In order to hydrolyse amides, the least reactive of the carboxylic acid derivatives, we have a choice: we can persuade the amine leaving group to leave by protonating it, or we can use brute force and forcibly eject it with concentrated hydroxide solution. Amides are very unreactive as electrophiles, but they are also rather more basic than most carboxylic acid derivatives: a typical protonated amide has a pKa of –1; most other carbonyl compounds are much less basic. You might therefore imagine that the protonation of an amide would take place on nitrogen—after all, amine nitrogen atoms are readily protonated. And, indeed, the reason for the basicity of amides is the nitrogen atom’s delocalized lone pair, making the carbonyl group unusually electron rich. But amides are always protonated on the oxygen atom of the carbonyl group, never the nitrogen, because protonation at nitrogen would disrupt the delocalized system that makes amides so stable. Protonation at oxygen gives a delocalized cation (Chapter 8).

Protonation of the carbonyl group by acid makes the carbonyl group electrophilic enough for attack by water, giving a neutral tetrahedral intermediate. The amine nitrogen atom in the tetrahedral intermediate is much more basic than the oxygen atoms, so now it gets protonated, and the RNH₂ group becomes really quite a good leaving group. Once it has left, it will immediately be protonated again, and therefore become completely non-nucleophilic. The conditions are very vigorous—70% sulfuric acid for 3 hours at 100 °C.

Hydrolysis of amides in base requires similarly vigorous conditions. Hot solutions of hydrox ide are sufficiently powerful nucleophiles to attack an amide carbonyl group, although even when the tetrahedral intermediate has formed NH₂ − (pKa of the ammonium ion 35) has only a slight chance of leaving when HO− (pKa of water 15) is an alternative. Nonetheless, at high temperatures amides are slowly hydrolysed by concentrated base since one product is the carboxylate salt and this does not react with nucleophiles. The ‘base’ for the irreversible step might be hydroxide or NH₂ −.

Secondary and tertiary amides hydrolyse much more slowly under these conditions. With all these amides a second mechanism kicks in if the hydroxide concentration is large enough. More hydroxide deprotonates the tetrahedral anion to give a dianion that must lose NH₂ − as the only alternative is O²–. This leaving group deprotonates water so the second molecule of hydroxide ion is simply a catalyst.

A similar mechanism is successful with only a little water and plenty of strong base, then even tertiary amides can be hydrolysed at room temperature. Potassium tert-butoxide is a strong enough base (pKa of t-BuOH about 18) to deprotonate the tetrahedral intermediate.

مواضيع ذات صلة

Aldehydes can react with alcohols to form hemiacetals

Making the products less reactive

Making the starting materials more reactive

A bit of shorthand

Making alcohols instead of ketones

Making ketones from esters: the problem

Acid chlorides can be made from carboxylic acids using SOCl2 or PCl5

Hydrolysing nitriles: how to make the almond extract, mandelic acid

Base-catalysed hydrolysis of esters is irreversible

Acid-catalysed ester hydrolysis and transesterification

Ester formation is reversible: how to control an equilibrium

Acid catalysts can make bad leaving groups into good ones