Preparation of Morphine Derivatives Using Ionic Liquids

1,4-Dihydropyridines (1,4-DHPs) are well known as Ca channel blockers, and have emerged as one of the most important classes of drugs for the treatment of cardiovascular diseases. Dihydropyridines have been classically synthesized using the Hantzsch synthesis described in 1882, which is one-pot condensation of aldehydes with ethyl acetoacetate, and ammonia in acetic acid or in refluxing alcohol. However, this method involves long reaction time, harsh reaction conditions, the use of a large quantity of volatile organic solvents and generally gives low yields. Therefore, it is necessary to develop an efficient and versatile method for the preparation of 1,4DHPs and there were several efficient methods developed for the synthesis of 1,4-dihydropyridines, comprising the use of microwave, ionic liquid, solvent-free, TMSClNaI, solar energy, and so on. Green chemistry is a major issue of modern chemistry currently. The use of environmentally benign solvent instead of traditional organic solvents is the important and efficient strategy in green chemistry. Water is a promising green solvent for use in chemistry because it is cheap, readily available, and nontoxic. There is increasing recognition that organic reactions carried out in water may offer advantages over those in organic solvents. However, the poor solubility of reactants in water is the main obstacle to the use of water as reaction solvent. In previous studies, many additives, such as ionic liquid (ILs), poly(ethylene glycol) (PEG), and sodium dodecyl sulfate(SDS) have been successfully applied in cross-coupling reaction of arylboronic acid with carboxylic derivative as useful promoters. As a part of our program aiming at developing selective and environmental friendly methodologies for the preparation of fine chemicals and in continuation of our interest in PEG or ionic liquid promoted organic reactions, in this paper, we report on the evaluation of Hantzsch’s dihydropyridine synthesis in the H2O-PEG system. The method is straightforward and the 1,4-dihydropyridines can be synthesized under mild reaction conditions in high yields in short reaction times.

Ionic liquids (ILs) are low-melting organic salts that are being researched intensively as possible environmentally friendly replacements for volatile organic solvents. Despite their nonmeasurable vapor pressure, some quantities of ILs soon will be present in effluent discharges because solubility of ILs in water is small, but far from negligible. Therefore, it is important to understand how ILs will influence aquatic ecosystems. In the present study, the toxic effects of imidazolium-based ILs (1-butyl-3-methylimidazolium cation associated with bromide [BMIM] [Br] and tetrafluoroborate [BMIM] [BF4]) to the freshwater green alga Selenastrum capricornutum were investigated. Two approaches were followed to quantify toxicity of these compounds: Analyses of photosynthetic activity and cell proliferation. The obtained data showed that the relative declines of growth rates generally were more pronounced than those of photosynthetic activity. The ecotoxicity of a range of common organic solvents also was examined. It was revealed that both imidazolium-based ILs studied were some orders of magnitude more toxic than methanol, isopropanol, and dimethylformamide. In addition, with respect to IL incorporating perfluorinated anion, EC50 values (concentrations which lead to a 50% reduction of the exposed organisms relative to control) of the previously prepared stock solution were significantly lower compared to those of the freshly made one. This might be due to hydrolytic effects of [BMIM][BF4] leading to fluoride formation, which was confirmed by ion chromatography analysis. This indicates that, after ILs are discharged into the aqueous system, they can become more toxic than expected by laboratory data with fresh ILs.

Ionic systems in materials research : new materials and processes based on ionic polymerizations and/or ionic liquids

Comparative study on effect of ionic liquids on static stability of green emulsion liquid membrane

Use of solvents and environmental friendly materials for applications in Green Chemistry

