Ionic liquids in capillary electrophoresis for enantioseparation

Ionic liquids in capillary electrophoresis for enantioseparation

Accepted Manuscript Ionic liquids in capillary electrophoresis for enantioseparation Qi Zhang PII: S0165-9936(17)30169-3 DOI: 10.1016/j.trac.2018.0...

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Accepted Manuscript Ionic liquids in capillary electrophoresis for enantioseparation Qi Zhang PII:

S0165-9936(17)30169-3

DOI:

10.1016/j.trac.2018.01.001

Reference:

TRAC 15085

To appear in:

Trends in Analytical Chemistry

Received Date: 14 May 2017 Revised Date:

18 November 2017

Accepted Date: 1 January 2018

Please cite this article as: Q. Zhang, Ionic liquids in capillary electrophoresis for enantioseparation, Trends in Analytical Chemistry (2018), doi: 10.1016/j.trac.2018.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Ionic liquids in capillary electrophoresis for

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enantioseparation

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Qi Zhang * School of Pharmacy, Jiangsu University, Zhenjiang 212013, P.R. China

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*

Corresponding author at: School of Pharmacy, Jiangsu University, 301 Xuefu

Road, Zhenjiang, Jiangsu 212013, P. R. China.

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E-mail: [email protected]

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Tel./fax: +86 511 85038451

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Abstract: Ionic liquids (ILs) have received considerable attention in the separation science

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community due to their unique physical and chemical properties. Several excellent

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review articles on the application of ILs in analytical chemistry have been published.

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Rather than provide another comprehensive overview, this review focuses on the

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development and state-of-the-art of ILs in capillary electrophoresis (CE) for

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enantioseparation. The contents are divided into six sections according to the

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application modes of ILs, including achiral ILs modified conventional chiral

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separation

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ligand-exchange CE (LE-CE) system, ILs in micellar electrokinetic chromatography

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(MEKC), the development of novel ILs chiral selectors, and some other applications.

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The critical research questions and solutions of each application modes are

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systematically summarized. Existing problems and future prospects are also

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discussed.

ILs

synergistic

separation

system,

chiral

ILs

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chiral

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system,

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Keywords: Capillary electrophoresis; Enantioseparation; Ionic liquids; Chiral ionic

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liquids;

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chromatography; Chiral selectors

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Synergistic

system;

Ligand-exchange;

Micellar

electrokinetic

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Abbreviations: AAILs, Amino acid chiral ILs; BGE, Background electrolyte;

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[BMIM][OAc],

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1-Butyl-3-methylimidazolium L-Orn; CE, Capillary electrophoresis; CEC, Capillary

1-butyl-3-methylimidazolium

2

acetate;

[BMIM][L-Orn],

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electrochromatography; [CnMIM], 1-alkyl-3-methylimidazolium; [C2NH2MIM][Br],

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1-aminoethyl-3-methylimidazolium bromide; D-AlaC4Lac, D-Alanine tert butyl ester

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lactate;

[DMP][NTf2], (+)-N,N-dimethylephedrinium-bis(trifluoromethanesulfon)

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imidate;

[EMIM][L-lactate],

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electroosmotic flow; EtCholNTf2, Ethylcholine-bis(trifluoromethylsulfonyl) imide;

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[HPTMA-β-CD][BF4],

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tetrafluoroborate; ILs, Ionic liquids; K, Binding constants; L-AlaC4NTf2, L-alanine

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tert butyl ester bis(trifluoromethane) sulfonamide; L-Lys, L-lysine; L-Orn, L-ornithine;

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L-Pro, L-proline; L-UCLB,

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L-valine

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MEKC, Micellar electrokinetic chromatography; MWNTs, Multi-walled carbon

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nanotubes;

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oleyl-L-leucylvalinate;

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TMA-L-Asp,

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Tetramethylammonium-chloride;

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pantothenate

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Tetramethylammonium-L-arginine;

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hydroxyproline;

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Tetramethylammonium hydroxide; αeff, Effective selectivity factor.

L-lactate;

EOF,

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1-ethyl-3-methylimidazolium

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6-O-2-hydroxypropyltrimethylammonium-β-cyclodextrin

Undecenoxycarbonyl-L-leucinol bromide; L-ValC4NTf2,

tert butyl ester bis(trifluoromethane) sulfonamide; LE, Ligand-exchange;

Nonhydrolytic

sol–gel;

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NHSG,

TBA-L-Asp,

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TMA-D-PAN,

acid;

TMA-L-Hyp,

TMA-CL,

TMA-L-Arg,

Tetramethylammonium-L-

Tertramethylammonium-D-quinate;

3

acid;

Tertramethylammonium-D-

Tetramethylammonium-lactobionate;

TMA-D-QUI,

Polysodium

Tetrabutylammonium-L-aspartic

Tetramethylammonium-L-aspartic

TMA-LA,

poly-L-SOLV,

TMA-OH,

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1. Introduction Chirality is an intriguing feature of nature. It is also one of the intrinsic properties

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of biomolecules such as amino acids, proteins and carbohydrates (which in life

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science are known as the ‘‘building blocks of life’’). Thus, it is not difficult to

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understand that the biological systems are often sensitive to the stereoselectivities.

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This phenomenon is of particular relevance especially for the pharmaceutical science.

