Ionic liquids-based monolithic columns: Recent advancements and their applications for high-efficiency separation and enrichment

Accepted Manuscript Ionic liquids-based monolithic columns: Recent advancements and their applications for high-efficiency separation and enrichment Rui Chen, Hongwei Zhou, Mingchen Liu, Hongyuan Yan, Xiaoqiang Qiao PII:

S0165-9936(18)30500-4

DOI:

https://doi.org/10.1016/j.trac.2018.11.026

Reference:

TRAC 15328

To appear in:

Trends in Analytical Chemistry

Received Date: 25 September 2018 Revised Date:

7 November 2018

Accepted Date: 17 November 2018

Please cite this article as: R. Chen, H. Zhou, M. Liu, H. Yan, X. Qiao, Ionic liquids-based monolithic columns: Recent advancements and their applications for high-efficiency separation and enrichment, Trends in Analytical Chemistry, https://doi.org/10.1016/j.trac.2018.11.026. 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 1

Ionic liquids-based monolithic columns: Recent advancements and

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their applications for high-efficiency separation and enrichment

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Rui Chen a, Hongwei Zhou b, Mingchen Liu a, Hongyuan Yan c, Xiaoqiang Qiao a,*

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a

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Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education,

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College of Pharmaceutical Sciences, Hebei University, Baoding 071002, China

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b

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Key Laboratory of Analytical Science and Technology of Hebei Province, Key

Institute of Basic Research in Clinical Evaluation, China Academy of Chinese

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Medical Sciences, Beijing 100700, China

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c

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Education, College of Public Health, Hebei University, Baoding 071002, China

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Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of

Corresponding author:

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*Professor Dr. Xiaoqiang Qiao, Key Laboratory of Analytical Science and

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Technology of Hebei Province, Key Laboratory of Medicinal Chemistry and

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Molecular Diagnosis, Ministry of Education, College of Pharmaceutical Sciences,

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Hebei University, Baoding 071002, China

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Tel.: +86-312-5971107

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Fax: +86-312-5971107

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E-mail: [email protected]; [email protected]

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ACCEPTED MANUSCRIPT 1

ABSTRACT Because of their excellent physicochemical characteristics, ionic liquids (ILs) have

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been widely reported as new monomers to fabricate versatile monolithic columns with

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improved separation efficiency and excellent selectivity. In this study, a systematic

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summary of the recently reported ILs-based monolithic columns was performed. We

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paid much attention to the characteristics of the introduced ILs as well as the

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fabrication methods for the monolithic columns. Furthermore, the ILs-based

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monolithic columns were respectively discussed based on their applications in high

9

performance liquid chromatography, capillary electrochromatography and solid phase

10

extraction. Moreover, ILs as the porogenic solution for fabrication of monolithic

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columns were also included.

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Keywords: Ionic liquids; monolithic column; fabrication method; high efficiency

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separation; enrichment

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1. Introduction Ionic liquids (ILs) are generally defined as a group of salts in liquid state under

3

ambient temperature. Usually, IL is comprised of an organic cation and an organic or

4

inorganic anion. ILs often display low volatility, high viscosity and density, excellent

5

thermal stability as well as broad soluble and miscible ranges from non-polar to polar

6

compounds [1]. All these inherent merits of ILs render them extensively applied in a

7

variety of disciplines of chemistry, such as organic synthesis [2], catalysis [3],

8

electrochemistry [4], green chemistry [5] and separation science [6]. Recently, ILs

9

also have been successfully utilized for assisted solubilization of membrane proteins

10

[7,8]. For example, by combination of sequential extraction of Hela cell proteins via

11

urea and IL 1-dodecyl-3-methylimidazolium chloride, the largest data set from Hela

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cell were achieved which included 11313 proteins and 1916 transmembrane proteins

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[9]. Furthermore, the versatile structures of ILs incorporating with different

14

functionalized groups could provide multiple interactions, such as hydrophilicity,

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hydrophobicity, ion-exchange, H-H and π-π interactions [10]. Thus, they are the good

16

choices as new organically functionalized reagents for fabrication of high

17

performance liquid chromatography (HPLC) stationary phases with improved

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chromatographic separation efficiency and enhanced selectivity [11]. Several

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important reviews referring to ILs modified particle-based stationary phases have

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been published [12,13].

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The concept of monolithic column was firstly proposed by Hjertén and Svec as a

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new separation technology in the late 1980s and early 1990s [14,15]. The congenital 3

ACCEPTED MANUSCRIPT virtues of monolithic columns, such as ultrahigh column efficiency, fast mass transfer

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and high permeability, render them attracting much attention and a variety of

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monolithic columns based on different matrix materials have been designed and

4

reported for high-efficiency separation of both small molecules and macromolecules

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[16-18]. The first IL modified monolithic column was reported by Jia et al. in 2011

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[19]. Thereafter, versatile ILs-based monolithic columns have sprung up in the recent

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years [20-26]. However, to the best of our knowledge, so far there was not a

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systematic review focusing on this subject.

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Herein, for in-depth understanding them, the present work systematically

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summarized the recently reported ILs-based monolithic columns. We paid much

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attention to the preparation methods of the monolithic columns and their further

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applications in HPLC, capillary electrochromatography (CEC) and solid phase

13

extraction (SPE). Besides as new monomers to fabricate monolithic columns, the

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application of ILs as the porogenic solution was also summarized.

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2. ILs for fabrication of the monolithic columns

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2.1. The characteristics of the ILs

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For

fabrication

of

the

ILs-based

monolithic

columns,

alkyl-substituted

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imidazolium-based ILs were largely utilized because of their availability and

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convenient tenability. As shown in Fig. 1, imidazolium-based ILs with versatile -R2

20

groups were successfully introduced for fabrication of a series of monolithic columns

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[20-26]. Furthermore, the type of anion also notably affected the separation

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performances of the monolithic columns. Thus, different anions (Cl-, Br-, 4

ACCEPTED MANUSCRIPT (PF6-),

(BF4-)

hexafluorophosphate

tetrafluoroborate

or

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bis(trifluoromethane)sulfonimide (NTf2-)) [27-29] were also selected for fabrication

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of the ILs-based monolithic columns. Some references also reported using

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trioctyl(3/4-vinylbenzyl)phosphonium chloride ([P888VBn]Cl) [30], 4,4′-dipyridyl

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[31,32] and N-methylimidazole [19,33] to fabricate the ILs-based monolithic columns.

