Mechanism-based Development of New Nickel-catalyzed Stereospecific Cross-electrophile Coupling Reactions

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With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Elizabeth Jarvo of the University of California at Irvine is studying the development of new nickel-catalyzed processes for the formation of carbon-carbon bonds. Nickel is more earth-abundant than the metals typically used to catalyze CC bond formation and so synthetic methods that use it are advantageous from the standpoint of environmental sustainability; however, the chemistry of nickel is complex and not well understood. To overcome the challenges of realizing effective and reliable forms of nickel catalysis, process development is being coupled with detailed mechanistic experiments designed to elucidate the fundamental attributes responsible for the control of reaction selectivity. The methods under investigation offer the promise of new approaches for the conversion of simple precursors into value added products with potential applications as pharmaceutical agents, agrochemicals, and other advanced materials. The broader impacts of the funded project extend to the benefits accrued to society as Professor Jarvo and her coworkers engage in a variety of educational and outreach activities. Among them, the unique LEAPS (Laboratory Experiments and Activities in Physical Sciences) program is directed at increasing participation in, and awareness of, chemical research by middle school students from groups traditionally underrepresented in STEM (science, technology, engineering and mathematics) fields. In other supported activities that likewise promote broadening participation in the scientific enterprise, mentoring and career-development workshops that target female and other minority faculty, graduate students, and undergraduate students are also being diligently pursued by the lead investigator and her team.The funded research focuses on study of new nickel-catalyzed intramolecular cross-electrophile coupling reactions of esters, sulfonamides, and imides. It is anticipated that these efforts will provide useful methods for late-stage functionalization as well as strategies for the synthesis of 1,1-diarylalkanes and heterocycles, important moieties for medicinal chemistry. Mechanistic experiments being performed will inform on the rational design of new nickel-catalyzed reactions and the identification of key catalytic intermediates will be attempted to address existing knowledge gaps concerning reaction pathways. A central aim of the research being pursued is to obtain experimental evidence establishing the ligand features necessary to support one- and/or two-electron elementary redox steps as nickel complexes navigate the cross-electrophile coupling catalytic cycle. The odd or even nature of oxidation state changes at nickel during the reaction cycle is a critical determinant for the stereochemical outcome of reactions of alkyl electrophiles in cross-coupling and cross-electrophile coupling reactions. Ultimately, by refining basic understanding of the mechanism of nickel-catalyzed reactions, the research seeks to remove a significant obstacle that has hindered the wider adoption of base metal catalytic manifolds for organic synthesis, namely, mechanistic ambiguity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.