Liquid-Assisted Grinding-Triggered Monohalogenation and Dihalogenation of 8-Aminoquinoline Derivatives

Abstract Herein, we report the first liquid-assisted grinding (LAG)-controlled mechanochemical protocol for the tunable halogenation of 8-aminoquinoline amides. The selectivity can be tuned simply by omitting or adding a minimal amount of biodegradable PEG-400 (η = 1 μL/mg). Under neat grinding conditions, C5-monohalogenated products are formed exclusively, whereas under LAG conditions (with PEG-400 added), the corresponding C5,C7-dihalogenated derivatives are obtained. Notably, this switch is achieved without altering any other reaction parameters or components. This operationally straightforward, nearly solvent-free protocol provides a sustainable and highly modular synthetic route to both mono- and di-halogenated products from identical starting materials, highlighting the remarkable power of LAG parameters in fine-tuning reaction outcomes in solid-state organic synthesis.