PROJECT SUMMARY/ABSTRACT Despite advances in high-throughput screening methods leading to a surge in the discovery of catalytic reactions, our knowledge of the molecular-level interactions in the rate- and selectivity-determining steps of catalytic reactions involving highly unstable and reactive open-shell intermediates is rudimentary. These knowledge gaps prevent control, suppression or enhancement, of competing reaction channels that can drive development of new catalytic reactions. Built on strong computational and experimental preliminary results, this program seeks to understand and guide design of new sustainable, catalytic, and asymmetric transformations. Overall, our goals are to develop predictive models of reactivity and selectivity of first-row, open-shell transition metal-catalyzed carbon-carbon bond formations that can be adapted by the organic, organometallic, and bio(in)organic community in the synthesis of medicinally-active compounds. To accomplish this overarching goal, we have identified two areas of research for the next 5 years and plans for beyond. In the first area, we will use combined experimental and computational tools to understand and develop new asymmetric iron-catalyzed radical cascade/cross-coupling reactions. In the second area, through collaborative efforts, we will target the synthesis of quaternary centers via metallophotoredox-catalyzed cross-couplings. These reactions proceed through carbon-centered radical intermediates, open-shell organometallic species, and photoexcited electronic state species where evaluating the mechanisms has been historically hampered by the inherent complexity associated with the high reactivity and instability of these species. High-level quantum mechanical calculations, rigorously calibrated against experimental data, will be used to interrogate the mechanisms and to guide the development of new catalysts and reagents for currently sluggish or unselective reactions. In addition, we will exploit selected potential energy surfaces susceptible to dynamic effects, single-electron transfers, and intersystem crossings to gain a deeper understanding of the factors determining product selectivity and inform catalyst and reaction design. Overall, these efforts will push the limits of accurate molecular modeling of increasing complex catalytic reactions and potentially impact the fields of organic, bio(in)organic, and transition-metal catalysis.