On the disappearance of the gem-dimethyl effect: the base-catalysed cyclization of ethyl hydantoates†

Abstract

Buffer catalysis and solvent kinetic isotope effects in the cyclization of methyl-substituted ethyl hydantoates with ω-N-methyl (MUE) and ω-N-phenyl groups (PUE) have been studied in an attempt to elucidate the changes in mechanism and eventual reversal of relative reactivities caused by increasing the number of substituent methyl groups (the gem-dimethyl effect). (Rate constants for the hydroxide-catalysed cyclization are actually reduced on going to the fully methylated compounds.) For catalysis by hydroxide inverse isotope effects are generally consistent with specific base-catalysed cyclization, but the cyclizations of the most heavily substituted compounds show normal isotope effects, indicating a change of mechanism. It is suggested that proton transfer to the ethoxide leaving group is slowed by steric hindrance, and becomes rate determining for the most substituted compounds 3. Eclipsing strain in the tetrahedral intermediate may also be involved. The Brönsted plots for general base catalysis show distinctly different slopes of 0.2 for MUE and 0.6 for PUE, respectively. These are assigned to hydrogen bond preassociation and concerted catalysis mechanisms, of the attack of the ureido group nitrogen on the ester group. Rate constants for the reaction of the substrate anion would fall in the region of 10¹⁰ s^–1 for esters 3 if the gem-dimethyl effect were fully expressed.