1 H NMR and Molecular Dynamics Evidence for an Unexpected Interaction on the Origin of Salting-In/Salting-Out Phenomena Mara G. Freire, † Catarina M. S. S. Neves, ‡ Artur M. S. Silva, § Luı ´s M. N. B. F. Santos, | Isabel M. Marrucho, †,‡ Luı ´s P. N. Rebelo, † Jindal K. Shah, ⊥ Edward J. Maginn, ⊥ and Joa ˜o A. P. Coutinho* ,‡ Instituto de Tecnologia Quı ´mica e Biolo ´gica, ITQB2, UniVersidade NoVa de Lisboa, AV. Repu ´blica, Apartado 127, 2780-901 Oeiras, Portugal, CICECO, Departamento de Quı ´mica, UniVersidade de AVeiro, 3810-193 AVeiro, Portugal, QOPNA, Departamento de Quı ´mica, UniVersidade de AVeiro, 3810-193 AVeiro, Portugal, CIQ, Departamento de Quı ´mica, Faculdade de Cie ˆncias da UniVersidade do Porto, R. Campo Alegre 687, 4169-007 Porto, Portugal, and Department of Chemical and Biomolecular Engineering, UniVersity of Notre Dame, Notre Dame, Indiana 46556 ReceiVed: October 6, 2009; ReVised Manuscript ReceiVed: December 2, 2009 By employing 1 H NMR spectroscopy and molecular simulations, we provide an explanation for recent observations that the aqueous solubilities of ionic liquids exhibit salting-out to salting-in regimes upon addition of distinct inorganic salt ions. Using a typical ionic liquid [1-butyl-3-methylimidazolium bis(trifluorometh- ylsulfonyl)imide], we observed the existence of preferential specific interactions between the low electrical charge density (“apolar moiety”) parts of the ionic liquid cation and the inorganic salts. These a priori unexpected interactions become increasingly favorable as one moves from salting-out to salting-in effects. More specifically, this interpretation is validated by distinct aqueous solution 1 H NMR data shifts in the ionic liquid cation upon inorganic salt addition. These shifts, which are well noted in the terminal and preterminal hydrogens of the alkyl chain appended to the imidazolium ring, correlate quantitatively with solubility data, both for cases where the nature of inorganic salt is changed, at constant concentration, and for those where the concentration of a given inorganic salt is varied. Molecular simulations have also been performed permitting us to garner a broader picture of the underlying mechanism and structure of this complex solvation phenomenon. These findings can now be profitably used to anticipate solution behavior upon inorganic salt addition well beyond the specificity of the ionic liquid solutions, i.e., for a diversity of distinct solutes differing in chemical nature. Introduction The effect of common salts on the aqueous solubility of charged molecules such as proteins has been well described for many years. 1 The qualitative order of the ions’ salting-in or salting-out inducing ability on macromolecules is known as the Hofmeister series. 1 While this effect is phenomenologically well- established, there is a renewed interest in this subject concerning the molecular level mechanisms by which ions operate and which are still elusive and not well understood. Common knowledge usually classifies the salting-out inducing ions as “kosmotropes” while the salting-in inducing ions are typically referred to as “chaotropes”, based on their supposed ability to “create” or “destroy” the water bulk structure, as this was believed to be the central mechanism behind the Hofmeister series. 1-4 Recent experimental data and simulation results have cast doubts on this paradigm of the change in the bulk water structure as the main phenomenon behind the effect of salts on the molecules’ aqueous solubility. 4-10 Both experimental studies 4-7 and molecular simulation calculations 8-10 are converging upon the idea that ions of high charge densityswith water-ion interactions stronger than water-water interactionssare ex- cluded from the vicinity of the solute due to their preferential hydration, decreasing the solute’s solubility in water. On the other hand, low charge density ionsswith water-ion interac- tions weaker than water-water interactionssdirectly interact with the solute thus stabilizing it in water, and therefore increasing the solute’s solubility. 11,12 Recently, Zhang et al. 13 proposed a model to describe the specific ion effects on the lower critical solution temperature (LCST) of the water + PNIPAM [poly(N-isopropylacrylamide)] + inorganic salt systems. In previous works we have success- fully extended this model to the description of the solubility of ionic liquids (ILs) in aqueous salt solutions. 11,12 Essentially, the model is based on three effects to describe the interactions between the salt ions and solutes on aqueous solutions, two of which seem to be predominant and are thus highlighted: (i) an entropic effect associated with the salting-out that results from the ability of high charge density ions to form hydration complexes away from the solute; and (ii) a direct interaction of the low charge density ions with the solute (in the case of PNIPAM, a direct interaction of the anion with the amide group was suggested 13 ) that would be responsible for the salting-in. The entropic effects leading to salting-out are well supported by the experimental results reported previously. 11-13 Evidence for the direct interaction between the ions and the solute at the basis of the salting-in phenomenon remains elusive, 11,12 and alternative/supplementary approaches, capable of providing * Corresponding author. Telephone: +351-234-370200. Fax: +351-234- 370084. E-mail: jcoutinho@ua.pt. † Universidade Nova de Lisboa. ‡ CICECO, Departamento de Quı ´mica, Universidade de Aveiro. § QOPNA, Departamento de Quı ´mica, Universidade de Aveiro. | Universidade do Porto. ⊥ University of Notre Dame. J. Phys. Chem. B 2010, 114, 2004–2014 2004 10.1021/jp9095634  2010 American Chemical Society Published on Web 01/20/2010