Synthesis and Physical Properties of Choline ... - ACS Publications

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Synthesis and Physical Properties of Choline Carboxylate Ionic Liquids Nawshad Muhammad,† M. Ismail Hossain,† Zakaria Man,† Mohanad El-Harbawi,*,† M. Azmi Bustam,† Yousr Abdulhadi Noaman,‡ Noorjahan Banu Mohamed Alitheen,‡ Mei Kee Ng,‡ Glenn Hefter,§ and Chun-Yang Yin*,§ †

PETRONAS Ionic Liquid Center, Chemical Engineering Department, Universiti Teknologi PETRONAS, 31750 Tronoh, Perak, Malaysia ‡ Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia § School of Chemical and Mathematical Sciences, Murdoch University, Murdoch, 6150 WA, Australia ABSTRACT: A series of choline carboxylate ionic liquids (ILs) have been synthesized by neutralization of choline hydroxide solution with acetic, propanoic, butanoic, pivalic, and hexanoic acids. The salts so obtained were characterized by NMR spectroscopy, thermal methods, and elemental analysis. Key physical properties (density, viscosity, and refractive index) were measured for the propanoate, butanoate, and hexanoate salts at temperatures from (293.15 to 353.15) K. The densities were used to estimate the molecular volumes, standard entropies, crystal lattice energies, and thermal expansion coefficients. All five choline carboxylates were found to have cytotoxicities (IC50 values) above 10 mM toward the human breast cancer cell line, MCF-7, indicating they are much less toxic than common imidazolium-based ILs.

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INTRODUCTION Room temperature ionic liquids (ILs) are typically salts that contain at least one organic cation or anion and have melting points below or not far above ambient temperatures. Such materials are in demand as alternatives to traditional molecular solvents owing to their desirable properties such as their high chemical and thermal stabilities and their extremely low flammabilities and vapor pressures.1−3 The wide range of possible cation−anion combinations enables ILs to be developed to have a specific set of physicochemical properties or to be designed for particular applications. On the negative side, many ILs have a significant solubility in water, which raises concerns about their toxicity to aquatic organisms.4−6 As such, it is of interest to develop ILs that are likely to be more benign to aquatic organisms and to exert fewer detrimental impacts on the environment in general. Choline, the N,N,N-trimethylethanolammonium cation, is an essential nutrient7 and therefore a good candidate for combining with appropriate anions to produce ILs of relatively low toxicity. Not surprisingly, choline-based ILs have received considerable attention. Indeed, as early as 1960 choline salicylate was reported to melt at approximately 50 °C.8,9 More recently, Abbott and co-workers10 reported the synthesis of a number of ILs from choline chloride, while Pernak et al.11 prepared a total of 63 choline-based ILs. The latter group also reported various physical properties for these salts as well as establishing the © 2012 American Chemical Society

antimicrobial activities of a range of choline acesulfamates. Petkovic and co-workers12 synthesized some choline-based ILs by neutralizing choline hydrogen carbonate with carboxylic acids and evaluated their toxicity toward filamentous fungi. In terms of potential applications, choline-based ILs have been used for the preparation of a solvent eutectic for lipase activation, and for the enzymatic preparation of biodiesel13 and electrochemistry.14 In this study, choline acetate, propanoate, butanoate, hexanoate, and pivalate (2,2-dimethylpropanoate) have been prepared by neutralizing an aqueous solution of choline hydroxide with the appropriate acid. To the best of our knowledge, synthesis of choline pivalate has not been previously reported. These ILs were characterized by elemental and Karl Fischer analyses, NMR spectroscopy, and thermogravimetry or differential scanning calorimetry. Some key physical properties (density, viscosity, and refractive index) have been measured as a function of temperature, while cytotoxicities toward the human breast cancer cell line, MCF7,15,16 have also been determined. Received: January 18, 2012 Accepted: June 29, 2012 Published: July 16, 2012 2191