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Although 4,4′-dipyridyl and N-methylimidazole are actually not ILs, they could

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directly graft on the halide modified monolithic matrix materials via nucleophilic

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substitution to obtain the ILs-modified monolithic columns.

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ILs used for fabrication of monolithic columns also bear different reactive groups

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so as to further react or modify the matrix materials. The most commonly used ILs

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possess reactive vinyl- or allyl- groups since they are more easily to copolymerize

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with vinyl-containing monomers and crosslinkers [23,34,35]. Some ILs were also

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designed with terminal amino groups in the -R2 substitution [26,36]. These ILs could

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be easily grafted on the carboxyl groups modified matrix materials. Furthermore,

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acetylamino-functionalized IL was also used to fabricate ILs-based monolithic

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column [21].

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2.2. The methods for fabrication of the monolithic columns

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The ideal monolithic columns should possess the characteristics of ease of

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fabrication, pretty structural uniformity, good reproducibility as well as high stability.

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Furthermore, they should provide ultrahigh column efficiency and excellent

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separation or enrichment selectivity for target samples. Thus, versatile fabrication

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methods with multiple reaction mechanisms as well as different matrix materials were 5

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exploited to prepare ILs-based monolithic columns.

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2.2.1. Direct one-pot polymerization Direct one-pot polymerization is the most commonly used method for fabrication

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of ILs-based monolithic columns. If further consider the reaction mechanism,

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traditional free radical copolymerization is the most popular method [27,37]. ILs with

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reactive vinyl- or allyl- groups could easily polymerize with various monomers and

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crosslinkers via 2,2-azobisisobutyronitrile (AIBN) initiation [35,38].

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Furthermore, living/controlled atom transfer radical polymerization (ATRP) is also

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used to fabricate ILs-based monolithic columns. Usually, with CCl4 as the initiator

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and FeCl2 as the catalyst, the monolithic columns could be facilely prepared within 24

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h in water bath. Compared with the traditional free radical copolymerization,

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monolithic columns prepared via the ATRP method are more inclined to form

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homogenous and uniform pore structures with narrow molecular weight distribution

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which benefit for subsequent HPLC separation [20].

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Urea-formaldehyde polycondensation [39] is another step-growth polymerization

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method which is also reported to fabricate ILs-based monolithic columns. For this

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method, acylamino-functionalized IL was used as the monomer and it could rapidly

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polymerize in acylamino-modified capillary with the presence of urea and

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formaldehyde [21]. One of the important characteristics of the urea-formaldehyde

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polycondensation reaction is the rapid fabrication time and it could be shortened to

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about 10 min.

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Thiol-ene click reaction can also be used to prepare ILs-based monolithic columns. 6

ACCEPTED MANUSCRIPT Usually, vinyl-containing ILs and multiple thiol-containing compounds are

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respectively used as the monomers and crosslinkers and further initiated via AIBN

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[23]. The thiol-ene click reaction is of the merits of mild reaction conditions, high

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yield and insensitive for oxygen and moisture. Thus, the monolithic columns could be

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easily fabricated under mild conditions [40].

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2.2.2. ILs post-modified monolithic columns

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The post-modified method is obviously different with the direct one-pot

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polymerization. Usually, the monolithic matrix is firstly fabricated. Then, ILs with

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different reactive groups are further used to functionalize the monolithic matrix so as

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to obtain the ILs-modified monolithic columns. Since the fabrication procedures are

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divided into two steps, the porous properties of the matrix materials could be

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independently optimized without needing to consider the ILs post-modified procedure

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[41]. Furthermore, it is more easily to introduce a diversity of functionalized reagents

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on the monolith. However, the post-modified method is more complex and

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time-consuming.

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For fabrication of the monolithic matrix, different materials have been used, such as

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inorganic silica matrix [42], organic polymer matrix [26,36] and organic-silica hybrid

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matrix [31-33,43]. Recently, new nanoparticles (such as gold nanoparticles [44]) are

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also introduced for fabrication of the monolithic matrix.

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For further introduction of ILs, the most important methods is direct grafting of

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N-methylimidazole or 4,4′-dipyridyl on the halide-substituted monolithic matrix to

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obtain ILs-modified monolithic columns [19,31,32]. Direct condensation of 7

ACCEPTED MANUSCRIPT 1-aminopropy-functionalized ILs [26,36] on carboxyl-containing monolithic matrix

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with the presence of N,N'-dicyclohexylcarbodiimide (DCC) is also an efficient

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method to fabricate ILs-based monolithic columns. Furthermore, free radical

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copolymerization and thiol-ene click reaction which are often used in direct one-pot

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polymerization are also exploited for fabrication of ILs-based monolithic columns via

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post-modified method [30,43].

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3. Chromatographic applications

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3.1. Applications for HPLC

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One of the most important applications of the ILs-based monolithic columns is for

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HPLC. Both the conventional and capillary ILs-based monolithic columns have been

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reported, as summarized in Table 1.

Bai and coauthors developed several organic polymer ILs-based monolithic

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columns

stainless

steel

column

(4.6

×

50

mm

i.d.).

With

IL

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1-allyl-3-methy-imidazolium chloride (AMIM+Cl-) and triallyl isocyanurate (TAIC)

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as the co-monomers, ethylene dimethacrylate (EDMA) as the crosslinker, a

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poly(IL-co-TAIC-co-EDMA) monolithic column was firstly fabricated via one-pot

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ATRP method [20]. The column exhibited high thermal stability and uniform

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macroporous structure and was further exploited for separation of alkylbenzenes,

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acidic & basic compounds and isomers m-hydroquinone, p-hydroquinone,

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a-hydroquinone via reversed-phase liquid chromatography (RPLC). Most importantly,

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it displayed higher column efficiency and resolution compared with the monolithic

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columns that fabricated without IL AMIM+Cl- or that via the traditional free radical

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copolymerization. In the same group, AMIM+Cl- and trimethylol propane triacrylate (TMPTA)

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modified poly(IL-co-TMPTA-co-EDMA) monolithic column was further fabricated

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[45]. The column efficiencies of the poly(IL-co-TMPTA-co-EDMA) monolithic

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column reached 24,300-27,000 plates/m for benzene, toluene, p-xylene and

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baseline-separation of isomers m-phenylenediamine, p-phenylenediamine and

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o-phenylenediamine could be achieved within 6 min, outperforming their reported

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poly(IL-co-TAIC-co-EDMA) monolithic column [20]. In their recent work, with

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ethylene glycol dimethacrylate (EGDMA) as the crosslinker, AMIM+Cl− and stearyl

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methacrylate (SMA) modified poly(IL-co-SMA-co-EGDMA) monolithic column was

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also fabricated for specific separation of complex protein samples, such as snailase,

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egg white proteins, tryptic digests of bovine serum albumin (BSA) and human plasma

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proteins [46].

