Solubility of Bioactive, Inorganic and Polymeric Solids in Ionic Liquids — Experimental and Prediction Perspectives

networks of polyrotaxane swollen with ILs, using an integrative non-drying technique followed by optimized solvent exchange method.


Introduction
Ionic Liquids (ILs) are a well-established class of organic compounds characterized as liquid salts until 100 o C as well as higher thermal and chemical stability, negligible volatility, high conductivities and large electrochemical window. Usually the adequate cation and anion combinations from ILs can modulate their thermal, physical and chemical properties. Many experimental and theoretical studies, highlight a regular pattern of variation of the properties of ILs by the introduction of elements, functional groups or specific ions, however due to the complexity associated to such compounds, in many cases, it is not possible to establish a straightforward relation between the variation of a specific property and the introduction of a particular component. Despite very low vapor pressure of ILs, several publications reported significant toxicity behavior associated to several classes of ILs. In this line, the development of biocompatible ILs and derived systems is actually being subject of intense research by the scientific community in order to open new perspectives for the application of this class of compounds. Since the advent of ILs in extractions and chemical reactions, the range of applications, in many areas of knowledge, never stopped to grow. One of the major reasons for such expansion is due to the inherent complexity of this class of compounds, associated with the virtually infinite possibilities of combination between cations and anions. In this context, the search for an ionic liquid with the desirable physical, chemical and biological properties by trial and error is not feasible without aid of background knowledge and predictive tools. Solubility is an essential property, being present in all stages of ILs research activities. The intrinsic complexity of this class of compounds associated to the many different types of possible interactions allows the dissolution of a wide range of different solutes. The most common interactions observed in ILs classes can be coulombic, hydrogen bonding, permanent dipole -permanent dipole, permanent dipole -inducted dipole, inducted dipole -Inducted dipole, π-π and n-π interactions. According the solubility properties of the system, should be possible to modify, stabilize, capture, control, enhance or mitigate such properties of specific solute molecules.
In this chapter, we are interested to overview the solubility of different classes of solids such as inorganic salts including metals; bioactive compounds including active pharmaceutical drugs; biopolymers and polymers in ionic liquids in particular comparing experimental and predicted research studies. Moreover a rationalization of the inherent structural characteristics behind the observed values of solubility in relevant cases will be also explored.

Solubility of inorganic compounds in ionic liquids
This section includes solubility of inorganic salts, elements, metal oxides and organometallic compounds in reference and task-specific ionic liquids. The later class includes ionic liquids with coordinating and common ions which can improve their solubility capacity. Whenever its possible experimental and modeled solubility will be compared and discussed accordingly, otherwise only experimental values will be presented and discussed. In order to contextualize this section a series of applications of such systems will be also described, and the experimental and types of models used in the referenced studies will be presented and discussed.

Inorganic salts (Halides)
Yang et al [1] reported the solubility of alkali chlorides in [EMIM][EtSO 4 ] at temperatures from 293.15 to 343.15 K. In this study the experimental solubility was determined by slow addition of metal halide to the ionic liquid until precipitate remain after 8h, afterwards the chloride content was determined by the Mohr method and consequently, the solubility of the metal halide was calculated. The experimental values were fitted with an exponential equation as expressed in the legend of Table 1 with a good agreement between experimental and fitted values. Such systems can be useful in synthesis as well as extraction processes. In the same year, Wang et al. [2] reported the solubility of alkali bromides in the same ionic liquid. Similarly with Yang and co-workers study a broad range of temperatures was tested with the solubility increasing with the increase of the temperature, in good agreement between experimental and fitted values as presented in Table 2. The experimental method to obtain solubility of these salts is identical when compared with Yang´s work.  In these two studies, the solubility measurements were performed in a thermostated cell in a glove box under dry atmosphere. In a study of preparation and characterization of alcohol and ether functionalized ionic liquids [3] (Figure 1) was measured the solubility of LiCl, HgCl 2 , LaCl 3 . The obtained values were expressed in the form of massic solubility constant. The quantification of Hg and La was performed using plasma spectroscopy (ICP), differently the amount of Li was attained by flame photometry. The tested salts are more soluble in these series of alcohol and ether based RTILs than in conventional alkyl based ionic liquids as can be observed in Table 3. These salts represent examples of alkaline, transition metal, lanthanide based halides and the high solubility presented in some cases constitutes potential model systems with application in green chemistry and clean synthesis.   Table 3.

Inorganic salts (Miscellaneous)
Rosol et al. [5] reported the solubility of lithium based salts, commonly used as lithium batteries, in alkyl methylimidazolium based RTILs ( Pereiro et al. [7] reported the solubility of diverse salts in a wide range of ionic liquids at 298.15 K (Table 7), the authors described that dissolving salts in a ionic liquid is a way to boost ionicity but at same time having the possibility of working in a liquid media, these systems can be potentially applied in batteries. The solubility study was obtained by the visual method, with the more promising systems measured by spectroscopic ATR-FTIR method, such compounds were also fitted by a linear equation with a good correlation between experimental and fitted values.

