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-氮和其他类型的键很有价值，这些键用于构建复杂的有机分子，用于药物设计、新的生物材料设计和其他先进制造应用。在交叉偶联反应中，反应选择性的控制常常是具有挑战性的。如果催化剂不能区分分子上几个可能的反应位置，就会产生产物的混合物。提纯这种混合物会增加成本和浪费。在这个项目中，纽菲尔特博士正在开发能有效区分相似反应部位的交叉偶联催化剂。基于实验室和计算机的研究都被用来了解催化剂结构如何影响催化剂与细微不同的位置相互作用的方式。这些信息正被用于设计改进的催化剂，以实现更高的选择性和效率。作为该项目的一部分，纽菲尔特博士参与了鼓励少数族裔参与科学研究的活动，并改善了本科水平的计算化学教育。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，以及与当地学校和部落学院进行接触。NeuFeldt博士正在确定和开发新的机制，通过这些机制，膦和N-杂环卡宾(NHC)配体可以影响镍(Ni)和钯(Pd)催化的交叉偶联反应中的位置选择性。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的选择性的能力。此外，在Pd催化的偶联反应中，NHC配体影响三氟代芳烃和氯化物之间的选择性的能力正在接受调查。通过实验和计算研究相结合的方法，研究了这些体系中选择性的来源。本文还利用密度泛函理论在计算机上设计了新的择位催化剂。该项目的工作对于提高交叉偶联的官能团容忍度、促进顺序偶联或迭代偶联以及深入了解催化剂的结构-选择性关系具有重要意义。该项目的更广泛影响包括让美国印第安人学生参与科学、技术、工程和数学(STEM)学科的研究，以及向不同年龄段的学生介绍计算化学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.