Reaction Kinetics of Cyanide Binding to a Cobalt Schiff-Base Macrocycle Relevant to Its Mechanism of Antidotal Action

Abstract

The Co(II/III)-containing macrocycle, cobalt 2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]-heptadeca-1(17)2,11,13,15-pentaenyl cation, or CoN₄[11.3.1], is a potential cyanide-scavenging agent. The rate of reduction of Co(III)N₄[11.3.1] by ascorbate is reasonably facile under pseudo-first-order conditions; a second-order rate constant of 11.7(±0.4) M^-1 s^-1 was determined at 25 °C and pH 7.4, along with the activation parameters for the reaction (ΔH^⧧ = 53.9(±0.8) kJ mol^-1; ΔS -79(±3) J mol^-1 K^-1). It follows that any cyanide-decorporating capability of the cobalt complex should depend more on the cyanide-binding characteristics of Co(II)N₄[11.3.1] than the oxidized form. The kinetics of the reaction of cyanide with Co(II)N₄[11.3.1] under anaerobic pseudo-first-order conditions is rapid and resulted in a linear dependence on the cyanide concentration, k_HCN = 8 × 10⁴ M^-1 s^-1, with a nonlinear intercept of 420 s^-1 at 10 °C, pH 7.6. The observed reaction rate increases significantly with increasing pH. A rate law is suggested, k_obs = k'[X] + (k_HCN + k_CNK_a/[H⁺])[HCN], where k_CN is estimated to be ∼2 × 10⁶ M^-1 s^-1. Activation parameters for the reaction with HCN (ΔH^⧧ = 10.7(±0.4) kJ mol^-1; ΔS^⧧ = -153(±1) J mol^-1 K^-1) suggest an associative mechanism. In the presence of excess oxygen, i.e., at higher levels than free oxygen in vivo, the reaction rate was too fast to be measured, and the final product was the oxidized complex, Co(III)N₄[11.3.1], where any cyanide ligands had been lost. This is much more rapid than the oxidation of the parent compound by oxygen, for which a second-order rate constant of 0.5(±0.02) M^-1 s^-1 at 25 °C was obtained. The study has gone some way toward enhancing our understanding of the reaction of Co(II)N₄[11.3.1] with cyanide. The fast reaction rate implies a high efficacy of the cyanide-scavenging capability of the complex and further supports the suggestion stemming from our previous work that Co(II)N₄[11.3.1] could prove to be a better and more cost-effective cyanide antidote than the FDA-approved hydroxocobalamin.