NSF-ANR CHE: Insights into Alkene Hydrofunctionalization from Mechanistic and Reactivity Studies

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Patrick Holland of Yale University is studying catalysts for the transformation of simple chemical feedstocks into more complex molecules under efficient conditions. Specifically, they will evaluate cobalt catalysts that add nitrogen, oxygen, sulfur, and phosphorus groups to natural or petroleum-based olefins through a metal-catalyzed hydrogen atom transfer mechanism. This mechanism has been controversial, and the research will answer fundamental questions about how the reaction occurs. Using this information, it will become possible to expand the scope of the reaction, and to improve the yields and effectiveness of the reactions. The research will involve a combination of synthesis, mechanism, computations, and advanced spectroscopic and mass spectrometry methods. Therefore, in addition to the scientific outcomes, it will be an excellent training opportunity for trainees in organic and inorganic chemistry. This will enhance the skills and experience of the U.S. scientific workforce. This project is being conducted in collaboration with Professors Eric Manoury and Rinaldo Poli of the Institut National Polytechnique Toulouse, who are separately supported by the French National Research Agency (ANR). With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Patrick Holland of Yale University is studying the hydrofunctionalization of alkenes with Earth-abundant metal catalysts using oxidative metal-catalyzed hydrogen atom transfer (MHAT) reactions. The main goals are to improve the mechanistic understanding, nucleophile scope, and selectivity of MHAT reactions, and these will be accomplished using organic and inorganic synthesis, kinetic studies, mass spectrometry, DFT computations, and virtual ligand screening. The guiding hypothesis is that learning mechanistic detail enables rational improvement in scope and selectivity. The team will start by characterizing transient cobalt(IV) species, and the research will use kinetic studies to distinguish whether these are involved in the mechanism. They will then use a combination of these mechanistic results and computational virtual ligand screening to obtain better catalyst designs. Finally, they will use intermolecular and intramolecular competition experiments to systematically determine the relative reactivity of various nucleophiles, setting up a guide to chemoselectivity in MHAT. One advantage of this approach is the potential to form various heterocycles with controllable selectivity, which gives facile methods for preparing pharmaceutically relevant ring systems. This project has broad scientific because oxidative MHAT enables late-stage formation of heterocycles and C-X bonds for pharmaceutical synthesis. These syntheses enable the easier preparation of life-saving drugs and other bioactive molecules. In addition to these practical impacts, the grant will involve the training of graduate students, who will encounter a broad suite of methods that provides them with wide-ranging skills. These include modern computational methods for virtual ligand screening. Trained in these methods, the students will have the ability to address a variety of challenges in their careers. 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.