Versatile ligands for high-performance liquid chromatography: An overview of ionic liquid-functionalized stationary phases

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Analytica Chimica Acta xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Analytica Chimica Acta journal homepage: www.elsevier.com/locate/aca

Review

Versatile ligands for high-performance liquid chromatography: An overview of ionic liquid-functionalized stationary phases Mingliang Zhang a,b , Abul K. Mallik c, Makoto Takafuji c, Hirotaka Ihara c , Hongdeng Qiu a, * a Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China b University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China c Department of Applied Chemistry and Biochemistry, Kumamoto University, Kurokami, Kumamoto 860-8555, Japan

H I G H L I G H T S

G R A P H I C A L A B S T R A C T


Ionic liquids (ILs) are amazing ligands for HPLC stationary phases.
IL-functionalized materials are classified according to HPLC modes.
We illustrate strategies for preparation of IL-functionalized stationary phases.
We describe characterizations and LC evaluations of IL-based stationary phases.
We put forward trends and perspectives on IL-based stationary phases.

A R T I C L E I N F O

A B S T R A C T

Article history: Received 19 February 2015 Received in revised form 9 April 2015 Accepted 10 April 2015 Available online xxx

Ionic liquids (ILs), a class of unique substances composed purely by cation and anions, are renowned for their fascinating physical and chemical properties, such as negligible volatility, high dissolution power, high thermal stability, tunable structure and miscibility. They are enjoying ever-growing applications in a great diversity of disciplines. IL-modified silica, transforming the merits of ILs into chromatographic advantages, has endowed the development of high-performance liquid chromatography (HPLC) stationary phase with considerable vitality. In the last decade, IL-functionalized silica stationary phases have evolved into a series of branches to accommodate to different HPLC modes. An up-to-date overview of IL-immobilized stationary phases is presented in this review, and divided into five parts according to application mode, i.e., ion-exchange, normal-phase, reversed-phase, hydrophilic interaction and chiral recognition. Specific attention is channeled to synthetic strategies, chromatographic behavior and separation performance of IL-functionalized silica stationary phases. ã 2015 Elsevier B.V. All rights reserved.

Keywords: Ionic liquids High-performance liquid chromatography Stationary phase Reversed-phase Hydrophilic interaction Enantioseparation

* Corresponding author. Tel.: +86 931 4968877; fax: +86 931 8277088. E-mail address: [email protected] (H. Qiu). http://dx.doi.org/10.1016/j.aca.2015.04.022 0003-2670/ ã 2015 Elsevier B.V. All rights reserved.

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Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Application of ionic liquid-modified stationary phases Ion-exchange mode . . . . . . . . . . . . . . . . . . . . . . 2.1. Normal-phase mode . . . . . . . . . . . . . . . . . . . . . . 2.2. Reversed-phase mode . . . . . . . . . . . . . . . . . . . . . 2.3. Hydrophilic interaction mode . . . . . . . . . . . . . . 2.4. 2.5. Chiral separation . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Mingliang Zhang has been working in Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (Lanzhou, PR China), for his Ph.D. degree under the supervision of Prof. Hongdeng Qiu and Prof. Shengxiang Jiang. His research interests include the preparation and utilization of ionic liquids in sample handling and separation, as well as surface modification of silica materials.

Abul K. Mallik is a Postdoctoral Research Fellow under the Japan Society for the Promotion of Science, JSPS (Pathway to University Positions in Japan) at Kumamoto University, Japan. He has been working for several years on the development of new high-selective stationary phases for reversedphase liquid chromatography, normal phase liquid chromatography, and hydrophilic interaction chromatography. His research interests also include polymer and supramolecular chemistry.

Makoto Takafuji is an associate professor and a member of the Supramolecular Chemistry Group at the Department of Applied Chemistry and Biochemistry, Kumamoto University, Japan. He is working on the field of materials chemistry. His research interests include the development of organic– inorganic hybrid materials based on self-assembling systems.

Hirotaka Ihara is a professor and the leader of the Supramolecular Chemistry Group at the Department of Applied Chemistry and Biochemistry, Kumamoto University, Japan as well as Vice President of Kumamoto University for International Affairs. He has been working on the functional materials based on molecularly-ordered fibrous self-assemblies. Application for molecular shaperecognitive HPLC using ordered polymer-grafted silicas is one of his successful achievements.

Hongdeng Qiu is a full professor in Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences under the support of the support of the “Hundred Talents Program” from CAS. He obtained B.S. from Nanchang University (2003) and Ph.D. from Lanzhou Institute of Chemical Physics (2008). He did his postdoctoral research in Kumamoto University from 2009 to 2012 under the G-COE Program and Japan Society for the Promotion of Science (JSPS). His research interests are the applications of new materials in chromatography and biosensors, especially ionic liquids for chemical separation.

1. Introduction Ionic liquids (ILs), are a class of ionic, non-molecular substances, most of which are in liquid form at room temperature. Usually an IL has two components, namely an organic cation and an organic or inorganic anion (Fig. 1). The beneficial characteristics of ILs, such as high thermal stability, recyclability, negligible vapor pressure, non-flammability, tunable viscosity, miscibility in different solvents and conductivity etc., have greatly contributed to the successes in many fields, such as catalysis [1–3], energy reservation [4,5], biotechnology [6,7] and functional materials [8,9]. Applications of ILs in so many fields are closely connected to the rapid evolution of ILs, which is indispensably facilitated by the

exchangeability and modifiability of the cation and anion parts. As a result of the simplicity in modifying the cation and/or anion component and varying the combinations of the cation and anion, “task-specific” ILs can be obtained via incorporation of various functional groups, such as ester, urea, carbamate, amino, hydroxyl and carboxyl groups, to fulfill specific demands [10,11]. The electrostatic interactions involved in the cation/anion pairs, and their ability to interact with other molecules through ion exchange, hydrogen bond, p–p stacking and hydrophobic (hydrophilic) interactions, have imparted ILs versatile properties. In view of the unique properties, ILs have attracted tremendous attention in analytical chemistry. In recent years, an avalanche of successful applications has been emphatically summarized in

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Fig. 1. Structures of common cations and anions used in analytical chemistry.

many review articles [12–18]. In separation science, ILs play a very important role in extraction, either as a biphasic solvent for dispersive liquid–liquid microextraction [19–24] or immobilized ligands on supports for SPE and SPME [12,25–27], due to their convenient tunability to realize selective extraction and high preconcentration of target molecules; taking advantage of their high thermal stability and multiple interactions, ILs have also been used as stationary phases (SPs) for gas chromatography (GC) [28–31]; capillary electrochromatography (CEC) and capillary electrophoresis (CE) have as well benefitted immensely from the usage of ILs in modifying capillary [32–36]. In high-performance liquid chromatography (HPLC), ILs, imidazolium salt in most cases, are exceptionally useful. Initially, they were used as additives to mobile phase (MP), leading to decreased zone broadening and improved peak symmetry in separation of basic analytes [37–39], more interestingly, addition of chiral ILs could afford better enantioseparation efficiency [40,41]. The ILs in MP are believed to superiorly improve the chromatographic performance because of their participation in multiple interactions with the analytes and their capability to shield the silanol groups, but they also cause interference during detection and are not compatible with certain detectors, such as evaporative light-scattering detector and mass spectrometry detector, due to their negligible volatility. Beyond all doubt, the usefulness of ILs has been successfully preserved via covalent immobilization onto the silica surface to constitute surface-confined ILs (SCILs). There are a substantial amount of publications involving SCIL SPs in HPLC [42–51]. In spite of the variation in their morphology upon immobilization, the characteristics depending on the structure of the cation, anion and

