Ionic liquids have been proposed to induce a mechanistic change in the reaction pathway for the fundamentally important base-induced β-elimination class compared to conventional solvents. The role of the reaction medium in the elimination of 1,1,1-tribromo-2,2-bis(3,4-dimethoxyphenyl)ethane via two bases, piperidine and pyrrolidine, has been computationally investigated using methanol and the ionic liquids 1-butyl-3-methylimidazolium tetrafluoroborate and hexafluorophosphate [BMIM][BF(4)] and [BMIM][PF(6)], respectively. QM/MM Monte Carlo simulations utilizing free-energy perturbation theory found the ionic liquids did produce a reaction pathway change from an E1cB-like mechanism in methanol to a pure E2 route that is consistent with experimental observations. The origin of the ionic liquid effect has been found as: (1) a combination of favorable electrostatic interactions, for example, bromine-imidazolium ion, and (2) π-π interactions that enhance the coplanarity between aromatic rings maximizing the electronic effects exerted on the reaction route. Solute-solvent interaction energies have been analyzed and show that liquid clathrate solvation of the transition state is primarily responsible for the observed mechanistic changes. This work provides the first theoretical evidence of an ionic liquid dependent mechanism and elucidates the interplay between sterics and electrostatics crucial to understanding the effect of these unique solvents upon chemical reactions.

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.

The mononuclear rearrangement of heterocycles (MRH) reaction of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into 4-benzoylamino-2,5-diphenyl-1,2,3-triazole derives a sizable rate enhancement in the 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF] ionic liquid as compared to the hexafluorophosphate-based [BMIM][PF] and conventional organic solvents. However, the origin of the rate difference between [BMIM][BF] and [BMIM][PF] has proven difficult to rationalize as no experimental trend relates the physical properties of the solvents, e.g., polarity and viscosity, to the rates of reaction. QM/MM calculations in combination with free-energy perturbation theory and Monte Carlo sampling have been carried out for the MRH reaction to elucidate the disparities in rates when using ionic liquids, methanol, and acetonitrile. Activation barriers and solute-solvent interactions have been computed for both an uncatalyzed and a specific base-catalyzed mechanism. Energetic and structural analyses determined that favorable π-π interactions between the BMIM cation, the substrate phenyl rings, and the bicyclic quasi-aromatic 10π oxadiazole/triazole transition state region imposed a pre-ordered geometric arrangement that enhanced the rate of reaction. An ionic liquid clathrate formation enforced a coplanar orientation of the phenyl rings that maximized the electronic effects exerted on the reaction route. In addition, site-specific electrostatic stabilization between the ions and the MRH substrate was more prevalent in [BMIM][BF] as compared to [BMIM][PF].

Any adequate explanation or understanding of chemical equilibria must involve a detailed examination of the relevant thermodynamic functions, and in particular of the change in entropy concerned; such an examination is especially important when considering small differences between equilibria involving related substances.

Data for many non-aqueous solvents appear to demonstrate a correlation similar to that between enthalpies of hydration and ionisation energies.IT is known 1-3 (cf. also Irving and IVilliams *) that for '' closed shell " cations a graph of -AHl/.", where AH, is the standard AH for the process (l), against f, the W + ' ( g ) + xK+(aq) MZ+(aq) + zH+(g) (1) average of the first x ionisation energies of M, is linear and of slope unity; points for other cations lie systematically below this line.An almost equivalent relation, considered by Ros-seinsky5 to be more fundamental, is that for "closed shell " cations AH,/z, where AH, is the standard AH for the process (2), is approximately constant (ca. -85 kcal. mole-l) ; with other cations giving scattered values. This near-constancy applies to " closed shell " cations irrespective of whether they be singly, doubly, or triply charged. It should be noted that 2 1 is very nearly equal to AH for the process (3), and therefore relation (4) holds. Equation (4) shows that each of the two empirical relations implies the other.Data for non-aqueous solvents show signs that such relations are of very wide applicability.(i) Enthalpies of solution of alkali halides in form-amide6 (and to some extent those in X-methylform-amide7) (except for lithium) conform7 with van Eck's relation.(ii) Such values as are avaiable8 for AH, for liquid ammonia give graphs (Figures 1 and 2) similar to those for water as solvent.(iii) From the data on many non-aqueous solvents discussed by Izmailov? it is possible to deduce the standard AG's for processes (1) and (2), as follows. Both can be obtained from the standard AG for the reaction (5), M(s) + zH+(solv) _ . t M*+(solv) + ;H&) (5) and this standard AG (a) is equal to the product of +zF and the standard electrode potential of metal M for the solvent in question, and (b) is deducible from