Héctor Rodríguez

The third evolution of ionic liquids: active pharmaceutical ingredients

A modular, ionic liquid (IL)-based strategy allows compartmentalized molecular level design of a wide range of new materials with tunable biological, as well as the well known physical and chemical, properties of ILs, which thus deserve consideration as ‘tunable’ active pharmaceutical ingredients (APIs) with novel performance enhancement and delivery options. IL strategies can take advantage of the dual nature (discrete ions) of ILs to realize enhancements which may include controlled solubility (e.g., both hydrophilic and hydrophobic ILs are possible), bioavailability or bioactivity, stability, elimination of polymorphism, new delivery options (e.g., slow release or the IL-API as ‘solvent’), or even customized pharmaceutical cocktails. Here we exemplify this approach with, among others, lidocaine docusate (LD), a hydrophobic room temperature IL which, when compared to lidocaine hydrochloride, exhibits modified solubility, increased thermal stability, and a significant enhancement in the efficacy of topical analgesia in two different models of mouse antinociception. Studies of the suppression of nerve growth factor mediated neuronal differentiation in rat pheochromocytoma (PC12) cells suggests potential differences between LD and lidocaine hydrochloride at the cellular level indicating an entirely different mechanism of action. Taken together these results suggest that the unique physiochemical properties of ILs in general, may confer a novel effect for the bioactivity of an API due to (at least) slow-release properties in addition to novel delivery mechanisms.

Demonstration of Chemisorption of Carbon Dioxide in 1,3‐Dialkylimidazolium Acetate Ionic Liquids

Driven by increasing environmental concerns about greenhouse gas emissions (particularly carbon dioxide) and global warming, a growing amount of research has been carried out over the last decade on the use of ionic liquids (ILs), among other options, as a potential alternative to conventional processes based on aqueous amine solutions for CO2 capture. The tethering of an amine functional group to the cation was one of the initial possibilities investigated, while more recently, absorption of CO2 in ILs with amine functionality in the anion has also been reported. Still, even without amine functionalization, ILs do generally dissolve CO2 to a certain extent and CO2 is generally much more soluble than other gases such as N2 or O2. [4] In most cases, solubilization of CO2 in the nonfunctionalized IL occurs through physisorption, although chemisorption has been suggested for ILs with anions of remarkable basicity (e.g., carboxylate-derived anions). The mechanisms proposed have typically involved an interaction between the acidic CO2 and the basic anion; the only exception being a grant report by Maginn in 2005 where, to explain the absorption of CO2 in 1-butyl-3methylimidazolium acetate, he used NMR results to propose the abstraction of the proton at the C(2) position of the imidazolium ring by the basic acetate anion, followed by reaction of CO2 with the carbene species thus formed. [5a] Interestingly, we could not find any further reference to this mechanism in the literature and we assume the idea was not pursued due to concerns about the lack of explanation for the presence of an a priori unstable N-heterocyclic carbene in a relatively stable IL. The weak acidity of the proton at the C(2) position of 1,3dialkylimidazolium rings is one of the major pathways for reactivity of imidazolium species, in particular of imidazolium ILs. Wang et al. made use of this to achieve an equimolar CO2 capture in 1,3-dialkylimidazolium ILs by addition of a superbase, 1,8-diazabicyclo[5.4.0]undec-7-ene, with formation of the corresponding 1,3-dialkylimidazolium-2-carboxylate. We have recently shown that the C(2) proton can be abstracted to some extent in neat 1,3-dialkylimidazolium ILs if they are paired with a basic enough anion such as acetate even in the absence of any external base. For example, the carbene concentration in 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) and 1-butyl-3-methylimidazolium acetate ([C4mim][OAc]) is high enough to enable formation of imidazole-2-chalcogenones by the direct addition of elemental chalcogens to these ILs. However, we also realized that complex anion formation (e.g., acetic acid/ acetate) resulted in stabilization of the volatile acetic acid thus formed, preventing further decomposition reactions and allowing these ILs to act as stable reservoirs of carbenes for direct carbene-based chemistry. Recently reported quantum chemical calculations support this concept. Here, we report direct experimental evidence in the form of single-crystal X-ray structures of solid-state products resulting from the reaction of CO2 with acetate ILs, which confirm both the reaction mechanism and the role of complex anion formation. Since to the best of our knowledge there were no reported crystal structures of 1,3-dialkylimidazolium acetate salts, we first investigated the crystal structure of 1,3diethylimidazolium acetate ([C2C2im][OAc]), an off-white crystalline solid with a melting temperature of 30 8C (Figure 1

Separation of aromatic hydrocarbons from alkanes using the ionic liquid 1-ethyl-3-methylimidazoliumbis{(trifluoromethyl) sulfonyl}amide

The liquid–liquid equilibrium for the ternary system formed by hexane, benzene and the ionic liquid 1-ethyl-3-methylimidazoliumbis{(trifluoromethyl)sulfonyl}amide, [C2mim][NTf2], has been experimentally determined at 25 °C and 40 °C. The results show that the [C2mim][NTf2] can selectively remove benzene from its mixtures with hexane, suggesting that this ionic liquid can be used as an alternative solvent in liquid extraction processes for the removal of aromatic compounds from their mixtures with alkanes.

