Electrochemically Generated Hypervalent Iodoarenes: An Addressable and Sustainable Catalytic Platform for Difluorination and Trifluoromethylation

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Project Abstract The controlled introduction of fluorine into biologically relevant compounds helps prevent, diagnose, and treat disease. The deployment of this element in drug design has been shown to modulate key biochemical properties, such as metabolic stability, solubility, and activity. Among the diverse-array of fluorinated building blocks, trifluoromethyl groups and vicinal difluorides are targeted motifs due to their potential to serve as stable, non-toxic mimics of methyl groups or to induce chiral bioisosteres, respectively. Therefore, the continued development of methodologies that can access and manipulate both moieties are of synthetic and medicinal value. To this end, hypervalent iodoarenes (I(III)Ar) have emerged as a promising, versatile, and metal-free fluorinating and trifluoromethylating agent. However, their catalytic utilization remains rare due to fundamental challenges associated with the rate and methods of their regeneration, resulting in parasitic side reactions and limiting the substrate scope. In order to selectively and controllably install difluorinated and trifluoromethylated motifs, a catalytic, sustainable, and addressable system is required. This proposal puts forth a new molecular electrocatalytic strategy to solve challenges of selectivity and to install rare vicinal difluoride C-F bonds and O-CF3 bonds. Molecular electrocatalysts are developed based on the known thermal chemistry of I(III)Ar. The molecular electrocatalysts can be tailored, enabling the development of a new class of catalysts for difluorination and trifluoromethylation. The electrochemical mechanism of I(III)Ar is inspired by the analysis of existing electrochemical data on related compounds. Detailed studies of the rate of electrocatalyst generation will provide insights into the mechanism of the organic electrosynthesis strategy. The anticipated selectivity of the molecular electrocatalyst to a wide array of differing substrates will also facilitate the controlled difluorination of electron-rich substrates for the first time. In addition to enabling the synthesis of fluorinated and trifluoromethylated compounds, these studies will provide a framework for the development of other molecular electrocatalysts for further complex organic transformations.