How to Track Mechanochemical Reactions in Resonant Acoustic Mixers by in Situ Raman Spectroscopy.

Mechanochemical processes have traditionally been explored using ball mills; however, resonant acoustic mixers (RAM) offer a compelling alternative, operating without milling media and enabling scalable, solvent-free synthesis. Despite their advantages, direct transfer of reaction conditions from ball mills to RAM has proven nontrivial, requiring careful optimization of key parameters. In this study, we systematically define an operational window for effective in situ Raman monitoring in RAM. Critical parameters-including vessel material, applied gravitational force, filling degree, substrate rheology, and reaction time-were assessed to ensure high-quality spectral acquisition. Utilizing a sapphire-glass window and a precisely aligned laser setup, we achieved strong, reproducible Raman signals under controlled conditions. The optimal window was found to include a minimum filling degree of 10% and applied g-forces between 20 and 70 g. This framework was validated across diverse mechanochemical reactions, including organic condensations (Knoevenagel and quinoxaline), metal-organic framework formation (ZIF), and catalytic coupling (Glaser reaction), demonstrating the robustness and versatility of in situ Raman spectroscopy in RAM-based synthesis.