Atom-efficient direct amidation by thermo-mechanochemistry

Direct amide bond formation involving carboxylic acids and amines predominantly involves solution-based reactions with coupling reagents and catalysts that result in poor sustainability performance. Here, we present a conceptually different approach, which includes simultaneous mechanical and thermal activation. Such an approach enables direct and quantitative conversion to amides starting from carboxylic acids and amines and avoids using activators and additives. As a model reaction, we studied the thermo-mechanochemical condensation of benzoic acid and p-toluidine, which gave N-(p-tolyl)benzamide almost quantitatively in gram-scale. We show that crystalline supramolecular arrangements between reactants act as intermediates that precede the formation of amides. The applicability of the methodology was demonstrated by a quantitative synthesis of moclobemide, a valuable active pharmaceutical ingredient. Finally, the sustainability assessment by green chemistry metrics highlights the atom-efficiency of our methodology.