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Methodology to Access Sulfonyl Fluorides

thesis
posted on 2023-08-21, 14:01 authored by Rockwell James PokrantRockwell James Pokrant

In recent years, sulfonyl fluorides have garnered significant attention in the synthetic organic and biochemical communities. Sulfonyl fluorides exhibit unique reactivity, as nucleophilic addition to the sulfur atom and subsequent elimination of fluoride only occurs under specific reaction conditions (otherwise known as SuFEx). Due to their inherent stability, sulfonyl fluorides are commonly used as biochemical probes to elucidate the structure of proteins. Sulfonyl fluorides also hold promise as irreversible covalent inhibitors. Despite the many potential applications of sulfonyl fluorides, methods to access this functional group remain underdeveloped, often requiring complex starting materials, or the use of hazardous reagents.

Electrochemistry offers an attractive alternative to standard preparations of sulfonyl fluorides. Chapter 1 provides an overview of modern methods employed to synthesize sulfonyl fluorides, as well as key developments in synthetic organic electrochemistry. Chapter 1 closes with how the standardization of electrochemical reactions has allowed synthetic organic chemists to accurately reproduce electrochemical transformations.

In Chapter 2, we developed an electrochemical method to access sulfonyl fluorides. The developed method operates by subjecting sulfones to electrochemical conditions, which initiates fragmentation of C–S bonds, and subsequent fluorination of a radical intermediate to realize the sulfonyl fluoride functional group. Early optimization focused on the synthesis of an optimal leaving group to bias the system towards formation of the desired sulfonyl fluoride in the presence of AgF2. Once a leaving group was established, Lewis acids were screened in an attempt to activate the sulfone for substitution. Lewis acidic additives were later determined to serve as sacrificial oxidants as they did not chelate the sulfone starting materials. Reactions were run in divided and undivided electrochemical cells depending on the fluorinating reagent. Reactions with AgF2 were run in an undivided electrochemical cell to prevent cathodic plating of Ag0. However, comparable results were achieved in an undivided electrochemical cell if AgF2 was replaced with Selectfluor. Investigation into the incorporation of the leaving group into other substrates is ongoing. We hope to further develop this methodology to access complex sulfonyl fluorides and encourage the development of electrochemical methods in synthetic organic chemistry.

History

Degree Type

  • Master of Science

Department

  • Chemistry

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Ryan Altman

Additional Committee Member 2

Mark Lipton

Additional Committee Member 3

Christopher Uyeda

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