New Low-Toxicity Cholinium-Based Ionic Liquids ... - ACS Publications

Research Article pubs.acs.org/journal/ascecg

New Low-Toxicity Cholinium-Based Ionic Liquids with Perfluoroalkanoate Anions for Aqueous Biphasic System Implementation David J. S. Patinha,† Liliana C. Tomé,† Catarina Florindo,† Hugo R. Soares,†,‡ Ana S. Coroadinha,†,‡ and Isabel M. Marrucho*,† †

Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. República, 2780-157 Oeiras, Portugal iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal

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‡

S Supporting Information *

ABSTRACT: This work explores the widening of properties of cholinium-based ionic liquids (ILs) through their combination with perfluoroalkanoate anions so that higher number of aqueous biphasic systems (ABSs) containing nontoxic cholinium-based ILs is available. For that purpose, six cholinium perfluoroalkanoate ILs were synthesized and their cytotoxicity was evaluated using three different animal cell lines, envisaging biotechnology applications. Ternary phase equilibrium data for ABSs composed of the cholinium perfluoroalkanoate, with fluoroalkyl chains from C2 up to C7, using a strong salting out agent, K3PO4, were determined at 25 °C. The results show the relevant role of the size of fluorinated alkyl chain length in the anion since, contrary to other ABSs containing ILs with increasing alkyl chain length in the anion, the ABSs with cholinium perfluoroalkanoates present well-spaced solubility curves, allowing the conclusion that these ABSs can be tuned by a proper choice of the IL. The phase splitting mechanism was also disclosed through water activity measurements. KEYWORDS: Aqueous biphasic systems, Cholinium perfluoroalkanoate ionic liquids, Cytotoxicity and biocompatibility, Phase diagrams, K3PO4

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INTRODUCTION Ionic liquids (ILs) have emerged as a new class of compounds, whose properties can be fine-tuned by the appropriate combination of cations and anions with specific functional groups allowing their advantageous application in a wide range of fields.1−3 Due to their almost null vapor pressure,4 ILs are usually looked upon as green solvents.5 However, and although they do not enter the atmosphere, not all ILs are intrinsically green. In order to avoid negative effects, the development of cholinium-based ILs, combining the cholinium cation and anions derived from natural compounds, in particular those prepared from carboxylic acids and amino acids, has received considerable attention in the past few years for diverse applications.6−11 Ohno’s group published a series of cholinium carboxylate ILs,12 prepared by a two-step anion exchange reaction, the so-called bio-ILs, completely obtained from naturally derived compounds. After this publication, the properties of this family of ILs have been widely studied, from their thermophysical properties13−15 and behavior in water16−18 to their toxicity,19−22 biodegradability,19,22 and biocompatibility.19 Due to ever more restrictive environmental laws, and the large costs usually attributed to separation and purification © 2016 American Chemical Society

processes, the use of ILs to implement aqueous biphasic systems (ABSs) has attracted high interest since they were proposed in 2003.23 Typically, an ABS consists in two aqueous rich phases that can be formed by polymer + polymer, polymer + salt, or salt + salt combinations, and nowadays, ABSs formed by IL + salt, IL + polymer, and IL + salt + polymer have also been explored. Cholinium-based ILs were introduced as constituents of ABSs by Liu et al.24 who combined cholinium cations with different carboxylate anions such as lactate, glycolate, butyrate, formate, propionate, benzoate, oxalate, citrate, and acetate along with poly(propylene glycol) 400 (PPG400). The nontoxic and biodegradable characteristics of both cholinium-based ILs and PPG400 allowed the implementation of a green separation system specially designed to be used in the separation and purification of biological material, such as proteins. Moreover, and making use of the thermoreversible behavior of PPG aqueous solutions, changes in temperature allow the recovery and reuse of the polymer. Since then, ABSs based on other cholinium-based ILs and salts Received: January 27, 2016 Revised: March 24, 2016 Published: April 5, 2016 2670

DOI: 10.1021/acssuschemeng.6b00171 ACS Sustainable Chem. Eng. 2016, 4, 2670−2679

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ACS Sustainable Chemistry & Engineering

Figure 1. Synthetic pathway and chemical structures of the prepared cholinium-based ionic liquids ([Ch][X]) with the perfluoroalkanoate anions: (a) trifluoacetate ([TFAc]−), (b) perfluoropropanoate ([PFProp]−), (c) perfluorobutanoate ([PFBut]−), (d) perfluoropentanoate ([PFPent]−), (e) perfluorohexanoate ([PFHex]−), and (f) perfluoroheptanoate ([PFHept]−).

