Harnessing the copper surface for direct mechanocatalysis: a case study on mechanochemical sulfonylurea synthesis

Direct mechanocatalysis has arisen as a promising tool to achieve synthetic transformations by utilizing reaction vessels and/or media made of a material capable of acting as a source of catalysis. One common metal utilized for this purpose is copper, the surface of which is not a static environment but rather undergoes many transformations (particularly upon exposure to water and oxygen). Here we have utilized in-house developed equipment for work under controlled atmosphere milling, including a composite milling jar design that enables investigating the behaviour of the copper surface in either impact- or shear-dominated milling regimes. We exploit the unique sensitivity to Cu(ii) species of the mechanocatalytic coupling of isocyanate and sulfonamide to form the sulfonylurea diabetic drug tolbutamide to establish methods to control the copper surface composition and reveal the factors that influence copper transformation into different states during milling. We reveal the active catalyst formed through direct mechanocatalysis to be a hydroxylated copper species and demonstrate that the reaction proceeds <i>via</i> surface wear and subsequent catalyst formation. Any initial surface oxide is observed to be insignificant to the overall process. The use of the composite reaction jar further revealed that wear dominates from the end regions of the vessel, undergoing primarily impact forces. Based on these finding and density functional theory (DFT) calculations, we present a reaction mechanism which explains the different yields of <i>in situ</i> generated Cu(OH)₂ and a traditional CuCl₂ pre-catalyst. These results highlight the importance of systematic investigations of surface characteristics for understanding and controlling direct mechanocatalysis and demonstrate methods to realize these goals.