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Review

Chiral ionic liquids in chromatographic and electrophoretic separations Constantina P. Kapnissi-Christodoulou ∗ , Ioannis J. Stavrou 1 , Maria C. Mavroudi 1 Department of Chemistry, University of Cyprus, 1678 Nicosia, Cyprus

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Article history: Received 15 April 2014 Received in revised form 17 May 2014 Accepted 20 May 2014 Available online xxx Keywords: Ionic liquids Chiral ionic liquids Capillary electrophoresis Chromatography Chiral separations Review

a b s t r a c t This report provides an overview of the application of chiral ionic liquids (CILs) in separation technology, and particularly in capillary electrophoresis and both gas and liquid chromatography. There is a large number of CILs that have been synthesized and designed as chiral agents. However, only a few have successfully been applied in separation technology. Even though this application of CILs is still in its early stages, the scientific interest is increasing dramatically. This article is focused on the use of CILs as chiral selectors, background electrolyte additives, chiral ligands and chiral stationary phases in electrophoretic and chromatographic techniques. Different examples of CILs, which contain either a chiral cation, a chiral anion or both, are presented in this review article, and their major advantages along with their potential applications in chiral electrophoretic and chromatographic recognition are discussed. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fundamental aspects of CILs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Application of CILs in enantiomeric separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. CILs in chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. CILs in gas chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. CILs in liquid chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. CILs in capillary electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. CILs as background electrolyte additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. CILs as chiral ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. CILs as chiral selectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Ionic liquids (ILs) are unique solvents with melting points at or below 100 ◦ C. They are composed entirely of ions, and in most cases, they are composed of an organic cation and an organic or inorganic anion. In recent years, ILs have drawn scientific interest due to their unique properties, which involve good thermal

∗ Corresponding author. Tel.: +357 22 892774; fax: +357 22 892801. E-mail address: [email protected] (C.P. Kapnissi-Christodoulou). 1 These authors contributed equally to this work.

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stability, miscibility in different solvents, tunable viscosity, conductivity, negligible vapor pressure, and non-flammability. Some properties primarily depend on the anion, while others depend on the length of the alkyl chain in the cation, the shape or the symmetry [1,2]. The synthesis and application of ILs in analytical chemistry has attracted considerable attention. For more than a decade, a large number of ILs have been designed, synthesized and used in extractions [3–9], gas chromatography (GC) [10–13], liquid chromatography (LC) [14–19], capillary electrophoresis (CE) [20–25], mass spectrometry (MS) [26–29], infrared (IR) and Raman spectroscopy [30–32], fluorescence spectroscopy [33,34], nuclear

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magnetic resonance (NMR) spectroscopy [35,36] and electrochemistry [37,38]. In addition, numerous review articles have, over the years, been published regarding the significance of the ILs in analytical chemistry [1,2,39–46]. Chiral ionic liquids (CILs) are a subclass of ILs that have a chiral moiety. In CILs, the cation, the anion or both may be chiral. They are of increasing importance due to their potential chiral discrimination capabilities. During the last decade, the CILs have been applied as chiral media in asymmetric reactions [47–51], extractions [52], membrane separation [53], NMR spectroscopy [54–57], IR spectroscopy [58], luminescence spectroscopy [59,60], fluorescence spectroscopy [54,56,61,62], GC [63–66], LC [64,67–70] and CE [64,68,71–87]. Although numerous studies on the applications of CILs have been reported, a surprisingly limited number of review articles have been published on their utility in analytical separations [40,88–90]. In 2007, Shamsi and Danielson [40] covered reports on ILs that were published from the mid 1980s to early 2007. Their main objective was to provide an overview on the utility of ILs in GC, LC, and CE, as well as to highlight new developments for chiral and achiral separations. In 2010, a book on chiral recognition in separation methods was released that included a chapter on CILs in chromatographic separation and spectroscopic discrimination [90]. In this chapter, various applications of CILs in chromatographic and spectroscopic techniques were described and the enantiomeric discrimination mechanisms using CILs as chiral solvents or chiral selectors were explained. As stated by the authors, further investigations are required in regard to the chiral recognition mechanism, the structure–property relationship and the physicochemical properties of new CILs. In 2012, Tan et al. [88] provided an overview of different applications of ILs in the major sub-disciplines of analytical chemistry, including extraction, characterization, detection and separation. In regard to the last area, their goal was to highlight the advances using ILs as separation media in GC, LC and CE. However, only a few studies were reported on the use of CILs in GC and HPLC. In the same year, Payagala and Armstrong [89] compiled a database, which included structures and physical properties of CILs that were designed and synthesized from 2005 to 2012. They also provided numerous publications that explored the possibilities of CILs, mainly, in asymmetric synthesis and spectroscopy, and secondarily, in chromatography.