the subsituents can be maintained for modification of the silica support. Moreover, the properties of ILs can be intentionally tuned by introducing desirable substituents. As a result, there is hardly a class of compounds comparable to ILs in performance as HPLC ligands suitable for a wide variety of separation modes. The novelty and designability of ILs ensure that SCIL SPs have enjoyed lots of successes after their introduction in 2004 [52]. Since then a considerable amount of works has been performed by many authors, notably those by A.M. Stalcup’s group, K.H. Row’s group and us, to exhibit the meritorious qualities of SCIL SPs and to facilitate a better comprehension of IL in analytical chemistry. Previously we presented an overview of the SCIL SPs focusing on the preparation strategies [48], in which detailed information on the synthetic pathways was given. Monomeric and polymeric routes were proposed on the basis of viable immobilization techniques (Fig. 2). In efforts to keep the interested researchers updated with the advance of IL-functionalized silica materials, we attempt to offer a summary of the progresses in SCIL SPs, especially those appeared in the last two years, including synthetic methods and applications. According to the chromatographic modes, this review will divide these SCIL SPs into four main groups, namely ion-exchange (IE), normal-phase (NP), reversed-phase (RP) and hydrophilic interaction (HILIC), with highlights on the specific retention mechanisms of each group. In particular, attention will be directed to chiral SPs involving ILs. For each of the existing IL-modified silica SPs, general information on the structure, characterization technique and corresponding LC mode is compiled in Table 1. Abbreviations for SCIL SPs were given as well when necessary.

Fig. 2. Scheme for preparation of surface-confined ionic liquid stationary phases via monomeric and polymeric strategies.

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Structure

Characterization technique

SiO2

O Si O OH

SiO2

O Si O OH

O Si O OH

SiO2

O Si O OH

O Si O OH

[55]

EA

NP

[64]

EA, IR, XPS

RP, IE

[72]

EA, IR, XPS, BET

NP, RP, IE

[73]

EA, IR, XPS

IE, RP

[57,58,81,82]

EA, IR, TGA, XPS, XRD

IE, RP

[56,62,63,81,82,87]

N Br

N

N

Cl

N Cl

N Cl

N

BF4 NTf2

Cl Br SiO2

EA, TGA, IR, solid state 13C and 29Si NMR IE

N Cl

O Si O OH

SiO2

Reference

N

N

SO3 SO3

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SiO2

Application mode

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Table 1 General information on SCIL stationary phases.

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[76] RP

RP

[76]

[74–78] RP

[60] RP

RP

[60]

[59]

5

N Br

O Si O OH

O Si O OH

O Si O OH

O Si O OH

O Si O OH

SiO2

SiO2

SiO2

SiO2

SiO2

SiO2

N

EA

N Br

O Si O OH

SiO2

N Cl

N

N Cl

Cl

Br

N

N

N

N N

N N Cl

Br

O Si O OH

N O Si O OH SiO2

N

N

EA

EA

EA

SO3H

EA

EA, TGA, XPS

XPS

EA, TGA, solid state

13

C and

29

Si NMR

IE

RP

RP

[62]

[81,82]

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Cl

RP

[76]

EA

HILIC

[107]

EA, IR

RP, NP

[91]

ESD, EA

RP, IE

[90]

2Br

EA, IR

HILIC

[108]

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EA

SiO2

SiO2

N N N N n S

2Br O Si O OH SiO2

N N N N

O O Cl

O H N H N O O Si O OH

SO3 N N n O Si O OH

S

SO3 N N

N N m m = 1 or 3

[80]

SiO2

N

RP

O Si O OH

n N

EA, CA

OH O Si O O Si O OH

2NTf2

[80]

SiO2

S

N

RP

N

EA, CA

O Si O OH

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Table 1 (Continued)

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Cl

Reference

SiO2

O Si O OH SiO2

N

Application mode

N

Characterization technique Structure

O Si O OH

S

n N

O Si O OH

S

n N

O Si O OH

S

n

N

N

SiO2

O Si O OH

S

n N

N

SiO2

SiO2

O Si O OH

[61,83]

EA, Raman spectra

RP

[52]

EA, Raman spectra, XPS

RP

[61]

EA, TGA, IR

IE, RP, HILIC

[89]

EA, TGA, IR

RP

[84–86]

EA, TGA, IR

RP, HILIC

[92]

SO3H CF3SO3

O

O Si O OH

IE, RP

N

SiO2

O Si O OH

EA, Raman spectra, IR, TGA, XPS Solid state 13C NMR

Br OH OH OH

BF4

SiO2

[109]

OH

Br SiO2

HILIC

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SiO2

EA, IR

S

n O

N

N

Br

N n

S

N Br

N N

H S

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OH OH

SO3

n

n N O

NH

N SO3 7

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[99,100] EA, IR, CA

EA, TGA, IR, solid state 13C and 29Si NMR RP

RP

[88]

[97]

N

N H

N H

O Si O OH

O Si O OH

SiO2

SiO2

O

N H

N H O SiO2

S O Si O OH

SiO2

S O Si O OH

SiO2

S O Si O OH Structure

Table 1 (Continued)

Br

Br

N

N

N Br

N

N

n N

17

O

n O n

H

N

N

n

17

n

H

SO3

N

N H

O

N H

N N

SO3

RP EA, TGA, IR

EA, TGA, IR, solid state 13C and 29Si NMR RP, HILIC

Application mode Characterization technique

[92,93]

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Reference

8

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BET: specific surface area measurement; CA: water contact-angle test; EA: elemental analysis; ESD: energy-dispersive spectroscopy; IR: infrared spectroscopy; TGA: thermal gravimetric analysis; XPS: X-ray photoelectron spectroscopy; XRD: X-ray diffraction analysis.

SiO2

O Si O OH

Br

N

N

HO

EA

Chiral

[119]

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2. Application of ionic liquid-modified stationary phases 2.1. Ion-exchange mode The ion-exchange behaviors of pyridinium and imidazolium salts covalently anchored on silica gel were first observed by Tundo et al. [53] and Moreira and Gushikem [54], respectively in 1980s. Based on their findings, a pyridinium-modified anion-exchange silica phase was introduced by Auler et al. for the first time [55]. In their report, pyridine was heterogeneously immobilized onto chloropropylated silica to prepare pyridinium-modified SP (Sil-C3Py-Cl), the covalent bond between pyridinium cation and propyl chain was validated by solid-state 13C nuclear magnetic resonance (NMR) (Fig. 3). The alkylpyridinium cation was beneficial for separation and quantification of some inorganic anions, such as chloride, nitrite, bromide and nitrate, using a phthalate buffer aqueous solution as eluent. Good results for separation of benzene, anthracene, benzyl alcohol, benzonitrile and nitronaphthalene demonstrated the possibility of using Sil-C3Py-Cl in NP mode. Utilization of imidazolium salts in preparation of HPLC SP took place shortly after pyridinium salts. In 2006, two anion-exchange SPs based on N-methylimidazolium (Sil-C3ImC1-Cl) [56] and imidazolium (Sil-C3ImH-Cl) cations [57] were synthesized through the same procedure for Sil-C3Py-Cl. These new phases could be used in analyses of anions with great prospects, familiar anions (iodate, chloride, bromide, nitrate, iodide and thiocyanate; benzoate, salicylate and hydrogen phthalate) and some other organic compounds (N-ethylaniline, N,N-dimethylaniline,

Fig. 3. Solid-state 13C NMR spectrum for covalently immobilized pyridium cation upon silica surface. Reproduced from Ref. [55].

