Room temperature ionic liquid calculations require extensive sampling due to the large degree of localized structuring in the liquid phase relative to conventional solutions. Consequently, a large amount of computer time is required for the convergence of solvent properties, much of which is spent evaluating long-range electrostatics via Ewald summations. The damped Coulomb potential and cutoff-neutralized method of Wolf et al. (J. Chem. Phys.1999, 110, 8254) provides the framework for an accurate, linear-scaling alternative to Ewald in the ionic liquid simulations. The method has been the subject of multiple modifications for improved accuracy, including the damped Coulombic potential of Zahn et al. (J. Phys. Chem. B2002, 106, 10725), the damped shifted force method of Fennell and Gezelter (J. Chem. Phys.2006, 124, 234104), and the shifted force gradient of Kale and Herzfeld (J. Chem. Theory Comput.2011, 7, 3620). These pairwise electrostatic interaction alternatives along with the CHARMM shifted force potential and a new method proposed herein, the shifted force third derivative (SF3), have been examined on 59 unique ionic liquid combinations of 1-alkyl-3-methylimidazolium [RMIM] (R = M (methyl), E (ethyl), B (butyl), H (hexyl), and O (octyl)) and N-alkylpyridinium [RPyr] cations, along with Cl(-), PF6(-), BF4(-), NO3(-), AlCl4(-), Al2Cl7(-), and TfO(-) anions. Monte Carlo simulations utilizing our custom OPLS-AA ionic liquid force field and employing the pairwise alternatives with multiple cutoff distances and electrostatic damping values are compared to the energetics from full Ewald sums.

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.

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Experimental free energies of tautomerization, ΔGT, were used to benchmark the gas-phase predictions of 17 different quantum mechanical methods and eight basis sets for seven keto-enol tautomer pairs dominated by their enolic form. The G4 method and M06/6-31+G(d,p) yielded the most accurate results, with mean absolute errors (MAE's) of 0.95 and 0.71 kcal/mol, respectively. Using these two theory levels, the solution-phase ΔGT values for 23 unique tautomer pairs composed of aliphatic ketones, β-dicarbonyls, and heterocycles were computed in multiple protic and aprotic solvents. The continuum solvation models, namely, polarizable continuum model (PCM), polarizable conductor calculation model (CPCM), and universal solvation model (SMD), gave relatively similar MAE's of ∼1.6-1.7 kcal/mol for G4 and ∼1.9-2.0 kcal/mol with M06/6-31+G(d,p). Partitioning the tautomer pairs into their respective molecular types, that is, aliphatic ketones, β-dicarbonyls, and heterocycles, and separating out the aqueous versus nonaqueous results finds G4/PCM utilizing the UA0 cavity to be the overall most accurate combination. Free energies of activation, ΔG(‡), for the base-catalyzed keto-enol interconversion of 2-nitrocyclohexanone were also computed using six bases and five solvents. The M06/6-31+G(d,p) reproduced the ΔG(‡) with MAE's of 1.5 and 1.8 kcal/mol using CPCM and SMD, respectively, for all combinations of base and solvent. That specific enolization was previously proposed to proceed via a concerted mechanism in less polar solvents but shift to a stepwise mechanism in more polar solvents. However, the current calculations suggest that the stepwise mechanism operates in all solvents.

Computer-aided molecular design and high-throughput screening of viable host architectures can significantly reduce the efforts in the design of novel ligands for efficient extraction of rare earth elements. This paper presents a computational approach to the deliberate design of bis-phosphine oxide host architectures that are structurally organized for complexation of trivalent lanthanides. Molecule building software, HostDesigner, was interfaced with molecular mechanics software, PCModel, providing a tool for generating and screening millions of potential R2(O)P-link-P(O)R2 ligand geometries. The molecular mechanics ranking of ligand structures is consistent with both the solution-phase free energies of complexation obtained with density functional theory and the performance of known bis-phosphine oxide extractants. For the case where the link is -CH2-, evaluation of the ligand geometry provides the first characterization of a steric origin for the "anomalous aryl strengthening" effect. The design approach has identified a number of novel bis-phosphine oxide ligands that are better organized for lanthanide complexation than previously studied examples.