inorganic salts. Finally, it was found that the phase splitting mechanism of these PPG containing systems is different from that observed for IL + inorganic salt, since the IL acts as the salting out agent and therefore the most hydrophilic IL gives origin to larger biphasic region, due to its highest hydration capacity. In this line, Mourão et al.28 studied ABS of choliniumbased ILs with PEG600 and PEG4000. Cholinium cation combined with conjugated basis of diacids (oxalate, malonate, succinate, L-malate, fumarate, glutarate) and triacids (citrate) were tested and the authors referred their inability to promote ABS with K3PO4, due to their high hydration capacity, measured through the IL water activity. Recently, Taha et al.29 prepared ILs based on cholinium cation combined with anions derived from good’s buffers anions (2-(N-morpholino) ethanesulfonate (MES), N-[tris(hydroxymethyl)methyl] glycinate (tricine), 2-cyclohexylamino) ethanesulfonate (CHES), 2[4-(2-hydroxyethyl) piperazin-1-yl] ethanesulfonate (HEPES), and 2-[(2-hydroxy-1,1-[bis(hydroxymethyl)ethyl)amino] ethanesulfonate) (TES)). The ability to implement an ABS with these ILs and PPG400 was investigated, and the resulting ABSs were successfully applied to the extraction and purification of immunoglobulin Y from egg yolk. In a recent work, Á lvarez et al.30 showed that it is possible to perform ABS using nonionic surfactants and a choline based salt. In this work, choline chloride was used to determine the respective ABS at different temperatures and, the higher the temperature the higher the immiscibility between the components.

or polymers have been approached to implement versatile extractive schemes. Regarding inorganic salts, potassium phosphate (K3PO4) is the most used due to its kosmotropic nature.25 Cholinium-based IL ABSs with K3PO4 were reported by Shahriari et al.,26 where the authors combined the cholinium cation with levulinate, glutarate, acetate, salicylate, and succinate anions and showed that the mechanism of phase splitting of the proposed systems is similar to that observed for ABSs of other families of ILs with inorganic salts. That is, the lower the affinity of the IL for water, the higher the capacity to promote phase splitting. Consequently, the hydrophilic nature of cholinium-based ILs hinders their use in ABS with other weaker salting out salts. To overcome this disadvantage, several authors studied cholinium-based IL ABSs using polymers such as poly(ethylene glycol) (PEG) or PPG as phase splitting agents. For example, Liu et al.27 studied ABSs composed of PPG400, PPG1000, or poly(ethylene glycol)-block-poly(propylene glycol)-poly(ethylene glycol) (EO10PO90), and cholinium-based ILs, such as cholinium glycolate, cholinium propanoate, cholinium lactate, and choline chloride. The effect of polymer molecular weight, temperature, and anion structure was investigated. The results showed that the polymer with the highest molecular weight presents the best phase forming ability, which can be explained by its increased hydrophobicity. In what concerns the temperature effect on the phase splitting behavior, for all studied cholinium-based ILs, the biphasic region becomes larger as temperature increases, similarly to what happens in other IL-based ABS containing PPG and 2671


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aqueous cholinium bicarbonate solution, as shown in Figure 1. The mixtures were stirred at ambient temperature and pressure for 12 h. The resulting products were washed with diethyl ether to remove unreacted acid. Excess of water and traces of other volatile substances were then removed by rotary evaporation under reduced pressure. The chemical structures and purities of synthesized cholinium perfluoroalkanoates were confirmed by 1H- and 19F-NMR, electrospray ionization mass spectrometry (ESI-MS), and elemental analysis (see the Supporting Information for further details). Note that the quantitative integration of the cholinium perfluoroalkanoates’ characteristic 1H- and 19F-NMR resonance peaks revealed the expected equimole cation/anion correlations, using 4-(trifluoromethyl)benzaldehyde as an internal standard. All the prepared cholinium perfluoroalkanoates were dried by stir-heating under vacuum at moderate temperature (40−50 °C) for at least 4 days immediately prior to use. Their water contents (0.01 NA >0.01 >0.01 >0.01 >0.01 >0.01 >0.01 >0.01 0.0031 0.0020

95% confidence interval

Huh7

0.0028−0.0035 0.0018−0.0021

NA >0.01 NA >0.01 >0.01 0.0075 0.0079 0.0059 0.0034 0.0031 0.0012 0.0011


HEK293


0.0052−0.0106 0.0064−0.0096 0.0048−0.0072 0.0030−0.0038 0.0026−0.0037 0.0010−0.0015 0.0009−0.0014

