strong metal hydride reagents such as LiAlH₄. However, the rate of reduction is far slower in comparison to esters. The first stage involves nucleophilic addition to the carbonyl centre (common with ester reduction) and the tetrahedral intermediate then decomposes in a different fashion to that observed for esters. Whereas in the case of ester reduction, decomposition of the tetrahedral intermediate occurs with cleavage of the backbone, in the case of the amide adduct, decomposition occurs with carbon-oxygen cleavage and the original C–N backbone is retained. This marked difference in adduct decomposition arises as a result of the poor leaving group characteristics of the R’₂N– moiety.

If LiAlH₄ reductions are performed at lower temperatures, then the decomposition rate of the tetrahedral intermediate will be decreased and aqueous work-up will release aldehyde derivatives. This approach works efficiently only if the amide precursor possesses structural features (i.e. strained rings) that inhibit collapse of the intermediate by preventing electron release from the nitrogen atom.

In a similar fashion, grignard reagents react with N,N-disubstituted amides to yield the corresponding ketones. Organolithium reagents react with N, N-disubstituted amides to produce tetrahedral intermediates that collapse to produce ketones. Further reaction between the ketone so produced and the organolithium reagent serve to produce the tertiary alcohol after acidic aqueous work-up. However, this route can be overcome if the adduct is stabilised by chelation.