dx.doi.org/10.1021/je300086w | J. Chem. Eng. Data 2012, 57, 2191−2196

Journal of Chemical & Engineering Data

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EXPERIMENTAL SECTION Synthesis. All chemicals used were of analytical grade. Choline hydroxide solution (46 wt %, Sigma-Aldrich) and acetic, propanoic, butanoic, pivalic, and hexanoic acids (Merck) were used without further purification. All solutions were made up with Millipore-grade water. The ILs were synthesized via neutralization of the base with the appropriate acid. By way of example, acetic acid (0.1 mol) was added dropwise into an aqueous solution of choline hydroxide (0.1 mol). The mixture was stirred continuously for 12 h at room temperature (∼27 °C). The obtained IL was dried for 6 h under vacuum using a rotary evaporator, followed by further vacuum drying at 70 °C for 24 h. Characterization. A Bruker Avance 400 spectrometer was used to record 1H NMR spectra in D2O/DMSO-d6, while a CHNS-932 (LECO) apparatus was used for elemental analysis. The water content of the synthesized ILs was determined by coulometric Karl Fischer titration (Mettler Toledo DL 39) with Hydranal Coulomat AG reagent (Riedel-de Haen). Thermal Properties. Melting temperatures (Tm) of the solid choline carboxylates were determined using differential scanning calorimetry (Mettler Toledo DSC 1, STARe Software v9.30). Each sample was ∼8 mg and was contained in a tightly sealed aluminum pan. The measurements were performed at a scan rate of 2 K·min−1 and involved several cooling and heating cycles over the range 313 ≤ T/K ≤ 393 in a flowing nitrogen atmosphere (50 mL·min−1). The DSC was calibrated with a 99.9999 % purity indium sample. Temperature accuracy and precision were ± 0.2 °C and ± 0.05 °C, respectively. Thermal decomposition temperatures, Td, were measured using a Perkin-Elmer, Pyris V-3.81 thermogravimetric analyzer via the highest peak intensity of the derivative weight loss curve. The samples were placed in an aluminum pan under a nitrogen atmosphere and heated at 10 K·min−1, with a temperature control precision of ± 3 K. Physical Properties. All instruments used for physical property measurements were calibrated using Millipore-quality water as described elsewhere.17,18 The instruments were also checked with previously investigated ILs, namely, 1-hexyl-3methylimidazolium bis(trifluoromethylsulfonyl)imide, [C6mim]Tf2N, 1-butylpyridinium bromide, [C4py]Br, and 1propyronitrile-3-butylimidazolium bromide, [C2CN Bim]Br. An Anton Paar viscometer (model SVM3000) and Anton Paar densimeter (model DMA5000) were used to measure viscosities and densities, respectively, over the temperature range (293.15 to 353.15) K with a temperature control of ± 0.01 K and uncertainties of ± 0.3 % and ± 5·10−4 g·cm−3, respectively.17,19 Refractive indices were determined at temperatures from (293.15 to 333.15) K using an ATAGO programmable digital refractometer (RX-5000α) with a measuring accuracy of 4·10−5 and a temperature precision of ± 0.05 K. The apparatus was calibrated using purified organic solvents of known refractive index.17,19 Cytotoxicity Determination. The cytotoxicities of the synthesized ILs were determined for the human breast cancer cell line, MCF-7. Closely following the procedure of Kumar et al.20 and our previous work,21 the MCF-7 cells, originally purchased from the American type culture collection (ATCC), were cultured in an Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 1 % penicillin/streptomycin and 10 % horse serum at 37 °C (5 % CO2). After tripsinization, most of the cells were removed from contact with the plate and

then centrifuged (1000 rpm for 10 s). The plates were resuspended with phosphate buffer saline (PBS) solution (with (5 to 10) % dimethylsulfoxide, DMSO). Cell counting was done in hemocytometer via a microscope where the cell concentration was maintained at a density of ca. 106 cells/mL via dilution with RPMI medium. To each well was added freshly prepared media (100 μL) followed by the test-IL solution (100 μL) using serial dilution. Seven different concentrations of ILs in the cell solutions were used together with one control. The plates were then transferred to the incubator after adding 100 μL of the cell suspension to each well. After 48 h of growth, cell viability was measured with the MTT (1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan, Sigma-Aldrich) assay22 as follows: to each well was added 20 μL of 2.5 mg·mL−1 MTT in PBS followed by incubation for 3 h at 37 °C. The liquid (170 μL) was then aspirated, and the purple crystals of the formazan product were dissolved in DMSO (100 μL). Absorbance was measured in a UV−vis spectrophotometer at 570 nm using an ELISA (enzyme-linked immunosorbent assay) microplate reader (MQX2000, JICA Technical Corporation, Japan). The experiments were performed in triplicate at each IL concentration. The dose− response curves were plotted, and IC50 values, the testsubstance concentration that resulted in 50 % growth inhibition,20 were determined.

