Friday, May 9, 2025
5/9/2025
Electrochemical Fluorination for Organic Synthesis - PROJECT SUMMARY Fluorination of an organic compound affects physicochemical properties, which in medicinal settings perturbs pharmacodynamic, pharmacokinetic, distribution, and/or metabolic profiles both in vitro and in vivo. Thus, the ability to selectively install fluorinated groups, such as sulfonyl fluorides (SO2F) and aryl fluorides (ArF), under mild conditions, is essential for accessing new therapeutics and biological probes. SO2F are privileged functional groups that act as covalent warheads to evaluate substrate-protein interactions and elucidate residues in the enzyme binding site. As a result, this group serves as a significant tool in medicinal chemistry and chemical biology. Furthermore, ArF are common motifs seen in FDA approved drugs and drug candidates due the ability to improve a compound’s drug-like properties. However, the unique physical properties of fluorinated substrates and/or reagents typically perturb fundamental organic reactivities, which can complicate synthetic sequences to access fluorinated compounds. Thus, many routine organic reactions simply do not work in the presence of fluorinated reagents or with fluorinated substrates. Additionally, the unique properties of fluorinated substrates enable new reactivities that cannot be achieved by the respective non-fluorinated counterparts, which provides opportunities to develop innovative strategies for accessing medicinally relevant substructures. In this proposal, we aim to synthesize these fluorinated substructures using electrochemical synthesis rather than utilizing traditional methods of synthesizing SO2F and ArF, which includes harsh reagents and expensive photocatalysts. Previously underutilized by organic chemists, electrochemical synthesis has seen a revival within the past few decades due to its sustainability, unique reaction tunability, and mild conditions. In the proposed research, we aim to synthesize a more diverse scope of sulfonyl fluorides. While there have been many methods for synthesizing aryl sulfonyl fluorides, the generation of alkyl and vinyl sulfonyl fluorides is underexplored. We also aim to use electrochemical synthesis to create a direct method for synthesizing aryl fluorides without the need for leaving groups. Aim 1 will deliver optimized conditions for aryl, alkyl and vinyl sulfonyl fluorides alongside computational studies to provide insight into our proposed mechanism. Aim 2 will involve optimizing electrochemical conditions to selectively generate ArF. Once optimized conditions are delineated, we will generate a varied substrate scope of selectively fluorinated (hetero)arenes. Development of the proposed strategies will enable medicinal chemists to access new and unique biological probes and therapeutics through facile late-stage fluorination of drug candidates and yield diverse aryl, alkyl and vinyl SO2F, thus broadening the field of both medicinal and electrochemistry simultaneously.
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