The past decade has seen a reawakening of solid-state approaches to chemical synthesis, driven by the search for new, cleaner synthetic methodologies. Mechanochemistry, i.e., chemical transformations initiated or sustained by mechanical force, has been advancing particularly rapidly, from a laboratory curiosity to a widely applicable technique that not only enables a cleaner route to chemical transformations but offers completely new opportunities in making and screening for molecules and materials. This Outlook provides a brief overview of the recent achievements and opportunities created by mechanochemistry, including access to materials, molecular targets, and synthetic strategies that are hard or even impossible to access by conventional means.

Mechanochemical reactions effected by milling or grinding are an attractive means to conduct chemical reactions dependent on molecular recognition and to systematically explore different modes of molecular self-assembly. The natural relationship between milling mechanochemistry and supramolecular chemistry arises primarily from the ability to avoid bulk solvent, which simultaneously avoids limitations of solution-based chemistry, such as solubility, solvent complexation, or solvolysis, and makes the resulting process highly environmentally friendly. This tutorial review highlights the use of mechanochemistry for the synthesis of supramolecular targets in the solid state, such as molecular hydrogen- or halogen-bonded complexes, molecular and supramolecular cages, open frameworks and interlocked architectures. It is also demonstrated that the molecular self-assembly phenomena that are well-established in solution chemistry, such as reversible binding through covalent or non-covalent bonds, thermodynamic equilibration and structure templating, are also accessible in milling mechanochemistry through recently developed highly efficient methodologies such as liquid-assisted grinding (LAG) or ion- and liquid-assisted grinding (ILAG). Also highlighted are the new opportunities arising from the marriage of concepts of supramolecular and mechanochemical synthesis, including organocatalysis, deracemisation and discovery of new molecular recognition motifs.

Inspired by recent commercialisation of metal–organic frameworks, this review highlights challenges and recent advances in developing scalable and sustainable metal–organic synthesis.

Development of mechanochemistry for API synthesis and pharmaceutical solid form screening signals the emergence of medicinal mechanochemistry – a discipline at the interface of medicinal chemistry and sustainable synthesis.