Imagine yourself in a chemistry lab. You are probably picturing a scene featuring a whole load of liquids 鈥 fluids bubbling in round-bottomed flasks, solutions swirling in test tubes, droplets running down condensers. It is a clich茅, but one that accurately describes what these spaces have looked like for centuries the world over.
There isn鈥檛 much frothing or bubbling going on in 鈥檚 lab, though. That鈥檚 because he and his team at the University of Birmingham, UK, are trying to do away with liquid chemistry. The tools of their trade are powerful machines like the ball mill, a grinder full of metal spheres that resembles a mini cement mixer. It may seem brutal, but this hardball approach could shake up the way chemists work, freeing them from the 鈥渕ental prison鈥, as Fri拧膷i膰 puts it, of having to dissolve everything.
Chemistry creates many of the wonders of modern life, from the medicines that heal us to the screens with which we communicate. When researchers want to make these things from scratch, they often start by assuming they must dissolve their materials. But mechanochemistry, the burgeoning field Fri拧膷i膰 is fascinated by, shows this isn鈥檛 always necessary. 鈥淢echanochemistry gives you the intellectual freedom to think: 鈥楲et me just try this reaction by grinding it鈥,鈥 says Fri拧膷i膰. 鈥淎nd, in many cases, it works.鈥
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Now, a growing number of chemists are recognising the merits of this radically different way of doing chemistry. One prime benefit is that eschewing solvents could make the chemical underpinnings of society far more environmentally benign. So, could this radical idea catch on?
To be fair, chemists haven鈥檛 always been so strongly tethered to solvents. The 1st-century Greek alchemists who made the red pigment cinnabar did so by simply . Apothecaries in the Middle Ages to make medicines. But they may not have regarded this as chemistry, per se: scholars as far back as Aristotle often could cause chemical reactions between solids, arguing instead that heat or tiny amounts of liquid must be responsible.
In the late 19th century, US chemist and photographer realised that pressing hard on the silver compounds he used to develop his photos made them change colour, similar to how they did when they were exposed to light. In , he noted that 鈥渧ery little, if anything, is known鈥 about the relationship between mechanical and chemical energy. But he adopted the term mechanochemistry, coined by German scientist Wilhelm Ostwald two years earlier. After that, though, interest fizzled out. For much of the 20th century 鈥 with the exception of scientists in the Soviet Union 鈥 few paid attention to mechanochemistry.
Wet chemical reactions
Meanwhile, researchers were busy continuing to develop the recipes and rulebooks of wet chemistry. Making a drug or a fancy new material often involves stitching together different groups of atoms with fresh chemical bonds. At each stage, chemists dissolve the required ingredients in a solvent, usually heating them, then evaporate or filter away the solvent to get their product. Catalysts can be added too, to accelerate reactions. Working in this way has its advantages. Solvents help molecules to scoot around and crash into each other. They can be piped around and stirred, creating a more even reaction. And you can house them in glassware, making it easy to see colour changes or other signs of the otherwise imperceptible dance of the atoms.
But solvents also come with huge disadvantages. Plenty of carbon-based, or organic, chemicals won鈥檛 dissolve in water, so chemists must use other solvents 鈥 things like chloroform, acetonitrile and tetrahydrofuran 鈥 many of which are toxic. Making and disposing of these solvents consumes huge amounts of energy and contributes to air pollution and climate change. Demand for the products that power modern life 鈥 medicines, cosmetics, cleaning products and plastics 鈥 means the need is vast. Global solvent production is forecast to reach by 2026.
One answer is green solvents that are less toxic and made via less environmentally damaging routes. Another is to employ no solvent at all. And that鈥檚 exactly what a new generation of chemists realised when they rediscovered mechanochemistry. In 2012, Fri拧膷i膰 collaborated with at Queen鈥檚 University Belfast, UK, and others on a introducing the field and the opportunities it offered for cleaning up the chemical industry.