2. Fundamental aspects of CILs CILs have recently been used as chiral selectors, background electrolyte (BGE) additives, chiral ligands and chiral stationary phases in chromatographic and electrophoretic techniques for the analysis of chiral molecules. They are considered very promising in chiral analysis because they combine the advantages of ILs with the properties of a chiral moiety. The CIL molecules possess either a chiral cation or a chiral anion, or both ions may be chiral. The chiral cationic part of a CIL may be a chiral imidazolium, pyridinium, ammonium or azolinium. The chiral anion may include an amino acid, lactic acid, borate or camphorsulfonate [90]. For more than five decades, there has been a growing interest in the separation of enantiomers in pharmaceutical, clinical, environmental and food analysis, because, usually, only one enantiomer is active while the other may be less active, inactive or has adverse effects. Various chiral selectors, such as cyclodextrins (CDs) and cyclofructans (CFs), linear oligo- and polysaccharides, branched polysaccharides, monomeric and polymeric surfactants, macrocyclic and lincomycin antibiotics and crown ethers, have widely been applied due to their chiral recognition abilities [91]. However, there are some problems that usually limit the use of these chiral selectors. These problems include low solubility, high UV Please cite this article in press as: http://dx.doi.org/10.1016/j.chroma.2014.05.059

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absorptivity, instability at high temperatures, complicated organic synthesis procedures and high cost. Another drawback, in some cases, is the requirement of using one or more solvents as mobilephase additives [54]. The potential use of CILs as solvents and chiral selectors may circumvent the problems mentioned above. CILs can dissolve various polar and nonpolar analytes, and, at the same time, they may provide chiral selectivity. In addition, the synthesis of CILs is simple, and they are stable at high temperatures [62]. In recent years, a large number of reviews have been provided on the synthesis of CILs and their applications in asymmetric reactions and spectroscopy [88,89,92–94]. In contrast, this review is focused on the applications of CILs in enantiomeric chromatographic and electrophoretic separation. To the best of our knowledge, this is the first review that focuses exclusively on this kind of application. In particular, it provides the progress of CILs as chiral selectors, BGE additives, chiral ligands and chiral stationary phases in GC, LC and CE. 3. Application of CILs in enantiomeric separation Various protocols have been developed for enantioseparations, and the most widely used ones include high-performance liquid chromatography (HPLC), GC, and CE. The chiral separations achieved by use of CILs are summarized and discussed below. 3.1. CILs in chromatography 3.1.1. CILs in gas chromatography GC with a chiral stationary phase is one of the most important approaches for the separation of chiral compounds. Preparation of the chiral column, and particularly the stationary phase, is critical for GC. The use of ILs in GC, as a new type of stationary phase, has attracted considerable attention for more than a decade due to their unusual properties (high thermal stability, variable stability, nonflammability) [95]. However, only a few studies reported the use of CILs in GC, and the first enantiomeric separations were performed and presented by Ding et al. [63]. They used N,N-dimethylephedrinium-based ILs as chiral stationary phases in GC, and they demonstrated their enantioselectivity by separating alcohols, diols, sulfoxides, epoxides, and acetylated amines. The separation factors, ␣, ranged from 1.01 for the analytes p-methylphenylmethyl sulfoxide, p-chlorophenylmethyl sulfoxide and p-bromophenylmethyl sulfoxide, to 1.11 for the analytes sec-phenethyl alcohol and 1-phenyl-1-propanol. Fig. 1 demonstrates the chiral separation of the last two alcohols and the diol trans-1,2-cyclohexanediol. In an effort to reverse the enantioselectivity and the elution order of the separated compounds, and to study the separation mechanism, three versions of a basic CIL, in which only the stereochemistry differed, were synthesized [(1S,2R)-(+)-N,N-dimethylephedriniumbis(trifluoromethanesulfon)imidate, (1R,2S)-(+)-N,N-dimethylephedrinium-bis(trifluoromethanesulfon)imidate, (1S,2S)-(+)-N,Ndimethylephedrinium-bis(trifluoromethanesulfon)imidate]. The elution order was indeed reversed when the analytes were enantiomerically separated by use of the (1S,2R)- versus the (1R,2S)-dimethylephedrinium-based chiral stationary phase. In addition, it was concluded that the separation of some analytes was sensitive to the configuration of both stereogenic centers of the CIL, while in other cases, the separation was mainly controlled by the configuration of one stereogenic center. Yuan et al. [64] studied the application of the CIL (R)-N,N,Ntrimethyl-2-aminobutanol-bis(trifluoromethanesulfon)imidate in GC, HPLC, and CE. In the case of GC, the CIL demonstrated sufficient enantiomeric recognition for alcohols, amines, ketones, esters and amino acids. The best separation factors were obtained for the

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efficiency, provided selectivity factors that ranged from 1.001 for menthol to 1.019 for citronellal.

Fig. 1. GC chromatogram showing the enantiomeric separation of (from left to right) sec-phenethyl alcohol, 1-phenyl-1-butanol, and trans-1,2cyclohexanediol. Chromatographic conditions: column = 8 m long × 250 ␮m (i.d.) fused-silica capillary coated with (1R,2S)-(+)-N,N-dimethylephedriniumbis(trifluoromethanesulfon)imidate. Temp = 120 ◦ C, He flow rate = 1.0 mL/min, split ratio = 100:1, FID. Reprinted with permission from Ref. [63].

