A High-Efficiency Skeletal Editing Reaction that Freely Reconstructs Benzene Rings
NAGOYA, Japan, November 27, 2025 — A research group led by Professor Norio Shibata at the Nagoya Institute of Technology has developed a revolutionary “skeletal editing” technique using next-generation fluorine functional groups—hypervalent sulfur fluorides (SF₅ and SF₄)—that do not rely on PFAS (per- and polyfluoroalkyl substances).
This research, conducted in collaboration with Professor Jorge Escorihuela of the University of Valencia, Spain, was published online in the Royal Society of Chemistry’s international journal, Chemical Science, on November 19, 2025.
Key Highlights
- PFAS-Free Promotion: The use of PFAS-free SF₅ and SF₄ groups significantly accelerates skeletal editing reactions.
- High Efficiency: Achieved a high-efficiency conversion from benzene rings to azepine rings (7-membered nitrogen heterocycles).
- World First: Successfully synthesized SF₅- and SF₄-azepines for the first time.
- New Foundation: Established a new foundational technology for environmentally friendly “PFAS-free fluorine design.”
Research Overview
Fluorine-containing organic compounds are essential for pharmaceuticals, agrochemicals, and electronic materials due to their stability and functionality. However, many fluorinated compounds, particularly those classified as PFAS (often referred to as “forever chemicals”), face tightening global regulations due to their environmental persistence.
To address this, Professor Shibata’s team focused on hypervalent sulfur fluorides (SF₅ and SF₄) as alternatives to the commonly used trifluoromethyl group (CF₃). While CF₃ often degrades into persistent trifluoroacetic acid (TFA), SF₅ and SF₄ groups possess similar properties but do not fall under the OECD definition of PFAS.
The Innovation: Light-Driven Skeletal Editing
The researchers developed a method to irradiate benzene derivatives containing SF₅ or SF₄ groups with visible light (Blue LEDs). This process triggers a skeletal editing reaction that converts the aromatic benzene ring into a 7-membered azepine ring.
Breakthrough in Yield: In coupling reactions involving phenols, conventional methods typically yielded only about 7%. This new method achieved yields of up to 83%.
Mechanism: Detailed analysis revealed that the strong electron-withdrawing nature of the SF₅ group stabilizes the reaction intermediates, drastically promoting the ring expansion.
Reversible “Green” Conversion
The team further demonstrated a “reverse skeletal editing” reaction, converting the generated azepine structure back into a benzene ring. By using difluoroacetic anhydride (DFAA) as a reagent, they successfully synthesized “COCF₂H-substituted aromatic compounds,” which are not classified as PFAS under OECD definitions. This proves that reversible skeletal transformation is possible under PFAS-free conditions.
Social Significance and Future Outlook
This research presents a concrete solution to the global PFAS problem by redesigning molecules from the ground up.
- Sustainable Chemistry: The ability to “edit” molecular skeletons acts as a form of molecular-level resource circulation.
- Applications: The technology is expected to accelerate the development of environmentally friendly pharmaceuticals, agrochemicals, and functional polymers.
Professor Shibata’s team aims to contribute to the establishment of new international standards for “fluorine chemistry that does not accumulate in the environment,” strengthening the competitiveness of Japanese chemical technology.
Funding
This research was supported by the JST Strategic Basic Research Programs (CREST) under the project “Precise Degradation of Fluorinated Materials for a Fluorine-Circulating Society” (JPMJCR21L1), and by Dr. Seiji Motojima (CMC General Research Institute).
Paper Information
- Title: High-valent sulfur fluorides as reactivity switches for PFAS-free benzene-azepine skeletal editing
- Journal: Chemical Science
- DOI: 10.1039/D5SC08177G
- URL: https://pubs.rsc.org/en/Content/ArticleLanding/2025/SC/D5SC08177G
