Potassium fluoride activation for the nucleophilic fluorination reaction using 18-crown-6, [2.2.2]-cryptand, pentaethylene glycol and comparison with the new hydro-crown scaffold: a theoretical analysis

Abstract

Activation of potassium fluoride salt for selective and fast nucleophilic fluorination requires its solubilization and stabilization of the respective transition state. This goal can be achieved through control of the nano-environment around the reactants via cation or ion-pair binding catalysis. In this work, six different species were theoretically investigated as promoters and catalysts for nucleophilic fluorination: tri-tert-butanolamine, 18-crown-6, pentaethylene glycol, [2.2.2]-cryptand, and two new hydroxylated crown ethers (hydro-crowns). Calculations using the PBE functional and the LPNO-CEPA method, as well as the SMD continuum model, were carried out for the S_N2 reaction of KF with ethyl bromide in toluene solution as a model system. The present study points out that [2.2.2]-cryptand is the most effective promoter of the reaction when using stoichiometric quantities. In the case of a catalytic process, the new DB18C6-4OH is the most effective molecule considering only a 1 : 1 complex. The hydroxyl groups are important for the solubilization of potassium fluoride and for the catalytic cycle. Nevertheless, the DB18C6-4OH hydro-crown can form a 2 : 2 complex and is needed to add bulk groups close to the hydroxyls to avoid dimerization. The calculated overall free energy of activation for reactions promoted by 18-crown-6, pentaethylene glycol, and [2.2.2]-cryptand is in good agreement with the experimental data.