Cyclizations involving oxyanions as nucleophiles towards the carbamate linkage in the rate-determining step

Abstract

The rate of hydrolysis of phenyl N-(o-carboxyphenyl)carbamate (4) is rapid (k_obs= 1·0 × 10^–3 s^–1) and pH independent over a wide range (5 < pH < 11) in 4 : 1 water–dioxan at 25°. The ultimate products of hydrolysis are anthranilic acid and phenol but it is demonstrated that initial cyclization [to form isatoic anhydride (8; R = H)] occurs. A mechanism involving ready nucleophilic attack by the ionized carboxy-group is proposed based on the low-deuterium isotope solvent effect (k_H2O/k_D2O= 1·2) and data for the model compounds phenyl N-(p-carboxyphenyl)carbamate (5) and phenyl N-(o-ethoxycarbonylphenyl)carbamate (6). Similar criteria are also used to confirm that phenyl N-(o-hydroxyphenyl)carbamate (11; R = H) cyclizes to benzoxazolinone by the same mechanism, involving in this case the ionized phenoxy-group as an internal nucleophile. Both cyclizations are markedly dependent on the nature of the leaving group [e.g. the Hammett ρ=+2·0 for the cyclization of aryl N-(o-carboxyphenyl)carbamates to isatoic anhydride], contrasting with the bimolecular reaction of hydroxide ion with carbamates which is relatively independent of the nature of the leaving group. This is rationalized in terms of a different rate-determining step for the intramolecular reactions possibly involving breakdown of a tetrahedral intermediate. The effect of substituents in the N-aryl ring of the phenol (11; R = H) was also examined and it was shown that the rate of cyclization was very sensitive to the positioning of the substituent relative to the nucleophilic and carbamate groups. Thus a nitro-group can either enhance the rate of cyclization (when para to the carbamate group) or reduce it (when para to the hydroxy-group); the rate difference between the two phenyl N-(2-hydroxynitrophenyl)carbamates is 800-fold.