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 Ϫ with 2-UA is caused at low pH by acid catalysis of the reversion of the tetrahedral intermediate (T Ϫ ) to reactants, while with 3-UA at high pH this takes place through T 2Ϫ . 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 H 3 O ϩ and OH Ϫ , respectively: both reactions are presumed to go through early transition states.

7 Reaction mechanisms. Part (i) Polar reactions

“…The rate of HO 2 -catalyzed cyclization of fully methylated hydantoic acid 135 (R 1 = Me; R 2 = OH) to hydantoin 136 (R 1 = Me) was found to be 15-fold higher than for reaction of the less-substituted acid 135 (R 1 = H; R 2 = OH), which represents a normal gem-dimethyl effect (GDME) for ring closure. 111 This result was suggested to support the proposal that the absence of a GDME in the corresponding cyclization reactions of hydantoic esters 135 (R 1 = Me, H; R 2 = OEt) was due to a change in rate-determining step for the latter reactions.…”

gem-Disubstituent Effect: Theoretical Basis and Synthetic Applications

“…In 1989, Kirby et al described an interesting example of the consequences of gem -dimethyl substitution. Their study involved the gem -dialkyl effect on the base- and acid-catalyzed cyclizations of three hydantoate esters (Scheme ) 39a. They observed that at low pH, the introduction of one and two methyl groups increased the cyclization rate by 30- and 1100-fold, respectively.…”

Structure–reactivity relationships in the inactivation of elastase by β-sultams

“…13 there is a pH-independent reaction presumably due to a reversible ionisation of the aryl-NH group of (2) consistent with the pK a of simple p-nitroanilides. 20 The overall pathway for the hydroxide ion hydrolysis of N-suc-(-Ala) 3 p-nitroanilide (2) is shown in Scheme 2.…”