Project Summary/Abstract The discovery of new potential drugs and biological tools is necessarily limited to the conveniently-available chemical space. Historically, this space has been dominated by biaryls because their synthesis is reliable and amenable to the needs of medicinal chemistry, where a core structure is diversified and built outwards by iterative rounds of synthesis. Recently, cross-electrophile approaches show promise for providing convenient access to more C(sp3)-rich molecules, a feature predicted to improve the odds of success in drug development. Despite recent advances, cross-electrophile coupling of aryl electrophiles with alkyl electrophiles has yet to realize its considerable potential. This is because many of the most abundant pools of substrates have very different reactivity. We propose to develop new strategies in cross-electrophile coupling that address these challenges and are adapted to modern medicinal chemistry approaches. 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 a postdoc will build upon the advances of the previous grant period to develop protocols to cross- couple starting materials sourced from the largest substrate pools (organic chlorides, alcohols, amines, and carboxylic acids), access more hindered C(sp2)–C(sp3) bonds, and shed light on how the nature of the coupling partners and ancillary ligands govern success. Our guiding hypothesis is that these challenges can be addressed by a combination of mechanistic studies, mechanism-guided tuning of catalysts and activating agents, 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) develop protocols for C(sp2)–C(sp3) cross-electrophile coupling between the largest pools of aryl, vinyl, and alkyl substrate pools; (2) address the challenge of forming C(sp2)–C(sp3) bonds by developing new catalysts based upon nickel and cobalt; (3) study how ancillary ligands influence the stability and reactivity of arylnickel(II) complexes to both improve catalytic reactions and to enable new types of stoichiometric reactions for medicinal chemistry applications, such as DNA-encoded libraries. 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.