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o-nitroaniline and benzidine; 2-aminopyrimidine, adenine and 6-chlorouracil) were separated with high resolution and efficiency using phosphate buffer solution or water as MP. Apart from ionexchange characteristics, Sil-C3ImC1-Cl also offered RP interactions and hydrogen bonding, indicating its possible application in separation of biological samples. Surprisingly, though only imidazole was attached, Sil-C3ImH-Cl packed into microcolumn was able to perform good resolution of phenolic compounds in highly aqueous MP in RP mode [58]. Another zwitterionic phase based on silica bonded with 1-propyl3-(propyl-3-sulfonate)imidazolium cation (Sil-C3ImC3SO3H-Cl) had also been investigated [59]. This new phase was essentially the result of derivatization of Sil-C3ImH-Cl by 1,3-propanesultone. It could be used for simultaneous separation of cations (K+ and Ca2+) and anions, using potassium hydrogen phthalate buffer. Interestingly, three imidazolium-based ILs (1-ethyl-3-methylimidazolium, 1-butyl-3methylimidazolium and 1-hexyl-3-methylimidazolium tetrafluoroborate) were also separated on this new SP. To study the hydrophobic interaction and compare the chromatographic properties of Sil-C3ImC3SO3H-Cl with Sil-C3ImC1-Cl and Sil-C3ImH-Cl, bases and vitamin B series were separated. The retention mechanisms of vitamins herein was quite different from those in cation-exchange mode and RP mode, illustrating that the zwitterionic SP behaved through a combination of ion-exchange, electrostatic and hydrophobic interactions with different specimens. This multimodal retention property was doubtlessly advantageous for HPLC separation. Further investigation into the anion-exchange SP based on imidazolium salts with longer alkyl chain (Sil- C3ImC6-Cl and SilC3ImC10-Cl) [60] indicated that the hydrophobicity of the alkyl chain had little impact on the anion-exchange process, but affected the hydrophobic interaction significantly, this would allow for a modulation of hydrophobic property of the SCIL SP via attachment of different alkyl chains, which hereafter was achieved in our following attempts, as described later. New synthetic strategies were adopted, outside of the above heterogeneous monomeric immobilization. One of them was polymerization through surface radical chain-transfer reaction between mercaptopropylated silica and 1-allyl-3-(butyl-4-sulfonate)imidazolium trifluoromethanesulfonic (Sil-C3SC3ImC3SO3HCF3SO3) and 1-allyl-3-butylimidazolium bromide (Sil-C3SC3ImC4Br) [61], which ensured a higher bonding amount (2.06 and 1.68 mmol m2, respectively) and better thermal stability of the resultant silica phases. The new phases exhibited ion-exchange behaviors similar to those tested before. Nevertheless, the new strategy based on polymerization of alkenylimidazolium salts was intriguing, as it made modification of imidazolium salts more convenient, in light of the availability of a vast array of polymerizable groups. Another new strategy was homogeneous formation of ILs prior to immobilization. Two “ionosilane” derivatives were synthesized by quaternization of N-methylimidazole and N-butylimidazole with 3-bromopropyltrimethoxysilane in Colon’s laboratory [62]. The bonding amounts of the SPs (Sil-C3ImC1-Br and Sil-C3ImC4-Br) were however lower (<0.8 mmol m2). The selectivity towards three carboxylic acids was observed to be influenced by multiple interactions. New support other than silica was utilized, such as ZrO2/SiO2 composite. This new composite support was studied by Liang et al. with anchored 1-methylimidazolium salt [63]. This new composite phase (Zr/Sil-C3ImC1-Cl) was found to offer higher resolution and selectivity for organic anions and anilines than Sil-C3ImC1-Cl under optimized MP conditions, due to its Lewis acidic sites. A distinct advantage of this new phase was its operability in NP mode for separation of basic compounds. However, because of the Lewis acidic sites, Lewis bases such as phenols were held strongly, which

could only be eluted by adding competitive Lewis base to the eluent. 2.2. Normal-phase mode It is well-established that polar ligands, such as aminopropyl, cyano and diol, can provide electron donor/acceptor, dipole–dipole and hydrogen bonding interactions under NP conditions, these intermolecular interactions are advantageous for separation of polar analytes. Likewise, pyridinium and imidazolium cations are of high polarizability, thus it would be practicable to use SCIL SPs for separation in NP mode. As evidenced by abovementioned SCIL SPs, NP operation had been carried out for separation of relatively limited number of analytes, yet investigation into the retention mechanisms involved were seldom presented. Thus far, there has been a narrow scope of studies on SCIL SPs concerning NP evaluation. Among these studies, an exhaustive characterization of pyridinium-based phase reported by Van Meter et al. was of great interest [64]. The pyridinium cation was tethered to silica by quaternization of pyridine with 8-bromooctyltrimethoxysilane. Using linear solvation energy relationships (LSER) model, this new SCIL SP (Sil-C8Py-Br) was characterized with a set of aromatic probe solutes under NP condition. It is noteworthy that LSER model has been used extensively to investigate retention mechanisms in RP mode [65–68]. Its usual representation is: SP = c + eE + sS + bB + aA + vV where SP can be any free energy related property, commonly taken as log k in LC, k is experimental retention factor for a given analyte on a SP with specific MP composition at a fixed temperature; c is a system constant; E, S, A, B and V are solute descriptors already determined and available for plentiful analytes. Individually, E stands for solute’s excess molar refraction, S dipolarity (polarizability), A hydrogen bond donating capacity, B hydrogen bond accepting capability, and V McGowan molecular size. The parameters e, s, a, b and v represent the solvation properties of a LC system. Specifically, e denotes charge transfer and p–p stacking, s dipole–dipole interaction, a and b hydrogen bond acidity and basicity respectively, v hydrophobic interaction. They are obtained by multiple linear regression analysis of the solute descriptors and retention factors. A positive value means such interaction is predominant in SP; a negative value symbolizes a more significant interaction in MP. Generally, in RPLC, e and v are positive, the rest are negative; but on the contrary in NPLC. In Stalcup’s study, it was found that the pyridinium-based phase behaved similarly to other NP SPs [69–71], i.e., s, a and b were positive, and the s term was decisive for the retention, and there was a strong resemblance between the SCIL SP and cyano SP. Pyridinium-modified phases could also be synthesized from larger pyridine derivatives, such as 4,40 - dipyridine [72] and quinoline [73]. Dipyridinium-modified silica (Sil-C3DiPy-Cl) could be used for IE separation of organic anions and RP separation of polycyclic aromatic hydrocarbons (PAHs) and phenols. Quinoliniummodified silica (Sil-C3BnPy-Cl) had distinctive mixed-modal characteristics; its versatility had been exhibited by separation of PAHs, phthalates, paraben, phenols and anilines in both NP (Fig. 4) and RP mode, as well as by separation of inorganic anions in IE mode. 2.3. Reversed-phase mode Up to now, the applications of SCIL SPs are preponderantly performed in RP mode. At the early stage, experiments on the imidazolium salts with short alkyl chains (C1–C10) indicated their hydrophobic characters in addition to ion-exchange ability. Their

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respectively for acidic and basic solutes [78]. The new form of the LSER model was: log k0 = c + eE + sS + bB + aA + vV + d+D+ + dD

Fig. 4. Chromatogram for N,N-dimethylaniline (1), N-ethylaniline (2), diphenylamine (3), p-methylaniline (4), aniline (5), o-nitroaniline (6), m-nitroaniline (7), and p-nitroaniline (8) obtained on quinolinium-modified silica stationary phase. Mobile phase: hexane–ethanol (80/20, v/v); flow rate: 1.0 mL min1; UV 254 nm; column temperature: 25  C. Reproduced from Ref. [73].

