Reimagining Sulfohydroxamic Acid Formation through Mechanochemical Solid-State Activation

Abstract

Sulfohydroxamic acids (–SO₂–NHOH), including classical Piloty’s acid derivatives, are key NO/HNO donors and valuable building blocks, but their synthesis still relies on hazardous hydroxylamine solutions and solvent-intensive protocols. Here we report a simple, solvent-free mechanochemical route based on milling sulfonyl chlorides with hydroxylamine hydrochloride in the presence of an inorganic base. Magnesium oxide (MgO) emerges as an ideal promoter, combining sufficient basicity with low nucleophilicity to release hydroxylamine in situ while preserving both the sulfonyl chloride and the sulfohydroxamic product. Under optimised conditions, a broad range of aromatic sulfonyl chlorides bearing electron-donating and electron-withdrawing substituents are converted into the corresponding sulfohydroxamic acids. The method efficiently produces sulfohydroxamic acids with yields ranging from 18% to 81% under mild conditions and is adaptable to standard milling equipment, enabling scalable synthesis. The protocol can be readily extended to O- and N,O-substituted hydroxylamine derivatives by using appropriately functionalized hydroxylamine salts. This mechanochemical strategy drastically reduces solvent consumption and streamlines work-up, providing a safer, cleaner, and scalable approach to sulfohydroxamic acids and their NO-donor analogues.