Kinetics and mechanism of the cyclization of ω-(p-nitrophenyl)-hydantoic acid amides: steric hindrance to proton transfer causes a 104-fold change in rate

Abstract

The pH-rate profiles for the cyclization of primary 2,3-dimethyl and 2,2,3-trimethyl-hydantoinamides (2-UAm and 3-UAm respectively) differ strikingly from those for the cyclizations of the corresponding N-methylated amides 2-MUAm and 3-MUAm; which are dominated by the water reaction, spanning some 6 pH units. For the cyclization of UAm the plateau extends over no more than two pH units. The difference is due to the slower base-catalyzed cyclization of the N-methylamides. The solvent kinetic isotope effect for this hydroxide-catalyzed reaction is close to 1.2, consistent with a slow protonation by water of the amino-group of the negatively charged tetrahedral intermediate. General base catalysis was observed with bases of pK_BH⁺ up to 8. The Brønsted β are compatible with a hydrogen bonding mechanism for the GBC. In the gem-dimethyl compounds 3 the leaving group is flanked by substituents on both sides. The N-methyl group in 3-MUAm hinders frontal access of the proton, causing a 14000 fold decrease in rate. This is only 3800 fold in the compound with one methyl group at position 2.