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The most obvious manifestation is that the enantiomers of a racemic drug often

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exhibit different pharmacological, toxicological, and biological activities. Taking

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β-adrenoreceptor blocking agents, one of the most commonly used antihypertensive

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drugs, as an example, their S-enantiomers usually possess great affinity for the

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β-adrenergic receptors, while the R-enantiomers may be much less active, inactive, or

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even have adverse effects. Therefore, the development of chiral separation methods is

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of great importance for drug discovery and quality control research. [1-3].

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A variety of analytical techniques have been developed for enantioseparation

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over the past few decades [4-9]. In addition to conventional chromatographic

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techniques (e.g. HPLC, GC), capillary electrophoresis (CE) has been shown to be a

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high-performance separation tool for enantiomeric separation due to its several

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advantages such as high separation efficiency, flexibility, as well as low consumption

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of sample, solvent and chiral selectors [10-13]. In CE, chiral separation is mainly

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achieved by the direct method in which a chiral selector is simply added to the

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background electrolyte (BGE). In many cases, however, satisfactory separation could

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not be achieved in these conventional separation systems without any modification.

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Therefore, researchers have been carrying out experiments to establish novel CE

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chiral separation systems by introducing various types of materials into the BGE such

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as ionic liquids (ILs), nanoparticles, metal–organic frameworks, etc. [14-17]. Among these materials, ionic liquids (ILs) are a group of organic salts with

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melting points below 100 °C or more often close to (or even below) room temperature.

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ILs possess unique physical and chemical properties, such as negligible vapor

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pressure, good thermal stability, relatively high conductivity, and moderate

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dissolvability. Besides, it is feasible to design and synthesize various task-specific ILs

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by changing their anion–cation combinations [18-20]. ILs have successfully been

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applied to many areas, including organic or inorganic synthesis [18, 19],

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electrochemical reactions [21], analytical chemistry [22-25], etc.

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The use of ILs in CE for enantioseparation has recently proven to be a promising

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approach. However, research in this area is still in its infancy and, to date, there are no

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systematic reviews focusing on the different application modes of ILs in CE

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enantioseparation. In 2014, Tang et al. [17] provided a comprehensive overview of

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recent advances of ILs in CE and capillary electrochromatography (CEC).

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Enantioseparation was mentioned, but only briefly discussed in short paragraphs.

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Kapnissi-Christodoulou et al. [26] later published a well-summarized review on the

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use of chiral ILs in chromatographic (HPLC, GC) and electrophoretic separations.

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However, “achiral ILs”-involved CE chiral separation systems were not mentioned.

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Also, the application modes of chiral ILs in CE can now be more specific since an

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increasing number of studies have been published in the past couple of years (Fig. 1).

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Readers can refer to these two papers and several latest published reviews [27, 28] for

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general background information about recent applications of ILs in chromatographic

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and capillary electrophoretic techniques. Rather than provide another overview of the applications of ILs in separation

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science, this review focuses on the development and state-of-the-art of ILs (including

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achiral and chiral ILs) in CE for enantioseparation. The contents are divided into six

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sections according to the application modes of ILs, including achiral ILs modified

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conventional chiral separation system, chiral ILs synergistic separation system, chiral

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ILs

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chromatography (MEKC), the development of novel ILs chiral selectors, as well as

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other applications. The critical research questions and solutions of each application

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mode are systematically summarized. Existing problems and development

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perspectives are also discussed.

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CE

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ligand-exchange

(LE-CE)

system,

ILs

in

micellar

electrokinetic

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Figure 1

2. ILs in CE chiral separation

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2.1 Achiral ILs modified conventional chiral separation system

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Typical achiral ILs used in CE enantioseparation include tetraalkylammonium

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ILs, alkylimidazolium ILs and alkylpyridinium ILs. Inorganic anions (e.g., OH , Cl ,

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Br , [BF4] , [PF6] ) usually serve as the anionic partners. Achiral ILs are able to

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modify the conventional chiral separation system and the mechanism is generally

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attributed to the following factors:

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(1) the ionic strength of running buffer could be changed with the addition of

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achiral ILs. This variation may affect the magnitude of electroosmotic flow (EOF) and

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the current strength, and thus cause changes in migration times as well as the

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separation efficiency [29-31].

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(2) the adsorption of IL cations on the capillary inner surface would reduce or even reverse the EOF, so as to influence the separation [29-31].

(3) the peak tailing of some basic enantiomers could be suppressed to some extent by the competitive adsorption of IL cations on the capillary inner wall [32].

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(4) some achiral ILs can participate in the enantiorecognition process, especially

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when cyclodextrins or their derivatives are used as chiral selectors (e.g. by influencing

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the formation of inclusion complex [30, 31]).

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Compared

with

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alkylimidazolium

or

alkylpyridinium-based

ILs,

tetraalkylammonium-based ILs seem to be a better choice in more cases, mainly due

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to two reasons: (1) tetraalkylammonium-based ILs are relatively more hydrophilic and

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less likely to occupy the hydrophobic cavity of chiral selectors (e.g. cyclodextrins or

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their derivatives). (2) tetraalkylammonium-based ILs are relatively less conductive

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and are UV transparent at wavelengths at which enantiomers are usually detected, so

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that they can be used in higher concentrations.

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In the reported literatures, the presence of achiral ILs was found essential for

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successful enantioseparation. However, the chiral recognition was still dependent on

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the interaction between enantiomers and chiral selectors according to the research by

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the authors. The main contribution of achiral ILs is to influence the EOF and peak

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efficiency of analytes, just as the mechanisms mentioned above. In other words, even

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ACCEPTED MANUSCRIPT though it is feasible to increase the resolution (Rs) of enantiomers to some extent by

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achiral ILs modification, the “achirality” of these ILs determines that the

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“enantiorecognition” capability (enantioselectivity, α) of chiral separation systems

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could not be significantly improved.

