METAL-ION EFFECTS ON INTRA-MOLECULAR GENERAL BASE AND NUCLEOPHILIC CARBOXYL GROUP PARTICIPATION IN ESTER HYDROLYSIS - HYDROLYSIS OF SALICYL PHENANTHROLINE-2-CARBOXYLATE AND 8-(2-CARBOXYQUINOLYL) HYDROGEN GLUTARATE

A plot of log kobsd vs. pH for hydrolysis of salicyl phenanthroline-2-carboxylate at 50 °C has a pH-independent region from pH 5 to 7, indicating participation by the carboxylate anion or a kinetically equivalent reaction (kH/kD = 1.9). Plots of log kobsd vs. pH for hydrolysis in the presence of divalent metal ions (CO2+, Ni2+, Zn2+, and Cu2+) in the pH range 2-7 are linear with slopes of 1.0. Saturating concentrations (5 × 10-3 M) of the divalent metal ions produce enhancements in A:qh. the second-order rate constant for hydroxide ion catalysis, ranging from 3 × 103 with Zn2+ to 8 × 104 with Cu2+. The order of hydrolytic reactivity of the metal ion complexes is Cu(II) > Ni(II) > Co(II) > Zn(II), which is also the order of the equilibrium constants for binding of metal ion to 1, 10-phenanthroline. The reactions involving metal ion promoted attack of hydroxide ion on the ester carbonyl proceed with such facility that mechanisms utilizing carboxyl group general base participation cannot compete. The pH-log (rate constant) profile for hydrolysis of 8-(2-carboxyquinolyl) hydrogen glutarate at 30 °C has a bell-shaped region at pH 2-7 due to intramolecular nucleophilic attack by the glutarate carboxyl of the zwitterionic species. From pH 7 to 9 there is a plateau due to a nucleophilic reaction of the dianionic species, and at pH greater than 9 hydroxide ion catalysis occurs. In the presence of 0.01 M Co2+ and Ni2+ (nonsaturating) and 0.01 M Zn2+ and 0.001 M Cu2+ (saturating) the pH-log (rate constant) profiles show hydroxide ion catalysis with enhancements in Zc0h ranging from 2 × 106 (Ni2+) to 4 × 107 (Cu2+). The order of reactivity of the metal ion complexes is Cu2+ Zn2+ > Co2+ ~ Ni2+, again paralleling the order of the equilibrium constants for metal ion binding, although differences in reactivity within the series are small. Upper limits for rate enhancements due to metal ion catalysis of the carboxylate anion nucleophilic reaction are 102 with Ni2+ and Co2+ and 103 with Cu2+ and Zn2+. These enhancements could arise from a transition-state effect in which the leaving group is stabilized. However, it is likely that the observed reactions only involve metal ion facilitated -OH catalysis at all pH values. Thus, an intramolecular nucleophilic reaction can also be overcome by a metal ion promoted -OH reaction when the nucleophilic reaction does not proceed with maximum efficiency because of the presence of degrees of freedom for rotation of the carboxyl away from the carbonyl. For the occurrence of significant intramolecular nucleophilic attack by a neighboring carboxyl group in systems in which a metal ion is strongly chelated, the steric fit of the carboxyl and the carbonyl must be excellent. The mechanistic implications of these results for carboxypeptidase A catalyzed hydrolysis of esters are discussed. © 1979, American Chemical Society. All rights reserved.