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
3
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
12
community due to their unique physical and chemical properties. Several excellent
13
review articles on the application of ILs in analytical chemistry have been published.
14
Rather than provide another comprehensive overview, this review focuses on the
15
development and state-of-the-art of ILs in capillary electrophoresis (CE) for
16
enantioseparation. The contents are divided into six sections according to the
17
application modes of ILs, including achiral ILs modified conventional chiral
18
separation
19
ligand-exchange CE (LE-CE) system, ILs in micellar electrokinetic chromatography
20
(MEKC), the development of novel ILs chiral selectors, and some other applications.
21
The critical research questions and solutions of each application modes are
22
systematically summarized. Existing problems and future prospects are also
23
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
26
liquids;
27
chromatography; Chiral selectors
28
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Synergistic
system;
Ligand-exchange;
Micellar
electrokinetic
29
Abbreviations: AAILs, Amino acid chiral ILs; BGE, Background electrolyte;
30
[BMIM][OAc],
31
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],
33
1-aminoethyl-3-methylimidazolium bromide; D-AlaC4Lac, D-Alanine tert butyl ester
34
lactate;
[DMP][NTf2], (+)-N,N-dimethylephedrinium-bis(trifluoromethanesulfon)
35
imidate;
[EMIM][L-lactate],
36
electroosmotic flow; EtCholNTf2, Ethylcholine-bis(trifluoromethylsulfonyl) imide;
37
[HPTMA-β-CD][BF4],
38
tetrafluoroborate; ILs, Ionic liquids; K, Binding constants; L-AlaC4NTf2, L-alanine
39
tert butyl ester bis(trifluoromethane) sulfonamide; L-Lys, L-lysine; L-Orn, L-ornithine;
40
L-Pro, L-proline; L-UCLB,
41
L-valine
42
MEKC, Micellar electrokinetic chromatography; MWNTs, Multi-walled carbon
43
nanotubes;
44
oleyl-L-leucylvalinate;
45
TMA-L-Asp,
46
Tetramethylammonium-chloride;
47
pantothenate
48
Tetramethylammonium-L-arginine;
49
hydroxyproline;
50
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
53
of biomolecules such as amino acids, proteins and carbohydrates (which in life
54
science are known as the ‘‘building blocks of life’’). Thus, it is not difficult to
55
understand that the biological systems are often sensitive to the stereoselectivities.
56
This phenomenon is of particular relevance especially for the pharmaceutical science.
57
The most obvious manifestation is that the enantiomers of a racemic drug often
58
exhibit different pharmacological, toxicological, and biological activities. Taking
59
β-adrenoreceptor blocking agents, one of the most commonly used antihypertensive
60
drugs, as an example, their S-enantiomers usually possess great affinity for the
61
β-adrenergic receptors, while the R-enantiomers may be much less active, inactive, or
62
even have adverse effects. Therefore, the development of chiral separation methods is
63
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
65
over the past few decades [4-9]. In addition to conventional chromatographic
66
techniques (e.g. HPLC, GC), capillary electrophoresis (CE) has been shown to be a
67
high-performance separation tool for enantiomeric separation due to its several
68
advantages such as high separation efficiency, flexibility, as well as low consumption
69
of sample, solvent and chiral selectors [10-13]. In CE, chiral separation is mainly
70
achieved by the direct method in which a chiral selector is simply added to the
71
background electrolyte (BGE). In many cases, however, satisfactory separation could
72
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
74
chiral separation systems by introducing various types of materials into the BGE such
75
as ionic liquids (ILs), nanoparticles, metal–organic frameworks, etc. [14-17]. Among these materials, ionic liquids (ILs) are a group of organic salts with
77
melting points below 100 °C or more often close to (or even below) room temperature.
78
ILs possess unique physical and chemical properties, such as negligible vapor
79
pressure, good thermal stability, relatively high conductivity, and moderate
80
dissolvability. Besides, it is feasible to design and synthesize various task-specific ILs
81
by changing their anion–cation combinations [18-20]. ILs have successfully been
82
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
85
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
87
enantioseparation. In 2014, Tang et al. [17] provided a comprehensive overview of
88
recent advances of ILs in CE and capillary electrochromatography (CEC).
