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发挥着核心作用，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，药物等）。在工业中广泛使用的一类反应，包括用于构建受欢迎的药物分子的制药工业，被称为C-N/O交叉偶联。这种转化允许碳与氮或氧之间的连接，通常通过使用分子钯催化。这样的催化剂络合物由结合到一个或多个供电子辅助配体分子（“配体”）的基于钯的片段组成;配体的明智选择在使感兴趣的反应能够成功结果方面是至关重要的。然而，钯的成本和稀有性，以及以新的和更通用的方式进行反应的需要，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，许多与钯作用最佳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”（PhosphaADamantane-DALhousie PHOSPHINE）和相关配体，其能够以与钯催化竞争的方式实现原本困难且受欢迎的镍催化的C-N/O交叉偶联，并且在某些情况下上级于钯催化。我们最先进的PAd-DalPhos/Ni交叉偶联催化剂已经商业化，并正在国际上被学术界和工业界的最终用户探索，包括在廉价和丰富的芳基氯化物（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，但我们对我的小组和其他人开发的镍催化剂的作用方式（“反应机理”）知之甚少;需要这种理解来指导新配体/催化剂的开发，以应用于广受欢迎的合成。在这项拟议的研究中，将进行实验研究（由计算分析支持），以确定反应分子和催化剂的结构控制所观察到的反应机制的方式。有了这种理解，将开发和部署符合这些标准的新的最高级配体，以解决镍催化的C-N/O交叉偶联中一些最突出的挑战（例如，类肽芳基化），以及能够进行新的和有用的化学转化（例如，酮氢化芳基化）。总的来说，拟议的合成，结构，机理和催化研究将扩大我们对碱金属催化反应及其他反应中的连接效应的概念理解，并为有益于加拿大社会的新药和功能材料提供实际的进展。

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.