Lanthanides
Lanthanide based systems are very useful in the fields of advanced catalysis and as luminescent materials, one of the major problems that restricts their use is the poor solubility observed for this class of compounds. In order to circumvent this obstacle Li et al [8] developed carboxylate functionalized TSILs ( Figure 2) for the dissolution of Europium (III) and Terbium (III) oxides (Table 8). The dissolution of the Lanthanides has been attained by addition to specific ionic liquids which they were mixed with an alcohol, and then the suspension was filtered and the alcohol evaporated under vacuum.   Table 5.

Organometallics
The importance of the solubility studies of organometallic complexes is addressed to their applications in catalysis and photo/electrochemical studies as well as material chemistry field. Testing a phenantrolinium based TSIL, Villar-Garcia et al. [9]

Elements
Finally, regarding solubility of elements, such studies are important in order to optimize systems in synthesis, electrochemistry and catalysis, among other applications. Boros et al. [11] reported the solubility of sulfur (Table 11) and phosphorous (  [12] that observed a solubility of 80 mM using two independent techniques such as electrochemical and by microwave study of sulfur vapor measurements. The possibility to use ionic liquids as alternative and efficient media to solubilize inorganic compounds could open new horizons to develop novel materials, many of them not be possible using conventional solvents. The complexity associated to ionic liquids and the possibility to establish different interactions with solute molecules are mainly reasons behind optimal dissolution performances. In this context, the introduction of task specific ionic liquids with specific groups/moieties can be able to establish a preferential interaction with the solutes. Different experimental techniques have been used based on visual and spectroscopic techniques. Additionally, in this field the introduction of predictive tools is still in his infancy with a limited number of studies establishing a comparison between experimental and predictive measures. It can be expected that by the increment of the number of experimental measures extended to a wider range of inorganics and ionic liquids as well, more robust models with predictive capability could be defined in a near future. The introduction of non-linear machine learning methods such as neural-networks, support vector machines or random forests could propel this subject of study.

Solubility of bioactive compounds in ionic liquids
Bioactive compounds have been subject of great attention regarding their interaction with several ILs. Indeed, various synthetic pharmaceutical ingredients and their precursors, as well as, proteins and natural bioactive compounds, have been processed using ILs, mainly foreseeing applications in the pharmaceutical, cosmetic and agro-food sectors. Driven by a more demanding and strict regulation on the use of hazardous substances, particularly the pharmaceutical sector, for which 80% of waste generated in APIs synthesis, is related to solvent use, is being forced to look to greener alternatives. [13,14] In an attempt to meet this necessity, several scientific papers reporting successful new strategies for the synthesis of different kinds of APIs using ILs, have been reported. [15,16] Another challenge faced by the pharmaceutical industry, relies on the development of efficient drug carrier systems, which are fundamental to overcome barriers to drug bioavailability. In this context, mixtures of ILs have been used as delivery systems, to increase solubility of poorly water-soluble drugs. Briefly, an hydrophobic IL is used as the drug reservoir, completely dissolving the bioactive substance, while another IL, this time a hydrophilic one, is used as co-solvent, with the purpose of increasing the water solubility of the system. [17,18] Also with interest for the pharmaceutical industry, the utilization of ILs for proteins stabilization and biopreservation, have also been subject of great attention. [19] A further relevant field on the context of bioactive compounds processing with ILs, is the treatment of wastes contaminated with significant quantities of substances possessing biological activity. For example, in respect to wastewater effluents, numerous studies have alerted for the presence of a wide variety of bioactive substances, which are not eliminated by conventional treatment plants. Under this perspective, many authors have reported successful results on using ILs for the extraction of bioactives from it aqueous solutions. An interesting approach are the well-known Aqueous Biphasic Systems (ABS) that have been the focus of a significant amount of research, extensively reviewed in 2012 by Freire M.G. et al. [20] More recently, the extraction of natural bioactive ingredients from food industry wastes and other biomass resources has emerged. In this case, the IL is used to recover these high-added value substances from cheap and available raw materials and meant for human consumption. [21] The market for natural ingredients is one of the most attractive markets of the moment and in which the use of clean technologies for extraction, fractionation and purification, is of crucial importance. It is interesting to note that ILs applications involving products for human consumption were triggered with the effort of the scientific community on the development of nontoxic (or less toxic) ILs, by selecting more biocompatible organic cations and inorganic anions. [22] Finally, also in the field of analytical chemistry, the processing of bioactive compounds using ILs, has considerably grown. [23] Process design and success of all above referred applications, strongly relies on the interactions between bioactive compounds and ILs, which in