The hydrolysis of amides and ureas in acid solutions
Despite the vast amount of research reported on the acid-catalysed hydrolysis of amides, the mechanism of reaction has remained a source of controversy. The various literature results have been summarised in the introduction. Two series of amides have been studied in this investigation, one a series of N-substituted, 4-chlorobenzamides, the other a series of substituted acetanilides. Their basicity (or acid-dissociation) constants have been evaluated in sulphuric acid, and the rates of hydrolysis measured over a wide range of acid concentrations. Within each series, variation of the substituent causes the rate constant to vary in a way which is typical of a bimolecular reaction involving rate-determining nucleophilic attack of water on the protonated intermediate. By drawing a comparison between the two series of amides, (i.e. the difference in basicities and rates of hydrolysis) it becomes apparent that the 0-protonated amide, which is thermodynamically favoured, is not the kinetically active species, A new rate equation is proposed, the equation being based on a mechanism in which water attacks the carbonyl carbon in the rate-determining step. The equation confidently predicts the experimental rate-profiles for the acid-hydrolysis of simple amides. It has been applied, in two forms, to the experimental rate data; the first form allows for the involvement of three water molecules in the slow step of hydrolysis, and the second form allows for the involvement of only two water molecules. The rate equation, in these two forms, has also been applied to much of the hydrolysis data reported in the literature and again it has proved to be very successful. In contrast to the amides, ureas have not been subjected to extensive research. In this investigation, the basicity constants of a series of substituted phenylureas have been measured, (if not already available) and the hydrolysis reactions carried out over a wide range of sulphuric acid concentrations, as well as in water. The 4-methyl and 4-chloro-phenylureas have also been hydrolysed in a range of hydrochloric and perchloric acid solutions; the effects of added salt were studied and the solvent isotope effects on the rate were evaluated. All these results, together with information obtained from application of the Hammett equation to the rate data, were in agreement with a mechanism involving a pre-equilibrium protonation to form the minor, N-protonated conjugate acid. This is followed by a slow transfer of the proton attached to the alternate nitrogen atom to form the appropriately substituted phenylisocyanate, and rapid reaction of this intermediate to form products. The substituent effects on the n.m.r. spectra of the substituted acetanilides and phenylureas have also been reported.