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RESULTS AND DISCUSSION Characterization and Physical Properties. Table 1 lists the thermal, NMR-spectroscopic, and analytical data for the synthesized ILs. All of these salts were liquid at room temperature except for choline acetate and pivalate, which melted at temperatures below 100 °C. The experimental densities (ρ), viscosities (η), and refractive indices (nD) of choline propanoate, butanoate, and hexanoate at (depending on the property) 293.15 ≲ T/K ≲ 353.15 are presented in Table 2 and are plotted against appropriate functions of T in Figure 1. Over the present temperature range, ρ and nD decrease linearly with increasing T. For viscosities, log η increases smoothly with T−1, implying Vogel−Fulcher− Tammann (VFT) behavior, which is typical of IL systems.23,24 As would be anticipated, the alkyl chain length of the carboxylate anion influences the physical properties of the synthesized ILs. For example, the densities decrease with increasing alkyl chain length of the carboxylate anion, a phenomenon also observed for ILs containing alkyl-substituted imidazolium ions.25,26 On the other hand, the viscosities and refractive indices increase with increasing alkyl chain length. For viscosities, this increase may reflect increasing entanglement of the alkyl chains or possibly increased interaction between the carboxylate moiety and the −OH group of the choline cation due to the electron donating characteristic of the alkyl chain. For refractive indices, the increase is probably due to the higher polarizability associated with the increase in the anion size. The physical properties obtained for the present ILs were fitted to the following equations:18,19 ρ = A 0 + A1T

log η = A 2 +

(1)

A3 T

nD = A4 + A5T 2192

(2) (3)


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Table 2. Experimental Densities (ρ),a Dynamic Viscosities (η),b and Refractive Indices (nD)c of Choline Propanoate, Butanoate, and Hexanoate as Functions of Temperature

C, 51.41 (51.51); H, 10.57 (10.49); N, 8.60 (8.58) C, 54.17 (54.20); H, 10.83 (10.80); N, 7.89 (7.90) C, 56.48 (56.51); H, 10.15 (10.01); N, 7.36 (7.30) C, 58.53 (58.50); H, 11.28 (11.29); N, 6.80 (6.81) C, 60.21 (60.24); H, 11.50 (11.48); N, 6.37 (6.38)

T/K

choline propanoate

choline butanoate

choline hexanoate

−3 a

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15 338.15 343.15 348.15 353.15

366

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15 338.15 343.15 348.15 353.15

1.0746 1.0715 1.0686 1.0657 1.0628 1.0600 1.0572 1.0543 1.0514 1.0486 1.0458 1.0429 1.0401 395.8 290.2 215.6 163.2 125.8 98.5 78.3 63.0 51.4 42.4 35.4 29.8 25.4

Calculated values are given in brackets. bExists as a solid at room temperature.

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

1.4705 1.4686 1.4668 1.4650 1.4631 1.4611 1.4592 1.4573 1.4555

ρ/(g·cm ) 1.0495 1.0465 1.0434 1.0405 1.0376 1.0346 1.0319 1.0290 1.0262 1.0234 1.0205 1.0172 1.0145 η/(mPa·s)b 833.1 630.6 459.3 344.2 254.0 193.8 150.2 118.2 94.3 76.1 62.2 51.4 42.9 n Dc 1.4716 1.4700 1.4683 1.4667 1.4650 1.4633 1.4617 1.4600 1.4585

1.0188 1.0157 1.0125 1.0098 1.0068 1.0039 1.0013 0.9984 0.9955 0.9926 0.9897 0.9868 0.9840 929.2 710.7 530.4 400.3 298.0 225.9 175.3 140.3 110.9 89.7 73.7 60.9 51.0 1.4726 1.4709 1.4692 1.4675 1.4658 1.4640 1.4624 1.4607 1.4590

Estimated uncertainty = ± 5·10−4 g·cm−3. bEstimated uncertainty = ± 0.3 %. cEstimated measurement accuracy = 4·10−5.