Apparent molar volume, isentropic compressibility, refractive index, and viscosity of DL-alanine in aqueous NaCl solutions

New experimental data at 25°C for the density, velocity of sound, refractive index, and viscosity of aqueous solutions of DL-alanine and NaCl are reported. The apparent molar volume and isentropic compressibility of DL-alanine in aqueous electrolyte solutions have been calculated from the measured properties. The results show that DL-alanine exhibits a positive volume transfer to solutions of a higher NaCl concentration and a negative apparent isentropic compressibility for DL-alanine in the presence of NaCl. These effects indicate that the apparent volume of DL-alanine is larger in solutions with higher electrolyte concentration and the water molecules surrounding the DL-alanine molecules are less compressible than the water molecules in the bulk solution. The results also show an increase in the viscosity of the solution with an increase in both DL-alanine and NaCl concentrations. These effects are attributed to the two charged groups of DL-alanine and the interactions between the charged groups and the hydrocarbon backbone of DL-alanine with the ions. A model, consisting of a short-range interaction term represented by a virial expansion and a Debye-Hückel term that considers long-range interactions, has been developed to correlate the measured experimental data.

Mutually immiscible ionic liquids

This work presents the novel discovery of room-temperature ionic liquids that are mutually immiscible, some of which are also immiscible with solvents as diverse as water and alkanes; an archetypal biphasic system is trihexyltetradecylphosphonium chloride with 1-alkyl-3-methylimidazolium chloride (where the alkyl group is shorter than hexyl).

Use of a green and cheap ionic liquid to purify gasoline octane boosters

This work demonstrates the ability of the ionic liquid 1-ethyl-3-methylimidazolium ethylsulfate ([emim][EtSO4]) to act as an extraction solvent for liquid–liquid extraction and as an azeotrope breaker for extractive distillation, to separate the azeotropic mixture ethyl tert-butyl ether (ETBE) + ethanol, thus purifying the tertiary ether, which is the most used additive to improve the octane index of gasolines. To assess the suitability of [emim][EtSO4] to perform the mentioned separation, the liquid–liquid equilibrium (LLE) at 298.1 K and the isobaric vapour–liquid equilibrium (VLE) at 101.3 kPa have been determined for the ternary system ETBE + ethanol + [emim][EtSO4]. The separation sequence for the extractive distillation has been obtained from the residue curve map and checked by simulation. The equilibrium data have been adequately correlated by means of the NRTL equation, thus facilitating their computerized treatment.

Ionic liquids for liquid-in-glass thermometers

The varied portfolio of applications of ionic liquids (ILs) is broadened in this work by presenting the possibility of their use as thermometric fluids in liquid-in-glass thermometers. Two ILs, namely tris(2-hydroxyethyl)methylammonium methylsulfate ([TEMA][MeSO4]) and trihexyl(tetradecyl)phosphonium bis{(trifluoromethyl)sulfonyl}amide ([P66614][NTf2]), have been selected for the construction of thermometers with ranges of operation tuned to general and speciality applications. The regular expansion of the IL volume with changes in temperature has been tested, and successful prototypes have been built, consisting of liquid-in-glass devices with an approximately spherical reservoir and a capillary tube attached. These devices have the advantage of operating with a fluid of ionic nature and a practically negligible vapor pressure. In addition, the inherent tunability of IL properties is a powerful tool in the possible design of speciality thermometers.

