CAREER: Combined Experimental and Computational Approach to Controlling Site Selectivity in Cross Coupling Chemical Reactions

交叉偶联是一种化学反应，其中两个不同的分子通过金属催化剂连接在一起。这些反应对于形成碳-碳、碳-氮和其他类型的键具有价值，用于构建复杂的有机分子，用于药物设计、新生物材料设计和其他先进制造应用。在交叉偶联反应中，反应选择性的控制往往是一个难题。如果催化剂不能区分分子上几个可能的反应位点，就会产生混合产物。这种混合物的净化会增加成本和浪费。在这个项目中，Neufeldt博士正在开发用于交叉耦合的催化剂，这种催化剂可以有效地区分相似的反应位点。基于实验室和计算的研究都被用来了解催化剂结构如何影响催化剂与微妙的不同位点的相互作用方式。这些信息正被用于设计改进的催化剂，以达到更高的选择性和效率。作为该项目的一部分，Neufeldt博士参与了一些活动，以鼓励代表性不足的少数民族参与科学研究，并改善本科阶段的计算化学教育。这些活动包括让邻近部落学院的学生参与计算化学研究，将计算化学实验室纳入蒙大拿州立大学的有机课程，并参与到当地学校和部落学院的推广活动中。Neufeldt博士正在确定和开发新的机制，通过该机制，膦和n -杂环碳（NHC）配体可以影响镍（Ni）和钯（Pd）催化的交叉偶联反应中的位点选择性。人们正在研究膦配体在镍催化的交叉偶联中控制苯酚衍生物和氯化物之间选择性的能力。此外，NHC配体在pd催化偶联中影响芳基三氟酸酯和氯化物之间选择性的能力也在研究中。这些系统中选择性的起源是通过实验和计算研究相结合来研究的。密度泛函理论也被用于在计算机上设计新的位点选择性催化剂。本项目的工作对于提高交叉耦合的官能团耐受性，促进顺序或迭代耦合，以及深入了解催化剂的结构-选择性关系具有重要价值。该项目的更广泛影响包括让美国印第安学生参与科学、技术、工程和数学（STEM）学科的研究，以及向不同年龄的学生介绍计算化学。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。

Cross couplings are a type of chemical reaction in which two different molecules are joined together by a metal catalyst. These reactions are valuable for forming carbon-carbon, carbon-nitrogen, and other types of bonds for the construction of complex organic molecules for use in drug design, the design of new biomaterials, and other advanced manufacturing applications. In cross coupling reactions the control of reaction selectivity is often challenging. If the catalyst cannot differentiate between several possible reaction sites on the molecules, a mixture of products will result. Purification of that mixture increases cost and waste. In this project, Dr. Neufeldt is developing catalysts for cross coupling that efficiently differentiate between similar reactive sites. Both laboratory-based and computational studies are being employed to understand how the catalyst structure influences the way the catalyst interacts with subtly different sites. This information is being used to design improved catalysts to achieve higher selectivity and efficiency. As part of this project, Dr. Neufeldt is involved in activities to encourage participation of underrepresented minorities in scientific research and improve computational chemistry education at the undergraduate level. These activities include involving students from neighboring tribal colleges in computational chemistry research, implementing computational chemistry labs into the organic curriculum at Montana State University, and engaging in outreach to local schools and tribal colleges. Dr. Neufeldt is identifying and exploiting new mechanisms by which phosphine and N-heterocyclic carbene (NHC) ligands can influence site selectivity in nickel (Ni)- and palladium (Pd)-catalyzed cross coupling reactions. Phosphine ligands are being studied for their ability to control selectivity between phenol derivatives and chlorides in Ni-catalyzed cross couplings. In addition, NHC ligands are under investigation for their ability to influence selectivity between aryl triflates and chlorides in Pd-catalyzed couplings. The origin of selectivity in these systems is examined through a combination of experimental and computational studies. Density functional theory is also employed to design new site-selective catalysts on the computer. The work in this project is valuable for improving the functional group tolerance of cross couplings, facilitating sequential or iterative couplings, and providing insight into catalyst structure-selectivity relationships. The broader impacts of this project include engaging American Indian students in research in science, technology, engineering, and mathematics (STEM) disciplines, as well as introducing students of diverse ages to computational chemistry.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.