Ionic liquids (ILs) are low-melting organic salts that are being researched intensively as possible environmentally friendly replacements for volatile organic solvents. Despite their nonmeasurable vapor pressure, some quantities of ILs soon will be present in effluent discharges because solubility of ILs in water is small, but far from negligible. Therefore, it is important to understand how ILs will influence aquatic ecosystems. In the present study, the toxic effects of imidazolium-based ILs (1-butyl-3-methylim-idazolium cation associated with bromide [BMIM][Br] and tetrafluoroborate [BMIM][BF4]) to the freshwater green alga Selenastrum capricornutum were investigated. Two approaches were followed to quantify toxicity of these compounds: Analyses of photosynthetic activity and cell proliferation. The obtained data showed that the relative declines of growth rates generally were more pronounced than those of photosynthetic activity. The ecotoxicity of a range of common organic solvents also was examined. It was revealed that both imidazolium-based ILs studied were some orders of magnitude more toxic than methanol, isopropanol, and dimethylformamide. In addition, with respect to IL incorporating perfluorinated anion, EC50 values (concentrations which lead to a 50% reduction of the exposed organisms relative to control) of the previously prepared stock solution were significantly lower compared to those of the freshly made one. This might be due to hydrolytic effects of [BMIM][BF4] leading to fluoride formation, which was confirmed by ion chromatography analysis. This indicates that, after ILs are discharged into the aqueous system, they can become more toxic than expected by laboratory data with fresh ILs.

Ionic liquids (ILs) represent a fascinating and potentially very valuable group of new solvents, which have the benefit of zero vapor pressure and therefore easier handling than many conventional solvents. They are attracting a lot of attention as volatile organic compound-free solvents, eco-friendly and green media. Room-temperature ionic liquids (RTILs) and particularly those based on substituted imidazolium cations, which can be synthesized easily from the commercially available starting material N-trimethylsilylimidazole and alkyl halides, are currently being extensively studied for a variety of applications. In this study a facile and efficient synthesis of heterocyclic polyamides by polycondensation of 4-(4-dimethylaminophenyl)-1,2,4-triazolidine-3,5-dione with various commercially available aliphatic diacid chlorides in the presence of RTILs and molten tetrabutylammonium bromide as an IL was performed. The effect of various reaction parameters, including the nature of the ILs, the amount of IL, the reaction temperature, and the reaction time were investigated to optimize the conditions for the preparation of heterocyclic polyamides. The polymerization proceeded well in ILs without any catalyst and polyamides were obtained with high yields and moderate inherent viscosities. A comparative study between the effects exerted by different ILs and the conventional polymerization method is also reported.

Cytocompatible drug delivery devices based on poly[(2-dimethylamino) ethyl methacrylate]/chondroitin sulfate polyelectrolyte complexes prepared in ionic liquids

Chapter 18 - Ionic liquids and their beneficial contributions to enzyme-catalyzed reactions, catalytic biomass conversion and energy conversion and storage systems

Efficient extraction of lipids from primary sewage sludge using ionic liquids for biodiesel production

Covalent organic frameworks (COFs) are highly porous crystalline polymers with uniform pores and large surface areas. Combined with their modular design principle and excellent properties, COFs are an ideal candidate for separation membranes. Liquid-liquid interfacial polymerization is a well-known approach to synthesize membranes by reacting two monomers at the interface. However, volatile organic solvents are usually used, which may disturb the liquid-liquid interface and affect the COF membrane crystallinity due to solvent evaporation. Simultaneously, the domain size of the organic solvent-water interface, named the reaction zone, can hardly be regulated, and the diffusion control of monomers for favorable crystallinity is only achieved in the water phase. These drawbacks may limit the widespread applications of liquid-liquid interfacial polymerization to synthesize diverse COF membranes with different functionalities. Here, we report a facile strategy to synthesize a series of imine-linked freestanding COF membranes with different thicknesses and morphologies at tunable ionic liquid (IL)-H2O interfaces. Due to the H-bonding of the catalysts with amine monomers and the high viscosity of the ILs, the diffusion of the monomers was simultaneously controlled in water and in ILs. This resulted in the exceptionally high crystallinity of freestanding COF membranes with a Brunauer-Emmett-Teller (BET) surface area up to 4.3 times of that synthesized at a dichloromethane-H2O interface. By varying the alkyl chain length of cations in the ILs, the interfacial region size and interfacial tension could be regulated to further improve the crystallinity of the COF membranes. As a result, the as-fabricated COF membranes exhibited ultrahigh permeance toward water and organic solvents and excellent selective rejection of dyes.