For James, it all started 20 years ago, when he was working in the fledgling field of metal-organic frameworks (MOFs). These crystalline, honeycomb-like materials, which have large pores surrounded by clusters of metal atoms connected with carbon-based bridges, are now finding applications in gas storage. Back then, it was taking chemists hours or days to make MOFs in 鈥渉orrible鈥 solvents, says James. But after hearing about mechanochemistry at a conference, he decided to give it a whirl. 鈥淚 just thought: 鈥極K, we buy a little ball mill, put it in the lab, ask people to have a play with it and, you know, see what happens鈥,鈥 he says.
Mechanochemistry is enabling chemists to make molecules they have found impossible to create using traditional means
What happened was that the ball mill sat unused for a while. Then, one day, , a student in James鈥檚 lab at the time and now a senior opinion editor at the journal Nature, decided to try using it to . This involved a reaction that could be easily followed by watching the colour change from green to blue. Pichon put two powders 鈥 a copper salt and an organic compound for making the carbon-based bridges 鈥 into the ball mill and whizzed them together with no solvent. Ten minutes later, to her surprise, the mixture was blue.
Since then, the team has installed an array of MOF-making devices, including 鈥渢win screw extruders鈥, which are more common in plastics manufacturing. Speaking on a video call, James carries his laptop into the lab in search of an extruder, where he finds one that has been dismantled on the benchtop to reveal the key parts: two giant metal screws, each longer than his forearm. The screws rotate next to each other in the machine to mash materials together. In 2012, a spin-off company now known as , which uses patented screw-extrusion techniques to make MOFs at the scale of kilograms per hour and is testing them as a way to filter carbon dioxide out of industrial waste gases.
Impossible drug synthesis
Chemists have also used grinding techniques to , which are composed of 聽drugs weakly bonded to other molecules that improve their absorption in the body. But in truth, neither MOFs nor co-crystals are all that hard to create. Far more challenging are complex organic molecules 鈥 the sorts of things that make up the active ingredients of drugs 鈥 which often require a series of expertly designed reactions to ensure the right product comes out at the end. Yet those working with the tools of mechanochemistry now also have these tougher targets in sight. 鈥淲hat I believe is really exciting about mechanochemistry is that it can lead 鈥 and this sounds crazy 鈥 to a complete industrial revolution,鈥 says Fri拧膷i膰. 鈥淚 think it could open the door to making targets which are more complicated and which are scalable.鈥
at the University of Montpellier in France coordinates , a major collaboration that aims to use mechanochemistry to revolutionise how drugs are produced. She and her colleagues have (acetaminophen), and the anti-seizure drug . In both cases, her team used milling to trigger a type of chemical reaction called a rearrangement, where a molecule reorganises its bonds and atoms into a new chemical structure.
Mechanochemistry is even enabling chemists to make molecules they have found impossible to create using traditional means. A co-authored by Colacino cites multiple examples of the production of these 鈥渋naccessible鈥 molecules. In some cases, ball milling got reactions out of compounds that chemists have struggled to dissolve 鈥 and which therefore have always been considered unreactive 鈥 including complicated, ring-structured chemicals called polyaromatics, which feature in cutting-edge electronic materials, among other things.
Meanwhile, Fri拧膷i膰, who has emerged as a key player in the field, is expanding his toolkit to help run mechanochemical reactions at larger scales. For this purpose, he is a big fan of resonant acoustic mixing (RAM), basically a mixer sitting on a vibrating plate that gently jiggles the reaction mixture rather than smashing it about with balls. 鈥淸RAM] was developed to blend,鈥 says Fri拧膷i膰. 鈥淎nd it turns out you can also mix substances this way to achieve a chemical transformation.鈥 It works best with a small dab of liquid, though far less than is used in traditional solution chemistry. Ditching the balls also means it is simpler to separate out the products, and there is less chance of them being contaminated, for instance by flecks of metal chipped off the balls.
Fri拧膷i膰 has used his shaking machines to of the diabetes drug tolbutamide. And, more recently, when he and his team (COFs) 鈥 the more stable cousins of MOFs 鈥 they did it 100 times faster and with 20 times less solvent compared with traditional processes. Along with others in the field, they have also that have had a huge impact on synthetic chemistry by enabling molecules to be clicked together like Lego bricks. Fri拧膷i膰鈥檚 team wedged a simple 鈥 and easily extracted 鈥 coil of copper inside the mixer to act as a catalyst, but another approach is to build custom mixers containing catalysts in the walls.
