Supramolecular intermediates in thermo-mechanochemical direct amidations

We present a solvent-free thermo-mechanochemical approach for the direct coupling of carboxylic acids and amines, which avoids activators and additives. Detailed analysis of the reactions by ex situ and in situ monitoring methods led to the observation, isolation, and characterisation of multicomponent crystalline intermediates that precede the formation of amides. We applied our methodology for the quantitative synthesis of the active pharmaceutical ingredient moclobemide. We present a solvent-free thermo-mechanochemical approach for the direct coupling of carboxylic acids and amines, which avoids activators and additives. Non-covalent interactions between the reagents guide the formation of the amide bond.