analytes citronella (˛ = 1.06), N-benzyl-1-phenylethylamine (˛ = 1.08), and N,N-dimethylethylamine (˛ = 1.09). It is worth here to note that five years later, Zhao et al. from the same research group [96] used single-walled carbon nanotubes in the CIL stationary phase mentioned above for improved enantioseparations in GC. The evaluation of this type of column was performed by preparing and comparing two modified capillary columns. The first one contained solely the CIL, while the other one contained the CIL coated onto the layer formed by the single-walled carbon nanotubes. Twelve chiral analytes were separated by using these two modified columns. When the second column was used, eight analytes provided separation factors above 1.00, while in the case of the first column, only four analytes were able to be resolved. According to the authors, this improvement in enantioseparation by using the CILs and the single-walled carbon nanotubes is possibly due to an increase in surface area, which, in turn, increases the interactions between the chiral stationary phase and the analytes. In 2013, new permethylated mono-6-deoxy-6-pyridin-1-ium and mono-6-deoxy-6-(1-vinyl-1H-imidazol-3-ium)-␣- and -␤-CD trifluoromethanesulfonate ILs were synthesized and evaluated as potential chiral stationary phases in GC by Costa et al. [65]. The chiral discrimination performance of the modified capillary as a new separation medium was evaluated by use of esters, lactones, and epoxides as analytes. The new CD-based IL stationary phase demonstrated good chiral recognition, and in some cases, its performance was even better than the performance of a commercial CD stationary phase. It is also important to mention that the synthesis of the CD-based IL was a one-pot reaction and a solvent-free procedure. In an effort to develop new CIL stationary phases in GC, Sun et al. [66] synthesized a CIL from natural amino acids. Amino-acid derived ILs (AAILs) are considered biorenewable, and they have weak UV absorption, stable chirality, high biocompatibility and easy availability [83,88]. In their work, they used the CIL l-1-butyl3-(2-propionic-1-ether) imidazolium bromide ([BAlaIM]Br) mixed with the polymeric IL [PSOMIM][NTf2 ] at different ratios (4:1, 2:1, and 1:1). The CIL stationary phase demonstrated satisfactory enantioselectivity for analytes, such as carvones, citronellals, limonenes, and camphors. However, the last mixing ratio, which demonstrated the best enantioseparation characteristic and the highest column Please cite this article in press as: http://dx.doi.org/10.1016/j.chroma.2014.05.059

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3.1.2. CILs in liquid chromatography The application of CILs in LC has been predominantly as chiral ligands [68–70], and secondarily as stationary phases [67,97], and chiral selectors [64]. The study performed by Yuan et al. is the only study that used a CIL as a chiral selector in LC [64]. Eight analytes were enantiomerically separated using a C18 HPLC column and the CIL (R)-N,N,N-trimethyl-2-aminobutanolbis(trifluoromethanesulfon)imidate. Most of the analytes were well resolved with selectivity factors as high as 3.86, which corresponded to the analyte 1-phenyl-1,2-ethanediol. In 2010, Zhou et al. [97] were the first to use an IL-based chiral selector as a stationary phase in LC. In particular, four novel ILs functionalized ␤-CDs were prepared and bonded to silica gel, and their separation performances were evaluated by examining twelve ␣nitroalcohols, two ␣-hydroxylamines, two aromatic alcohols and two racemic drugs as test analytes. These four novel ILs functionalized ␤-CDs consisted of imidazolium and 1,2,3-triazolium derivatives, while the counter anions were the nitrate and/or the tosylate ones. All chiral stationary phases displayed excellent enantioselectivity for most of the analytes under study, since the resolution values, in most of the cases, were above 1.5. The potential of a new CIL stationary phase for HPLC was examined by Kodali and Stalcup in 2014 [67]. For the preparation of the stationary phase, the chiral selector 2-(1H-imidazol-1yl)cyclohexanol was firstly synthesized and, then, added to the modified endcapped silica. Its performance as a CIL stationary phase was evaluated by examining the chiral separation of phenanthro [3,4-c] phenanthrene (hexahelicene). Chiral partial separation was achieved by using a mobile phase of 10:90 dichloromethane/hexane and a flow rate of 0.3 mL/min. The resolution value was 0.91, and the selectivity factor was 1.07. The first application of AAILs as chiral ligands in chiral separation was reported by Liu et al. [68] in 2009. They used 1-alkyl-3methylimidazolium [Cn mim] l-proline (l-Pro) as a chiral ligand coordinated with copper (II), and four underivatized amino acids (phenylanaline, histidine, tryptophan, and tyrosine) as test analytes in HPLC and CE. In regard to the first technique, the AAIL was evaluated by comparing its chromatographic performance with the performance of the amino acid l-Pro as a chiral ligand and the performance of a common IL and l-Pro as a binary mobile-phase additive. The AAILs proved to be effective chiral ligands, even at low concentrations (i.e. 0.25 mM), because they provided very high separation factors and resolution values. The enantioselectivity of l-Pro was poorer than that of l-Pro ILs, even though baseline separation was obtained. In the case of the binary additive, the resolution was even lower than that of pure l-Pro. Fig. 2 illustrates the enantioseparations of all four amino acids in HPLC by using the AAIL coupled to copper (II) as the chiral ligand and the optimum conditions based on the enantioseparation of phenylanaline. The separation factors and the resolution values ranged from 1.27 to 2.16 and from 3.26 to 10.81, respectively. According to the authors, this superiority over the conventionally used amino acid ligands is possibly related to the ion pairing of the alkylimidazolium cations and l-Pro on the surface of the stationary support or the capillary wall. A more recent study was performed on the use of [Cn mim][Pro] in ligand-exchange chromatography for the chiral separation of tryptophan [69]. In this work, more extensive results were presented on the tryptophan enantioseparation by examining different parameters that affect the retention, separation and resolution factors. The main parameters examined involve AAIL alkyl chain length (C6 ), copper (II) and [C6 mim][Pro] concentrations (8 mmol/L and 4 mmol/L, respectively), mobile-phase pH (4.0), methanol volume fraction (20%, v/v), flow rate (1.0 mL/min), and temperature

