Monoselective Mechanochemical Aromatic Nucleophilic Substitution Enabled by Crystal‐Engineering‐Guided Reaction Design

ABSTRACT 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 N Ar) reactions. The mechanochemical solid‐state S N Ar 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.