Mechanochemistry 101: mashing molecules towards greener syntheses

Grinding stuff sounds simple. In fact, it’s oddly one of the oldest ways to carry out chemical reactions. And, although solvent-based chemistry still dominates the industry, mechanochemistry –transformations enabled by mechanical force– experiences a new surge, an exciting era of rediscovery. Inspired by the 12 principles of green chemistry, mechanochemistry could really reshape chemical and pharmaceutical manufacturing. Read on to discover how mechanochemistry could catalyse cleaner and greener synthetic solutions.

Mechanochemistry mashes molecules together towards greener chemistry. It’s mechanical force what drives reactions, thanks to technologies such as ball mills, grinding, extrusion, and even soundwaves. Mainly, mechanochemistry avoids the use of solvents – deeply connected to chemical syntheses in several steps, including the reaction itself but also work-up, extraction, and purification. Bypassing solvents seems impossible to most chemists; nevertheless, it’s an interesting approach to increase efficiency while improving the overall sustainability and atom-economy of chemical transformations. In the recent decades, mechanochemistry has experienced an extraordinary surge – the number of peer-reviewed publications in the field have skyrocketed, and industrial applications have started emerging all around the globe. Mechanochemistry has found applications in different areas of chemistry. Our project IMPACTIVE will focus on finding new opportunities for pharmaceutical research, to make drugs greener and reduce our dependence on solvents.

a graph representing the growth of publications in mechanochemistry

Mechanochemistry isn’t new. In fact, grinding stuff is –probably– one of the oldest forms of chemistry. Ancient civilisations undoubtedly mashed and mixed stuff to make pigments to paint walls and objects – with some examples dating back 70.000 years. In a book on minerals and mining written in the fourth century BCE, one of Aristotle’s disciples describes the obtention of mercury from its ore, cinnabar, using a copper mortar and pestle – as well as a bit of vinegar as a catalyst. It’s the first-ever documented mechanochemical reaction. In the 17th century, while some alchemists still searched for the philosophers’ stone, the scientist and philosopher Francis Bacon described milling as “one of the most important methods to make solids” in one of his best-selling books.

The famous chemist Michael Faraday also experimented with mechanochemistry to obtain silver from one of its salts. Years later, before the expansion and spread of solvent-based chemistry, big companies like BASF used mechanochemistry in the manufacturing of key chemical products, such as pigments and dyes. Workers would load large ball mills named mühlenbetriebe with different raw materials and metal balls, then shaken and stirred vigorously to obtain the desired dyes – including the very popular Heliogen® Blue, still sold today. It was around this time that physical chemist Wilhelm Ostwald first introduced the term “mechanochemistry” in one of his textbooks. Although the idea caught on, and chemists started using this term to speak about mashing molecules in mills and mortars, it wasn’t until 1997 that IUPAC – the international body in charge of chemical nomenclature and terminology – officially adopted the definition.

At the end of the 20th century, mechanochemistry experimented a truly noticeable upsurge – thanks partly to the creation of international associations and conferences in the late 1980s and early 1990s. Soon, scientific papers started soaring, and patents promptly followed the trend. Only twenty years after recognising the term “mechanochemistry”, IUPAC selected this technology as one of the most exciting developments of the current chemical landscape, and remarked its huge potential to make industry more sustainable. Now, different teams around the world –among them the IMPACTIVE consortium– work across disciplines to fully understand the mechanisms of mechanochemistry and promote technology transfer and industrial innovation. Mechanochemical methods offer new opportunities, both in batch and continuous processes that have attracted the interest of pharmaceutical companies, including our partners Novartis and Merck. Some of the success surfaces from standardisation – mortar and pestle have been replaced by reproducible modern tools, such as mills, mixers, shakers, twin-screw extruders, and many more. The different devices allow for controlled and well-defined reaction conditions, enabling extremely efficient processes and optimised reactivity. Moreover, many machines have already been adopted by other industrial sectors; extrusion equipment is common in the production of plastics from polymer pellets, as well as simpler processes like the kneading of dough in bread-making and baking. Therefore, repurposing and retrofitting should be straightforward, and scaling up mechanochemistry industrially could soon become a reality. Already in 2020, methods of mechanochemical extrusion developed by researchers now part of IMPACTIVE enabled a solvent-free synthesis of value-added pharmaceuticals with higher production rates than traditional solvent-based methods.

The 12 principles of green chemistry (From: E. Harrison, H. Smith, I. Dekker, University of Victoria).

Moreover, mechanochemistry has gained significant attention in recent years due to its connections to green and sustainable chemistry. Mechanochemistry not only avoids solvents, but also often offers opportunities for milder reaction conditions, evading extreme temperatures and pressures and therefore ensuring energy efficiency and reduced environmental impact. This unique combination of factors could reduce the ecotoxicity and climate impact of pharmaceutical production, cutting carbon dioxide emissions by over 85% and reducing the overall cost of the process. There’s a clear correlation between the benefits of mechanochemistry and the 12 principles of green chemistry, originally proposed by Paul Anastas and John Warner to outline a realistic framework towards a sustainable future. Mechanochemical methods have smaller environmental footprints. Beyond bypassing solvents they also require fewer reactants, reagents, and streamline purification. Additionally, mechanochemistry maximises atom economy – a measurement that looks into the number of atoms in the starting materials are incorporated into the final product, as an indication of efficiency and reduction of waste. Mashing molecules allows amines and carbonyls to react and form amides without the need for a base, which is typically required in solution. This makes condensation reactions more efficient in terms of atom economy and minimises waste generation.

Another breakthrough of mechanochemical methods is the unlocking of pathways to “impossible reactions”, similarly to techniques like photochemistry and electrochemistry. Traditional chemical methods often encounter limitations, related to high energy barriers and unfavourable reaction conditions. Mechanochemistry offers a unique approach to circumvents these hurdles. The mechanical energy of grinding, crushing, milling and shearing breaks down strong bonds and induces reactions that were previously considered unattainable. Moreover, mechanochemistry provides a promising platform for reactions hindered by solubility issues. The kinetics and thermodynamics of mechanochemical reactions have proven intriguing, yet interesting. Mechanochemistry means creating and inventing a new set of rules for reactions, which will push the boundaries of what’s possible in the world of chemistry and lead to unexplored and unexpected products. Overall, mashing molecules enables chemists to explore uncharted territories and discover new reaction pathways. On top of enhancing efficiency and sustainability, in line with the principles of green chemistry, mechanochemistry is continuously expanding the horizons of chemical transformations, opening doors to novel compounds and synthetic routes, previously totally out of reach.

Mechanochemistry is emerging from the realm of academic research towards industrial applications. The unique advantages in terms of versatility, efficiency, and sustainability make it an especially attractive option for the pharmaceutical industry – it’s an opportunity to diversify drug portfolios and democratise the development of life-saving medicines, and to reduce the reliance on shaky supply chains and strengthening European leadership during emergencies. The future of mechanochemistry is incredibly bright. And IMPACTIVE will become a reference in the field, contributing to cross-collaboration between academia and industry to boost progress and possibilities of greener manufacturing methods, thanks to mechanochemistry.