Advances of Ionic Liquids in Analytical Chemistry - ACS Publications

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Advances of Ionic Liquids in Analytical Chemistry Maria Jose Trujillo-Rodríguez, He Nan, Marcelino Varona, Miranda Emaus, Israel D Souza, and Jared L. Anderson Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b04710 • Publication Date (Web): 17 Oct 2018 Downloaded from http://pubs.acs.org on October 18, 2018

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Analytical Chemistry

1

Advances of Ionic Liquids in Analytical Chemistry

2 3

María J. Trujillo-Rodríguez,1 He Nan,1 Marcelino Varona,1 Miranda N. Emaus,1

4

Israel D. Souza,1 Jared L. Anderson*,1

5

1Department

of Chemistry, Iowa State University, Ames, Iowa 50011 USA

6 7 8

*Corresponding author at: Department of Chemistry, Iowa State University, 1605 Gilman

9

Hall, Ames, IA, 50011, USA.

10

E-mail: [email protected]

1 ACS Paragon Plus Environment

Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Introduction

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Sample preparation

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Solid-phase (micro)extraction

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Ionic liquids and polymeric ionic liquids in solid-phase extraction

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Ionic liquids and polymeric ionic liquids in solid-phase microextraction

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Liquid-phase (micro)extraction

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Ionic liquids and magnetic ionic liquids in dispersive liquid-liquid

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microextraction

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Ionic liquid dispersive liquid-liquid microextraction

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Magnetic ionic liquid dispersive liquid-liquid microextraction

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Ionic liquids and magnetic ionic liquids in single-drop microextraction

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Ionic liquids in hollow fiber liquid-phase microextraction

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Two phase ionic liquid-hollow fiber liquid-phase microextraction

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Three phase ionic liquid-hollow fiber liquid-phase microextraction

26 27 28

Ionic liquids and magnetic ionic liquids in aqueous biphasic systems Chromatographic and electrophoretic separations Gas chromatography

29

Monocationic ionic liquid-based stationary phases

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Di- and polycationic ionic liquid-based stationary phases

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Polymeric ionic liquid-based stationary phases

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Metal-containing ionic liquid-based stationary phases

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Commercial ionic liquid-based stationary phases

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High Performance Liquid Chromatography Ionic liquids as mobile phase additives 2 ACS Paragon Plus Environment

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Ionic liquids as components of the stationary phase

36 37

Counter-current chromatography

38

Capillary electrophoresis

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Mass spectrometry

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Ionic liquids as matrixes in matrix-assisted laser desorption ionization

41

Ionic liquids as additives in electrospray ionization mass spectrometry

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Electrochemical sensing systems

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Ionic liquids as electrolyte media

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Ionic liquids/carbon-based composite electrochemical sensing systems

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Ionic liquid/metal-based composite electrochemical sensing systems

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Ionic liquid/hybrid carbonaceous-metal-based composite electrochemical sensing

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systems

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Biosensors based on ionic liquids

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Conclusions and perspectives

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Author information

51

Corresponding author

52

Notes

53

Biographies

54

References

55



56

Introduction

57

Ionic liquids (ILs) are a highly unique class of non-molecular solvents that possess melting

58

points below 100 ºC.1 ILs that have melting points below room temperature are often referred

59

to as room temperature ionic liquids (RTILs). ILs possess a wide variety of unique physico-

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chemical properties, including low or negligible vapor pressure at room temperature, high

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thermal and electrochemical stability, and high conductivity.2

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ILs are composed completely of ions and are typically asymmetric organic cations containing

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nitrogen or phosphorous heteroatoms as well as both inorganic and organic anions. Figure 1

64

shows a representative series of typical IL cations and anions. Due to the large diversity of

65

cations and anions, it has been estimated that more than 1018 possible combinations of cations

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and anions can be created.2 It is often the case that small modifications to the cation/anion

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chemical structure or cation/anion combination are accompanied by dramatic modifications

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to their physical properties, including viscosity and water solubility. At the same time, the

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incorporation of polar or non-polar moieties to the IL structure can promote different

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interactions with solutes and impressive solvation capabilities for different classes of

71

compounds. For all of these reasons, ILs are normally referred to as designer solvents.

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Since the introduction of ILs, several subclasses of ILs have been popularized and studied

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within the analytical sciences, including task-specific ILs (TSILs), chiral ILs, polymeric ionic

74

liquids (PILs) and magnetic ionic liquids (MILs). TSILs are ILs with functional groups that

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impart specific properties or reactivity to the IL.3 PILs are polymeric materials generated

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through the polymerization of IL monomers.4,5 In comparison to ILs, PILs generally possess

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higher thermal and mechanical stability, and their viscosities are not significantly reduced

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under high temperature conditions, making them interesting materials for high temperature 4 ACS Paragon Plus Environment

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applications. MILs have been more recently introduced and contain a paramagnetic

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component in either the cation or the anion of the IL.6 Therefore, they can be manipulated

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using externally magnetic fields, making them particularly interesting in magnet-assisted

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separation systems where the movement of flow or the MIL can be induced by the application

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of static or dynamic magnetic field gradients.

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Studies involving ILs have impacted many areas of science, including material science,

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chemical engineering, environmental science, biochemistry, genetics, molecular biology, and

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chemistry. Thus, the number of scientific publications related to ILs have increased

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exponentially since 1992. Furthermore, in 2017 more than 6000 articles related to the topic

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of ILs have been published. In the field of analytical chemistry, the unique properties of ILs

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has led to their study in virtually every branch of the field, from sample preparation, mass

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spectrometry and electrochemical sensing. The tuneability, versatility and selectivity of ILs

91

have been exploited in a wide variety of extraction and preconcentration methods7, including

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both solid phase (micro)extraction8 and liquid phase (micro)extraction,9-11 to improve the

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resolution and efficiency of chromatographic12-14 and electrophoretic separations,15 as

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matrixes in mass spectrometry,16 and to provide high conductivity and wide electrochemical

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windows in electrochemical sensing systems.17

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In 2014, we published a review included within the Fundamental and Applied Reviews in

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Analytical Chemistry special issue of Analytical Chemistry in which the use of ILs in all of

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these areas was discussed.2 The current review provides an update to the fundamental study

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and applications of ILs in the field of analytical chemistry over the last several years. To

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address a rapidly growing area of study, we highlight new areas within bioanalysis where the

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unique features of ILs are being exploited.18 5 ACS Paragon Plus Environment


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Sample preparation

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Solid-phase (micro)extraction

105

Ionic liquids and polymeric ionic liquids in solid-phase extraction

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ILs and PILs are attractive materials for the development of solid-phase extraction (SPE)

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sorbents due to their easily tunable nature. In general, the majority of IL-based sorbent

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materials described in the literature are IL-modified silica sorbents, IL-modified polymers or

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IL-modified carbonaceous materials. This section summarizes the most recent applications

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regarding the use of IL-based sorbents for SPE and micro-SPE.

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Wang et al. functionalized polymethyl(methacrylate) with ILs for the post-combustion

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capture of carbon dioxide.19 The studied ILs were based on the 1-ethyl-3-methylimidazolium

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([C2MIM+]) cation paired with different amino acid-based anions (e.g., Lys, Gly, Ala, and

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Arg). The [C2MIM+][Lys-] IL was found to have the highest sorption capacity for CO2 (1.67

115

mmol·g-1 sorbent), which was explained by the multiple amine groups within the [Lys-] anion

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that can interact with CO2.

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Metal determination is of particular significance as even trace amounts can have detrimental

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physiological effects in human health. Tokalıoğlu et al. developed a method for the

119

enrichment of Cu2+ and Pb2+ from water samples using IL-functionalized carbon nanospheres

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(CNSs).20 An imidazolium-based IL containing the 1,8-napthalene monoimide functional

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group was used as a chelating agent towards metal ions within the CNSs. In this particular

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study, the IL acted as a chelating agent of the metal ions. Limits of detection (LODs) of 0.30


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and 1.76 µg L-1 were achieved for Cu2+ and Pb2, respectively. The method also proved to be

124

resilient towards the addition of other monovalent and divalent metal ions.

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Wang et al. developed a low cost SPE sorbent by functionalizing luffa sponge fibers via

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physisorption of the 1-hexadecyl-3-methylimidazolium bromide ([C16MIM+][Br-]) IL.21 The

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sorbent was used in dispersive solid phase extraction (DSPE) for the determination of four

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common benzoyl urea pesticides from water and tea samples. By using only 70 mg of the

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sorbent, LODs ranging from 0.14–0.21 µg·L-1 in water and from 0.19–0.23 µg·L-1 in tea were

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obtained. In another study, Zhang et al. developed IL-modified silica gel for the

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preconcentration of polyphenols from green tea leaves.22 The developed sorbent was able to

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extract and preconcentrate the target analytes with no significant decrease in antioxidant

133

properties. The extraction mechanism was determined to be a combination of hydrogen

134

bonding, hydrophobic interactions, and π -π interactions.

135

Zhang et al. developed a pipette-tip SPE method using an IL-functionalized graphene sorbent

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for the extraction of auxins from soybean sprouts.23 The sorbent was created by modifying

137

the graphene surface with thiol groups via thiol-ene click chemistry. The modified graphene

138

was subsequently reacted with the 1-allyl-3-pentafluorobenzylimidazolium bromide

139

([Al(BeF5)IM+][Br-]) IL and 2,2′-azobis(2-methylpropionitrile) (AIBN) to obtain the

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corresponding IL-functionalized thiol graphene. The IL prevented the aggregation of

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graphene while simultaneously affording the sorbent with π -π, ion exchange, and hydrogen

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bonding interaction capabilities. Good linearity was achieved using the optimized method,

143

with LODs ranging from 2.6–4.0 ng g-1 for 1-naphthaleneacetic acid, 2,4-

144

dichlorophenoxyacetic acid, and indole-3-acetic acid. Han et al. determined 6‑benzyladenine

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and 4‑chlorophenoxyacetic acid in bean sprouts using an IL-hybrid molecular imprinted 7 ACS Paragon Plus Environment


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polymer (MIP).24 The prepared IL-hybrid MIP was capable of extracting 6‑benzyladenine

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through molecular recognition as the main mechanism while 4‑chlorophenoxyacetic acid was

148

extracted via electrostatic and π -π interactions.

149

Ferreira et al. developed an fully automated online SPE method in combination with high-

150

performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for the

151

determination

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butylsulfonateimidazolium ([VIMC4SO3-]) zwitterionic IL was synthesized and covalently

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confined to a silica substrate for the preparation of the packed SPE column. The developed

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material was employed in more than 100 sequential analyses without showing any loss of the

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extraction efficiency.

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Wang et al. recently developed crosslinked PIL microspheres based on the 1-vinyl-3-

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methylimidazolium hexafluorophosphate ([VMIM+][PF6-]) IL monomer for the rapid

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extraction of plasmid DNA from aqueous samples.26 Extraction/desorption of DNA was

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achieved by modulating the ionic strength of the solution. Low ionic strength conditions

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facilitated ion exchange between the anion of the PIL with the phosphate backbone of DNA.

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Conversely, high ionic strength (1 M NaCl) was used to strip DNA from the sorbent. The

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microspheres possessed high sorptive capacity (190.7 µg·mg-1) and excellent DNA

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recoveries (80.7%).

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For the extraction of proteins, Dang et al. synthesized a series of PIL sorbents containing 2-

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acrylamido-2-methylpropane sulfonate ([AMPS-])-based IL monomers with different cations

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(e.g. imidazolium, phenylimidazolium, and butylimidazolium).27 Sorption capacities for

167

bovine hemoglobin as high as 983.4 mg·g-1 were achieved. Furthermore, the materials were

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capable of extracting hemoglobin directly from bovine blood followed by sodium dodecyl

of

the

antibiotic

ceftiofur

in

milk


samples.25

The

1-vinyl-3-

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sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser

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desorption/ionization- time of flight (MALDI-TOF) analysis, demonstrating the material’s

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usefulness in complex matrixes.

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Dai et al. synthesized porous PILs by polymerizing the [VMIM+][Cl-] IL and ethylene glycol

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dimethacrylate within the framework of Mobil Composition of Matter No. 48 (MCM-48)

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spheres.28 This material was applied in on-line SPE of hydroxybenzoic acids from pollen

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extract. The extraction efficiency of the six studied analytes was not dependent on the pH of

176

the extraction solution and an extraction time of 5 min was sufficient to reach equilibrium.

177

Recoveries from pollen extract were acceptable for all analytes (82.7-102.4%) with LODs as

178

low as 2 µg·L-1 for 4-hydroxybenzoic acid.

179

On-line PIL-SPE has also been applied for the determination of antihypertensives in human

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plasma.29 A poly(IL-glycidylmethacrylate-co-ethyleneglycol dimethacrylate) monolithic

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SPE phase was prepared using the [VMIM+][Cl-] IL as a functional monomer. The optimized

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method extracted nifedipine, nitrendipine, and felodipine spiked in human plasma from

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patients that previously ingested nifedipine and nitrendipine tablets. In another application,

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Pang et al. used a similar PIL-monolithic column for the determination of steroid drugs in

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plasma.30 The monolith was based on the use of the 1-vinyl-3-hexylimidazolium bromide

186

([VC6IM+][Br-])

187

trimethylolpropane triacrylate as crosslinkers.

IL

as

functional

monomer

with

ethylenedimethylacrylate

188 189

Ionic liquids and polymeric ionic liquids in solid-phase microextraction


and


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Solid-phase microextraction (SPME) combines sample preparation and sampling resulting in

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reduced analysis times and increased sample throughput. The limited selection of

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commercially-available coatings necessitates the need for new sorbents with improved

193

selectivity towards specific groups of analytes. ILs and PILs have been explored as sorbent

194

coatings for SPME due to their tunable nature. This section provides an overview of IL- and

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PIL-based SPME sorbent coatings over recent years.

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Two recent studies have used ILs as SPME sorbents for the analysis of organophosphate

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esters in environmental water samples.31,32 Shi et al. used the 1-hexyl-3-methylimidazolium

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tris(pentafluoroethyl)trifluorophosphate ([C6MIM+][FAP-]) IL coated on a modified stainless

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steel wire.31 The extraction was performed in the direct immersion (DI)-SPME mode and

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subsequently coupled with gas chromatography (GC)-MS for the determination of

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organophosphate esters. The ultra-hydrophobicity and hydrolytic stability of the IL allowed

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for up to 65 consecutive extractions without a decrease in extraction efficiency. In another

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study, Pang et al. developed a hybrid SPME coating via sol-gel chemistry by combining a

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silica-based

205

bis[(trifluoromethyl)sulfonyl]imide ([C16MIM+][NTf2-]) IL.32 For this application, HS-

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SPME was performed and LODs lower than 1 µg·L-1 for all of the studied analytes were

207

obtained.

208

One significant area where PILs have been effectively utilized as sorbent coatings is in

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environmental analysis, where the robustness and unique selectivity afforded by PILs can

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facilitate the detection of many contaminants. Crosslinked PILs were effectively applied for

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the extraction of polar contaminants via DI-SPME in combination with HPLC- ultraviolet

212

detection (UV).33 The crosslinked PILs were chemically attached to the surface of derivatized

material

with

the

1-hexadecyl-3-methylimidazolium


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213

nitinol, which allowed the desorption of analytes from the fibers using organic solvents.

214

Partition coefficients of the studied analytes showed that the developed PILs were especially

215

selective for the determination of polar compounds. An et al. recently developed PIL sorbent

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coatings that were remarkably stable under high ionic strength conditions (25% NaCl).34 The

217

fibers were applied for the determination of UV filters from water samples using the DI-

218

SPME mode in combination with HPLC-UV. By incorporating polymerizable styrene

219

sulfonate anions into the PIL structure, the lifetime of the fibers increased drastically when

220

compared to analogous PIL fibers containing halide anions. Similarly, commercial fibers also

221

exhibited significantly shorter lifetimes than the optimal PIL fiber. LODs as low as 0.2 µg

222

L-1 were achieved using the newly developed PIL fibers. In another study, crosslinked PILs

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were successfully employed in headspace (HS)-SPME for the determination of UV filters in

224

water samples with subsequent analysis by GC-MS.35 LODs in the range of 2.8–26 ng·L-1

225

were achieved for the optimal PIL.

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Sun et al. developed graphene oxide (GO) reinforced PIL-SPME monoliths for the extraction

227

of six phenolic compounds from environmental aqueous samples, followed by HPLC-UV.36

228

To determine the effects of GO on the extraction of the target compounds, a comparison was

229

made with neat PIL-SPME fibers and neat GO reinforced fibers. For the latter fibers, an order

230

of magnitude lower LOD was obtained. A multiple monolithic SPME phase based on the

231

poly(1-allyl-3-methylimidazolium

232

dimethacrylate) polymer was used in DI-SPME in combination with HPLC-UV for the

233

determination of steroid sex hormones.37 Similarly, other studies have focused on the

234

extraction of endocrine disrupting chemicals (EDCs) with functionalized IL monoliths.38

bis[(trifluoromethyl)sulfonyl]imide-co-ethylene



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A new class of silver-based PIL sorbent coatings have been recently developed and applied

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in both HS- and DI-SPME.39 The sorbent coatings were based on IL monomers formed by

237

cations containing the Ag+ ion coordinated with two 1-vinylimidazole ligands. The fibers

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were generated by polymerizing the silver-IL monomer in the presence of either [Ag+][NTf2-]

239

and/or a dicationic IL crosslinker. The fibers possessed adequate thermal stability (more than

240

175 ºC) despite the presence of the Ag+ ions and were used for the determination of alkene

241

and alkyne mixtures with different degree of unsaturation via HS-SPME, and for the

242

determination of oleic acid, linoleic acid and linolenic acid in wastewater via DI-SPME.

