Illuminating milling mechanochemistry by tandem real-time fluorescence emission and Raman spectroscopy monitoring.

In pursuit of accessible and interpretable methods for direct and real-time observation of mechanochemical reactions, we demonstrate a tandem spectroscopic method for monitoring of ball-milling transformations combining fluorescence emission and Raman spectroscopy, accompanied by high-level molecular and periodic density-functional theory (DFT) calculations, including periodic time-dependent (TD-DFT) modelling of solid-state fluorescence spectra. This proof-of-principle report presents this readily accessible dual-spectroscopy technique as capable of observing changes to the supramolecular structure of the model pharmaceutical system indometacin during mechanochemical polymorph transformation and cocrystallisation. The observed time-resolved in situ spectroscopic and kinetic data are supported by ex situ X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy measurements. The application of first principles ( ab initio ) calculations enabled the elucidation of how changes in crystalline environment, that result from mechanochemical reactions, affect vibrational and electronic excited states of molecules. The herein explored interpretation of both real-time and ex situ spectroscopic data through ab initio calculations provides an entry into developing a detailed mechanistic understanding of mechanochemical milling processes and highlights the challenges of using real-time spectroscopy.