Mechanistic Investigation into Modern Catalytic Reactions

项目摘要：对新兴催化方法的机理理解是一个重要因素 在成功应用新的转换合成药物和其他高， 价值化学品。尽管如此，在新反应的发现和其应用之间存在显著的滞后。 机械描述这项研究计划在两个重要领域解决了这一挑战， 当代催化-光氧化还原催化和生物催化工程酶。 光催化剂利用可见光的力量产生高活性自由基中间体 可以战略性地引导参与各种有价值的债券形成。有 各种生物物理方法的检测和表征这些开壳 中间体的然而，过渡态的几何结构，键形成和 光氧化还原催化中的键断裂事件实际上不存在。在此背景下，本研究 该计划确立了13 C动力学同位素效应作为过渡态的难以捉摸的实验探针 光氧化还原反应的几何学。除了阐明这些复杂的反应机制外， 该测量作为校准理论方法的重要实验基准， 准确评估这些反应中的速率和选择性决定步骤。 细胞色素P450的定向进化导致了碳烯和氮烯转移的发现 这些含血红素的酶的活性。对这些系统的机制研究在很大程度上 由于与执行标准相关的固有挑战， 酶系统中的物理有机实验。该计划利用新开发的 分子内13 C动力学同位素效应技术沿着经典kH/kD实验以获得深入了解 这些反应中C-C和C-N键形成步骤的过渡态几何结构。高级别 QM/MM计算和MD模拟也被用来解释实验结果， 了解这些生物催化反应中选择性的起源。

Project Summary: Mechanistic understanding of emerging catalytic methodologies is an important factor in the successful application of novel transformations to the synthesis of pharmaceuticals and other high- value chemicals. Despite this, there is a significant lag between new reaction discovery and its mechanistic description. This research program addresses this challenge in two important areas of contemporary catalysis – photoredox catalysis and biocatalysis by engineered enzymes. Photocatalysts harness the power of visible light to generate highly reactive radical intermediates that can be strategically channeled to participate in a variety of valuable bond-formations. There are a variety of photophysical approaches for the detection and characterization of these open-shell intermediates. However, experimental probes of the transition state geometry, of key bond-forming and bond-breaking events in photoredox catalysis, are virtually non-existent. In this context, this research program establishes 13C kinetic isotope effects as the elusive experimental probe of the transition state geometry of photoredox reactions. In addition to shedding light on these complex reaction mechanisms, this measurement serves as an important experimental benchmark to calibrate theoretical methods to accurately evaluate the rate- and selectivity-determining steps in these reactions. Directed evolution of cytochromes P450 has led to the discovery of carbene- and nitrene-transfer activity of these heme-containing enzymes. Mechanistic investigations of these systems have largely been limited to theoretical studies due to the inherent challenges associated with conducting standard physical organic experiments in enzymatic systems. This program utilizes a newly developed intramolecular 13C kinetic isotope effect technique along with classical kH/kD experiments to gain insight into the transition state geometry of C–C and C–N bond-forming steps in these reactions. High-level QM/MM calculations and MD simulations are also utilized to interpret experimental findings and understand the origin of selectivity in these biocatalytic reactions.