Project Summary: Our research program investigates reaction mechanisms in asymmetric organocatalysis and palladium catalyzed cross-coupling reactions. We utilize 13C and 2H kinetic isotope effects (KIEs) in combination with theoretical calculations as design tools to evaluate fine details of the transition state (TS) of the rate-determining step (RDS) under unmodified reaction conditions. Our studies in the area of asymmetric organocatalysis (2013-present) have resolved long-standing debates, uncovered novel mechanistic pathways, and probed origins of enantioselectivity in a wide variety of reaction types. In 2018, NIH funding enabled us to expand our research program to the study of palladium catalyzed cross-coupling reactions – an area of catalysis that is central to medicinal chemistry. We have discovered that the magnitude of 13C KIE is highly sensitive to minor changes in the carbon-palladium distance at the TS of the RDS – allowing us to distinguish between competing pathways and probe the ligand environment at the metal center, all under catalytic conditions. Finally, we have developed a novel methodology that utilizes symmetric reactants to obtain this information at a fraction of the time and effort of traditional KIE approaches. This MIRA proposal seeks to further expand our research program to include new modes of catalysis at the frontier of modern-day organic synthesis: (a) palladium catalyzed C-H bond-activation and functionalization, and (b) nickel metallophotoredox catalysis. Over the next five years, our goal is to establish our combined experimental and theoretical approach as the state-of-the-art to gain atomistic understanding of the mechanistic underpinnings of these reactions. We chose these two areas to expand our research program for two reasons – (a) new reaction discovery has far outpaced mechanistic understanding of these reactions, and (b) our discoveries in palladium catalyzed cross- coupling chemistry strongly indicate that our approach is ideally suited to resolve key mechanistic questions in these contemporary areas of catalysis. The overall vision of our research program is to develop probes that can rapidly evaluate the mechanism of catalytic reactions. We seek to change the paradigm that rigorous mechanistic understanding follows new reaction discovery. We envision that the high-resolution mechanistic insight that is delivered by our studies will inspire the discovery of new and more robust catalytic methods that will enable organic synthesis.