turn, depends on several distinct and complex factors, such as chemical structure, polarity, hydrophilicity and other physico-chemical properties of both solute and solvent. Therefore, phase equilibrium data of the binary systems (IL+ bioactive compound) is of crucial importance to understand, predict and take control of existing, as well as, to figure new applications. Bogel-Lukasik E. and co-workers are the most active research group working on the experimental determination of solubilities of bioactive compounds in ILs. , at around 380 K, the solubility of phenols particularly gallic acid and quercetin are close to or higher than 0.4 mol fraction of phenolic compound. However, the experimental liquid curve trend is difficult to explain, specially for gallic acid that at lower temperatures is the most soluble phenol, but for higher temperatures stands as the less soluble. In fact, after around 330 K and above 0.2 mol fraction, the solubility of gallic acid increases much more slowly with temperature in comparison with the solubility of tannic acid and quercetin. Curiously, the temperature at which this reversed behavior occurs is around the same temperature at which the thermoghraph of gallic acid presents a solid-solid phase transition (β 1 crystalline form undergoes to a α 1 plastic form at 351 K). The same phenomena but much less pronounced is observed for tannic acid. This kind of phenomena can be exploited to achieve separation of different compounds by varying temperature conditions. In another work addressing the interaction between natural bioactive compounds and ILs, that was recently published by Alevizou and Voutas [25], the authors measured the solubilities of p-coumaric acid and caffeic acid in six 1alkyl-3-methyl imidazolium based ionic liquids composed of the same anions, BF 4 -, PF 6 -, OTf -, NTf 2 -. Caffeic acid was found to be less soluble in all ILs due to higher melting temperature and heat of fusion comparing to p-coumaric acid. Furthermore hydrophilic ILs based on BF 4 and OTfwere better solvents that hydrophobic ones based on PF 6 and NTf 2 -. This is due to the fact that hydrophilic ILs interact more stongly with both compounds through hydrogen bonds. Comparing ILs with same imidazolium cation, solubility decreased in the following order BF 4 ->OTf ->PF 6 ->NTf 2 -. The authors highlighted that results obtained are in agreement with relative polarity, hydrophilicity and hydrogen bond basicity of studied ILs. For the case of BF 4 -and OTfthey were even better solvents than pentanol and ethyl acetate. Comparing ILs with the same anion, as the alkyl chain increases, the solubility of both compounds decreases in the case of hydrophilic BF 4 -, and increases in the case of PF 6 -. For biomass-derived compounds, Carneiro et al. [26] proposed the utilization of ionic liquids as future solvents for biorefining. In this context, the authors investigated the potential of three ionic liquids for the processing of the sugar alcohols sorbitol and xylitol, obtained respectively from glucose/ frutose and xilose. The authors [26] measured the solubility of sorbitol and xylitol within the temperature range of 288 K to 328 K in three ionic liquids, specifically,  3 ], the additional OH group does not play such an important role. The authors also noted that the solubility of the two sugar alcohols could be connected with their melting properties, as lower attraction between solutes and Aliquat based ILs occurs. In this way, because melting enthalpy is lower for sorbitol, its solubility is expected to be higher The first work regarding solubility of pharmaceutical compounds in ILs was published in 2008 by the group of Florence and co-workers. [18] In this study, different drugs were used as models for water-insoluble drugs (albendazole and danazol) and water-soluble drugs (acetaminophen and caffeine). Their solubility in different ionic liquids were measured.ILs formed by the cation 1-alkyl-3-methylimidazolium with butyl, hexyl or octyl as alkyl chains and by the anions, [PF 6 ] and [BF 4 ] were studied. The authors [18] underlined that drug structures indicate that solute-solvent interactions are likely to involve hydrogen bonds, van der Waal's forces as well as π-π interactions between aromatic ring. For the case of hydrophobic drugs, albendazole presented precisely the expected results, in other words, a higher solubility for ILs with the [PF 6 ] anion and an increase in the solubility with an increase in the alkyl chain, was observed. For the case of danazole, an increase in the alkyl chain has also resulted in an increase in the solubility, but curiously, danazole presented a higher solubility in ILs with [BF 4 PO 2 ]. Since in this case an increase in the hydrophobicity was not observed, the authors concluded that the solubility depends not only of each ion separately but also on a combined cation-anion effect. The future of processing bioactive compounds, either synthetic or natural, with ILs, is certainly very promising, which was evidenced by the number of articles published, reporting successful results on several applications. However, with respect to experimental data regarding fundamental studies, to determine interactions between bioactives and ILs (e.g. solubility), until now, very few compounds were explored. Also very few ILs have been tested. Actually most of the authors, have addressed classic imidazolium cations combined with [BF 4 ], [PF 6 ], [OTf] and [NTf 2 ] anions, which are the most studied in terms of thermophysical properties. In this way, some of the authors have actually correlated their results, mainly using local composition models like UNIQUAQ and NRTL, with acceptable deviations and good representations of the experimental data. Nevertheless fundamental data is scarce and it is necessary to further understand and design new successful processes.