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In recent years, monolithic-based capillary columns have been paid increasing

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attention. Wang et al. [34] developed a zwitterionic organic polymer based monolithic

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column by one-pot free radical copolymerization of IL 1-vinyl-3-(butyl-4-sulfonate)

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imidazolium (VBSIm), N,N'-methylenebisacrylamide (MBA) and acrylamide (AM).

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The authors systematically investigated the factors that affected the retention of the

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monolithic column, such as acetonitrile content, buffer salt concentration and pH of

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mobile phase. The developed poly(VBSIm-AM-MBA) monolithic column was

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successfully used for the separation of 5 nucleosides and 3 benzoic acids via

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hydrophilic interaction liquid chromatography (HILIC).

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ACCEPTED MANUSCRIPT With IL 1-vinyl-3-octadecylimidazolium bromide ([VC18Im]Br) and EDMA as the

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monomers, pentaerythritol tetra-(3-mercaptopropionate) (PETMP) as the crosslinker,

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Ye et al. [23] further fabricated [VC18Im]Br modified organic polymer based

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monolithic column via one-pot thiol-ene click reaction, as shown in Fig. 2. The C18

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groups and imidazolium rings on the monolithic column could provide hydrophobicity,

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charge-charge and π-π interactions. Therefore, it can be used for high-efficiency and

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fast separation of alkylbenzenes, PAHs, ethylbenzene & styrene, phenols, aromatic

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amines and aromatic acids. The column efficiency reached 87,500 plates/m for

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thiourea.

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Jia et al. [19] prepared N-methylimidazolium grafted silica based monolithic

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column via the post-modified method. For fabrication of the column, silica-based

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matrix was firstly fabricated via the reaction of tetramethoxysilane (TMOS) and

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methyltrimethoxysilane (MTMS). Then, 3-chloropropyltrimethoxysilane was further

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used to modify the matrix so as to introduce γ-chloropropyl groups on the monolith.

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Finally, N-methylimidazole could be directly grafted on the γ-chloropropy-modified

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matrix to obtain N-methylimidazolium modified monolithic column. Similarly,

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multiple retention mechanisms, including hydrophobic, hydrophilic, anion-exchange,

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dipole-dipole and π-π interactions, were observed from the fabricated monolithic

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column and it was further exploited for the separation of a variety of hydrophobic and

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hydrophilic compounds. However, tailing peaks were often observed via the

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developed monolithic column.

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Moravcová et al. [30] firstly reported and fabricated phosphonium IL modified 10

ACCEPTED MANUSCRIPT silica-based

monolithic

column

via

directly

grafting

[P888VBn]Cl

onto

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3-trimethoxysilylpropyl methacrylate (γ-MAPS) functionalized silica matrix. The

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column mainly displayed HILIC retention mechanism and the column efficiency

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reached 137,400 plates/m for toluene. When it was used for separation of 12 purine

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and pyrimidine bases and nucleosides, the column exhibited better separation

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selectivity compared with bare silica, phenyl or zwitterionic sulfobetaine columns

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(Fig. 3).

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Since pentafluorobenzyl groups could always provide unique selectivity in RPLC

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separation, Xu et al. [24] firstly fabricated a new hybrid monolithic column which

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combined

IL

and

pentafluorobenzyl

groups.

With

synthesized

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1-vinyl-3-(perfluorobenzyl)-imidazolium bromide (VIMPFP) as the monomer,

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polyhedral oligomeric silsesquioxane methacryl substituted (POSS-MA) as the

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crosslinker, the POSS-VIMPFP hybrid monolithic column was facilely fabricated via

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the one-pot free radical copolymerization (Fig. 4). The POSS-VIMPFP column could

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not only provide multiple separation mechanisms like the other imidazoliumn-based

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monolithic columns but it was also specifically suitable for separation of halogenated

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compounds. For example, compared with the commercial ODS and pentafluorophenyl

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(PFP) columns, the POSS-VIMPFP column exhibited best separation selectivity for

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1,2,4,5-tetrafluorobenzene, 2,3,4,5,6-pentafluorotoluene, pentafluorobenzyl bromide

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and heptafluorobenzyl iodide in shortest analytical time.

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In our group, with 1-vinyl-3-octylimidazolium bromide (VOI) as the monomer,

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POSS-MA as the crosslinker, new imidazolium embedded C8 POSS-VOI hybrid 11

ACCEPTED MANUSCRIPT monolithic column was facilely fabricated

via the one-pot free radical

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copolymerization [35]. The column displayed RPLC retention mechanism and higher

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column efficiency (101,000-124,000 plates/m for alkylbenzenes), outperforming that

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via the previously reported POSS-VIMPFP column (72,000 plates/m for

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alkylbenzenes). The column was further used for the separation of 5 PAHs, 5 phenols

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and 4 basic aromatic amines with good planar selectivity.

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Moreover, a highly cross-linked periodic imidazolium-bridged hybrid monolithic

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column (POSS-AVI) was also fabricated by the introduction of diene IL

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1-allyl-3-vinylimidazolium

(Fig.

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[25].

Compared

with

the

traditional

imidazolium-embedded monolithic column, the bonded amount of IL of the highly

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cross-linked imidazolium-bridged monolithic column increased about 2-folds. The

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highest column efficiency could reach 151,000 plates/m for alkylbenzenes. One of the

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most important applications of the POSS-AVI column is the successful separation of 5

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hydrophilic nucleosides and nucleic acid bases with pure water as the mobile phase.

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Thus, the developed column is of the merits of environmentally-friendly characteristic

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and

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1-vinyl-3-butylimidazolium bromide (VBIBr) and amino acid L-cysteine (Cys)

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modified POSS-VBI-Cys hybrid monolithic column was also fabricated for separation

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and purification of intact proteins from expressed TARG1 sample [47].