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2.2 Chiral ILs synergistic separation system

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“Synergism” usually means one plus one equals more than two (by cooperation).

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Chiral ILs, which have either a chiral cation or a chiral anion, or both, are particularly

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attractive for their potential applications to chiral discrimination (see typical chiral ILs

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used for CE enantioseparation in Fig. 2). A prominent advantage of chiral ILs

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compared with achiral ILs is that they can bring extra “enantiorecognition” capability

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while retaining the “system modification” capability. So here the term “synergistic

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system” is used because, in a number of cases (see representative electropherograms

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in Fig. 3), the enantioseparations can be remarkably improved with the cooperation of

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chiral ILs and traditional chiral selectors.

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Figure 2 Figure 3

The first report exploring the synergistic effect between chiral ILs and traditional

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chiral selectors was performed by François et al. in 2007 [33]. Two chiral ILs (ethyl-

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and

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Enantioseparation of selected model analytes was at first not obtained with chiral ILs

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alone. However, an increase in enantioresolution was observed when they were added

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into dimethyl-β-CDs or trimethyl-β-CDs separation system. The authors concluded

phenylcholine

of

bis(trifluoromethylsulfonyl)

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imide)

were

evaluated.

ACCEPTED MANUSCRIPT that the improvement in most cases was due to the increase in salt concentration and a

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possible wall adsorption (similar to the mechanism of achiral ILs). However,

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simultaneous increase in αeff (effective selectivity factor) and Rs was observed in

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several cases as compared to the simple salt effect, suggesting the existence of

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synergistic effect between chiral ILs and β-CDs.

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Several papers regarding the chiral ILs synergistic separation system have been

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published since then [34-43], but the conventional chiral selectors used in most cases

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were β-CDs or their derivatives (Table 1). Recently, a series of papers exploring the

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synergistic effect of chiral ILs with different types of conventional chiral selectors

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were also reported, including polysaccharides [44-46], antibiotics [47, 48], and

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cyclofructans [49]. Significantly improved enantioseparations were obtained in these

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synergistic systems compared with single chiral selector systems.

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Here in the synergistic systems, a critical issue is to prove whether the chiral ILs

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have truly participated in the enantiorecognition process. Take amino acid ILs

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(AAILs), the most commonly used chiral ILs, for example. Many attempts have been

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made by researchers and most of which are indirect methods, including:

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(1) the comparison of AAILs with EOF suppressor, e.g. AAILs versus organic

solvent [38].

(2) the comparison of chiral AAILs with achiral ILs which have the same achiral

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cation or anion, e.g. Tetramethylammonium-L-arginine (TMA-L-Arg) versus

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Tetramethylammonium-hydroxide (TMA-OH) [44].

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(3) the comparison of different AAILs with similar structures, e.g. TMA-L-Arg

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versus Tetramethylammonium-L-aspartic acid (TMA-L-Asp) [44]. (4) the comparison of AAILs with opposite configurations, e.g. TMA-L-Arg

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versus TMA-D-Arg [46, 50]. As expected, all these results validated the superiority of chiral AAILs; however,

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still no direct evidence was found to support the hypothesis that AAILs were involved

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in the enantiorecognition process because, in all the above studies, enantiomers cannot

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be separated when AAILs were used alone. It is worth mentioning that Rizvi and

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Shamsi first reported the use of amino acid (leucine and proline)-based long chain ILs

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as sole selector in 2006 [51]. Nice enantioseparations of some anionic compounds

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were obtained in MEKC mode. However, the long chain part of the AAILs is crucial

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because they can act as surfactants to form micelle in BGE. According to the authors,

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the electrostatic interaction between the acidic analyte and cationic micelle (AAILs)

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plays an important role in enantioseparation. That is, it is still uncertain whether the

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commonly used (e.g. short chain) AAILs have the “enantiorecognition” contribution

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during separation. Eventually in 2013, Stavrou et al. [52] first reported the use of

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chiral AAILs as a sole chiral selector in CZE for direct enantioseparation. Five amino

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acid

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diylhydrogenphosphate as a model analyte. In particular, the effect of amino acid

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cation configuration (L-alanine methyl ester lactate and D-alanine methyl ester lactate)

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on enantioseparation was studied and, as expected, a reversed elution order was

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observed, which sufficiently proved the enantiorecognition capability of AAILs.

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ester-based

chiral

ILs

were

evaluated

with

binaphthyl-2,2-

The chiral ILs synergistic separation system is the most studied application mode

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ACCEPTED MANUSCRIPT of ILs in chiral CE (see Fig. 1) due to their outstanding separation performance and

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convenient establishment. However, most papers were still restricted to the report of

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the separation results with the combinations of various chiral ILs and conventional

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chiral selectors, rather than explore the separation mechanisms and, especially, the

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combination rules. This is understandable because the chiral ILs synergistic separation

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system is a very complex ternary system of chiral ILs, chiral selectors, and

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enantiomers. Some approaches such as the spectroscopy and molecular simulation [42,

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45] have recently been introduced to analyze the separation mechanism, but the

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results are still preliminary. Further investigations are warranted to define the precise

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role of chiral ILs during separations.

