THE GEM-DIMETHYL EFFECT ON REACTIVITIES IN CYCLIZATIONS THROUGH TETRAHEDRAL INTERMEDIATES - CYCLIZATION OF METHYL-SUBSTITUTED METHYL AMIDESOF 5-(P-NITROPHENYL)HYDANTOIC ACIDS

The cyclization of the title hydantoinamides, UA, to 3-(4-nitrophenyl) hydantoins, Hyd, is general-base catalysed. Reversible hydrolysis of t he product hydantoin from the 2,3-dimethylhydantoinamide, 2-UA, above pH = 7 is a complicating feature. The rate profiles for cyclization co mprise one acid-catalysed, two neutral and two hydroxide-catalysed reg ions in the pH-region 0-10. Solvent kinetic isotope effects indicate r ate-determining expulsion of the methylamino group in the acid-catalys ed reaction. These also agree with general-base catalysis at low pH be ing concerted with nucleophillic attack of the ureido group, At high p H the tetrahedral intermediate is in equilibrium with the reactants an d the rate is limited by proton transfers producing T-+/-. The acceler ations upon methyl substitution vary strongly with the various process es observed and may be explained in terms of a general gem-dimethyl ef fect increasing along the reaction coordinate from reagent through cyc lic tetrahedral intermediate to final ring product. As the effects for the breakdown of the intermediate are opposite in the forward and rev erse directions, this changes the partitioning ratio and in turn could change the rate-determining step.