Direct Preparation of Sulfide Semiconductor Nanoparticles from the Corresponding Bulk Powders in an Ionic Liquid

The physicochemical properties of materials depend on their particle size. Appealing properties can be imparted to different materials at nanometric levels, thus generating a new range of interesting and promising products with different optical, electronic, magnetic, chemical, and mechanical properties from those of the bulk materials. In particular, semiconductor nanoparticles, and more specifically chalcogenide nanoparticles, have been intensively studied because of their quantum confinement effects and size-dependent photoemission characteristics. These semiconductor nanoparticles are widely used for biological labeling and diagnosis, light-emitting diodes, electroluminescent and photovoltaic devices, lasers, single-electron transistors, and catalysis. Over the last decades, a great effort has been made in the development of approaches for the synthesis of nanoparticles with controlled size and shape, as well as on the study of their properties. Among these approaches, liquid-phase methods (which comprise both microemulsion and reaction techniques) are the most relevant because of their simplicity and ability to control the nanoparticles morphology according to the operation conditions. Ionic liquids are salts with low (< 100 8C) melting temperatures. They typically exhibit properties such as extremely low vapor pressures, wide liquid ranges, ability to dissolve a broad variety of compounds, and good thermal and chemical stabilities. Moreover, by judicious selection of the cation– anion combination (“design” of the ionic liquid), it is possible to adjust the properties of the ionic liquid to a considerable extent to match those required for a given application. These characteristics render them as interesting compounds for the development of more sustainable processes in a great variety of applications in different fields. Subsequent to a burgeoning in research on ionic liquids in the late 1990s, they were first used in a method for the preparation of nanoparticles about a decade ago. Since then, it has been proposed that ionic liquids may provide both steric and electrostatic stabilization to nanoparticles, and they have been used in a variety of roles (e.g., (co)solvents, reactants, templates) in a good number of methods for the synthesis of inorganic nanoparticles with novel morphologies and improved properties. Nanomaterials preparation methods involving ionic liquids have been mostly applied to the synthesis of metal nanoparticles, although the preparation of metal oxide nanoparticles is gaining increasing attention. Also, other nanoparticles of interest such as metal chalcogenides, in particular sulfides, have been synthesized using methods based on ionic liquids. For example, CdS and PbS nanoparticles were prepared in the ionic liquid 1-ethyl-3-methylimidazolium ethylsulfate, using ultrasonic irradiation, with thioacetamide and the corresponding metal acetate as precursors. In another example, ZnS nanoparticles were prepared from zinc acetate in the ionic liquid 1-butyl-3methylimidazolium tetrafluoroborate, by a microwaveassisted method. In spite of the introduction of ionic liquids in liquid-phase methods for the preparation of nanoparticles, the utilization of organic solvents and/or solid precursors, which have associated undesired effects from a perspective of sustainability, has remained necessary. Herein, we present a novel method (Figure 1), in which only an ionic liquid and the bulk powder of the material of the target nanoparticle are used,

Properties modification by eutectic formation in mixtures of ionic liquids

The composition and temperature of three eutectic mixtures were determined at atmospheric pressure in systems resulting from the combination of pairs of ionic liquids where each ionic liquid was constituted by only one type of cation and only one type of anion. In addition, the three pairs investigated had a common ion (either the cation or the anion), thus totalising just three different ions in the resulting mixture. All three eutectic mixtures had a temperature near the ambient one, meaning a decrease of up to ca. 50 K with regard to the melting temperature of the parent ionic liquids. A characterisation of physical properties (density, viscosity, and surface tension) of the eutectic mixtures was carried out, and compared as appropriate with those of the parent compounds.

Mixtures of ionic liquids as more efficient media for cellulose dissolution

The ability to dissolve cellulose, by using mixtures of ionic liquids, has been studied and compared with results obtained for the corresponding single ionic liquids. The ionic liquid mixtures tested were a 3:7mol/mol mixture of 1-ethyl-3-methylimidazolium chloride ([C2mim]Cl) and 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]), and the eutectic mixture (i.e., a 5.1:4.9mol/mol ratio) of [C2mim]Cl and 1-butyl-3-methylimidazolium chloride (C4mim]Cl). The amount of dissolved cellulose was investigated at three different temperatures (323, 348, and 373K) for each system. The greatest amount of dissolved cellulose was obtained for the [C2mim]Cl+[C2mim][OAc] mixture, at 373K, and it was 40g per 100g of solvent. Moreover, attempts were made to lower the viscosity of the resulting systems and improve the dissolution capacity by addition of dimethylsulfoxide (DMSO) as co-solvent. Results showed that addition of DMSO at 50mol% allows the dissolution of even greater amounts of cellulose (up to 43g per 100g of solvent). To the best of our knowledge, this is the largest ever reported amount of dissolved cellulose in ionic liquid media. Additionally, physical properties (density, surface tension, and viscosity) of the investigated ionic liquid mixtures were determined and compared with the values of the corresponding parent salts. The dissolved cellulose could be easily reconstituted from its solution in ionic liquid mixtures by addition of water. The regenerated cellulose was characterized by powder X-ray diffraction (pXRD), thermogravimetric analysis (TGA), and optical microscopy. The analyses confirmed the conversion of the crystal structure of cellulose from cellulose I to cellulose II during the dissolution and regeneration process.