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Table 1

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2.3 Chiral ILs ligand-exchange system

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The mechanism of chiral LE-CE is based on the different mobility of the

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diastereomeric ternary mixed metal complexes between chiral ligands (CL) and

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different enantiomers [53]:

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( L-AA + [CL]nM ↔ [CL]n-1M[L-AA] + CL )

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( D-AA + [CL]nM ↔ [CL]n-1M[D-AA] + CL ) Chiral ILs can be used as ligands and their first application in LE-CE was

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reported by Liu et al. in 2009 [54], in which four pairs of underivatized amino acid

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enantiomers (phenylalanine, histidine, tryptophane and tyrosine) were successfully

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separated

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([CnMIM][L-Pro]), as a chiral ligand. Here, a natural question is whether it is

by

using

an

AAILs,

1-alkyl-3-methylimidazolium

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L-proline

ACCEPTED MANUSCRIPT necessary to use AAILs in LE-CE since it is well known that the amino acids

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themselves (e.g. L-Pro) are already qualified as chiral ligands [53]. For comparison,

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the performance of another two LE-CE systems were evaluated in this work including

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“single L-Pro ligand” system and “the combined use of L-Pro and [CnMIM][Br] salt”

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system. As a result, their performances were both inferior to the AAIL ligands,

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because the formation of alkylimidazolium cations and L-Pro ion pairs on the capillary

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inner surface without the [Br]- interference can induce an ion-exchange type of

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retention for the DL-enantiomers.

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A series of novel chiral ILs were synthesized and applied as chiral ligands in CE

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by Qi’ group [55-60]. AAILs with L-lysine (L-Lys) as anions and [CnMIM] as cations

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was used to separate dansylated amino acids enantiomers, seven pairs of model

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analytes were baseline separated in the Zn(II)-[C6MIM][L-Lys] system [57]. A follow

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up study with L-lysine (L-Lys) as anions and pyridinium as cations was performed

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recently [58], the best chiral separation of dansylated amino acids could be achieved

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when [1-ethylpyridinium][L-Lys] was chosen as the chiral ligand and Zn(II) as the

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central ion. In both studies, “Single amino acid ligand” systems and “the combined

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use of amino acids and imidazolium/pyridinium salt” system were also tested to

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validate the superiority of AAIL ligands. Another chiral ILs with L-ornithine (L-Orn)

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and L-alanine (L-Ala) as anion were synthesized by the same group and successfully

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used to establish LE-CE system for enantioseparation [56, 59].

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It is worth noting that the amino acid residues all existed as anions in AAILs in

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above studies (Table 2). In an effort to evaluate the enantiorecognition capability of

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ACCEPTED MANUSCRIPT AAILs with amino acid as cations, four novel chiral ILs with (L-Pro) as cations,

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including [L-Pro][CF3COO], [L-Pro][NO3], [L-Pro][BF4] and[L-Pro2][SO4], were

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successfully synthesized [55]. Effective separations could be achieved by using these

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AAILs as ligands and Cu(II) as the central ion, indicating that AAILs with amino

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acids as cations also have the potential to establish LE-CE system.

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In 2015, a ligand-exchange micellar electrokinetic chromatography system

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(LE-MEKC) was reported by Liu et al. [61], in which a novel AAIL,

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tetramethylammonium L-hydroxyproline (TMA-L-Hyp), was synthesized and utilized

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as a ligand. The authors evaluated both LE-CE and LE-MEKC system and it turned

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out that the LE-MEKC system yielded better separations toward most selected

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aromatic amino acids.

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Table 2

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2.4 ILs in micellar electrokinetic chromatography MEKC has been proved to be a powerful technique for the separation of both

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charged and neutral analytes [62]. Usually, a surfactant is added to the run buffer to

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form micelles as a pseudo-phase. In some cases, additional modifiers are also needed

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in order to improve separation efficiency and selectivity. Herein, ILs can be used as

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either modifiers or surfactants.

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2.4.1 ILs as modifiers

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Mwongela et al. [63] reported the first use of ILs as modifiers for the separation

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of

three

chiral

binaphthyl

derivatives

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alky-imidazolium/pyridinium ILs were tested with polysodium oleyl-L-leucylvalinate

13

in

MEKC.

Three

short-chain

ACCEPTED MANUSCRIPT (poly-L-SOLV) as surfactant. The ILs were shown to improve the resolution and peak

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efficiency of the analytes while maintaining adequate background current. The same

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group later investigated the effects of adding [CnMIM][BF4] ILs as compared to

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adding conventional molecular organic solvents (MeOH, 1-PrOH and ACN) on chiral

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separation in MEKC [64]. As observed by the authors, the ILs generally led to faster

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separations of chiral analytes without adversely affecting the current, while high

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volumes of molecular organic solvents in the buffer led to current breakdowns. In

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addition, smaller IL volumes were needed, as compared to molecular organic solvents,

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in order to achieve equivalent separations.

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2.4.2 ILs as surfactants

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Long chain ILs can also be used as surfactant in MEKC for enantioseparation.

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For

this

purpose,

two

amino

acid-derived

chiral

ILs,

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undecenoxycarbonyl-L-pryrrolidinol bromide, and undecenoxycarbonyl-L-leucinol

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bromide were synthesized in both monomeric and polymeric forms by Rizvi and

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Shamsi [51] to separate several acidic analytes. Electrostatic interaction between the

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acidic analytes and cationic micelle was found to be critical to chiral recognition.

