Challenges of Mechanochemistry: Is In Situ Real‐Time Quantitative Phase Analysis Always Reliable? A Case Study of Organic Salt Formation

Abstract

Mechanochemical methods offer unprecedented academic and industrial opportunities for solvent‐free synthesis of novel materials. The need to study mechanochemical mechanisms is growing, and has led to the development of real‐time in situ X‐ray powder diffraction techniques (RI‐XRPD). However, despite the power of RI‐XRPD methods, there remain immense challenges. In the present contribution, many of these challenges are highlighted, and their effect on the interpretation of RI‐XRPD data considered. A novel data processing technique is introduced for RI‐XRPD, through which the solvent‐free mechanochemical synthesis of an organic salt is followed as a case study. These are compared to ex situ studies, where notable differences are observed. The process is monitored over a range of milling frequencies, and a nonlinear correlation between milling parameters and reaction rate is observed. Kinetic analysis of RI‐XRPD allows, for the first time, observation of a mechanistic shift over the course of mechanical treatment, resulting from time evolving conditions within the mechanoreactor.

The effect of ball mass on the mechanochemical transformation of a single-component organic system: anhydrous caffeine

“…For each experiment, 300 mg of pure anhydrous caffeine powder was used. Samples were loaded into Perspex milling vessels (internal volume 14.5 mL), which have been previously demonstrated to be suitable for in situ X-ray diffraction experiments [15,16,19,46]. Jars were generated in line with the engineering specifications in [47].…”

“…Mixing efficiency therefore becomes one of the most important parameters of the powder sample. It follows that problems can arise in the case of rheological changes, which can have drastic effect on the flowability and mixing of the sample [19,22]. The observed reaction rates therefore become a convolution of changes in processability with the true kinetics of the transformation.…”

“…In a number of examples, in situ monitoring of multi-component cocrystallisations has revealed previously unknown reaction intermediates, which in some cases could be isolated if treatment were stopped [20]. The use of in situ, real-time techniques has also allowed insights into the macroscopic rates of mechanochemical processes and has revealed a number of complex phenomena, unknown to solution and gas-phase reactions [19].…”

“…These issues prompted the rapid development of techniques to probe mechanochemical reactions in situ and in real time. To date, this has been performed using X-ray powder diffraction at synchrotron sources, laboratory-based Raman spectroscopy, or a simultaneous combination of the two [3,[15][16][17][18][19]. In situ, real-time monitoring has proven a great advantage to identifying processes and control parameters in mechanochemistry.…”

“…In addition to the qualitative monitoring of mechanochemical transformations, in situ technologies have been used to systematically investigate the effects of various process parameters on the rates and products of transformation. To date, this has included such effects as milling frequency, milling ball mass and temperature [17][18][19]23]. This style of investigation is critical for the rational design of targeted mechanochemical procedures.…”