243

The identification and determination of contaminants in food is of importance for human

244

health and safety. Recently, Cagliero et al. developed a PIL-SPME method for the

245

determination of acrylamide in both brewed coffee and coffee powder.40 The PIL sorbent

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coatings used in this application were developed by a spin coating method, allowing for a

247

larger film thickness. The developed DI-SPME-GC-MS method was able to detect

248

acrylamide with low limit of quantification (LOQ) (10 µg·L-1). This value was comparable

249

to the conventional ISO method for determining acrylamide while exhibiting a shorter

250

analysis time. In a subsequent study, nine PIL fibers were screened for the extraction of

251

acrylamide from coffee and compared to the best performing fiber from the initial study.41

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Among all of the tested fibers, better extraction performance was achieved with the fiber

253

composed of 1,12-di(3-vinylbenzylimidazolium)dodecane [NTf2-] ([(VBeIM)2C122+]2[NTf2-

254

])

255

([V(C10OH)IM+][NTf2-]) IL monomer, with a LOQ as low as 0.5 µg L-1. Figure 2 shows GC-

256

MS chromatograms in the selected ion monitoring (SIM) mode obtained from the analysis of

257

blank and spiked brewed coffee samples using this PIL-sorbent coating.

as

the

IL

crosslinker

in

1-vinyl-3-(10-hydroxydecyl)imidazolium


[NTf2-]

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258

Hou et al. prepared hybrid SPME fibers based on GO-coated stainless steel wires modified

259

with either ILs or PILs for the determination of polycyclic aromatic hydrocarbons (PAHs)

260

and phthalate esters in food-wrap.42 Two different ILs, namely 1-aminoethyl-3-

261

methylimidazolium

262

methylimidazolium [NTf2-] ([(C2NH2)MIM+][NTf2-]), were directly attached to the GO

263

layer, while the two studied PILs, poly-1-vinyl-3-hexylimidazolium bromide (poly-

264

[VC6IM+][Br-]) and poly-1-vinyl-3-hexylimidazolium [NTf2-] (poly-[VC6IM+][NTf2-]), were

265

chemically attached by using the 3-mercaptopropyltriethoxysilane coupling agent. Recently,

266

Gionfriddo et al. exploited the tunability of PILs for both pesticide and metabolite analysis

267

from grape homogenate.43 The developed HS-SPME-GC-MS method required relatively

268

high temperatures (60 °C) due to the physicochemical properties of the analytes. The robust

269

nature of the PILs allowed for more than 20 extractions at this temperature without any loss

270

in the fiber performance. LOQs in the microgram per liter level were obtained for the studied

271

pesticides using the optimal PIL sorbent coating. In another study, PIL-SPME was performed

272

with comprehensive two-dimensional GC in combination with MS detection for the

273

characterization of the wine aroma profiles.44 This approach allowed for the identification of

274

>350 compounds from two different types of wine and facilitated their differentiation based

275

on their profiles.

276

ILs have also been explored as extraction phases for in-tube SPME. Sun et al. developed an

277

extraction phase by functionalizing copper wires with an imidazolium-based IL via thiol-ene

278

chemistry.45 The functionalized copper wires were subsequently placed in a copper tube to

279

create the in-tube sorbent. The developed in-tube SPME sorbent was applied for the

280

extraction of estrogens from water samples with acceptable recoveries (84–114%). In another

bromide

([(C2NH2)MIM+][Br-])


and

1-aminoethyl-3-


281

study, Feng et al. followed a similar strategy by functionalizing basalt fibers with

282

imidazolium-based ILs.46 These sorbents were applied through in-line SPME-HPLC. The

283

extraction method was directly coupled to HPLC via a six-port valve, allowing for

284

automation. Other materials that have also been modified using ILs for SPME include carbon

285

nanotubes (CNTs)47,48, polycarbazole49 and stainless steel tubes via physical adhesion.50

286

Souza et al. developed wall-coated open tubular capillary columns with PILs for the

287

determination of endocannabinoids in plasma samples.51 The inner wall of the capillary was

288

functionalized with vinyltrimethoxysilane (VTMS) and subsequently coated with a mixture

289

containing an IL monomer ([VC6IM+][Cl-] or [VC16IM+][Br-]), the 1,12-di(3-

290

vinylimidazolium)dodecane bromide [(VIM)2C102+]2[Br-] IL crosslinker, and AIBN as the

291

initiator. Following thermal polymerization, crosslinked PILs with a film thickness of 1.7 µm

292

were obtained. To achieve proper extraction of the selected group of analytes, pH 7 was

293

required. Extractions from plasma resulted in a wide linear range, from 0.05-100 ng mL-1.

294

A new class of electropolymerizable thiophene-functionalized PILs has recently been

295

developed and applied in HS-SPME.52 The thiophene ILs were prepared by reacting the

296

corresponding haloalkyloxythiophene with 1-methylimidazole, 1-vinylimidazole or 1-

297

benzylimidazole, followed by metathesis reaction with the [NTf2-] anion. Potential cycling

298

was subsequently applied on Pt wires covered in a solution of the IL to obtain the

299

corresponding PIL sorbent coatings. The resulting fibers possessed interesting

300

electrochemical properties and were also used for the determination of polar analytes. In

301

another study, Devasurendra et al. developed PILs based on the 3-(6-(1H-pyrrol-1-yl)hexyl)-

302

1-methyl-1H-imidazol-3-ium hexafluorophosphate ([pyrrole-C6MIM+][PF6-]) IL monomer

303

by its electro-polymerization on macro- and micro-electrode materials of Pt.53 The PILs were 14 ACS Paragon Plus Environment

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304

also doped with single walled carbon nanotubes (SWCNTs), where thicker PIL/SWCNT

305

films were obtained compared to polymerizing the neat IL (42 µm versus 17 µm). These

306

fibers possessed high selectivity and good fiber-to-fiber reproducibility for the extraction of

307

aromatic compounds.

308

PIL-based sorbent coatings have also been applied for the analysis of nucleic acids, yielding

309

a faster, more effective and reusable method in comparison to conventional liquid-liquid

310

extraction (LLE) and silica-based SPE approaches. The initial studies of Anderson and co-

311

workers were focused on the development and characterization of crosslinked PIL sorbent

312

coatings that possessed selectivity towards DNA and RNA.54,55 Real-time quantitative

313

polymerase chain reaction (qPCR) and reverse-transcription qPCR (RT-qPCR) were used to

314

evaluate the extraction performance of the fibers for DNA and RNA, respectively. Among

315

all of the tested crosslinked PILs, the highest extraction efficiency was achieved using the

316

fiber based on the 1-vinyl-3-decan-10-oic-imidazolium bromide ([V(C9COOH)IM+][Br-]) IL

317

monomer and the [(VIM)2C122+]2[Br-] IL crosslinker. The mechanism for nucleic acid

318

extraction was investigated by comparing the performance of the developed halide-based

319

PILs with analogous fibers containing the styrene sulfonate anion. The introduction of both

320

a polymerizable cation and anion in the structure of the PIL led to a drastic decrease in

321

extraction efficiency. This result indicated that the extraction mechanism of the fibers

322

towards nucleic acid could be a combination of both ion exchange and electrostatic

323

interactions. In a subsequent study, Varona et al. developed a PIL-SPME method for the

324

extraction of DNA from mycobacteria in artificial sputum at clinically relevant

325

concentrations (107 colony forming units mL-1).56 In this study, a vortex-assisted DI-SPME

326

method was employed for the extraction of DNA from lysed cells, resulting in faster



327

enrichment of the nucleic acid, followed by isothermal multiple-self-matching-initiated

328

amplification (IMSA) using hydroxynaphthol blue (HNB) to afford the visual detection of

329

the amplified nucleic acid.

330 331

Liquid-phase (micro)extraction

332

Ionic liquids and magnetic ionic liquids in dispersive liquid-liquid microextraction

333

ILs have been extensively used in dispersive liquid-liquid microextraction (DLLME) for the

334

extraction and preconcentration of a wide variety of analytes. In the majority of the described

335

IL-DLLME applications, hydrophobic ILs are employed as extraction solvents. However,

336

hydrophilic ILs have also been exploited for in situ DLLME. In this DLLME mode, a

337

hydrophilic IL and metathesis reagent such as [Li+][NTf2-] is added to a sample solution,

338

allowing for the formation of microdroplets of hydrophobic IL containing the

339

preconcentrated analytes. In addition to the use of ILs and IL-based surfactants, an increasing

340

number of publications have described the use of MILs in DLLME. This section highlights

341

the use of ILs and MILs in DLLME in recent years, showing their applicability towards the

342

extraction of metal ions, organic pollutants, pharmaceuticals, and biomolecules.

343 344

Ionic liquid dispersive liquid-liquid microextraction

345

Cacho et al. developed an in situ DLLME method in combination with thermal desorption

346

gas chromatography-mass spectrometry (TD-GC-MS) for the determination of bisphenols.57

347

Different 1-alkyl-3-methylimidazolium chloride ([CnMIM+][Cl-], with n = 6, 8, 10 and 12)

348

ILs were used as extraction solvents. Derivatization of the analytes was performed prior to 16 ACS Paragon Plus Environment

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349

the DLLME step to increase the sensitivity of the method. LODs in the nanogram per liter

350

level were achieved from aqueous solutions. In addition, the method was effectively applied

351

for the analysis of plastic containers. Wang et al. developed a DLLME method for the

352

determination for bisphenols using the [C8MIM+][PF6-] IL.58 Analytes were extracted

353

through a combination of hydrophobic and hydrogen bonding interactions. The obtained

354

LODs ranged between 0.5 ng mL-1 for bisphenol A and 1.5 ng mL-1 for bisphenol AP.

355

ILs have also been employed as extraction solvents for in-syringe DLLME.59,60 For example,

356

Wang et al. developed an in-syringe in situ DLLME method for the extraction of benzoylurea

357

insecticides from honey samples.59 The procedure involved the metathesis reaction of the

358

tetrabutylammonium chloride ([N4,4,4,4+][Cl-]) IL with NaPF6 to generate the corresponding

359

water insoluble IL. The procedure utilized a medical syringe as the extraction vessel,

360

permitting the dispersion of the insecticide enriched-IL without the need of any dispersive

361

solvent or stirring, and its isolation without centrifugation. LODs ranging from 0.21–0.42 µg

362

L-1 were achieved with the method. In another application, Suárez et al. developed an on-line

363

in-syringe DLLME method for the extraction of UV filters.60 The [C6MIM+][PF6-] IL was

364

dispersed using a stir bar within a multi-syringe pump, followed by sequential dilution and

365

HPLC-UV analysis. Enrichment factors ranging from 11 to 23 were achieved for the six UV

366

filters. LODs in the microgram per liter level and adequate recoveries for the analysis in

367

seawater and swimming pool water were obtained.

368

The in situ DLLME mode was also applied towards the extraction of polychlorinated

369

biphenyls (PCBs) and acrylamide from coffee and milk samples.61 In this approach, the

370

analyte-enriched ILs were subjected to headspace sampling-GC-MS (HS-GC-MS),

371

facilitating desorption of the analytes from the IL to the headspace of the extraction vial while 17 ACS Paragon Plus Environment


372

preventing the non-volatile ILs from entering the GC. LODs in the nanogram per liter and in

373

the microgram per liter level were achieved for PCBs and acrylamide, respectively. The

374

method was applied for the analysis of several food samples, including coffee and milk.

375

An effervescence-assisted IL-DLLME procedure was developed for the determination of

376

fungicides in environmental water samples.62 In this application, a magnetic effervescent

377

tablet composed of sodium carbonate and sodium dihydrogen phosphate as effervescent

378

precursors, the [C6MIM+][NTf2-] IL as extraction solvent, and Fe3O4 magnetic nanoparticles

379

were added to the aqueous solution containing the analytes. The reaction between the

380

effervescent precursors in water generated CO2 bubbles that assisted the homogeneous

381

dispersion of the IL in the sample. In addition, magnetic nanoparticles allowed the magnetic

382

separation of the analyte-enriched IL with the aid of a Nd-core magnet, thereby avoiding

383

centrifugation. LODs ranging between 0.02–0.10 g·L-1 and acceptable reproducibility and

384

recoveries were achieved.

385

Concerning the determination of metals, a gas assisted-DLLME method was developed for

386

the determination of Cu2+ from mineral water samples.63 Cu2+ was reduced to Cu+ using

387

hydroxylamine hydrochloride followed by its selective chelation using neocuproline and

388

extraction of the Cu+-complex using the [C6MIM+][PF6-] IL. Argon was used as a disperser

389

to eliminate the use of toxic organic solvents. The gas assisted-DLLME method was found

390

to achieve enrichment factors as high as 122 and no significant matrix effect was observed

391

in the analysis of mineral water.

392

Extraction from biological matrices can be difficult due to the high concentration of matrix

393

components such as albumin in plasma and serum samples or urea in urine. De Boeck et al.

394

used 1-alkyl-3-methylimidazolium [PF6-] ([CnMIM+][PF6-], with n = 4, 6, 8) ILs, together 18 ACS Paragon Plus Environment

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the

1-butyl-1-methylpyrrolidinium

[NTf2-]

([C4MPy+][NTf2-])

and

the

395

with

396

butyltrimethylammonium [NTf2-] ([N1,1,1,4+][NTf2-]) ILs for the determination of

397

antidepressants in whole blood.64 After 5 min of mixing, the IL was diluted in methanol and

398

subjected to liquid chromatographic analysis (LC-MS/MS). Among the studied ILs, the

399

[C4MIM+][PF6-] IL provided the smallest chromatographic background with seventeen of the

400

eighteen tested antidepressants being properly analyzed in tablets.

401

Wang et al. developed an ultrasound-assisted IL-DLLME method for the determination of

402

triclosan and methyltriclosan using a system composed of the [C8MIM+][PF6-] IL as

403

extraction solvent and a mixture of the [C4MIM+][BF4-] and 1-butyl-3-methylimidazolium 1-

404

naphthoic acid salt ([C4MIM+][NPA-]) ILs as disperser solvents.65 Ammonium

405

hexafluorophosphate was also added during the extraction as an ion pair reagent. Adequate

406

recoveries and LODs between 0.12–0.15 µg L-1 in plasma and urine samples were achieved.

407

In another application, the low cytotoxic decylguanidinium chloride ([C10Gu+][Cl-]) IL was

408

used as extraction solvent in salt-induced DLLME for the determination of a group of

409

hydroxylated PAHs in urine samples.66 The preconcentration method is similar to the in situ

410

DLLME mode; however, NaClO4 was used to promote the insolubility of the IL, avoiding

411

the use of toxic fluorine-based salts that are often employed in other in situ DLLME methods.

412

LODs ranging from 0.5 to 1 ng·L-1 and adequate precision was achieved.

413

The methyltrioctylammonium thiosalicylate ([N1,8,8,8+][TSC-]) TSIL was applied in a

414

DLLME method in combination with electrothermal atomic absorption spectroscopy

415

(EAAS) for the extraction of Cd2+ from human blood, serum, and urine samples.67 This TSIL

416

permitted Cd2+ to be extracted without a chelating agent. At the same time, the ammonium-

417

based IL provided higher extraction efficiency than analogous imidazolium-based ILs. 19 ACS Paragon Plus Environment


418

Fernández et al. employed the [C6MIM+][NTf2-] IL to extract Hg2+ from urine samples using

419

vortex-assisted DLLME.68 Ammonium pyrrolidinedithiocarbamate was used as a chelating

420

agent to aid the partitioning of Hg2+ to the hydrophobic IL phase. The Hg2+-complex was

421

then re-extracted from the IL-rich phase using HCl and detected using a gold nanoparticle

422

modified screen printed electrode. The obtained LODs in urine ranged from 0.5–1.5 µg L-1.

423

Arain et al. extracted Cu2+ from drinking water and serum samples of hepatitis C patients

424

using a microemulsion-DLLME method.69 The [C4MIM+][PF6-] IL was used as extraction

425

solvent while Triton X-100 was used to stabilize the generated microemulsion by reducing

426

the interfacial tension of the IL. Cu2+ was extracted to the IL phase using 8-hydroxyquinoline

427

as a chelating agent. The Cu2+-complex rich-IL was isolated using micellar cloud point

428

extraction (MCPE), followed by flame atomic absorption spectroscopy (FAAS). Enrichment

429

factors as high as 7 and a LOD of 0.132 µg L-1 were obtained.

430 431

Magnetic ionic liquid dispersive liquid-liquid microextraction

432

The inherit magnetism of MILs makes them attractive extraction solvents in DLLME. For

433

that reason, an increasing number of publications within the past several years have reported

434

MIL-DLLME methodologies. In these applications, magnetic separation is carried out to

435

recover the MIL solvent after extraction, eliminating the need of centrifugation and filtration

436

steps that are often necessitated with DLLME procedures.6,18,70,71 Table 1 includes several

437

applications that use MILs in DLLME and other liquid-phase microextraction (LPME)

438

techniques.72-84

439

MIL-DLLME has been applied for the determination of PAHs in environmental water and

440

tea.72 Three different iron-based MILs were studied as possible extraction solvents, including 20 ACS Paragon Plus Environment

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441

two

monocationic

442

([N8,8,8,B+][FeCl3Br-])

443

([N8,8,8,MOB+][FeCl3Br-]), and a dicationic MIL, 1,12-di(3-benzylbenzimidazolium)dodecane

444

[NTf2-] [FeCl3Br-] ([(BBnIM)2C12+][NTf2-][FeCl3Br-]). It is interesting to mention that the

445

mixed anions of the [(BBnIM)2C12+][NTf2-][FeCl3Br-] MIL aided in controlling the

446

hydrophobicity of the solvent. The highest extraction performance was achieved using the

447

[N8,8,8,B+][FeBrCl3-]

448

tetrachloromanganate(II) ([MnCl42-])-based MILs as extraction solvents in DLLME for the

449

determination of pharmaceutical drugs, phenolics, insecticides, and PAHs.73 The [MnCl42-]-

450

based MILs exhibited less UV absorption and limited hydrolysis in water, which are

451

advantages over MILs based on tetrachloroferrate (III) ([FeCl4-]) and [FeCl3Br-]. Adequate

452

analytical performance was observed using the [MnCl42-]-based MILs with LODs ranging

453

from 0.25 to 1.00 µg L-1.

454

Chisvert et al. developed an extraction method termed stir bar dispersive liquid extraction

455

(SBDLME) for the determination of PAHs.74 In this approach, the MIL solvent was dispersed

456

using a Nd-core magnetic stir bar at high stirring rates. Under these stirring rates, the MIL

457

was dispersed in the sample solution as fine microdroplets. When the stirring was stopped,

458

the analyte-enriched MIL was collected by the stir bar due to its magnetic attraction. The stir

459

bar was subsequently subjected to TD-GC-MS analysis. For this application, the studied

460

MILs

461

([P6,6,6,14+][Ni(hfacac)3-]),

462

([P6,6,6,14+][Co(hfacac)3-]),

463

([P6,6,6,14+][Dy(hfacac)4-]). These MILs exhibited lower viscosity in comparison to the

were

MILs,

benzyltrioctylammonium

and

MIL

bromotrichloroferrate

[FeCl3Br-]

methoxybenzyltrioctylammonium

for

all

of

the

trihexyl(tetradecyl)phosphonium [P6,6,6,14+] and

PAHs

tested.