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Wang et al. [65, 66] published two consecutive articles demonstrating the

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combination of ILs surfactants and β-CDs for MEKC. Five profen drugs were

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simultaneously separated by MEKC with the combined use of trimethyl-β-CDs and a

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chiral cationic IL, undecenoxycarbonyl-L-leucinol bromide (L-UCLB), which formed

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micelles in aqueous buffers [65]. The concepts of enzymatic reactions were then

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successfully applied to determine the competitive inhibition mechanism of the

AC C

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14

ACCEPTED MANUSCRIPT separation system [66]. In a recent work by Liu and Shamsi [67], five long chain ILs

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with different amino acid head groups were synthesized and employed as surfactants

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to establish MEKC system with trimethyl-β-CDs as chiral selector. It was found that

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the IL head groups had a significant effect on enantioseparation of neutral compounds

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(Fig. 4). The binding constants (K) between the ILs–CDs complexes and the

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enantiomers were estimated using a y-reciprocal linear method. The K values of each

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enantiomer was found to be increased with increasing size of the head group,

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indicating strong contribution from hydrophobic interaction imparted by the amino

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alcohol side chain of the IL surfactants.

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Figure 4

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2.5 Development of ILs chiral selectors

The development of novel chiral selectors remains an interesting work [68].

305

However, research regarding the development of ILs as chiral selectors has been

306

making slow progress. This is due to that, most chiral ILs synthesized in the past years

307

were designed for asymmetric synthesis or as stationary phase materials in

308

chromatographic

309

enantioseparation by electrophoretic techniques. Some of these existing chiral ILs

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were selected and tested as chiral selectors in CE, but relevant reports are still scarce

311

because of the above reason. Interestingly, new ideas have recently emerged on how

312

to “design” novel ILs chiral selectors. Related works are summarized as follows.

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2.5.1 By screening

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(or

other

applications),

rather

than

for

direct

AC C

studies

An (R)-N,N,N-trimethyl-2-aminobutanol-bis(trifluoromethanesulfon) imidate IL

15

ACCEPTED MANUSCRIPT was synthesized in 2002 by Wasserscheid et al. [69]. The authors indicated that the IL

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may be an interesting solvent for enantioselective reactions and also useful in chiral

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separation techniques. It was then selected by Yuan et al. [70] and successfully used

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as sole chiral selector in CE. Several drug enantiomers were separated with the

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resolution values varied from 0.60-6.80.

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An ephedrine-based chiral IL, (+)-N,N-dimethylephedrinium-bis(trifluoro-

321

methanesulfon) imidate ([DMP][NTf2]), was at first synthesized and utilized as the

322

stationary phase in GC for enantioseparation [71]. It was then selected by Ma et al.

323

[72] and served as both a chiral selector and a BGE in nonaqueous CE. According to

324

the authors, the ion-pair interaction between the ephedrine cation and the negatively

325

analytes (rabeprazole and omeprazole) as well as the supplementary hydrogen

326

bonding were the main mechanism for enantioseparation.

TE D

M AN U

SC

320

AAILs are extensively studied in the past decade for asymmetric synthesis and

328

other purposes. The structures of AAILs can be various as shown in Fig. 2. In 2013,

329

Stavrou et al. [52] first reported the use of chiral AAILs as sole chiral selector in CZE

330

for direct enantioseparation and, thus, explicitly demonstrated the enantiorecognition

331

capability of AAILs (Fig. 5, see details in Section 2.2).

333

AC C

332

EP

327

Figure 5

2.5.2 By design

334

New ideas have recently emerged on how to “design” novel ILs chiral selectors,

335

that is, the evolution of ILs chiral selectors from conventional chiral selectors (e.g.

336

β-CDs, saccharides).

16

ACCEPTED MANUSCRIPT 337

Yu

et

al.

[73]

synthesized

a

β-CDs-based

chiral

ILs,

6-O-2-hydroxypropyltrimethylammonium-β-cyclodextrin

tetrafluoroborate

339

([HPTMA-β-CD][BF4]). The novel chiral IL not only has better solubility in aqueous

340

buffer but also provided a stable reversed EOF during separation. Eight pairs of drug

341

enantiomers were separated with [HPTMA-β-CD][BF4] as the chiral selector, and

342

remarkable improved enantioseparation capability was observed in comparison with

343

the parent β-CDs.

SC

RI PT

338

Another work was reported recently by Zhang et al. [32], in which the authors

345

designed a lactobionic acid (LA)-based IL, tetramethylammonium-lactobionate

346

(TMA-LA), and found that the chiral separation capability can be significantly

347

improved when the conventional saccharide chiral selector (LA) evolved into an IL

348

chiral selector (TMA-LA). A comparative study using LA as the chiral selector and

349

tetramethylammonium chloride (TMA-Cl) as a buffer additive (LA + TMA-Cl system)

350

was performed to evaluate whether it was necessary to synthesize IL chiral selector

351

(TMA-LA), and the results indicated that the use of TMA-LA IL cannot be

352

considered as a simple combination of LA and TMA salt. It is worth noting that the

353

peak tailing problems can also be improved in the TMA-LA system due to the

354

existence of TMA+ in the run buffer. These observations showed the theoretical

355

possibility of developing multifunctional ILs chiral selectors which have the

356

combined properties of “enantiorecognition” and “system modification”.

357

2.6 Other applications

358

AC C

EP

TE D

M AN U

344

Some other applications of ILs for CE chiral separation can also be found in

17

ACCEPTED MANUSCRIPT recent publications. An IL-mediated nonhydrolytic sol–gel (NHSG) protocol was

360

explored by Wang et al. [74] for the fabrication of new molecularly imprinted

361

silica-based hybrid monoliths. The role of the incorporated ILs ([BMIM][PF6] and

362

[BMIM][BF4]) was to reduce gel shrinkage and also to act as the pore template.