During the last decade there has been an explosion of interest in ionic liquids. If the keywords “ionic liquid” or “ionic liquids” are used for a literature research in the Web of Science, more than seven thousand entries can be found for 2011. That is a tenfold increase in the number of publications dealing with ionic liquids over the past decade, and the field shows no signs of slowing down. Ionic liquids have changed from a lab curiosity to materials of tremendous academic and industrial interest. This new and remarkable liquid substance with unique and fascinating properties offers a phenomenal opportunity for new science and technology. The interest in these new materials is due to their wide range of possible applications as solvents for reaction and material processing, as extraction media or as working fluids in mechanical applications. Originating in the field of electrochemistry and based upon their wide electrochemical windows and good conductivities, ionic liquids have found useful applications in sensors, solar cells, solid-state photocells, batteries, separation devices and as thermal fluids, lubricants, hydraulic fluids, ionogels and fuels. The generally accepted definition of an ionic liquid is a salt composed solely of ions with melting points below 100 °C. New combinations of ions provide changing physical properties and thus novel potential applications for this class of liquid material. To a large extent, the structure and properties of ionic liquids are determined by the intermolecular interaction between anions and cations. In particular, the subtle balance between Coulomb forces, hydrogen bonds, π stacking and repulsion–dispersion forces is of great importance for understanding the properties of ionic liquids. All the important properties such as structure, diffusion, viscosity, conductivity or melting points depend on these interactions between cations and anions in ionic liquids. Thus, an important goal is to develop a fundamental understanding of their chemical and physical properties at the molecular level. Reliable structure–property relationships can help us to synthesize ionic liquid compositions with the desired set of properties. Since 2005 a number of research programs have been set up worldwide to advance ionic liquids research. Among those, the Japanese Priority Area “Science of Ionic Liquids” running from 2005 to 2009 and the priority programme SPP 1191 “Ionic Liquids” implemented by the German Science foundation (DFG) in 2006 and finished at the end of this year may be the most prominent ones in the academic arena. The efforts and developments achieved in ionic liquids research from these and other programmes are presented in this special issue. On the occasion of the International Bunsen Meeting 2012 in Leipzig, we put together a collection of almost forty articles that show the growing diversity within the field. In this special issue of ChemPhysChem, developments in experiment, theory and simulations for investigating ionic liquids are presented. The articles highlight the interaction within ionic liquids between anions and cations studied by a variety of experimental and theoretical methods including spectroscopy, ab initio simulations, classical molecular dynamics simulations and quantum molecular dynamics simulations. A particular focus is put on hydrogen bonding and dispersion forces, which are often assumed to be unimportant in Coulomb systems but are absolutely crucial to understanding ionic liquids. The critical review of theoretical and simulation approaches for describing the properties of ionic liquids is an important issue in this respect. Another topic is the interaction of ILs with water and organic solvents leading to modified local structures and polarities (Figure 1). In general, IL mixtures with water, alcohols and amines allow interesting tuning of important IL physical properties, including structural and transport properties such as diffusion coefficients, viscosities and conductivities. Walden plots, which compare the molar conductivity as a function of fluidity (inverse viscosity), show deviations from ideal, linear behaviour derived from well-understood aqueous solutions. Ionic liquids in its pure state (left) and in a mixture with an organic solvent (blue). Why not consider mixing ILs themselves to change properties? Thus another focus is put on mixtures of ILs including different anion–cation combinations. By varying the cation or the anion only, structure and interaction strength can be modified in the desired way. Several examples are given for structure–property relations in ionic liquids, which may allow predictions for physical properties for a set of specially synthesized ILs. Chemical reactions and coordination in ionic liquids are also attracting increasing interest. In several articles the effects on physical properties of other materials such as gels and micelles in IL environments are reported. ILs have also become increasing important in biology. The behaviour of biomolecules, such as the folding and unfolding of proteins, are developing into an important facet in ionic liquids research. Of course, after having an idea about the origin of the physical properties, new ionic liquids need to be synthesized and characterized. New and special ionic liquids and their properties are introduced in some of the contributions. An important aspect in and of itself is the liquid/gas or the liquid/liquid interface of ionic liquids (Figure 2). How do these interfaces look like with respect to the polar and hydrophobic parts of anions and cations? How do the IL properties change at the interfaces? Combinations of experimental and theoretical methods try to provide answers to these questions. Ion-pair evaporating from the surface of an imidazolium-based ionic liquid. All these fundamental issues are addressed in this special issue of ChemPhysChem. We hope that this compilation improves our understanding of the fascinating physical chemistry of ionic liquids. An understanding at the molecular level opens new potential for fundamentals and applications. Ralf Ludwig 1 Ed Maginn 1 Bala Sundaram 1

