In our beautiful crystalline world, we continuously make new compounds and materials, search for new crystal phases through a series of crystallizations, and grow quality crystals in a variety of approaches. At almost every step of the way, we deal with an agent that is both friend and fiend: solvents.
“Chemistry doesn’t pollute the environment, irresponsible management of solvents does”, explains Ivan Halasz, senior research associate at the Laboratory for Green Synthesis at the Ruđer Bošković Institute. “However, reducing the amount of solvents used in chemistry labs also reduces the amount of globally produced solvents and waste. Hence, solvent-free chemistry has a positive effect on the environment”, Halasz concludes.
An alternative way of preparing a wide range of solid-state materials without using bulk solvents is by subjecting the (solid) reactants to mechanical stress – a field called mechanochemistry.
“In our lab we use mechanical milling to produce functional materials ranging from supramolecular receptors and organic compounds to microporous metal-organic frameworks (MOFs) and organometallic catalysts or chromogenic sensors”, says Krunoslav Užarević, the head of the laboratory.
However, the process is not easy. First, the outcome of the synthesis depends on milling parameters: duration, rotations, and type and size of the milling media. Second, reaction paths of mechanochemical reactions are not well known. Third, it is relatively difficult to recognize when the reaction has ended successfully.
All three challenges were addressed with a single solution, a mill that allows for in situ and real-time monitoring of milling reactions using Powder X-ray Diffraction (PXRD) the ID15B beamline at the European Synchrotron Radiation Facility [1,2]. Shortly thereafter, the ID15A and ID31 beamlines upgraded this innovative setup with the PILATUS3 X CdTe 2M detector, which resulted in a series of exciting experiments.
Figure 1. A powerful combination of the mill, the PILATUS3 X CdTe and high energies of the ID15A beamline (ESRF) allow for in situ and real-time monitoring of milling reactions using Powder X-Ray Diffraction (PXRD).
During a mechanochemical reaction, a series of PXRD patterns are recorded in real time. High resolution of the data and high sensitivity of the setup enables detection and characterization of the reactants, intermediates and products of the reaction, even if the phases are present in low amounts. The approach gives insights in the reaction paths of mechanochemical reactions, as well as facilitates the scale up of the production of the targeted product.
“The setup was used to study reaction mechanisms of MOFs . We were able to detect intermediate phases and solve their crystal structures“, comments Tomislav Stolar, a PhD student at the laboratory. “Another interest of ours is the preparation and control of the polymorphism of pharmaceutical cocrystals. We are taking the idea a step further to tackle these phenomena on an industrial scale“, Stolar continues.
Indeed, Stolar and his colleagues managed to prepare a thermodynamically stable cocrystal of Vitamin C and B3. Selective synthesis and polymorph control were successfully scaled up to the 10 g scale on a planetary ball mill and continuous manufacturing using a twin-screw extruder . Mechanochemical stress or inclusion into a cocrystal did not deteriorate the activity of vitamin C, and the cocrystals showed excellent tableting properties.
The efforts and creativity of the Laboratory for Green Synthesis do not end here. The researchers have successfully exploited the flexibility of the setup to extend their investigations to Raman spectroscopy and to carry out tandem PXRD-Raman in situ experiments in real time.
Figure 2. Tandem in situ monitoring: two complementary techniques, PXRD and Raman spectroscopy, are synchronized to give real-time information on the molecular and crystal level.
The combination of two complementary techniques, X-ray diffraction and Raman spectroscopy, makes it possible to observe mechanochemical reaction paths on the molecular and on the crystal scale. The PXRD-Raman tandem setup allows for a better control over polymorphism, more reliable quantitative assessments of reactions, and easier identification of new phases. Stipe Lukin, a PhD student at the lab, and his colleagues have demonstrated the use of the tandem setup for preparing new polymorphs of pharmaceutically-relevant cocrystals  and for understanding the selectivity in mechanochemical cocrystallization . Quantitative assessment and kinetic analysis of the mechanochemical reactions could be performed even when involving unknown crystal structures and short-lived intermediates.
“In one of our latest in situ tandem experiments, we have used isotope labeling to investigate the milling reactions ”, explains Lukin. “We found out that milled crystalline solids rapidly exchange hydrogen atoms and whole molecules, with or without a net chemical reaction. We expect this method to become an indispensable tool to study mechanochemical reaction mechanisms not only on the level of molecular transformations but also on the level of bulk solids”, says Lukin.
We do not doubt that this lab, together with the high-energy beamlines at the ESRF, has the potential to make chemical processes greener, more sustainable and more user-friendly. We are looking forward to their new experiments and publications. In the meantime, recycle, bicycle, upcycle, and stay tuned for the next edition of the SciRes meeting the group is organizing. Go green.
Figure 3. The Laboratory for Green Synthesis at the Ruđer Bošković Institute.
 Halasz, I. et al. (2013) Nature Protocols 8(9), 1718-1729.
 Friščić, T. et al. (2013) Nature Chemistry 5, 66-73.
 Stolar, T. et al. (2017) Inorg. Chem. 56, 6599–6608.
 Stolar, T. et al. (2019) ACS Sustainable Chem. Eng. 7, 7102-7110.
 Lukin, S. et al. (2017) Chem. Eur. J. 23(56), 13941-13949.
 Lukin, S. et al. (2018) Cryst. Growth Des. 18, 1539-1547.
 Lukin, S. et al. (2019) J. Am. Chem. Soc. 141, 1212-1216.