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

金属催化剂在促进化学反应方面发挥着核心作用，这些化学反应产生了我们在日常生活中使用的分子和材料(例如燃料、塑料、药品等)。C-N/O交叉偶联反应是一类在工业上被广泛使用的反应，包括用于构建受欢迎的药物分子的制药工业。这种转化允许碳与氮或氧之间的连接，通常是通过分子钯催化。这类催化剂络合物是由一个基于钯的片段组成的，它与一个或多个给电子的辅助配体分子(S)(“配体(S)”)结合在一起；明智地选择配体对于实现感兴趣的反应的成功结果至关重要。然而，钯的成本和稀缺性，以及以新的和更一般的方式进行反应的需要，为基于更丰富的贱金属(包括镍)的分子催化剂的开发创造了动力。不幸的是，许多与钯作用最好的配体对贱金属无效。在这方面，我的研究小组最近开发了专有的“Pad-DalPhos”(磷酸盐-金刚烷-达尔豪西膦)和相关的配体，使镍催化的C-N/O交叉偶联变得困难和抢手，其方式与钯催化竞争，在某些情况下甚至优于钯催化。我们最先进的Pad-DalPhos/Ni交叉偶联催化剂已经商业化，并正在由学术界和工业领域的最终用户在国际上进行探索，包括作为廉价和丰富的芳基氯化物(ArCl)转化中的钯催化剂的替代产品。尽管取得了这一成功，但对我的团队和其他人开发的镍催化剂的作用方式(反应机理)知之甚少；这种理解是指导开发应用于热门合成的新配体/催化剂所必需的。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理的方式。有了这一认识，符合这些标准的新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交叉偶联中的一些最突出的挑战(例如，肽类芳基化)，以及实现新的和有用的化学转化(例如，酮氢芳基化)。总的来说，拟议的合成、结构、机理和催化研究将扩大我们对贱金属催化反应中和其他反应中连接效应的概念性理解，并为有益于加拿大社会的新药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.