NA >0.01 >0.01 0.8077 0.0046 0.0031 0.0049 0.0047 0.0016 0.0031 0.0045 0.0011

0.0025−0.0039 0.0048−0.0051 0.0043−0.0052 0.0015−0.0017 0.0026−0.0037 0.0004−0.0005 0.0009−0.0014

a

For compounds that showed no toxicity at the tested conditions, IC50 is described as not applicable (NA), while those that are partially toxic are described with an IC50 above 10 mM, as no accurate number can be calculated. For all other compounds, a 95% confidence interval IC50 and Hill slope is shown.

tional Organization for Standardization (ISO 10993-5:2009). It evaluates mitochondrial activity by the conversion of the tetrazolium salt into formazan crystals in living cells. As the mitochondrial activity is constant, an increase or decrease in the number of viable cells has a direct correlation with the number of formazan crystals. To evaluate the biocompatibility of cholinium-based ILs combined with linear perfluoroalkanoate anions, three different cell-lines were used. MRC-5 cells are nontransformed human lung fibroblast, these cells are mentioned in ISO 10993-5:2009 as suitable human cells for in vitro cytotoxic studies. HEK293 (transformed human kidney fibroblasts) were used as these are largely used in biotechnology for both fundamental and applied research and for industrial applications. The third cell line used is Huh-7. This transformed human liver cell-line was selected due to its hepatocyte-like nature as hapatocytes play an important role in the clearance of drugs and toxins. Aiming to determine the concentration range of ILs to test in cellular assays, we first determine the concentration limit for which IL addition had no effect on cell culture medium pH and osmolarity. For all ILs tested, interferences in pH and medium osmolarity were registered for concentration above 10 mM (Figure S13, see the Supporting Information), therefore 10 mM was selected as the initial concentration to use in subsequent

analysis. Results are depicted in Figure 2 and summarized in Table 2. The first observation concerns cell line susceptibility to IL solutions. The present data suggests that HEK293 is the most sensitive cell line, MRC-5 is the most resistant, while Huh-7 has an intermediate behavior. It is also possible to observe that cytotoxicity increases with the increase in the number of fluorine atoms in the anion. Ionic liquids with three to four CF2/CF3 groups display attenuated toxicity when compared to their respective acid. Nonetheless, this effect is lost when the number of CF2/CF3 groups is equal to or higher than 5 (see Figure S14, Supporting Information). Two ILs, [Ch][TFA] and [Ch][PFProp], show a safe profile in all the tested concentrations and cell lines and hence they are compatible with biotechnological applications. On the other hand, [Ch][PFHep] shows a cytotoxic profile to all tested conditions and therefore its use for biotechnological applications should be carefully considered. The mechanism by which these ILs promote cytotoxicity is not known. Phase Diagrams: Solubility Curves and Tie Lines. In this work, new aqueous biphasic systems were successfully implemented using the synthesized cholinium perfluoroalkanoate ILs and K3PO4 as salting out agent. The choice of this salting-out agent relies on its strong salting-out effect. It has 2674