Yu

(III)

et

al.

studied

tris(hexafluoroacetylaceto)nickelate(II) tris(hexafluoroacetylaceto)cobaltate(II)

[P6,6,6,14+]

tris(hexafluoroacetylaceto)dysprosate(III)



Page 22 of 99

464

previous generations of MILs, which facilitated the dispersion of the MIL during the

465

extraction and, as a consequence, improved the extraction performance of the method.

466

Several MIL-DLLME methods have also been developed for the determination of

467

biomolecules. Clark et al. utilized thiol-ene click chemistry to synthesize ion-tagged

468

oligonucleotides (ITO) capable of selectively annealing to complementary DNA sequences.75

469

Once

470

tris(hexafluoroacetylaceto)manganate(II) ([P6,6,6,14+][Mn(hfacac)3-]) MIL, which exhibited

471

low DNA extraction efficiency without the ITO. Hydrophobic interactions between the ITO

472

and MIL were largely responsible for the capture of ITO by the MIL. The MIL-ITO

473

procedure was found to outperform commercial magnetic beads when extracting target DNA

474

in the presence of background DNA and in complex matrices. In a similar approach, Peng et

475

al. found that the [P6,6,6,14+][Co(hfacac)3-] MIL exhibited high extraction efficiencies for poly-

476

cytosine (poly-C) tagged DNA oligonucleotides.76 DNA oligonucleotides were designed

477

containing a complementary sequence to the target DNA and a poly-C tail. The poly-C tagged

478

duplex was found to selectively extract approximately 300-fold more DNA compared to a

479

direct extraction method without the poly-C probe. Higher extraction efficiencies were also

480

achieved when extractions were performed with the poly-C tagged oligos in the presence of

481

background DNA.

482

Different MILs were also studied as solvents in DLLME for the extraction of viable E. coli

483

cells.77 The [P6,6,6,14+][Ni(hfacac)3-], [P6,6,6,14+][Co(hfacac)3-], [P6,6,6,14+][Dy(hfacac)4-], and

484

[P6,6,6,14+] tetrakis(hexafluoroacetylaceto)dysprosate(III) ([P6,6,6,14+][Nd(hfacac)4-]) MILs

485

were capable of extracting viable cells from aqueous solutions for detection using either

486

culture or qPCR-based detection methods. Enrichment factors as high as 44.6 were achieved

hybridized,

the

duplex

was

capable

of

partitioning


to

the

[P6,6,6,14+]

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487

using the [P6,6,6,14+][Ni(hfacac)3-] MIL in less than 10 min. Preconcentration of the E. coli

488

cells using the MIL-DLLME method allowed for lower LOD using qPCR compared to direct

489

sampling of the aqueous cell suspensions, suggesting that this method has potential for

490

detecting food-borne pathogens.

491

MIL-DLLME was designed for the extraction of the hormones estriol and extrone in urine

492

samples

493

tetrachloromanganate(II) [Aliquat+]2[MnCl42-] MILs.78 Estriol was detected in an unspiked

494

urine sample from a pregnant volunteer, indicating that the MIL-DLLME method is a viable

495

approach towards extracting hormones from complex biological samples.

using

the

[P6,6,6,14+]2[MnCl42-]

and

trioctylmethylammonium

496 497

Ionic liquids and magnetic ionic liquids in single-drop microextraction

498

Although both hydrophobic and hydrophilic ILs have been used in single-drop

499

microextraction (SDME),9 the majority of reported applications in recent years using SDME

500

with IL-based materials have utilized MILs as extraction solvents (Table 1). In MIL-SDME

501

applications, a rod Nd-core magnet aids in suspending the MIL directly in the aqueous

502

solution or in the headspace of the extraction vial, depending on the SDME mode. With this

503

configuration, a higher microdroplet volume can be suspended from the rod magnet for

504

prolonged sampling time, even under strong stirring.

505

An et al. compared the extraction performance of MIL-HS-SDME and MIL-DLLME for the

506

determination of 12 aromatic compounds.79 Two different MILs, namely [P6,6,6,14+]2[MnCl42-]

507

and [Aliquat+]2[MnCl42-], were studied. The results indicated that the optimized HS-SDME

508

procedure provided higher enrichment factors for volatile aromatic compounds, whereas the



Page 24 of 99

509

MIL-DLLME procedure was effective for the extraction of analytes possessing low vapor

510

pressures.

511

In another application, the [P6,6,6,14+][Mn(hfacac)3-] MIL was used in HS-SDME under low

512

pressure conditions (vacuum HS-SDME).82 The procedure was compared with the

513

conventional HS-SDME method under atmospheric conditions for the determination of short

514

chain free fatty acids. It was concluded that the vacuum HS-SDME method reached

515

equilibrium faster while providing low LODs, in the range of 14.5 to 216 g·L-1.

516

In

517

tetraisothiocyanatocobaltate(II) ([C2MIM+]2[Co(NCS)42-]) MIL was applied in HS-SDME

518

for the extraction of nine chlorobenzenes from tap, pond, and wastewater.83 The extraction

519

was accomplished in only 10 min, with LODs ranging from 4-8 ng L-1.

520

Several MIL-SDME methods have been developed for the analysis of biomolecules. Emaus

521

et al. developed a DI-SDME method to extract short cell-free DNA fragments.80 The DNA-

522

enriched MIL was incorporated into a specially designed qPCR buffer to remove the need

523

for an added DNA desorption/recovery step. The results indicated that the addition of the

524

MIL did not affect the amplification efficiency during qPCR. The MIL method was compared

525

to commercial magnetic beads used for DNA extraction and similar extraction efficiencies

526

for double stranded DNA were observed. However, the magnetic beads significantly

527

decreased the amplification efficiency of qPCR when they were directly added to the qPCR

528

reaction.

529

MIL-SDME was also applied towards the extraction of DNA from a cell lysate, followed by

530

thermal desorption of DNA during loop-mediated isothermal amplification (LAMP) and

531

isothermal multiple-self-matching-initiated amplification (IMSA).81 The addition of MILs to

another

study,

the

hydrophilic


1-ethyl-3-methylimidazolium

Page 25 of 99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


532

the amplification buffer resulted in reduced background fluorescence associated with primer-

533

dimer based nonspecific amplification and allowed for the visual detection of PCR products.

534 535

Ionic liquids in hollow fiber liquid-phase microextraction

536

ILs have been used as extraction solvents in both two-phase and three-phase hollow fiber

537

liquid-phase microextraction (HF-LPME).9 Among the common advantages of ILs as

538

extraction solvents, the elevated viscosity of ILs prevents their loss during the extraction,

539

allowing for higher extraction efficiencies and better reproducibility. This section

540

summarizes recent applications involving the use of ILs in HF-LPME in both modes.

541 542

Two phase ionic liquid-hollow fiber liquid-phase microextraction

543

The two phase HF-LPME system is comprised of an acceptor phase located within the lumen

544

of a porous fiber and the donor phase (i.e., the sample). This microextraction mode has been

545

applied towards the extraction of Co2+ and Ni2+ from human urine samples.85 The chelating

546

agent 1-(2-pyridylazo-2-naphthol (PAN) was added to the sample solution to aid in the

547

partitioning of Co2+ and Ni2+ to the hydrophobic [C6MIM+][PF6-] IL phase. NaPF6 was also

548

added to the sample to assist in ion-pairing with the Co2+ and Ni2+ anions. LODs as low as

549

0.09 and 0.03 ng mL-1 for Co2+ and Ni2+, respectively, were obtained using FAAS with

550

enrichment factors ranging from 66-82 in human urine.

551

One limitation of HF-LPME is the potential loss of the extraction phase during the extraction.

552

To combat this, López-López et al. sealed both ends of the HF containing the IL extraction



553

solvent to prevent the IL from leaching into the sample solution during the extraction.86 In

554

this application, the trioctylmethylammonium thiosalicylate ([Aliquat+][TS-]) and

555

trioctylmethylammonium 2-(methylthio)benzoate ([Aliquat+][MTBA-]) ILs were capable of

556

extracting Cd2+, Cr4+, Cu2+, Ni2+, and Pb2+ with the HF-LPME method while [P6,6,6,14+]-based

557

ILs were able to quantitatively extract Ag+ after a 24 h extraction.

558 559

Three phase ionic liquid-hollow fiber liquid-phase microextraction

560

In three phase HF-LPME, also called liquid-liquid-liquid microextraction (LLLME), the

561

extraction phase is not in direct contact with the donor phase and acts as a supported liquid

562

membrane (SLM) on the HF. An extra component, the acceptor phase, is used during the

563

extraction. Analytes undergo partitioning from the donor phase to the extraction phase and

564

finally to the acceptor phase. Wang et al. developed a three-phase HF-LPME approach for

565

the determination of phthalate esters from tea using the [C4MIM+][PF6-] IL as acceptor

566

phase.87 The high viscosity of the IL prevented the loss of the acceptor phase into the aqueous

567

solution during the extraction but also prevented the IL from fully impregnating the

568

membrane pores. In this application, 1-nonanol was used as the SLM phase to ensure higher

569

recoveries. Enrichment factors as high as 200 were achieved. In another study, the

570

trioctylmethylammonium chloride ([N1,8,8,8+][Cl-]) IL was employed in HF-LPME for the

571

extraction of tetracyclines from diluted milk samples.88 The donor solution was pumped

572

though the fiber and subsequently eluted with the aid of a peristaltic pump. The results

573

indicated the tetracyclines formed an ion pair complex with the [N1,8,8,8+] cation during the


Page 26 of 99

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574

extraction process. Relative recoveries in diluted milk ranged between 92–108% with the

575

proposed method.

576

Pimparu et al. developed an on-line HF-LPME method for the extraction of Cr6+ from

577

environmental water samples using the commercial Aliquat 336 IL as a SLM.89 In the

578

reported method, the HF was attached to a six-port injection valve and multi-position

579

selection valve, and the donor solution flowed outside of the HF while the acceptor phase

580

flowed within the membrane’s lumen. A 1,5-diphenylcarbazide solution was injected onto

581

the membrane to chelate the metal, and the Cr6+-complex was subsequently detected using

582

UV-vis spectroscopy. The HF-IL-LPME method allowed for a 41-fold enrichment with

583

LOQs below the maximum allowable concentration of Cr6+ set by the California

584

Environmental Protection Agency (EPA). Alahmad et al. developed an IL-HF-LPME

585

method using the Aliquat® 336 IL as extraction phase and NaCl as acceptor solution for the

586

extraction of Cr6+.90 The extraction was facilitated using an ion exchange transport process

587

through the IL support, and spectroscopic detection was performed using 1,5-

588

diphenylcarbazide as chelating agent. Enrichment factors as high as 60 were achieved,

589

allowing for faster visual detection of the Cr6+-complex.

590 591

Ionic liquids and magnetic ionic liquids in aqueous biphasic systems

592

ILs have been used as phase-forming components in aqueous biphasic systems (ABS) to

593

introduce polarity differences in the two phases that constitute the ABS, in general salt-salt,

594

salt-polymer, or polymer-polymer.91-93 In addition, the structural tailoring ability of ILs make

595

them ideal for ABS to impart selectivity towards specific analytes. For these reasons, IL-



596

ABS have been developed and applied for the extraction, preconcentration and/or

597

purification of metal ions, organic compounds and biomolecules.

598

The majority of applications describing the extraction and separation of metal ions have

599

utilized acidic water/IL or salt/water/IL systems for developing the ABS.93,94 In these studies,

600

the addition of the acid (or the salt) prevented hydrolysis and precipitation of the target metal

601

ions while promoting the formation of metal complexes able to be extracted into the IL-rich

602

phase. For example, Gras et al. developed an ABS based on HCl and the

603

tributyltetradexylphosphonium chloride ([P4,4,4,14+][Cl-]) IL for the extraction of Ni2+, Co2+,

604

Pt4+ and Fe3+.94 It was found that under elevated temperatures Ni2+ could be separated into

605

the HCl-rich phase while Co2+, Pt4+, and Fe3+ were extracted into the [P4,4,4,14+][Cl-]-rich

606

phase, as demonstrated in Figure 3. Separation was facilitated by the formation of metal

607

chloride complexes able to undergo ion exchange with the [P4,4,4,14+][Cl-] IL. Chen et al.

608

separated Nd3+ from Co2+ and Ni2+ using an ABS based on the tetrabutylphosphonium nitrate

609

([P4,4,4,4+][NO3-]) IL and NaNO3.95 The extraction of metal ions to the IL-rich phase was

610

achieved through an anion exchange mechanism, resulting in a 96% extraction efficiency of

611

Nd3+ compared to only 7.8% and 5.9% for Co2+ and Ni2+, respectively. Nd3+ was selectively

612

extracted because Co2+ and Ni2+ ions were unable to form anionic metal complexes capable

613

of undergoing ion exchange with [P4,4,4,4+][NO3-]. In addition, the possibility of recovering

614

and reusing the IL in successive extractions was possible by using oxalic acid to precipitate

615

the extracted Nd3+.

616

Speciation of metal ions is of importance as detection methods such as EAAS and inductively

617

coupled plasma-mass spectrometry (ICP-MS) cannot differentiate between oxidation states.

618

Therefore, Sadeghi et al. designed an IL-ABS using the [C8MIM+][salicylate-] TSIL, sodium 28 ACS Paragon Plus Environment

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619

acetate and Triton X-114 to selectively extract Cr3+ while leaving the mutagenic Cr4+ in the

620

aqueous layer.96 The IL-ABS approach was able to extract 11.1% of Cr4+ and 92.5% of Cr3+

621

from aqueous solution.

622

Dimitrijević et al. used an IL-ABS containing the 1-butyl-3-ethylimidazolium dicyanamide

623

([C4C2IM+][DCA-]) IL and K2CO3 for the extraction of pesticides of varying polarity.97

624

Quantitative extraction was achieved using the [C4C2IM+][DCA-]-ABS, likely because the

625

IL exhibited higher binding energies towards acetamiprid and imidacloprid. In another study,

626

aluminum-based salts used as coagulants/flocculants in wastewater treatment were employed

627

in an IL-ABS approach to extract fluoroquinolones.98 Different imidazolium- and

628

phosphonium-based ILs were examined in this application, and extraction efficiencies

629

ranging from 27.6 to 97.8%, depending on the IL, were achieved. The extraction efficiency

630

decreased with increasing chain length of the imidazolium cation and increased when the

631

anion contained an aromatic functional group. Fluoroquinolones were subsequently

632

recovered by its precipitation using K3PO4 and the IL could be reused without losses in its

633

extraction performance.

634

A pH-driven ABS using imidazolium-, piperidinium-, pyrrolidinium- or phosphonium-based

635

ILs along with citrate/citric acid were applied for the separation of dehydrate fructose and 5-

636

hydroxy-methylfurfural.99 In this study, 5-hydroxy-methylfurfural was extracted into the IL-

637

rich phase with extraction efficiencies of 92–96 % while fructose preferred the salt-rich phase

638

(45–59% extraction efficiency) due to differences in polarity.

639

Quental et al. developed an ABS extraction method using tetraalkylphosphonium or

640

tetraalkylammonium-based ILs and carbohydrates.100 Carbohydrates acted as salting-out

641

agents due to the number and positioning of alcohol groups. The developed IL-ABS method 29 ACS Paragon Plus Environment


642

extracted 65–99% of the antioxidants gallic acid, syringic acid, and vanillic acid through

643

hydrogen bonding, hydrophobic interactions, and dispersion forces. Antioxidants were

644

subsequently recovered from the IL-rich phase using SPE.

645

The 1,1,3,3-tetramethylguanidinium 2,2,6,6-tetramethylpiperidine ([TMG+][TEMPO-SO3-])

646

MIL was used as an ABS component for the extraction of chloramphenicol from

647

environmental water samples.84 This MIL was designed without any paramagnetic metal in

648

the cationic/anionic moieties. The developed biphasic system was formed by the addition of

649

K3PO4 in the aqueous solution of the MIL. ABS extraction was accomplished in only 1 min,

650

and the MIL-phase was then isolated with the aid of an external magnet. A LOD of 0.14 ng

651

mL-1 and relative recoveries in river and lake water ranging from 94.6–99.7% were achieved.

652

Since ABS are mainly composed of water, they can be considered biocompatible systems for

653

biomolecules such as proteins, enzymes, antibodies, and nucleic acids.91 Bogdanov et al.

654

investigated the use of an IL-ABS containing the choline saccharinate ([Ch+][Sac-]) IL and

655

Na2CO3 for the extraction of the acetylcholinesterase inhibitors galantamine N-desmethyl

656

galantamine and ungiminorine.101 Enrichment factors as high as 153 were achieved, and no

657

matrix effect was observed when the method was applied for the analysis of Nivalin pills.

658

Acceptable recoveries were also noted when applying the IL-ABS extraction method towards

659

human urine. Zawadzki et al. developed an IL-ABS method for the extraction of amitriptyline

660

hydrochloride, an antidepressant drug, using a biphasic system composed by either

661

[N4,4,4,4+][Cl-] or [N4,4,4,4+][Br-] with K2HPO4/KH2PO4.102 The phosphate salts promoted

662

salting out of the desired analytes to the IL-rich phase. The analytes were then re-extracted

663

from the IL-rich phase by adjusting the pH. The optimized extraction procedure was capable

664

of quantitatively extracting the antidepressant drugs from ADT 25 mg pills. 30 ACS Paragon Plus Environment

Page 30 of 99

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665

Yang et al. extracted L-phenylalanine as a model amino acid in an IL/polymer/inorganic salt

666

ABS.103 Different imidazolium-based ILs were introduced to the polymer-rich phase to better

667

tune the physicochemical properties of the PEG600-rich phase. Generally, imidazolium

668

cations with longer alkyl chain length substituents resulted in an increased partition

669

coefficient of L-phenylalanine to the IL/polymer phase, with the exception of the 1-decyl-3-

670

methylimidazolium chloride ([C10MIM+][Cl-]) IL. Introducing the more hydrophobic acetate

671

anion into the IL structure also effected the partition coefficient to the IL/polymer-rich phase.