89
Enantioseparation was mentioned, but only briefly discussed in short paragraphs.
90
Kapnissi-Christodoulou et al. [26] later published a well-summarized review on the
91
use of chiral ILs in chromatographic (HPLC, GC) and electrophoretic separations.
92
However, “achiral ILs”-involved CE chiral separation systems were not mentioned.
93
Also, the application modes of chiral ILs in CE can now be more specific since an
94
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
96
general background information about recent applications of ILs in chromatographic
97
and capillary electrophoretic techniques. Rather than provide another overview of the applications of ILs in separation
99
science, this review focuses on the development and state-of-the-art of ILs (including
100
achiral and chiral ILs) in CE for enantioseparation. The contents are divided into six
101
sections according to the application modes of ILs, including achiral ILs modified
102
conventional chiral separation system, chiral ILs synergistic separation system, chiral
103
ILs
104
chromatography (MEKC), the development of novel ILs chiral selectors, as well as
105
other applications. The critical research questions and solutions of each application
106
mode are systematically summarized. Existing problems and development
107
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
112
ILs, alkylimidazolium ILs and alkylpyridinium ILs. Inorganic anions (e.g., OH , Cl ,
113
Br , [BF4] , [PF6] ) usually serve as the anionic partners. Achiral ILs are able to
114
modify the conventional chiral separation system and the mechanism is generally
115
attributed to the following factors:
116
(1) the ionic strength of running buffer could be changed with the addition of
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ACCEPTED MANUSCRIPT 117
achiral ILs. This variation may affect the magnitude of electroosmotic flow (EOF) and
118
the current strength, and thus cause changes in migration times as well as the
119
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
125
when cyclodextrins or their derivatives are used as chiral selectors (e.g. by influencing
126
the formation of inclusion complex [30, 31]).
127
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
129
to two reasons: (1) tetraalkylammonium-based ILs are relatively more hydrophilic and
130
less likely to occupy the hydrophobic cavity of chiral selectors (e.g. cyclodextrins or
131
their derivatives). (2) tetraalkylammonium-based ILs are relatively less conductive
132
and are UV transparent at wavelengths at which enantiomers are usually detected, so
133
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
135
successful enantioseparation. However, the chiral recognition was still dependent on
136
the interaction between enantiomers and chiral selectors according to the research by
137
the authors. The main contribution of achiral ILs is to influence the EOF and peak
138
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
140
achiral ILs modification, the “achirality” of these ILs determines that the
141
“enantiorecognition” capability (enantioselectivity, α) of chiral separation systems
142
could not be significantly improved.
143
2.2 Chiral ILs synergistic separation system
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“Synergism” usually means one plus one equals more than two (by cooperation).
145
Chiral ILs, which have either a chiral cation or a chiral anion, or both, are particularly
146
attractive for their potential applications to chiral discrimination (see typical chiral ILs
147
used for CE enantioseparation in Fig. 2). A prominent advantage of chiral ILs
148
compared with achiral ILs is that they can bring extra “enantiorecognition” capability
149
while retaining the “system modification” capability. So here the term “synergistic
150
system” is used because, in a number of cases (see representative electropherograms
151
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
156
chiral selectors was performed by François et al. in 2007 [33]. Two chiral ILs (ethyl-
157
and
158
Enantioseparation of selected model analytes was at first not obtained with chiral ILs
159
alone. However, an increase in enantioresolution was observed when they were added
160
into dimethyl-β-CDs or trimethyl-β-CDs separation system. The authors concluded
phenylcholine
of
bis(trifluoromethylsulfonyl)
8
imide)
were
evaluated.
ACCEPTED MANUSCRIPT that the improvement in most cases was due to the increase in salt concentration and a
162
possible wall adsorption (similar to the mechanism of achiral ILs). However,
163
simultaneous increase in αeff (effective selectivity factor) and Rs was observed in
164
several cases as compared to the simple salt effect, suggesting the existence of
165
synergistic effect between chiral ILs and β-CDs.
