Luís C. Branco

Preparation and Characterization of New Room Temperature Ionic Liquids

A new series [C(n)O(m )mim][X] of imidazolium cation-based room temperature ionic liquids (RTILs), with ether and alcohol functional groups on the alkyl side-chain has been prepared. Some physical properties of these RTILs were measured, namely solubility in common solvents, viscosity and density. The solubility of LiCl, HgCl(2) and LaCl(3) in room temperature ionic liquids was also determined. The features of the solid-liquid phase transition were analysed, namely the glass transition temperature and the heat capacity jump associated with the transition from the non-equilibrium glass to the metastable supercooled liquid. These properties were compared with those reported for the 1-n-alkyl-3-methylimidazolium [C(n )mim][X] series. While the density and solid-liquid phase transition properties are similar for both series, the new RTILs present a considerably lower viscosity and an increased ability to dissolve HgCl(2) and LaCl(3) (up to 16 times higher).

Highly Selective Transport of Organic Compounds by Using Supported Liquid Membranes Based on Ionic Liquids

The selective separation of organic compounds is a critical issue in the chemical industry. In case of readily crystallized molecules, selective crystallization is the most practical method for selective separation, whereas for solutes that are liquid at room temperature, separation by fractional distillation, solvent extraction, or chromatographic methods are more convenient. Some of the above-mentioned methods are technically demanding, involve considerable energy costs, and/or result in large amounts of waste solvents. Membranes, defined as permeable and selective barriers between two phases, have been successfully applied in a large diversity of separation processes, including bioseparations, in which classical separation methods are less convenient, undesirable or even not applicable. The reason for the successful use of membrane-based separation processes stems from the fact that these processes have a high energy efficiency, can be used under moderate temperature and pressure conditions, do not require any additional separating agents or adjuvants, and therefore they are regarded as environmentally friendly.[1] Solute extraction and recovery by using supported liquid membranes is recognized as one of the most promising membrane-based processes. In a supported liquid-membrane system, a defined solvent or solvent/carrier solution is immobilized inside the porous structure of a polymeric or ceramic membrane, which separates the feed phase (in which the solutes of interest are solubilized) from the receiving phase (in which these solutes will be transferred and, eventually, concentrated). This configuration has attracted a great deal of interest because the amount of solvent/carrier needed is minimal, the solvent/carrier is continuously regenerated as a result of solute transport to the receiving phase, and loss of the solvent/carrier phase is negligible if an appropriate supported liquid membrane is designed.[2] The use of a room-temperature ionic liquid (RTIL) as an immobilized phase in the supporting membrane between two organic phases in the feed and the receiving compartments is particularly interesting owing to the nonvolatile character of RTILs and their solubility in the surrounding phases, which allows very stable supported liquid membranes to be obtained without any observable loss of the RTIL to the atmosphere or the contacting phases. Herein we show the potential for continuous separation of organic compounds based on the selective transport through supported liquid membranes that contain RTILs. RTILs that involve a 1,3-dialkylimidazolium cation are attracting increasing interest as new media, mainly because of the advantage of being nonvolatile. Depending on the anion and on the alkyl group of the imidazolium cation, the RTIL can solubilize supercritical CO2 (scCO2), a large range of polar and nonpolar organic compounds, and also transitionmetal complexes. Simultaneously, they have low miscibility with water, alkanes, and dialkyl ethers[3] and are insoluble in scCO2. As a result of these properties, they are emerging as an alternative recyclable, environmentally benign, reaction medium for chemical transformations, including transitionmetal catalysis[3] and biocatalysis.[3f, 5] Their use has also been successfully extended as a potential stationary phase for gas chromatography,[6] in pervaporation,[7] and for the substitution of traditional organic solvents (OS) in aqueous ±OS[7a, 8] and OS± scCO2 biphasic extractions.[4, 9] It is assumed that the 1,3dialkylimidazolium RTIL are not a statistical aggregate of anions and cations, but instead a more organized structure that contains polar and nonpolar regions as a result of the formation of weak interactions, mainly as hydrogen bonds, with 2-H of the imidazolium ring.[10] The above information prompted us to study the potential of using RTIL in supported liquid membranes for selective separation processes. To illustrate the concept, and as a result of transport studies with representative organic functional compounds, we used a mixture of the organic isomeric amines hexylamine, diisopropylamine, and triethylamine (1:1:1 molar ratio) in diethyl ether in side A of the cell (Figure 1). The two sides of the cell were separated by the RTIL 1-n-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) immobilized in the por[5] [Pt2(nBuCS2)4] and [Pt2(nBuCS2)4I2] were prepared by the similar procedures with literature methods using toluene and n-hexane.[4] [6] P. M. Chaikin, R. L. Greene, S. Etemad, E. Engler, Phys. Rev. B 1976, 13, 1627 ± 1632. [7] S. A. Borshch, K. Prassides, V. Robert, A. O. Solonenko, J. Chem. Phys. 1998, 109, 4562 ± 4568. [8] H. Tanaka, K. Marumoto, S. Kuroda, M. Mitsumi, K. Toriumi, unpublished results. [9] O. Kahn, Molecular Magnetism, VCH, New York, 1993, pp. 251 ± 286. [10] Field dependence of M of 1 was also measured near the phasetransition temperature under the magnetic field of H 1 ± 5 T. No variation was observed up to 5 T. [11] a) A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr. 1994, 27, 435 (SIR92); b) G. M. Sheldrick, SHELXL-97, University of Gˆttingen, Gˆttingen (Germany), 1997; c) Crystal Structure Analysis Package, Molecular Structure Corporation, 1985, 1999 ; d) A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, J. Appl. Crystallogr. 1999, 32, 115 ± 119 (SIR97). [12] Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307 ± 326.

