Grinding chemistry

European Synchrotron Radiation Facility,
March/April 2014
Mechanochemistry, where reactions are primarily driven by mechanical­ action, is being touted as a greener and more effective­ way of developing­ new polymers, crystals and salts.

Basic  chemistry has seldom been better captured by Hollywood than when Tom Hanks built a fire in Castaway. Stranded alone on a desert island, a man employs one of humanity’s oldest innovations — the humble fire drill — to create heat and light from simple ingredients. His celebratory dance afterward might be shared by anyone who has suffered through this same brute force exercise.

Although fire making was a major milestone for civilization, the chemical sciences subsequently moved on to less strenuous, more elegant reactions. Chemistry is still widely perceived as getting more-or-less liquid agents to do interesting things with one another through far more subtle interactions that take place at the molecular or atomic level. Bashing things together is for those on desert islands with few options. Or perhaps not.

Tomislav Friscic and his colleagues have been using the European Synchrotron Radiation Facility, which is nestled in the mountains of southeastern France, to open up frontiers of mechanochemistry, grinding molecules together to promote hydrogen bond associations. Photo creadit: S. Evans & G. Garner

A growing body of research literature is breathing new life into the field of mechanochemistry, where reactions are primarily driven by mechanical action of one sort or another. If that sounds a lot like rubbing two sticks together, it can also look that way in practice. Just ask Tomislav Friscic, a solid-state chemist who began his career as a crystallographer but now spends much of his time studying what he dubs “the second oldest trade known to man.” 

A member of McGill University’s chemistry department, Friscic’s interest was piqued during post-doctoral work with William Jones at the Pfizer Institute for Pharmaceutical Materials in the United Kingdom. This was where he learned that grinding molecules together can promote hydrogen bond associations without the need for a solvent or catalyst. “They are very likely to undergo a diffusion between solids, form hydrogen bonds and recrystallize into new solids that contains both compounds,” he says. “This is pharmaceutically of great interest, but for us it was the process behind it that was interesting.”

Drug companies have a vested interest in anything that could simplify the many steps leading to a new polymer, crystal, or salt. Taking solvents out of the equation not only reduces costs, but eliminates some of the most toxic constituents of the whole enterprise, a guiding principle of green chemistry. Above all, as Friscic points out, it also eliminates the entire question of solubility. “This means that you can start playing around and doing chemistry with things that are normally insoluble and therefore under classical conditions are not going to react,” he says.
His favourite example of this approach is a revised procedure for making the venerable stomach remedy Pepto-Bismol. The active ingredient is bismuth subsalicylate, the latest in a series of compounds containing the heavy metal element bismuth that have been used to make digestive aids for more than a century. Currently the necessary ingredients are combined in water, which must be removed afterward, adding to the energy and expense invested in manufacturing, as well as creating secondary compounds for disposal. However, Friscic and his colleagues were able to make their own bismuth subsalicylate by loading the dry components into a mixing vessel with some metal or ceramic balls, then shaking everything thoroughly. Although the shaking step did require an energy input, it was much lower; nor were there any by-products to pose environmental challenges.

A glowing porthole offers a direct look at one of the high-energy beam lines at the European Synchrotron Radiation Facility in Grenoble, France. Photo credit: T. Friscic /S. A. J. Kimber

Surprisingly, he notes, no one had ever attempted the reaction in this manner. And it might have been easy to overlook this intriguing outcome from the title of the resulting 2011 paper, “Mechanosynthesis of the metallodrug bismuth subsalicylate from Bi2O3 and structure of bismuth salicylate without auxiliary organic ligands,” which appeared in Angewandte Chemie, International Edition. Nevertheless, this finding is part of a small but steady output of mechanochemical investigations that Friscic is determined to augment.

Toward that end, he has joined a scientific committee of mechanochemists from the United States, Russia, Germany and the UK, mounted by the Royal Society of Chemistry, which is holding a prestigious Faraday Discussions meeting on the subject at McGill University in Montreal May 21-23. The event will showcase the full spectrum of the field, including its inorganic and organic applications, relationship to the sister field of sonochemistry, as well as how it might be scaled up for industrial purposes.

This gathering gives unprecedented profile to a discipline whose roots have been traced by Laszlo Takacs, a physicist at the University of Maryland, Baltimore County. He has profiled Matthew Carey Lea, an obscure 19th century chemist living in New England, who published the first formal papers on matters such as how mechanical action — as opposed to heat — successfully decomposes silver halides or reduces ferric ammonia alum to ferrous. Such pioneering inquiries continue to make their way into the forefront of science, as demonstrated by a 2012 article in Nature Chemistry, “Mechanochemistry: Measuring the force of sound,” which describes how ultrasonic pulses can break up molecules consisting of long polymer chains. 

