Low-melting sugar–urea–salt mixtures as solvents for Diels–Alder reactions

Abstract

Sweet solutions are obtained upon heating mixtures of simple carbohydrates, urea and inorganic salts to moderate temperatures, to give new chiral media for organic reactions.

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The reduction of the use of organic solvents is one goal in current efforts towards more environmentally benign chemical processes. Organic solvents are typically used in large excess compared to the reactants and have the tendency to escape into the environment by evaporation or leakage. Therefore the scope of reaction media for chemical transformations in solution has been extended in the past years to ionic liquids,¹ water² and scCO₂.³ In principle, water is the ideal solvent being non-toxic, cheap and available, but its use is limited because most organic compounds do not dissolve in pure water and many reactive substrates or reagents decompose in water.⁴ scCO₂ is an interesting environmentally friendly, non-toxic alternative to organic solvents with additional benefits as a reaction medium, such as its ready availability, ease of removal, disposal or recycling. However, its use requires more sophisticated equipment than standard lab apparatus. Ionic liquids have received a lot of attention as green solvents for their properties: no measurable vapour pressure, stability in a wide temperature range and recyclability. However, in most cases their preparation uses non-renewable resources⁵ and toxicity issues remain to be addressed. We report here the use of low-melting mixtures of sugars or sugar alcohols, urea and inorganic salts as solvents for Diels–Alder reactions. The reaction medium consists only of non-toxic compounds from readily available resources and has, like ionic liquids, small vapour pressure.

An initial screening identified stable and low-melting mixtures of bulk carbohydrates, urea and inorganic salts. Table 1 summarizes the most suitable melts in terms of stability and melting temperature (see ESI for additional data†). To evaluate the thermal stability of the melts all mixtures were analysed by differential scanning calorimetry (DSC), through three heating–cooling cycles, which showed no thermal decay. In addition, the mixtures were heated for 4 h to 95 °C without any evident decomposition.

Table 1 Stable melts of carbohydrates, urea and inorganic salts

Melting points^a	Carbohydrate	Urea	Salt
a Melting points are at normal pressure in air. b w/w percent of the compounds in the mixture. c DMU = N,N-dimethylurea
65 °C	Fructose (60%)^b	Urea (40%)	—
67 °C	Sorbitol (70%)	Urea (20%)	NH4Cl (10%)
73 °C	Maltose (50%)	DMU^c (40%)	NH4Cl (10%)
75 °C	Glucose (50%)	Urea (40%)	CaCl2 (10%)
75 °C	Mannose (30%)	DMU^c (70%)	—
77 °C	Sorbitol (40%)	DMU (60%)	—
77 °C	α-Cyclodextrin (30%)	DMU^c (70%)	—
65 °C	Citric acid (40%)	DMU^c (60%)	—

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The fructose–urea mixture gives a clear viscose melt at 65 °C, while for sorbitol the addition of NH₄Cl was necessary to achieve such low melting temperature (see Fig. 1). Other carbohydrate, urea and salt mixtures with melting temperatures around 75 °C were identified and surprisingly even a citric acid–urea mixture gave a stable melt at 65 °C. Our survey is not comprehensive and we presently cannot derive simple indicators to predict stability and melting temperature of such mixtures, but the examples show that the concept is rather general.

Fig. 1 Sorbitol (left) and a mixture of sorbitol/urea/NH₄Cl (70∶20∶10) (right) at 80 °C.

The water content of a solvent is an important parameter, which was determined to be exemplary for the mixture of sorbitol (70), urea (20) and NH₄Cl (10) by Karl Fischer titration. Using vacuum-dried raw materials for preparation of the mixture, a typical water content of 0.07% was found; using raw materials as received, the water content is approx. 1.3% (see ESI†). A vapour pressure of 1.2 × 10⁻¹ mbar at 70 °C was determined for a melt of this composition. The thermal stability of some mixtures was investigated by differential scanning calorimetry (see ESI for data†). The melts are stable in subsequent heating–cooling cycles to 120 °C. For the mixture sorbitol (70), urea (20), NH₄Cl (10) a decomposition temperature of 220 °C was determined. The thermal behaviour is identical for mixtures prepared from dried or as-received raw material.