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< [PFBut]− < [PFProp]− < [TFAc]−. Such a trend is in agreement to what was previously observed for ABS containing 1-alkyl-3-methylimidazolium alkylsulfonate ILs and K3PO4,16 where the binodal curves became closer to the origin with the increase of the alkyl chain in the anion. In general, it can be stated that an increase of the alkyl/perfluoroalkyl chain length either in the cation,57 or in the anion,58 will lead to an increase in the biphasic region due to the increased hydrophobicity of the ILs. Nevertheless, for 1-alkyl-3-methylimidazolium alkylsulfonate ILs + K3PO4 ABS, the increase of the alkyl chain in the anion had a small influence on the phase diagram and the binodals of the systems become closer to each other. In the present work, this behavior was not observed since all the phase diagrams are well spaced among each other, thus indicating that the inclusion of perfluoroalkyl chains in the anion has a stronger influence in the ILs hydrophobicity, and consequently on the phase forming ability, than that observed for hydrogenated alkyl chains. To better understand the observed behaviors, the intermolecular interactions present in the system, water−IL, water− IS, and IL−IS, need to be taken into account. For ABS containing ILs + ISs it has been shown that the ruling effect is the solvation of the ISs, that triggers the phase splitting. However, for the ILs + PEG ABS28 there is a delicate balance between water−IL and IL−IS depending on the hydrophilicity of the IL, since the magnitudes of the corresponding interactions are similar. The cholinium perfluoroalkanoate IL−water and K3PO4−water interactions can be assessed by measuring the corresponding water activities. This parameter, defined by the ratio of the partial vapor pressure of water in a certain solute to the partial vapor pressure of pure water at the same temperature, was measured for these systems under study and the results are depicted in Figure 5. A higher deviation of the water activity from the unit means a stronger interaction with water. The water activities of cholinium acetate [Ch][Ac] were also measured for comparison purposes. The obtained order of the water activities regarding the synthesized ILs and inorganic salt decrease in the following order: K3PO4 > [Ch][Ac] > [Ch][TFAc] > [Ch][PFProp] > [Ch][PFBut]. As expected, it is clear from the Figure 5 that K3PO4 establishes preferential interactions with water when compared to the cholinium perfluoroalkanoate ILs and other cholinium-based ILs/salts. The inorganic salt presents a higher depression in water activity, which enables the formation of stronger, more stable, hydrated complexes. On the other hand, [Ch][PFBut] is the most hydrophobic IL, presenting lower affinity for water. This trend follows the order of the ABS phase splitting ability for the studied cholinium perfluoroalkanoate ILs. Moreover, it is also interesting to compare the water activity values for [Ch][Ac] with that for [Ch][TFA]. It can be observed that the synthesized [Ch][TFA] is more hydrophobic than its hydrogenated analogous [Ch][Ac]. To further understand this data, the already published ABS composed of [Ch][Ac] + K3PO4 + H2O26 is compared to the data obtained in the present work for the system [Ch][TFA] + K3PO4 + H2O in Figure 6. A larger biphasic region is achieved when [Ch][TFA] is used when compared to [Ch][Ac], in agreement with the measured water activities. This kind of behavior has already been found for other families of ILs, for example, when performing ABS using K3PO4 with 1-butyl-3-methylimidazolium acetate [C4mim][Ac] and 1-butyl-3-methylimidazolium trifluoroacetate [C4mim][TFA].58 However, the advantage of the cholinium perfluor-

been shown by several authors that, for IL-based ABSs, the ability to undergo phase splitting follow the position of the inorganic salt in the Hoffmeister series. Therefore, the use of a strong kosmotropic salt such as K3PO4 (ΔGhyd of PO4−3 = −663 kcal·mol−1)56 results in binodals closer to the origin, which means that less salt and IL are needed to obtain a biphasic region. The binodal data determined at 25 °C and atmospheric pressure for the cholinium perfluoroalkanoate ILs + K3PO4 ABSs are given in the Supporting Information (Table S1) and plotted in Figure 3. Molality (mol·kg−1) was adopted

Figure 3. Binodal curves of the cholinium perfluoroalkanoate ionic liquids obtained at 25 °C and 1 atm, represented in terms of molality: (■) [Ch][TFAc], (▲) [Ch][PFProp], (□) [Ch][PFBut], (▼) [Ch][PFPent], (○) [Ch][PFHex], and (●) [Ch][PFHept]. The lines correspond to the respective correlations derived from eq 1.

as concentration unit in order to avoid inconsistencies due to the different molecular weights of the ILs. The coefficients of eq 1 obtained from the correlation of the experimental data are given in Table 3. The tie lines measured for each system are Table 3. Correlation Parameters of Equation 1 Adjusted to Binodal Experimental Data and Respective Standard Deviations (σ) and Correlation Coefficients (R2) ionic liquid

A±σ

[Ch][TFAc] [Ch][PFProp] [Ch][PFBut] [Ch][PFPent] [Ch][PFHex] [Ch] [PFHept]a

95 ± 1 95 ± 2 114 ± 2 129 ± 3 59 ± 12

B±σ −0.248 −0.546 −0.309 −0.344 −0.043

± ± ± ± ±

0.034 0.005 0.006 0.009 0.065

105(C ± σ)

R2

3.17 ± 0.06 5.36 ± 0.06 7.90 ± 0.06 10.0 ± 0.25 43.0 ± 1.60

0.9997 0.9999 0.9998 0.9996 0.9991

a

Fitting parameters were not considered due to the atypical shape of the binodal.

