Theoretical design of new macrocycles for nucleophilic fluorination with KF: thiourea-crown-ether is predicted to overcome [2.2.2]-cryptand

Abstract

New macrocycles derived from dibenzo-18-crown-6 and molecules derived from pentaethylene glycol were designed and investigated as catalysts for nucleophilic fluorination of alkyl mesylates with potassium fluoride by reliable computational methods. In addition, 3 known catalysts (18-crown-6, [2.2.2]-cryptand, and pentaethylene glycol) were also simulated. In the kinetic model, the solubilization of the salt by the macrocycle, the possible dimerization of the KF(cat) complex and the reaction of the solubilized KF(cat) complex were considered. The calculated free energy barriers for the known catalysts are in very good agreement with published experimental data. For the new designed catalysts, all of them were predicted to be effective in promoting fluorination. A novel macrocycle based on a thiourea-crown-ether structure, named TCEbut, was calculated to be the most effective catalyst, even overcoming [2.2.2]-cryptand. This catalyst works by complexing the potassium ion and making four hydrogen bonds provided by the thiourea groups to the S_N2 transition state.