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Fig. 3. Schematic description of the interaction system between anionic profen A− , CIL cation, free in the BGE or adsorbed onto the capillary wall, and ␤-CD derivatives. Reproduced from Ref. [77].

Fig. 2. Enantioseparations of phenylanaline, histidine, tryptophan, and tyrosine by HPLC. Mobile phase: 1 mM [C6 mim][Pro], 0.5 mM Cu(Ac)2 , and MeOH (15%, v/v) in water (pH 5.8); fluorescence detection: ex /em = 280 nm/348 nm for histidine, 215 nm/295 nm for phenylanaline, 270 nm/304 nm for tryptophan, 216 nm/295 nm for tyrosine; column: Ultimate XB C18 (150 mm × 4.6 mm i.d.); flow rate, 1 mL/min; temperature, 25 ◦ C. Reprinted with permission from Ref. [68].

(25 ◦ C). The application of all the optimum conditions (written in parentheses) provided a successful separation of the tryptophan enantiomers with a resolution value of 2.30, a selectivity factor of 1.25, and an elution time of 21 min. In 2014, Qing et al. from the same group utilized more AAILs in ligand-exchange chromatography for the separation of tryptophan. The same parameters mentioned above were examined in order to determine the optimum separation conditions. In addition, four kinds of AAILs were examined, and these include [l-Pro][CF3 COO], [l-Pro][NO3 ], [l-Pro]2 [SO4 ], and [l-Phe][CF3 COO]. The optimal separation conditions were: 8 mmol/L Cu(OAc)2 , 4 mmol/L [l-Pro][CF3 COO], 20% v/v methanol, and mobile-phase pH 3.6. Although, under these conditions, the tryptophan enantiomers were baseline separated, the resolution value (1.89) was smaller than that obtained in the previous study [70]. 3.2. CILs in capillary electrophoresis In contrast to HPLC and GC, there are more studies on the application of CILs in CE. However, in this case, the CILs are mainly used as BGE additives, and secondarily as chiral ligands and chiral selectors. Compared with the above-mentioned techniques, CE exhibits excellent chiral recognition power due to its advantages, which include low consumption of samples and solvents, high separation efficiency, fast migration times, versatility, and simple instrumentation [72,91]. 3.2.1. CILs as background electrolyte additives Thus far, most of the applications of CILs in analytical separations have been in the area of CE, and particularly as BGEs. In an attempt by Francois et al. [77] to demonstrate the chiral recognition ability of the CILs, they utilized two CILs (ethyland phenylcholine bis(trifluoromethylsulfonyl)imide, EtCholNTf2 , PhCholNTf2 ) for the enantioseparation of 2-arylpropionic acids (profens). However, no direct enantioselectivity was observed with regard to these model analytes; so, a CIL and a chiral selector (di- or Please cite this article in press as: http://dx.doi.org/10.1016/j.chroma.2014.05.059

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trimethyl-␤-cyclodextrin) were added in the BGE, and their effects on the above-mentioned enantioseparations were investigated. In particular, the synergistic effect between the two chiral selectors was examined by evaluating the nature and the concentration of both the CIL and CD, and the BGE concentration and hydro-organic composition. In some cases, the addition of the CIL resulted in an increase in selectivity and resolution. This is probably attributed to the increase in electroosmotic flow (EOF), which resulted from the increase in IL concentration and a possible wall adsorption. Even though no general trend was established, this last observation suggests that the synergistic effect observed may be due to specific ion-pairing interactions between the analyte and the CIL cation. Fig. 3 provides a schematic description of the interaction system that brings into play the three different entities: the analyte, the CIL and the ␤-CD derivative. Wang et al. reported two studies in 2009 about the combined use of 2,3,6-tri-O-methyl-␤-cyclodextrin (TM-␤-CD) and the CIL Nundecenoxy-carbonyl-l-leucinol bromide (l-UCLB), which formed micelles in aqueous BGEs, for the separation of profen drugs [78,79]. In the first study [78] different parameters were altered, such as the CIL concentration and chain length, in order to optimize the simultaneous enantioseparations of fenoprofen, ibuprofen, ketoprofen, suprofen, and indoprofen. The use of l-UCLB as a single chiral selector did not result in any enantioseparation, while the use of TM-␤-CD exhibited slight enantioselectivity. The association though between the CIL and the CD resulted in a baseline enantioseparation of almost all analytes (except from ibuprofen, which provided a resolution value of 1.32) (Fig. 4), and in an improvement in peak efficiency. The authors hypothesized that this improvement is due to the interaction between the two chiral selectors, which, in turn, reduces the interaction of the CIL with the capillary wall. In addition, they proved the applicability of the CIL to the quantitative determination of ibuprofen in commercial tablets. Their second study [79] was an investigation of the interactions among TM-␤-CD, l-UCLB and profens in affinity CE. Fenoprofen was used as a model compound that strongly interacts with TM-␤-CD. The apparent binding constant of the last to the CIL was estimated by nonlinear and linear plotting methods, while the binding constants of fenoprofen to the two chiral selectors were estimated by a secondary plotting approach. The analyte enantiomers have different binding constant values due to the synergistic effect of the chiral selectors, which, in turn, results in an effective enantioseparation. In a study performed by Hadjistasi et al. [80], two electrophoretic methods were developed for the chiral separation of the compounds fucose and pipecolic acid. In the case of pipecolic acid, whose detectability and sensitivity were improved by reacting it with 9-fluorenylmethoxycarbonyl chloride (FMOC-Cl), the addition of the CIL D-alanine tert-butyl ester lactate into the BGE improved

