A normal gem-dimethyl effect in the base-catalyzed cyclization of ω-(p-nitrophenyl)hydantoic acids: evidence for hindered proton transfer in the permethylated esters

Abstract

The cyclization of hydantoic acids 2-UA and 3-UA – kinetics, solvent kinetic isotope effects (SKIE) and buffer catalysis – were studied in an attempt to explain the disappearance of the gem-dimethyl effect (GDME) in the specific base-catalyzed cyclization of hydantoic esters. pH-Rate profiles for both acids (after correction for ionization and for reversibility at high pH) show two regions of unit slope corresponding to different mechanisms. For 2-UA at high pH and 3-UA at lower pH the mechanism is considered to involve rate-determining attack by the ureido anion on the neutral carboxy group, consistent with the observed inverse SKIE. The normal GDME of 15 provides strong evidence that anomalies observed with the esters do indeed result from steric hindrance to proton transfer. The change to rate determining departure of OH⁻ with 2-UA is caused at low pH by acid catalysis of the reversion of the tetrahedral intermediate (T⁻) to reactants, while with 3-UA at high pH this takes place through T²⁻. The GDME favours attack on the carboxylate anion but makes ring opening more difficult, thus decreasing acid inhibition. The observed β = 0.44 for general base catalysis of the cyclization of 2-UA is consistent with concerted deprotonation and attack of the ureido group. With 3-UA two simultaneous general base-catalyzed reactions take place: slow deprotonation of the ureido group (β = 1.0) and attack of the ureide anion on the carboxy anion aided by the buffer conjugate acid. The estimated GDME is 2800 for the equilibrium between acid anion and hydantoin, but only 45 and 15 for catalysis by H₃O⁺ and OH⁻, respectively: both reactions are presumed to go through early transition states.