PROJECT SUMMARY/ABSTRACT Transition metal-catalyzed cross-coupling methods are important in the context of human health because they play a central role in the synthesis of small-molecule therapeutics and molecular probes. Although cross-coupling methodologies are dominated by palladium catalysis, newer methodologies utilizing terrestrially abundant 3d metals (such as nickel) enable cross-coupling with polar C–O and C–N electrophiles. This feature is important because O- and N-containing functional groups are common in bioderived and bioactive small molecules and could therefore offer a greatly expanded scope of sustainably sourced cross-coupling partners. However, nickel catalyzed methodologies for cross-coupling with acyl C–O and C–N electrophiles remain in early stages, and (i) face practical limitations due to a pronounced sensitivity to changes in substrate structure, (ii) generally require high precatalyst loadings, and (iii) often utilize high reaction temperatures or long reaction times. Attempts to address these limitations are stymied by a lack of detailed mechanistic into the features responsible. This proposal addresses these ambiguities through systematic mechanistic investigation of three distinct classes of nickel-catalyzed cross-coupling with biologically important acyl C–O and C–N electrophiles with a specific focus on (i) C–X activation steps, (ii) selectivity-determining features, and (iii) speciation of key organometallic intermediates. This approach leverages ligand design and organometallic synthesis, structure elucidation through spectroscopic and crystallographic studies, and reaction kinetics, supported by state-of-the-art computational analysis to derive insights into the reactivity and selectivity-determining features of catalytic reactions. These insights will be leveraged to elucidate key reactivity and selectivity relationships and to offer methodological improvements that address current inefficiencies. As an Early-Stage Investigator (ESI), the PI is uniquely suited to build this research program due to their extensive prior experience working across the organic– inorganic and synthetic–mechanistic axes to interrogate, improve, and invent methodologies with translational potential. The PI’s program will build on this expertise to offer conceptually innovative, mechanism-driven, strategies to meet key synthetic needs. Successful completion of the proposed research will result in detailed insight into the mechanisms and limiting features of nickel-catalyzed acyl C–N and C–O activation and cross coupling. These insights will be translated into development of a suite of single-component precatalysts with enhanced activity and selectivity along with a practical “user’s guide to catalyst selection” to enable expanded application to the synthesis and elaboration of biologically important small molecules. The ultimate goal of this project area is to achieve mechanism-driven improvements bringing these methodologies—which us...