Nickel Catalyzed C-H Functionalization: Development, Application and Mechanistic Investigation

C−H bonds are ubiquitous in nature. The direct conversion of C−H bonds into desired functionalities holds great promises in fields of natural product total synthesis, agricultural, biomedicine, and material science. However, the fact that C−H bonds being prevalent in organic molecules not only indicates their relative inert nature, but also renders their selective functionalization a daunting challenge. Moreover, the development of C−H functionalization methodology has been long hampered due to the obstacles in mechanistic investigations, thus often preventing further reaction development and application. New opportunities have become available for achieving site-selective C−H functionalization as transition metal (TM) catalyzed cross coupling revolutionized organic synthesis with myriad of methods being developed for diverse categories of coupling partners. Through these studies, the synthetic community started to recognize C−H bonds being latent nucleophiles, the use of which would bypass the reductant synthetic handle installation, offering unprecedented routes towards target structures. This dissertation focuses on developing C−H functionalization using nickel (Ni) catalysis, a sustainable, earth-abundant transition metal. Application has sequentially been demonstrated by applying the developed methodologies to enantioselective catalysis and polymer synthesis. The reaction development has been guided by the exploration in organometallic catalyst synthesis and mechanistic investigations which were conducted both experimentally and computationally including reaction progress kinetic analysis (RPKA), kinetic isotope effect (KIE) same excess experiments and density functional theory (DFT). The first chapters revisit a unique, nickel mediated C−H activation pathway, ligand-to-ligand hydrogen transfer (LLHT). The successful synthesis of unprecedented 1,5-hexadiene supported chiral nickel catalysts enabled a novel, intermolecular asymmetric C–C cross coupling. Experimental evidence from RPKA and KIE experiments were consistent with the proposed LLHT pathway, where the C−H activation precedes a rate-determining reductive elimination step. The implication of this methodology was translated to a defect-free polymer synthesis. High molecular weight polymers (Mn >17 kDa) have been synthesized with readily available monomers under mild condition in stereo-regulated manners. Being not only a cost-effective replacement for precious transition metals, nickel is also appealing for its unique reactivities, single electron transfer (SET) being one of them. The radical nature of odd oxidation states (NiI, NiIII) has been highlighted in the mechanistic study of a-arylation of N-alkylbenzamides catalyzed by a dual nickel/photoredox system where tetrabutylammonium bromide (TBAB) was a potent HAT agent. Moreover, this additive effect was demonstrated with improved reactivities and better access to valuable C(sp3)-arylated products. Intrigued by the versatilities of hydrogen atom transfer (HAT) for activating C–H bonds that are otherwise hard to approach, the final chapters focus on the cross coupling between aldehydes and carbamates via a dual HAT process. Supported both by experimental evidence and quantum chemical simulations, the unconventional combination of oxidants and reductants was deemed vital in this redox-buffered dehydrogenative coupling. Building on this seminal report, ongoing efforts are harvesting nickel as a powerful carbon centered radical mediator to attain modular synthesis of targeted structures under diverse manifolds. Considering the pivotal role that N-heterocycles play in the bioactive molecules, we surmise future application in structural elaboration of amine-containing targets.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/176526/1/mochem_1.pd