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Fig. 4. Simultaneous enantioseparation of profens in the absence (A) and presence (B) of l-UCLB. CE conditions: 5 mM NaOAc, 2.63 mM HOAc (pH 5.0) containing 35 mM TM-␤-CD (A), and 35 mM TM-␤-CD, 1.5 mM l-UCLB (B). Fused-silica capillary, 64.5 cm total length and 50 ␮m i.d.; separation temperature, 16 ◦ C; applied voltage, +30 kV; pressure injection, 30 mbar, 8 s. UV detection at 214 nm. Peaks identification: 11 = R-, S-ibuprofen; 22 = R-, S-fenoprofen; 33 = R-, S-indoprofen; 44 = R-, S-suprofen; 55 = R-, S-ketoprofen. Reprinted with permission from Ref. [78].

the resolution of the enantiomers. In particular, this CIL provided an increase in resolution from 1.41, obtained when ␤-CD was used as the sole chiral selector, to 1.87, obtained when both chiral selectors were added in the BGE. It is worth here to mention that this was the first time that an AAIL was used as an additive in the BGE to improve electrophoretic separations. Researchers from the China Pharmaceutical University investigated the synergistic effect with AAILs as additives for enantioseparations in CE [81–83]. In their first report [81], two novel AAILs, tetramethylammonium-l-arginine (TMA-l-Arg) and tetramethylammonium-l-aspartic acid (TMA-l-Asp), were applied, for the first time, in CE, in order to evaluate their potential synergistic effect with glycogen as chiral selector. Glycogen is an electrically neutral and branched polysaccharide that proved to be a good chiral selector for various basic and acidic drug compounds [98]. The chiral separation performance of the synergistic systems was evaluated by using three racemic drugs as model analytes (nefopam hydrochloride, citalopram hydrobromide, and duloxetine hydrochloride) and by varying several electrophoretic conditions, such as concentrations and BGE pH. When the TMA-lArg/glycogen and TMA-l-Asp/glycogen systems were applied, both resolution and selectivity were significantly improved, when compared to the single glycogen separation system. This suggests the existence of synergistic effect. In regard to the two AAIL/glycogen systems, TMA-l-Arg exhibited better enantioselectivity toward the examined drug compounds. This observation demonstrates that the structure and the properties of the chiral part of an AAIL have a significant effect on enantiorecognition. Another comparative study was performed between the performance of AAILs and an achiral IL (tetramethylammoium hydroxide, TMA-OH) in order to validate the puperiority of the synergistic effect. The results indicated that the achiral IL with the same cation can improve the enantioseparation, but not as much as in the case of the AAILs/glycogen synergistic systems. All these observations are illustrated in Fig. 5. Finally, the optimum separation parameters determined involved an AAIL concentration of 60 mM, a glycogen concentration of 2.5% (w/v), and a BGE pH of 3.0. A similar study was performed by using the AAILs l-alanine and l-valine tert butyl ester bis(trifluoromethane)sulfonamide

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Fig. 5. Typical electropherograms of the chiral separations of (A) nefopam hydrochloride, (B) citalopram hydrobromide, (C) duloxetine hydrochloride in different separation systems. Conditions: fused-silica capillary, 50 cm (41.5 cm effective length) × 50 ␮m i.d.; capillary temperature, 15 ◦ C; applied voltage, 20 kV; BGE, 40 mM Tris/H3 PO4 buffer (pH 3.0) containing: (a) 2.5% glycogen; (b) 2.5% glycogen + 60 mM TMA-OH; (c) 2.5% glycogen + 60 mM TMA-l-Asp; (d) 2.5% glycogen + 60 mM TMA-l-Arg. Reprinted with permission from Ref. [81].

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Fig. 6. Structures of the CILs l-AlaC4NTf2 and l-ValC4NTf2. Reproduced from Ref. [82].