applications in separation of small aromatic solutes were successful. To gain more insights into the retention characteristics of SCIL SPs, Stalcup et al. conducted a series of systematic studies on the RP retention mechanisms involved in the SCIL SP (Sil-C8ImCx-Br)-MP system via LSER model [74–76]. The chromatographic evaluations revealed that the e, v terms were always positive, while s negative, a and b fluctuated around zero. A positive e, similar to the case of phenyl SP, was an indicative of the polarizability and aromaticity of the imidazolium core. The fluctuation of a and b highlighted these two parameters’ reliance on MP composition. In the case of above zero, the SCIL SPs were more capable of interacting with solutes through hydrogen bonding than MP. The positive v term suggested the overall SCIL SPs were hydrophobic. However, short alkyl chains combined with the hydrophilic cation core would hardly lead to an elevated overall hydrophobicity of the SCIL SPs. Alternation of anions indicated that the identity of anion significantly impacted the retention of neutral aromatic solutes and the retention properties of the SPs. This is an interesting finding, as it points out a complementary pathway to modify the SCIL SP besides changing substituents of the cation. Their subsequent study on the butylimidazolium-based phase (Sil-C8ImC4-Br) demonstrated that the SCIL SPs were promising for multi-modal separation [77]. This multi-modal character was validated by separation of five peptides (Gly-Tyr, Val-Tye, leucine enkephalin, methionine enkephalin and angiotensin-II). In less than five minutes, separation of these peptides was achieved with satisfactory resolution. The effect of trifluoroacetic acid on the separation was evaluated with results confirming that the acid was not functioning as ion-pairing agent in the separation, but instead formic acid could lead to a better separation. The SCIL SP exhibited some reversed-phase character; electrostatic interactions were dominant at high organic and/or low pH modifier concentrations. In their latest work with respect to LSER model, Stalcup et al. proposed a modified model which encompasses an extra solute descriptor, D, ionization terms for weakly acidic and basic solutes, expressed by: D¼

10pHpK a pHpK a

1 þ 10

and

10pK a pH 1 þ 10pK a pH

When applied to Sil-C8ImC4-Br with solutes containing both neutral and acidic compounds, improved correlation (R2) and diminished standard error (SE) were obtained in presence of the D descriptor (R2: 0.987 vs 0.846; SE: 0.051 vs 0.163 in 60% methanol (MeOH) in water). Coefficients obtained from the multiple regression for the test set with D descriptors were more consistent with those obtained when only neutral solutes were used. In addition, the modified LSER model was useful in predicting elution order for the ionizable solutes. This work provided further supporting evidence for the multi-modal nature (hydrophobic and electrostatic) of the SCIL SPs. Taking advantage of this modified equation, they succeeded in identifying the effects of different cations on selectivity [79]. The substituents upon N3 position were found to impact the orientation of imidazolium cation, which, together with concentration of salt in MP affected the retention of anions (ionic retention). Employing the same mathematic model, SCIL silica with longer aliphatic chain has been characterized in our work [80]. Comparative study of an octadecylimidazolium column (polar-embedded, Sil-EImC18-Cl) prepared from N-octadecylimidazole along with a methylimidazolium/C18 column (polar-spaced, Sil-S-ImC18-Cl) prepared from N-methylimidazole and octadecyltrichlorosilane demonstrated N-alkylimidazoles with longer chain led to a lower bonding density (0.53 mmol m2 for N-octadecylimidazole, 1.37 for N-methylimidazole), the presence and distribution patterns of imidazolium cations would substantially influence the property of the stationary phase. The effect of the hydrogen-bond acceptor nature (hydrogen-bond basicity) of imidazolium cation was proportionate to its density on the silica surface on both columns. Apart from Stalcup’s meticulous works in depicting the retention characteristics of the SCIL SPs, study on the applications of SCIL SPs functionalized with short alkyl chains was conducted by Bi et al. [81,82] and our group [56,57,59,60]. Given the improved RP performance of SCIL SP prepared via polymerization procedure, large aromatic probes, such as PAHs, were included in the chromatographic assessment [83]. In this work, 1-allyl-3-butylimidazolium-modified phase (Sil-C3SC3ImC4-Br) previously for IE separation was investigated. Comparative study on Sil-C3SC3ImC4Br, C18 and a polystyrene phase showed that Sil-C3SC3ImC4-Br was less sensitive to the hydrophobicity of samples, or only had weak hydrophobic interaction with neutral PAHs, but more sensitive to the aromaticity of the analyte. Sil-C3SC3ImC4-Br resembled phenyl phase in aspect of aromatic selectivity, but showed better planarity selectivity (atriphenylene/o-terphenyl = 3.89, atrans-/cis-stilbene = 1.68) than the latter (atriphenylene/o-terphenyl = 2.04, atrans-/cis-stilbene = 1.16) and C18 (atriphenylene/o-terphenyl = 1.57, atrans-/cis-stilbene = 1.08). Enhanced selectivity towards positional isomers of polar-substituted aromatics, such as dinitrobenzenes, dichlorobenzenes and naphthalenes, hydroxyl and aminonaphthalenes, was observed, ascribing to the ion-dipole interaction between the analytes and imidazolium cation. Even though a short alkyl chain was in service, the multiple interactions involved in the retention process were pronounced. Our following effort was to exploit the advantages of C18 chain/ imidazolium combination [84–86]. For this purpose, a C18functionalized imidazolium salt, i.e., 1-vinyl-3-octadecylimidazolium bromide ([C18VIm]Br), was synthesized and grafted to the mercaptopropylated silica. The new phase, Sil-PImC18-Br, was further modified through exchange of counter-anions from bromide to methyl orange (MO), either by metathesis of anions before polymerization or on-column anion-exchange, resulting in

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Fig. 5. Stepwise preparation of Sil-PImC18-MO via polymeric strategy and ionic self-assembly (A) and comparative chromatograms for SRM869b among different stationary phases (B). Mobile phase: 100% MeOH; flow rate: 1.0 mL min1; UV 254 nm; column temperature: 10  C. Reproduced from Ref. [85].

another phase, Sil-PImC18-MO (Fig. 5A). The bonding amount of C18VIm cation was remarkably high, up to 3.74 mmol m2. The long hydrophobic chain and strong p–p stacking from the rigid MO structure and imidazolium cation imparted Sil-PImC18-MO ultrahigh shape selectivity towards PAH isomers. For triphenylene/oterphenyl, planarity selectivity factor a was 6.39, 9.03, 1.78 and 4.02 on Sil-PImC18-Br, Sil-PImC18-MO, commercial C18 and C30 stationary phases, respectively; for four-ring isomers tetraphene/chrysene, linearity selectivity factor a was 1.72 and 1.07 for Sil-PImC18-MO and C30, respectively. It was of great interest that these separations could also be performed in NP mode without compromising selectivity, emphasizing the exceptional role of MO in enhancing the molecular recognition ability of the SCIL SP. Baseline separations of standard reference material (srm) 869b and SRM 1647e mixture were achieved on Sil-PImC18-MO with higher resolution than that on C30 (Fig. 5B). Furthermore, six isomeric steroids were fully separated on Sil-PImC18-MO using 90% MeOH in water, while other phases failed. The ultra-high shape selectivity exhibited by Sil-PImC18-MO was the result of the reduced mobility of C18 chains induced by the rigid MO (azobenzene), as consolidated by the solid-state 13C NMR spectroscopy, which revealed an increased amount of trans arrangement of the C18 chains, viz., a more orderly arrangement, after replacement of bromide with MO. It was safe to argue that functionalized anions could induce considerable changes in the SCIL SP, exchange of anions was a new and simple way to tune selectivity and even to prepare new phase, given the large amount of available anions. However, buffer solutions could not be used as MP, because of the undesirable substitution of MO with other anions. Very recently, Sun et al. reported another two anions suitable for improving the chromatographic performance of Sil-C3ImC1-Cl, originally investigated in IE mode [87]. In their work, dodecyl sulfonate and dodecylbenzene sulfonate anions were employed to substitute the chloride anion on-column, respectively. The new

phases (Sil-C3ImC1-Ds and Sil-C3ImC1-Dbs) demonstrated significantly enhanced hydrophobicity, resulting in better separation performances for PAHs, phthalates, parabens and phenols. In particular, the phenyl group of dodecylbenzene sulfonate anion could provide enhanced selectivity towards aromatic solutes by p–p interaction (Fig. 6). We also synthesized another polar-embedded silica phase functionalized by 1-allyl-3-octadecylimidazolium salt (SilC3SC3ImC18-Br) [88]. In this work, a lower bonding amount of the alkylimidazolium salt was obtained (0.97 mmol m2), due to

Fig. 6. Separation of dimethyl phthalate (1), diethyl phthalate (2), diallyl phthalate (3), methyl 4-hydroxybenzoate (4), ethyl 4-hydroxybenzoate (5), propyl 4-hydroxybenzoate (6), di-n-butyl phthalate (7), n-butyl 4-hydroxybenzoate (8) and di-n-amyl phthalate (9) on N-methylimidazolium modified stationary phase with chloride (Sil-C3ImC1-Cl), dodecyl sulfonate (Sil-C3ImC1-Ds) and dodecylbenzene sulfonate (Sil-C3ImC1-Dbs), respectively. Mobile phase: 55% MeOH in water; flow rate: 1.0 mL min1; UV 254 nm; column temperature: 25  C. Reproduced from Ref. [87].