Solubility of biopolymers in ionic liquids
Biomass is regarded as a permanent source of renewable feedstock on the planet for both material and energy [34]. Various lignocellulosic materials, such as agricultural residues, forestry wastes, waste paper, and energy crops, have been recognized as potential sustainable fonts of sugars for transformation into fuel or value-added products currently derived from petroleum [35]. Biomass primarily consists of polymeric carbohydrates: cellulose and hemicellulose, and the aromatic polymer lignin. These components are firmly cross-linked by numerous inter-and intramolecular hydrogen bonds making processing of biomass an extremely challenging task. In order to access the carbohydrates in the biomass an additional deconstruction step (so called pretreatment) is required. The goal is to disrupt the lignin-carbohydrate complex, decrease cellulose crystallinity and partially remove lignin and hemicelluloses. Traditional methods currently used either for pretreatment or carbohydrates dissolution typically demand harsh conditions (elevated temperature, and often also elevated pressure, usage of strong acids or bases), and sometimes cause serious environmental, energy, or safety problems [36]. Less energy consuming, more environmentally friendly, and highly efficient approaches are in great need. New solvents systems are crucial for not only deconstruction and separation of biomass components, but also for successful regeneration or derivatisation of sugar polymers under homogeneous conditions. The capability of ILs to act as media for biomass processing has already been reported [37][38][39][40][41][42]. After Rogers et al. [43] first reported in 2002 that cellulose could be dissolved in IL, 1-butyl-3methylimidazolium chloride ([BMIM][C1]), the research on application of ILs to carbohydrate chemistry started to attract a great deal of attention. This subchapter is meant to provide an update on recent advances in the field of solubility of carbohydrates in ILs which has already been reviewed elsewhere [44]. This work covers the solubility data that were published since 2009 till present. Since many comprehensive and excellent reviews on modification of carbohydrates in ILs are already available [45][46][47], this subject is omitted in the subsequent discussion. Interest in using ILs as media for carbohydrates has so far been centered on the dissolution and processing of cellulose [48][49][50][51][52][53]. One of the major drawbacks of cellulose concerning its industrial application is the insolubility in water and most of conventional solvents due to its compact structure and chemical complexity. The capacity of certain ILs to dissolve cellulose is primarily related with strong hydrogen bonding between the ILs anion and the hydroxyl groups of cellulose [48,[54][55][56][57]. This association was confirmed for cellulose or glucose/glucose oilgomer models by means of NMR [58][59][60], neutron scattering [60], molecular dynamic [61][62][63][64][65] and density functional theory computational approaches [66]. It is commonly accepted that the anion of the ILs plays a predominant role in dissolution. A high basicity of the anion is considered as a major criterion to effectively dissolve cellulose [67,68]. The stronger the hydrogen bond basicity of the anion, the stronger the ability of the IL to dissolve cellulose. However, the exact mechanism of cellulose dissolution has not been completely understood so far. In particular, some speculations exist into the role of the cation [48,[69][70][71][72][73][74]. Most of the researchers attribute the dissolution ability of ILs only to the anion, while the interactions between the cation and the carbohydrate play secondary role [58,60,61,65,75]. However, the idea that both IL ions, anion and cation, participate in the dissolution process by formation of hydrogen bonds has been considered as well [52,71,74,76,77]. Some data have even suggested that since cellulose is amphiphilic the hydrophobic interactions between the IL cation and the cellulose are responsible for the dissolution of cellulose [41,70].