672

ILs have also been used as adjuvants in a polyethylene glycol (PEG) 3350/(NH4)2SO4 ABS

673

for the extraction of myoglobin.104 In this study, it was concluded that the addition of shorter

674

alkyl chains within imidazolium ILs enhanced the two-phase separation. Therefore, the

675

addition of 5 wt% of the IL adjuvant increased the extraction efficiency from 9.96% to

676

62.7%, whereas the addition of 7.5 wt% of the 1-butyl-3-methylimidazolium acetate

677

([C4MIM+][CH3CO2-]) IL resulted in the quantitative extraction of myoglobin.

678

A series of Good’s buffers ILs (GBILs) were designed by Gupta et al. to act as buffers during

679

the ABS extraction of α-chymotrypsin.105 The GBILs maintained a constant pH in the ABS,

680

preventing conformation changes of the enzyme and the loss of its activity while also

681

providing quantitative extraction of α-chymotrypsin.

682

IL-ABS have also been applied towards the purification of IgG antibodies.106 ABS composed

683

of polypropylene glycol and different choline-based ILs were able to quantitatively extract

684

IgG from both aqueous solutions and rabbit serum samples. In addition, the ABS did not

685

affect the stability of the IgG antibody when the choline glycolate ([Ch+][Gly-]) and choline

686

L-ascorbate ([Ch+][Asc-]) ILs were used as extraction solvents.

687

Chromatographic and electrophoretic separations 31 ACS Paragon Plus Environment


688

Gas chromatography

689

ILs have been studied as stationary phases in GC and multidimensional GC (MDGC) due to

690

their high thermal stability, high polarity, and tunable selectivity.14,107-109 An important

691

number of publications have examined the polarity of the developed IL-based stationary

692

phases and have compared then to conventional stationary phases. The commercially-

693

available IL-based columns from Millipore Sigma (e.g., SLB-IL59, SLB-IL100, and SLB-

694

IL111) utilize the polarity number (PN) reported by Mondello and co-workers.110 In addition

695

to the PN, the Abraham solvation parameter model provides unique insights into the solvation

696

capabilities of the IL-based GC columns. The Abraham model characterizes the solvation

697

properties of the IL-based stationary phases towards analytes by measuring five different

698

types of interactions, namely, π-π or n-π interaction, polarizability/dipolarity, hydrogen

699

bonding basicity and acidity of the stationary phase, and dispersive-type interactions. Lenca

700

and Poole have thoroughly investigated different commercial IL-based columns, including

701

SLB-IL60, SLB-IL61, and SLB-IL76 using the solvation parameter model.111-113 Other

702

important parameters of IL-based stationary phases are the operating temperature range,

703

column efficiency, peak symmetry, and inertness. Among these, the thermal stability is of

704

specific importance for high temperature applications.114,115 This section describes recent

705

publications that examine IL-based stationary phases for both GC and MDGC.

706 707

Monocationic ionic liquid-based stationary phases

708

GC applications examining monocationic IL stationary phases have utilized different

709

combinations of cations (e.g., phosphonium, ammonium, sulfonium, imidazolium, and

710

pyridinium) and anions (e.g., halide, triflate – [TfO-], tetrafluoroborate – [BF4-], 32 ACS Paragon Plus Environment

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711

hexafluorophosphate – [PF6-], and [NTf2-]). Recently, a number of studies using

712

phosphonium-based ILs have appeared as these ILs typically exhibit higher thermal stability

713

than ammonium or imidazolium-based ILs.116 Hantao et al. employed different IL-based GC

714

stationary phases for the separation of aliphatic hydrocarbons by comprehensive two-

715

dimensional gas chromatography (GC × GC).117 The GC stationary phases based on

716

trihexyl(tetradecyl)phosphonium

717

[P6,6,6,14+][FAP-] ILs provided the better separation of aliphatic hydrocarbons compared to

718

commercial columns (e.g., OV-1701, SUPELCOWAX10, SLB-IL60, SLB-IL100, and SLB-

719

IL111). High thermal stability was also achieved with these stationary phases (with

720

maximum allowable operating temperatures, MAOT, of 320 ºC). Despite the fact that most

721

IL-based stationary phases are used as wall coated open tubular (WCOT) columns, Regmi et

722

al. described the coating of two different ILs, namely [P6,6,6,14+][NTf2-] and 1-butylpyridinum

723

[NTf2-] ([C4Py+][NTf2-]), into the channels of micro-fabricated semi-packed columns (SPCs)

724

for GC.118 The developed IL-coated SPCs produced sharp and symmetrical peaks, offered

725

high separation efficiency, and increased the separation speed.

726

ILs containing imidazolium cations are generally the most widely examined IL-stationary

727

phases;

728

decomposition/volatilization at elevated temperature. To further improve their thermal

729

stability as well as the separation performance, Pello-Palma et al. reported a covalently

730

bonded IL-based GC stationary phase for the determination of volatile compounds in cider

731

apple juices.119 The stationary phase was prepared by covalently reacting the imidazolium

732

monolith to the free silanol groups within the inner capillary surface. The developed IL

733

stationary phase exhibited a thermal stability up to 290 ºC and column efficiency of 2000

however,

they

are

tetrachloroferrate(III)

also

among

the

most


([P6,6,6,14+][FeCl4-])

susceptible

at

and

the

undergoing


734

plates·meter-1. In a similar application, Dai et al. immobilized the 1-butyl-3-[(3-trimethoxy-

735

silyl)propyl]imidazolium chloride ([C4((MOSi)3C4)IM+][Cl-]) IL onto the inner wall of a

736

fused-silica capillary to improve thermal stability.120 However, peak tailing of common

737

analytes such as octane and butanol was observed to be a major challenge for further

738

application. Nan et al. reported lipidic imidazolium IL-based stationary phases for the

739

determination of aliphatic hydrocarbons by GC × GC.121 These ILs possessed long alkyl side

740

chains (from C16 to C18) as well as low melting points, which provided enhanced dispersive-

741

type interactions suitable for the separation of aliphatic hydrocarbons in the second

742

dimension.

743 744

Di- and polycationic ionic liquid-based stationary phases

745

Dicationic ILs have been known to exhibit significantly higher thermal stability compared to

746

traditional monocationic ILs.115,116 The thermal decomposition pathways of various

747

dicationic ILs were thoroughly investigated by Patil et al.114 In this study, the selectivity of

748

nine different dicationic imidazolium and pyrrolidinium IL-based stationary phases was

749

examined. In a subsequent study using the same stationary phases performed by the same

750

authors, it was concluded that the polarity of the stationary phase was affected by the choice

751

of cations and anions as well as the length of the alkyl linker chain.122 Talebi et al. reported

752

twelve dicationic IL-based stationary phases for the separation of fatty acid methyl esters

753

(FAMEs).123 Structural differences of the alkyl linker chain were found to strongly influence

754

both the polarity and selectivity of the stationary phase in the separation of FAMEs. Several

755

physicochemical properties including viscosity, density, and thermal stability of branched-

756

chain ILs were also reported.124 Jiang et al. investigated the separation performance and 34 ACS Paragon Plus Environment

Page 34 of 99

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757

solvation properties of four different geminal ILs with p-xylene as linker chain.125 These ILs

758

exhibited excellent separation performance for aromatic positional isomers. In addition, the

759

ILs containing [NTf2-] anions possessed better selectivity for alcohols and aromatic positional

760

isomers compared to ILs comprised of [BF4-] and [PF6-] anions. Heydar et al. reported a new

761

dicationic IL with naphthalenyl moieties.126 McReynolds constants and the Abraham

762

solvation parameter model were used to characterize the polarity of the IL-based stationary

763

phase. The developed stationary phases possessed an average polarity of 667 (PN = 75), and

764

presented strong intermolecular interactions (dipole-dipole, H-bonding basicity and

765

dispersive-type interactions) with analytes. The study also suggested that the IL-based

766

stationary phase is especially suitable for the separation of polyaromatic compounds. Talebi

767

et al. investigated the effect of anionic moieties on the thermal stability and selectivity of

768

dicationic IL-based stationary phases.127 Unique selectivities toward unsaturated FAMEs and

769

PAHs were observed when employing these ILs with different anion moieties. Among the

770

developed

771

fluorosulfonylalkylated anion exhibited the highest thermal stability (above 300 ºC).

772

Mono- and dicationic pyridinium IL-based GC columns were employed as the first

773

dimension column for the separation of phenol-containing pyrolysis products using GC × GC

774

with the pyridinium IL × HP-5 column set.128 Compared to the ZB-Wax × HP-5 column set,

775

the dicationic pyridinium IL × HP-5 column set provided better performance in the separation

776

of diaromatics and phenols, especially for the 2,4-dimethylphenol/ 4-methylphenol pair. The

777

separation was achieved due to the high polarity of the IL and the low contribution of

778

dispersive-type interactions compared to the ZB-WAX column.

GC

stationary

phases,

dicationic

ILs

779


containing

the

symmetrical


780

Polymeric ionic liquid-based stationary phases

781

The polymerization of IL cations/anions to produce PILs is a strategy to increase the thermal

782

stability of IL-based stationary phases and to reduce their tendency of pooling or forming

783

droplets at high temperatures. Roeleveld et al. developed two PIL-based stationary phases

784

via both the chain-growth and step-growth methods.129 The results indicated that PILs

785

generated by the step-growth method produced higher thermal stability (up to 325 ºC)

786

compared to the chain-growth PIL (decomposition temperature of 250 ºC).

787

Zhang et al. examined a crosslinked PIL-based stationary phase for the GC × GC separation

788

of kerosene and diesel.130 The crosslinked PIL-based stationary phase possessed a MAOT of

789

325 ºC and provided better selectivity in the separation of aliphatic hydrocarbons when it

790

was used as the second-dimension column compared to the commercial carbowax and DB-

791

17 columns.

792 793

Metal-containing ionic liquid-based stationary phases

794

Metal salt additives have been reported to exhibit a significant effect on the selectivity of GC

795

stationary phases and have historically been widely used in packed GC columns.131,132

796

However, few studies have reported the use of metal salt additives in WCOT columns due to

797

their limited solubility and poor mixing in traditional stationary phases.133,134 Metal-

798

containing ILs are a subclass of ILs containing a metal center in either the cation or the anion.

799

These ILs are liquids at room temperature despite incorporating a metal center, making them

800

of interest in GC applications. Anderson and co-workers have studied silver-based ILs with

801

various chelating ligands to separate paraffin and olefins.135 These stationary phases were


Page 36 of 99

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802

found to be highly selective in the separation of volatile hydrocarbons of various size and

803

containing double and triple bonds of varied geometry. In another study, different metal-

804

containing IL stationary phases with transition and rare earth metals (e.g., Ni2+, Mn2+, and

805

Dy3+) coordinated with different chelating ligands were investigated.136 The stationary phases

806

were characterized by the Abraham solvation parameter model. The results showed

807

significant differences in the solvation properties depending on both the metal center and the

808

ligand employed to generate the metal-containing IL. The Mn2+-based IL stationary phase

809

possessed the highest hydrogen bonding basicity, where the Dy3+-based column provided

810

higher dipolarity/polarizability. Higher hydrogen bonding acidity was also observed when

811

the hexafluoroacetylacetonate ligand was coordinated with the metal, in comparison to a

812

similar IL with no ligands.

813 814

Commercial ionic liquid-based stationary phases

815

In the last several years, new IL-based columns have been introduced to the market. The

816

Watercol series of columns were developed and introduced specifically for the analysis of

817

water. In addition, IL-stationary phases within the i-series (e.g., SLB-IL76i and SLB-IL11i)

818

have been developed to provide enhanced inertness to previous versions of structurally

819

similar stationary phases. Finally, a new IL-based stationary phase intended for separating

820

mixtures of PAHs, namely SLB-ILPAH, has become commercially- available. Recent

821

applications of these stationary phases, along with new applications of IL-based commercial

822

columns, are summarized in this section.

823

Armstrong and co-workers developed water-compatible IL-based stationary phases

824

(commercially available as Watercol 1460, Watercol 1900, and Watercol 1910) for the 37 ACS Paragon Plus Environment


Page 38 of 99

825

separation and detection of trace water, with a working range between 12–3258 mg·kg-1 (see

826

Figure 4).137-139 The precision of the method was verified by using NIST and American

827

Society for Testing and Materials (ASTM) methods. The analysis of samples containing

828

water presents another major challenge. When conventional stationary phases are employed,

829

direct injection of aqueous samples is normally avoided since water induces peak asymmetry,

830

poor sensitivity and efficiency, strong adsorption, as well as stationary phase degradation.

831

Cagliero et al. demonstrated that water compatible IL-based columns can be routinely used

832

for the direct analysis of samples with water as the main solvent, making them very promising

833

for the analysis of fragrances and essential oils.140

834

The inertness of IL-based columns is a major concern for end-users. Studies have shown that

835

IL-based stationary phases provide excellent resolution and efficiency, but their lack of

836

inertness can make them less attractive.141 To overcome this limitation, different inert IL-

837

based

838

MilliporeSigma in 2016. Retention times and elution orders of analytes separated on these

839

new inert columns were highly comparable with the previous generation of stationary phases.

840

However, significantly reduced peak widths, peak tailing, and lower column bleed was

841

observed, making them very attractive to complex sample analysis. These columns were

842

further examined for the analysis of fragrance and essential oils.142 It was found that the inert

843

stationary phases are highly competitive with most of the common PDMS or PEG-based

844

columns. Pojjanapornpun et al. evaluated the separation performance of the SLB-IL111i

845

stationary phase for the separation of FAMEs using GC × GC.143 Compared with the previous

846

generation SLB-IL111 column, the SLB-IL111i stationary phase exhibited reduced column

847

bleed, higher profiling speed, and better repeatability. Figure 5 shows representative contour

columns

(SLB-IL60i,

SLBIL76i,

and SLB-IL111i)


were introduced by

Page 39 of 99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


848

plots of a 37 FAME mix obtained with the SLB-IL111i stationary phase in the first dimension

849

combined with different IL-based stationary phases in the second dimension. Less bleeding

850

can also be observed with the inert SLB-IL111i stationary phase (see Figure 5c versus Figure

851

5d).

852

IL-based GC columns are commonly used as alternatives to PEG-based stationary phases in

853

applications where both high polarity and high thermal stability are needed. IL-based GC

854

columns have been widely applied for the analysis of FAMEs using one dimensional GC as

855

well as MDGC.13,144-146 In one dimensional GC applications, Gómez-Cortés et al. employed

856

the SLB-IL111 stationary phase to discriminate odd and branched-chain fatty acids from

857

other milk fatty acids eluting within the same chromatographic regions.144 IL-based

858

stationary phases have also been applied for the analysis FAMEs in GC × GC.145-147 Marriot

859

and co-workers developed a heart-cutting MDGC-MS method with a unique column set (100

860

m HP-1 PONA × 30 m SLB-IL60) to analyze trace-level contamination of FAMEs in diesel

861

fuel.147 In this application, the SLB-IL60 stationary phase provided unique selectivity, high

862

polarity, and high thermal stability (with MAOT of 300 °C). The obtained LODs of

863

individual FAMEs ranged from 0.5 to 5.0 mg·L-1, which was two orders of magnitude lower

864

than previously reported methods.

865

Sciarrone et al. reported a MDGC method using a combustion-isotope ratio MS/ quadrupole

866

MS (C-IRMS) detector and a low-bleed SLB-IL59 second dimension column for the analysis

867

of food products containing truffles.148 In comparison to a PEG column, the IL-based

868

stationary phase provided lower noise at the elution temperature of vanillin (about 210 °C).

869

This high efficiency MDGC-C-IRMS system was applied for monitoring of bis(methylthio)-



870

methane, which is responsible for the white truffle aroma. The analyte was successfully

871

resolved from other components in different commercial products investigated in the study.

872

Ramos and co-workers examined six IL-based stationary phases for the separation and

873

detection of a mixture of 69 environmentally-related polychlorinated biphenyls (PCBs).149

874

Different selectivity was achieved depending on the employed GC stationary phase. In

875

addition, it was found that the SLB-IL59 stationary phase was able to resolve the most toxic

876

non-ortho congeners (77, 126, and 169) from other PCBs in the test mixture.

877

Wilson et al. investigated the retention behavior of polycyclic aromatic sulfur heterocycles

878

(PASHs) on IL-based GC columns.150-151 The retention index of 10 sets of alkyl-substituted

879

PASH isomers (total of 80 PASHs) and 48 polycyclic aromatic PASHs were determined

880

using the commercial SLB-ILPAH stationary phase.

881 882

High Performance Liquid Chromatography

883

High performance liquid chromatography (HPLC) is a major analytical technique used for

884

the separation of complex mixtures of analytes. In HPLC, ILs have been used as mobile phase

885

modifiers, substituting for conventional organic modifiers such as acetonitrile, methanol or

886

tetrahydrofuran. They have also been employed in low concentrations as mobile phase

887

additives, pseudo-stationary phases in micellar liquid chromatography (MLC), and as

888

components of the stationary phase. Table 2 shows representative applications in which ILs

889

have been studied with these purposes in HPLC within the period between 2016-2018. Most

890

of the literature within this time period deals with the use of ILs as mobile phase additives or

891

as components in stationary phases.152-161


Page 40 of 99

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892 893

Ionic liquids as mobile phase additives

894

ILs have been added at low concentrations to the mobile phase in HPLC separations to

895

suppress the effect of free silanol groups in common silica-based stationary phases. In these

896

cases, the IL cation can strongly interact with the stationary phase by an ion exchange

897

process, thereby masking or blocking the residual free silanol groups of the phase. As a result,

898

the chromatographic behavior is often improved with regard to the peak shape, resolution,

899

band broadening, and analysis time.

900

Caban and Stepnowski have studied the effect of both the cation and anion of the IL in the

901

mobile phase for the separation of tri-cyclic basic antidepressants by reversed phase (RP)-

902

HPLC.162 The authors hypothesized that typical anions of ILs (e.g. [PF6-] > perchlorate,

903

[ClO4-] > trifluoroacetate, [CF3COO-], chloride, [Cl-] > acetate, [HCOO-] >

904

dihydrogenphosphate, [H2PO4-], in agreement with the Hofmeister series) can influence the

905

retention of the analytes. In these cases, the anions break the solvation shells around the

906

analytes, making them more hydrophobic resulting in improved retention in RP-HPLC.

907

Binary mobile phases of acetonitrile and different aqueous phases containing the

908

[C4MIM+][Cl-] or the [C4MIM+][PF6-] ILs were evaluated in the study. Overloading studies

909

of clomipramine revealed that the IL-based mobile phases possessed a higher sample loading

910

capacity than conventional mobile phases containing ammonium acetate and triethylamine-

911

based compounds.