presented in Figure 4 for all the systems studied, and the respective values of the composition of initial mixtures and phases in equilibrium are listed in the Supporting Information (Table S2). From Figure 3 it can be seen that the phase-forming ability of the cholinium perfluoroalkanoate ILs + K3PO4 ABS is directly related to the perfluoroalkyl chain length of the anion: the longer the perfluoroalkyl chain, the easier it is for the IL to undergo liquid−liquid demixing. Thus, the size of monophasic regions follows the order: [PFHept]− < [PFHex]− < [PFPent]− 2675


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Figure 4. Tie lines and binodals of the studied cholinium perfluoroalkanoate ILs determined at 25 °C and 1 atm, represented in terms of weight fraction.

oalkanoate ILs, up to fluorinated chain of five carbon atoms, is their low citoxicity for the studied cells. It is worth mentioning the atypical behavior in shape of the binodal curve for the ABS containing the two cholinium perfluoroalkanoates with the longest chain length, [Ch]-

[PFHex] and [Ch][PFHept]. This type of behavior was also observed for unsubstituted and monosubstituted imidazolium chloride ILs + K3PO4 systems,57 as well as for systems based on PEG and low molecular weight polysaccharides.59,60 However, the inversion of order in the formation of ABS reported by 2676


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perfluoroalkyl chain length. Another interesting observation is that ILs display attenuated toxicity when compared to their respective acids and thus the formation of ILs can be put forward as a strategy to reduce toxicity of chemical compounds. Regarding ABS formation, the ternary phase diagrams, tie-lines, and tie-line lengths were determined at 25 °C and atmospheric pressure. The ability of the synthesized cholinium perfluoroalkanoates to undergo phase splitting increases with the increase of perfluoroalkyl chain length of the anion. This trend together with water activity measurements reveal that the inorganic salt acts as the salting out species, leading to the formation of a second phase rich in the IL. The well-spaced solubility curves of the cholinium perfluoroalkanoate ABSs support the conclusion that these ILs expanded the profiles of behaviors of ABSs containing ILs with increasing alkyl/ perfluoroalkyl chains in the anion.

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Figure 5. Experimental water activities measured at 25 °C and 1 atm: (⧫) K3PO4, (◊) [Ch][Ac], (■) [Ch][TFAc], (▲) [Ch][PFProp], and (□) [Ch][PFBut].

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.6b00171. 1 H and 13C NMR spectra of the synthesized cholinium perfluoroalkanoate ionic. Effect of ionic liquid supplementation on the pH and osmolarity of cell culture medium. Side-by-side comparison between ionic liquids and the corresponding perfluoroalkyl acid cytotoxicity. Experimental weight fraction data of the ternary systems (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +351-21-4469724. Fax: +351-21-4411277. E-mail address: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.J.S.P., C.F., H.R.S., and L.C.T. are grateful to FCT (Fundaçaõ para a Ciência e a Tecnologia) for the PhD research grants (SFRH/BD/97042/2013, SFRH/BD/102313/2014, and SFRH/BD/81598/2011) and the post-doctoral research grant (SFRH/BPD/101793/2014), respectively. I.M.M. acknowledges the financial support of FCT/MCTES (IF/363/2102). The NMR spectrometer used is part of the National NMR Facility supported by FCT (RECI/BBB-BQB/0230/2012). This work was partially supported by Research Unit GREEN-it “Bioresources for Sustainability” (UID/Multi/04551/2013).

Figure 6. Comparison between the already published results for the aqueous biphasic system composed of (◇) [Ch][Ac] + K3PO4 + H2O along with the obtained (■) [Ch][TFA] + K3PO4 + H2O.

Freire et al.,61 for systems of 1-alkyl-3-methylimidazolium chloride (with alkyl chain lengths longer than hexyl) + K3PO4, was not observed herein. This asymmetry in the phase diagram can probably be attributed to the large increase in the surfactant behavior of these ILs. Unpublished results from our group show that [Ch][PFHex] and [Ch][PFHept] behave as surfactants with critical micellar concentration of 4.275 and 2.625 mM at 25 °C.

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REFERENCES

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CONCLUSIONS This work unveils the formation of novel aqueous biphasic systems composed by cholinium perfluoroalkanoate ILs and a strong salting out agent, K3PO4. Six cholinium-based ILs with anions comprising variable alkyl chain lengths, from trifluoroacetate to perfluoroheptanoate, were synthesized and the thermal properties determined. The cytotoxicity of the prepared ILs was evaluated using three different cell lines and it was observed that [Ch][TFA] and [Ch][PFProp] show a safe profile in all the tested concentrations and cell lines, while for the other ILs the toxicity increases with the increase of 2677


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