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3.2. Applications for CEC

be

used

with

low

cost.

In

our

most

recent

work,

IL

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As a hybrid separation technique of HPLC and capillary electrophoresis (CE), CEC

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could always provide higher separation efficiency and powerful separation selectivity 12

ACCEPTED MANUSCRIPT 1

for both small molecules and macromolecules. Recently, ILs-based monolithic

2

columns were also fabricated for CEC separation, as summarized in Table 2. Wang and coauthors fabricated a series of ILs-based monolithic columns for CEC.

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With 1-vinyl-3-octylimidazolium chloride (ViOcIm+Cl-) and lauryl methacrylate

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(LMA) as the binary monomers, EDMA as the crosslinker, the new ViOcIm+Cl-

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modified organic polymer-based monolithic column was prepared via the one-pot free

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radical copolymerization [27]. This is the first report that utilized IL to fabricate

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organic polymer-based monolithic column for CEC separation. Since the ViOcIm+Cl-

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modified monolithic column possessed cationic imidazolium groups, it could produce

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anodic electroosmotic flow (EOF) from pH 2.0 to 12.0. Furthermore, the research

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found that the separation of hydrophobic alkylbenzenes was based on RPLC property

12

of the column while the separation of charged amino acids, thiourea and its analogues

13

mainly based on electrophoretic mobility, hydrophobic and strong anion exchange

14

(SAX) interactions.

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Wang et al. [48] further prepared and compared a series of ViOcIm+ based

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monolithic columns with different anions (Br-, BF4-, PF6-, NTf2-) for separation of

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intact proteins. For fabrication of these monolithic columns, both the one-pot and

18

“anion-exchange” methods were used. The ViOcIm+NTf2- modified monolithic

19

column that fabricated via the one-pot approach exhibited the highest column

20

efficiency for separation of 4 model proteins (479,000 plates/m for cytochrome c).

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The chromatographic performance of the column was further verified via separation

22

of egg white proteins. This is the first research that discussed the effect of anions of

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ACCEPTED MANUSCRIPT 1

ILs on the separation performances of the ILs-based monolithic columns. Moreover,

2

1-vinyl-3-dodecylimidazolium

3

1-vinyl-3-octadecylimidazolium

4

columns were further fabricated and exploited for CEC separation of alkylbenzenes,

5

basic compounds, anilines, amino acids, standard protein mixture and egg white

6

proteins [22,28].

bromide

(VC18HIm+Br-)

modified

and monolithic

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bromide

(VC12Im+Br−)

In the same group [26], an interface-free boronate-functionalized graphene-coupled

8

poly(guanidinium IL) 2D materials were further developed for enrichment and

9

separation of glycoproteins. For fabrication of the 2D monolithic column,

10

boronate-functionalized graphene segment was firstly prepared via one-pot thiol-ene

11

click

12

4-vinylphenylboronic acid (VPBA) and EDMA. This part can be used for

13

glycoprotein enrichment. The separation segment was prepared via three steps. Firstly,

14

poly(MBA-co-methacrylic acid (MAA)) matrix was fabricated via free radical

15

copolymerization of MBA and MAA. Then, 1-aminopropyl-3-methylimidazolium

16

bromide (ApMeIm+Br-) was directly grafted on the matrix via the reaction between

17

the carboxyl groups on MAA and the amino groups of ApMeIm+Br-. Finally, arginine

18

was used to exchange the Br− on the monolithic column to obtain the final

19

guanidinium-grafted separation materials (Fig. 6). The developed 2D monolithic

20

column was exploited to preconcentrate and separate of 4 non-glycoproteins and 5

21

glycoproteins,

22

ribonudease A (RNase A), transferrin (TF) and α-fetoprotein (AFP). Compared with

and

free

radiation

copolymerization

of

ViOcIm+Cl-,

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including

horseradish

peroxidase

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(HRP),

ovalbumin

(OVA),

ACCEPTED MANUSCRIPT the single separation monolithic column, preconcentration monolithic column or the

2

ApMeIm+Br−-grafted 2D monolithic column, baseline-separation of these proteins

3

could be uniquely achieved via the developed 2D monolithic column. Subsequently,

4

the poly(guanidinium IL) monolithic column was further developed for detection of

5

AFP in human serum by combination of CEC immunoassay and laser induced

6

fluorescence detector [36].

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Lin and coauthors [21] firstly exploited using urea-formaldehyde polycondensation

8

method to fabricate ILs-based monolithic column. For more efficient preparation of

9

the monolithic column, 3-aminopropyltrimethoxysilane (APTMS) modified capillary inner

was

firstly

prepared.

Then,

acylamino-functionalized

IL

11

1-acetylamino-propyl-3-methylimidazolium bromide ([AAPMIm]Br) was directly

12

polycondensated on the monolith with the presence of urea and formaldehyde. The

13

urea-formaldehyde polycondensation reaction is very fast and can be shortened to 10

14

min. Multiple retention mechanisms, including H-H, hydrophilicity, anion-exchange,

15

cation-exclude interactions, could be observed from the column when it was used for

16

separation of enkephalins, phenols, benzoic acid and its homologues. The column

17

efficiency reached 80,200 plates/m.

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With IL 1-allylmethylimidazolium chloride (AlMeIm+Cl-) and styrene as

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bifunctional monomers, EDMA as the crosslinker, Chen et al [38] further developed

20

AlMeIm+Cl- modified organic polymer based monolithic column via one-pot free

21

radical copolymerization. The introduced styrene on the monolithic column could

22

provide with more hydrophobic and aromatic characteristics while the introduction of 15

ACCEPTED MANUSCRIPT IL AIMeIm+Cl- rendered the monolithic column possessed hydrophilicity and

2

anion-exchange sites. Thus, successful separation of alkylbenzenes, phenols, amino

3

acids and benzoic acids could be achieved via the developed monolithic column. The

4

highest column efficiency reached 270,000 plates/m for toluene.

