Unbalanced Ion Pairs Catalyzed Nucleophilic Substitutions

The bimolecular nucleophilic substitutions（S_N2）are among the most fundamental and widely used textbook reactions in organic synthesis.In a solvent of relatively low dielectric constant and low solvation power（e.g.,dichloromethane,THF）,the ionic nucleophiles（Nu^-M⁺）are generally not soluble or exist as ion pairs than dissociated free ions.The S_N2 of paired nucleophiles is often low due to the hindrance of counterion.Part Ⅰ.An unbalanced ion pair promoter（e.g.,tetrabutylammonium sulfate）,consisting of a bulky and charge delocalized cation and a small and charge-localized anion,greatly accelerates nucleophilic fluorinations using easy handling KF.We also successfully converted an inexpensive and commercially available ion exchange resin to the polymer-supported ion pair promoter(A26-SO₄^2-),which could be reused after filtration.Moreover,A26-SO₄^2-can be used in continuous flow conditions.Under the condition of tert-butanol as solvent,the water tolerance is very good,and the yield can reach more than 90%.Part Ⅱ.A conceptually new nucleophilic substitution pathway,which we named S_Nip（ip=ion pair）is proposed based on the theoretical DFT approach and kinetic studies.Weakly solvated contact ion pairs—being highly polar species—facilitate a nucleophilic attack by a cyclic transition state,thus significantly influencing the course of the reaction.The transition structures and IRC were fully characterized by model systems.We demonstrated the proof of concept in many nucleophilic processes.