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the lower reactivity of allyl group than that of vinyl group. Similar to its vinyl counterpart, the new phase demonstrated enhanced selectivity towards PAHs and isomers over C18 phase. By comparison between the log k/log k(o/w) (octanol/water partition coefficient) plots for alkylbenzenes and linear PAH analogues obtained on Sil-C3SC3ImC18-Br and C18, it could be clearly seen that different from the two parallel slopes on C18, the slope for linear PAHs was steeper than that for alkylbenzenes on Sil-C3SC3ImC18Br, as a result of the p–p interaction between the imidazolium cation and electron-rich aromatic rings. On the other hand, SilC3SC3ImC18-Br showed higher selectivity towards polar-substituted analytes, which was visualized by separation of dinitronaphthalene. Due to the presence of the hydrophilic cation core, Sil-C3SC3ImC18-Br did not suffer from de-wetting in 100% water when separating nucleosides and bases. Polymeric SCIL SP could be prepared not only from imidazoles with alkenyl as substituent, but also from imidazole with substituent containing alkenyl group [89]. An v-bromoester synthesized from acryloyl chloride and 11-bromoundecanol was employed to quaternize 1-methylimidazole, the obtained polymerizable IL possessed two polar sites. Silica modified by this IL (Sil-pC11ImC1-Br) was suitable for mixed-mode separation. Firstly, we testified its ion-exchange capacity by separating inorganic ions (nitrite, nitrate and iodide) in IE mode. In the elution, iodate was excessively retained, possibly due to the hydrophobic characteristic of Sil-pC11ImC1-Br. Seeing this, RP separation of terphenyl isomers and triphenylene was conducted, which indicated that SilpC11ImC1-Br offered much higher planarity selectivity (atriphenylene/o-terphenyl = 6.19) than C18 (atriphenylene/o-terphenyl = 1.78). The reason for this exceedingly high planarity selectivity might reside in the carbonyl group and imidazolium cation, both of which were very capable of p–p stacking. Further evidence for its hydrophobicity was acquired by separation of SRM 869b, where in contrast to the case of Sil-PImC18-MO, selectivity factor for tetrabenzonaphthalene (TBN) and benzo[a]pyrene (BaP) was 1.43, larger than 1, highlighting the monomeric C18-like retention behavior and reduced shape selectivity of Sil-pC11ImC1-Br. Finally, the polar imidazolium cation and ester group, as well as shorter alkyl chain than C18, in Sil-pC11ImC1-Br gave the possibility of multiple interaction mechanisms, which prompted us to assess its performance in HILIC mode. It was observed that the retentions of hydrophilic solutes increased with the increase of organic modifier content in the binary acetonitrile (MeCN)/ammonium acetate solution. Six nucleosides or their bases (caffeine, thymine, thymidine, 5-bromouracil and cytidine) were separated. The investigations in different modes confirmed that Sil-pC11ImC1-Br was a true multi-modal SP. Quite remarkably, a dicationic IL was utilized by Sun et al. to fabricate novel mixed-mode silica surface [90]. In their work, two N-vinylimidazole molecules were tethered by 1,6-dibromohexane to form 1,10 -(1,6-hexanediyl)bis(1-vinylimidazolium)dibromide, which was subsequently grafted to mercaptopropyl-functionalized silica. Elution of organics (PAHs and anilines) and that of anions (inorganic and organic ones) revealed the recommendable mixedmode behaviors of the new SP (Sil-C3S[C2Im]2C6-2Br). On account of the significant electron-involved interactions provided by imidazolium cations, it would be of more interest if the authors had put forth chromatographic information on the difference between dicationic and monocationic ligands. The applicability of IL with two imidazole moieties was further proved by Liu et al. [91]. In their work, a geminal imidazole precursor (not imidazolium salt at this stage) with carbamatefunctionalized linker was prepared, and then immobilized onto chloropropylated silica to form a new SP, applicable in RP and NP modes due to the presence of multiple polar groups and aromatic rings. Judging from the difference between separations of phenols

13

and organophosphorus pesticides in both modes, this carbamatefunctionalized IL SP was less hydrophobic, but more able to hold the solutes via polar interactions, such as hydrogen-bonding, p–p stacking and dipole/dipole interaction, therefore more favorable for NP application. Since the alternation of anion could be of great use in improving the column performance, yet the new anion was not resistant to gradual run-off or substitution by other anions, this was a serious drawback from the viewpoint of column stability. As a countermeasure, a new co-polymerization strategy was adopted to prepare stable polymeric SCIL SP with desirable anions [92]. In this strategy, the polymerizable IL monomer pair, [C18VIm]SS, was prepared by anion-exchange reaction between [C18VIm]Br and sodium p-styrenesulfonate. The IL monomer pair was then copolymerized on silica as aforementioned. Evaluation of the new phase (Sil-P(ImC18-SS)) with PAHs revealed that under same MP conditions, retention factors were lower than that obtained on C18, but the selectivity factors were always higher. The specific selectivity was reflected by larger separation factors for o-terphenyl and triphenylene (a = 5.04), phenanthrene and cis-stilbene (a = 2.43), as well as diphenylmethane/fluorene (a = 2.03) than C18 (a = 1.57, 1.08 and 1.26 in turn). Very recently, the application of Sil-P(ImC18-SS) has been expanded to the separation of nucleosides and flavonoids [93]. There was a clear behavioral distinction between Sil-P(ImC18-SS) and C18, the former could resolve seven analytes in 18 min using KH2PO4 buffer, whereas C18 resolved four of the same analytes in the same span, the last three were held so strongly that only addition of organic solvent in MP could achieve complete elution in shorter time. The results demonstrated that the new phase might have prospects in per-aqueous LC to diminish the consumption of organic solvents in separation of highly polar solutes [94–96]. Under optimized MP conditions (10 mM NaH2PO4/MeOH = 40/60 (v/v), pH 3.0), we also successfully separated eight flavonoids, including naringenin, baicalein, apigenin, iso-rhamnetin, luteolin, kaempferol, quercetin and myricetin, whose separation was deemed difficult because of their structural resemblance between each other (Fig. 7). Regardless of all the optimizations, C18 could not achieve baseline separation. This was additional evidence for the positive effect of multiple interactions on the separation process. The stability and column efficiency were almost invariant after long time service, hence it was reasonable to state that the

Fig. 7. Separation of flavonoids including (1) naringenin, (2) baicalein, (3) apigenin, (4) isorhamnetin, (5) luteolin, (6) kaempferol, (7) quercetin, (8) myricetin with different column. Mobile phase: 10 mmol L1 NaH2PO4: MeOH (40/60, v/v), pH 3.0; flow rate: 1.0 mL min1; UV 360 nm; column temperature: 25  C. Reproduced from Ref. [93].

