Recent Progress in Mechanochemical Organocatalysis
Abstract
Mechanochemical activation has emerged as a powerful enabling strategy for sustainable organic synthesis, offering reduced solvent consumption, shorter reaction times, and access to reactivity patterns that may differ from conventional solution chemistry. This review summarizes recent progress in mechanochemical organocatalysis, with particular emphasis on asymmetric transformations performed under solvent‐free or liquid‐assisted grinding conditions. After outlining the historical development of the field, including early grindstone chemistry, liquid‐assisted grinding, and pioneering ball‐milling studies, we discuss representative advances in covalent and noncovalent organocatalysis. Proline‐derived catalysts, peptides, primary and secondary amines, iminium catalysts, hydrogen‐bond donors, squaramides, thioureas, and Brønsted acids have enabled efficient aldol, Michael, Mannich, cycloaddition, annulation, cascade, and heterofunctionalization reactions, often with high yields and stereoselectivities. Recent nonstereoselective applications, including ring‐opening polymerizations, multicomponent reactions, biomass‐derived condensations, and heterocycle syntheses, further demonstrate the expanding scope of this approach. The reviewed examples highlight mechanochemistry as more than an alternative mixing method; it provides a distinct reaction environment that can influence catalyst performance, chemoselectivity, and selectivity. Remaining challenges include mechanistic understanding, scalability, reproducibility, and rational additive selection.