Room-temperature ionic liquids that dissolve carbohydrates in high concentrations

Abstract

Carbohydrates are only sparingly soluble in common organic solvents as well as in weakly coordinating ionic liquids, such as [BMIm][BF₄]. Ionic liquids that contain the dicyanamide anion, in contrast, dissolve approx. 200 g L⁻¹ of glucose, sucrose, lactose and cyclodextrin. Candida antarctica lipase B mediated the esterification of sucrose with dodecanoic acid in [BMIm][dca].

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Introduction

There is considerable current interest in the utilization of carbohydrates as readily available, relatively inexpensive and renewable feedstocks for the chemical and related industries. Examples of the latter trend are sugar-derived biosurfactants¹ and esters of sugars with fatty acids.² The transformation of underivatised carbohydrates is still quite challenging due to their low solubility in almost any solvent but water. The few exceptions, such as DMF and DMSO, have many undesirable characteristics and are not compatible with many intended applications of carbohydrate-derived products.

Ionic liquids are currently the focus of increasing attention as reaction media for organic synthesis in general and enzymatic transformations in particular.³ Their potential as media for carbohydrate transformations was first pointed out by us⁴ and subsequently confirmed by Park and Kazkauskas⁵ who described the lipase-catalysed acylation of glucose and maltose in ionic liquids. The best results were obtained in 1-methoxyethyl-3-methylimidazolium tetrafluoroborate, [MOEMIm][BF₄], which dissolved 5 g L⁻¹ of glucose at 55 °C.⁵ More recently, the dissolution of high concentrations of α-cyclodextrin (350 g L⁻¹) in 1-methoxymethyl-3-methylimidazolium bromide has been reported.⁶ 1-Butyl-3-methylimidazolium chloride passed the ultimate test as a solvent for carbohydrates by dissolving 100 g L⁻¹ of cellulose at 100 °C.⁷

MacFarlane and coworkers were the first to note that ionic liquids containing the dicyanamide (dca) anion dissolved glucose in high (>100 g L⁻¹) concentrations.^8,9 These ionic liquids were also able to dissolve di- and trisaccharides in considerable but unspecified amounts.^9,10

These observations prompted us to undertake a systematic study of the effects of the anion and substituents in the cation on the ability of dialkylimidazolium ionic liquids to dissolve mono-, di- and polysaccharides, the ultimate goal being their use as reaction media for performing (bio)catalytic transformations of industrially relevant carbohydrates. Herein we report our preliminary results in which we will show that certain room-temperature ionic liquids are able to dissolve high concentrations of carbohydrates and we will show that these solutions can be used for lipase-catalysed acylations.

Results and discussion

The ionic liquids were synthesised according to slightly modified literature procedures¹¹ (see Scheme 1). Chloride ion may severely affect the properties of ionic liquids even in trace amounts.¹² Hence, it was removed via column chromatography,⁵ which reduced the chloride contents from approx. 1% (w/w) in the crude ionic liquid to 200–300 ppm. Rigorous drying reduced the water contents to <500 ppm.

Scheme 1 Synthetic scheme.

The solvatochromic shifts of the dca-containing ionic liquids were measured with Nile Red. The excitation energies ranged from 213–215 kJ mol⁻¹, which is well within the expected range and close to the value of the corresponding bis(trifluoromethylsulfonyl)imide compounds.^12,13 These results seem to confirm the notion that the solvatochromic shift of betaine dyes mainly depends on the nature of the cation.¹⁴