912

The majority of the reported studies regarding this field have utilized imidazolium- or

913

ammonium-based ILs.162 However, a new class of TSILs as terpene derivatives (1-

914

[(1R,2S,5R)-(−)-menthoxymethyl]-3-methylimidazolium chloride, [(CH2O-Men)MIM+][Cl41 ACS Paragon Plus Environment


and

Page 42 of 99

915

],

1-[(1R,2S,5R)-(−)-menthoxymethyl]-3-pentylimidazolium

916

Men)C5IM+][Cl-]) were used as mobile phase additives to enhance the separation of acidic

917

enantiomers on a glycopeptide stationary phase.152 It was proved that the addition of the

918

chiral [CH2O-MenC5IM+][Cl-] IL to the mobile phase was responsible for the best

919

improvement in the enantioresolution of the analytes. Docking simulations of the system

920

were in agreement with the obtained chromatographic results. In another study, geminal

921

dicationic ILs based on imidazolium, piperidinium, morpholinium, pyrrolidinium,

922

piperazinium, and ammonium cations were used as mobile phase additives in RP-HPLC for

923

the separation of auxinic herbicides, a group of polar compounds with high acidic character

924

that are extremely difficult to separate using traditional C18 silica stationary phases.153

925

Analyte retention in these separations was modulated by repulsive forces between the IL

926

cation / anion and analytes present in their neutral form, hydrophobic interactions between

927

the carbon chains of the IL and the neutral analytes, and ionic interactions with ionized

928

analytes.

929

Deep eutectic solvents (DES) based on ILs have also been added as additives to the mobile

930

phase for the separation of bioactive quaternary alkaloids by RP-HPLC.154 The studied DES

931

were

932

tetraalkylammonium chloride ([Nn,n,n,n+][Cl-], with n = 1, 2 or 3) ILs at different ratios. The

933

ILs acted as hydrogen bond acceptors in the DES while ethylene glycol, urea, citric acid or

934

glycerol were used as hydrogen bond donors. The results demonstrated that the addition of

935

DESs to the mobile phase at the appropriate pH improved the separation of these basic

936

compounds. LODs between 0.006 and 0.020 µg·mL-1 were achieved, and both herbal oral

937

solutions and tablets were successfully analyzed with the method.

prepared

by

mixing

either

choline

chloride


chloride,

([Ch+][Cl-])

or

[(CH2O-

different

Page 43 of 99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


938

ILs have also been employed to improve the separation of metal ions.155,163 Mercury and its

939

different chemical species Hg2+, methylmercury (CH3Hg+) and ethylmercury (C2H5Hg+),

940

were determined by RP-HPLC with UV and cold vapor generation atomic fluorescence

941

spectrometry (CV-AFS). In this study, the separation was achieved using mobile phases

942

composed of methanol and citric acid/citrate buffer in an aqueous solution of NaCl in which

943

different ILs were used as additives.155 The studied ILs included on [CnMIM+][Cl-] (with n

944

=4, 6, 8, and 12) and tributylmethylphosphonium methylsulfate ([P4,4,4,1+][CH3SO4-]). With

945

regards to the imidazolium-based ILs, the proposed mechanism for the successful separation

946

of ions began with the formation of negatively charged chlorocomplexes with the mercury

947

ions, followed by ion-pairing with the IL cations and their retention on the C18 stationary

948

phase. In another application, mobile phases composed of several 1-alkyl-3-

949

methylimidazolium tetrafluoroborate ([CnMIM+][BF4-], with n = 2,3,4 or 6) ILs and oxalic

950

acid were used in ion chromatography for the determination of alkaline earth metal ions,

951

including Mn2+, Ca2+, and Sr2+.163 Indirect UV detection of the ions was possible because the

952

ILs within the mobile phase served as background UV absorption reagents. Separation of the

953

ions using a carboxylic acid cation exchange column was achieved due to the presence of

954

oxalic acid. The length of the alkyl substituent of the imidazolium cation also influenced the

955

retention behavior of the metal ions. Therefore, a decrease in the retention times of the ions

956

was observed with increased length. The authors noted that stronger bonding of ILs to the

957

ion exchange sites of the stationary phase resulted when larger ILs were added as additives

958

to the mobile phase, causing a decrease in the retention of the ions of interest.

959

In addition to HPLC, ILs have been applied as mobile phase additives in high-performance

960

thin-layer chromatography (HPTLC) for the determination of haloperidol and its two



961

metabolites in human plasma.156 In particular, the studied analytes were separated on glass

962

plates percolated with silica gel in a glass chamber using a mobile phase consisting of

963

acetonitrile: water: 1-ethyl-3-methylimidazolium tetrafluoroborate ([C2MIM+][BF4-])

964

(50:50:1.5, v/v). The separation was achieved in only 25 min, and the HPTLC was coupled

965

with MS to increase the sensitivity of the method. In another study, mobile phases containing

966

ILs were used in two-dimensional TLC (2D-TLC) for the separation of alkaloids and its

967

identification in plant extracts.164 The separations were performed on glass cyanopropyl

968

plates using a mixture of methanol, diisopropyl ether, ammonia and acetic acid in the first

969

dimension, and acetonitrile, water, formic acid, and 1-butyl-3-methylimidazolium

970

tetrafluoroborate ([C4MIM+][BF4-]) in the second dimension.

971 972

Ionic liquids as components of the stationary phase

973

ILs have been used as structural components in HPLC stationary phases. A wide number of

974

applications have developed surface-confined ionic liquid (SCIL) stationary phases by

975

attaching the IL to a silica substrate using a coupling agent, in general, a type of

976

organoalkoxysilane. For the synthesis of the corresponding SCIL, both monomeric or

977

polymeric processes have been employed. Qiao et al. reported SCIL stationary phases using

978

an amide-functionalized imidazolium IL.157 A monomeric heterogeneous process was used

979

for the preparation of the stationary phase, with (3-mercaptopropyl)trimethoxysilane being

980

employed as a coupling agent followed by thiol-ene click chemistry for grafting the IL onto

981

the surface of the modified silica. The developed stationary phases were successfully applied

982

in hydrophilic interaction liquid chromatography (HILIC) for the separation of flavonoids in

983

soybean and urine samples. 44 ACS Paragon Plus Environment

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984

Chiral SCIL stationary phases based on IL chiral selectors were prepared and applied for the

985

enantioseparation of chiral acids.165 The IL chiral selectors were prepared by the ring opening

986

of cyclohexene oxide with imidazole or 5,6-dimethylbenzimidazole, and then chemically

987

modified with different substituent groups. The main driving force of the separations using

988

these chiral stationary phases was ion exchange, and retention in the chiral acids was

989

influenced by the type of substituent and the counterion of the chiral SCIL. In another study,

990

a chiral SCIL stationary phase was prepared by the modification of oxazolinyl-substituted -

991

cyclodextrin with a pyridinium IL followed by its covalent bonding to silica.158 Excellent

992

enantioseparations were achieved using this chiral stationary phase. The IL introduced a

993

stronger electrostatic effect onto the stationary phase, making it suitable for the separation of

994

polar compounds.

995

Wang, Xu and Xue developed a zwitterionic SCIL stationary phase based on quaternary

996

ammonium, a tertiary amine, and sulfonate groups.159 The stationary phase acted as a RPLC/

997

HILIC mixed-mode stationary phase and was especially selective for the separation of polar

998

and ionizable analytes. In addition, the stationary phase separated six non-steroidal anti-

999

inflammatory drugs (NSAIDs) from plant extracts. The separation was achieved in less than

1000

20 min using a gradient linear elution of a binary mobile phase composed of an aqueous

1001

solution of ammonium formate and acetonitrile.

1002

Wu et al. prepared stationary phases based on IL/graphene quantum dots/silica

1003

composites.160 The stationary phases were evaluated in different separation modes, including

1004

normal phase (NP)-LC, RP-LC, ion exchange chromatography (IEC), and HILIC. The

1005

stationary phase was also compared with analogous graphene quantum dots/ silica or IL/



1006

silica phases. The results indicated that the combination of both materials had a synergistic

1007

and complementary effect in the separation of the studied analytes.

1008

The aforementioned applications utilized packed SCIL stationary phases based on ILs. As an

1009

alternative, other applications have reported the development and use of monolithic

1010

stationary phases based on ILs.161,162 Han et al. developed a polyhedral oligomeric

1011

silsesquioxane-based hybrid monolithic column that contained the L-cysteine hydrochloride

1012

amino acid and the [VC4IM+][Br-] IL as functionalized monomers.161 The monoliths were

1013

prepared in an one step process via free radical co-polymerization using the thiol-ene click

1014

reaction. The stationary phases were used for different applications in capillary

1015

chromatography, including the separation of alkylbenzenes and hydrophilic amides with

1016

mobile phases composed of acetonitrile and water, the purification of the TARG1 protein, an

1017

adenosine diphosphate ribose protein glycohydrolase, as well as the separation of a group of

1018

glycoproteins (ovalbumin, horseradish peroxidase and -transferring) and non-glycopotreins

1019

(ribonuclease A, bovine serum albumin, BSA, and myoglobin). The selectivity of the

1020

developed stationary phase was directly related to the presence of the amino acid, while

1021

stronger retention of proteins was linked to the nature of the IL. In another study, a polymer

1022

monolith was prepared using the 1-allyl-3-methylimidazolium chloride ([AMIM+][Cl-]) IL

1023

and triallyl isocyanurate as monomers, ethylene dimethacrylate as crosslinker, and different

1024

porogen components.166 The stationary phases presented uniform macroporous structures,

1025

which resulted in better chromatographic efficiency than traditional polymer monoliths

1026

prepared via similar polymerization procedures.

1027 1028

Counter-current chromatography 46 ACS Paragon Plus Environment

Page 46 of 99

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1029

ILs have been added as modifiers in biphasic liquid systems used in counter-current

1030

chromatography (CCC). For example, a Cu2+ complexed amino acid IL, namely Cu(II)-[1-

1031

butyl-3-methylimidazolium][L-proline] (Cu(II)-[C4MIM+][L-Pro-]), was added as a

1032

modifying additive in high speed CCC to improve the enantioseparation of naringenin, a

1033

flavanone found in citrus fruits.167 The biphasic system used in this application was

1034

composed of a n-heptane- ethyl acetate- acetonitrile - 0.2 mol·L-1 sodium acetate aqueous

1035

solution (7:3:3:7, v/v/v/v) at pH 5.5. The system contained the chiral IL selector together

1036

with hydroxypropyl--cyclodextrin. UV-vis absorption and NMR studies demonstrated that

1037

the chiral recognition mechanism resulted from the formation of a quaternary complex

1038

composed of Cu2+, the chiral IL, hydroxypropyl--cyclodextrin, and naringenin.

1039

In another study, a method was developed using CCC as a sample pretreatment step followed

1040

by HPLC for the enrichment of mycotoxins in wine and juice.168 The biphasic system was

1041

composed of ethyl acetate- water (1:1, v/v), which contained the IL. Among the different

1042

imidazolium-based ILs tested as modifiers, the 1-carboxymethyl-3-methylimidazolium

1043

chloride ([(HOOCM)MIM+][Cl-]) IL provided the highest enrichment of the mycotoxins,

1044

with partition coefficients to the ethyl acetate layer ranging from 297 to 3478 and LODs of

1045

the entire CCC-HPLC methodology ranging from 0.03 to 0.14 g·L-1. The results also

1046

indicated that both the nature of the cation and anion of the IL significantly impacted the

1047

extraction efficiency of the mycotoxins.

1048

Müller et al. reported IL-based biphasic systems for CCC that were applied for the

1049

purification of extremely non-polar lipid compounds, followed by GC-MS.169 Miscibility

1050

studies were conducted to select the most suitable biphasic system for the separation of the

1051

analytes. The obtained results showed that the system comprised of n-heptane- chloroform47 ACS Paragon Plus Environment


1052

1-decyl-3-methylimidazolium trifluoromethanesulfonate ([C10MIM+][TfO-]) (3:3:1, v/v/v)

1053

provided a partial separation of tripalmitin and cholesteryl stearate, highlighting that ILs are

1054

suitable for use in non-polar CCC.

1055 1056

Capillary electrophoresis

1057

ILs with high conductivity and tunable miscibility can serve as excellent additives in capillary

1058

electrophoresis (CE). In particular, an important number of studies have used ILs as

1059

background electrolytes. In these applications, the IL cations can interact with deprotonated

1060

silanol groups on the capillary surface in order to modify the electroosmotic flow. In addition,

1061

various chiral cations and anions have been investigated in chiral CE separations. The

1062

applications of ILs in CE have been summarized by Holzgrabe et al. in 2016.170 This section

1063

describes the most recent developments of IL-assisted CE analysis.

1064

Imidazolium-based ILs are generally the most commonly used in CE. Kolobova et al. used

1065

different imidazolium-based ILs as dynamic and covalent modifiers within the background

1066

electrolyte for the separation of catecholamines.171 IL coatings prevented sorption of

1067

catecholamines on the inner capillary wall resulting in improved separation efficiency and

1068

peak symmetry. Memon et al. used the [C4MIM+][PF6-] IL as an additive in CE for the

1069

separation of flavonoids.172 The results indicated that the IL improved separation and reduced

1070

analysis time. The separation was achieved due to the formation of an electrically neutral

1071

single layer of the imidazolium cations on the inner capillary, resulting in faster migration of

1072

the negatively charged flavonoids.


Page 48 of 99

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1073

Chiral IL additives have attracted significant attention in CE enantioseparations.15,173 The

1074

majority of studies combined the use of cyclodextrins (CDs) with ILs as chiral selectors in

1075

the CE buffer. Greño et al. have compared the enantioseparation of homocysteine using either

1076

neutral CDs or chiral ILs as CE chiral selectors.174 The best enantioseparation was achieved

1077

using a combination of the (R)-N,N,N-trimethyl-2-aminobutanol [NTf2-] IL and β-CD as

1078

chiral selectors in a phosphate run buffer (pH 7.0). Interestingly, the migration order of the

1079

D- and L-homocysteine enantiomers was reversed when both selectors were added in

1080

comparison to the order obtained when a chiral selector was employed. Wahl et al. studied

1081

ILs with [N4,4,4,4+] cations and chiral amino acid-based anions as background electrolyte

1082

additives for the electrophoretic enantioseparation of ephedrine, pseudoephedrine, and

1083

methylephedrine isomers.175 The best separation was obtained using a combination of the

1084

[N4,4,4,4+] L-argininate ([N4,4,4,4+][L-Arg-]) IL and β-CD in phosphate buffer (pH 1.5). Wang

1085

et al. employed hydroxypropyl-β-CD (HP-β-CD) and the [N4,4,4,4+] L-glutaminic acid

1086

([N4,4,4,4+][L-Glu-]) IL as additives in the separation of corynoxine and corynoxine B using

1087

field-amplified sample stacking (FASS)-CE.176 The combination of FASS as a

1088

preconcentration technique and CE provided a 700–900 fold increase in the sensitivity

1089

(stacking efficiency). Yang et al. designed two hydroxy acid-based chiral ILs, namely,

1090

tetramethylammonium D-pantothenate ([N1,1,1,1+][D-PAN-] and [N1,1,1,1+] D-quinate

1091

([N1,1,1,1+][D-QUI-]), as chiral additives together with maltodextrin as co-selectors in CE.177

1092

The addition of the IL to the maltodextrin chiral CE system significantly improved the

1093

separation of four racemic drugs (nefopan, ketoconazole, econazole, and voriconazole). Li et

1094

al. used a newly synthesized amino triazolium functionalized β-CD derivative (mono-6-

1095

deoxy-6-(4-amino-1,2,4-triazolium)-β-cyclodextrin chloride) for the enantioseparation of



1096

dansyl amino acids and naproxen by CE.178 This IL functionalized chiral selector exhibited

1097

enhanced enantioselectivity and improved solubility in water.

1098 1099

Mass spectrometry

1100

Mass spectrometry (MS) is among the most powerful analytical techniques employed for the

1101

characterization of a wide range of compounds, ranging from small organic molecules to

1102

large biomolecules such as proteins and nucleic acids. ILs have been applied in MS as ionic

1103

matrixes for matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS)

1104

and as additives in electrospray ionization mass spectrometry (ESI-MS). This section

1105

summarizes developments in the last several years regarding these two areas.

1106

Ionic liquids as matrixes in matrix-assisted laser desorption ionization

1107

MALDI-MS is often used for imaging applications and for the analysis of large molecular

1108

weight compounds. MALDI utilizes a pulsed laser along with a matrix (often organic) to aid

1109

in the desorption and ionization of the analyte(s) of interest. Some disadvantages of

1110

commonly used organic matrixes include lack of matrix spot-homogeneity and low

1111

ionization efficiency of some analytes. IL matrixes have continued to be successfully applied

1112

for both large biomolecule characterization as well as for the analysis of organic molecules

1113

and polymers.

1114

Ling et al. employed an IL matrix based on the 1,1,3,3-tetramethylguanidinium salt of 2,4,6-

1115

trihydroxyacetophenone for the MALDI-MS detection of phosphopeptides in the negative

1116

ion mode.179 Adding phosphoric acid resulted in a significant enhancement to the signal-to-

1117

noise (S/N) ratio when compared to S/N ratios resulting from the neat IL. Another study used


Page 50 of 99

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1118

ILs as a derivatizing agent prior to analysis by MALDI-MS.180 The method used ILs with

1119

allyl functional groups to break apart Cys-Cys disulfide bridges through thiol-ene click

1120

chemistry. The resulting proteins undergo in-source decay and allow for easy identification

1121

of mutation sites due to higher fragmentation.

1122

Carbohydrate analysis with MALDI-MS is a challenge due to low ionization efficiency when

1123

conventional matrixes are employed. Zhao et al. demonstrated that IL matrixes can be used

1124

to improve carbohydrate analysis with MALDI-MS.181 A set of 12 ILs possessing 2,5-

1125

dihydroxybenzoate ([DHB-]) anions and different cations were synthesized. When

1126

maltohexaose was analyzed, the IL matrixes [DHB-]/N-methylaniline (N-MA) and [DHB-]/

1127

N-ethylaniline (N-EA) provided LODs of 10 fmol, which was two orders of magnitude lower

1128

than the standard [DHB-] matrix. The stark difference in ionization efficiency can be

1129

observed in Figure 6, where analysis of neutral polysaccharides (D2000 and D4000) was

1130

enhanced using IL matrixes ([DHB-]/N-MA and [DHB-]/N-EA) compared to [DHB-]. One

1131

possible explanation for this enhancement is that the developed [DHB-]/N-MA and [DHB-

1132

]/N-EA matrixes possess higher absorbances, 0.555 and 0.538, respectively, than DHB

1133

(0.404) at a laser wavelength of 355 nm.

