HYDROGEN ATOM TRANSFER REACTIONS OF METALLOENZYMES

氧化C-H键的金属酶的研究受到缺乏 过渡金属中心如何氧化有机物 印刷受体. 这项工作的目标是提供新的机制 这种反应的范例。 一个特别的重点将是氧化， 氢原子的抽象，这被认为是 许多重要金属酶的底物活化步骤， 包括细胞色素P-450、脂氧合酶和多巴胺β-羟化酶。 夺取氢原子也是C-H键形成的关键步骤 通过高锰酸盐和有机化学中使用的其它试剂的氧化， 并且涉及工业上重要的烃氧化。 的 目前对这些反应的看法是，在反应的起始点必须有一个自由基， 活性位点-如在活性位点上具有自由基特征的氧代铁基团。 如细胞色素P-450和博来霉素所建议的氧。 我们提出了一个新 这些反应的方法，基于活性位点的亲和力， 一个氢原子，换句话说，形成的O-H键的强度。 一 关于氢原子提取反应的大量文献占主导地位 通过讨论键的强度，而不是自由基的性质。 活性位点或试剂对氢原子的亲和力可以是 根据其氧化还原电位和pKa计算，采用一种程序， 对于有机化合物和有机金属化合物来说是非常发达的。 初步 对铬酰氯和高锰酸盐氧化作用的研究表明， 这一观点不仅是定性的， 为什么以及如何发生反应，而且是定量的：氢的速率 CrO 2Cl 2或MnO 4-的原子提取可以根据以下公式粗略预测： 形成的O-H键的强度。 这一预测是基于 自由基反应速率与其驱动力之间的波兰尼关系 力，一个简单的处理，这是有关马库斯理论， 电子转移速率 铬（VI）和 提出高锰酸盐氧化来检验这一假设。 相关 还将探索通过初始氢化物转移发生的反应。 我们预测，各种配位络合物也应该能够 氧化C-H键，以及对铜、铁、镍、锰和 描述了钌化合物。 我们将开始与已知的铜（三） 和铁（III）配位络合物，这应该是优秀的 多巴胺β-羟化酶激活步骤的功能模型 羟化酶和脂氧合酶。 初步结果表明， 铜（III）亚胺-肟络合物确实通过氢原子氧化底物 转移 证实我们的假设将有助于准备 更好的模型，这些氧化酶，并将导致更好的理解 并预测其选择性。

The study of metalloenzymes that oxidize C-H bonds is hampered by a lack of understanding of how transition metal centers oxidize organic substrates. The goal of this work is to provide new mechanistic paradigms for such reactions. A particular focus will be oxidation by hydrogen atom abstraction, which has been implicated as the key substrate-activating step for a number of important metalloenzymes, including cytochrome P-450, lipoxygenase, and dopamine Beta-hydroxylase. Hydrogen atom abstraction also appears to be a key step in C-H bond oxidation by permanganate and other reagents used in organic chemistry, and is involved in industrially important hydrocarbon oxidations. The current picture of these reactions is that there must be a radical at the active site -- such as an oxo-iron group with radical character at the oxygen as suggested for cytochrome P-450 and bleomycin. We propose a new approach to these reactions, based on the affinity of the active site for a hydrogen atom, in other words the O-H bond strength formed. The very extensive literature on hydrogen atom abstraction reactions is dominated by such discussions of bond strengths, not radical character. The affinity of an active site or reagent for a hydrogen atom can be calculated from its redox potential and pKa, adapting a procedure that is well developed for organic and organometallic compounds. Preliminary studies of oxidations by chromyl chloride and permanganate suggest that this perspective is not only qualitative, providing an explanation for why and how reactions occur, but also quantitative: the rate of hydrogen atom abstraction by CrO2Cl2 or MnO4- can be roughly predicted based on the strength of the O-H bond formed. This prediction is based on the Polanyi relation between the rate of radical reactions and their driving force, a simple treatment that is related to the Marcus theory of electron transfer rates. Further studies of chromium (VI) and permanganate oxidations are proposed to test this hypothesis. Related reactions that occur by initial hydride transfer will also be explored. We predict that a variety of coordination complexes should also be able to oxidize C-H bonds, and studies of copper, iron, nickel, manganese, and ruthenium compounds are described. We will begin with known copper(III) and iron(III) coordination complexes, which should be excellent functional models for the C-H activation step in dopamine Beta- hydroxylase and lipoxygenase. Preliminary results suggest that a copper(III) imine-oxime complex does oxidize substrates by hydrogen atom transfer. Confirmation of our hypothesis will facilitate preparation of better models for these oxidases, and will lead to better understanding and prediction of their selectivity.