The solubility of β-D-glucose in the newly synthesised ionic liquids, as well as that in [BMIm][BF₄] and [BMIm][PF₆] was measured, using a spectrophotometric assay.¹⁵ The solubilities of glucose in the various ionic liquids at 25 °C are shown in Table 1. Glucose dissolved in the ionic liquids to a much higher concentration than in tert-butyl alcohol and the expected positive effect of the oxygenated side-chains could indeed be observed (see Table 1). However, much to our surprise, the solubility of glucose was influenced much more by the nature of the anion than that of the cation. Ionic liquids containing the dicyanamide anion dissolved glucose more than an order of magnitude better than their tetrafluoroborate counterparts. MacFarlane and coworkers have asserted⁹ that the high solubility of carbohydrates can be attributed to the H-bond acceptor properties of the dca anion, which was recently recognised as a prerequisite for dissolving complex molecules.¹⁶ It would seem, in hindsight, that the high solubility of carbohydrates in [MOMMIm][Br] and [MOEMIm][Br]⁶ can probably be attributed to the bromide anion rather than the oxygenated imidazolium cation.¹⁶ It came to us as a final surprise that [BMIm][dca] was a much better solvent for glucose than its oxygenated counterparts.

Table 1 Solubility of β-D-glucose in ionic liquids at 25 °C

Solvent	R	X	Solubility / g L^−1
tert-Butyl alcohol	—	—	0.3
[BMIm][BF4]	C4H9	BF4	<0.5
[BMIm][PF6]	C4H9	PF6	<0.5
[MOMMIm][Tf2N]	CH3OCH2	(CF3SO2)2N	0.5
[MOMMIm][BF4]	CH3OCH2	BF4	4.4
[MOMMIm][TfO]	CH3OCH2	CF3SO3	4.3
[MOEMIm][Tf2N]	CH3OCH2CH2	(CF3SO2)2N	0.5
[MOEMIm][PF6]	CH3OCH2CH2	PF6	2.5
[MOEMIm][BF4]	CH3OCH2CH2	BF4	2.8
[MOEMIm][TfO]	CH3OCH2CH2	CF3SO3	3.2
[EOEMIm][Tf2N]	C2H5OCH2CH2	(CF3SO2)2N	0.5
[EOEMIm][PF6]	C2H5OCH2CH2	PF6	0.7
[EOEMIm][BF4]	C2H5OCH2CH2	BF4	2.8
[MOMMIm][dca]	CH3OCH2	(CN)2N	66
[MOEMIm][dca]	CH3OCH2CH2	(CN)2N	91
[EOEMIm][dca]	C2H5OCH2CH2	(CN)2N	70
[BMIm][dca]	C4H9	(CN)2N	145

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The solubility of glucose in these ionic liquids increased by a factor of 2.5–5 when the temperature was raised to 75 °C. Thus, [BMIm][dca] dissolved 211 and 405 g L⁻¹ at 40 and 75 °C, respectively.

The solubility of the disaccharide sucrose in [MOEMIm][[Tf₂N] and similar ionic liquids was much less than that of glucose, in spite of the oxygen atom in the side chain. The dca-containing ionic liquids, in contrast, dissolved sucrose even better than glucose, with [EOEMIm][dca] as a notable exception (Table 2). A further increase in solubility was observed when the temperature was raised to 60 °C.

Table 2 Solubility of sucrose in ionic liquids

Solvent	Solubility / g L^−1
	25 °C	60 °C
a From ref. 15.
[MOEMIm][Tf2N]	0.13
[MOEMIm][BF4]	0.4
[MOEMIm][PF6]	0.7
[MOEMIm][TfO]	2.1
[MOMMIm][dca]	249	352
[MOEMIm][dca]	220
[EOEMIm][dca]	50	240
[BMIm][dca]	195	282
tert-Butyl alcohol		0.5^a

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The effort required to obtain these ionic liquids in a halide-free state prompted us to assess the influence of chloride ions on the solubility of sucrose in [BMIm][dca]. We found the effect to be small, as the solubility of sucrose (at 60 °C) increased from 282 g L⁻¹ to 294 g L⁻¹ in the presence of 1% of chloride.

As the use of ionic liquids as reaction media is our ultimate objective, we have investigated the acylation of sucrose by dodecanoic acid. Preliminary experiments showed that Novozym 435 catalysed the conversion of sucrose in [BMIm][dca] medium. Further work is in progress.