363

Successful separation of zolmitriptan enantiomers was achieved by CEC. Effects of

364

ILs on the performance of the polymer monoliths were investigated, and the results

365

showed that the incorporation of ILs increased the porosity, and thus improved the

366

selectivity of the prepared hybrid monoliths.

M AN U

SC

RI PT

359

Stavrou et al. [75] described an ILs-involved facile preparation of

368

polysaccharide-coated capillaries for CEC. Three water-insoluble cellulose-based

369

polysaccharides (cellulose acetate, cellulose acetate phthalate, and cellulose acetate

370

butyrate) were each dissolved into a 1-butyl-3-methylimidazolium acetate IL

371

([BMIM][OAc]) to prepare stationary phases. The IL can be easily removed by

372

rinsing the modified capillary with water after the coating process. Enantioseparations

373

were achieved by CEC using these cellulose-coated capillaries. Another application

374

utilizing the dissolving power of ILs was reported by Zhang et al. [76], in which a

375

1-aminoethyl-3-methylimidazolium bromide ([C2NH2MIM][Br]) IL was used to

376

disperse water-insoluble multi-walled carbon nanotubes (MWNTs). The ILs coated

377

MWNTs was then used as a modifier in CE to enantioseparate several basic drugs

378

with chondroitin sulfate E as the chiral selector.

379

3. Conclusions and perspectives

380

AC C

EP

TE D

367

As summarized in this review, the attractive feature of ILs makes them possible

18

ACCEPTED MANUSCRIPT 381

to be performed in various modes for CE chiral separation. Achiral ILs modified conventional chiral separation system is a simple and

383

convenient way to improve enantioseparation. However, chiral ILs synergistic system

384

has recently attracted more attention, and has shown its superiority because chiral ILs

385

can usually bring extra enantiorecognition capability to the separation system while

386

retaining the system modification capability.

RI PT

382

Chiral ILs LE-CE or LE-MEKC system will continue to be an effective way to

388

separate amino acid enantiomers. It is worth noting that research on Chiral ILs as

389

ligands in dual central metal ion LE-CE system and dual chiral selector system is still

390

scarce.

M AN U

SC

387

ILs-MEKC system is a flexible method because ILs here can be used as either

392

modifiers (short chain ILs), or surfactants (long chain ILs). Moreover, when a chiral

393

long chain IL is used, enantiomers are likely to be separated without the help of

394

additional chiral selectors. But long chain ILs are not easily available. Existing

395

systems should be expanded to cover more types of long chain ILs and analytes.

EP

TE D

391

The development of novel ILs chiral selectors will receive more attention in

397

future research, because the design and synthesis of various task-specific ILs enable

398

researchers to explore versatile chiral selectors which have multiple recognition and

399

modification functions.

AC C

396

400

It is worth mentioning that, there is a debate in the chiral CE community over the

401

state of ILs in the separation process. Some analysts argue that once an IL is dissolved

402

in a solvent, there is no longer an IL present but merely the independent cations and

19

ACCEPTED MANUSCRIPT anions. Thus, it is not necessary to use an IL since the addition of the independent

404

cations and anions seems able to do the same work. But In fact more and more

405

comparison studies have proved that the use of ILs cannot be considered as a simple

406

combination of cations and anions. Unique properties can always be found when

407

using ILs in chiral CE. Nevertheless, the mechanism underlying the superior

408

performance of ILs (especially chiral ILs) is still not completely elucidated. Further

409

investigations are needed to define the precise role of ILs during separation, which in

410

turn helps researchers to develop ILs-involved chiral separation systems more

411

efficiently.

M AN U

SC

RI PT

403

Also, it is expected that some novel application modes of ILs in chiral CE will be

413

explored, among which the design of chiral ILs stationary phase in CEC is worthy of

414

attention considering its successful application in GC and HPLC chiral columns.

EP AC C

415

TE D

412

20

ACCEPTED MANUSCRIPT 416

Acknowledgements This work was supported by the Project of National Natural Science Foundation

418

of China (No.: 81703465), the Natural Science Foundation of Jiangsu Province (No.:

419

BK20170533), and the Senior Talent Cultivation Program of Jiangsu University (No.:

420

16JGD055).

421

Conflict of interest

423

The authors have declared no conflict of interest.

M AN U

422

SC

RI PT

417

424

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[71] J. Ding, T. Welton, D.W. Armstrong, Chiral Ionic Liquids as Stationary Phases in

634

Gas Chromatography, Anal. Chem. , 76 (2004) 6819-6822.

635

[72] Z. Ma, L. Zhang, L. Lin, P. Ji, X. Guo, Enantioseparation of rabeprazole and

AC C

EP

TE D

M AN U

SC

RI PT

614

30

ACCEPTED MANUSCRIPT omeprazole by nonaqueous capillary electrophoresis with an ephedrine-based ionic

637

liquid as the chiral selector, Biomed. Chromatogr. , 24 (2010) 1332-1337.

638

[73] J. Yu, L. Zuo, H. Liu, L. Zhang, X. Guo, Synthesis and application of a chiral

639

ionic liquid functionalized β-cyclodextrin as a chiral selector in capillary

640

electrophoresis, Biomed. Chromatogr. , 27 (2013) 1027-1033.

641

[74] H. Wang, Y. Zhu, J. Lin, X. Yan, Fabrication of molecularly imprinted hybrid

642

monoliths via a room temperature ionic liquid-mediated nonhydrolytic sol-gel route

643

for

644

Electrophoresis, 29 (2008) 952-959.

