Monoselective Mechanochemical Aromatic Nucleophilic Substitution Enabled by Crystal-Engineering-Guided Reaction...

Mechanochemical solid-state organic transformations using ball milling not only represent a sustainable and efficient synthetic approach but also exhibit reactivity patterns that are remarkably different from conventional solution-phase reactions. However, the rational design of site- and chemoselective synthetic strategies that harness the distinct behavior of solid-state molecules remains largely unexplored. Here, we present a new reaction based on an organic crystal-engineering approach to achieve monoselective nucleophilic aromatic substitution (S_NAr) reactions. The mechanochemical solid-state S_NAr reactions of perfluoroarene derivatives with carbazoles as nucleophiles selectively afforded the monosubstituted products. In contrast, the corresponding solution-based reactions yielded a mixture of mono- and disubstituted products. Single-crystal X-ray diffraction analysis of the monosubstituted products revealed strong π-π interactions between the electron-deficient perfluoroarene moiety and the electron-rich carbazole unit. These arene-perfluoarene interactions lead to the formation of crystalline solids that are less reactive than the starting materials, thereby suppressing the second substitution and ensuring pronounced monoselectivity. The present study represents a novel approach that leverages a crystal-engineering principle to design selective solid-state organic transformations that are difficult to achieve via conventional solution-based synthesis.