Additional experiments demonstrated the potential of [BMIm][dca] for dissolving carbohydrates (see Table 3). Lactose, which is extremely sparingly soluble in organic solvents, such as tert-butyl alcohol, dissolved readily. β-Cyclodextrin dissolved in [BMIm][dca] very slowly, but the final concentration was so high (see Table 3) that the mixture solidified upon cooling. Amylose, which is only sparingly (<0.5 g L⁻¹) soluble in water, dissolved in [BMIm][dca] to a final concentration of 4 g L⁻¹.

Table 3 Solubility of di- and polysaccharides in [BMIm][dca]

Sugar	Solubility / g L^−1
	25 °C	60 °C	75 °C
Sucrose	195	282
Lactose	51		225
β-Cyclodextrin			750
Amylose	4

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In conclusion, we have shown that ionic liquids based on the dicyanamide anion are highly effective, non-protic solvents that dissolve carbohydrates from glucose to starch and even cellulose in large amounts. We have furthermore shown that enzymatic acylation with a fatty acid takes place in such a medium. Investigations are underway to ascertain the scope of carbohydrate conversions in dca ionic liquids, including ones containing other classes of cations.

Experimental

Materials

All chemicals were purchased from Aldrich. Novozym 435 was received from Novozymes (Bagsvaerd, Denmark) as a gift.

Instruments

NMR spectra were measured on a Varian VXR400 spectrometer. UV measurements were performed on a Cary 3 spectrometer. Chloride contents were measured on a Dionex DX-120 instrument.

Synthesis of ionic liquids

All ionic liquids were dried under vacuum over P₂O₅ until the water contents were <500 ppm according to Karl Fischer titration.

[MOMMIm][Cl]. Chloromethyl methylether (30 mL, 0.4 mol CAUTION: carcinogenic) was added dropwise to 1-methylimidazole (32 mL, 0.4 mol) under stirring at 0 °C, then kept at 50 °C for 1 h. The mixture was cooled to room temperature and washed three times with 70 mL ethyl acetate. After removal of the solvent by rotary evaporation the residual liquid solidified at room temperature (61.4 g, 95%), mp 66–68 °C.

[MOMMIm][Tf₂N]. To a solution of [MOMMIm][Cl] (6 g, 36.9 mmol) in acetone (40 mL) was added LiN(Tf)₂ (14.6 g, 5.1 mmol) and the mixture was stirred for 3 h. The acetone was removed by rotary evaporation and dichloromethane (40 mL) was added. The resulting mixture was stirred overnight, brought on a silica gel column and eluted with dichloromethane. The eluate was twice washed with water (40 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporation (12.2 g, 81%).

[MOMMIm][PF₆]. A 60% aqueous solution of HPF₆ (17.5 mL, 0.13 mol) was slowly added dropwise to a stirred solution of [MOMMIm][Cl] (16.2 g, 0.1 mol) in water (50 mL) at 0 °C. Subsequently the mixture was stirred at room temperature for 12 h, the solids were obtained by filtration, washed two times with water (50 mL) and dried under vacuum (21.2 g, 80%), mp 67–69 °C. ¹H NMR (DMSO-d₆): δ = 9.18 (s, 1H), 7.85 (d, 1H), 7.80 (d, 1H), 5.69 (s, 2H), 4.12 (s, 3H), 3.46 (s, 3H). IR (KBr): 3179, 3128, 2963, 2942, 1582, 1563, 832 cm⁻¹.

[MOMMIm][BF₄]. To a solution of [MOMMIm][Cl] (16.2 g, 0.1 mol) in acetone (40 mL) was added NaBF₄ (13.2 g, 0.12 mol). The mixture was stirred for 48 h, the solid NaCl was removed by filtration and the filtrate was concentrated. The residual oil (22.1 g) was brought on a silica gel column and eluted with acetone–chloroform (50 ∶ 50, v/v). The eluate was concentrated by rotary evaporation; the residue was dissolved in dichloromethane (50 mL), washed twice with saturated aqueous sodium carbonate solution (50 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum (18.4 g, 86%). ¹H NMR (acetone-d₆): δ = 9.03 (s, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 5.62 (s, 2H), 4.05 (s, 3H), 3.42 (s, 3H). IR (film): 3163, 3119, 2957, 2840, 1580, 1561, 1063 cm⁻¹.