Yet if mechanochemistry is so brilliant, why aren鈥檛 chemists everywhere running their reactions through ball mills? One reason is that it can be disconcerting for chemists to see reactions that may have taken hours or days in solution completed in 15 minutes with such devices, says , who directs the at Texas A&M University. When dealing with solutions, chemists can watch chemical changes happening or pipette out samples to check. But when the changes are reliant on molecules being roughed up inside an opaque metal box, that is far tougher. 鈥淚t鈥檚 not clear how the reaction is proceeding,鈥 says Batteas. And while chemists already have a good grasp of how bonds are made and broken in wet chemistry, mechanochemical reactions might be happening through completely different, unknown mechanisms.
Mastering mechanochemistry
With this challenge in mind, Batteas鈥檚 colleague created a patented ball mill with integrated sensors to in test reactions. Work like this is also key to teasing apart the influence of physical force versus, say, increasing surface area during reactions. 鈥淭his is where we feel it鈥檚 very critical in order to be predictable, to understand these different effects,鈥 says Batteas.
Others are trying to get a better handle on the kinetics of mechanochemical reactions, or the rate at which reactants turn into products. Often, says James, these reactions start quickly and then slow, potentially due to changes in viscosity. 鈥淭his isn鈥檛 something you have to think about in solution-state chemistry,鈥 he says. 鈥淏ut if you鈥檝e got two solids, sometimes you start with powder and you end up with [powder], but, in the meantime, it鈥檚 gone through some weird, rubbery sort of thing.鈥
Ultimately, chemists crave a molecular-level understanding of what is going on. For this, they need techniques like Raman spectroscopy and X-ray diffraction (XRD) to peer into mechanochemical reaction mixtures and uncover the identities and structures of the molecules within. Fri拧膷i膰鈥檚 team, for example, has used see-through milling jars to that form as intermediates during the synthesis of the sulphur compound thiourea, as well as modified XRD set-ups to formed during milling reactions. Combined with modelling, these techniques can help reveal the pathways that atoms take on their way to forming products.
What I believe is really exciting about mechanochemistry is that it can lead 鈥 and this sounds crazy 鈥 to a complete industrial revolution
As well as creating new chemicals, mechanochemistry can be destructive 鈥 in a good way. At Utrecht University in the Netherlands, 鈥檚 lab has been meticulous in trying to work out what happens when plastic waste is broken down in a ball mill. Vollmer came to mechanochemistry looking for a greener way to take spent plastics like polyethylene and polypropylene and turn them back into their chemical building blocks. 鈥淲e were really thinking about it for circularity and recycling, to make these polymers again,鈥 she says.
Such chemical recycling is already possible, but it requires temperatures of around 300掳C (570掳F), meaning plastics are usually melted and reshaped instead. However, Vollmer鈥檚 team recently succeeded at doing it at room temperature using an in which the catalysts driving the reactions are stuck to the balls themselves. They can throw in pellets of plastic 鈥 from old garden chairs and toys, for example 鈥 and get out hydrocarbon gases like propene. According to Vollmer, the team is now building a bigger ball mill and founding a start-up to commercialise the process. It is a stunning example of what mechanochemistry can do, says Fri拧膷i膰.
Still, some chemists remain reticent about swapping their beakers for ball mills due to the outlay involved. With certain models costing north of 拢15,000, purchasing a ball mill could put a dent in funds earmarked for, say, paying laboratory staff. Fri拧膷i膰鈥檚 answer to this dilemma is to make his university鈥檚 new mechanochemistry centre open access. He plans to make it a demonstration station for chemists who will bring in their reactions to see what mechanochemistry can do with them, before investing in their own equipment.
One final hint that mechanochemistry is starting to hit the mainstream may lie in a simple symbol. When chemists describe their reactions, they do so with a system of diagrams and equations. In 2016, two chemists from Vanderbilt University in Tennessee to signify mechanochemistry, one that is now increasingly popping up in reaction schemes in chemistry papers. It consists of three tiny circles, a nod to the trusty ball mill, and it means simply this: put your powders together and give them a good old shake.