(l-AlaC4 NTf2 and l-ValC4 NTf2 ) (Fig. 6) as additives and ␤-CD derivatives (methyl-␤-CD, hydropropyl-␤-CD, glucose-␤-CD) as chiral selectors in CE enantioseparations [82]. The synergistic effect was significant for half of the analytes examined, and particularly for naproxen, pranoprofen and warfarin. The novel synergistic system was optimized by using methyl-␤-CD/AAILs as model systems. Parameters similar to the previous study were examined, and the optimum conditions included 15 mM AAIL, 20 mM methyl-␤-CD, 30 mM sodium citrate/citric acid, and pH 5. Another important observation, in this study, was the improvement of both resolution and effective selectivity factor with the addition of an organic modifier, possibly due to a decrease in electroosmotic mobility, which, in turn, increases the interactions between the AAIL, methyl-␤-CD and analyte. In a more recent study, the vancomycin-based synergistic system with l-AlaC4 NTf2 and l-ValC4 NTf2 as additives was evaluated for the enantioseparation of five profens by using CE [83]. All enantioseparations were again significantly improved when the binary systems were used, and the resolution values were much higher than in the case where vancomycin was used as the sole chiral selector. More researchers from the Shenyang Pharmaceutical University focused on the combination of CILs that are commercially available and ␤-CDs for improved electrophoretic enantioseparations [84–86]. In one of their studies, they investigated the enantioseparation of twelve pharmaceutical compounds by adding ␤-CD and 1-alkyl-3-methylimidazolium-l-lactate in BGEs [84]. Their initial experiments involved the sole addition of ␤-CD. However, only partial chiral separation for most of the drug compounds was observed. Therefore, 1-alkyl-3-methylimidazolium-based IL, and particularly 1-ethyl-3-methylimidazolium-l-lactate, [EMIM][l-lactate], was added into the BGE, and the resolution improved significantly. For example, in the case of zopiclone and brompheniramine maleate, resolution was improved from 0.78 and 1.30 to 5.20 and 4.52, respectively. Only the enantiomers of venlafaxine were not baseline separated, even though the CIL addition provided an increase in resolution from 0.76 to 1.26. They also examined the effect of the chain length of the IL cations on the enantioseparations. The CILs differed only in terms of the alkyl group (ethyl- and butyl) in the imidazolium cation. [BMIM][l-lactate] provided slightly higher enantiomeric resolution in comparison to that observed

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in the presence of [EMIM][l-lactate], at the expense though of a longer analysis time. According to the authors, this observation was expected since shorter alkyl chains are less hydrophobic than the longer ones, and they form a less-stable bilayer inside the capillary. In another study performed by the same group, [EMIM][llactate] or [EMIM][dl-lactate] was used in combination with hydroxypropyl-␤-CD for the enantioseparation of ten drug compounds [85]. Their results proved once again that there was a synergistic effect between the two additives. In addition, in an effort to explore whether the chirality of the anionic part of the CIL affected the enantioseparation, [EMIM][dl-lactate] instead of [EMIM][l-lactate] was used in their experiments. The racemic CIL did not have an impact on either the migration time or the resolution of all analytes under study. Finally, the optimum conditions were applied to commercial tablets for the determination of the enantiomeric purity of S-ofloxacin. In one of their most recent reports, they employed a dual system of hydroxypropyl-␤-CD and three different types of ILs ([EMIM][l-lactate], N-methyl-N-ethylpyrrolidinium tetrafluoroborate (P12BF4), and dodecyl trimethyl ammonium chloride (DTAC)) for the simultaneous enantioseparation of four azole antifungals for the first time [86]. It should be noted that only one of the ILs used in this study was chiral ([EMIM][l-lactate]). All three ILs though were individually added in the optimum BGE, and the performance of the enantioseparation was evaluated in regard to resolution and effective electrophoretic selectivity. The presence of DTAC though proved to be more effective when compared to the other ILs, since all enantiomers were separated with resolution values higher than 2.5. 3.2.2. CILs as chiral ligands As mentioned in Section 3.1.2, the first application of AAILs as chiral ligands was reported by Liu et al. [68] in 2009. The AAIL [Cn mim][l-Pro] was used as a chiral ligand coordinated with copper (II), and four underivatized amino acids (phenylanaline, histidine, tryptophan, and tyrosine) were utilized as test analytes in HPLC and CE. In CE, the enantioselectivity was clearly lower than that in HPLC. According to the authors, this means that the separation in HPLC is facilitated more effectively by the different retention of amino acid-copper (II) complexes and uncomplexed amino acids

