Co-Hydrofunc

Overview Mild hydrofunctionalization of alkenes with Earth-abundant metal catalysts has been revolutionized by the development of oxidative MHAT reactions. However, the mechanistic understanding, nucleophile scope, and selectivity of these reactions are limited. In the proposed research, a team of chemists will use organic and inorganic synthesis, kinetic studies, mass spectrometry, DFT computations, and virtual ligand screening together to greatly expand the capabilities of oxidative MHAT chemistry. This broad-ranging set of approaches depends upon the three-PI team of experts from the USA and France. Intellectual Merit Our guiding hypothesis is that learning mechanistic detail enables rational improvement in scope and selectivity. Members of this team have already characterized cobalt(IV) species that have been postulated as part of the mechanism, but it is not certain that these are on-cycle for all oxidative MHAT reactions. We will use kinetic studies to distinguish between potential mechanisms, and DFT calculations will complement the experimental studies. Using these results, we can use the Maestro package to do virtual ligand screening that leads to better ligand designs. Thus we will utilize cutting-edge computational methods. In addition, we will characterize catalytically relevant species using various spectroscopies including mass-selected infrared spectroscopy that have the potential to show fleeting hydride intermediates. Finally, we will use intermolecular and intramolecular competition experiments to systematically determine the relative reactivity of various nucleophiles. 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. Broader Impacts Because oxidative MHAT gives facile and selective functionalization of alkenes that cannot be otherwise efficiently transformed, it 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 in the USA and France, who will encounter a broad suite of methods that provides them with wide-ranging skills. These include the most up-to-date computational methods for virtual ligand screening. Trained in these methods, the students will have the ability to address new problems in their later careers. Finally, these students will be adept at international collaboration that crosses borders and traditional boundaries.