The Role of Crystalline Intermediates in Mechanochemical Cyclorhodation Reactions Elucidated by in‐Situ X‐ray Powder Diffraction and Computation

The occurrence of crystalline intermediates in mechanochemical reactions might be more widespread than previously assumed. For example, a recent study involving the acetate‐assisted C−H activation of N−Heterocycles with [Cp*RhCl 2 ] 2 by ball milling revealed the formation of transient cocrystals between the reagents prior to the C−H activation step. However, such crystalline intermediates were only observed through stepwise intervallic ex‐situ analysis, and their exact role in the C−H activation process remained unclear. In this study, we monitored the formation of discrete, stoichiometric cocrystals between benzo[ h ]quinoline and [Cp*RhCl 2 ] 2 by ball milling using in‐situ synchrotron X‐ray powder diffraction. This continuous analysis revealed an initial cocrystal that transformed into a second crystalline form. Computational studies showed that differences in noncovalent interactions made the [Cp*RhCl 2 ] 2 unit in the later‐appearing cocrystal more reactive towards NaOAc. This demonstrated the advantage of cocrystal formation before the acetate‐assisted metalation–deprotonation step, and how the net cooperative action of weak interactions between the reagents in mechanochemical experiments can lead to stable supramolecular assemblies, which can enhance substrate activation under ball‐milling conditions. This could explain the superiority of some mechanochemical reactions, such as acetate‐assisted C−H activation, compared to their solution‐based counterparts.