[MOMMIm][Tf]. To a solution of [MOMMIm][Cl] (6.0 g, 36.9 mmol) in 20 mL acetone was added NaCF₃SO₃ (6.35 g, 36.9 mmol). The resulting mixture was stirred for 24 h, the solid NaCl was removed by filtration, the filtrate was brought on a silica gel column and eluted with acetone. The eluate was concentrated by rotary evaporation (8.3 g, 81.4%).

[MOMMIm][dca]. To a solution of [MOMMIm][Cl] (9.4 g, 57.7 mmol) in 50 mL acetone was added NaN(CN)₂ (5.2 g, 57.7 mmol). The mixture was stirred for 24 h and the solid NaCl was removed by filtration. The filtrate was brought on a silica gel column and eluted with acetone. The eluate was concentrated by rotary evaporation (7.6 g, 83.8%). ¹H NMR (acetone-d₆): δ = 9.27 (s, 1H), 7.84 (m, 1H), 7.79 (m, 1H), 5.67 (s, 2H), 4.10 (s, 3H), 3.42 (s, 3H). MS (esp⁻): m/z 66.2 (100%, dca⁻).

[MOEMIm][Cl]. 2-Chloroethyl methyl ether (36.5 mL, 0.4 mol) was added to 1-methylimidazole (32 mL, 0.4 mol) under stirring. After 48 h at 80 °C the mixture was cooled to room temperature, washed three times with ethyl acetate (70 mL) and concentrated by rotary evaporation. The residual yellow oil solidified at room temperature (64 g, 92%), mp 65–68 °C.

[MOEMIm][Tf₂N] was synthesised from [MOEMIm][Cl] and LiN(Tf)₂ as described for [MOMMIm][Tf₂N] (79%).

[MOEMIm][PF₆] was synthesised from [MOEMIm][Cl] and HPF₆ as described for [MOMMIm][PF₆] (30.5%). ¹H NMR (acetone-d₆): δ = 8.90 (s, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 4.51 (t, 2H), 4.04 (s, 3H), 3.81 (t, 2H), 3.44 (s, 3H). IR (film): 3172, 3126, 2943, 2903, 2840, 1576, 1454, 824 cm⁻¹.

[MOEMIm][BF₄] was synthesised from [MOEMIm][Cl] and NaBF₄ as described for [MOMMIm][BF₄] (49.3%). ¹H NMR (acetone-d₆): δ = 8.88 (s, 1H), 7.68 (d, 1H), 7.65 (d, 1H), 4.48 (t, 2H), 4.01 (s, 3H), 3.79 (t, 2H), 3.34 (s, 3H). IR (film): 3164, 3123, 2932, 1576, 1455, 1058 cm⁻¹.

[MOEMIm][TfO] was synthesised from [MOEMIm][Cl] and NaCF₃SO₃ as described for [MOMMIm][Tf] (81%).

[MOEMIm][dca] was prepared from [MOEMIm][Cl] and NaN(CN)₂ as described for [MOMMIm][dca] (83%). ¹H NMR (acetone-d₆): δ = 9.08 (s, 1H), 7.75 (m, 1H), 7.72 (m, 1H), 4.54 (t, 2H), 4.07 (s, 3H), 3.83 (m, 3H). MS (esp⁻): m/z 66.2 (100%, dca⁻).

[EOEMIm][Cl]. 2-Chloroethyl ethylether (44 mL, 0.4 mol) was added to 1-methylimidazole (32 mL, 0.4 mol) while stirring. After 48 h at 100 °C the mixture was cooled to room temperature and washed three times with ethyl acetate (70 mL). Removal of the solvent by rotary evaporation afforded a brown oil (69.0 g, 90.6%).