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Ye et al. [44] firstly fabricated the ILs-gold nanoparticles (GNPs) modified

6

silica-based monolithic column for CEC. For preparation of the monolithic column,

7

the silica matrix was firstly fabricated via hydrolysis and condensation of TMOS and

8

MTMS. Then, 10% 3-mercapto-propyltrimethoxysilane (MPTMS) was further used to

9

functionalize the matrix at 110 °C for 1 h so as to introduce thiol groups on the

10

monolith. Thirdly, the synthesized GNPs were immobilized on the monolithic matrix

11

via Au-S bonds. Finally, the synthesized IL 1-methyl-2-mercapto-3-butylimidazolium

12

bromide could be introduced into the monolith via the same method to obtain the final

13

ILs-GNPs-silica based monolithic column. The developed monolithic column was

14

especially suitable for separation of basic compounds with reduced “silanol effect”.

15

For example, when it was used for separation of basic caffeine, atenolol and

16

metoprolol, higher separation efficiencies and good peak shapes were achieved,

17

outperforming that via only GNPs or ILs modified silica based monolithic columns.

18

The main drawback of the ILs-GNPs-silica column is the fabrication procedures are

19

relatively complex.

AC C

EP

TE D

M AN U

SC

5

20

Liu et al. [33] further grafted N-methylimidazole on chloropropyl-functionalized

21

silica (CP-silica) that was fabricated via co-condensation of TMOS and

22

(3-chloropropyl)-trimethoxysilane (CPTMS) to prepare N-methylimidazolium based 16

ACCEPTED MANUSCRIPT 1

monolithic column for CEC. The authors exploited its performances for separation of

2

4 PAHs and 7 inorganic anions. The column efficiencies could reach 140,000-290,000

3

plates/m for bromide and iodide which were higher than that via the CP-silica hybrid

4

monolithic

5

1-viny-3-octylimidazolium bromide ([C8VyIm]Br) modified polymeric IL hybrid

6

monolithic column was also fabricated via the post-modified method [43]. For

7

fabrication of the hybrid matrix, 3-mercaptopropyltrimethoxysilane (MPTS) was used

8

so as to introduce thiol groups on the monolith. Then, [C8VyIm]Br could be directly

9

grafted on the matrix via thiol-ene click reaction. Although successful separation of

10

alkylbenzenes, PAHs and phenols was achieved, the developed column displayed

11

relatively low column efficiency. For example, it was only 15,000-52,000 plates/m for

12

PAHs.

plates/m).

In

the

same

group,

With

M AN U

SC

RI PT

(27,000-110,000

TE D

13

column

1-butyl-3-vinylimidazolium-bis[(trifluoromethyl)sulfonyl]imide

(VBIMNTf2) as the monomer, POSS-MA as the crosslinker, Wu et al. [29] firstly

15

exploited using photoinitiated free radical copolymerization to ultrafast prepare of

16

ILs-based monolithic column. The POSS-VBIM monolithic column could be

17

fabricated within 7 min and the column efficiency reached ~98,000 plates/m for

18

amylbenzene. Furthermore, the POSS-VBIM column was successfully applied to

19

separate of alkylbenzenes, PAHs, phenols and anilines via mixed-mode retention

20

mechanisms.

AC C

EP

14

21

Compared with the commonly used imidazole-based ILs, 4,4'-dipyridy is more

22

inclined to form hydrogen bonds. Thus, it could potentially provide more polarity 17

ACCEPTED MANUSCRIPT characteristic when used as the monomer for fabrication of monolithic column [49].

2

Lin et al. [31] firstly reported using 4,4'-bipyridy to fabricate pyridinium-based hybrid

3

monolithic column (BiPy-silica column). For fabrication of the monolithic column,

4

the CP-silica hybrid matrix was firstly fabricated. Then, 4,4'-dipyridyl could be

5

directly grafted on the CP-silica matrix via nucleophilic substitution reaction. The

6

authors mainly researched its HILIC retention characteristics in CEC and it was

7

successfully used for separation of PAHs, nucleotides and phenols. Furthermore, the

8

column also indicated with satisfactory column efficiency for separation of basic

9

nicotines

(8,200-106,000

M AN U

SC

RI PT

1

plates/m),

nucleosides

and

nucleic

acid

bases

(120,000-164,000 plates/m), as shown in Fig. 7. Furthermore, Jiang et al. [32] also

11

investigated its mixed-mode retention mechanisms for separation of neutral PAHs,

12

alkylbenzenes, phenols via hydrophobic, π-π interactions and inorganic anions,

13

organic acids via anion-exchange, hydrophobic and electrophoretic mobility

14

interactions.

15

3.3. Applications for SPE

EP

TE D

10

Since the ILs-based monolithic columns could provide multiple interaction sites as

17

well as low back pressure, they were also successfully used for off-line or on-line

18

enrichment of specific molecules, as summarized in Table 3.

19

AC C

16

With glycidyl methacrylate modified ApMeIm+Cl− and AM as the monomers, MBA

20

as the crosslinker, Wang et al. [50] firstly fabricated a new organic-polymer based

21

monolithic column via one-pot free radiation copolymerization and it was further

22

exploited for in-tube extraction of acidic food additives. Since the introduced IL 18

ACCEPTED MANUSCRIPT possessed both hydrophobic and anion-exchange sites, the new column exhibited high

2

extraction efficiency for the test benzoic acid, cinnamic acid, 3-hydroxybenzoic acid,

3

3-(trifluoromethyl)-cinnamic acid and 2,4-dichlorophenoxyacetic acid. Under the

4

optimal extraction conditions, the adsorption capacities of the column reached

5

0.18-1.74 µg/cm. Furthermore, the column was successfully used to determinate the

6

content of benzoic acid in Sprite sample.

RI PT

1

Because of the endocrine disrupting properties, organic UV filters are of great risk

8

for both humans and other organisms. Huang et al [37] developed a

9

magnetism-enhanced IL-based monolithic column for on-line extraction of 5 organic

10

UV filters in environmental water samples. With IL AlMeIm+NTF2-, synthesized

11

Fe3O4@SiO2@γ-MAPS magnetic nanoparticles (MNPs) and EDMA as the

12

prepolymerization mixture, the PIL-MCC/MNPs monolithic column was facilely

13

fabricated via one-pot free radical copolymerization (Fig. 8). The authors

14

systematically optimized the extraction conditions, including magnetic intensity, flow

15

rate for sampling and desorption, solvent volume for sampling and desorption as well

16

as ionic strength and pH of sample matrix. The limit of detections (LODs) of the

17

method reached 0.04-0.26 µg/L and it was successfully used to detect trace UV filters

18

in waste water, river water and lake water. The proposed method indicated the merits

19

of fast extraction time, low cost and well sensitivity.

