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

Abstract

Nucleophilic aromatic substitution (SNAr) reactions are particularly sensitive to medium effects and have been reported to benefit from ionic liquids. The SNAr 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 SNAr 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.

Reaction-Based Amine and Alcohol Gases Detection with Triazine Ionic Liquid Materials

“…It is also reported in literature that S N Ar reactions proceed with faster reaction rates in ionic liquids than those performed in molecular solvents [10][11][12][13]. These rate accelerations were primarily attributed to both the enhanced nucleophilicity of the nucleophiles such as amines in ionic liquids and the favorable π + -π interactions between cations of ionic liquids and aromatic rings present on the substrates, rendering a more positive charge on the reacting ipso carbon [14]. Moreover, with comparison to the electrostatically neutral reactants, ionic liquids stabilize the charged transition states and also the intermediate Meisenheimer complexes formed [15].…”

Computational approaches to understanding reaction outcomes of organic processes in ionic liquids

“…The calculated activation parameters closely matched the experimentally derived parameters, once again concluding that the rate increase was due to an enthalpic benet. 282 The computational work also suggested an increased amine nucleophilicity in the ionic liquids, compared to methanol, as well as signicant p-p interactions between the [Bmim] + cation and nitrothiophene 21 substrate. Interestingly, they also found that the transition state in the ionic liquid more closely resembled the Meisenheimer complex than it did in methanol, and that there was a signicant increase in the electrostatic interactions between the ionic liquid and the transition state, compared to the reagents.…”

The Role of Water in the Catalyst‐Free Aldol Reaction of Water‐Insoluble N‐Methyl‐2,4‐thiazolidinedione with N‐Methylisatin from QM/MM Monte Carlo Simulations

“…The aldol reactions were probed by using QM/MM/MC calculations, as implemented in BOSS 4.9 treated with the PDDG/PM3 semiempirical QM method, which was extensively tested for gas‐phase structures and energies, with excellent results in the solution‐phase QM/MM studies of Diels–Alder reactions, S N Ar reactions, decarboxylations, and cycloaddition reactions . Computations of the QM energy and atomic charges were performed for each attempted move of the solute, which occurred every 100 configurations.…”