1134

Leipert et al. developed a method using an IL matrix for the detection of Pseudomonas

1135

aeruginosa virulence factors and bacterial communication molecules.182 The method

1136

consisted of a rapid DLLME procedure to isolate the compounds of interest followed by

1137

MALDI-MS analysis. A α-cyano-4-hydroxycinnamic acid/3-aminopentane matrix was

1138

synthesized and found to be the most efficient IL matrix for the analytes of interest. Once

1139

optimized, the method was used to detect three target molecules (2-heptyl-4(1H)-quinolone

1140

and 2-heptyl-3-hydroxy-4(1H)-quinolone) in clinical sputum samples from cystic fibrosis 51 ACS Paragon Plus Environment


1141

patients. Furthermore, quantification of the virulence factor pyocyanin formed by the Gram-

1142

negative bacterium Pseudomonas aeruginosa was achieved by using internal standards. In

1143

another study, an IL matrix was used to generate a high throughput matrix-enhanced

1144

secondary ion mass spectrometry (ME-SIMS) method for single cell profiling of neuronal

1145

cells.183 Abdelhamid et al. developed a series of IL matrixes by ultrasonication and applied

1146

them for the analysis of bacterial toxins without requiring any sample pretreatment.184 The

1147

use of these matrixes allowed for the efficient ionization of the toxins even in the presence

1148

of macromolecules.

1149

Shrivas et al. developed a DLLME method using an IL-matrix for the extraction and

1150

subsequent detection of phospholipids in soybean by MALDI-MS.185 A two-fold benefit was

1151

observed in using the IL as both matrix and extraction solvent, as the analytes were first

1152

preconcentrated and then efficiently ionized with the matrix. Kosyakov most recently

1153

employed IL matrixes for the analysis of lignin.186

1154

MALDI-MS is commonly used for the analysis and characterization of polymers. However,

1155

the analysis is often hindered by the lack of spot homogeneity which leads to irreproducible

1156

results. Gabriel et al. studied several IL matrixes for the analysis of polymers that possessed

1157

higher homogeneity than traditional matrixes.187 Furthermore, low laser power could be used

1158

while maintaining a high response, decreasing polymer fragmentation. In another study, the

1159

quantitative analysis of polyhexamethylene guanidine oligomers via MALDI-TOF was

1160

possible by using a 1‐methylimidazolium α‐cyano‐4‐hydroxycinnamate IL matrix.188 In this

1161

application, higher reproducibility was obtained when compared to an analogous

1162

α‐cyano‐4‐hydroxycinnamate matrix, likely due to improved spot homogeneity.


Page 52 of 99

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1163

The analysis of small molecules using MALDI-MS poses a challenge due to high background

1164

interference in the lower m/z region of the mass spectrum. Highly stable matrixes with low

1165

background are therefore highly desired for small molecule analysis. Liu et al. recently

1166

developed a hybrid material by immobilizing α‐cyano‐4‐hydroxycinnamate and (3-

1167

aminopropyl)triethoxysilane on a TiO2 surface.189 This matrix possessed a lower background

1168

than traditional α‐cyano‐4‐hydroxycinnamate matrixes while enhancing the signal for the

1169

studied analytes.

1170 1171

Ionic liquids as additives in electrospray ionization mass spectrometry

1172

Electrospray ionization (ESI) is a commonly used soft-ionization technique for the analysis

1173

of large biomolecules. A solution is flowed through a thin capillary in which a voltage is

1174

applied. This potential difference generates charged droplets to the entrance of the mass

1175

spectrometer that undergo evaporation to produce gas phase ions. The identification of

1176

compounds at the level of tissues and single-cells normally provide insufficient signal

1177

intensity in MS or high matrix interference, particularly when the low-intensity target signals

1178

overlap with high-intensity signals of other substances present in the cells. To overcome this

1179

limitation and improve the LODs in ESI-MS, drugs in the IL-form have been designed.

1180

Kucherov et al. synthesized a mitoxantrone-IL tagged conjugate and studied its cytotoxic

1181

behavior and detection using ESI-MS.190 By using the 1-decanoic-3-methylimidazolium

1182

[BF4-] ([(C9COOH)MIM+][BF4-]) IL as a tag, significant enhancement in the MS detection

1183

of the drug in cells was achieved. The ESI-MS sensitivity of the mitoxantrone-IL was an

1184

order of magnitude higher compared to the sensitivity of untagged mitoxantrone.

1185

Additionally, the mitoxantrone-IL was easily identified in the sample containing 53 ACS Paragon Plus Environment


1186

approximately 100 cells. This strategy has potential to be expanded to other drugs in order to

1187

easily quantify them in small amounts of cells.

1188

To overcome limitations in the low sensitivity of negative ion mode in ESI-MS, paired-ion

1189

electrospray ionization (PIESI) was developed.191,192 In PIESI, adduct formation is exploited

1190

by adding small quantities of polycationic species to form singly-charged complexes with

1191

negative species that can be detected using positive ion mode, greatly enhancing the

1192

sensitivity of the analysis.193

1193

Xu et al. discovered that the structure of the cationic species has significant effects on the

1194

ionization efficiency and sensitivity in ESI-MS.193 The ionization efficiency of a variety of

1195

anionic species was analyzed with either symmetrical or asymmetrical dicationic ILs. By

1196

introducing asymmetry into the dicationic IL structure, similar or lower detection limits were

1197

found for all but one of the studied compounds when compared to using highly symmetrical

1198

cationic species. The authors suggested that the difference in enhancement arises from the

1199

surface active nature of asymmetrical species that is not shared by their symmetrical

1200

counterparts.

1201

Lee et al. used dicationic-based IL pairing reagents for the detection of fatty acids with CE-

1202

MS.194 By using the N,N’-dibutyl 1,1’-pentylenedipyrrolidium-based IL, enhanced

1203

ionization efficiency was observed for the studied fatty acids, particularly short and medium

1204

chained fatty acids. Xu et al. evaluated a series of IL-based ion pairing reagents for the

1205

detection of sphingolipids.195 Up to a 4000-fold enhancement in LODs was observed for

1206

some of the studied analytes when PIESI was used instead of traditional ESI.

1207

Detecting drug metabolites is of significant interest in clinical and forensic applications. Guo

1208

et al. explored PIESI-MS for the detection of glucorinide and sulfate conjugates due to the 54 ACS Paragon Plus Environment

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1209

fact that their low ionization efficiency in negative ion mode is not ideal for trace level

1210

analysis.196 LODs in the low microgram per liter level were obtained, representing up to a

1211

48-fold improvement with respect to previously reported methods using negative ion mode.

1212

Furthermore, the use of asymmetric pairing reagents resulted in increased sensitivity for over

1213

half of the tested metabolites.

1214

PIESI has also been coupled with the single-probe, a surface microextraction sampling and

1215

ionization device, for MS imaging of biological tissues.197 A wide range of compounds were

1216

identified including adenosine monophosphate, which could not be observed in negative

1217

mode. A total of 1200 metabolites were identified using the dicationic reagent 1,5-

1218

pentanediyl-bis(1-butylpyrrolidinium)

1219

comparison

1220

tripropylphosphonium) fluoride ([C3(P3,3,3,H)22+]2[F-]) IL was used. In another study, the

1221

PIESI-Single probe capabilities were further expanded for single cell analysis.198 Figure 7

1222

shows typical phosphatidylglycerol (PG) mass spectra using traditional ESI-MS (Figure 7a),

1223

and PIESI-MS (Figure 7b and 7c). The formation of the IL-PG complex caused a mass shift

1224

that improved the resolution and resulted in a 28–200 fold improved signal intensity

1225

depending on the IL used as paired ion.

1226

Wang et al. utilized PIESI for the detection of N-blocked amino acids.199 Several polycationic

1227

ILs were studied as paired ions, including dicationic IL-based pyridinium and phosphonium,

1228

and tricationic and tetracationic phosphonium ILs. For the PIESI analysis, the amino acids

1229

were first functionalized with 9-fluorenylmethyl chloroformate. The LODs for the studied

1230

amino acids were 5–100 times lower when using PIESI than when performing the analysis

to

828

metabolites

fluoride identified

([C5(C4Pyr)22+]2[F-]) when


the

IL

reagent

in

1,5-propanediyl-bis(1-


1231

by traditional ESI in negative ion mode. Moreover, PIESI was easily compatible with both

1232

linear ion trap and triple quadrupole (QqQ) MS instruments.

1233

Santos et al. used PESI coupled with QqQ MS/MS for the quantification of anionic

1234

surfactants in water.200 Four different dicationic-based ILs containing imidazolium,

1235

phosphonium and pyrrolidinium cations were studied as ion pairing reagents. Among all, the

1236

[C3(P3,3,3,H)22+]2[F-] provided the lowest LODs for the majority of the tested analytes.

1237

Interestingly, similar or higher LODs were achieved using the selected reaction monitoring

1238

and single ion monitoring modes, possibly due to neutral/unknown fragmentation pathways

1239

that reduced the abundance of the monitored ion. The method was coupled with SPE and

1240

applied for the analysis of different water samples. Wastewater was found to contain the

1241

highest amount of anionic surfactants among the analyzed samples.

1242

Matrix effects are well known to be detrimental in analyses performed by LC-ESI-MS, often

1243

hindering quantification and reproducibility. Guo et al. exploited the ion-pairing capabilities

1244

of various dicationic-based ILs for the analysis of four anionic analytes from groundwater

1245

and urine.201 Severe matrix effects were observed when ESI-MS analysis was performed in

1246

the negative SIM mode. However, the addition of ILs significantly reduced the matrix effect

1247

in both of the studied matrixes. When using QqQ as a mass analyzer, slopes that were one to

1248

two orders of magnitude greater than negative ion mode were obtained with PIESI. In

1249

comparison, slopes obtained using a linear ion trap were lower.

1250

PIESI has also been applied for the study of dicamba (3,6-dichloro-2-methoxybenzoic acid)

1251

residues, a broad-spectrum herbicide, from raw agricultural commodities (RACs).202 The

1252

effect of the matrix on the ionization was studied using a post-connector infusion of the


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1253

standard, which showed minimal effects under the optimized method. Acceptable recoveries

1254

for the three studied analytes were obtained with RSD values ranging from 1-10%.

1255 1256

Electrochemical sensing systems

1257

ILs and PILs have been exploited in the field of electrochemistry for different analytical

1258

purposes due their excellent electrocatalytic properties including high chemical and thermal

1259

stability, high conductivity and wide electrochemical window. In particular, ILs have been

1260

used as electrolytes or as electrode devices in traditional carbon paste electrodes (CPE),

1261

glassy carbon electrodes (GCE) or screen-printed electrodes (ScPE). The main innovations

1262

in this topic within the past several years can be divided into five subsections: ILs as

1263

electrolyte media, IL/carbon-based composite electrochemical sensing systems, IL/metal-

1264

based composite electrochemical sensing systems, IL/hybrid carbon-metal-based composite

1265

electrochemical sensing systems, and biosensors based on ILs.

1266 1267

Ionic liquids as electrolyte media

1268

ILs have been studied in numerous electrochemical applications as electrolyte media due to

1269

their wide electrochemical potential windows compared to traditional electrolytes. These

1270

electrochemical properties, as well as the solubility of the ILs in different media, is highly

1271

dependent on the cation/anion combinations. Abu-Lebdeh et al. designed a new group of

1272

hydrophobic ILs based on amidinium cations.203 The highly-delocalized positive charge and

1273

long alkyl groups of the ILs enabled good miscibility in organic solvents. At the same time,

1274

they presented good ionic conductivities and electrochemical activity, overcoming the



1275

limitations of traditional electrolytes which are not soluble in non-polar media. Baldo et al.

1276

reported a new voltammetric/ amperometric method for the determination of oleic acid in

1277

olive oil samples.204 To bypass problems related to the low conductivity of the investigated

1278

samples, the olive oils were mixed with the [P6,6,6,14+][NTf2-] IL, which acted as a supporting

1279

electrolyte. More recently, Rizzo et al. used a dialkyl-1,1′-bibenzimidazolium IL as chiral

1280

additive to provide the enantiodiscrimination of N,N′-dimethyl-1-ferrocenyl-ethylamine in

1281

voltammetry experiments.205

1282

ILs have also allowed for electrochemical studies in non-polar mediums. Mousavi et al.

1283

investigated the electrochemical stabilities of several RTILs based on imidazolium,

1284

pyridinium, pyrrolidinium, piperidinium or quaternary ammonium cations with different

1285

alkyl substituents paired with [NTf2-], [BF4-] or [TfO-] anions.206 The authors found that the

1286

type and size of cation had a major effect on the electrolyte stability, viscosity and

1287

conductivity. Saturated cations with quaternary ammonium substituents generally provided

1288

the highest cathodic stabilities, whereas ILs with aromatic cations were less stable toward

1289

reduction. In addition, ammonium-based ILs offered potential windows much larger than

1290

imidazolium and pyridinium ILs.

1291

Using a unique approach, Joshi et al. reported a non-enzymatic H2O2 sensor.207 This sensor

1292

combined the synergistic effects of catalytically active Pt nanoparticles, the high surface area

1293

of MWCNTs, and the conducting characteristic of the 1-butyl-4-methylpyridinium

1294

hexafluorophosphate ([C4MPy+][PF6-]) IL to achieve high sensitivity for H2O2 oxidation in

1295

saliva samples. The use of IL significantly improved the sensitivity of the sensor by 40%.

1296

Moreover, the pyridinium hexafluorophosphate-based IL showed lower background currents

1297

without any heat pretreatment and was able to achieve lower detection limit. 58 ACS Paragon Plus Environment

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1298

Ionic liquid/carbon-based composite electrochemical sensing systems

1299

Different carbonaceous materials such as carbon nanotubes (CNTs),208,209 graphene,210-212

1300

and fullerene213 have been combined with ILs to improve the electrochemical properties of

1301

sensing systems. The carbonaceous materials are generally used as CPEs where the ILs are

1302

applied as binders due to their high solvation capacity, substituting for the conventional non-

1303

conductive binding liquids.214,215

1304

Chaiyo et al. prepared a ScPE using a composite consisting of nafion, graphene and 1-butyl-

1305

2,3-dimethylimidazolium tetrafluoroborate ([C4MMIM+][BF4-]) to determine zinc, cadmium

1306

and lead in water simples.216 The presence of the IL in the composite generated well-defined

1307

and enhanced redox peaks, which could be ascribed to the high ionic conductivity of the IL.

1308

Sanati et al. developed an IL/graphene quantum dot modified CPE.212 In this study, the

1309

[C4MIM+][PF6-] IL was used as a binder to increase the electrical conductivity of the

1310

electrode. As a result, good electron mediating behavior and separated oxidation signals of

1311

the analytes were achieved. A study published by Ueda et al. evaluated the electrochemical

1312

properties of fullerene C60 and C70 in ammonium- and pyrrolidinium-based ILs.213 The

1313

authors found that the cation, anion, as well as the chemical structure of the fullerene

1314

influenced the electrochemical band gaps of fullerene. Gomes et al. have developed different

1315

GCEs based on the [C4MIM+][PF6-] IL functionalized with multi-walled carbon nanotubes

1316

(MWCNTs).209 In this application, the electrochemical properties of the GCE were

1317

modulated based on the amount of IL. Therefore, the current signal increased two times for

1318

the MWCNT-[C4MIM+][PF6-]/GCE (1:10) when compared with the [C4MIM+][PF6-]/GCE,

1319

and 1.1 times higher than the MWCNT/GCE. In addition, the MWCNT-[C4MIM+][PF6-

1320

]/GCE presented enhanced electrochemical reactivity compared to the bare GCE, 59 ACS Paragon Plus Environment


1321

[C4MIM+][PF6-]/GCE and MWCNT/GCE. The high surface energy of the MWCNT was

1322

effectively appeased since they were surrounded by the ILs, providing π-π stacking and

1323

cation-π interactions.

1324 1325

Ionic liquid/metal-based composite electrochemical sensing systems

1326

IL/metal-based composite electrochemical sensing systems are obtained by the combination

1327

of a metal element with ILs and can be applied as CPE, GCE or ScPE. The metal is normally

1328

used either in its oxide form or as nanoparticles. The association of the metal and the IL

1329

contributes a large specific surface area, strong surface reactivity, high conductivity, an

1330

improvement of overpotentials, and an enhancement of response signal in cases where the

1331

composite is used for the fabrication of electrochemical nanosensors or nano-biocomposites.

1332

Gold nanoparticles have been electrodeposited onto the surface of a CPE modified with the

1333

1-butylpyridinium hexafluorophosphate ([C4Py+][PF6-]) IL to immobilize a thyroid

1334

stimulating hormone antibody (anti-TSH).217 In another approach, a CPE modified with CdO

1335

nanoparticles and the [C4MIM+][Br-] IL provided lower oxidation overpotential of vitamin

1336

C and a 5.0-fold increment in the oxidation current studied.218 A sensor constructed using

1337

CuFe2O4 nanoparticles and the 1,3-dipropylimidazolium bromide ([C3C3IM+][Br-]) IL

1338

provided a voltammetric sensor with high sensitivity and electrocatalytic activity.219 The

1339

electronic properties of CuFe2O4 together with the IL promoted charge transfer reactions

1340

when the composite was used as electrode. Regarding its long-term stability, the sensor

1341

response current was able to remain almost constant upon continuous 15 cyclic sweeps over

1342

the applied potential ranging from 0.0 to + 0.60 V and was able to be stored in refrigerator at

1343

4 °C for 30 days. In another study, ZnO and the [C4MIM+][BF4-] IL were added as modifiers 60 ACS Paragon Plus Environment

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1344

of a CPE, increasing the oxidation current of anticancer drugs.220 This system presented a

1345

sensitivity of 0.0284 μA·μM-1 and 0.0296 μA·μM-1 for doxorubicin and dasatinib,

1346

respectively. Using ZnO nanoparticles combined with the [C6MIM+][PF6-] IL, Karimi-Maleh

1347

et al. constructed a CPE to simultaneously determine isoprenaline and aspirin.221 The

1348

presence of ILs in CPE enhanced the peak currents and decreased the oxidation potential

1349

(decreasing the over potential).