645

[75] I.J. Stavrou, L. Moore, Jr., V.E. Fernand, C.P. Kapnissi-Christodoulou, I.M.

646

Warner, Facile preparation of polysaccharide-coated capillaries using a room

647

temperature ionic liquid for chiral separations, Electrophoresis, 34 (2013) 1334-1338.

648

[76] Q. Zhang, Y. Du, S. Du, Evaluation of ionic liquids-coated carbon nanotubes

649

modified chiral separation system with chondroitin sulfate E as chiral selector in

650

capillary electrophoresis, J. Chromatogr. A 1339 (2014) 185-191.

zolmitriptan

by

SC

of

capillary

electrochromatography,

M AN U

separation

AC C

EP

TE D

chiral

RI PT

636

31

ACCEPTED MANUSCRIPT 651

Figure captions:

652 653

Fig. 1. Number and distribution of publications using ILs in CE for chiral separation.

655

RI PT

654

Fig. 2. Structures of the typical chiral ILs used for enantioseparation.

656

Fig. 3. Typical electropherograms with the absence and presence of chiral ILs for

658

enantioseparation with (A) Me-β-CD for naproxen, (B) Me-β-CD for pranoprofen, (C)

659

HP-β-CD for naproxen and (D) Glu-β-CD for naproxen.

660

CE Conditions: fused-silica capillary, 33 cm (24.5 cm effective length) × 50 µm id; 30

661

mM sodium citrate/citric acid buffer solution with 20% (v/v) ethanol for naproxen or

662

20% (v/v) acetonitrile for pranoprofen, containing (A) and (B) (a) 20 mM

663

Methyl-β-CDs; (b) 20 mM Methyl-β-CDs + 15 mM

664

Methyl-β-CDs + 15 mM L-ValC4NTf2; (C) (a) 30 mM Hydropropyl-β-CDs; (b) 30

665

mM Hydropropyl-β-CDs + 15 mM L-AlaC4NTf2; (c) 30 mM Hydropropyl-β-CDs +

666

15 mM L-ValC4NTf2, (D) (a) 30 mM Glucose-β-CDs; (b) 30 mM Glucose-β-CDs +

667

15 mM L-AlaC4NTf2; (c) 30 mM Glucose-β-CDs + 15 mM L-ValC4NTf2; pH 5.0;

668

applied voltage, 20 kV; capillary temperature, 25 °C. Adapted from [38].

M AN U

TE D

(c) 20 mM

EP

L-AlaC4NTf2;

AC C

669

SC

657

670

Fig. 4. Enantioseparation of BOH using 30 mM TM-β-CD only and 30 mM

671

TM-β-CD with 1 mM of IL surfactant with various head groups. Running buffer: 10

672

mM NaOAc, pH 5.0. Adapted from [67].

32

ACCEPTED MANUSCRIPT Fig. 5. Electropherograms of racemic BNP obtained with different chiral ionic liquids

674

in the BGE. (A) 60 and 100 mM L-AlaC2Lac; (B) 60 and 100 mM L-AlaC4Lac. Other

675

conditions: BGE, 100 mM Tris/10 mM borate pH 8, applied voltage 30 kV, capillary

676

temperature 25 °C, detection wavelength 214 nm. Adapted from [52].

RI PT

673

AC C

EP

TE D

M AN U

SC

677

33

Table 1. Chiral ILs synergistic separation systems Chiral selectors

Analytes

Ref.

Dimethyl-β-CDs; Trimethyl-β-CDs

Ethyl-bis(trifluoromethylsulfonyl)imide; Phenylcholine-bis(trifluoromethylsulfonyl) imide

Carprofen; Suprofen; Naproxen; Ketoprofen; Indoprofen; Ibuprofen

[33]

Heptakis(2,3-di-O-methyl6-O- sulfo)-β-CDs (HDMS-β-CDs)

Ethylcholine-bis(trifluoromethylsulfonyl) imide (EtCholNTf2)

Benzopyran derivatives

[34]

Methyl-β-CDs; Hydropropyl-β-CDs; Glucose-β-CDs

tert butyl ester bis (trifluoromethane) sulfonamide (L-AlaC4NTf2); L-valine tert butyl ester bis (trifluoromethane) sulfonamide (L-ValC4NTf2)

β-CDs

D-alanine

Naproxen; Pranoprofen; Warfarin

[38]

DL-pipecolic

[37]

SC

tert-butyl ester lactate

RI PT

L-alanine

acid

Zopiclone; Repaglinide; Chlorphenamine; Brompheniramine; Dioxopromethazine, etc (12 drugs).

1-ethyl-3-methylimidazolium- L-lactate ([EMIM][L-lactate])

β-CDs

Tetrabutylammonium- L-aspartic acid (TBA- L-Asp)

β-CDs

Tetrabutylammonium-L-arginine Ephedrine; (TBA-L-Arg) Pseudoephedrine; Different AAILs with TBA as a cation and Methylephedrine AA as an anion

TE D

M AN U

β-CDs

Hydroxypropyl-β-CDs

Trimethyl-β-CDs

Hydropropyl-β-CDs; Methyl-β-CDs; Glucose-β-CDs

DL-phenylalanine; DL-tryptophan

[35]

[40]

[43]

1-ethyl-3-methylimidazolium- L-lactate ([EMIM][L-lactate])

Ofloxacin; Propranolol; Dioxopromethazine; Isoprenaline; Chlorpheniramine; Liarozole, etc (10 drugs).

