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

金属基催化剂在促进化学反应中起着核心作用，这些化学反应产生了我们日常生活中使用的分子和材料（例如燃料、塑料、药品等）。有一类反应被广泛应用于工业，包括制药工业，用于构建受欢迎的药物分子，称为C-N/O交叉偶联。这种转化允许碳和氮或氧之间的连接，通常是通过使用分子钯催化。所述催化剂配合物由钯基片段组成，该片段与一个或多个供电子辅助配体分子（“配体”）结合；配体的明智选择是至关重要的，以使成功的结果感兴趣的反应。然而，钯的成本和稀有性，以及以新的和更普遍的方式进行反应的需求，为开发基于更丰富的“贱金属”（包括镍）的分子催化剂创造了动力。不幸的是，许多与钯最有效的配体对贱金属无效。在这种情况下，我的研究小组最近开发了专有的“PAd-DalPhos”（phosphaadamamant - dalhousie PHOSphine）和相关配体，它们以一种与钯催化竞争，甚至在某些情况下优于钯催化的方式，实现了镍催化的C-N/O交叉偶联。我们最先进的PAd-DalPhos/Ni交叉偶联催化剂已经商业化，并正在国际学术界和工业界的最终用户中进行探索，包括在廉价和丰富的芳烃（ArCl）转化中作为钯催化剂的“直接”替代品。尽管取得了这一成功，但关于我的团队和其他人开发的镍催化剂的作用方式（“反应机制”），人们知之甚少；需要这样的理解来指导新的配体/催化剂的开发，以应用于受欢迎的合成。在本研究中，将进行实验研究（以计算分析为支持），以确定反应分子和催化剂的结构如何控制所观察到的反应机理。有了这样的理解，新的匹配这些标准的最高级配体将被开发和部署，以寻求解决镍催化的C-N/O交叉偶联（例如，肽基芳化）中的一些最突出的挑战，以及实现新的和有用的化学转化（例如，酮氢芳化）。总的来说，拟议的合成、结构、机制和催化研究将扩大我们对贱金属催化反应中结扎效应的概念理解，并为加拿大社会的新药物和功能材料提供实用的途径。

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.