Ionic Liquid Effects on Nucleophilic Aromatic Substitution Reactions from QM/MM Simulations

Nucleophilic aromatic substitution (S_NAr) reactions are particularly sensitive to medium effects and have been reported to benefit from ionic liquids. The S_NAr reaction between cyclic secondary amines (i.e., piperidine, pyrrolidine, and morpholine) and the 2-L-5-nitrothiophene (para-like) and 2-L-3-nitrothiophene (ortho-like) isomers, where L = bromo, methoxy, phenoxy, and 4-nitrophenoxy, has been computationally investigated in 1-butyl-3-methylimidazolium tetrafluoroborate and hexafluorophosphate [BMIM]­[BF₄] and [BMIM]­[PF₆], respectively. QM/MM Monte Carlo simulations utilizing free-energy perturbation theory were used to characterize the solute–solvent interactions over the addition–elimination reaction pathway. Energetic and structural analyses determined that the improved S_NAr reactivity in [BMIM]­[BF₄] and [BMIM]­[PF₆] can be attributed to (1) an enhanced nucleophilicity of the cyclic amines in the ionic liquids with an order of Pyr ≥ Pip > Mor, (2) beneficial π⁺–π interactions between the BMIM cations and the aromatic rings present on the substrate that enhanced coplanarity between the thiophene ring and the aromatic substituents, resulting in a larger positive charge on the reacting ipso carbon, and (3) a highly ordered ionic liquid clathrate formation that, despite an entropy penalty, provided reduced activation free-energy barriers derived from an increasing number of solvent ions favorably interacting with the emerging charge separation at the rate-limiting addition step