1350 1351

Ionic liquid/hybrid carbonaceous-metal-based composite electrochemical sensing systems

1352

Some published works have been reported in the construction of hybrid systems for the

1353

fabrication of highly sensitive electrochemical sensors. These electrodes bring together the

1354

properties of ILs, metals and carbonaceous materials.

1355

Gold nanoparticles anchored to [C4MIM+][Br-] IL-functionalized GO have been reported for

1356

the determination of dopamine.222 In this system, the IL enhanced the conductivity of the

1357

electrode by preventing the agglomeration of GO. In another application, Cheraghi et al.

1358

described a CPE modified with cadmium oxide nanoparticles decorated with SWCNT

1359

(CdO/SWCNTs) and the [C3C3IM+][Br-] IL as binder between the two components.223 The

1360

developed CPE significantly enhanced the electro-oxidation signal of vanillin in food

1361

samples. Moreover, with this modification the sensitivity increased by ∼5 times with a ∼85

1362

mV reduction in overvoltage. In another study, a nanocomposite consisting of platinum-

1363

tungsten alloy nanoparticles, sheets of reduced GO and the [C4MIM+][Cl-] IL were deposited

1364

onto the surface of a GCE.224 The modified GCE exhibited excellent electrocatalytic activity

1365

towards the oxidation of NO with a strong peak at 0.78 V versus Ag/AgCl due to the

1366

synergistic effects of the electrode components. Damiri et al. described the development of 61 ACS Paragon Plus Environment


1367

a CPE modified with [C4MIM+][Cl-]/cobalt hexacyanoferrate nanoparticles.225 The presence

1368

of both cobalt hexacyanoferrate nanoparticles and the IL caused a decrease of the

1369

overpotential for the anodic oxidation of diclofenac and an increase in the rate of

1370

heterogeneous electron transfer.

1371

Other different IL/metal/carbonaceous material composites used as electrochemical systems

1372

include IL/cobalt nanoparticles/CNTs226 and IL/MgO/CNTs.227

1373 1374

Biosensors based on ionic liquids

1375

The electrochemical analysis of different compounds in biological samples is a major

1376

challenge. This is largely because target analytes are normally present at trace levels, and the

1377

matrix often contains endogenous compounds such as proteins, lipids, ions, and water that

1378

may interfere in the measurements. However, developments made in this area by combining

1379

ILs with different carbonaceous materials, metal or oxide nanoparticles in the traditional

1380

CPE, GCE, ScPE have improved the electrochemical response of these biosensors, allowing

1381

their application in complex matrices such as plasma, urine, tissues, blood, serum, and saliva.

1382

Table 3 summarizes a number of important examples that have employed IL-modified

1383

biosensors in numerous applications.208,210-212,217,219-221,224-238

1384

The 1-butyl-1-methylpiperidinium hexafluorophosphate ([C4MPip+][PF6-]) IL was applied in

1385

a GO/CD GCE to determine neurotransmitters in human urine samples.228 This electrode

1386

possessed good electron mobility, large surface area, and high ionic conductivity and

1387

stability. A hybrid IL/PtPd alloy nanoparticles/functionalized graphene paper electrode was

1388

fabricated and exhibited high selectivity and sensitivity in bio-catalytic processes and in real-


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1389

time tracking of hydrogen peroxide secretion by living human cells.239 The live cells

1390

maintained ∼90% viability after 4 h incubation using this electrochemical device, indicating

1391

that the hybrid electrodes possess high biocompatibility. El-Hady et al. reported two novel

1392

sensors based on human serum albumin (HSA)/IL and BSA/IL composites.229 These GCEs

1393

were used for the determination of vitamins B2, B6 and C in human plasma using analyte

1394

focusing by ionic liquid micelle collapse (AFMC). In this study, the [C8MIM+][PF6-] IL was

1395

used to prepare the electrode. An enhancement in vitamin stability was observed when this

1396

IL was used in the electrode above its critical micelle concentration due to the formation of

1397

complexes with IL micelles. An antibody–antigen based impedimetric immunosensor was

1398

fabricated by the immobilization of monoclonal HER2 antibody on a CPE composite based

1399

on gold nanoparticles/[C2MIM+][PF6-]/CNTs.230 The high conductivity of the IL significantly

1400

enhanced the sensitivity of the immunosensor, which was applied for low level detection of

1401

HER2 in serum samples of breast cancer patients. Another example of an electrochemical

1402

immunosensor was reported by Mazloum-Ardakani et al.234 In this study, a composite based

1403

on [C4MIM+][NTf2-]/fullerene-functionalized MWCNTs/antibody was successfully applied

1404

for detection of tumor necrosis factor α in serum samples for protein diagnostics and

1405

bioassays. The use of the IL promoted a more uniform composite film. In another approach,

1406

the [C4MIM+][PF6-] IL was used to modify the surface of a ScPE for the further

1407

electrodeposition of gold nanoparticles.235 The specific antibody for the electrochemical

1408

detection of Salmonella pullorum and Salmonella gallinaru was immobilized on gold

1409

nanoparticles. This IL-based bionsensor was compared with an analogous sensor based β-

1410

CB, sodium alginate, and chitosan. Among these four different modified electrodes, the

1411

activity of the antibody against bacteria was highest under IL modified conditions. In this

1412

case, the IL provided a friendly microenvironment for proteins while maintaining the 63 ACS Paragon Plus Environment


1413

biological activity of the antibody and enzyme. An IL/quantum dot fluorescence sensing

1414

array system was reported by Chen et al. for the discrimination of 8 proteins at 500 mmol·L-1

1415

in urine samples.240 The prepared IL/quantum dot conjugate was mixed with the sample

1416

containing the proteins, and fluorescence measurements were used for their determination.

1417

Among the different ILs, the [C4MIM+][Br-] IL provided the highest fluorescence.

1418

Molecularly imprinted polymer (MIP) electrochemical sensors exhibit high selectivity to

1419

determine analytes in complex matrixes. These materials possess specific molecular cavities

1420

that can mimic the shape of the target molecule, resulting in a surface with complementary

1421

chemical functionality to the target molecule.236 When ILs or PILs are used to prepare MIPs,

1422

the imprinted IL-polymer shows fast rebinding rates and high adsorption capacity for the

1423

target analyte.238 The 1,3-di(3-N-pyrrol-propyl)imidazolium bromide ([(PyrC3)2IM+][Br-])

1424

IL and neuron specific enolase were used as functional monomer and template, respectively,

1425

to fabricate an IL-MIP sensor. This sensor was able to determine neuronspecific enolase in

1426

the presence of human serum albumin, human immunoglobulin, hemoglobin, glycine, L-

1427

cysteine, L-histidine, and ascorbic acid at 0.1 ng mL-1. Additional IL-MIP modified based

1428

sensors were reported to determine diclofenac225 and ractopamine237 in urine samples. Wang

1429

et al. fabricated a MIP-hydrogel for the determination of Epididymis Protein 4 (HE4).241 The

1430

IL contained special moieties (amino, carboxyl groups, and the imidazolium cation) that

1431

resulted in active sites to interact with Epididymis HE4 by hydrogen bonding and

1432

electrostatic attractions, which enhanced the selectivity of the imprinted sensor. A MIP-

1433

electrochemical sensor was reported to recognize large molecules such bovine serum

1434

albumin.238 The authors used a reaction mixture consisting of 3-(3-aminopropyl)-1-

1435

vinylimidazolium tetrafluoroborate as functional monomer, N, N′-methylenebisacrylamide


Page 64 of 99

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1436

as crosslinker, ammonium persulfate and N,N,N′,N′-tetramethylethylenediamine as

1437

initiators, and BSA as template to produce the polymer. The synthesis was carried out in the

1438

presence of carboxyl functionalized MWCNTs, which acted as a support to coat the MIP.

1439 1440

Conclusions and perspective

1441

The unique features of ILs and corresponding derivatives continue to be exploited in many

1442

ways within all of the major fields of analytical chemistry. In sample preparation, ILs have

1443

been effectively used as solvents in liquid-phase (micro)extraction and as customizable

1444

sorbent materials in solid-phase (micro)extraction. In these applications, ILs often have been

1445

shown to exhibit better extraction performance than conventional solvents or commercially-

1446

available sorbent materials. TSILs, such as choline amino acids, have continued to show

1447

remarkable selectivity when used as extraction solvents. Over the last several years, studies

1448

demonstrating the use of MILs in a variety of platforms have increased dramatically and are

1449

expected to increase as fundamental studies provide insight into their ordering in magnetic

1450

fields. Additionally, it is expected that more efficient synthetic methods will continue to be

1451

reported describing the preparation of low viscosity solvents with high magnetic

1452

susceptibility.

1453

In chemical separations, ILs continue to be explored as unique selectivity stationary phases

1454

in one and two-dimensional GC. Continual efforts in further understanding the

1455

decomposition/volatilization of IL and PIL-based stationary phases is needed to assist in the

1456

design of more thermally-stable compounds. In HPLC and CE separations, ILs exhibit unique

1457

features that make them interesting additives and chiral selectors in chiral separations. An

1458

understanding of how ILs order on the nanoscale will further advance the field of separations 65 ACS Paragon Plus Environment


1459

science. In mass spectrometry, IL-based matrixes continue to be explored in MALDI-MS to

1460

enhance the ionization of large molecules, and as additives in PIESI-MS for increasing the

1461

sensitivity of the traditional ESI-MS in negative ion mode. New approaches that are capable

1462

of merging sample preparation with MALDI-MS using IL-based solvents/matrixes offer

1463

promise in decreasing sample preparation time and complexity.

1464

ILs have been also employed for the development of different electrodes, including CPE,

1465

GCE or ScPE. In particular, ILs have been added in carbonaceous, metal or hybrid

1466

composites for the development of a wide variety of electrochemical sensors and biosensors.

1467

Many of these studies have exploited the chemical tunability of ILs to design conductive

1468

solvents that can be incorporated into the function of the electrode. ILs will undoubtedly

1469

continue to be highly studied in electroanalytical chemistry, particularly in areas where their

1470

unique features can be exploited in chip-based platforms. Finally, this critical review

1471

highlights the numerous advances that ILs have made in biomolecule analysis, which has

1472

increased significantly over the past several years. As they continue to be explored in

1473

bioanalytical applications, IL solvents that are greener alternatives should be investigated.


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1474 1475


Author information Corresponding author

1476

Department of Chemistry, Iowa State University, 1605 Gilman Hall, Ames, IA, 50011, USA,

1477

E-mail: [email protected]

1478

Notes

1479

Biographies

1480

Jared L. Anderson is a Professor of Chemistry at Iowa State University. His research

1481

focuses on the development of stationary phases for multidimensional chromatography,

1482

alternative approaches for sample preparation, particularly in nucleic acid isolation and

1483

purification, and developing analytical tools for trace-level analysis within active

1484

pharmaceutical ingredients.

1485

María J. Trujillo-Rodríguez obtained her B.S. degree in chemistry in 2012, M.S. in

1486

research in chemistry in 2013 and Ph.D. in chemistry in 2017 in Universidad de La Laguna,

1487

Spain. She has worked as Postdoctoral Research Associate in Professor Anderson’s research

1488

group in Iowa State University since 2017. Her research interests include the development

1489

of new microextraction procedures using ionic liquids and derivatives for environmental and

1490

food analysis.

1491

He Nan completed his B.S. degree in chemistry at Heilongjiang University in China and

1492

M.S. degree in analytical chemistry at Kyung Hee University in Korea. He is currently a

1493

Ph.D. student in the Department of Chemistry at Iowa State University working under the

1494

supervision of Professor Anderson. His research focuses on developing new sample



1495

preparation methods, new stationary phases in chromatographic separations, and using

1496

comprehensive two-dimensional gas chromatography in the resolution of complex samples.

1497

Marcelino O. Varona obtained his B.S. degree in chemistry and biology at Concordia

1498

University in 2016. He is currently a Ph.D. student in the Department of Chemistry at Iowa

1499

State University working under the supervision of Professor Anderson. His research focuses

1500

on the use of polymeric ionic liquids and solid-phase microextraction for bioanalytical

1501

applications.

1502

Miranda N. Emaus obtained her B.S. degree in chemistry and forensic chemistry at Lake

1503

Superior State University in 2016. She is currently a Ph.D. student in the Department of

1504

Chemistry at Iowa State University working under the supervision of Professor Anderson.

1505

Her research involves the use of magnetic ionic liquid for achieving sequence selective DNA

1506

extraction.

1507

Israel D. Souza received his B.S. and M.S. degree at University of Sao Paulo, Brazil, in 2013

1508

and 2015, respectively. He is currently a Ph.D. student at University of Sao Paulo working

1509

under Professor Maria Eugênia Queiroz; in 2018, he spent 6 months as a visiting Ph.D.

1510

student at Iowa State University in the laboratory of Professor Anderson. His research

1511

focuses on development of selective and innovative materials including ionic liquids,

1512

polymeric ionic liquids, molecularly imprinted polymer, and restricted access materials to

1513

apply as stationary phases in gas chromatography and as sorbents in microextraction

1514

techniques.


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1916

Figure Captions

1917

Figure 1.

1918

derivatives.

1919

Figure 2.

1920

after PIL-SPME for the determination of acrylamide in (A) in-solution brewed coffee spiked

1921

with 100 g·L-1, and (B) brewed coffee un-spiked (pink) and spiked with 50 g·L-1 (blue)

1922

and 100 g·L-1 (black). Reprinted from J. Chromatogr. A, Vol. 1459, Cagliero, C.; Nan, H.;

1923

Bicchi, C.; Anderson, J. L. Matrix-compatible sorbent coatings based on structurally-tuned

1924

polymeric ionic liquids for the determination of acrylamide in brewed coffee and coffee

1925

powder using solid-phase microextraction, pp. 17–23 (ref 41). Copyright 2018, with

1926

permission from Elsevier.

1927

Figure 3.

1928

using the IL-ABS based on tetrabutyltetradecylphosphonium chloride ([P4.4.4.14+][Cl-]) and

1929

HCl. Reproduced from Ionic-liquid-based acidic aqueous biphasic systems for simultaneous

1930

leaching and extraction of metallic ions, Gras, M.; Papaiconomou, N.; Schaeffer, N.; Chainet,

1931

E.; Tedjar, F.; Coutinho, J. A. P.; Billard, I. Angew. Chem. - Int. Ed., Vol. 57, Issue 6 (ref

1932

94), Copyright 2018 Wiley.

1933

Figure 4.

1934

based GC stationary phases of the Watercol series. The CLP oil was analyzed using the

1935

following IL-based GC stationary phases: Watercol 1460 at 70 ºC (A), Watercol 1900 at 70

1936

ºC (B), and Watercol 1910 at 150 ºC (C). The transformer oil (RM 8506a) was analyzed

1937

using the followed IL-based GC stationary phases: Watercol 1460 at 50 ºC (D), Watercol

1938

1900 at 50 ºC (E), and Watercol 1910 at 50 ºC (F). Reproduced from Frink, L. A.; Armstrong,

Chemical structures of the major cations and anions that compose ILs and IL

GC-MS chromatogram in the selected ion monitoring (SIM) mode obtained

Influence of the extraction temperature in the separation of Co2+ and Ni2+ ions

Representative chromatograms of the determination of water in oil using IL-



1939

D. W. Anal. Chem. 2016, 88, 8194–8201 (ref 137). Copyright 2016 American Chemical

1940

Society.

1941

Figure 5.

1942

obtained using the SLB-IL111i stationary phase in the first dimension combined with

1943

different IL-based stationary phases in the second dimension: (a) SLB-IL76, (b) SLB-IL60,

1944

and (c) SLB-IL59. The conventional SLB-IL111/SLB-IL59 column set was included for

1945

comparison in (d). Reprinted by permission from Springer Nature GmbH: Springer Nature,

1946

Anal. Bioanal. Chem., Ionic liquid phases with comprehensive two-dimensional gas

1947

chromatography of fatty acid methyl esters, Pojjanapornpun, S.; Nolvachai, Y.; Aryusuk, K.;

1948

Kulsing, C.; Krisnangkura, K.; Marriott, P. J. (ref 143). Copyright 2018 Springer.

1949

Figure 6.

1950

a traditional matrix based on 2,5-dihydroxybenzoate (DHB, on the top), and IL-based

1951

matrixes (2,5-dihydroxybenzoate/N-methylaniline, DHB/N-MA, at the middle, and 2,5-

1952

dihydroxybenzoate/N-ethylaniline, DHB/N-EA, at the bottom). The mass spectra were

1953

acquired in reflectron mode. The analyzed sample was 0.5 mL of solution (before drying)

1954

containing 10 pmol of the analyte. The degrees of polymerization were annotated with red

1955

dashed line. Reprinted from Anal. Chim. Acta, Vol. 985, Zhao, X.; Shen, S.; Wu, D.; Cai, P.;

1956

Pan, Y. Novel ionic liquid matrices for qualitative and quantitative detection of carbohydrates

1957

by matrix assisted laser desorption/ionization mass spectrometry, pp. 114–120 (ref 181).

1958

Copyright 2017, with permission from Elsevier.

1959

Figure 7.

1960

metabolites (phosphoethanolamines, PEs, and phosphatidylglycerols, PGs) in single cells.

1961

(a) Mass spectra obtained after ESI-MS: the [PG (34:1) + Na]+ (771.5152 m/z) is

Representative contour plots of the separation of a 37 FAME mix in GC × GC

MALDI-TOF spectra of the polysaccharides D2000 (A) and D4000 (B) using

Comparison between ESI-MS and PIESI-MS for the determination of


Page 80 of 99

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1962

indistinguishable from a 13C isotopic peak of [PE(P-38:6) + Na]+ (771.5125 m/z). (b) Mass

1963

spectra obtained after PIESI-MS, showing the [PG (34:1) − H +[C5(C4Pyr)22+]]+ (1071.8672

1964

m/z) peak. (c) Mass spectra obtained after PIESI-MS, showing the [PG (34:1) − H +

1965

[C3(P3,3,3)22+]]+ (1109.8389 m/z) peak. PE(P-38:6) was detected [C43H74NO7P+Na]+

1966

(771.5125 m/z) in (b) and (c) using the dicationic compounds (not shown). [C5(C4Pyr)22+] is

1967

the 1,5-pentanediyl-bis(1-butylpyrrolidinium) cation, and [C3(P3,3,3)22+] is the P,P’-propyl-

1968

bis(tripropylphosphonium) cation. Reproduced from Pan, N.; Rao, W.; Standke, S. J.; Yang,

1969

Z. Anal. Chem. 2016, 88, 6812–6819 (ref 198). Copyright 2016 American Chemical Society.

1970


Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

Table 1.

