Mechanochemical Methods for Amide Bond Formation

Mechanochemical methodologies are reshaping synthetic organic chemistry by enhancing practicality and reducing environmental impact. This review presents a comprehensive account of mechanochemical methods for amide bond formation, arguably the most developed and industrially relevant area within mechanochemical organic synthesis. Covering literature from early contributions to the present (September 2025), the review organization follows key substrate classes and methodological strategies: amide bond formation via coupling of carboxylic acids or their activated derivatives with amines (Section 2), followed by unconventional approaches (Section 3) employing carboxylic acid and amine surrogates, redox chemistry, rearrangements, and transition metal-mediated reactions leading to amide products through alternative bond-forming pathways. Mechanoenzymatic transformations are treated separately (Section 4), with stereochemistry-related issues, such as the preservation of enantiomeric purity, discussed in Section 5. Section 6 highlights the use of amide bond formation as a model system for probing mechanochemical driving forces. Special attention is given to scalability and successful scale-up examples, alignment with green chemistry principles, limitations, unexplored areas, and challenges requiring further development. This review is intended as an accessible and thorough resource for synthetic chemists in both academia and industry, including those newly exploring the field of mechanochemistry, and it provides practical guidance for process optimization and scale-up.