a

where T is the temperature (in K) and Ai (0 ≤ i ≤ 5) are empirical correlation coefficients established from the data using the method of least-squares. The standard deviations (SDs) of the fits were calculated as: N

SD =

∑i (Zexp − Zcalc)2 N

(4)

where N is the number of experimental points and Zexp and Zcalc are the individual experimental and calculated values, respectively. The correlation coefficients and standard deviations so determined are listed in Table 3. The isobaric coefficient of thermal expansion (αp) can be determined from the experimental densities using the temperature derivative of eq 1:

a

96

209

204

δH (400 MHz; DMSO-d6; Me4Si): 0.96 (3H, t, CH3CH2), 1.24 (4H, m, CH3(CH2)2); 1.64 (2H, m, CH3CH2), 2.16 (2H, q, CH2CO), 3.23 (9H, s, 3·CH3N), 3.51 (2H, t, CH2CH2OH), 4.02 (2H, s, CH2OH);

321

353

δH (400 MHz; D2O; Me4Si): 1.13 (3H, t, CH3CH2), 2.19 (2H, q, J = 7.63 Hz, CH2CO), 3.20 (9H, s, 3·CH3N), 3.50 (2H, t, CH2CH2OH), 4.02 (2H, s, CH2OH) δH (400 MHz; D2O; Me4Si): 0.96 (3H, t, CH3CH2), 1.64 (2H, m, CH3CH2), 2.16 (2H, q, J = 7.63 Hz, CH2CO), 3.23 (9H, s, 3·CH3N), 3.51 (2H, t, CH2CH2OH), 4.03 (2H, s, CH2OH) δH (400 MHz; D2O; Me4Si); 1.18 (9H, s, 3·CH3C), 3.23 (9H, s, 3·CH3N), 3.51 (2H, t, CH2CH2OH), 4.02 (2H, s, CH2OH) 212

δH (300 MHz; D2O; Me4Si): 1.95 (3H, s, CH3CO), 3.20 (9H, s, 3·CH3N), 3.51 (2H, m, CH2CH2OH), 4.02 (2H, m, CH2OH) 72

choline acetateb choline propanoate choline butanoate choline pivalateb choline hexanoate

H NMR (δ ppm) 1

Tm/°C Td/°C choline carboxylate

Table 1. Thermal, NMR Spectroscopic, and Analytical Data for Choline Carboxylate ILs

water content (ppm)

elemental analysis (mass %)a


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Table 3. Values of the Empirical Coefficients, Ai, in Equations 1 to 3 and the Overall Standard Deviation of Fit (SD) for Choline Propanoate, Butanoate, and Hexanoate salt

A0

104 A1

104 SD

choline propanoate choline butanoate choline hexanoate salt

1.24220 1.21933 1.18736 A2

−5.72527 −5.78000 −5.76044 A3

0.93013 1.50524 1.49458 SD

choline propanoate choline butanoate choline hexanoate salt

−4.4433 −4.8362 −4.5746 A4

2054.31 2273.14 2209.65 104 A5

0.01973 0.02011 0.01438 104 SD

choline propanoate choline butanoate choline hexanoate

1.58096 1.56896 1.57342

−3.76667 −3.31667 −3.43667

0.67847 1.39301 1.51107

Table 4. Thermal Expansion Coefficients (αp) of Choline Propanoate, Butanoate, and Hexanoate as a Function of Temperature at Atmospheric Pressure 104 αp/K−1 T/K

choline propanoate

choline butanoate

choline hexanoate

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15 338.15 343.15 348.15 353.15

5.32 5.34 5.35 5.37 5.38 5.40 5.41 5.43 5.44 5.46 5.47 5.49 5.50

5.52 5.54 5.55 5.57 5.58 5.60 5.62 5.63 5.65 5.66 5.68 5.70 5.71

5.65 5.67 5.68 5.70 5.72 5.73 5.75 5.77 5.78 5.80 5.82 5.83 5.85

where M is the molar mass in g·mol−1, NA is Avogadro’s constant in mol−1, and ρ is the density (in g·cm−3). Standard entropies (S°) were determined using Glasser’s theory:31,32 S° = 1246.5VM + 29.5

(7) 3

where here VM is the molecular volume in nm and S° is the standard entropy in J·K−1·mol−1. The crystal or lattice energies, UPOT in kJ·mol−1, of the solid forms of the present ILs were estimated using the empirical equation:33

Figure 1. (a) Densities (ρ), (b) dynamic viscosities (η), and (c) refractive indices (nD) of ●, choline propanoate; ■, butanoate; and ▲, hexanoate as functions of temperature.

