Mechanism-Guided Development of Fluorination Chemistries

With the support of the Chemical Mechanism, Function, and Properties Program of the Division of Chemistry, Professor Mathew J. Vetticatt of the Department of Chemistry at Binghamton University is developing a robust suite of novel reactions for the incorporation of fluorine atom(s) into organic molecules. The synthetic methods described in this proposal utilize a single reagent – silver (II) fluoride in acetonitrile – to accomplish the conversion of cheap, abundantly available chemical feedstock into high-value fluorine-containing molecules that are important and relevant to drug discovery. The project addresses a long-standing gap in fluorination chemistries – the development of an operationally simple radical fluorination reagent that will offer complementary reactivity to existing nucleophilic and electrophilic fluorination reagents. The fundamental nature of the proposed chemistry provides an excellent platform for the training of scientists at all levels. Mechanistic understanding of organic reactions provides valuable clues for the discovery of novel reactivity. This proposal describes a mechanism-guided discovery of a novel platform technology in silver chemistry that will lead to the development of a range of important transformations involving the incorporation of fluorine into organic molecular scaffolds. Specifically, the project uses silver (II) fluoride in acetonitrile as a multipurpose reagent to carry out a range of transformations including fluorination of sp2 and sp3 C–H bonds, difluorination of olefins and aromatic heterocycles, and site-specific substitution of readily available starting materials like carboxylic acids into the corresponding fluorides. The project also will elucidate the mechanistic details of these newly discovered reactions using kinetic isotope effects and DFT calculations to provide a framework for the expansion of this chemistry to a broader range of reaction manifolds. 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.