More Sustainable Approaches for the Synthesis of N-Based Heterocycles† ‡

Centro de Quı́mica-Fı́sica Molecular (CQFM) and Institute of Nanosciences and Nanotechnology (IN), Departamento de Engenharia Quı́mica e Biológica, Instituto Superior Técnico, 1049-001 Lisboa, Portugal, REQUIMTE, Departamento de Quı́mica, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal, and iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal

Studies on the selective transport of organic compounds by using ionic liquids as novel supported liquid membranes

The possibility of using room-temperature ionic liquids (RTILs) in bulk (nonsupported) and supported liquid membranes for the selective transport of organic molecules is demonstrated. A systematic selective transport study, in which 1,4-dioxane, propan-1-ol, butan-1-ol, cyclohexanol, cyclohexanone, morpholine, and methylmorpholine serve as a model seven-component mixture of representative organic compounds, and in which four RTILs based on the 1-n-alkyl-3-methylimidazolium cation (n-butyl, n-octyl, and n-decyl) are used together with the anions PF(6)(-) or BF(4)(-), immobilized in five different supporting membranes, confirms that the combination of the selected RTILs with the supporting membranes is crucial to achieve good selectivity for a specific solute. The use of the RTIL 1-n-butyl-3-methylimidazolium hexafluorophosphate, immobilized in a polyvinylidene fluoride membrane, allows an extremely highly selective transport of secondary amines over tertiary amines (up to a 55:1 ratio). The selective transport of a given solute through the RTIL/membrane system results from the high partitioning of the solute to the liquid membrane phase which, in the case of amines, is rationalized mainly by the formation of a preferential substrate/H[bond]C(2) hydrogen bonding to the imidazolium cation.

Ionic Liquids as Active Pharmaceutical Ingredients

Ionic liquids (ILs) are ionic compounds that possess a melting temperature below 100 °C. Their physical and chemical properties are attractive for various applications. Several organic materials that are now classified as ionic liquids were described as far back as the mid‐19th century. The search for new and different ILs has led to the progressive development and application of three generations of ILs: 1) The focus of the first generation was mainly on their unique intrinsic physical and chemical properties, such as density, viscosity, conductivity, solubility, and high thermal and chemical stability. 2) The second generation of ILs offered the potential to tune some of these physical and chemical properties, allowing the formation of “task‐specific ionic liquids” which can have application as lubricants, energetic materials (in the case of selective separation and extraction processes), and as more environmentally friendly (greener) reaction solvents, among others. 3) The third and most recent generation of ILs involve active pharmaceutical ingredients (API), which are being used to produce ILs with biological activity. Herein we summarize recent developments in the area of third‐generation ionic liquids that are being used as APIs, with a particular focus on efforts to overcome current hurdles encountered by APIs. We also offer some innovative solutions in new medical treatment and delivery options.

Synthesis and properties of tetra-alkyl-dimethylguanidinium salts as a potential new generation of ionic liquids

New room temperature ionic liquids based on the tetra-alkyl-dimethylguanidinium cation present high stability under thermal, basic, acid, nucleophilic and oxidative conditions, low temperature glass transition phases and peculiar solubility properties in common solvents.