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Fig. 8. Formation of urea-functionalized imidazolyl silane in homogeneous conditions and subsequent immobilization onto silica spheres. Reproduced from Ref. [100].

covalent bond between the polymerized cationic and anionic parts upon the support was stable. Co-polymerization of IL monomer pairs on supports may lead to diverse functionalized materials because of the combination of cationic and anionic monomers, as long as there are alkenyl group contained in both of them. Bulky anion that has rigid structure could produce quite distinctive chromatographic properties, as substantiated by another piece of our work involving the polymerizable azobenzene moiety (AzO) [97]. Polymerizable vinyl group was introduced into the Azo moiety by a ureido linker, after conventional metathesis the new IL monomer pair (AzO-ImC18) was afforded, which was then immobilized via physical coating onto silica. The resultant silica phase (Sil-P(AzO-ImC18)) had a much lower bonding amount (0.84 mmol m2) compared to SilPImC18-Br [86] (3.14 mmol m2), probably due to the steric hindrance from the bulky Azo moiety. The chromatographic behavior of Sil-P(AzO-ImC18) was similar to that of Sil-PImC18-MO, in aspect of planarity selectivity. The advantages of specific chromatographic performance were in connection with the AzO group, which boosted the separation capacity of SCIL SPs vastly. This inference was confirmed by our investigation into a silica phase modified only by AzO ligand (Sil-PAzO) [98]. In the investigation, it was observed that the elution order of seven Tanaka test analytes on Sil-PAzO was highly similar to that on Sil-P (AzO-ImC18), but different notably from that on C18; selectivity towards steroids was fine, and the elution order was similar to that on Sil-PImC18-MO. The versatility of Sil-PAzO was further embodied by separation of abovementioned flavonoids (without apigenin) in RP mode, seven nucleoside and three ginsenosides in HILIC mode, and ten nucleosides and bases in per-aqueous mode. It was obvious that Sil-PAzO presented unique selectivity compared with C18, due to mixed-modal properties derived from the multifunctional groups. These unique characters were vividly noticeable when applied as SCIL SPs. Lately, a multicomponent one-pot strategy for preparation of SCIL SPs based on g-isocyanatopropyltriethoxysilane (ICPTES), 3aminopropylimidazole (APIm) and v-haloalkanes was introduced in our works [99,100] (Fig. 8). Unlike most of the heterogeneous methods reported in literatures, an imidazolium-silane was obtained in homogeneous conditions prior to immobilization onto silica spheres. Firstly, ICPTES reacted with APIm to afford a new urea-functionalized imidazole-silane (UIm silane), which was then

quaternized by v-haloalkanes to form urea-functionalized imidazolium-silane (UIm-R silane); finally silica spheres were added to conduct bonding. Several advantages of this new synthetic method, such as simplicity and high conversion rate, made it convenient to produce a series of polyfunctional SCIL SPs (Sil-UImR). The resulted bonding density was remarkable when using aliphatic chains, for example, C18 and C8 chains led to a density of ca. 2 mmol m2, much higher than abovementioned 0.53 mmol m2 from heterogeneous conditions. For the first time, SCIL SP with bulky aromatic substituent was prepared using 9-bromomethylanthracene, with a surface density of 0.81 mmol m2. This discrepancy in bonding density may be ascribed to the significant steric hindrance of anthracene. It was observed during contact angle tests that a hydrophilic silica surface was constructed by UIm silane; more interestingly, attachment of anthrylmethyl group induced an even more hydrophilic surface. In addition to hydrophobic surface, hydrophilic surface could also be constructed via this method to meet the demands of HILIC applications, considering the great availability of hydrophilic substituents. Indepth chromatographic evaluation of Sil-UIm-C18 demonstrated the merits of urea group, such as the enhanced p–p stacking with condensed-ring PAHs and high affinity for phenolic compounds (hydrogen-bond accepting ability of urea group) (Fig. 9). Predominant electrostatic interactions were observed in separation of a diversity of anilines, notably in the cases of nitro group and naphthyl ring. 2.4. Hydrophilic interaction mode HILIC is an interesting alternative for the analyses of polar substances that held poorly in RPLC and NPLC. It can be defined as a separation mode that combines the SP usually used in NP mode and MP in RP mode. Typically, highly hydrophilic SPs are applied in HILIC mode, e.g., bare silica or chemically modified hydrophilized silica. The MP is often a binary polar solvent composed of mostly MeCN and water. Since its introduction by Alpert in 1990 [101], HILIC mode has been increasingly applied. There are several review articles giving exhaustive description of HILIC applications [102–106]. Currently there are limited types of commercial SPs for HILIC [104]. The fundamental requirement of such SP is the ligand must be of sufficient hydrophilicity. The imidazole and imidazolium cation

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Fig. 9. Separation of p-aminophenol (1), m-aminophenol (2), phenol (3), mnitrophenol (4), p-cresol (5), p-chlorophenol (6), 2-naphthol (7), o-tert-butylphenol (8) and 1-naphthol (9). Mobile phase: 60% MeOH in water; flow rate: 1.0 mL min1; UV 254 nm; column temperature: 25  C. Reproduced from Ref. [99].

are clearly hydrophilic, and there is commercial SP based on imidazole. Moreover, the multiple interactions provided by SCIL are beneficial for HILIC separation. In our preliminary research [89,92], it was discovered that SCIL SP had great potential for HILIC application. For the first time, Qiao et al. proposed a SCIL SP exclusively characterized in HILIC mode [107]. Taking advantage of the polymerization strategy, a novel IL-functionalized zwitterionic SP was (Sil-C3SC2ImC3SO3) synthesized via mercaptopropylated silica and 1-vinyl-3-(butyl-4-sulfonate) imidazolium. The zwitterionic phase exhibited good selectivity and favorable retention for a wide range of polar solutes (nucleoside, nucleic acid bases, benzoic acids, uric acid and its methyl derivatives, water-soluble vitamins) as compared to base silica phase. The effects of MeCN content, buffer salt concentration, pH and temperature were studied. By thermodynamic study, it was found that the retention of most solutes vs column temperature exhibited a linear Van’t Hoff plot with negative DH, confirming the retention mechanisms were a mixed-mode one (i.e., a combination of adsorptive and partitioning interactions). Overall, the new zwitterionic SCIL SP showed excellent LC performance for a variety of polar solutes, the column efficiency was high, for example, efficiency close to 100,000/m was obtained for cytosine. More recently, two dicationic ILs were utilized by Qiao et al. for preparation of SCIL SPs for HILIC [108]. The dicationic ILs have the potential to enhance the ionic nature and hydrophilicity, which are greatly favored for retention of hydrophilic and ionic compounds in HILIC mode. These geminal dicationic ILs, 1,4-bis(3-allyimidazolium) butane dibromide and 1,8-bis(3-allylimidazolium) octane dibromide, were immobilized onto silica via the same procedure

