A panel of five zinc-chelated aza-macrocycle ligands and their ability to catalyze the hydration of carbon dioxide to bicarbonate, H2O + CO2 -> H+ + HCO3-, was investigated using quantum-mechanical methods and stopped-flow experiments. The key intermediates in the reaction coordinate were optimized using the M06-2X density functional with aug-cc-pVTZ basis set. Activation energies for the first step in the catalytic cycle, nucleophilic CO2 addition, were calculated from gas-phase optimized transition-state geometries. The computationally derived trend in activation energies was found to not correspond with the experimentally observed rates. However, activation energies for the second, bicarbonate release step, which were estimated using calculated bond dissociation energies, provided good agreement with the observed trend in rate constants. Thus, the joint theoretical and experimental results provide evidence that bicarbonate release, not CO2 addition, may be the rate-limiting step in CO2 hydration by zinc complexes of aza-macrocyclic ligands. pH-independent rate constants were found to increase with decreasing Lewis acidity of the ligand-Zn complex, and the trend in rate constants was correlated with molecular properties of the ligands. It is suggested that tuning catalytic efficiency through the first coordination shell of Zn2+ ligands is predominantly a balance between increasing charge-donating character of the ligand and maintaining the catalytically relevant pK(a) below the operating pH.