The most suitable mixtures were then used as solvent for a Diels–Alder reaction. The reaction of cyclopentadiene with methyl (2a) and n-butyl acrylate (2b) (Scheme 1) proceeded cleanly and with high conversions in 8 h. Table 2 summarizes the results (for more data see ESI†). Work up and product isolation requires simply addition of water to the reaction mixture while still hot. The reaction medium dissolves, leaving an aqueous phase and the organic product for isolation.⁶ Alternatively, products with a low boiling point can be removed from the reaction mixture by applying high vacuum, which allows a simple reuse of the melt for several reaction runs.

Scheme 1 Diels–Alder reactions performed in carbohydrate melts.

Table 2 Diels–Alder reactions in carbohydrate–urea–salt melts

Composition of melt	Reaction temp. (°C)	Dienophile	Yield^a (%)	Endo/exo ratio^b
a Isolated yields after extraction. b Determined by gas chromatography (GC). c DMU = N,N-dimethylurea. d Quantitative conversion as monitored by GC. e Selectivity ratio with addition of 10 mol% of Sc(OTf)3.
Fructose/DMU^c (70∶30)	71	2a	quant.	2.9∶1
		2b	95	3.0∶1
Maltose/DMU/NH4Cl (50∶40∶10)	83	2a	79	3.3∶1
		2b	80	3.9∶1
Lactose/DMU/NH4Cl (60∶30∶10)	88	2a	83	3.6∶1
		2b	72	2.1∶1
Mannitol/DMU/NH4Cl (50∶40∶10)	89	2a	74	2.7∶1
		2b	92	3.5∶1
Glucose/urea/CaCl2 (50∶40∶10)	75	2a	76	3.2∶1
		2b	93	2.6∶1
Sorbitol/DMU/NH4Cl (70∶20∶10)	67	2a	quant.	5.0∶1
				(6.0∶1)^e
		2b	83	3.7∶1
				(10∶1)^e
Citric acid/DMU (40∶60)	65	2a	quant.^d	3.6∶1
		2b	quant.^d	2.6∶1
α-Cyclodextrin/DMU (30∶70)	77	2a	quant.^d	3.5∶1
		2b	quant.^d	3.6∶1

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The observed endo–exo selectivity of the Diels–Alder reactions of 2a and 2b with cyclopentadiene in the melted mixtures range from 2.5∶1 to 5∶1, with the highest selectivity in the sorbitol melt. These ratios are comparable to selectivities reported for other green solvents, such as scCO₂ (2a at 50 °C, 3∶1),⁷ water (85 °C; 2a, 3∶1; 2b, 2.5∶1),⁸ 1-butyl-3-methylimidazolium trifluoromethanesulfonate (20 °C, ethyl acrylate, 6∶1),⁹ 1-butyl-3-methylimidazolium tetrafluoroborate (−15 °C, ethyl acrylate, 5∶1) or 1-butyl-3-methylimidazolium hexafluorophosphate (20 °C, ethyl acrylate, 8∶1). As well known for reactions in organic solvents, Lewis acids catalyze Diels–Alder reactions and can improve rate and selectivity in alternative reaction media too.^7,10 Therefore the reactions in carbohydrate–urea melts were repeated with the addition of 1 equiv. of LiClO₄ or 10 mol% of Ce(OTf)₃, but selectivity ratios did not change significantly (see ESI for data†). Interestingly the addition of 10 mol% of Sc(OTf)₃ to the sorbitol/DMU/NH₄Cl (70∶20∶10) melt improved the endo–exo selectivity to 6∶1 for 2a and 10∶1 for 2b. The effect of this Lewis acid is comparable to selectivity improvements observed for Diels–Alder reactions in toluene [50 °C, 10 mol% Sc(OTf)₃: 2a, 4∶1; 2b, 10∶1], but smaller than in scCO₂ [50 °C, 10 mol% Sc(OTf)₃: 2a, 10∶1; 2b, 24∶1]. All of the reaction media used in this study are chiral solvents and therefore the possibility of a stereoinduction was investigated. However, the analysis of the products by chiral GC did not reveal any significant stereoinduction, as for many other attempts using chiral solvents.^11,12