[EOEMIm][Tf₂N] was prepared from [EOEMIm][Cl] and LiN(Tf)₂ as described for [MOMMIm][Tf₂N] (91%).

[EOEMIm][PF₆]. A 60% aqueous solution of HPF₆ (17.5 mL, 0.13 mol) was slowly added dropwise to a stirred solution of [EOEMIm][Cl] (20.0 g, 0.1 mol) in water (50 mL) at 0 °C. After 12 h at room temperature, the ionic liquid bottom layer was separated, washed twice with water (50 mL) and with aqueous saturated sodium carbonate solution (50 mL). Purification according to literature method B (ref. 5) afforded a yellow oil (25.6%). ¹H NMR (acetone-d₆): δ = 8.89 (s, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 4.50 (t, 2H), 4.04 (s, 3H), 3.84 (t, 2H), 3.56 (q, 2H), 1.16 (t, 3H). IR(film): 3171, 3125, 2979, 2936, 2877, 1575, 1451, 841 cm⁻¹.

[EOEMIm][BF₄] was synthesised from [EOEMIm][Cl] and NaBF₄ as described for [MOMMIm][BF₄]. Purification according to method B (ref. 5) afforded a yellow oil (35.5%). ¹H NMR (acetone-d₆): δ = 8.90 (s, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 4.48 (t, 2H), 4.02 (s, 3H), 3.84 (t, 2H), 3.55 (q, 2H), 1.2 (t, 3H). IR (film): 3163, 3123, 2977, 2933, 2874, 1575, 1453, 1059 cm⁻¹.

[EOEMIm][TfO] was synthesised from [EOEMIm][Cl] and NaCF₃SO₃ as described for [MOMMIm][TfO] (90.6%).

[EOEMIm][dca] was obtained from [EOEMIm][Cl] and NaN(CN)₂ as described for [MOMMIm][dca] as a yellow oil (90.1%). ¹H NMR (acetone-d₆): δ = 9.09 (s, 1H), 7.76 (d, 1H), 7.72 (d, 1H), 4.54 (t, 2H), 4.07 (s, 3H), 3.87 (m, 2H), 3.57 (m, 2H), 1.16 (t, 3H). MS (esp⁻): m/z 66.2 (100%, dca⁻).

[BMIm][dca]. To a solution of [BMIMm][Cl] (8.7 g, 5 mmol) in acetone (20 mL) was added NaN(CN)₂ (4.45 g, 5 mmol); the mixture was stirred for 24 h and the solid NaCl was removed by filtration. The filtrate was brought on a silica gel column and eluted with dichloromethane–acetone (30 ∶ 70, v/v). The eluate was concentrated by rotary evaporation (8.5 g, 83.3%). ¹H NMR (acetone-d₆): δ = 9.13 (s, 1H), 7.80 (m, 1H), 7.73 (m, 1H), 4.39 (t, 2H), 4.07 (s, 3H), 1.95 (m, 2H), 1.42 (m, 2H), 0.976 (t, 3H). MS (esp⁻): m/z 66.2 (100%, dca⁻).

Solvatochromic shift measurements

Nile Red (0.4 mg) was dissolved in the ionic liquid (0.5 mL) and λ_max (in nm) was measured at 25 °C. The molar transition energy (E_NR in kJ mol⁻¹) was calculated from:

E_NR = 1196251/λ_max

where 1196251 = hcN_A × 10⁶.

Enzymatic esterification of sucrose

Sucrose (0.5 g, 1.46 mmol), dodecanoic acid (0.585 g, 3.0 mmol), immobilised Candida antarctica lipase (Novozym 435, 100 mg) and activated molecular sieve A4 were mixed with 8 mL [BMIm][dca] and stirred at 55 °C. Samples were taken and analysed by TLC. The product was identified by comparison with an authentic sample.

Acknowledgements

A donation of Novozym 435 by Novozymes (Bagsvaerd, Denmark) is gratefully acknowledged. Q.L. thanks the CSC for financial support.

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Footnote

† Visiting Scholar from Hebei Normal University (China)

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