Tomislav Friščić

Mechanochemistry: opportunities for new and cleaner synthesis

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).

Supramolecular Control of Reactivity in the Solid State: From Templates to Ladderanes to Metal−Organic Frameworks

We describe how reactivity can be controlled in the solid state using molecules and self-assembled metal-organic complexes as templates. Being able to control reactivity in the solid state bears relevance to synthetic chemistry and materials science. The former offers a promise to synthesize molecules that may be impossible to realize from the liquid phase while also taking advantage of the benefits of conducting highly stereocontrolled reactions in a solvent-free environment (i.e., green chemistry). The latter provides an opportunity to modify bulk physical properties of solids (e.g., optical properties) through changes to molecular structure that result from a solid-state reaction. Reactions in the solid state have been difficult to control owing to frustrating effects of molecular close packing. The high degree of order provided by the solid state also means that the templates can be developed to determine how principles of supramolecular chemistry can be generally employed to form covalent bonds. The paradigm of synthetic chemistry employed by Nature is based on integrating noncovalent and covalent bonds. The templates assemble olefins via either hydrogen bond or coordination-driven self-assembly for intermolecular [2 + 2] photodimerizations. The olefins are assembled within discrete, or finite, self-assembled complexes, which effectively decouples chemical reactivity from effects of crystal packing. The control of the solid-state assembly process affords the supramolecular construction of targets in the form of cyclophanes and ladderanes. The targets form stereospecifically, in quantitative yield, and in gram amounts. Both [3]- and [5]-ladderanes have been synthesized. The ladderanes are comparable to natural ladderane lipids, which are a new and exciting class of natural products recently discovered in anaerobic marine bacteria. The organic templates function as either hydrogen bond donors or hydrogen bond acceptors. The donors and acceptors generate cyclobutanes lined with pyridyl and carboxylic acid groups, respectively. The metal-organic templates are based on Zn(II) and Ag(I) ions. The reactivity involving Zn(II) ions is shown to affect optical properties in the form of solid-state fluorescence. The solids based on both the organic and metal-organic templates undergo rare single-crystal-to-single-crystal reactions. We also demonstrate how the cyclobutanes obtained from this method can be applied as novel polytopic ligands of metallosupramolecular assemblies (e.g., self-assembled capsules) and materials (e.g., metal-organic frameworks). Sonochemistry is also used to generate nanostructured single crystals of the multicomponent solids or cocrystals based on the organic templates. Collectively, our observations suggest that the organic solid state can be integrated into more mainstream settings of synthetic organic chemistry and be developed to construct functional crystalline solids.

A Cocrystal Strategy to Tune the Luminescent Properties of Stilbene-Type Organic Solid-State Materials†

The one- and two-photon luminescence of stilbene-type solid-state materials can be tuned and controlled from blue to yellow color by a supramolecular cocrystal method.

The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome

Mechanochemical liquid-assisted grinding (LAG) and sonochemical (SonicSlurry) techniques have been compared as methods to construct four model pharmaceutical cocrystals involving theophylline and caffeine as pharmaceutical ingredients and L-malic or L-tartaric acid as pharmaceutical cocrystal formers. For these model systems, the results are interpreted using the parameter η, the ratio of solvent volume to sample weight. Each if the four cocrystals was studied in four different solvents using LAG at η = 0.25 and 10 µL mg−1, as well as SonicSlurry experiments at η = 2, 6 and 12 µL mg−1. The formation of the cocrystal is observed in all standard LAG experiments when η = 0.25 µL mg−1. Cocrystal formation by neat grinding, i.e. with no liquid added, was observed only for the cocrystal of theophylline and L-malic acid. LAG experiments at very low η values (below 0.5 µL mg−1) revealed that the rate of cocrystal formation depended on the choice of the liquid and increases with η. SonicSlurry experiments performed at higher η values of 2, 6 and 12 µL mg−1 provided three different outcomes: the pure cocrystal, a mixture of the cocrystal with a cocrystal component, or a single cocrystal component. LAG experiments at η = 10 µL mg−1 produced results consistent with the SonicSlurry experiments at η = 12 µL mg−1. Measuring approximate solubilities of individual cocrystal components revealed that product formation is not dictated by the specific processing method but by saturation levels of reactants. An experimental approach based on approximate solubilities of cocrystal components has been developed to qualitatively predict the outcome of cocrystallization experiments at different η values. As a general guideline, cocrystal formation is expected under conditions in which all cocrystal components remain saturated.

