CAREER: Synthesis and Applications of Multipurpose Halomucononitrile Linchpin Reagents

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With the support of the Chemical Synthesis Program in the Division of Chemistry, Sidney Wilkerson-Hill of the University of North Carolina at Chapel Hill is studying the synthesis and reactivity of a class of hitherto little studied molecules called halomucononitriles. These versatile materials are well-behaved surrogates for highly reactive intermediates and the unique transformations to be explored are anticipated to lead to improvements in chemical manufacturing with positive impacts in disparate areas ranging from drug discovery to materials science. The broader impacts of the funded project will extend to the benefits accrued to society as the PI and other members of the Wilkerson-Hill research group engage in a wide range of educational and outreach activities involving partnerships between UNC Chapel Hill and organizations such as the National Association for the Professional Advancement of Black Chemists and Chemical Engineers (NOBCChE) and the Allies for Minorities and Women in Science and Engineering (AMWISE). A significant portion of these efforts focus on increasing participation in the scientific enterprise by individuals belonging to groups traditionally underrepresented in STEM (Science, Technology, Engineering and Mathematics) fields.Halomucononitriles [bis-3,3´-(2-haloacrylonitriles)] are valuable linchpin reagents containing a 1,4-dicyanobutadiene motif that permits the sequential formation of C-C and C-N bonds through a variety of controllable multistep reaction sequences. The synthetic utility of halomucononitriles and new routes for their formation will be explored in the context of three aims: (1) synthesis of medicinally-relevant 7-alkylazaindoles from pyridinimines generated by addition of primary amines to halomucononitriles, (2) use of halomuconitriles as a synthetic equivalent of bisketene to access 1,4-diketones via double ([4+2], [3+2], or [2+2]) cycloadditions followed by alpha-halonitrile to ketone conversion, and (3) generation of halomucononitriles from haloanilines by oxidative ring-opening processes. The last aim paves the way for a new arene deconstruction strategy enabling the net transmutation of benzene derivatives into pyridines and other important azacycles. Beyond its immediate benefits to synthetic organic chemistry, the new knowledge gained from these studies may enable researchers from different fields to use halomucononitrile linchpin chemistry for diverse applications such as lysine conjugation strategies, DNA-encoded library synthesis, and polymer science. Finally, it is noted that the research supported by the award will provide valuable training opportunities for graduate students to enable their pursuit of future careers in the chemical sciences and allied disciplines.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.