15

for monocationic ILs. The new silica phases (Sil-C3S[C3Im]2C4-2Br and Sil-C3S[C3Im]2C8-2Br) displayed typical HILIC retention behavior with outstanding chromatographic performance, column efficiency varied in the range of 77,100–114,500 plates/m for cytosine for these columns. The selectivity towards nucleosides was much higher than that of the analogue monocationic ILs columns (Sil-C3SC3ImC4-NTf2 and Sil-C3SC3ImC8-NTf2) under the same conditions. The carbon chain linkers were likely to influence the separation behaviors significantly; the longer linker decreased the hydrophilicity and retention, while the anions had indiscernible effect on the retention, due to the exchangeability in the buffer eluent. The retention behaviors were investigated by evaluating the effects of different chromatographic factors, including water content, pH of MP and buffer salt concentration. The retention of nucleosides and nucleic base decreased with the increase of water content, while acidic (benzoic acids) solutes displayed different trends at high and low pH values as the retention might be dominated by complex mechanisms, depending on the existing forms of them, ions or molecules, lower pH value was unfavorable for formation of ions and anion-exchange. Effects of the pH value and buffer salt concentration were reflected by the variation of electrostatic interactions between chromatographic system and nucleosides and basic compounds. All the results revealed that dicationic ILs were promising ligands for HILIC SPs, and the retention was enhanced by the mixed-mode mechanism thereof, such as HILIC mechanism and anion-exchange interaction. A piece of innovative work by Qiao et al. reported the preparation of HILIC SP using glucaminium cation [109]. From the sense of chemical structure, this new class of ILs belonged to ammonium salts functionalized by glucosyl unit. Glucaminium salts were initially used as good media for selective extraction and high-sensitivity detection of boron-species from aqueous samples, due to their excellent complexation ability [110–112]. In view of the highly hydrophilic carbohydrate moiety and the ability to undergo multiple interactions, the precursor of glucaminium cation, Nmethylglucamine (also called meglumine), seemed very attractive for construction of hydrophilic silica surface. To obtain glucaminium-functionalized silica, the authors firstly introduced reactive group into meglumine by peralkylation with allyl bromide, then the polymerizable glucaminium salt was immobilized onto mercaptopropylated silica. The glucaminium-based IL SP (SilGluN-Br) presented good separation performances toward neutral polar solutes such as nucleosides and a set of flavonoids (Fig. 10). A mixed-mode HILIC/anion-exchange retention mechanism was

Fig. 10. Separation of sixteen flavonoids on glucaminium-based IL column (SilGluN-Br) in HILIC mode. Mobile phases: 0.1 mol L1 ammonium formate (A) and MeCN (B), with a gradient elution of 95%B maintained 6 min, linearly increased to 70%B from 6 to 12 min, maintained at 70%B from 12 to 17 min, to 95%B from 17 to 20 min, equilibration at 95%B to 35 min; flow rate 0.4 mL min1; column temperature 30  C; DAD 283 nm. Peaks: (1) 20 -hydroxychalcone, (2) prunetin, (3) chrysin, (4) hesperetin, (5) naringenin, (6) diosmetin, (7) daidzein, (8) apigenin, (9) ()-dihydrokaempferol, (10) phloretin, (11) genistin, (12) daidzin, (13) phlorizindihydrate, (14) hesperidin, (15) naringin, (16) vitexin. Reproduced from Ref. [109].

Please cite this article in press as: M. Zhang, et al., Versatile ligands for high-performance liquid chromatography: An overview of ionic liquidfunctionalized stationary phases, Anal. Chim. Acta (2015), http://dx.doi.org/10.1016/j.aca.2015.04.022

SCIL SP

Performance

Size Silica diameter (mm) Cation density (mm  mm) and surface area (mmol m2) (m2)

Analytes and MP

Selectivity (a) and resolution (Rs)

Efficiency (plates/m)

Reference

Sil-C3Py-Cl

150  3.9

10, 215

2.60

5% dichloromethane + 95% hexane for benzene, anthracene, benzyl alcohol, nitronaphthalene; 2.5 mM phthalate buffer (pH 4.2) for chloride, nitrite, bromide and nitrate

–

Sil-C3DiPy-Cl

150  4.6

5, 390

1.55

5 mM KCl solution (pH 5.5) for iodate, bromate, bromide, nitrate, iodide and thiocyanate; 85% MeOH in water for benzene, naphthalene, fluorene, anthracene, fluoranthene and tetraphene

–

Sil-C3BnPy-Cl

150  4.6

5, 390

1.15

100 mM KCl solution for iodate, bromate, bromide and nitrate

4.51 < Rs

Sil-C3ImH-Cl

150  4.6

5, 440

2.50

1.74 < Rs < 6.35

Sil-C3ImH-Cl Sil-C3ImC1-Cl Sil-C3ImH-BF4 Sil-C3ImH-NTf2 Sil-C3Im(C2C1)HCl Sil-C3ImC1-Cl

150  4.6

15, 540

3.23 2.32 2.67 1.24 1.35

200 mM phosphate buffer (pH 3.4) for iodate, chloride, nitrite, bromide, nitrate, iodide and thiocyanate Varying MeCN (60–90%) in water for glucose and xylose

29,800– 33,800 in NP 20,500– 22,200 in IE 28,300– 54,300 in IE 31,200– 43,000 in RP 31,400– 40,600 19,100– 54,200 –

150  4.6

5, 440

2.40

Sil-C3ImC1-Ds Sil-C3ImC1-Dbs

150  4.6

5, 390

2.20

Sil-S-ImC18

150  4.6

5, 400

1.38

Sil-C3SC2ImC4SO3 Sil-C3[C2Im]2C6-2Br Sil-C3[C3Im]2C42NTf2 SilC3[C3Im]2C82NTf2 Sil-GluN-Br

100  2.1 150  4.6 100  2.1

3, 310 6, 390 3, 310

2.50 0.50 2.56 1.72

150  3.0

5, 310

2.18

Sil-C3SC3ImC4-Br

150  4.6

5, 300

1.66

Sil-pC11ImC1-Br

150  4.6

5, 300

2.58

Sil-PImC18-MO

150  4.6

5, 300

3.14

Sil-P(ImC18-SS)

150  4.6

5, 300

1.73

Sil-UIm-C18

150  4.6

5, 400

1.98

0.31 < Rs < 4.03

20 mM potassium phosphate buffer (pH 4.6) and 20 mM sodium acetate (pH 4.6) for iodate, chloride, 1.45 < Rs < 3.99 bromide, nitrate, iodide and thiocyanate 80% MeOH in water for benzene, naphthalene, fluorene, anthracene, fluoranthene, chrysene and 2.89 < Rs < 4.12 benzo[a]pyrene

80% MeOH in water for isomeric terphenyls, naphthalene, biphenyl, fluorene, anthracene and fluoranthene and alkylbenzene series 95% MeCN + 5% 10 mM ammonium acetate for 2 purines, 2 pyrimidines and 6 nucleosides 150 mM KH2PO4 (pH 4.6) for bromate, bromide, nitrate, iodide and thiocyanate 95% MeCN + 5% 10 mM ammonium acetate for 8 nucleosides and substituted benzoic acids

85% MeCN + 15% 100 mM ammonium acetate for 5 nucleosides and substituted benzoic acids; gradient eluent for 16 flavonoids 60% MeOH in water for PAHs, including benzene/naphthalene/anthracene/tetracene, triphenylene/oterphenyl, cis-stilbene/phenanthrene, and diphenylmethane/fluorene; Various MeOH concentrations for isomeric polar-substituted aromatics 20 mM Na2SO4 (pH 3.3) for nitrite, nitrate and iodide 100% MeOH for triphenylene/o-terphenyl and TBN/BaP

–

20,700– 53,500 22,000– 39,000 29,000– 53,100 ca. 32,000

[55]

[72]

[73] [57] [82]

[56] [87]

– – –

99,900< ca. 43,700 103,000< 87,300<

[107] [90] [108]

–

ca. 70,000

[109]

a for PAH pairs: 2.46/ – 2.21/2.15, 3.89, 1.84 and 1.44 a for PAH pairs: ca. 6.19 and 1.43 52,000 in IE 80% MeOH in water for triphenylene/o-terphenyl; 100% MeOH for TBN/BaP a for PAH pairs: – 8.70 and 0.56 90% MeOH in water for o-terphenyl/triphenylene, cis-/trans-stilbene, cis-stilbene/ phenanthrene, and a for PAH pairs: – diphenylmethane/fluorene 5.04, 1.70, 2.43 and 2.03 a for PAH pairs: 38,000– 80% MeOH in water for benzene, naphthalene, anthracene and tetracene, and a series of 3.90, 1.66, 1.33 and 1.58 45,000 alkylbenzenes, as well as triphenylene/o-terphenyl, cis-/trans-stilbene, cis-stilbene/phenanthrene, and diphenylmethane/fluorene

[83]

[89]

[86] [92] [99]

M. Zhang et al. / Analytica Chimica Acta xxx (2015) xxx–xxx

Column property

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Table 2 Column properties and performances of representative SCIL stationary phases.

