A large gem-dimethyl effect in the cyclization of ω-phenylhydantoic acids: Computational modeling of the gem-dimethyl effect on the acid- or base-catalyzed cyclization of hydantoic acids and esters

The rates of the cyclization of methyl-substituted 5-phenylhydantoic acids were measured in acid solutions. A particularly strong gem-dimethyl effect (GDME) was observed with the N-methyl compounds amounting to an acceleration of six powers of ten for the 2,2,3-trimethyl derivative. The variations in the free energies of activation for the cyclization of hydantoic acids and esters were modeled by the strain energies of the tetrahedral intermediates and of the reactants calculated by the MM3 force field. The neutral tetrahedral intermediate T0 was used for reaction series involving acid catalysis and the negatively charged intermediate T- for base catalysis. Very good agreement with the experimental GDME was obtained for the acid-catalyzed cyclizations of the complete series of the N-methyl-substituted substrates, showing that the accelerations result from a greater strain increase in the reactants. The results with T- are closely parallel, indicating that the loss of GDME observed under base catalysis with 2,2,3-trimethylhydantoate esters is not due to intramolecular strain in T-. A linear correlation (slope 1.22, r=0.934) is obtained for a plot of the free energy variations against strain energies for the reaction series of 5-phenylhydantoic acids when the data for the strongly deviating parent acid is excluded. Excellent LFERs are obtained between the reaction series of esters and acids. The observed large rate enhancements induced by N-substituents explain the switches to cyclization routes in synthetic reactions. Copyright © 2004 John Wiley & Sons, Ltd.