Structure – Stability Relationships in Aryl- and Heteroarylmethanesulfonyl Chlorides and Fluorides

Sulfonyl chlorides are among the most widely used yet least storable building blocks in medicinal chemistry, and arylmethanesulfonyl chlorides in particular remain poorly represented in commercial catalogs because of their limited stability. In this work, the long-term stability of 23 aryl- and 36 heteroarylmethanesulfonyl chlorides and fluorides was evaluated systematically. Decomposition was monitored by 1 H NMR spectroscopy in THF- d 8 solution at 4 °C and 23 °C for up to 12 months; the solvent was chosen to avoid solvolysis and acidic admixtures, and to minimize water uptake. Whereas at least one batch of each compound remained unchanged in neat form for up to 14 years (median 5.5 years), their stability in solution varied widely, i.e., from complete decomposition of a pyridine derivative within one month to no detectable change over more than 12 months, and was governed by both the electronic nature and the position of the substituent. Notably, both strongly electron-withdrawing and strongly electron-donating substituents proved destabilizing, and the decomposition products differed accordingly: sulfonic acids for electron-poor and benzyl chlorides for electron-rich substrates. Sulfonyl fluorides proved considerably more robust: all heteroaromatic derivatives studied, except isothiazole (8% after 12 months) and pyridine (15% within one week), showed no detectable decomposition over 12 months. We believe that the resulting stability map, which assigns each compound to a defined storage class, will make arylmethanesulfonyl halides practical building blocks for early drug discovery in the near future.