The effect of alkyl substituent-groups on the base-catalysed hydrolysis of amides

The alkaline hydrolysis of amides follows a simple two stage mechanism, the first stage being addition of a hydroxyl ion and the second being addition of a hydroxyl ion and the second being decomposition to form the reaction products. The mechanism may be represented wither as a addition and retrogression reaction or as a nucleophilic substitution reaction. The addition reaction requires an intermediate with definite independent existence while the substitution reaction requires a transition complex with no finite period of existence. Ingold has discussed this question and has concluded that the position actually assumed is probably between the two extremes with an intermediate stabilised by mesomerism. The existence of an intermediate with a finite life has been experimentally established in the case of ester hydrolysis which is in many ways a similar reaction. The status of the intermediate in the amide reaction, as a molecule, can be assumed by analogy. The reaction is thus not a simple substitution reaction but on the other hand it is not necessarily an addition reaction as normally understood. The most acceptable interpretation of experimental results appears to be given by assuming a resonant intermediate of the dual reaction mechanism as suggested by Ingold. The rate-controlling step in the reaction mechanism is the addition of the hydroxyl ion and it is thus found that electron-attracting substituent groups on the amide accelerate, and electron-repelling groups retard, the reaction. Bevan, Hughes and Ingold have found that in some nucleophilic substitution reactions the loss of the displaced group constitutes the rate-controlling step in the reaction but experimental evidence shows that this is not so for the base-catalysed hydrolysis of amides. Alkyl-groups are electron-repelling in nature and, as expected, are found to reduce the rate of hydrolysis when compared with the unsubstituted amide. The electronic properties of alkyl groups are the sum of two different effects brought about in different ways, an inductive effect and a hyperconjugative effect. In the series methyl, ethyl, iso-propyl and tert-butyl, the inductive effect increases while the hyperconjugative effect decreases through the series. Published data on similar compounds suggests that, in the simple aliphatic amides where the alkyl groups are directly bonded to the reacting group, the order of reactivity should be dictated almost entirely by the inductive effects of the alkyl groups. In the para-substituted benzamides on the other hand, where the amide group is separated from the substituent by the conjugated unsaturated system of the benzene ring, the conditions for hyperconjugation are comparatively much more favourable. The reactivity order may then be either inductive, hyperconjugative, or a mixture of both. All three of these reactivity series have been observed experimentally for different compounds which were not greatly different structurally from the p-alkylbenzamides. The actual reactivity order existing in these amides under a give set of experimental conditions cannot be forecast in any way. In p-alkyl-aromatic compounds, the order or reactivity as well as being considerably effected by minor structural changes may also be altered by changing experimental conditions. This has been observed in ethyl p-alkylbenzoates when the solvent was changed from aqueous ethanol to aqueous acetone. In the work here reported, as study of the kinetics of hydrolysis, in excess of sodium hydroxide in water, of alkyl-substituted acetamides and of p-alkylbenzamides has been carried out. The significance of the experimental results so obtained is discussed