A1 1 ⎛ δρ ⎞ αp = − ⎜ ⎟ = − ρ ⎝ δT ⎠ p A 0 + A1T

UPOT = 1981.2(ρ /M )1/3 + 103.8

The values of these quantities are listed in Table 5 for the propanoate, butanoate, and hexanoate salts. The estimated molecular volumes lie within the range of values reported for imidazolium-based ILs.34 The estimated standard entropies are similar to those calculated for [Cnmim]glycinate, n = 2 to 6,

(5)

The values of αp for the present ILs (Table 4) do not change appreciably with temperature (ca. 3.5 % over the 60 K interval studied) as is also observed for imidazolium-based ILs.21,27,28 Interestingly, αp also increases with increasing alkyl chain length on the carboxylate anion, which may reflect coiling of the hydrocarbon chain. Derived Molecular Properties. The molecular volume (VM, in cm3) of the synthesized ILs is the sum of cation and anion volumes and can be calculated29,30 as: VM = M /(NAρ)

(8)

Table 5. Estimated Molecular Volumes (VM), Standard Entropies (S°), and Crystal Energies (UPOT) of Choline Propanoate, Butanoate, and Hexanoate at 298.15 K

(6) 2194

IL

Vm/cm3

S°/(J·K−1·mol−1)

UPOT/kJ·mol−1

choline propanoate choline butanoate choline hexanoate

2.74·10−22 3.03·10−22 3.58·10−22

371.0 407.2 475.7

464.71 452.90 434.03



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ILs.32 The estimated crystal energies for the synthesized ILs are comparatively low compared to simple inorganic salts such as CsI (ca. 600 kJ·mol−1) but similar to other ILs such as 1-ethyl3-methylimidazolium aminoacetate (469 kJ·mol−1).32 Cytotoxicities. The IC50 values of the synthesized ILs were: (10.5 ± 0.6, 11.2 ± 0.1, 12.1 ± 0.2, 14.6 ± 0.5, and 16.0 ± 0.5) mM for choline acetate, propanoate, butanoate, hexanoate, and pivalate, respectively, increasing with the alkyl chain length of the carboxylate anion. The decrease in cytotoxicity with increasing carboxylate chain length has not been previously reported (to the best of our knowledge). This is an interesting finding given that the effects of anion moieties on IL toxicities are not well-defined, certainly when compared with the effect attributed to side chain length on the cation.35 A representative viability−concentration curve for choline hexanoate is given in Figure 2. The cell response when treated with choline

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CONCLUSIONS The physical properties (densities, viscosities, and refractive indices) of a series of choline carboxylate ILs show simple systematic variations with temperature and with the alkyl chain length of the carboxylate anion. The comparatively low cytotoxicity of these ILs, at least toward human breast cancer cells relative to those with long chain carboxylate anions signifies a step toward development of ILs with milder environmental effects.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +605 368 7581; fax: +605 365 6176; e-mail address: [email protected] (M.E.-H.). Tel.: +614 3140 9216; fax: +618 9360 6452; e-mail addresses: c.yin@ murdoch.edu.au; [email protected] (C.-Y.Y.). Funding

The authors acknowledge the PETRONAS Ionic Liquid Center (PILC) and Chemical Engineering Department, Universiti Teknologi PETRONAS for their support in conducting this study. Notes

The authors declare no competing financial interest.

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REFERENCES

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Figure 2. A representative viability−concentration curve for choline hexanoate.

hexanoate at the IC50 value is compared with untreated cells in Figure 3. The present choline-based ILs exhibit lower cytotoxicities compared to most imidazolium, pyrrolidinium, and piperidinium ILs, which have IC50 values that are lower than 10 mM and often lower than 1 mM.20,21 This is consistent with the relatively benign characteristics that would be expected from the presence of the choline cation.

Figure 3. Microscopic images of MCF-7 cell viability (after 48 h): (a) with and (b) without choline hexanoate at IC50. 2195



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