To date, ILs that have been found suitable for cellulose dissolution contain imidazolium-or pyridinium-based cations combined with anions of basic character such as chloride [43,78], carboxylates (formate [79], acetate [56,78]), phosphates [80] or phosphonates [67]. On the other hand, some IL ions have been shown to be unable to dissolve cellulose. Examples include pyrrolidinium and piperidinium cations and tetrafluoroborate, hexafluorophosphate, dicyanamide, bis(trifluoromethanesulfonyl)amide or trifluoromethanesulfonate anions [40,53,56,74]. Bromide and dicyanamide ILs are known to dissolve cellulose only with low degree of polymerization [81][82][83]. Dicyanamide-based ILs are not efficient for cellulose dissolution but they are capable of dissolving monosaccharides [84][85][86]. Table 15 presents solubility data for main lignocellulosic polymers: cellulose, hemicelluloses and lignin [56,74,82,83,[87][88][89][90]. It is interesting to note, that replacing proton in the acetate anion with electron-withdrawing group, such as hydroxyl (-OH), thiol (-SH), amine (-NH 2 ) or hydroxymethyl (-CH 2 OH) group, results in a decreased solubility of cellulose [56]. Changes in the cation structure are also not insignificant. When the alkyl chain length in the cation is increased, the solvent power of ILs for cellulose seems to decrease [43]. Moreover, for the small alkyl chains (pentyl and shorter) of 1-alkyl-3-methylimidazolium chloride, the strong odd-even effect was observed [58]. Even-numbered alkyl side chains proved to be better suited for cellulose dissolution than odd-numbered chains. Alkyloxy and alkyloxyalkyl groups attached to the imidazolium ring may either enhance or decrease solubility of cellulose [74,91,92]. In some cases IL solvent systems can also be used. Mixtures of ILs and polar organic co-solvent (e.g, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) have been successfully applied [93,94], even at ambient temperature [90]. The great advantage of such mixtures is reduced viscosity of the cellulose solutions that leads to acceleration of the dissolution process from hours down to minutes. Addition of lithium salts (e.g., Li(OAc), LiCl, LiBr, LiNO 3 or LiClO 4 ) into [BMIM][OAc] significantly increases the solubility of cellulose [56]. This observation was studies by 13 C NMR spectra, and the results suggest that the enhanced solubility originates from the disruption of the intermolecular hydrogen bond owing to the interaction of lithium cations with the hydroxyl oxygen of cellulose.
The desired high basicity that allows an IL to dissolve cellulose unfortunately makes the IL very hydroscopic. Water is found to perturb the solvation of carbohydrates considerably [43,89,94]. It hydrogen-bonds to the ILs anion or to cellulose removing the primary driving force for the solubility of cellulose, the anion-cellulose hydrogen bonds. Amounts even as low as 0.15 wt% were reported to start precipitation of cellulose in the 1-ethyl-3-methylimidazolium chloride ([EMIM][C1]) [89]. On the other hand, this is very advantageous for the regeneration of carbohydrates already dissolved in ILs [95]. Cellulose can be easily precipitated from the cellulose-IL solution by addition of solvents, such as water, alcohol, acetone or acetonitrile [38,43,56,68,78]. The regenerated cellulose exhibits typically lower degrees of crystallinity compared to the native cellulose. Various novel cellulose materials can be prepared from cellulose-IL solutions, such as composites [96,97], membranes [98], films [78,99], fibers [100,101] or nanofibrillar cellulose aerogels [102]. The conventional pulping techniques are primarily focused on maximizing the cellulose yield neglecting the potential of lignin and hemicellulose. The first is typically degraded during the delignification step or used as a fuel in subsequent processing, often at really low efficiency [103]. The second can be isolated from cellulose, after the delignification, but this typically involves its partial degradation. The clean fractionation of these polymers is very important for the successful utilization of biomass [39]. Although it is difficult to achieve this goal, the possibility of separation of lignocelluloses components with ILs has already been explored [42]. There exist some reports on selective extraction of hemicellulose [104][105][106][107] or lignin [88,108]. Dissolution of wood in ILs has also been studied [38,42,[109][110][111]. However, the data on the solubility of the particular polymers is still scarce [82,88,[112][113][114]. DP-degree of polymerisation Chitin is structurally similar to cellulose with one hydroxyl group on each monomer replaced by an acetylamine group, while chitosan is N-deacetylated product of chitin. In contrast to cellulose, only a few examples of the dissolution of chitin or chitosan in ILs have been reported [87,115,116]. Recently, a series of ILs containing alkylimidazolium chloride, alkylimidazolium dimethylphosphate, and 1-allyl-3methylimidazolium acetate ([AMIM][OAc]) to dissolve chitin were used. It was noticed that the degree of acetylation, the crystallinity, the molecular weights of chitin, as well as the nature of the anion of the IL all affect the dissolution behavior of chitin in ILs [117]. The acetate anion was strong enough to cleave the hydrogen bond network of chitin, while the chloride anion and dimethylphosphate anion were less efficient. The same was observed for chitosan [118,119].  [87]. In the same study, the mixtures of ILs have been tested for the dissolution of chitosan and good results were obtained. Both chitin and chitosan due to their favorable properties such as good biocompatibility, biodegradability, absorptivity and nontoxicity find many applications in the field of tissue engineering, drug delivery, food preservation, waste water purification, packaging or cosmetics [120][121][122][123]. Very recently it was reported that chitosan together with agarose [124], or agarose on its own [125,126], were used to prepare ionogels which are shown to be smart polymeric conducting materials [127]. Agarose is an algal polysaccharide comprising alternating D-galactose and 3,6-anhydro-L-galactose repeating units, essentially uncharged. Over the years it was often use for its gelling properties. Similarly to cellulose, due to the large number of hydroxyl groups in its structure, agarose is insoluble in many common organic solvents and cold water. ILs that were found to dissolve agarose are of basic character and are able to disrupt the hydrogen-bonding network of the polymer leading to dissolution [125,126] DA-degree of acetylation; DC-degree of deacetylation Starch is another example of one the most abundant natural polymers. Its utilization in its native form is often limited though. This is due to some undesirable characteristics such as poor solubility, low mechanical properties, and instability at high temperature and pH during processing. The derivatisation of starch is typically required in order to overcome these shortcomings and improve its functionality for industrial applications [129]. During the last few years an increasing interest in manufacturing value-added products based on starch utilizing ILs has been observed, whilst much less attention has been paid to the subject of solubility of starch in ILs [130][131][132]. Very recently, reports comparing the dissolution of starch in IL, [EMIM][OAc], with gelatinization process in water ware published [133,134]. Consid-ering the mechanism of dissolution, it was stated that in case of pure IL, the solvent penetrates starch granule making outer layer slightly swollen and transparent. With time, less and less granules can be seen, up to complete visual disappearance. In water, starch granules first swell with temperature increase and then burst.  Hydrolysis of starch produces a group of low-molecular-weight carbohydrates named dextrins [135]. Dextrins are mixtures of linear and branched (1,4)-linked α-glucose polymers, while cyclodextrins are a series of cyclic oligosaccharides composed of 6, 7, or 8 D-(+)-glucose units named α-, β-, and γ-cyclodextrin, respectively. The structures of cyclodextrins are identical as each of them contains a molecular cavity. The hydroxyl groups of the oligomer are on the outside of the cavity, while the inner cavity is hydrophobic. Cyclodextrins are able to form inclusion complexes with a number of organic and inorganic guest molecules that are encapsulated in their molecular cavities. Most of the investigations concerning ILs and cyclodextrins are focused on understaning the nature of interactions [136][137][138][139][140][141][142][143].The solubility data are very limited [44]. Fan and co-workers investigated the solubility of β-cyclodextrin in six kinds of hydrophilic ILs [141]. It is shown that the solubilities were remarkable and followed the order Cl. Monosaccharides (especially glucose and fructose) and disaccharides (mainly sucrose), after cellulose, are the most studied carbohydrates in ILs. Table 18 and 19 summarizes the solubility data for disaccharides [85,133,[144][145][146] and monosaccharides [85,86,[144][145][146][147][148], respectively. Solubility of sugar in a given IL decreases in the following order: D-(-)-fructose > D-(+)-glucose > sucrose. It can be justified by the chemical structure of sugars and their basic thermal properties (i.e., temperature and enthalpy of fusion), independent of the IL [85,86,147]. The melting temperature and melting enthalpy of carbohydrates are related with their solubility and the larger the properties, the lower the solubility.
Regarding the influence of the cation and anion structure of the ILs on the solubility of carbohydrates, some general conclusions can be drawn from the collected data. Similarly as in the case of cellulose, the role of the cation is not insignificant. It was found that imidazoliumbased ILs are capable of dissolving monosaccharides, whereas pyridinium and phosphonium ILs are rather poor solvents for these sugars [145]. Novel ILs containing dimethylguanidinium cation and anions such as saccharine, acesulfame and thiocyanate has also been investigated and some remarkable results were obtained. It was demonstrated that introduction of functionality in the alkyl chain of the dimethylguanidinium-based ILs can improve the dissolution of carbohydrates [146]. Sugars are more soluble in ILs with shorter alkyl chains in their chemical structure. The same as for polycarbohydrates, increasing length of the chain results in a more hydrophobic nature of the cation and IL as a whole, and thus weakens the capacity of dissolving polar solutes like sugars [85,86]. [Cl] which have not much affinity with the hydroxyl groups of the sugars explains its poor solubility power [147]. Among hydrophobic ILs, the more bulky (more hydrophobic) [P 6,6,6,14 [145]. The authors of the study explained that it can be a result of a large affinity of anions towards monosaccharides. In particular, it can be caused by a highly acidic effect of [HSO 4 ] which acts as strong hydrogen bond donor, and [SCN] responsibility for the strong hydrogen bond accepting interactions due to a high polarizability of the anion and the specific structure stabilised by the resonance. Also, the study of cyano-based ILs revealed that, in general, the monocyano anion is a stronger hydrogen bond acceptor than a more complex multicyano anion.  