Methodological Development and Computational Investigations of Metal-Catalyzed Coupling Reactions

Chapter One describes the computational study of the asymmetric arylation of propargylic electrophiles. While previous mechanistic experiments have verified the general scheme of the catalytic cycle, it was still not known what the enantiodetermining step is, or how factors of the ligand and substrate influence reactivity. To answer these questions, a computational study to emulate the entire catalytic cycle was performed. It was determined that radical addition to the nickel catalyst was likely the enantiodetermining step. While the standard substrate and ligand combinations result was well predicted, the computational method was not widely applicable to different ligands. This implies that the catalytic cycle may not go through a discrete radical capture and reductive elimination step, but instead a more concerted process may be operating. Chapter Two details the development of the asymmetric cross-coupling between tertiary nucleophiles and secondary electrophiles. Specifically, α-zincated benzylic nitriles are asymmetrically coupling with secondary alkyl iodides under the influence of a nickel catalyst and iminopyrox ligand. This study represents the first report of such a ligand being use for any asymmetric nickel-catalyzed cross-couplings. Chapter Three describes computational work on three separate projects published by coworkers in the Fu lab. 1) The first section details work on the nickel-catalyzed asymmetric coupling of enynes with secondary racemic electrophiles to accomplish for the first time the simultaneous control of axial and point chirality. The computational work probed the possible steps of rearrangement of the putative nickel-propargyl species into nickel allenyl species, as well as rationalized the different reactivity of the catalyst towards different electrophiles. 2) The second project was investigations into the photocatalytic coupling of secondary and tertiary electrophiles with secondary amines by copper and a dual-ligand system. The computations shed light on possible C—N coupling mechanisms, as well as rationalized the differing photoactivity of the two CuI complexes present in the system. 3) The final work supported mechanistic studies into the photocatalytic asymmetric azidation of α-bromoamides by a copper-phosphine complex. DFT studies were performed to predict EPR spectra which were used to disambiguate the possible CuII species present in solution.