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than by their different electrophoretic mobilities in CE. Another important study involved the effect of the pH on the enantioseparation, since, in CE, the separation mainly depends on the difference in charge-to-mass ratio between amino acid-copper (II) complex and uncomplexed amino acid. At a low pH, the uncomplexed amino acid is more cationic than the neutral amino acid-copper (II) complex; so, it migrates faster than the latter. At a higher pH, the amino acid is less cationic, and the difference in electrophoretic mobilities between the ternary mixed complex and the uncomplexed amino acid is minimized. Thus, an increase in pH results in the deterioration of the enantioselectivity. Chiral ligand-exchange CE was also used by Zhang et al. [71] in order to evaluate the performance of [Cn mim][l-Lys] as chiral ligands in Zn(II) complexes. For this purpose, a comparative study was conducted between the performance of the systems Zn(II)-l-Lys and Zn(II)-[C6 mim][l-Lys]. The migration times of the three labeled amino acids in the first system were much shorter than the ones obtained when the second system was used. All the enantiomers eluted within 40 min in l-Lys system, while in the AAIL-mediated system, they eluted within ∼70 min. In both systems, the resolution values were very high, and they ranged from 3.8 to 5.6 (Zn(II)[C6 mim][l-Lys]) and from 2.1 to 6.5 (Zn(II)-l-Lys). More novel chiral ligands were synthesized by Mu et al. [72], and their performance was evaluated by using dansyl amino acids as model analytes. Four kinds of AAILs with l-proline (l-Pro) as the cation ([l-Pro][CF3 COO], [l-Pro][NO3 ], [l-Pro][BF4 ], and [lPro]2 [SO4 ]) were synthesized. [l-Pro][CF3 COO] was selected as the model ligand in order to optimize the separation parameters, which include the AAIL and the organic modifier (methanol) concentrations, and the BGE pH. Even though an increase in AAIL concentration increases resolution due to an increase in the adsorption onto the capillary wall and a decrease in the zeta potential and the EOF, a concentration of above 50 mM could not be used because of peak tailing, which resulted in a resolution decline. As far as the organic modifier is concerned, a 20% methanol was selected as the optimum condition. Enantioselectivity was indeed improved by the presence of methanol, possibly because the organic modifier influences the polarity and the viscosity of the BGE, and consequently the ligand-exchange reaction, which, in turn, results in an increase in resolution. Finally, a pH of 4.0 was considered as the optimum, since a further increase would cause high complex stability, which might cause a difficulty for the analytes to replace the ligands from the complexes. In 2014, new kinds of AAILs with pyridinium as cation and l-Lys as anion were developed and used as chiral ligands coordinated with Zn(II). Among the four AAILs that were synthesized and characterized, [1-ethylpyridinium][l-Lys] ([Epy][l-Lys]) was chosen as the optimum because it provided the best chiral separation of the dansyl amino acids. In this study, the effect of different key factors on the complex formation and the separation efficiency was investigated. A ratio of Zn (II) to ([Epy][l-Lys]) at 1:2 and a pH of 8.4 were then applied to investigate the specificity of substrates and the kinetic constants of l-amino acid oxidase (LAAO). Their results proved that this proposed method is a useful tool for studying the LAAO enzyme reaction mechanism. 3.2.3. CILs as chiral selectors Despite the numerous reports on the application of CILs in electrophoretic enantiomeric separation, only a few studies were performed by using CILs both as co-electrolytes and chiral selectors. In 2006, Yuan et al. [64], who was mentioned above in the sections of GC and HPLC, used the IL (R)-N,N,N-trimethyl2-aminobutanol-bis(trifluoromethanesulfon)imidate as the sole chiral selector in CE. This CIL was used as an additive in a BGE of 20 mM Na2 HPO4 –NaH2 PO4 or 20 mM Na2 B4 O7 . Fifteen enantiomeric compounds (tryptophan, 1-phenyl-1,2-ethanediol, Please cite this article in press as: http://dx.doi.org/10.1016/j.chroma.2014.05.059

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phenylalanine, 2-phenyl-1-propanol, tyrosine, propranolol, etc.) were examined, and the resolution values varied from 0.60 for di-O,O p-toluyl-tartaric acid to 6.80 for 3-benzyloxy-1,2-propane diol. An attempt was made by Tran and Mejac to utilize the CIL S-[3-(chloro-2-hydroxypropyl)trimethylammonium] [bis((trifluoromethyl)sulfonyl)amide] (S-[CHTA]+ [Tf2 N]− ) as a sole chiral selector for CE [74]. A number of pharmaceutical compounds were used to evaluate this new CIL, including ibuprofen, flurbiprofen, atenolol, and others. It is worth to mention that this CIL can be synthesized by a simple ion exchange reaction from the commercially available S-chloro-2-hydroxypropyl trimethylammonium chloride salt. Even though S-[CHTA]+ [Tf2 N]− can serve as a chiral selector, enantioseparation could not be achieved by using it as a sole chiral selector. Therefore, more BGE chiral additives were used, such as the chiral anion sodium cholate and the neutral chiral 1-S-octyl-␤-d-thioglucopyranoside (OTG). In the case of ibuprofen, the addition of the CIL and the anion chiral selector in the BGE resulted a better enantioseparation than in the case where all three chiral selectors were used. However, none of these BGE systems provided a baseline separation. On the other hand, a 20 mM of S-[CHTA]+ [Tf2 N]− , 30 mM of sodium cholate and a 10 mM of OTG resulted in a sufficient enantioseparation of fluriprofen (resolution though below 1.5). It is interesting to mention that no separation was obtained when sodium cholate was used as the sole chiral selector, while a slight enantiorecognition was observed when the CIL was also added into the BGE. These results are illustrated in Fig. 7. Ma et al. [75] explored the use of an ephedrine-based CIL, (+)N,N-dimethylephedrinium-bis(trifluoromethanesulfon)imidate ([DMP]+ [Tf2 N]− ) as both a chiral selector and a BGE in nonaqueous CE, and evaluated its performance by use of rabeprazole and omeprazole. The addition of [DMP]+ [Tf2 N]− resulted in a reversed EOF (anodic flow), possibly due to the adsorption of the cations onto the capillary wall. Therefore, the experiments were performed in the reversed polarity mode by using acetone as the EOF marker. Different separation conditions were examined, and the optimum BGE proved to be a mixture of acetonitrile–methanol (60:40) and 60 mM [DMP]+ [Tf2 N]− . The enantioseparations in this study were achieved mainly due to the different ion-pair formation equilibrium constants between the ephedrine-based CIL cations and the negatively charged enantiomers, and the hydrogen bonding, and secondarily due to other interactions, such as ␲–␲ interactions and dipole-dipole interactions. Yu et al. [76] from the same research group synthesized and applied a novel CIL functionalized ␤-CD (6-O-2tetrafluoroborate, hydroxypropyltrimethylammonium-␤-CD [HPTMA-␤-CD][BF4 ]) as a chiral selector in CE. Eight chiral drugs were examined, and their enantioseparations were optimized by studying the effect of the CIL concentration and the BGE pH. Increasing the concentration of [HPTMA-␤-CD][BF4 ] from 3 to 13 mg/mL, the migration times, the effective electrophoretic selectivity and the resolution were increased significantly. A further increase though to 27 mg/mL, resulted in an increase only in the elution times, while the other two examined factors were either reduced or unaffected. In addition, the excellent chiral discriminating ability of [HPTMA-␤-CD][BF4 ] was demonstrated by comparing the performance of the CIL with that of the native ␤-CD. Stavrou et al. [87] investigated the applicability of an AAIL as the sole chiral selector in CE for the first time. Five AAILs (l-alanine tert butyl ester bis(trifluromethane)sulfonamide (l-AlaC4NTf2), l-alanine methyl ester lactate (l-AlaC1Lac), l-AlaC2Lac and d-, l-AlaC4Lac) were synthesized and added separately in the BGE in order to evaluate their chiral recognition ability. Their performance was evaluated by using binaphthyl-2,2-diylhydrogenphosphate

