The Rates of Reaction Relevant to Aerobic Oxidation Catalysis by Palladium

项目摘要 分子氧非常接近理想的氧化剂：它价格便宜，储量丰富，毒性最小， 环境友好（即“绿色”）。由于大多数底物对O2是动力学惰性的，因此与O2的氧化必须 催化剂，通常是过渡金属。然而，O2很少用于活性物质的生产。 药物成分，部分原因是它的反应被认为是难以控制的，导致 过氧化或降低的选择性。这是一个直接的矛盾与丰富的温和和选择性 自然界催化的需氧氧化反应;许多这样的氧化反应在活性部位使用过渡金属。目标 这一建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前途的进一步发展。这些催化剂已经 在有氧氧化反应中使用，但与传统的Pd- 催化转化，如交叉偶联。问题在于再氧化步骤;如果用 O2更有效，那么催化剂将更耐用！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。这些因素将通过进行详细的 机理研究：分离和合成反应性Pd 0源，然后使其经受（和监测 与O2的反应。所得的PdII-过氧物质可以通过以下方式转化为有用的循环中间体： 质子化反应，因此也将对质子化进行仔细的机理研究。一 一系列的这些研究将提供全面的指导方针，配体和底物的选择，为所有有氧 钯催化反应，导致未来反应开发的加速时间轴，特别是 用于生产活性药物成分。

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.