HYDROGEN ATOM TRANSFER REACTIONS OF METALLOENZYMES

氧化C-H键的金属酶的研究因缺乏而受到阻碍 对过渡金属中心如何氧化有机的认识 底物。这项工作的目标是提供新的机制 这类反应的范例。一个特别的焦点将是氧化 氢原子抽象，这已经被认为是关键 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-羟基酶。 氢原子抽提似乎也是C-H键的关键步骤 有机化学中使用的高锰酸盐和其他试剂的氧化， 并参与了工业上重要的碳氢化合物氧化。这个 目前这些反应的图景是，肯定有一个激进的 活性中心--例如具有自由基性质的氧基铁基团 氧气，建议用于细胞色素P-450和博莱霉素。我们提出了一个新的 这些反应的方法，基于活性部位的亲和力 氢原子，也就是形成的O-H键的强度。最重要的 关于氢原子抽象反应的大量文献占主导地位 通过这种关于结合强度的讨论，而不是激进的性格。 活性中心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， 是非常适合有机和有机金属化合物的。初步 对氯化铬和高锰酸盐氧化作用的研究表明 这种观点不仅是定性的，还解释了 为什么和如何发生反应，但也是定量的：氢气的速率 CrO_2Cl2或MnO_4对原子的抽提可以根据以下公式进行粗略的预测 形成了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的Polanyi关系 力，这是一种与马库斯理论有关的简单处理 电子转移率。铬(VI)和铬(VI)的进一步研究 高锰酸盐氧化被提出来检验这一假说。相关 通过初始氢化物转移发生的反应也将被探索。 我们预测，各种配位络合物也应该能够 氧化C-H键，研究铜、铁、镍、锰和 描述了Ru化合物。我们将从已知的铜开始(III) 和铁(III)配位络合物，这应该是很好的 多巴胺的C-H激活步骤的功能模型-- 羟基酶和脂氧合酶。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 调职。证实我们的假设将有助于准备 这些氧化酶的更好的模型，并将导致更好的理解 以及对它们的选择性的预测。

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.