Tomislav Friscic, assistant professor in the Department­ of Chemistry at McGill­ University. Photo credit: Tomislav Friscic

Such developments also captured the imagination of Nick Mosey, a chemist at Queen’s University. As a tribologist studying the interaction of surfaces in relative motion, he focuses on the modelling of reactions. Mosey has always had a keen appreciation of the complexities of friction, wear and lubrication. The use of sonication to break chains stood out for him because it violates some well-established precepts for how such transformations should occur. More specifically, it violates the Woodward-Hoffmann rules, which classify permitted reactions based on how much energy it takes to retain the orbital symmetry of the affected atoms. For example, mechanical forces appear to use less energy than should be necessary to break up the chains in benzocyclobutane molecules, which makes a compelling­ case for further study. 

“It’s not necessarily limited to specific reactions,” Mosey says. “It may be possible to tune the ability to mechanochemically activate reactions by something as simple as changing the size of substituents on molecules. This can alter the forces experienced by the reactive portions of those molecules, as well as the mechanochemical reaction barriers.”

Mosey admits that it would be easy to assume that such fundamental aspects of the chemistry had already been addressed. “But since people haven’t been looking at the mechanochemical activation of reactions, they haven’t bothered exploring these details until recently.”
And just as chemists have sought the underlying mechanisms responsible for thermochemical or photochemical reactions, their efforts are dedicated to unravelling the mysteries of mechanical action. Unfortunately, merely making accurate observations of mechanochemistry at work can turn out to be a difficult affair. A straightforward milling machine containing reagents and a few metal balls, oscillating at a comparatively modest 25-30 Hz, is enough to prompt changes in otherwise stable agents such as copper or zinc oxides. Yet the interior of this system is as hostile as they come, so that any kind of sensor would be destroyed by the intense grinding.

Tomislav Friscic and his colleagues were able to observe mechanochemical processes in action­ at the European­ Synchrotron­ Radiation­ Facility, where the beam from this collimator revealed the dynamics inside an operating grinding mill. Photo credit: P.Ginter/ESRF

Aided by colleagues from Germany, his native Croatia, as well as generous help from the European Synchrotron Radiation Facility in Grenoble, France (ESRF), Friscic finally overcame this serious obstacle when his team obtained several days’ worth of research time on the ID15B beam line at the ESRF. There he was able to install one of his milling machines and subject it to the ultra-intense light from the synchrotron, allowing him to get his first good look inside. “This gave us a diffraction signature of the sample being milled, meaning we could detect all crystalline substances participating in the reaction,” he says. 

The technique got the synchrotron managers at Grenoble enthusiastic enough to grant his team another full week on their equipment this past summer. They were able to work around the clock and conduct as many as 10 to 20 iterations of this experiment each day. They enhanced their measurements by replacing the standard steel or tungsten carbide mixing vessels with home made ones from plexiglass, so the motion of the grinding balls could be observed directly. This extensive program allowed them to confirm the efficacy of this method with a variety of materials. The research continues this year also, with his European colleagues Ivan Halasz from Croatia and Robert Dinnebier in Germany. “We tried to show that you can do these kinetic measurements on pharmaceuticals, metal organic frameworks and metallo-drugs,” says Friscic. “You can look at transformations, not only of metal oxides and inorganic substances, but organic materials. We showed that you can use this methodology to monitor the transformation of pharmaceuticals. A lot of people should be interested.”

Friscic maintains that the ultimate prospects of mechanochemistry are just being realized. For instance, studies that take into account variations in temperature and pressure are only starting to be conducted. Among the materials most prized may be porous metal-organic frameworks (MOFs), which could prove to be the ideal medium for intermittently storing waste carbon dioxide or the hydrogen gas that is ultimately expected to replace petroleum as the staple energy source of our economy. When these materials are formed by milling under higher pressures, their ability to retain hydrogen significantly improves.

Friscic highlights the possibility of “cheating” — adding a liquid catalyst to optimize a known mechanochemical reaction — perhaps by way of ensuring complete conversion of the constituents. Meanwhile, even more precise analyses are possible with atomic force microscopes, which literally grind individual molecules together to observe the effect. “All we can do is perform experiments and make logical connections and draw conclusions,” Friscic says, which is why he is looking forward to this spring’s gathering in Montreal.  “We need to create a broad and modern definition of mechanochemistry. It’s not just milling, it’s not just alloying, it’s not just sonication or pulling molecules apart — it’s all of that. How can we all learn from each other to create a modern, 21st century discipline?”