The gem-dimethyl effect on reactivities in cyclizations through tetrahedral intermediates. Cyclization of methyl-substituted methyl amides of 5-(p-nitrophenyl)hydantoic acids

Abstract

The cyclization of the title hydantoinamides, UA, to 3-(4-nitrophenyl)hydantoins, Hyd, is general-base catalysed. Reversible hydrolysis of the product hydantoin from the 2,3-dimethylhydantoinamide, 2-UA, above pH = 7 is a complicating feature. The rate profiles for cyclization comprise one acid-catalysed, two neutral and two hydroxide-catalysed regions in the pH-region 0-10. Solvent kinetic isotope effects indicate rate-determining expulsion of the methylamino group in the acid-catalysed reaction. These also agree with general-base catalysis at low pH being concerted with nucleophillic attack of the ureido group. At high pH the tetrahedral intermediate is in equilibrium with the reactants and the rate is limited by proton transfers producing T^±. The accelerations upon methyl substitution vary strongly with the various processes observed and may be explained in terms of a general gem-dimethyl effect increasing along the reaction coordinate from reagent through cyclic tetrahedral intermediate to final ring product. As the effects for the breakdown of the intermediate are opposite in the forward and reverse directions, this changes the partitioning ratio and in turn could change the rate-determining step.