Abstract: 

Construction of carbon-carbon and carbon-heteroatom bonds has been achieved throughout the history of organic chemistry research via protonation of an alkene with a Bronsted acid, followed by trapping the resulting carbocation with a nucleophile. However, the strong acids and often elevated temperatures required to protonate an alkene and generate the high-energy carbocation result in poor chemoselectivity and limited scope. In the last decade, the development and study of metal-hydride-mediated hydrogen atom transfer (MHAT) radical-polar crossover reactions of alkenes has become a growing focus in the field of synthetic organic chemistry to obtain complex functionalized products in a mild, chemoselective fashion. This dissertation describes my efforts to better understand this mode of reactivity and to explore applications towards new synthetic methods.

First, my investigations into potential pathways accessed via cobalt-hydride-mediated hydrofunctionalizations of asymmetric 1,2-disubstituted alkenes. The factors contributing to the observed divergent reactivity of allylic alcohols towards cycloetherification, semipinacol rearrangement, and Grob fragmentation amongst others are scrutinized through analysis of structure-activity relationships with various cobalt salen catalysts and a series of mechanistic experiments. Hypotheses explaining possible driving forces behind the observed regioselectivity of HAT towards the alkene are evaluated based on literature precedent and experimental observations. Evidence is presented supporting an unprecedented directing effect guiding HAT to the alkene via associative interactions between the cobalt salen catalyst and a free alcohol.

Analysis of a novel cobalt-hydride-mediated radical-polar crossover method for fragmentation of homoallylic secondary and tertiary alcohols is also discussed. Comparisons are drawn to retro-Prins, Grob, and retro-carbonyl ene fragmentation reactions to assess the operative fragmentation pathway. Excellent functional group tolerance is demonstrated with a variety of acid-sensitive and redox-sensitive functionality. Interrogation of requisite structural features for fragmentation, limitations of the reaction, and potential solutions to these limitations was performed.

Finally, a cobalt-hydride-mediated radical-polar crossover hydroamidation reaction of alkenes, developed as a mild, chemoselective alternative to the classical acid-mediated Ritter reaction, is reported. Efforts to expand the substrate scope towards challenging, highly substituted, unactivated alkenes are presented. Effects of reaction system engineering are studied and structure-activity relationships with newly developed cobalt catalysts are explained. Implications of patterns observed through extensive optimization studies on a wide variety of substrate structures towards development of future cobalt-catalyzed HAT-RPC reaction methods are proffered.