Insights into the Relationship of Catalytic Activity and Structure: A Comparison Study of Three Carbonic Anhydrase Mimics

Density functional theory (DFT) calculations were used to study the mechanism of CO₂ hydrolysis by Zn‐(1,5,9‐triazacyclododecane) and Zn‐cyclam and evaluate the associated thermodynamic and kinetic parameters. Microkinetic models were then built based on the kinetics and thermodynamics derived from first principles. Both catalysts showed very similar behavior to Zn‐cyclen, which we have reported previously, but with multiple distinctions. The intrinsic reaction rate constants for Zn‐(1,5,9‐triazacyclododecane) and Zn‐cyclam were calculated to be 2693 and 4623 M^?1 s^?1, respectively, which is in reasonable agreement with experimental values reported or estimated. The CO₂ adsorption step was found to be a rate‐limiting step for all three catalysts. Zn‐cyclam has the lowest barrier for this step due to the highest pK_a or nucleophilicity of the Zn‐OH^? form, and_, therefore, the highest intrinsic activity. However, the observed reaction rate constant also depends on the availability of the catalyst. The decrease in the observed reaction rate constant over 0–12 ms was ascribed to the decrease in the concentration of the catalytic form, Zn‐OH^?, which was primarily converted to Zn‐HCO₃^?. The reaction rate constant of Zn‐cyclam dropped much faster than those of Zn‐cyclen and Zn‐(1,5,9‐triazacyclododecane) due to lower energy of the Zn‐HCO₃^? form. The conversion of CO₂ at 1000 ms as a function of pH was calculated to compare the relative activity of these catalysts, and Zn‐cyclen was found to be the best catalyst.