Physical organic studies of metal ion catalyzed acyl and phosphoryl transfer reactions in alcohols

由于最近研究成果的深远影响，我们将在未来五年继续探索拟议的研究计划，涉及开发几乎完全由我们的实验室开发的区域。在似乎是金属离子催化的酰基和磷酰基转移过程的简单扩展中，我们研究了金属催化的羧酸酯和磷酸酯在轻醇中的醇解反应，特别是甲醇和乙醇。在室温和pH基本为中性的乙醇中，锌、铜、镧等金属离子及其络合物极大地促进了酯类、活性酰胺类、磷酸二酯类和磷酸三酯类化合物的甲醇分解。这导致了以有机磷为基础的杀虫剂和化学武器去污的有效专利方法的发展。此外，最近的结果表明，各种双核锌(II)配合物对两个系列的磷酸二酯的裂解速度是通常用于RNA和DNA的简单模型的10^12-10^14倍。在拟议的工作中，我们打算用溶剂氘动力学同位素研究这些非常快的反应的机理，并用一组单和双锌(II)配合物在重氢甲醇和乙醇中促进RNA和DNA模型的裂解。我们将尽最大努力了解我们实验室最近的一项发现，在含有少量水的乙醇中，我们的一个双核锌(II)络合物可以将磷酸二酯的水解率提高约10^17倍。我们将研究这些双核和单核锌(II)配合物对一系列β-内酰胺类抗生素的催化裂解作用，作为锌(II)类金属β-内酰胺酶的模型，这种酶目前很受关注，因为产生这些酶的病原菌对β-内酰胺类抗生素的治疗具有很大的耐药性。这项研究计划将为几名学生和博士后提供培训，同时将为开发几种新的催化系统奠定基础，这些催化系统可能会在重要的生物和工业材料的转化中找到实际应用。

Due to the far reaching consequences of the recent research results, the proposed research program we will continue to explore over the next five year deals with exploitation of an area virtually exclusively developed in our labs. In what appears to be a simple extension of metal ion catalyzed acyl and phosphoryl transfer processes, we have studied metal catalyzed alcoholysis reactions of carboxylate and phosphate esters in the light alcohols, notably methanol and ethanol. Metal ions such as Zn^2+, Cu^2+ and lanthanides such as La3+ as well as complexes of these greatly accelerate the methanolysis of esters, activated amides, phosphate diesters and phosphate triesters at room temperature and essentially neutral pH in alcohol. This has led to the development of effective, patented methods for decontamination of organophosphorus based pesticides and chemical weapons. In addition, recent results have shown that various dinuclear Zn(II) complexes provide accelerations of 10^12-10^14-fold for the cleavage of two series of phosphate diesters that are commonly used as simple models for RNA and DNA. In the proposed work we intend to investigate the mechanism of these very fast reactions using solvent deuterium kinetic isotope studies for the cleavage of the RNA and DNA models promoted by a set of mono and di-Zn(II) containing complexes in deuterio-methanol and ethanol. We will mount a major effort to understand a very recent finding in our labs where one of our dinuclear Zn(II) complexes, in ethanol containing small amounts of water, can accelerate the hydrolysis of a phosphate diester by ~10^17-fold. We will investigate the catalysis of cleavage of a series of beta-lactams afforded by these di- and mononuclear Zn(II) complexes as models for the Zn(II) class B1 metallo-beta-lactamases, which are currently of interest as pathogenic bacteria that produce these enzymes have a great resistance to therapeutic treatment with beta-lactam antibiotics. This research program will provide training for several students and post-doctoral persons, and at the same time will lay the foundation for the development of several new catalytic systems that may find practical use for transformation of important biological and industrial materials.