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observed when separating benzoic acids. The multimodal retention capabilities were believed to offer a wider range of retention behaviors and flexible selectivity toward polar hydrophilic compounds. The quality of separations in various modes by representative SCIL SPs was evaluated by efficiency, selectivity factor and resolution factors for certain solutes of different natures, which are summarized in Table 2 along with the column properties, such as column size, silica size and bonding density. 2.5. Chiral separation To date, the use of ILs for enantioseparation is rare. In most of the reported applications, achiral ILs were tethered to b-cyclodextrin (CD) to form cationic derivatives. The CDs bearing anionic and cationic groups are more soluble in water and are able to establish ion pair interactions with charged chiral analytes. Muderawan et al. had prepared several cationic CDs substituted at the 6-position with imidazolium, pyridinium and quaternary ammonium moieties [113]. These cationic CDs were useful for CE enantioseparation of aromatic carboxylic acids (phenyl hydroxyl acids, phenyl carboxylic acids and dansyl-amino acids) at low concentrations (3–10 mM), due to the strong electrostatic interactions between cationic CD and anionic analytes [114]. Based on these findings, mono-6-(3-methylimidazlium)-6-deoxy-CD chloride was further treated with isocyanate to form mono-6-(3methylimidazolium)-6-deoxyperphenylcarbamoyl-CD (MPCCD), which was then immobilized onto silica as chiral selector, resulting in three chiral SPs (MPCCD-15, MPCCD-20 and MPCCD-35, figures were weight percentages of CD ligands in the silica phase) with different bonding amounts [115]. These new SPs were tested in NP mode for enantioseparation of racemic aromatic alcohols. Indeed, the enantiodiscrimination abilities of these SPs were found to be influenced by the loading amount of chiral selector, the best enantioseparation results were obtained using the column containing MPCCD-20, the resolution obtained for p-halophenylethanol (halo = F, Cl, Br and I) and p-fluorophenyl-3-buten-1-ol was considerably high, ranging from 3.83 to 5.65. The coated SPs also showed stability under supercritical fluid chromatography conditions. Chiral separation potential of CDs derivatized by 3octylimidazole and 3,5-dimethylphenyl isocyanates (MDPCCD, OPCCD and ODPCCD) was investigated in NP mode in their subsequent effort [116]. Racemates having electron-withdrawing groups at the para-positions of phenyl ring relative to the chiral center were separated with high selectivity on these IL-derivatized CD phases. The octyl chain on imidazolium showed greater advantage over methyl group. The phases with phenylcarbamate groups (MPCCD-20 and OPCCD-20) had better selectivity than those with 3,5-dimethylphenylcarbamate groups (MDPCCD20 and ODPCCD-20) for racemic phenyl alcohols, which might be resulted from their different molar loading concentrations. Because the CDs were coated rather than chemically immobilized on the silica, enantioseparation in RP mode was not performed. IL-functionalized CD-modified silica phases operable in RP mode were introduced by Zhou et al. [117]. In their work, 1,2dimethylimidazole precursor was used to derivatize the CD, resulting in mono-6-deoxy-(1,2-dimethylimidazolium)-CD (DMImCD) bearing different anions (nitrate and tosylate). The chemical immobilization was carried out via 3-glycidoxypropyltriethoxysilane. A series of racemates, including twelve a-nitroalcohol, two a-hydroxylamine, two aromatic alcohols and two compounds of pharmaceutical interests, were assessed on the ILmodified CD-bonded silica phases in RP mode. Under such conditions, the derivatized groups on the CD, instead of the cavity that could form inclusion complexation with analytes, played an important role. Though both phases with different anions could

17

resolve all the chiral compounds, the one with nitrate afforded higher resolution factor for most of the tested analytes. The superiority of nitrate over tosylate might be ascribed to its weaker alkalinity, i.e., it was more electronically stabilized and more ready to participate in anion-exchange, its rich hydrogen-bonding sites and smaller volume simplifying the approach of analytes. These properties might also explain the higher column efficiency. The bulkiness of the analytes had significant effect on the resolution, the separation of analytes with larger molecular size tended to be improved with tighter ion pairs in the charged moiety of the selector substituent. Meanwhile, the kinds and positions of substituent of the analytes were found to impact the resolution greatly, with electron-donating groups, the resolution was substantially enhanced due to their stronger hydrogen-bond capability compared to nitro group; reduced selectivity towards o-substituted isomer was observed, due to the increased steric hindrance exerted in the proximity of the chiral center. For different MP compositions, the ion-exchange equilibrium among analytes, chiral selectors and solvents and the relative interactions between the analytes and the chiral selector as well as between analytes and the solvents played important roles in chiral resolution. Later on, imidazolium salts having complex substituent were studied [118]. The ILs used here were 1-methyl-3-(pformylbenzyl) imidazolium with nitrate and tosylate, respectively. Through an imine bond, the ILs were anchored to aminocontaining CD, resulting in the desired IL-functionalized CDs, which were then immobilized onto silica. Two CD-bonded silica phases (IL-CD nitrate and IL-CD tosylate) were evaluated similar to the case of DMImCD. When MeOH was used in MP, better enantioseparation was ensured. On the whole, satisfactory selectivity (a > 1.02) and resolution (Rs > 1.5) were obtained on both phases. Again, the nitrate anion was observed to offer higher resolution than tosylate anion. It was clear that tosylate with large volume enhanced p–p and hydrogen bonding interactions, but it was unfavorable for separation of bulky analytes due to the steric hindrance effect. It was suggested that the larger substituents on CD-derivatives were beneficial for the separation of compounds with smaller volumes due to the weaker steric bulk. The enantiomeric separation of ferrocene derivatives was also successfully performed, showing the good separation capability of ILfunctionalized CD. The hydrogen-bonding, p–p, dipole–dipole and electrostatic interactions, as well as steric hindrance contributed synergically to the enantiomeric separation of analytes. Apart from the combination of achiral ILs and CD, chiral IL alone also found application in enantioseparation. Kodali and Stalcup synthesized a mixture of chiral 2-(1H-imidazol-1-yl) cyclohexanol stereoisomers from 1,2-epoxycyclohexane and imidazole, and resolved by R-mandelic acid to afford enantiopure isomer [119]. A new chiral SCIL SP was built from optically pure isomer and used for chiral separation of phenanthro[3,4-c]phenanthrene (hexahelicene), an atropoisomeric PAH, in NP mode. Fine selectivity was observed, but the resolution factor was somehow lower, baseline separation was not achieved. 3. Conclusion and perspectives The applications of SCIL SPs have been successful in separation of multitudinous analytes, ranging from inorganic ions, organic neutral compounds to organic bases, acids, because of the multiple mechanisms involved in the separation process. Their multi-modal behavior enables the applications in IE, HILIC, RP and NP modes. Recent studies have revealed the usefulness of SCIL SPs for HILIC and chiral separations. Currently, the SCIL SPs are overwhelmingly dedicated to analytical utilization. Most likely, the advantages of SCILs can be transplanted to preparative level, so that higher economic value can be created by preparative SCIL SPs.

Please cite this article in press as: M. Zhang, et al., Versatile ligands for high-performance liquid chromatography: An overview of ionic liquidfunctionalized stationary phases, Anal. Chim. Acta (2015), http://dx.doi.org/10.1016/j.aca.2015.04.022

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