Understanding the Mechanism and Selectivity of Oxidative Addition of Aryl (Pseudo)halides at Palladium(0)

在化学系化学催化项目的支持下，蒙大拿州立大学的Sharon Neufeldt正在研究钯催化剂如何破坏有机分子中的碳-卤素键和相关的碳-假卤素键，以激活它们以合成新分子。钯与有机卤化物的基本反应是交叉偶联反应的关键步骤。交叉偶联反应是有机合成的主要方法。然而，当有机分子含有多个卤素时，控制交叉偶联的选择性是有问题的。这项工作将使人们能够了解条件如何影响钯反应的确切途径，并且当分子上存在多个碳-卤素键时，这种新的理解将对控制反应位点产生影响。反过来，这项工作将促进更有效和选择性的有机合成方法的发展。作为该项目的一部分，还将开发一个教育计划，重点是促进有机反应机制在3D空间中的可视化，同时为学生提供使用计算工具进行分子建模的实践培训。蒙大拿州立大学的Sharon Neufeldt和她的研究小组正在研究（杂）芳基（伪）卤代物氧化加成到Pd(0)分子的机制。至少有两种途径已知是相关的，这项工作的一个中心假设是，可以根据钯配位数、配体立体和电子结构、有机亲电试剂的结构以及溶剂极性等其他因素来预测主导机制。了解这些因素有望使控制机制成为可能，并且使Pd倾向于一种机制而不是另一种机制的能力对于控制交叉偶联反应的化学和位点选择性具有广泛的意义。总体目标分为以下几个具体目标：(1)建立配位数、底物、配体类别和溶剂对氧化加成机理的影响模型；(2)考察亲核偶联伙伴对氧化加成反应的影响；(3)开发新的钯(0)源。这项工作将通过实验和计算技术来完成，包括碳动力学同位素效应研究、反应速率和选择性研究、有机金属合成和密度泛函理论计算。这项工作有望提高对Pd(0)/ArX体系中氧化加成过程的理解。这也将为交叉偶联反应的合理工程选择性提供一个起点，从而简化反应优化和改进合成设计原则。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Catalysis program in the Division of Chemistry, Sharon Neufeldt of Montana State University is studying how palladium catalysts break carbon–halogen and related carbon pseudohalogen bonds in organic molecules to activate them for the synthesis of new molecules. This elementary reaction between palladium and organohalides is a key step in cross-coupling reactions. Cross-coupling reactions are a mainstay of organic synthesis. However, controlling the selectivity of cross-couplings can be problematic when organic molecules contain multiple halogens. This work will enable understanding of how conditions influence the exact pathway by which palladium reacts, and this new understanding will have implications for controlling the reaction site when multiple carbon-halogen bonds are present on a molecule. In turn, this work will facilitate development of more efficient and selective methods for organic synthesis. As part of this project, an educational program will also be developed that focuses on facilitating visualization of organic reaction mechanisms in 3D space while also providing students with practical training in molecular modeling using computational tools.Sharon Neufeldt and her research team at the Montana State University are studying the mechanism of oxidative addition of (hetero)aryl (pseudo)halides to molecular Pd(0) species. At least two pathways are known to be relevant, and a central hypothesis of this work is that the dominant mechanism can be predicted based on palladium coordination number, ligand sterics and electronics, the structure of the organic electrophile, and other factors such as solvent polarity. Understanding these factors is expected to enable control of the mechanism, and the ability to predispose Pd toward one mechanism over the other can have broad implications for controlling chemo- and site-selectivity of cross-coupling reactions. The overall objective is divided into the following specific aims: (1) to develop a model for the influence of coordination number, substrate, ligand class, and solvent on the mechanism of oxidative addition; (2) to investigate the influence of nucleophilic coupling partner on oxidative addition; and (3) to develop new palladium(0) sources. This work will be accomplished through experimental and computational techniques including carbon kinetic isotope effect studies, reaction rate and selectivity studies, organometallic synthesis, and density functional theory calculations. This work is anticipated to improve understanding of how oxidative addition takes place in such Pd(0)/ArX systems. It will also provide a starting point for rationally engineering selectivity in cross-coupling reactions, thereby streamlining reaction optimization and improving synthesis design principles.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.