The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

The preparation of co-crystals via mechanochemistry combines the quest for clean and green processes with the investigation of multicomponent new materials, among the currently most fashionable systems in the crystal engineering field: the physico-chemical properties of the components add, merge or transform when co-crystals are formed, giving rise to potentially improved performance in “old” solid-state chemistry fields, as in the pharmaceutical industry field, where they represent a way to obtain new formulations and to improve the properties (solubility, thermal stability, compressibility, etc.) of both new and existing drugs.

This Dalton Perspective deals with solvent-free reactions taking place within solids or between solids or involving a solid and a vapour. The focus is on reactions involving organometallic and coordination compounds and occurring via reassembling of non-covalent bonding, e.g. hydrogen bonds, and/or formation of ligand–metal coordination bonds. It is argued that reactions activated by mechanical mixing of solid reactants as well as those obtained by exposing a crystalline solid to a vapour can be exploited to “make crystals”, which is the quintessence of crystal engineering. It is demonstrated through a number of examples that solvent-free methods, such as co-grinding, kneading, milling of molecular solids, or reactions of solid with vapours represent viable alternative, when not unique, routes for the preparation of novel molecular and supramolecular solids as well as for the preparation of polymorphic or solvate modifications of a same species. The structural characterization of the products requires the preparation of single crystals suitable for X-ray diffraction, a goal often achieved by seeding.

Pressing solid barbituric acid with KBr to prepare samples for IR spectroscopy leads to the formation of an ionic co-crystal, in which the co-former is a classical ionic salt; co-crystal formation is also obtained with the other alkali bromides (LiBr, NaBr, RbBr and CsBr) and with caesium iodide. The simultaneous presence of alkali and halide ions affects the dissolution properties of barbituric acid in water.

Engineering crystal properties by a choice of adequate molecular building blocks has to cope with the fact that a given molecule can be isolated in many, at times very many, solid forms (single entity crystals, solvates, salts, co-crystals and their polymorphs) each with its own characteristics and properties. Preparation of new crystal forms of a same molecule, and investigation of the relationship among new crystal forms represent not only a further challenge to the solid state chemists, but also an opportunity of modifying properties of crystals with applicative implications (pharmaceuticals, agrochemicals, pigments, organic semiconductors, etc.). This feature article elaborates on this concept via a number of examples of multiple crystal forms and test cases.