Ionic Liquids in Pharmaceutical Applications

In the past several years, ionic liquids (ILs) have been at the cutting edge of the most promising science and technology. ILs not only have found applications in classical areas of knowledge but also are important candidates to solve classical problems within several societal challenges, such as clean and efficient energy, through the development of a broad swath of energy technologies, such as advanced batteries, dye-sensitized solar cells, double-layer capacitors, actuators, fuel cells, thermo-cells, and water splitting, essentially related to highly efficient carbon capture and storage technologies and resource efficiency to date. This review focuses on the application of IL methodologies to solve critical pharmaceutical problems, in particular, the low solubility and thus bioavailability of pharmaceutical compounds and the presence of polymorphs, which severely hamper the efficacy of important commercially available drugs. The development of strategies to use ILs as carriers of pharmaceutical active compounds is an extremely promising and wide avenue. Further, the synthesis of liquid salts through the discerning combination of cations and anions with several distinct pharmaceutical roles provides answers to some of todays pharmaceutical industrial challenges.

Effect of ionic liquids on human colon carcinoma HT-29 and CaCo-2 cell lines

The toxicity of ionic liquids, involving different classes of cations and different types of anions, was evaluated by a colorimetric assay with 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) in two colon carcinoma HT-29 and CaCo-2 cell lines. Confluent CaCo-2 cells can undergo spontaneously an enterocytic differentiation and represent a good in vitro model of normal human intestinal epithelium. Ionic liquids are highly promising due to their low vapour pressures, however, toxicity evaluation of these ionic liquids is of great importance to assess the risk of these ionic liquids to humans and the environment.

Toxicological evaluation on human colon carcinoma cell line (CaCo-2) of ionic liquids based on imidazolium, guanidinium, ammonium, phosphonium, pyridinium and pyrrolidinium cations

Toxicological evaluation of a new group of ionic liquids was performed on human colon cancerous cells—CaCo-2. They belong to different classes of cations: imidazolium (IM), dimethyl-guanidinium (dmg) and tetramethyl-guanidinium (tmg), methyl-pyrrolidinium (MPyr), 2-methyl-1-ethyl-pyridinium (2-MEPy), quaternary ammonium (benzyltriethyl-ammonium–BzTEA; phenyltrimethyl-ammonium–PhTMA; tri-n-octyl-methylammonium-Aliquat) and tri-n-hexyl-tetra-n-decylphosphonium (P6,6,6,14). The new results were compared with data obtained in previous reported studies performed in our lab, and we clearly saw that toxicity can vary significantly with the type of anion. Dicyanoamide-[DCA] and bis(trifluoromethanesulfonyl)amide-[NTf2] were seen to visibly change the impact of some cations. Some were considerably less harmful for CaCo-2 monolayer when the anion was [DCA] or [NTf2], while others induced an abnormal increase of cellular metabolism when [NTf2] was present and therefore, they were considered toxic. However, some cations induced similar responses in the presence of a broad number of anions as (1-butyl-3-methylimidazolium)-[C4MIM] (with the exception of [FeCl4]), (1-(2-hydroxyethyl)-3-methylimidazolium)-[C2OHMIM] and [C4MPyr] and did not cause toxicity. Consequently, they are considered promising cations for building human friendlier solvents. But, a reasonable number of other combinations involving different classes of cations were also seen to not significantly affect viability of the CaCo-2 monolayer.

Studies on dissolution of carbohydrates in ionic liquids and extraction from aqueous phase

An extended study on the solubility of the carbohydrates glucose, fructose, sucrose and lactose in twenty eight different ionic liquids (ILs) was performed. These ILs were based on the combination of tetraalkylammonium, tetraalkylphosphonium, 1-methyl-3-alkylimidazolium and dimethyl-tetraalkylguanidinium cations containing alkyl and ether pendant substituent groups, and anions of chloride, dicyanamide, saccharine, acesulfame, acetate or thiocyanate. It was possible to achieve solubilities, at 35 °C, of each carbohydrate up to 43.9, 49.0, 17.1 and 16.6% (g of carbohydrate per 100 g of IL), respectively. The possibility to extract carbohydrates from an aqueous phase by hydrophobic ILs was also demonstrated. Besides, some selectivity for a mixture of two carbohydrates was also observed.