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Several papers regarding the chiral ILs synergistic separation system have been
167
published since then [34-43], but the conventional chiral selectors used in most cases
168
were β-CDs or their derivatives (Table 1). Recently, a series of papers exploring the
169
synergistic effect of chiral ILs with different types of conventional chiral selectors
170
were also reported, including polysaccharides [44-46], antibiotics [47, 48], and
171
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
174
have truly participated in the enantiorecognition process. Take amino acid ILs
175
(AAILs), the most commonly used chiral ILs, for example. Many attempts have been
176
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
180
cation or anion, e.g. Tetramethylammonium-L-arginine (TMA-L-Arg) versus
181
Tetramethylammonium-hydroxide (TMA-OH) [44].
182
(3) the comparison of different AAILs with similar structures, e.g. TMA-L-Arg
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ACCEPTED MANUSCRIPT 183
versus Tetramethylammonium-L-aspartic acid (TMA-L-Asp) [44]. (4) the comparison of AAILs with opposite configurations, e.g. TMA-L-Arg
184 185
versus TMA-D-Arg [46, 50]. As expected, all these results validated the superiority of chiral AAILs; however,
187
still no direct evidence was found to support the hypothesis that AAILs were involved
188
in the enantiorecognition process because, in all the above studies, enantiomers cannot
189
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
191
as sole selector in 2006 [51]. Nice enantioseparations of some anionic compounds
192
were obtained in MEKC mode. However, the long chain part of the AAILs is crucial
193
because they can act as surfactants to form micelle in BGE. According to the authors,
194
the electrostatic interaction between the acidic analyte and cationic micelle (AAILs)
195
plays an important role in enantioseparation. That is, it is still uncertain whether the
196
commonly used (e.g. short chain) AAILs have the “enantiorecognition” contribution
197
during separation. Eventually in 2013, Stavrou et al. [52] first reported the use of
198
chiral AAILs as a sole chiral selector in CZE for direct enantioseparation. Five amino
199
acid
200
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
203
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
10
ACCEPTED MANUSCRIPT of ILs in chiral CE (see Fig. 1) due to their outstanding separation performance and
206
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
208
chiral selectors, rather than explore the separation mechanisms and, especially, the
209
combination rules. This is understandable because the chiral ILs synergistic separation
210
system is a very complex ternary system of chiral ILs, chiral selectors, and
211
enantiomers. Some approaches such as the spectroscopy and molecular simulation [42,
212
45] have recently been introduced to analyze the separation mechanism, but the
213
results are still preliminary. Further investigations are warranted to define the precise
214
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
218
diastereomeric ternary mixed metal complexes between chiral ligands (CL) and
219
different enantiomers [53]:
221 222
( 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
224
enantiomers (phenylalanine, histidine, tryptophane and tyrosine) were successfully
225
separated
226
([CnMIM][L-Pro]), as a chiral ligand. Here, a natural question is whether it is
by
using
an
AAILs,
1-alkyl-3-methylimidazolium
11
L-proline
ACCEPTED MANUSCRIPT necessary to use AAILs in LE-CE since it is well known that the amino acids
228
themselves (e.g. L-Pro) are already qualified as chiral ligands [53]. For comparison,
229
the performance of another two LE-CE systems were evaluated in this work including
230
“single L-Pro ligand” system and “the combined use of L-Pro and [CnMIM][Br] salt”
231
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
234
retention for the DL-enantiomers.