AC C

EP

TE D

M AN U

SC

7

20

Jia et al. [51] firstly attempted to fabricate IL and melamine covalent organic

21

polymer (MCOP) hybrid composite modified organic polymer based monolithic

22

column for enrichment of synthetic phenolic antioxidants (SPAs). Firstly, MCOP was 19

ACCEPTED MANUSCRIPT synthesized with melamine (MA) and 2,5-dihydroxyl-1,4-benzenedicarboxaldehyde

2

(DHA) via Schiff base chemistry. After further hybridizing with pre-synthesized IL

3

3-bromo-hexyl-1-vinylimidazolium bromide, the obtained MCOP/IL composites

4

could further copolymerize with divinylbenzene (DVB) and 4-vinylbenzyl

5

trimethylammonium chloride (VBTA) to obtain the final poly(VBTA-MCOP/IL-DVB)

6

monolithic column. Compared with the poly(VBTA-DVB) column and direct HPLC

7

analysis, the poly(VBTA-MCOP/IL-DVB) monolithic column displayed higher

8

extraction efficiency for SPAs which could attribute to the multiple interaction

9

mechanisms (hydrophobic, π-π，H-H) as well as the large specific surface and pore

10

volume of the monolithic column. Thus, the LODs of the method could reach 0.1-0.3

11

ng/mL for SPAs. The method was further successfully used for extraction of SPAs in

12

skin toner and essence samples with good selectivity.

TE D

M AN U

SC

RI PT

1

As a tailor-made separation material, molecularly imprinted polymer (MIP) always

14

displays specific selectivity and high affinity for the given target molecules. Recently,

15

Liu et al. [52] further developed an IL based MIP monolithic column for specific

16

recognition

17

1-vinyl-3-ethylimidazolium tetrafluoroborate (VEImBF4) as the monomer, EGDMA

18

as the crosslinker, the MIP monolithic column was facilely fabricated in 4.6 mm ×

19

100 mm stainless tube via one-pot free radical copolymerization. For improving the

20

imprinting effect, crowding environment by employing of polystyrene tetrahydrofuran

21

solution was used. The authors systematically discussed the effect of molar ratio of IL

22

to aesculetin, the concentration and molecular weight of polystyrene, and the

EP

13

aesculetin.

With

aesculetin

as

the

template,

IL

AC C

of

20

ACCEPTED MANUSCRIPT composition of the organic phase on the imprinting and retention factors of the

2

monolithic column. Under the optimal conditions, the column was successfully used

3

for extraction of aesculetin from cichorium glandulosum and the LODs reached 0.05

4

µg/mL.

5

4. ILs as the porogenic solution

RI PT

1

Besides as the monomers to direct fabricate monolithic columns, ILs can also be

7

used as the porogenic solution during the fabrication procedures. However, ILs used

8

as porogenic solvent often bear no reactive groups so as to prevent them further

9

reacting with the monolithic columns. It is obviously different with the ILs that served

10

as the monomers. The most commonly used ILs are imidazolium-based reagents,

11

including 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM]BF4 [53-56],

12

1-hexyl-3-methylimidazolium

13

1-butyl-3-methylimidazolium chloride ([BMIM]Cl) [58]. These ILs have been

14

successfully used for fabrication of monolithic columns and they were further used for

15

HPLC [58], CEC [57] and MIP [53-56] analysis.

M AN U

SC

6

([HMIM]BF4)

[57]

and

EP

TE D

tetrafluoroborate

For example, Liu et al. [58] researched the addition of IL [BMIM]Cl as the

17

porogenic solvent to fabricate organic polymer based monolithic column for HPLC.

18

With vinyl ester resin (VER) as the monomer, EGDMA as the crosslinker, the

19

poly(VER-co-EGDMA) monolithic columns were respectively prepared with/without

20

[BMIM]Cl as the porogenic solvent. The monolithic column fabricated with the

21

presence of [BMIM]Cl displayed more uniform pore structure and higher macropore

22

surface area. Thus, it exhibited enhanced separation selectivity and higher column

AC C

16

21

ACCEPTED MANUSCRIPT 1

efficiencies for separation of model proteins and human plasma proteins. Liu et al. [59] further investigated the introduction of ILs as the porogenic solvent

3

for fabrication of metal-organic frameworks (MOFs) modified monolithic column for

4

CEC. They firstly compared the effect of imidazolium based ILs with different

5

cationic side chains (decyl-, octyl-, hexyl-, butyl-) but the same BF4- anion on the

6

separation performances of the prepared monolithic columns. Among them, the

7

column fabricated with [BMIM]BF4 as the porogenic solvent displayed highest

8

column efficiency. Furthermore, the anions of the ILs also affected the performances

9

of the prepared monolithic columns. In their latest work, IL [HMIM]BF4 and deep

10

eutectic solvents (DESs) were further exploited as the binary green porogenic solvent

11

to fabricate grapheme oxide incorporated organic polymer based monolithic column

12

[57].

TE D

M AN U

SC

RI PT

2

With [BMIM]BF4, dimethyl sulfoxide and dimethylformamide as the porogenic

14

solution, Liu et al. [53-56] fabricated a series of MIP monolithic column in 100 × 4.6

15

mm stainless-steel column. For example, they firstly used both IL and the pivot

16

strategy to fabricate R-mandelic acid MIP monolithic column. The addition of IL

17

could obviously improve the selectivity and column efficiency of the prepared

18

monolithic column and the resolution of the two enantiomers reached 1.87 [54].

19

Furthermore, methyl gallate [53], carprofen [55] and naproxen [56] MIP monolithic

20

columns were also fabricated via the similar method.

21

5. Conclusions and prospects

22

AC C

EP

13

Herein, we systematically summarized the recently reported ILs-based 22

ACCEPTED MANUSCRIPT monolithic columns. Imidazolium, phosphonium or pyridinium-based ILs were

2

facilely polymerized or directly grafted on the monolithic matrix to fabricate a series

3

of monolithic columns via both the one-pot and post-modified methods. Among them,

4

imidazoium-based ILs bearing multiple reactive side-chains were largely exploited.