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to be the optimum chiral selector because, at both concentrations, it provided resolution values of 1.94 and 2.43. As far as the anion is concerned, the resolution of BNP by use of l-AlaC4 NTf2 was slightly lower than the one obtained with the l-AlaC4 Lac, probably due to the low solubility of the first in water, which provides fewer cations and less interaction with the analyte. The configuration of the cation study did not result in any significant changes in resolution, even though a reversed elution order, as expected, was observed. According to the authors, it is concluded, from the studies performed in this report, that the enantioseparation mechanism is based on: (a) steric hindrance (tert butyl group), (b) electrostatic interactions (between the cation of the CIL and the negatively charged analyte) and (c) hydrogen bonding (hydrogen-bonding capability of the phosphate group in BNP). 4. Conclusion This review was performed to evaluate the suitability of the CILs in chiral analysis as chiral selectors, BGE additives, chiral ligands and chiral stationary phases. As demonstrated, CILs have, over the last few years, been proven to play a key role in enantioselective separation. Even though there are only a few studies, where CILs have been used in separation science, it is easy to conclude from the positive results mentioned above, that the future of CILs in this field is very promising and it is expected to expand substantially. References [1] [2] [3] [4] [5] [6] [7] [8] [9] Fig. 7. Electropherograms of a sample of (R,S)-flurbiprofen. Bare fused-silica capillary 50 cm (effective length, 37 cm) × 50 ␮m i.d. electrolyte: 50 mM sodium cholate (A); 20 mM S-[CHTA] + [Tf2 N]-, 30 mM sodium cholate (B); and 20 mM S[CHTA] + [Tf2 N]-, 30 mM sodium cholate and 10 mM OTG (C). Applied voltage: 18 kV for (A), 30 kV for (B) and (C). Reprinted with permission from Ref. [74].

(BNP) as the model analyte. Table 1 demonstrates the effect of the cation (different alkyl groups), the anion, and the configuration of the AAIL on resolution and Kaiser’s resolution factor (f/g). In the first case, l-AlaC1 Lac, l-AlaC2 Lac and l-AlaC4 Lac were used at concentrations of 60 mM and 100 mM. l-AlaC1 Lac did not demonstrate any enantioselectivity for BNP, while when l-AlaC2 Lac was used, at 60 mM a slight peak splitting was observed, and at 100 mM, BNP was partially separated. The CIL l-AlaC4 Lac proved Table 1 Effect of the cation, the anion and the configuration of the CIL on RS and f/g.

[10]

[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]

CIL

[CIL]a

tEOF

t1

t2

RS

f/g

[26] [27]

l-AlaC2 Lac

60 mM 100 mM

5.755 6.272

11.471 13.929

11.511 14.065

– 1.09

0.04 0.79

[28] [29]

l-AlaC4 Lac

60 mM 100 mM

6.207 6.650

12.702 13.064

12.922 13.377

1.94 2.43

1 1

D-AlaC4 Lac

60 mM

6.172

12.499

12.702

1.95

1

[30] [31] [32]

l-AlaC4 NTf2

60 mM

6.495

14.622

14.865

1.72

1

a

Concentration of the CIL added in the BGE. Other conditions: pH = 8; applied voltage, 30 kV; capillary temperature, 25 ◦ C; detection wavelength, 214 nm. Reproduced from Ref. [87].

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[33] [34] [35]

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Kapnissi-Christodoulou,

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al.,

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Chromatogr.

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(2014),