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A series of novel chiral ILs were synthesized and applied as chiral ligands in CE
236
by Qi’ group [55-60]. AAILs with L-lysine (L-Lys) as anions and [CnMIM] as cations
237
was used to separate dansylated amino acids enantiomers, seven pairs of model
238
analytes were baseline separated in the Zn(II)-[C6MIM][L-Lys] system [57]. A follow
239
up study with L-lysine (L-Lys) as anions and pyridinium as cations was performed
240
recently [58], the best chiral separation of dansylated amino acids could be achieved
241
when [1-ethylpyridinium][L-Lys] was chosen as the chiral ligand and Zn(II) as the
242
central ion. In both studies, “Single amino acid ligand” systems and “the combined
243
use of amino acids and imidazolium/pyridinium salt” system were also tested to
244
validate the superiority of AAIL ligands. Another chiral ILs with L-ornithine (L-Orn)
245
and L-alanine (L-Ala) as anion were synthesized by the same group and successfully
246
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
248
above studies (Table 2). In an effort to evaluate the enantiorecognition capability of
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250
including [L-Pro][CF3COO], [L-Pro][NO3], [L-Pro][BF4] and[L-Pro2][SO4], were
251
successfully synthesized [55]. Effective separations could be achieved by using these
252
AAILs as ligands and Cu(II) as the central ion, indicating that AAILs with amino
253
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
255
(LE-MEKC) was reported by Liu et al. [61], in which a novel AAIL,
256
tetramethylammonium L-hydroxyproline (TMA-L-Hyp), was synthesized and utilized
257
as a ligand. The authors evaluated both LE-CE and LE-MEKC system and it turned
258
out that the LE-MEKC system yielded better separations toward most selected
259
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
263
charged and neutral analytes [62]. Usually, a surfactant is added to the run buffer to
264
form micelles as a pseudo-phase. In some cases, additional modifiers are also needed
265
in order to improve separation efficiency and selectivity. Herein, ILs can be used as
266
either modifiers or surfactants.
267
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
268 269
of
three
chiral
binaphthyl
derivatives
270
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
272
efficiency of the analytes while maintaining adequate background current. The same
273
group later investigated the effects of adding [CnMIM][BF4] ILs as compared to
274
adding conventional molecular organic solvents (MeOH, 1-PrOH and ACN) on chiral
275
separation in MEKC [64]. As observed by the authors, the ILs generally led to faster
276
separations of chiral analytes without adversely affecting the current, while high
277
volumes of molecular organic solvents in the buffer led to current breakdowns. In
278
addition, smaller IL volumes were needed, as compared to molecular organic solvents,
279
in order to achieve equivalent separations.
280
2.4.2 ILs as surfactants
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Long chain ILs can also be used as surfactant in MEKC for enantioseparation.
281
For
this
purpose,
two
amino
acid-derived
chiral
ILs,
283
undecenoxycarbonyl-L-pryrrolidinol bromide, and undecenoxycarbonyl-L-leucinol
284
bromide were synthesized in both monomeric and polymeric forms by Rizvi and
285
Shamsi [51] to separate several acidic analytes. Electrostatic interaction between the
286
acidic analytes and cationic micelle was found to be critical to chiral recognition.
287
Wang et al. [65, 66] published two consecutive articles demonstrating the
288
combination of ILs surfactants and β-CDs for MEKC. Five profen drugs were
289
simultaneously separated by MEKC with the combined use of trimethyl-β-CDs and a
290
chiral cationic IL, undecenoxycarbonyl-L-leucinol bromide (L-UCLB), which formed
291
micelles in aqueous buffers [65]. The concepts of enzymatic reactions were then
292
successfully applied to determine the competitive inhibition mechanism of the
AC C
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282
14
ACCEPTED MANUSCRIPT separation system [66]. In a recent work by Liu and Shamsi [67], five long chain ILs
294
with different amino acid head groups were synthesized and employed as surfactants
295
to establish MEKC system with trimethyl-β-CDs as chiral selector. It was found that
296
the IL head groups had a significant effect on enantioseparation of neutral compounds
297
(Fig. 4). The binding constants (K) between the ILs–CDs complexes and the
298
enantiomers were estimated using a y-reciprocal linear method. The K values of each
299
enantiomer was found to be increased with increasing size of the head group,
300
indicating strong contribution from hydrophobic interaction imparted by the amino
301
alcohol side chain of the IL surfactants.
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293
Figure 4
302 303
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
310
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.
313
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
316
may be an interesting solvent for enantioselective reactions and also useful in chiral
317
separation techniques. It was then selected by Yuan et al. [70] and successfully used
318
as sole chiral selector in CE. Several drug enantiomers were separated with the
319
resolution values varied from 0.60-6.80.
RI PT
315
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.
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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
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EP
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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
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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
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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
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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
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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
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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.
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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.
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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.
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424
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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.