Mechanochemical S_NAr on Phthalonitriles: Distinct Reactivity and Selectivity in One-Pot Synthesis for Greener...

Traditional syntheses of functionalized phthalonitriles and phthalocyanines (Pcs) rely on solution-phase nucleophilic aromatic substitution (S_NAr) in high-boiling polar aprotic solvents, raising sustainability and safety concerns. Herein, we establish mechanochemical S_NAr under liquid-assisted grinding (LAG) as a robust and versatile platform for the solvent-minimized functionalization of phthalonitriles. Systematic optimization of base loading, ambient moisture, milling time, and LAG volume (η) enables highly reproducible, high-yielding reactions at η values as low as 0.03 µL mg^-1, four orders of magnitude lower than traditional synthesis. A broad scope of seven nucleophiles and nine electrophiles gives mono-, di-, and tetrasubstituted phthalonitriles, typically in near-quantitative conversion and without chromatographic purification. Mechanochemical conditions also unlock distinct reactivity. Product distributions in pyridyloxy systems can be tuned between keto- and enol-derived isomers by adjusting η, and optimized reaction of 4,5-dichlorophthalonitrile affords quantitative and highly selective monosubstitution, enabling controlled access to asymmetric phthalonitriles. The mechanochemical synthesis of phthalonitriles is directly integrated with solid-state cyclotetramerization, either in sequential steps or in a one-pot S_NAr-cyclotetramerization protocol, yielding a broad range of Pc substitution patterns and chemistries. The one-pot process provides a scalable and sustainable route to advanced Pc architectures.