Project Abstract Atmospheric CO2 concentrations have reached their highest to date, which holds immediate and dire consequences for the environment and all areas of human health. Based on these imminent and growing threats, there is an urgent need to transition our current infrastructure from fossil fuels to renewable energy sources. In this context, solar energy or renewable electricity could be used to drive the catalytic conversion of CO2 and H2O into energy-rich chemicals (similar to biological systems) whereby energy is stored indefinitely in chemical bonds for on-demand use. The chemical reduction of CO2 to other carbon compounds with higher chemical energy would close the carbon cycle and deliver chemical fuels that are compatible with existing infrastructure. However, existing CO2 catalysts often suffer from very high overpotentials, low turnover frequency and poor substrate selectivity in the presence of H2O. In contrast, carbon monoxide dehydrogenase (CODH) enzymes, such as the nickel-carbon monoxide dehydrogenase II from Carboxydothermus hydrogenoformans are able to extract energy from their environments in order to carry out the reversible conversion of CO to CO2 at high rates and selectivity while operating near the thermodynamic potential. Crystal structure of Ni-CODHCh II reveals the presence of an iron-sulfur cluster combined with a nickel atom, called C-cluster. One structural feature of this C-cluster is the presence of a Fe3S4 cluster, which bridges the nickel and iron atoms together. This cooperative Lewis acid-base pair is considered a key feature for the exceptional activity of Ni-CODHCh II. The long-term goal of this proposal is to employ computational chemistry in combination with complementary experimental efforts to design innovative catalysts that mimic essential structural features and functions of CODH enzymes for the selective conversion of CO2 to CO in the presence of H2O. We propose to accomplish this goal through the following specific aims: (i) To investigate earth-abundant materials supported by macrocyclic redox-active ligands; and (ii) To catalyze the production of carbon monoxide through the use of charged functional groups in the secondary coordination sphere. More specifically, this proposal outlines a plan for the rational design of innovative catalysts for CO2-to-CO conversion based on thermodynamic and kinetic properties. These principles have been established as critical in heterogeneous catalysis. For instance, in the Sabatier principle, the magnitude of the substrate binding energy at the metal in critical intermediates is related to the overall catalyst rate. The use of molecular catalysts will allow us to tune these crucial bond energies in order to achieve optimal values. In this context, electronic structure calculations will provide a straightforward approach to study the key thermodynamic and kinetic properties that are required in the development of molecular catalysts with (i) high selectivity for the desired product; and (ii) fast kinetics over a long period of time. Successful completion of these aims will produce general guidelines based on fundamental thermodynamic and kinetic properties for the design of next generation molecular catalysts for CO2 reduction to CO or any high value C1 product.