[36]

Tetrabutylammonium-L-aspartic acid (TBA-L-Asp)

Quinine/Quinidine; Cinchonine/Cinchonidine

[39]

tert butyl ester lactate (L-AlaC4Lac)

Ibuprofen; Ketoprofen; Carprofen; Indoprofen; Flurbiprofen; Naproxen; Fenoprofen

[41]

1-butyl-3-methylimidazolium(T-4)-bis[(2S) -2-(hydroxy-κO)-3-methyl-butanoato-κO] borate (BMIm+BLHvB-); 1-butyl-3-methylimidazolium(T-4)-bis[(αS) -α-(hydroxy-κO)-4-methyl-benzeneacetatoκO]borate (BMIm+BSMB-)

Amlodipine; Duloxetine; Nefopam; Propranolol; Tropicamide

[42]

EP

Hydroxypropyl-β-CDs

AC C

β-CDs

Chiral ILs

ACCEPTED MANUSCRIPT

L-alanine

Tetramethylammonium-L-arginine (TMA-L-Arg), Tetramethylammonium-L-hydroxyproline ACCEPTED (TMA-L-Hyp) MANUSCRIPT Tetramethylammonium-L-isoleucine (TMA-L-Ile)

Hydropropyl-β-CDs

[50]

Nefopam; Citalopram; Duloxetine

[44]

Maltodextrin

Tertramethylammonium-D-pantothenate (TMA-D-PAN), Tertramethylammonium-D-quinate (TMA-D-QUI)

Nefopam; Ketoconazole; Econazole; Voriconazole

[45]

Maltodextrin

Tetramethylammonium-L-arginine (TMA-L-Arg); Tetramethylammonium-L-aspartic acid (TMA-L-Asp)

Nefopam; Citalopram; Cetirizine; Duloxetine; Ketoconazole

[46]

Naproxen; Carprofen; Ibuprofen; Ketoprofen; Pranoprofen

[47]

Clindamycin phosphate

Tetramethylammonium-L-hydroxyproline (TMA-L-Hyp)

Propranolol; Nefopam; Citalopram; Chlorphenamine

[48]

Cyclofructans

D-Alanine tert butyl ester lactate (D-AlaC4Lac)

Huperzine A; Warfarin; Coumachlor

[49]

SC

RI PT

Glycogen

Tetramethylammonium-L-arginine (TMA-L-Arg); Tetramethylammonium-L-aspartic acid (TMA-L-Asp)

M AN U

Polysaccharides

Amlodipine; Duloxetine; Nefopam; Propranolol;

L-alanine

TE D

EP

Others

Vancomycin

AC C

Antibiotics

tert butyl ester bis (trifluoromethane) sulfonamide (L-AlaC4NTf2); L-valine tert butyl ester bis (trifluoromethane) sulfonamide (L-ValC4NTf2)

Table 2. Chiral ILs ligand-exchange systems

ACCEPTED MANUSCRIPT

1-alkyl-3-methylimidazolium L-proline ([CnMIM][L-Pro], n=2,4,6,8)

1-alkyl-3-methylimidazolium L-proline ([CnMIM][L-Lys], n=4,6,8)

Ref.

Cu(II)

Phenylalanine; Histidine; Tryptophane; Tyrosine

[54]

Zn(II)

Dansylated isoleucine; Dansylated methionine; Dansylated serine; Dansylated threonine; Dansylated tyrosine, etc. (7 dansylated AAs).

[57]

Dansylated alanine; Dansylated methionine; Dansylated serine; Dansylated threonine; Dansylated tyrosine, etc. (11 dansylated AAs).

[58]

Dansylated serine; Dansylated methionine; Dansylated isoleucine; Dansylated phenylalanine; Dansylated tyrosine, etc. (14 dansylated AAs).

[56]

Cu (II)

Tryptophan; Phenylalanine; Histidine; Tyrosine; DOPA

[61]

Mn(II)

Dansylated threonine; Dansylated tyrosine; Dansylated isoleucine; Dansylated serine, etc. (20 dansylated AAs).

[59]

Cu (II)

Dansylated alanine; Dansylated methionine; Dansylated serine; Dansylated threonine; Dansylated tyrosine, etc. (9 dansylated AAs).

[55]

Cu (II)

Dansylated asparagine; Dansylated methionine; Dansylated serine, etc. (8 dansylated AAs).

[60]

Zn(II)

M AN U

1-ethylpyridinium L-lysine; 1-butylpyridinium L-lysine; 1-hexylpyridinium L-lysine; 1-octylpyridinium L-lysine

Analytes

Zn(II)

TE D

1-butyl-3-methylimidazolium L-ornithine ([BMIM][L-Orn])

AC C

EP

Tetramethylammonium-L-hydroxyproline (TMA-L-Hyp)

1-butyl-3-methylimidazolium L-alanine ([BMIM]-[L-Ala])

Chiral cations

[L-Pro][CF3COO]; [L-Pro][NO3]; [L-Pro][BF4]; [L-Pro2][SO4]

[L-Phn][CF3COO]2

RI PT

Chiral anions

Central Metal Ions

SC

Chiral ILs

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 2

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 3

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 4

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 5

ACCEPTED MANUSCRIPT Highlights:  Achiral and chiral Ionic liquids used in CE enantioseparation are summarized.  Classification of ionic liquids-involved CE chiral separation systems.

AC C

EP

TE D

M AN U

SC

 The possible future trends are discussed.

RI PT

 Critical research questions and solutions of each application modes.