The evolution of organic synthesis in the solid-state approach: from grinding to mixing

The thesis entitled ‘The evolution of organic synthesis in the solid-state approach: from grinding to mixing’ focuses on the development of synthetic methodologies by addressing the problem of both sustainability and performance of these procedures. This problem represents a significant challenge, as the environmental impact of current protocols is too high to continue to be used as they are, especially on an industrial level. The main objective of the proposed research is to present solvent-free synthetic methodologies such as mechano-chemistry and high-frequency blending as new alternatives to those currently reported in the literature, and to provide new insights into these fields.To achieve these objectives, this research utilises a methodology based on grinding and blending of purely solid-state mixtures in the form of slurries, both in the presence and absence of any grinding/mixing media. This combination of approaches enabled reliable and detailed results to be obtained. The main results of the thesis highlight not only a greater sustainability of these methodologies, but also a different selectivity in specific processes, offering a deeper understanding of the reactivity of various classes of organic compounds in the solid state. These results are particularly significant because they avoid the use of bulk solvents, harmful and hazardous reagents for operators and drastic reaction conditions, contributing to the broad development of sustainable chemistry within the organic chemistry sector. Furthermore, the research provides a framework that could be applied widely at an industrial level, allowing these concepts to be implemented also on a large scale. Finally, the thesis highlights some unresolved questions and opportunities for future research, such as the study of the reactivity between gaseous and solid components in the absence of a solvent and the analysis of the selectivity of certain processes under neat grinding or liquid-assisted grinding conditions. These aspects provide an important basis for further studies and developments in this critical area, underlining the value of this work both theoretically and practically.