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The hydrolysis of isatoic anhydride 1, its 5-nitro 7; (X = NO,, R = H) and N-methyl derivatives in water at 25°C occurs mainly via direct HO-attack on the neutral substrate. At high pH where 1 and 7 (X = NO2, R = H) are ionized, the o-carboxyphenyl isocyanate 8b is formed in equilibrium with the anion 8a, and this undergoes a competing reaction with HO-(but at a slower rate).Reaction with amines at the anhydride carbonyl (C-4) which occurs at pH < 10 is characterized by a Pnuc value of +1.0 but is highly sensitive to the steric bulk of the attacking amine. In consequence reaction at the isocyanate in the anion 8 (X = H) is only important with bulky amines.With the 5-nitro derivative (pK, 6.7), reaction with the conjugate base can be measured even Paper 0/005021

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The rate of hydrolysis of phenyl N-(o-carboxypheny1)carbamate ( 4) is rapid (kobs = 1.0 x s-l) and pH independent over a wide range ( 5 < pH < 11) in 4 : l water-dioxan a t 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 (kHao/kn,o = 1 -2) and data for the model compounds phenyl N-(p-carboxy-pheny1)carbamate ( 5) and phenyl N-(o-ethoxycarbonylpheny1)carbamate (6). Similar criteria are also used to confirm that phenyl N-(o-hydroxypheny1)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 p = +2.0 for the cyclization of aryl N -( o -carboxypheny1)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 (1 1 ; R = H) was also examined and it was shown that the rate of cyclization w a s 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. INTRAMOLECULAR reactions have been studied inten-sively in an attempt to understand the mechanism of enzymic catalysis. This is because of the close analogy between an intramolecular reaction and an enzyme catalysed reaction which involves adsorption of the substrate and then proceeds through an enzymesubstrate comp1ex.l The various groups which occur on amino-acid side chains (e.g. carboxy, hydroxy, imidazolyl, amino) have been examined as intramolecular catalysts in this context .z Several proteolytic enzymes such as pepsin have a carboxy-group located at the active site and various modes of involvement of the carboxy-group, as a general acid or base or as a nucleophile, have been proposed. In model systems using simple esters and acetals as substrates it has been demonstrated that a suitably positioned carboxy-group can show each of these types of catalytic 1

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