The Rates of Reaction Relevant to Aerobic Oxidation Catalysis by Palladium

项目总结 分子氧非常接近理想的氧化剂：它便宜、丰富、毒性最小，而且 对环境无害(即“绿色”)。由于大多数底物对O2都是惰性的，所以与O2的氧化必须 被催化，最常见的是过渡金属。然而，氧气很少用于生产活性物质 药物成分，部分原因是它的反应被认为很难控制，导致 过氧化或选择性降低。这与温和和有选择性的丰富是直接矛盾的 自然界催化的有氧氧化作用；许多这样的氧化作用在活性中心使用过渡金属。目标是 这一提议的目的是为了更好地了解O2和各种过渡金属碎片的反应。 钯催化的反应特别有希望得到进一步的发展。这样的催化剂已经 用于好氧氧化反应，但与传统的Pd相比效率相对较低。 催化转化，如交叉偶联。问题出在再氧化步骤上；如果用 氧气更有效，那么催化剂就会更坚固！令人惊讶的是，人们对哪些因素知之甚少 导致清洁和快速的再氧化反应。这些因素将通过开展详细的 机理研究：分离和合成活性Pd0源，然后对它们进行(和监测) 与)O2的反应。由此产生的PdII-Peroxo物种可以通过以下方式转化为有用的、循环中的中间体 质子化反应，因此还将对质子化进行仔细的机理研究。一个 这一系列的研究将为所有需氧的配体和底物的选择提供全面的指导方针 钯催化的反应，导致加快了未来反应发展的时间表，特别是 用于活性药物成分的生产。

PROJECT SUMMARY Molecular oxygen is very close to the ideal oxidant: it is inexpensive, abundant, has minimal toxicity, and is environmentally benign (i.e. “green”). Since most substrates are kinetically inert to O2, oxidations with O2 must be catalyzed, most often by transition-metals. However, O2 is seldom used in the production of active pharmaceutical ingredients, in part because its reactions are thought to be hard to control, leading to overoxidation or diminished selectivity. This is a direct contradiction with the abundance of mild and selective aerobic oxidations catalyzed by Nature; many such oxidations use a transition-metal in the active site. The goal of this proposal is to gain a better understanding of the reactions of O2 and various transition-metal fragments. Palladium-catalyzed reactions are particularly promising for further development. Such catalysts have already been used in aerobic oxidation reactions, but are relatively inefficient when compared to traditional Pd- catalyzed transformations, such as cross-coupling. The problem lies in the reoxidation steps; if reoxidation with O2 were more efficient, then the catalyst would be more robust! Surprisingly little is known about what factors result in clean and fast reoxidation reactions. These factors will be elucidated by carrying out a detailed mechanistic study: isolating and synthesizing reactive Pd0 sources, then subjecting them to (and monitoring the reactions with) O2. The resulting PdII-peroxo species can be converted to useful, on-cycle intermediates by a protonation reaction, and so careful mechanistic studies will be carried out on the protonation as well. A series of these studies will provide comprehensive guidelines into ligand and substrate selection for all aerobic palladium-catalyzed reactions, leading to an accelerated timeline for future reaction development, especially towards the production of active pharmaceutical ingredients.