Innovations in Cross-coupling via Mechanistically Guided Base-Metal Catalyst Design

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Metal-based catalysts play a central role in promoting chemical reactions that give rise to the molecules and materials that we make use of in our everyday lives (e.g. fuels, plastics, medicines, etc.). One class of reactions that is used widely in industry, including the pharmaceutical industry for the construction of sought-after drug molecules, is called C-N/O cross-coupling. Such transformations allow connections to be made between carbon and either nitrogen or oxygen, typically by use of molecular palladium catalysis. Such catalyst complexes are comprised of a palladium-based fragment that is bound to one or more electron-donating ancillary ligand molecule(s) ("ligand(s)"); the judicious choice of ligand is crucial in terms of enabling the successful outcome of the reaction of interest. However, the cost and rarity of palladium, as well as the need to conduct reactions in new and more general ways, creates motivation for the development of molecular catalysts based on the more abundant `base metals', including nickel. Unfortunately, many of the ligands that work optimally with palladium are ineffective with the base metals. In this context, my research group has recently developed proprietary "PAd-DalPhos" (PhosphaADamantane-DALhousie PHOSphine) and related ligands, which enable otherwise difficult and sought-after nickel-catalyzed C-N/O cross-couplings in a manner that is competitive with, and in some cases superior to, palladium catalysis. Our state-of-the-art PAd-DalPhos/Ni cross-coupling catalysts have been commercialized and are being explored internationally by end users in both academia and industry, including as `drop-in' replacements for palladium catalysts in transformations of cheap and abundant aryl chlorides (ArCl). Despite this success, little is known regarding the way in which nickel catalysts developed by my group and others function ("reaction mechanism"); such an understanding is required to guide the development of new ligands/catalysts for application in sought-after syntheses. In this proposed research, experimental studies (supported by computational analysis) will be carried out to determine the way in which the structure of the reacting molecules and catalyst govern the observed reaction mechanism. With this understanding in hand, new superlative ligands matching these criteria will be developed and deployed in the quest to address some of the most outstanding challenges in nickel-catalyzed C-N/O cross-couplings (e.g., peptoid arylation), as well as enabling new and useful chemical transformations (e.g., ketone hydroarylation). Collectively, the proposed synthetic, structural, mechanistic, and catalytic studies will expand our conceptual understanding of ligation effects in base metal-catalyzed reactions and beyond, as well as providing practical in-roads to new medicines and functional materials that will be of benefit to Canadian society.