This chapter reviews the roles of ionic liquids (ILs) in pharmaceutical manufacturing processes, including the use of ILs as solvents in the synthesis of drugs or isolation of drug intermediates, the use of ILs in pharmaceutical crystallization, in pharmaceutical separation, for the extraction of drugs from natural products, to deliver drugs, to detect drugs, and even as active pharmaceutical ingredients (APIs). ILs have also been considered as alternatives to organic solvents in the pharmaceutical industry. A large volume of volatile organic solvents (VOCs) is used in the process of drug extraction from natural products, resulting in serious environmental problems and replacement of conventional solvents by ILs might prevent the emission of VOCs. While ILs have been shown to be efficient vehicles in transdermal drug delivery, until recently they were not studied as transdermal drugs themselves because ionized salts normally diffuse poorly through lipid membranes.

The exploitation of ionic liquids (IL)s for the preparation and use of non-vinyl macromolecules brings together two of the most stimulating and promising areas of research from recent years. In this study, IL, 1,3-dipropylimidazolium bromide, was examined as a replacement for volatile toxic organic solvents for the direct polycondensation of chiral dicarboxylic acid monomer, 5-[3-phenyl-2-(9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)propanoylamino]isophthalic acid (1) with diverse aromatic diamines (2a–2g). The optically active polyamides (PA)s were obtained in 80–98% yield and the inherent viscosities in the range of 0.39–0.69 dLg−1. The higher inherent viscosities and thermal stability were found in this IL compared to analogous compounds in organic solvents under milder reaction conditions. The yields of the PAs were comparable. All the polymers were amorphous and exhibited excellent solubility in many organic solvents. The procedure was found to be an efficient and green technique for the synthesis of the aforementioned PAs. The PAs were characterized by FTIR, specific rotation, 1H NMR, elemental analysis, thermogravimetric analysis (TGA), differential scanning calorimetry and X-ray diffraction. Open image in new window

Ionic liquids, also called molten salts, are mixtures of cations and anions that melt below 100 °C. Typical ionic liquids are dialkylimidazolium cations with weakly coordinating anions such as [MeOSO3] or [PF6]. Advanced ionic liquids such as choline citrate have biodegradable, less expensive and less toxic anions and cations. Deep eutectic solvents are also included in the advanced ionic liquids. Deep eutectic solvents are mixtures of salts such as choline chloride and uncharged hydrogen bond donors such as urea, oxalic acid, or glycerol. For example, a mixture of choline chloride and urea in 1:2 molar ratio liquifies to form a deep eutectic solvent. Their properties are similar to those of ionic liquids. Water-miscible ionic liquids as cosolvents with water enhance the solubility of substrates or products. Although traditional water-miscible organic solvents also enhance solubility, they often inactivate enzymes, while ionic liquids do not. The enhanced solubility of substrates can increase the rate of reaction and often increases the regio- or enantioselectivity. Ionic liquids can also be solvents for non-aqueous reactions. In these cases, they are especially suited to dissolve polar substrates. Polar organic solvent alternatives inactivate enzymes, but ionic liquids do not even when they have similar polarities. Besides their solubility properties, ionic liquids and deep eutectic solvents may be greener than organic solvents because ionic liquids are non-volatile and can be made from non-toxic components. This review covers selected examples of enzyme catalyzed reaction ionic liquids that demonstrate their advantages and unique properties and point out opportunities for new applications. Most examples involve hydrolases, but oxidoreductases and even whole cell reactions have been reported in ionic liquids.