As it was mentioned before, cellulose can be easily precipitated from the cellulose-IL solution by means of selective precipitation [38,43,56,68,78]. However, separation of smaller carbohydrates such as glucose from ILs remains a challenging task. Glucose and ILs have extremely low vapor pressure. Therefore, conventional vacuum distillation methods do not serve for their separation. Also, no suitable organic solvent capable of extracting sugar from ILs have been found. In 2011, it was reported for the first time that antisolvent method can be applied to the separation of glucose and IL [149]. An antisolvent method is based on discrepancies in the interactive forces between solute, solvent and antisolvent. An addition of an antisolvent to a binary solution (solute+solvent) causes a reduction in the original solubility of the solute in the binary solution, leading to its crystallization and precipitation. Very recently, the method was adopted for separation of other systems, differing in carbohydrates and ILs [150,144,148]. The ability to predict whether a given IL dissolves a particular carbohydrate or not is of outmost interest. There are several empirical and semi-empirical measuring techniques and polarity scales that can predict and explain the solubility of carbohydtares in a solution, e.g. COSMO-RS, Hansen solubility parameters and Kamlet-Taft solvent parameters [41]. The empirical Kamlet-Taft model [67,79] and the quantum mechanical COSMO-RS model [151][152][153] have been used most frequently to predict or explain the solubility of carbohydrates in ILs, while few literature data exist for Hansen solubility parameters of ionic liquids [154]. The Kamlet-Taft parameters (α, hydrogen bond acidity; β, hydrogen bond basicity; and π*, polarity) are determined by measuring the UV-VIS spectra of dyes when dissolved in a solvent of interest. It was suggested that solubility of carbohydrates increases with an increase of ILs basicity (ILs that are capable of dissolving carbohydrates are generally characterized by high hydrogenbond basicity parameter; β > 0.8), and polarity [41,56,74,119,126,144,148]. The potential of COSMO-RS-based screening of ILs with respect to their dissolving power for cellulose was evaluated in the pioneer research of Kahlen et al. [151]. Cellulose solubility was modeled for more than 2000 ILs using activity coefficients as reference property and the results were in good agreement with the data available in the literature. Later on, the work was extended to the computational COSMO-RS analysis of the affinity of both cellulose and lignin for 320 different ILs [153]. A new reference property, namely the excess enthalpy of the IL + lignin/ cellulose mixtures, was used to predict solubilites of lignin and cellulose in ILs. The conclusions achieved were validated in the laboratory for a selected set of ILs. The ability of more than 20 hydrophilic ILs to dissolve Miscanthus was also interpreted using Abraham solvation parameters obtained from COSMO-RS [151]. In case of smaller carbohydrates, Carneiro et al. were the first group to correlate the solubility data of monosaccharides in ILs using the NRTL and UNIQUAC thermodynamic models [147]. Following their success, other works on application of NRTL and UNIQUAC thermodynamic models for correlation of solubilities of glucose [86,148,144], fructose [86,144], sucrose and lactose [144] have been reported. Very recently, perturbed-chain statistical associating fluid theory (PC-SAFT) was applied to model experimental data on solubility of glucose, fructose and sucrose [85,154,155].This approach occurred to be more promising since it showed better predictive capacity and quite reasonable accuracy. As an equation-of-state model, it enables the capture of properties of both pure fluids and mixtures. Although some data concerning solubility of carbohydrates in ILs is already available in the literature, it is not sufficient to have a good knowledge of phase equilibra. These investigations cover essentially only the most well-known sugars, glucose, fructose, and sucrose, as well as polysaccharides such as cellulose.
In most cases, data are measured by using different experimental procedures and contain single data points at fixed temperature. It makes application of existent or the development of new thermodynamic models a very difficult task. Moreover, solubility of carbohydrates in ILs is sensitive to the presence of impurities, especially water, and even though authors do not report on the water content. ILs have provided a new processing platform for the dissolution, regeneration and functionalization of carbohydrates, thus increasing their chances of exploitation. However, for the purpose of successful process design and optimization, more reliable data on solubility of various carbohydrates in ILs is fundamental.

Solubility of specific polymers and macromolecules in ionic liquids
Concerning other classes of polymers and macromolecules, the use of Ionic Liquids represents real challenges in order to solubilize those allowing future modifications and depolymerization in the constitutive monomers.