In summary, we have reported the use of low-melting mixtures of bulk natural products, such as simple carbohydrates, sugar alcohols or citric acid, with urea and inorganic salts as reaction media for Diels–Alder reactions. In comparison to conventional organic solvents a fast conversion¹³ with good endo–exo selectivities was observed. The addition of Sc(OTf)₃ improved the endo–exo selectivity ratios similarly as observed for the reaction in toluene, but less than in scCO₂. Although chiral, no significant stereoinduction of the medium on the course of the reaction was detected. The non-toxic reaction media, made only from bulk, readily available compounds, qualify as green solvents. Their application as reaction media for other organic transformations and as a substitute to ionic liquids may be envisaged.

G. I. thanks the Deutsche Bundesstiftung Umwelt for a graduate scholarship. We thank Prof. A. Geyer and the referees for helpful comments.

Notes and references

1. J. D. Holbrey, M. B. Turner and R. D. Rogers, Ionic Liquids as Green Solvents, ACS Symposium Series, 2003, 856, 2–12.
2. R. Breslow, Green Chem., 1998, 225–233 ; for the use of water as solvent in asymmetric catalysis, see: K. Manabe and S. Kobayashi, Chem. Eur. J., 2002, 8, 4094–4101; S. Denis, Adv. Synth. Cat., 2002, 344, 221–237.
3. W. Leitner, Appl. Organomet. Chem., 2000, 14, 809–814; W. Leitner, Chem. Unserer Zeit, 2003, 37, 32–38.
4. Another drawback is the high heat capacity, which makes removal of the solvent from reaction mixtures or products very energy consumptive.
5. There are exceptions, e.g. ionic liquids based on fructose: S. T. Handy, M. Okello and G. Dickenson, Org. Lett., 2003, 5, 2513–2515.
6. For small scale reactions extraction with an organic solvent, such as pentane or toluene, is necessary to avoid loss of material.
7. R. S. Oakes, T. J. Heppenstall, N. Shezad, A. A. Clifford and C. M. Rayner, Chem. Commun., 1999, 1459–1460.
8. S. Otto and J. B. F. N. Engberts, Pure Appl. Chem., 2000, 72, 1365–1372; G. Jenner, J. Phys. Org. Chem., 1999, 12, 619–625; W. Blokziji, M. J. Blandamer and J. B. F. N. Engberts, J. Am. Chem. Soc., 1991, 113, 4241–4246; A. Meijer, S. Otto and J. B. F. N. Engberts, J. Org. Chem., 1998, 63, 8989–8994; G. K. van der Wel, J. W. Wijnen and J. B. F. N. Engberts, J. Org. Chem, 1996, 61, 9001–9005; R. Breslow, Acc. Chem. Res., 1991, 24, 159–164; J. Chandraesekhar, S. Shariffskul and W. L. Jorgensen, J. Phys. Chem. B, 2002, 106, 8078–8085.
9. M. J. Earle, P. B. McCormac and K. R. Seddon, Green Chem., 1999, 23–25.
10. K. Manabe, Y. Mori and S. Kobayashi, Tetrahedron, 1999, 55, 11203–11208; M.-J. Diego-Castro and H. C. Hailes, Tetrahedron Lett., 1998, 39, 2211–2214; J. Matsuo, T. Tsuchiya, K. Odashima and S. Kobayashi, Chem. Lett., 2000, 178–179.
11. No stereoinduction could be found for reactions in chiral ionic liquids, such as 1-butyl-3-methylimidazolium lactate, see ref. 9.
12. C. Baudequin, J. Baudoux, J. Levillain, D. Cahard, A.-C. Gaumont and J.-C. Plaquevent, Tetrahedron: Asymmetry, 2003, 14, 3081–3093.
13. The reaction rate constants are in the order of k₂ ∼ 10 × 10⁻³ mol L⁻¹ s⁻¹.

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Footnote

† Electronic supplementary information (ESI) available: tables of melting points of mixtures of carbohydrates, urea and inorganic salts in various compositions, endo–exo selectivities of Diels–Alder reaction in such melts, water content and thermal stability (determined by DSC) of mixtures. See http://www.rsc.org/suppdata/cc/b4/b414515a/

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