Computational Models for Reactivity and Selectivity in Transition Metal-Catalyzed Olefin Functionalization

过渡金属催化烯烃官能化反应性和选择性的计算模型

• 批准号: 10242139
• 负责人: Peng Liu
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242139
• 关键词: Address; Alkenes; Biological; Biomedical Research; Carbon; Collaborations; Complex; Computer Models; Coupling; Development; Five-Year Plans; Future; Goals; Hydrogen; Ligands; Manuscripts; Mediating; Methods; Modeling; Nature; Process; Publishing; Reaction; Research; Structure; Substrate Interaction; System; Theoretical model; Transition Elements; career; catalyst; computer studies; computerized tools; design; drug discovery; experimental group; functional group; innovation; insight; pi bond; programs

Transition metal-catalyzed reactions of alkenes are among the most powerful approaches to synthesize functionalized organic compounds for biomedical research. Recent experimental advancements have enabled promising catalytic methods for hydro- and difunctionalization of alkenes, which add a hydrogen and a functional group or two different functional groups across a carbon-carbon double bond in an atom- and step-economical fashion. These approaches can serve as an important new platform for the synthesis of biologically active organic molecules because they can be utilized to construct structurally diverse target molecules using a broad scope of coupling partners. However, it remains a significant challenge to effectively control regio- and stereoselectivity in the reactions with readily available, unactivated alkenes. The current state-of-the-art approach relies on experimental trial-and-error to screen ancillary ligands, additives, and directing groups. Rational catalyst design remains challenging, due to the lack of theoretical understanding about the mechanisms of these multistep catalytic processes and the complex nature of the catalyst-substrate interactions. The overall goal of this proposal is to develop and apply computational tools to address these challenges in the development of transition-metal-catalyzed functionalizations of alkenes. We will perform high-level computational studies to reveal the reaction mechanisms and develop generally applicable models for reactivity and selectivity. These theoretical models aim to provide quantitative and straightforward prediction of the effects of ligands and directing groups. Therefore, they can be effectively applied to various experimental systems to guide future development of new catalytic reactions. During the first three years of my independent career, my group has published 24 manuscripts that focused on three general experimental strategies for alkene functionalization: (1) catalyst-controlled hydrofunctionalization of unactivated alkenes; (2) hydro- and difunctionalization of alkenes utilizing directing groups; and (3) radical-mediated reactions with alkenes. In the next five years, we plan to expand our computational studies to a broader scope of reactions. We will further optimize and validate our theoretical models to enable more robust prediction of reactivity and selectivity. We also intend to establish more collaborations with experimental groups to streamline the use of theoretical insights to guide experimental discovery. The proposed research program is significant and innovative because it aims to address general challenges and provide predictions to a broad range of catalytic reactions, rather than to simply explain existing results for specific experimental systems. Our research is highly unique in collaborating with many prominent experimental groups. These fruitful collaborations allowed us to progress in not only the understanding of many specific examples of alkene functionalization reactions, but also the development of general rules of regio- and stereoselectivity in these processes.

烷烃的过渡金属催化反应是合成的最强大的方法之一 用于生物医学研究的功能化有机化合物。最近的实验进步已启用 烯烃的水力和五官能化的有前途的催化方法，这些方法添加了氢气和功能 在原子和逐步经济中，跨碳碳双键的组或两个不同的官能团 时尚。这些方法可以作为合成生物活性有机的重要新平台 分子是因为它们可以使用广泛的范围 耦合伙伴。但是，有效控制区域和立体选择性仍然是一个重大挑战 在易于获得的，未活化的烯烃的反应中。当前的最新方法依赖 对筛选辅助配体，添加剂和指导组的实验试验和错误。理性催化剂设计 由于对这些多步的机制缺乏理论理解，因此仍然具有挑战性 催化过程和催化剂 - 基底相互作用的复杂性。 该提案的总体目标是开发和应用计算工具来应对这些挑战 烷烃过渡金属催化的功能化的发展。我们将执行高级 计算研究揭示了反应机制并开发了通常适用于反应性的模型 和选择性。这些理论模型旨在提供对影响的定量和直接预测 配体和指导组。因此，它们可以有效地应用于各种实验系统 指导新的催化反应的未来发展。在我独立职业的头三年中 集团已经出版了24项手稿，这些手稿侧重于烷烃的三种一般实验策略 功能化：（1）未活化烷烃的催化剂控制的水功能化； （2）水力 - 和 利用指导基团的烷烃进行的烷烯; （3）自由基介导的反应与烷烃。在 接下来的五年，我们计划将计算研究扩展到更广泛的反应范围。我们将进一步 优化和验证我们的理论模型，以实现反应性和选择性的更强大的预测。我们 还打算与实验组建立更多合作，以简化理论见解的使用 指导实验发现。 拟议的研究计划具有重要的和创新性，因为它旨在应对一般挑战 并为广泛的催化反应提供预测，而不是简单地解释现有结果 特定的实验系统。我们的研究在与许多著名的实验合作方面非常独特 组。这些富有成果的合作使我们不仅能够了解许多特定的理解 烯烃官能化反应的例子，也是区域和区域的一般规则的发展 这些过程中的立体选择性。