Wang et al reported the possibility to dissolve and regenerate polybenzimidazole in 1-butyl-3methylimidazolium chloride, [BMIM][Cl] and other hydrophilic ionic liquids [156]. The authors describe ionic liquids as alternative solvents for dissolution of different organic polymers. Polybenzimidazole (PBI), also known as poly-2,20-(mphenylene)-5,50-bibenzimidazole), is a polymer composed by linear aromatic polymer chains as well as both donor and acceptor hydrogen-bonding sites. This class of polymers exhibits high thermal stabilities, chemical resistance, and mechanical strength [157]. According with their relevant properties, PBI has been developed as membranes [158], textile fibers [159], and high-temperature matrix resins [160]. One of the problems associated with PBI and similar polymers is their poor solubility and infusibility in common organic solvents. PBI is only soluble after heating highly polar aprotic solvents such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide. Watanabe and co-workers reported the solubility of poly(methyl methacrylate) (PMMA) in 1alkyl-3-methylimidazolium ionic liquids (ILs) with different anionic structures [163]. For evaluation of PMMA solubility in ILs were tested monodisperse PMMA-grafted silica nanoparticles (PMMA-g-NPs) as a measurement probe. The solubility was mainly affected by the anionic structures of the ILs rather than by the alkyl chain length of the cationic structure. . Single chain conformations have been observed in the case of DNA and polystyrene sulfonate as negative polyelectrolytes. The authors suggested the condensation of the polymer chains in ILs according with their smaller hydrodynamic polymer radius. In general, the solubility of homopolymers could be qualitatively explained by treating polymer/ IL as a ternary system: polymer, cation, and anion. The authors suggested that mutual interactions determined the polymer conformation and solubility in ILs. However, preliminary results indicated us those strong interactions between polymers and bulky cations in ILs are relevant for higher dissolution performance. Several publications proof an effective dissolution of different synthetic polymers in ILs (for example poly(ethylene oxide) (PEO) [168], poly(methyl methacrylate) [169], polyacrylonitrile [170], poly(m-phenylene isophthal amide) [171], and polyarylsulfone [172]) while many others (e.g. polyethylene, polyester, polyurethane, and nylon) were not soluble in the tested ILs.
In different perspective, efficient polymerization processes as well as preparation of specific polymeric materials using ILs have been also described. In this context, Zhang and co-workers [173] reported the polymerization of acrylonitrile in the presence of [BMIM][Cl] and then for the first time polyacrylonitrile fibers were directly produced from spinning process of the previous polymer solution. According to remarkable acrylic fibers properties (in particular soft and wool-like aesthetics and resistance ultraviolet fading) different fields of application (e.g. home furnishings, outdoor articles, aviation and space fields). From 1980s the wet and dry spinning technologies have been used as most effective processes for PAN fibers production. [174] For wet and dry spinning processes, the use of large amounts of unfriendly solvents to the environment have been required.

It seems that [BMIM]
[Cl] is a suitable solvent for the polymerization, spinning and dissolution of the acrylic fibers. In this context, different acrylic polymers with tunable properties (higher concentration of acrylonitrile, large molecular weight, and low polydispersitive index PDI).

The solutions of PAN and [BMIM]
[Cl] allowed the development of PAN fibers containing good mechanical properties and round profile after efficient spun using dry-jet wet spinning technology.
In 2009, Rodriguez et al [175] reported that 1-alkyl-3-methylimidazolium chloride ionic liquids (ILs) can form immiscible liquid mixtures with some polyethylene glycols (PEGs). PEGs have been largely used in industry because of their reduced toxicity and cost as well as higher biodegradability. [176] Additionally low volatility and melting points of PEGs facilitate their use as alternative solvents or additives in several aqueous biphasic systems. [177] Many publications indicate the possibility to tune PEG properties as relevant characteristic (for example PEGs with shorter chain lengths are liquid at room temperature and water miscible while PEGs with longer chain lengths melt at higher temperatures and with variable water solubility. Recently, PEGs and ILs have been combined for application as polymer electrolytes in batteries, [178]  Negative values for the change of enthalpy and entropy of IL/PEG mixtures have been observed by thermodynamic analysis of the liquid-liquid equilibrium data. The possible tunability according with adequate IL/PEG combinations could be applied for separation of complex solutes by solvent extraction processes at high temperature. The authors tried applied these biphasic, entirely liquid systems, with low volatility and good solvation properties, for the dissolution and separation of cellulose and lignin at elevated temperature, although only modest results have been achieved to date. Samitsu et al [180] reported the dissolution behavior of polyrotaxanes, consisting of alfa-cyclodextrin and poly(ethylene glycol), with different molecular weights (2000 and 35.000).
Harada et al. and other authors reported some polyrotaxanes, containing alfa-cyclodextrins (α-CD) as the cyclic molecules and poly(ethylene glycol) (PEG) as a linear polymer. [181,182] Polyrotaxanes have been largely applied in different fields, in particular drug delivery systems for biological applications [183], insulated molecular wires [184] and photo-induced energy transfer systems for electrical applications. [185] Interlocked polymer networks built from polyrotaxanes have been also tested as gels and rubbery materials for industrial applications.
Several studies reported polyrotaxane solubilities in several ionic liquids mainly based on The solubilities of two polyrotaxanes in ILs as well as the α-CD and PEG solubilities for comparison are summarize in Polyrotaxanes dissolved in ILs can be recovered by precipitation after simple addition of organic solvents or water to solution. The authors reported the use of ILs as new solvents for polyrotaxanes in order to develop ionic liquid-containing slide-ring gels (SR gels), that is supramolecular networks of polyrotaxane swollen with ILs, using an integrative non-drying technique followed by optimized solvent exchange method.