Real-time and in situ monitoring of mechanochemical milling reactions

Chemical and structural transformations have long been carried out by milling. Such mechanochemical steps are now ubiquitous in a number of industries (such as the pharmaceutical, chemical and metallurgical industries), and are emerging as excellent environmentally friendly alternatives to solution-based syntheses. However, mechanochemical transformations are typically difficult to monitor in real time, which leaves a large gap in the mechanistic understanding required for their development. We now report the real-time study of mechanochemical transformations in a ball mill by means of in situ diffraction of high-energy synchrotron X-rays. Focusing on the mechanosynthesis of metal-organic frameworks, we have directly monitored reaction profiles, the formation of intermediates, and interconversions of framework topologies. Our results reveal that mechanochemistry is highly dynamic, with reaction rates comparable to or greater than those in solution. The technique also enabled us to probe directly how catalytic additives recently introduced in the mechanosynthesis of metal-organic frameworks, such as organic liquids or ionic species, change the reactivity pathways and kinetics.

Rapid Room‐Temperature Synthesis of Zeolitic Imidazolate Frameworks by Using Mechanochemistry

Freshly ground: Improved mechanochemical methodologies, such as liquid-assisted grinding and ion- and liquid-assisted grinding enable the rapid and topologically selective synthesis of porous and nonporous zeolitic imidazolate frameworks with diverse topologies, at room temperature and directly from zinc oxide.

New opportunities for materials synthesis using mechanochemistry

Mechanochemical synthesis is experiencing a dynamic re-discovery in the areas of organic and metal–organic materials. Emerging mechanochemical methods, such as liquid-assisted grinding (LAG) or ion- and liquid-assisted grinding (ILAG) achieve enhanced molecular mobility through the addition of near-stoichiometric amounts of a liquid phase to a solid-state reaction, and are aided by catalytic and templating effects. This article highlights the exciting areas of application for these mild mechanochemical methods: one-pot assembly of “soft” metal–organic and organic materials, and the rapid room-temperature synthesis of porous metal–organic frameworks directly from a metal oxide.

Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogen-bonded cocrystal

The formation of stoichiometric variations, i.e. cocrystals composed of identical molecular building blocks in different stoichiometric ratios, has been investigated using cocrystals composed of the model pharmaceutical component nicotinamide (na) and 10 dicarboxylic acids as cocrystal formers. The comparison of cocrystallisation from solution, from the melt and by neat and liquid-assisted grinding revealed that the mechanochemical methods are more efficient in screening for stoichiometric variations of cocrystals. Using grinding, for example, the formation of stoichiometric variations could be readily controlled by modifying the composition of the reaction mixture. The ability of different stoichiometric variations to interconvert using liquid-assisted grinding was also investigated, providing a tentative qualitative assessment of the relative stabilities of different cocrystal compositions. Grinding for short periods was utilised to investigate the mechanism of formation for the hydrogen-bonded cocrystals of na and suberic acid (sub). The results suggest that the cocrystal formation occurs in a stepwise manner, wherein the cocrystal (na)·(sub) appears as an intermediate in the synthesis of the (na)2·(sub) cocrystal, most likely for kinetic reasons.

Benefits of cocrystallisation in pharmaceutical materials science: an update.

Objectives  We provide a brief overview of recent applications of cocrystals for improving the physico‐chemical and materials properties of active pharmaceutical ingredients, including solubility, humidity and thermal stability, dissolution rates and compressibility for tablet formation.

Shaping Crystals with Light: Crystal-to-Crystal Isomerization and Photomechanical Effect in Fluorinated Azobenzenes

Unusually long thermal half-lives of perhalogenated cis-azobenzenes enabled their structural characterization and the first evidence of a crystal-to-crystal cis → trans azobenzene isomerization. Irradiation with visible light transforms a perhalogenated cis-azobenzene single crystal into a polycrystalline aggregate of its trans-isomer in a photomechanical transformation that involves a significant, controllable, and thermally irreversible change of crystal shape. This is the first demonstration of permanent photomechanical modification of crystal shape in an azobenzene.