Project Summary/Abstract Rapid advancements in biological and computational tools to find new therapeutic targets have outstripped available synthetic tools to synthesize drug candidates. Many proposed molecules are not tested because of the synthetic and time constraints of medicinal chemistry, where lead cores must be rapidly diversified in a modular fashion using robust, well-established methods, such as palladium-catalyzed cross-coupling and Grignard reactions. The major hurdles are the limited accessibility of carbon nucleophiles and the limited tolerance of most methods for the broad range of functional groups and reactivity present in drug candidates. We propose to develop collections of cross-electrophile coupling reactions that address these challenges and are adapted to modern parallel synthesis. Cross-electrophile coupling leverages the increased diversity of carbon electrophiles compared to nucleophiles (100 to 1000 times more commercially available derivatives); but achieving selectivity for cross-coupled product over dimeric products can be challenging and the factors that govern successful coupling remain unclear. This program's long-term goals are the development of methods for the selective cross-coupling of every major class of electrophile and the discovery of the fundamental properties that control selectivity and reactivity. In the proposed grant, a team of graduate students and postdocs will build upon the advances of the previous grant period to develop fourteen new cross-electrophile coupling reactions, explore new ways to utilize the largest substrate pools (organic chlorides, alcohols, amines, and carboxylic acids), and shed light on the reactive nickel intermediates that govern these processes. Our guiding hypothesis is that these challenges can be addressed by a combination of mechanistic studies, mechanism-guided design of new electrophiles, and an optimization approach that focuses on a collection of substrates rather than a single substrate pair. The specific aims of this proposal are to: (1) improve Csp2–Csp3 cross-electrophile coupling by the development of methods to engage new electrophiles, new combinations of old electrophiles, and by tailoring our optimization to the needs of medicinal chemistry; (2) address challenging Csp2–Csp2 cross-couplings by developing new, universal routes to challenging di(hetero)aryl ketones and bi(hetero)aryls; (3) shed light on the principles that govern nickel- catalyzed reactions by using electrochemical methods to study otherwise inaccessible reaction intermediates. The approach is innovative because cross-electrophile coupling is less studied than other cross-coupling methods and the proposed mechanistic studies will shed light on these little-understood processes. The proposed research is significant because the chemistry is increasingly important to industrial and academic chemical synthesis and the development of nickel chemistry has outpaced our understanding.