The role of the milling environment on the copper-catalysed mechanochemical synthesis of tolbutamide†

We provide a systematic investigation of the role of atmospheric oxygen and choice of milling assembly (i.e., the milling jar and ball materials) on a prototypical medicinal mechanochemistry reaction: the copper-catalysed coupling of isocyanate and sulfonamide to form the sulfonylurea tolbutamide. Using in-house developed equipment for work under controlled-atmosphere milling conditions, we reveal that the reaction is in fact catalysed by Cu(II) species, with the conventionally used CuCl acting as a pre-catalyst, which becomes activated via aerobic oxidation during milling. Unexpectedly, the choice of milling jar material was found to have a profound effect on the coupling, with aluminium jars effectively “shutting down” reactivity, most likely by preventing CuCl oxidation. Hence, opposite to direct mechanocatalysis, a term used to describe reactions promoted by the milling jar or ball material, this observation reveals the possibility of direct mechanoinhibition – i.e., the inhibition of a mechanochemical reaction by the jar. These results highlight the importance of systematic investigations of both the milling assembly, as well as atmosphere, in understanding and controlling organic mechanochemical transformations.