5

The fabricated monolithic columns were successfully used for high-efficiency HPLC,

6

CEC separation as well as SPE enrichment of both small molecules and

7

macromolecules. The highest column efficiency reached 479,000 plates/m. However,

8

the applications of these columns for analysis of the real samples were still very

9

preliminary. For example, a promising application of the monolithic columns

10

(especially for the monolithic capillary columns) is combined with mass spectrometer

11

for proteomic analysis. However, it is rarely reported. Thus, further in-depth

12

exploitation and utilization of these reported monolithic columns for proteome

13

analysis is very interesting. Furthermore, the exploitation and fabrication of novel

14

ILs-based monolithic columns suitable for proteomic analysis or ILs and novel

15

nanomaterials modified hybrid monolithic columns will be another hot-pot in the

16

future research.

17

Acknowledgements

SC

M AN U

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EP

AC C

18

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1

We are grateful for the financial support from National Natural Science Foundation

19

of China (21675039), Young Talent of Hebei Province, and Project funded by China

20

Postdoctoral Science Foundation (2016M591401).

21

Notes

22

The authors declare no competing financial interest. 23

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liquids monolithic columns for protein separation in capillary electrochromatography,

19

Anal. Chim. Acta 804 (2013) 313-320.

20

[49] J. Smuts, E. Wanigasekara, D.W. Armstrong, Comparison of stationary phases for

21

packed column supercritical fluid chromatography based upon ionic liquid motifs: a

22

study of cation and anion effects, Anal. Bioanal. Chem. 400 (2011) 435-447.

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ACCEPTED MANUSCRIPT [50] T.T. Wang, Y.H. Chen, J.F. Ma, M.J. Hu, Y. Li, J.H. Fang, H.Q. Gao, A novel

2

ionic liquid-modified organic-polymer monolith as the sorbent for in-tube solid-phase

3

microextraction of acidic food additives, Anal. Bioanal. Chem. 406 (2014)

4

4955-4963.

5

[51] H. Wang, H. Zhang, S. Wei, Q. Jia, Preparation of ionic liquid hybrid

6

melamine-based covalent organic polymer functionalized polymer monolithic

7

material for the preconcentration of synthetic phenolic antioxidants, J. Chromatogr. A

8

1566 (2018) 23-31.

9

[52] M. Jia, J. Yang, Y.K. Sun, X. Bai, T. Wu, Z.S. Liu, H.A. Aisa, Improvement of

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imprinting effect of ionic liquid molecularly imprinted polymers by use of a

11

molecular crowding agent, Anal. Bioanal. Chem. 410 (2018) 595-604.

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[53] D.D. Zhong, Y.P. Huang, X.L. Xin, Z.S. Liu, H.A. Aisa, Preparation of metallic

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pivot-based imprinted monolith for polar template, J. Chromatogr. B Analyt. Technol.

14

Biomed. Life Sci. 934 (2013) 109-116.

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[54] L.H. Bai, X.X. Chen, Y.P. Huang, Q.W. Zhang, Z.S. Liu, Chiral separation of

16

racemic mandelic acids by use of an ionic liquid-mediated imprinted monolith with a

17

metal ion as self-assembly pivot, Anal. Bioanal. Chem. 405 (2013) 8935-8943.

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[55] L. Ban, X. Han, X.H. Wang, Y.P. Huang, Z.S. Liu, Carprofen-imprinted monolith

19

prepared by reversible addition-fragmentation chain transfer polymerization in room

20

temperature ionic liquids, Anal. Bioanal. Chem. 405 (2013) 8597-8605.

21

[56] F. Li, X.X. Chen, Y.P. Huang, Z.S. Liu, Preparation of polyhedral oligomeric

22

silsesquioxane based imprinted monolith, J. Chromatogr. A 1425 (2015) 180-188.

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ACCEPTED MANUSCRIPT [57] X.X. Li, L.S. Zhang, C. Wang, Y.P. Huang, Z.S. Liu, Green synthesis of

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monolithic column incorporated with graphene oxide using room temperature ionic

3

liquid and eutectic solvents for capillary electrochromatography, Talanta 178 (2018)

4

763-771.

5

[58] R. Guo, D. Zhang, X. Zhu, L. Tang, X. Zhang, L. Bai, H. Liu, Preparation of a

6

polymer monolithic column using ionic liquid as porogen and its application in

7

separations of proteins and small molecules, Chromatographia 80 (2017) 23-30.

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[59] L.S. Zhang, P.Y. Du, W. Gu, Q.L. Zhao, Y.P. Huang, Z.S. Liu, Monolithic column

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incorporated

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with

lanthanide

17 18 19

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metal-organic

framework

electrochromatography, J. Chromatogr. A 1461 (2016) 171-178.

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for

capillary

ACCEPTED MANUSCRIPT Fig.1 Chemical structures of the ILs used for fabrication of the monolithic columns.

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Fig.2 Scheme for fabrication of the [VC18Im]Br monolithic column via thiol-ene

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click reaction. (Reprint from [23]).

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Fig.3 HILIC separation of purine, pyrimidine bases and nucleosides via the developed

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phosphonium IL monolithic column (A), bare silica monolithic column (B),

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phenyl-stationary phase (C), and zwitterionic sulfobetaine-stationary phase (D).

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(Reprint from [30]).

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Fig.4 Scheme for fabrication of the POSS-VIMPFP hybrid monolithic column.

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(Reprint from [24]).

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Fig.5 Scheme for fabrication of the highly cross-linked POSS-AVI monolithic column

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(A) and traditional imidazolium-embedded monolithic column (B). (Reprint from

12

[25]).

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Fig.6 Scheme for fabrication of the boronate-functionalized graphene-coupled

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poly(guanidinium IL) interface-free 2D monolithic material. (Reprint from [26]).

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Fig.7 Separation of nucleic acid bases and nucleosides (A) and nicotines via the

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developed BiPy-silica hybrid monolithic column. (Reprint from [31]).

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Fig.8 Scheme for fabrication of the PIL-MCC/MNPs monolithic column. (Reprint

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from [37]).