Page 82 of 99

Representative microextraction procedures based on the use of magnetic ionic liquids (MILs).

Analytes

Sample

Extraction procedurea Dispersive liquid-liquid microextraction PAHs Water and DLLME tea infusion Pharmaceutical drugs, phenolics, insecticides, and PAHs UV filters

Water

DLLME

Water

SBDLME

Sequence specific DNA

Cell lysate

DLLME

Sequence specific DNA

Cell lysate

DLLME

-

DLLME

Escherichia Coli K12 Estrogens

Urine

DLLME

Organic pollutants

Water

DLLME

DNA

Plasma

DLLME

Extraction materialb

Analytical techniquec

LODd (µg·L1)

RSDe (%)

Ref.

[N8,8,8,B+][FeBrCl3-]g, [N8,8,8,MOB+][FeBrCl3-], or [(BBnIM)2C122+][NTf2,FeCl3Br-] [P6,6,6,14+]2[MnCl42-]g, [N1,8,8,8+]2[MnCl42-] or [Aliquat+]2[MnCl42-] [P6,6,6,14+][Dy(hfacac)4-], [P6,6,6,14+][Co(hfacac)3-], or [P6,6,6,14+][Ni(hfacac)3]g + [P6,6,6,14 ][Mn(hfacac)3-]

HPLC-FD

0.005–0.02

1.0–13

(72)

HPLC-UV

0.25–1.00

6.1-19.6

(73)

TD-GC-MS

0.01–0.03

1.4–15

(74)

HPLC-UV and qPCR HPLC-UV and qPCR

-

-

(75)

-

-

(76)

Cell culture and qPCR

100 CFU mL-

7–12.5

(77)

HPLC-UV

2

4.7–19

(78)

HPLC-UV

0.05–1.0

0.3–17

(79)

qPCR

-

8.5–12.8

(80)

[P6,6,6,14+][Co(hfacac)3-]g or [P6,6,6,14+][Ni(hfacac)3] [P6,6,6,14+][Ni(hfacac)3-]g, [P6,6,6,14+][Co(hfacac)3-], [P6,6,6,14+][Dy(hfacac)4-], [P6,6,6,14+]2[MnCl42-] or [Aliquat+]2[MnCl42-] [P6,6,6,14+]2[MnCl42-]g, or [Aliquat+]2[MnCl42-] [P6,6,6,14+][Ni(hfacac)3-]g, [P6,6,6,14+][Co(hfacac)3-],

1


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[P6,6,6,14+][Dy(hfacac)4-], or [P6,6,6,14+][Mn(hfacac)3-]

Single-drop microextraction DNA Cell lysate

DI-SDME

[P6,6,6,14+][Ni(hfacac)3-], [P6,6,6,14+][Co(hfacac)3-]

LAMP and IMSA

Organic pollutants

Water

HS-SDME

HPLC-UV

Free fatty acids

Milk

Vacuum HS-SDME

Chlorobenzenes DNA

Water Plasma

HS-SDME DI-SDME

[P6,6,6,14+]2[MnCl42-]g, or [Aliquat+]2[MnCl42-] [P6,6,6,14+]2[MnCl42-], [Aliquat+]2[MnCl42-], [P6,6,6,14+][Mn(hfacac)3]g, or [P6,6,6,14+][Dy(hfacac)4-] [C2MIM+]2[Co(NCS)42-] [P6,6,6,14+][Ni(hfacac)3-]g, [P6,6,6,14+][Co(hfacac)3-], [P6,6,6,14+][Dy(hfacac)4-], or [P6,6,6,14+][Mn(hfacac)3-]

203–2030 copies per reaction 0.04–1.0

-

(81)

2.3–15

(79)

HSD-GCMS

14.5–21

2.5–13

(82)

TD-GC-MS qPCR

0.004–0.008 -

3–18 8.5–12.8

(83) (80)

Aqueous biphasic system Chloramphenicol Water ABS [TMG+][TEMPO-SO3-]h HPLC-UV 0.14 2.42–4.45 (84) a Abbreviations: ABS for aqueous biphasic system, DLLME for dispersive liquid-liquid microextraction, HS-SDME for headspace single-drop microextraction, vacuum HS-SDME for headspace single-drop microextaction under reduced pressure conditions, DISDME for direct immersion-drop microextraction, and SBDLME for stir-bar dispersive liquid microextraction. b IL abbreviations: Cations: [Aliquat+] for trioctylmethylammonium, [(BBnIM)2C122+] for 1,12-di(3+ + benzylbenzimidazolium)dodecane, [C2MIM ] for 1-ethyl-3-methylimidazolium, [N1,8,8,8 ] for trioctylmethylammonium, [N8,8,8,B+] for benzyltrioctylammonium, [N8,8,8,MOB+] for methozylbenzyltrioctylammonium, [P6,6,6,14+] for trihexyltetradecylphosphonium, and [TMG+] for 1,1,3,3-tetramethylguanidine Anions: [Co(hfacac)3-] for tris(hexafluoroacetylaceto)cobaltate(II), [Co(NCS)42-] for tetraisothiocyanatocobaltate (II), [Dy(hfacac)4] for tetra(hexafluoroacetylaceto)dysprosate(III), [FeBrCl3-] for bromotrichloroferrate(III), [MnCl42-] for tetrachloromanganate(II),



Page 84 of 99

[Mn(hfacac)3-] for tris(hexafluoroacetylaceto)manganate(II), [Ni(hfacac)3-] for tris(hexafluoroacetylaceto)nickelate(II), [NTf2-] for bis[(trifluoromethyl)sulfonyl]imide, and [TEMPO-OSO3-] for 2,2,6,6-tetramethylpiperidine. c Abbreviations: FD for fluorescence detection, GC for gas chromatography, HPLC for high-performance liquid chromatography, HSD for headspace desorption, IMSA for isothermal multiple-self-matching-initiated amplification, LAMP for loop-mediated isothermal amplification, MS for mass spectrometry, qPCR for quantitative polymerase chain reaction, TD for thermal desorption, and UV for ultraviolet detection. d Limit of detection. e Relative standard deviation. g Selected as optimum MIL. h Molecularly imprinted polymer based on a MIL monomer.


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Table 2.

Representative applications involving the use of ILs in either the mobile phase or the stationary phase of LC applications.

Analyte / Mobile phasea Sample ILs as mobile phase additives Mandelic acid, Methanol: [(CH2O+ vanilmandelic acid, and Men)C5IM ][Cl ] aqueous solution phenyllactic acid/ (10:90, v/v) Auxinic herbicides/ Acetonitrile: 5 mmol·L-1 [(MIM)2C82+]2[BF4-] aqueous solution at pH 3 (300:7, v/v) Quaternary alkaloids/ Herbal solutions and tablets Hg2+, methylmercury and ethylmercury/ Sea food, yeast and garlic Metabolites/ Human plasma

Acetonitrile: 1% DESe aqueous solution at pH 3.3 (32:68, v/v) Methanol: [C8MIM+][Cl-] in 0.1 mol·L-1 NaCl and 0.02 mol L-1 citric/citrate buffer, pH 2.0 (99.6:0.4) Acetonitrile: water: [C2MIM+][BF4-] (50:50:1.5, v/v)

ILs as components of the stationary phase Flavonoids, nucleosides Acetonitrile: 10 mmol·L-1 and amino acids/ ammonium formate aqueous solution (90:10, v/v), gradient Soybeans, urine elution

Stationary phasea (dimensions)

Separation modeb

Analytical techniquec

LODd (µg·L-1)

Ref.

Astec Chirobiotic T column (150 mm L × 4.6 mm ID × 5 µm) Kromasil ODS C18 column (250 mm L × 4.6 mm ID × 5 µm) ODS C18 column (150 mm L × 4.6 mm ID × 5 µm) Hypersil GOLD aQ C18 column (150 mm L × 4.6 mm ID)

Chiral

HPLC-DAD

-

(152)

RP

HPLC-UV

-

(153)

RP

HPLC-UV

6–20

(154)

RP

HPLC-CVAFS

0.05–0.11 (155)

Silica gel F254 60RP-18 glass plate (20 cm × 10 cm)

RP

HPTLC-De

0.18–0.39 (156) µg·spot-1

SCIL amidefunctionalized based on [V(AcNH2)IM+][Br] column (150 mm L × 3 mm ID × 5 µm)

IEC / HILIC

HPLC-MS

-

(157)



-nitroethanol, aromatic alcohols, mandelic acid derivatives, amino acids, ferrocenes, and drugs Non-steroidal antiinflammatory drugs, nucleobases- nucleotides mixtures, and alkaloidsglycosides mixtures/ Cortex phellodendri extract

Anilines, phenols, and PAHsg/ -

Alkaloids, glycosides, aromatic acids and amino acids -

Chiral -CDf silica confined modified with pyridinium column based ILs (250 mm L × 4.6 mm ID × 5 µm) Acetonitrile: ammonium formate SCIL γaqueous solution (50:50, v/v), glycidoxypropylgradient elution functionalized zwitterionic IL with quaternary ammonium and sulfonate groups column (150 mm L × 2.1 mm ID × 5 µm) Methanol: water (different Graphene quantum compositions depending on the dot silica confined group of analytes) column modified with [(C2NH2)MIM+][Br] (250 mm L × 4.6 mm ID × 5 µm) Acetonitrile: ammonium acetate Graphene quantum (different compositions depending dot silica confined on the group of analytes) column modified with [(C2NH2)MIM+][Br] Methanol: water (50:50, v/v)

Page 86 of 99

RP

HPLC-UV

-

(158)

RP and HILIC

HPLC-UV

-

(159)

RP

HPLC-UV

-

(160)

HILIC

HPLC-UV

-

(160)


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(250 mm L × 4.6 mm ID × 5 µm) (250 mm L × 4.6 mm ID × 5 µm) Alkylbenzenes and Acetonitrile:water (70:30, v/v) POSMh hybrid RP Nano-LC(161) amides monolith modified UV with L-Cys and [VC4IM+][Br-] (100 µm ID) Glycoproteinnon0.1% trifluoroacetic acid in POSMh hybrid Mixed Nano-LC(161) glycoprotein mixtures, acetonitrile: 0.1% trifluoroacetic monolith modified mode UV and TARG1 protein/ acid in water, gradient elution with L-Cys and [VC4IM+][Br-] (100 µm ID) a IL abbreviations: Cations: [(CH O-Men)C IM+] for 1-[(1R,2S,5R)-(−)-menthoxymethyl]-3-pentylimidazolium, [C MIM+] for 22 5 2 ethyl-3-methylimidazolium, [(C2NH2)MIM+] for 1-aminoethyl-3-methylimidazolium, [C8MIM+] for 1-octyl-3-methylimidazolium, [(MIM)2C82+] for 1,12-di(3-methylmidazolium)octane, [V(AcNH2)IM+] for 1-vinyl-3-acetamideimidazolium, and [VC4IM+] for 1vinyl-3-butylimidazolum. Anions: [BF4-] for tetrafluoroborate, [Br-] for bromide, and [Cl-] for chloride. b Abbreviations: Chiral: chiral separation, HILIC: hydrophilic interaction liquid chromatography, and RP: reversed-phase. c Abbreviations: CV-AFS: cold vapor atomic fluorescence spectrometry, DAD: diode array detection, De: densitometry, HPLC: highperformance liquid chromatography, HPTLC: high performance thin layer chromatography, MS: mass spectrometry, Nano-LC: nano-liquid chromatography, and UV: ultraviolet detection. c Limit of detection. e Choline chloride as hydrogen bond acceptor and ethylene glycol as hydrogen bond donor, mixed in a 1:3 molar ratio. f -Cyclodextrin. g Polycyclic aromatic hydrocarbons. h Polyhedral oligomeric silesquioxane methacrylate.



Table 3.

Page 88 of 99

Representative IL-modified electrochemical biosensors to determine different compounds in biological samples.

Analyte Glassy Carbon Electrodes Ascorbic acid, dopamine and uric acid Glycoprotein hormone Nitric oxide Anti-hepatitis C drugs Neurotransmitters Vitamins B2, B6 and C Carbon Paste Electrodes 6-Mercaptopruine, 6thioguanine and dasatinib (anticancer drugs) Levedopa Thyroid stimulating hormone Adrenaline Doxorubicin and dasatinib Tramadol HER2 (enzyme)

Sample

ILa

LODb (µg·L-1)

Ref.

Urine

[C3MIM+][Cl-]

1760, 765, and 5 3.5·10-4 c 3.9

(210)

Serum Serum and urine Blood serum Urine Plasma

[C8MIM+][BF4-] [C4MIM+][Cl-] [C4MPip+][PF6-]

0.24

(226)

0.002 500–1000

(228) (229)

Urine

[C4MIM+][PF6-]

IL/Pt/carbon nanotubes

1.4, 8.4, and 488

(208)

Serum and urine Serum Urine Serum

[C4MIM+][PF6-]

IL/graphene quantum dots

2.7

(212)

[C4Py+][PF6-] [C3C3IM+][Br-] [C4MIM+][BF4-]

IL/nanogold/antibody IL/CuFe2O4 nanoparticles IL/ZnO nanoparticles

(217) (219) (220)

[C3C3IM+][Br-] [C2MIM+][PF6-]

IL/MgO/carbon nanotubes IL/Au nanoparticles / nanotubes

0.10 13 4887 and 244 2.1 10

Urine Serum

[C4MPip+][PF6-] [C8MIM+][PF6-]

Biosensor Graphene/IL Graphene/chitosan/IL IL/Pt and W nanoparticles anchored to reduced graphene oxide IL/multi-walled carbon nanotubes/cobalt nanoparticles IL/cyclodextrin IL/human serum albumin, and IL/bovine serum albumin

carbon

(211) (224)

(227) (230)

Screen Printed Electrodes


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Diclofenac

Urine

[C4MIM+][Cl-]

Uric acid and dopamine Hepatitis C virus

Urine Serum

[C4MIM+][BF4-] [C8MIM+][BF4-]

Thiocyanate

Saliva

[C10C10IM+][Br-]

Isoprenaline and aspirin

Urine

[C6MIM+][PF6-]

Factor α antigen (biomarker tumor necrosis)

Serum

[C4MIM+][NTf2-]

Salmonella pullorum and Salmonella gallinarum

Eggs and chicken meat

Molecularly Imprinted Materials Neuronspecific enolase Serum

Ractopamine

Urine

[C4MIM+][PF6-]

[(C3SH)VIM+][ BF4-] as MIL template and [(PyrC3)2IM+][Br-] as crosslinker [C4Py+][PF6-]

IL/cobalt hexacyanoferrate nanoparticles modified multi-walled carbon nanotubes IL/carbon nanotubes IL/nafion/TiO2

Screen-printed electrodes with IL solid-state ZnO/IL IL/fullerene-functionalized multiwalled carbon nanotubes/antibody IL/Au nanoparticles /antibody

MIP-PIL/PIL/GCE

89

(225)

24 and 29 2.5·10-5

(231) (232)

174

(233)

63.3 and 126

(221)

5·10-3

(234)

1x104 cfu · mL−1

(235)

2.6·10-3

(236)

MIP-PIL/gold 126 (237) nanoparticles/graphene Bovine serum albumin Milk [(NH2C3)VIM+][PF6-] MIP-PIL/ carboxyl functionalized 99 (238) multi-walled carbon nanotubes a IL abbreviations: Cations: [C C IM+] for 1,3-dipropylimidazolium, [C C IM+] for 1,3-didecylimidazolium, [C MIM+] for 1-ethyl3 3 10 10 2 3-methylimidazolium, [C3MIM+] for 1-propyl-3-methylimidazolium, [(C3SH)VIM+] for 1-(3-mercaptopropyl)-3-vinylimidazolium, [C4MIM+] for 1-butyl-3-methylimidazolium, [C6MIM+] for 1-hexyl-3-methylimidazolium, [C4MPip+] for 1-butyl-1methylpiperidinium, [C4Py+] for 1-butylpyridinium, [C8MIM+] for 1-octyl-3-methylimidazolium, [(NH2C3)VIM+] for 3-(3aminopropyl)-1-vinylimidazolium, and [(PyrC3)2IM+] for 1,3-di(3-N-pyrrolpropyl)imidazolium. 89 ACS Paragon Plus Environment


Page 90 of 99

Anions: [BF4-] for tetrafluoroborate, [Br-] for bromide, [Cl-] for chloride, [NTf2-] for bis[(trifluoromethyl)sulfonyl]imide, and [PF6] for hexafluorophosphate. b Limit of detection. C Milli-international units per milliliter.


Page 91 of 99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47


(A) Cations

(B) Anions

Imidazolium

Pyrrolidinium

Pyridinium

+

+

+

Bis[(trifluoromethyl)sulfonyl]amine

Alkylsulphonate

–

Triflate

–

Chloride

–

Cl

–

Bromide [R1R2IM+] Benzimidazolium

+

[NTf2

[R1R2Pyr+]

[R1Py+]

Ammonium

Phosphonium

+

–]

[RSO3

Tetrafluoroborate

+

–]

[CF3SO3

Hexafluorophosphate

–

–

–]

or

[TfO –]

[R1R2BIM ]

+

[NR1,R2,R3,R4 ]

F C2F5

P

–

[PR1,R2,R3,R4 ]

+

Guanidinium

+

Paramagnetic anions Tetrachloroferrate(III)

Tetrachloromanganate(II)

Cl

Cl [R1R2Pip+]

[(R1R2)(R3R4)(R5R6)Gu+]

F [FAP –]

[PF6–]

Choline

+

C2F5

C 2F 5

+

[BF4–] Piperidinium

–

Tris(pentafluoroethyl)trifluorophosphate

F +

Br

[Ch+]

Fe Cl

– Cl Cl

[FeCl4–]

Mn Cl

Tris(hexafluoroacetylaceto)manganate(II)

–

2– Cl Cl

[MnCl42–]

[Mn(hfacac)3 –]

Figure 1



Page 92 of 99

Figure 2


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Figure 3



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Figure 4


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Figure 5


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Figure 6



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Figure 7


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299x168mm (200 x 200 DPI)

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Advances of Ionic Liquids in Analytical Chemistry - ACS Publications

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