In the past decades, mechanical processing by ball milling has been subjected to intense studies in the light of its unique capability of inducing physical and chemical transformations. Successfully applied to broad areas of mineral processing, material science and engineering, biomass degradation and soil remediation, the methodology has attracted enormous interest in industry. Within this framework, scholars working in European countries played a primary role. Constituting the world largest community of researchers devoted to mechanochemistry, European scientists and engineers cover the entire spectrum of subjects within the field, with recognized excellence ranging from the preparation of materials to the design of novel ball milling and extrusion reactors and to niche industrial applications. For instance, at least 5 companies worldwide produce specialty materials by mechanical processing and 10 companies manufacture mechanochemical reactors of different scale.
Mechanochemistry has been applied, sometimes just as a “proof of concept”, to most organic reactions currently being performed by solution chemistry, resulting in the formation of covalent bonds as well as supramolecular assemblies. A comprehensive compilation of all the mechanochemical reactions, covalent, supramolecular (co-crystals, rotaxanes, cages, MOFs, CPs) and COFS and functionalisation of fullerenes and graphite sheets, can be found in “Mechanochemical organic synthesis” (Elsevier, 2016). The capability of ball milling to activate strong covalent bonds in the solid state under mild conditions of temperature and reagents is resulting in the formation of carbon-carbon and carbon-heteroatom bonds (C-N, C-O, C-halogen, C-S, C-Se and C-Te) and disulphide exchange reactions.
Examples of the formation of phosphorus, boron, silicon, bismuth and C-H bond has been also achieved by mechanochemistry. Crystal engineering also had its successes, achieving the synthesis of metalorganic frameworks (MOFs), covalent-organic frameworks (COFs) and coordination polymers (CPs). All these chemical transformations can be performed either by neat grinding (NG) or by liquid-assisted grinding (LAG) this latter is achieved by the addition of substochiometric amounts of solvent which can lead to different outcomes from NG. LAG is considered solvent-free technology, as the amount of solvent used in LAG reactions is much too small to become an environmental concern. Generally speaking, when referring to mechanochemistry both NG and LAG reactions are considered. Examples of covalent bond forming mechanochemical reaction are dehydrogenative coupling, oxidation, reduction and organo-catalytic reactions, also in their asymmetric version. Ball milling is being used for the synthesis of nanocarbon materials like the functionalisation of fullerenes and graphite sheets. Because of different pathway of the reactions used in ball milling, these reactions can often be successfully performed to high yields and high purity sometimes even in the absence of catalyst unlike solution based synthesis.
The formation of Active Pharmaceutical Ingredients (API) co-crystal can be better achieved by solid state reaction, instead of recrystallization from solution, to overcome the problem of poor solubility of the API. The pharmaceutical industry is interested in the pharmaceutical co-crystals to modify the API’s properties to improve poor bioavailability and/or other undesirable properties without altering the chemical structure of the API. In 2016, the FDA revised the guidance to the industry on the regulatory classification of pharmaceutical co-crystals elevating co-crystals to the status of APIs and classifying them in the same category as solvates and hydrates with the potential to be patented and therefore helping to extend the life of the drug. The milling equipment and vessels used by mechanochemists is imposing a limitation of scale as they are adaptation of milling equipment purposely manufactured for size reduction and homogenization; the scale (>100mg) is much too large for the laboratory synthetic chemists to consider mechanochemistry as a synthetic tool, and too small for industry to consider mechanochemistry for industrial scale. Fortunately, extrusion technology has found a niche for successful industrial scale of mechanochemical transformations forming covalent bonds and supramolecular assemblies (Adv. Mater. 2016, 28, 5747 and Green Chem. 2017, 19, 1507).
Progress beyond the state of the art
European COST Member countries are in the position of leading breakthrough innovation of its chemical industry by exploring the significant potential of mechanochemical processes. This COST Action Mech@SusInd aims at becoming a strong platform to promote and disseminate mechanochemistry across Europe. This can be achieved by effective coordination of activities, a flexible organization of work packages and problem solving analysis, and a fully cooperative interaction involving all the different stakeholders in the mechanochemistry field across Europe. At least three broad areas of activity are susceptible of significant progress beyond the current state of the art.
- the advance of scientific knowledge,
- the design and fabrication of innovative mechanochemical reactors and processing methodologies,
- the development of synthetic routes for specialty products for organic chemistry and pharmaceutical APIs.
Specifically, work packages structured to advance scientific knowledge of mechanochemistry can be expected to provide improved understanding on the mechanisms and driving forces of mechanochemical transformations, the identification of possible thermal components, the definition of factors influencing the solid-state reactivity of organic system, the role of substoichiometric amounts of solvents (liquid-assisted grinding, LAG) in the distribution of products, the optimal purification strategies in the presence of by-products, discovery of new reactivity and new synthetic chemistry opportunities. This could include, for example, enhanced reactant scope, access to poorly soluble, but less expensive or less toxic reactants, new control over stereoselectivity or stoichiometric efficiency/atom economy. Mechanochemistry is not only a means to make chemistry greener, but also to investigate products and molecules and types of reactions that have previously been either unknown, or even considered impossible to achieve. Mech@SusInd is already moving to next-generation mechanochemical reactions, which combine activation by mechanical impact with thermochemistry or photochemistry widening the scope for synthesis of potential products.
Since the transformation of simple organic chemicals and main group elements by mechanochemistry is well established, achieving product complexity is the next challenge – the formation of complicated, elaborate molecular architectures, such as rings, cages, and complex pharmaceutical ingredients. Mech@SusInd can be expected to identify the sources of inefficiency in the mechanochemical vessels and reactors, encouraging the manufacture of new lab equipment for fundamental studies, and for the scale-up of mechanochemical processes to industrial scale. Small- and large-scale pilot plants for the mechanochemical manufacture of chemicals should be designed to be compatible with existing facilities for chemical production in European countries.
Finally, Mech@SusInd will promote new ways of thinking in order to tackle the challenges addressed by the EU. Industrial processes need to be constantly revised to decrease the CO2 emission and reduce the cost. Using new reagents or new synthetic solvent-free reactions is a valid route to maintain the leadership, moreover an in-depth study of these processes allows to establish the Life Cycle Analysis (LCA) and to identify the best and most sustainable processes.
The development of synthetic routes for specialty products fundamental to the organic and pharmaceutical chemistry and agriculture industry should focus primarily in the preparation of:
- 20 top seller generic drugs, medical and personal care products (therapeutically active nanostructured compositions), drug/carrier composites with improved properties when prepared by mechanochemistry,
- fragrances and perfumes, prepared involving Schiff’s base and condensation reactions, which are known to be easily reproduced by mechanochemical reactions,
- discovery of new co-crystalline forms of APIs (to improve the solubility and bioavailability of drugs);
- coordination polymers (CPs) and porous Metal-Organic Frameworks (MOFs) for energy storage and sensing or separations;
- new materials which are investigated for the emergent technologies which are expected to play a crucial role in future applications, such as rotaxanes, catenanes, cages, highly aromatic compounds, graphenebased materials and nanoparticles.