Selective solvent-free substitution enabled by Mechanochemistry

Abstract: Mechanochemistry provides a sustainable alternative to solution-phase synthesis, yet solvent-free environments can enable reaction pathways inaccessible under conventional conditions. Here, we present a systematic experimental and computational study of nucleophilic substitution reactions under mechanochemical activation, focusing on the formation and selectivity of alkyl thiocyanates (R–SCN) and alkyl isothiocyanates (R–NCS). While aryl analogues have been previously prepared mechanochemically, alkyl variants and their stereochemical behavior have remained largely unexplored. Using chiral benzylic halides as model substrates, we demonstrate that reaction outcome can be selectively tuned yielding either thiocyanate or isothiocyanate products depending on mechanochemical parameters. Product distribution and stereochemical outcomes are strongly influenced by counterion identity, temperature, milling time, and milling-vessel composition. Under certain conditions, classical stereoinvertive SN2 substitution dominates, whereas elevated temperatures and specific metal surfaces promote racemization and isomerization consistent with radical-mediated pathways. Radical inhibition experiments and variation of milling materials reveal a critical role of metal surfaces, particularly iron-containing vessels, in enabling these alternative pathways. Density Functional Theory calculations support a concerted SN2 mechanism as the primary substitution route while highlighting the influence of cation–anion interactions on transition-state stabilization and selectivity. Deviations from classical solution behavior demonstrate that mechanochemical environments reshape substitution reactivity through ion pairing, surface effects, and mechanical activation. These findings show that mechanochemistry is not only a greener synthetic platform but also a means to access unconventional substitution pathways, expanding mechanistic understanding and offering new strategies for selective solvent-free synthesis.