Inter- and Intra-Molecular Organocatalysis of S(N)2 Fluorination by Crown Ether: Kinetics and Quantum Chemical Analysis

We present the intra- and inter-molecular organocatalysis of S(N)2 fluorination using CsF by crown ether to estimate the efficacy of the promoter and to elucidate the reaction mechanism. The yields of intramolecular S(N)2 fluorination of the veratrole substrates are measured to be very small (<1% in 12 h) in the absence of crown ether promoters, whereas the S(N)2 fluorination of the substrate possessing a crown ether unit proceeds to near completion (~99%) in 12 h. We also studied the efficacy of intermolecular rate acceleration by an independent promoter 18-crown-6 for comparison. We find that the fluorinating yield of a veratrole substrate (leaving group = −OMs) in the presence of 18-crown-6 follows the almost identical kinetic course as that of intramolecular S(N)2 fluorination, indicating the mechanistic similarity of intra- and inter-molecular organocatalysis of the crown ether for S(N)2 fluorination. The calculated relative Gibbs free energies of activation for these reactions, in which the crown ether units act as Lewis base promoters for S(N)2 fluorination, are in excellent agreement with the experimentally measured yields of fluorination. The role of the metal salt CsF is briefly discussed in terms of whether it reacts as a contact ion pair or as a “free” nucleophile F(−).