Highly NucleophilicPyridinamide Anions in ApolarOrganic Solvents due to Asymmetric Ion Pair Association

Free ions in organic solvents of low polarity would be valuable tools for the activation of low-reactivity substrates. However, the formation of unreactive ion pairs at concentrations relevant for synthesis has prevented the success of this concept so far. On the example of highly nucleophilic pyridinamide phosphonium salts in dichloromethane, we show that asymmetric aggregation offers a solution to this general problem. A combination of conductivity, diffusion-ordered NMR (DOSY), and kinetic measurements utilizing a refined ionic strength-controlled benzhydrylium ion methodology enables unique insight into the aggregation/association state of the ions and the nucleophilicity of the involved anions. This approach reveals that pyridinamide tetraphenylphosphonium salts aggregate in dichloromethane solution asymmetrically to form sandwich-type cations and anions together with their free counterions. The nucleophilicity of free pyridinamide ions exceeds that of the neutral reference nucleophile 9-azajulolidine (TCAP) by up to 2 orders of magnitude. Based on these results, we suggest that asymmetric aggregation in organic solvents of low polarity might be a general pathway to boost the reactivity of anionic nucleophiles.