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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ACCEPTED MANUSCRIPT 1 2 3 4

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ACCEPTED MANUSCRIPT

Table 1 ILs-based monolithic columns for HPLC Analytes

Poly(IL-co-TAIC-co-ED MA) organic polymer based monolithic column

RPLC

Alkylbenzenes, acidic & basic compounds, hydroquinone isomers

Poly(IL-co-TMPTA-co-E DMA) organic polymer based monolithic column

RPLC

Poly (IL-co-SMA-co-EGDMA) organic polymer based monolithic column

Column efficiency

SC

M AN U

EP

Poly(VBSIm-AM-MBA) organic polymer based monolithic column

ILs

Polycyclic aromatic hydrocarbons (PAHs), hydroquinone isomers, benzene homologues

Reference

[20]

24,300-27,000 [45] plates/m for benzene homologues

Hydrophilic, Snailase, egg white hydrophobic, π-π proteins, tryptic digests of interactions BSA, human plasma proteins

[46]

HILIC

[34]

AC C

Stationary phase

RI PT

Retention mechanisms

TE D

1

42

Nucleosides, benzoic acids

-

ACCEPTED MANUSCRIPT

[VC18Im]Br modified organic polymer based monolith column

Hydrophobic, charge-charge, π-π interactions

N-methylimidazolium grafted silica based monolithic column

Hydrophobic, Alkylbenzenes, PAHs, hydrophilic, inorganic anions, aromatic anion-exchange, acids, nucleotides, phenols dipole-dipole, π-π interactions

[19]

Phosphonium IL modified silica based monolithic column.

HILIC

[30]

POSS-VOI hybrid monolithic column

RI PT

SC

M AN U

Purine, pyrimidine bases, 137,400 nucleosides plates/m toluene

for

TE D AC C

EP

POSS-VIMPFP hybrid monolithic column

Alkylbenzenes, PAHs, 87,500 plate/m [23] ethylbenzene & styrene, for thiourea phenols, aromatic amines, aromatic acids

Hydrophobic, Alkylbenzenes, PAHs, 72,000 [24] ion-exchange, nucleosides, halogenated plates/m for electrostatic, compounds alkylbenzenes dipole-dipole, ion-dipole, π-π interactions RPLC

43

Alkylbenzenes, PAHs, 101,000-124,0 [35] aromatic amines, phenols 00 plates/m for alkylbenzenes

ACCEPTED MANUSCRIPT

Alkylbenzenes, PAHs, 126,000-151,0 [25] phenols, aromatic amines, 00 plates/m for nucleosides and nucleic alkylbenzenes acid bases, tryptic digests of BSA

POSS-VBI-Cys hybrid monolithic column

RPLC

Alkylbenzenes, amides, 85,000-220,00 [47] nucleosides and nucleic 0 plates/m for acid bases, model protein amides mixture, TARG1 protein sample

EP

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POSS-AVI hybrid monolithic column

44

ACCEPTED MANUSCRIPT

Table 2 ILs-based monolithic columns for CEC

1

ILs

Analytes

RI PT

Stationary phase

ViOcIm+Cl− modified organic polymer based monolithic column

Column efficiency

Reference

M AN U

SC

Alkylbenzenes, thiourea 147,000 plates/m [27] and its analogues, amino for thiourea. acids

ViOcIm+ modified organic polymer based monolithic columns with different anions

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Alkylbenzenes, phenols and anilines, thiourea and its analogs, model proteins, egg white proteins

45

479,000 plates/m [48] for cytochrome c via ViOcIm+NTf2− monolithic column

ACCEPTED MANUSCRIPT

hybrid

Alkylbenzenes, anilines, 165,000 plates/m [22] model proteins, egg white for thiourea proteins

RI PT

VC12Im+Br− modified monolithic column

VC18HIm+Br- modified hybrid monolithic column

M AN U EP

Model glycoproteins and non-glycoproteins mixture

[26]

AFP

[36]

Enkephalins, benzoic acid homologues

AC C

[AAPMIm]Br modified organic polymer based monolith column

TE D

Boronate-functionalized graphene-coupled poly(guanidinium IL) interface-free 2D organic polymer based monolithic column

poly(guanidinium IL) organic polymer based monolithic column

[28]

SC

Alkylbenzenes, basic compounds, amino acids, egg white proteins

46

-

phenols, 80,200 plates/m and its

[21]

ACCEPTED MANUSCRIPT

Alkylbenzenes, phenols, 270,000 plates/m [38] amino acids, benzoic acids for toluene

ILs-GNPs-silica monolithic column

Alkylbenzenes, PAHs, 62,000-110,000 [44] phenols, nucleic acid bases plates/m for and nucleosides alkylbenzenes

RI PT

AlMeIm+Cl- modified organic polymer based monolithic column

M AN U

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based

N-methylimidazolium grafted hybrid monolithic column

BiPy-silica hybrid monolithic column

EP

POSS-VBIM hybrid monolithic column

TE D

hybrid

AC C

[C8VyIm]Br modified monolithic column

PAHs, inorganic anions

Alkylbenzenes, phenols

PAHs, 15,000-52,000 plates/m for PAHs

Alkylbenzenes, phenols, anilines

PAHs, 98,000 plates/m for [29] amylbenzene

PAHs, phenols, nucleotides, nicotines, nucleosides and nucleic acids bases

47

140,000-290,000  [33] plates/m for bromide and iodide [43]

120,000-164,000 [31] plates/m for nucleosides and nucleic acid bases

ACCEPTED MANUSCRIPT

Alkylbenzenes, PAHs, 204,000 plates/m [32] phenols, inorganic anions, for benzene organic acids

RI PT

Dipyridine-modified silica hybrid monolithic column

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48

ACCEPTED MANUSCRIPT

1 2

Monolithic column

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Table 3 ILs-based monolithic columns for SPE ILs

Analytes

ApMeIm+Cl− modified organic polymer based monolithic column

3 4

[50]

Organic UV filters

0.04-0.26 µg/L

[37]

SPAs

0.1-0.3 ng/mL

[51]

Aesculetin

0.05 µg/mL

[52]

M AN U EP

VEImBF4 modified MIP monolithic column

AC C

poly(VBTA-MCOP/IL-DVB) organic polymer based monolithic column

TE D

PIL-MCC/MNPs organic polymer based monolithic column

49

Reference

food 1.2-13.5 ng/mL

SC

Antimicrobial additives

LODs

ACCEPTED MANUSCRIPT • The ILs-based monolithic columns are systematically summarized. • The review introduced the characteristics of the ILs and the fabrication methods. • The ILs columns were classified based on their applications in HPLC, CEC or SPE.

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• ILs as porogenic solution for fabrication of the monolithic column were included.