Matthew Nwerem
Computational Investigation of the Lewis-Acid Mediated Activation of Sulfonyl Fluorides
Overview: Nitrogen-containing sulfur (VI) compounds, such as sulfonamides, make up about 27% of all sulfur-based US FDA approved drugs, and 10% of the top 100 most prescribed US FDA approved drugs. These compounds serve as treatments against bacterial infections and cardiovascular diseases. I will present an improved method in synthesizing these compounds.Abstract: Nitrogen-containing sulfur (VI) compounds, such as sulfamides, sulfonamides, and sulfones, are found in ~27% of sulfur-containing drugs administered by the United States Food and Drug Administration. Synthesis of these compounds have been historically performed via the oxidation of thiols or the substitution of sulfur (VI) chlorides precursors. The former occurs under harsh conditions, limiting functional group compatibility; the latter is thermodynamically unstable and susceptible to hydrolysis and redox reactions. Sulfur (VI) fluorides have emerged as promising alternative precursors toward the synthesis of nitrogen-containing sulfur (VI) compounds via sulfur-fluorine exchange (SuFEx) chemistry. A recent experimental study has reported the use of stoichiometric calcium triflimide Ca(NTf2)2 – one of the few methods that employs a Lewis-acid mediated process. However, given the difficulty in isolating Ca2+ intermediates along the reaction pathway, the mechanism of this process is unknown. Our work uses DFT computations to probe plausible mechanisms for the Ca(NTf2)2 mediated S-F activation process, specifically unraveling the calcium coordination complexes responsible for S-F bond activation. Furthermore, we probe various fluoride and product inhibition equilibria to provide new hypotheses for the reason for stoichiometric Ca2+ . Results from this computational study will be presented.
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