Merging Computation and Experiment to Understand and Develop Asymmetric Open-Shell Radical Cross- Couplings

项目摘要/摘要 尽管高通量筛选方法的进步导致了催化剂发现的激增 反应，我们对决定反应速率和选择性的步骤中的分子水平相互作用的知识 涉及高度不稳定和活性开壳中间体的催化反应还很初级。这些 知识差距阻碍了对竞争反应通道的控制、抑制或增强 开发新的催化反应。建立在强大的计算和实验初步结果的基础上，这 该计划旨在了解和指导新的可持续、催化和非对称转型的设计。 总体而言，我们的目标是开发第一排开放式壳体的反应性和选择性的预测模型 过渡金属催化的碳-碳键的形成，可以被有机，有机金属， 和生物(在)有机社区中合成具有药用活性的化合物。要做到这一点 总体目标是，我们确定了未来5年的两个研究领域和未来的计划。在 第一个领域，我们将使用实验和计算相结合的工具来理解和开发新的 不对称铁催化的自由基级联/交叉偶联反应。在第二个领域，通过协作 通过努力，我们将通过金属光氧化还原催化的交叉偶联来合成四元中心。 这些反应通过以碳为中心的自由基中间体、开壳有机金属物种、 以及光激电子态物种，其评估机制在历史上一直受到阻碍 与这些物种的高反应性和不稳定性相关的固有复杂性。高水平 根据实验数据严格校准的量子力学计算将被用来审问 为指导目前低速矿用新型催化剂和药剂的开发提供依据。 非选择性反应。此外，我们还将利用选定的易受动态影响的势能面 效应、单电子转移和系统间交叉，以更深入地了解这些因素 确定产品的选择性，并为催化剂和反应设计提供信息。总体而言，这些努力将推动 对日益复杂的催化反应和潜在影响领域的准确分子模拟的局限性 有机、生物(In)有机和过渡金属催化。

PROJECT SUMMARY/ABSTRACT Despite advances in high-throughput screening methods leading to a surge in the discovery of catalytic reactions, our knowledge of the molecular-level interactions in the rate- and selectivity-determining steps of catalytic reactions involving highly unstable and reactive open-shell intermediates is rudimentary. These knowledge gaps prevent control, suppression or enhancement, of competing reaction channels that can drive development of new catalytic reactions. Built on strong computational and experimental preliminary results, this program seeks to understand and guide design of new sustainable, catalytic, and asymmetric transformations. Overall, our goals are to develop predictive models of reactivity and selectivity of first-row, open-shell transition metal-catalyzed carbon-carbon bond formations that can be adapted by the organic, organometallic, and bio(in)organic community in the synthesis of medicinally-active compounds. To accomplish this overarching goal, we have identified two areas of research for the next 5 years and plans for beyond. In the first area, we will use combined experimental and computational tools to understand and develop new asymmetric iron-catalyzed radical cascade/cross-coupling reactions. In the second area, through collaborative efforts, we will target the synthesis of quaternary centers via metallophotoredox-catalyzed cross-couplings. These reactions proceed through carbon-centered radical intermediates, open-shell organometallic species, and photoexcited electronic state species where evaluating the mechanisms has been historically hampered by the inherent complexity associated with the high reactivity and instability of these species. High-level quantum mechanical calculations, rigorously calibrated against experimental data, will be used to interrogate the mechanisms and to guide the development of new catalysts and reagents for currently sluggish or unselective reactions. In addition, we will exploit selected potential energy surfaces susceptible to dynamic effects, single-electron transfers, and intersystem crossings to gain a deeper understanding of the factors determining product selectivity and inform catalyst and reaction design. Overall, these efforts will push the limits of accurate molecular modeling of increasing complex catalytic reactions and potentially impact the fields of organic, bio(in)organic, and transition-metal catalysis.