Potential of Mean Force Calculations for an S_N2 Fluorination Reaction in Five Different Imidazolium Ionic Liquid...

The use of ionic liquids (ILs) as both catalysts and solvents in a wide range of chemical reactions has received considerable attention over the last few years due to their positive effects in enhancing reaction rates and selectivities. In this work, hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations were carried out in conjunction with umbrella-sampling techniques to study the bimolecular nucleophilic substitution (S_N2) fluorination reaction between propyl-mesylate and potassium fluoride using five ILs as solvents, specifically, 1-butyl-3-methylimidazolium mesylate ([C₄mim][OMs]), 1-butyl-3-methylimidazolium tetrafluoroborate ([C₄mim][BF₄]), 1-butyl-3-methylimidazolium trifluoroacetate ([C₄mim][CF₃COO]), 1-butyl-3-methylimidazolium bromide ([C₄mim][Br]), and 1-butyl-3-methylimidazolium chloride ([C₄mim][Cl]) at 373.15 K. The QM region (reactive part) in all QM/MM systems was simulated using the Parametric Method 6 (PM6) semiempirical methods, and for the MM region (IL solvent), classical force fields (FF) were employed, with the FF developed within the group. The calculated activation free energy barriers (ΔG^‡) for the S_N2 reaction in the presence of [C₄mim][OMs] and [C₄mim][BF₄] ILs were in agreement with the experimental values reported in the literature. On the other hand, only predicted values were obtained for the activation energies for the [C₄mim][CF₃COO], [C₄mim][Br], and [C₄mim][Cl] ILs. These activation energies indicated that the S_N2 reaction would be more facile to proceed using the [C₄mim][Cl] and [C₄mim][OMs] ILs, in contrast with the use of [C₄mim][Br] IL, which presented the highest activation energy. Energy-pair distributions, radial distribution functions, and noncovalent interactions (NCI) were also calculated to elucidate the molecular interactions between the reactive QM region and the solvents or reaction media. From these calculations, it was found that not only the reactivity can be enhanced by selecting a specific anion to increase the K-F separation but also the cation plays a relevant role, producing a synergetic effect by forming hydrogen bonds with the fluorine atom from KF and with the oxygen atoms within the mesylate leaving group. Three interactions are significant for the IL catalytic behavior, F_QM-HX, K_QM-anion, and O_QM-HX interactions, where the F_QM and K_QM labels correspond to fluorine and potassium atoms from the KF salt, O_QM corresponds to oxygen atoms within the mesylate leaving group (reactant), and HX refers to hydrogen atoms within the IL cation. The NCI analysis revealed that K_QM-anion interactions are of weak type, indicating the importance of hydrogen bond interactions from the cation such as F_QM-HX and O_QM-HX for the catalytic behavior of ILs.