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

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.