Quaternary ammonium zinc- or tin-containing ionic liquids: water insensitive, recyclable catalysts for Diels–Alder reactions

Abstract

Synthetically important Diels–Alder reactions occur in high yield in novel Lewis acidic ambient temperature ionic liquids composed of choline chloride–MCl₂ (1:2) (M = Zn or Sn). The liquids are not moisture-sensitive and after separation of the products they can be reused with no noticeable drop in activity.

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Green Context

There is considerable interest in using ionic liquids as solvents and catalysts for organic reactions that normally require acid catalysts. Thus it is known that these are suitable media for Diels–Alder reactions but problems remain, notably moisture sensitivity, high cost and difficult extraction procedures. Here relatively inexpensive and water-insensitive ionic liquids with good activity in Diels–Alder reactions are described.

JHC

Introduction

In the search for cleaner technologies for chemical synthesis finding alternatives to toxic, volatile organic solvents is a particularly important goal. Room temperature ionic liquids have a number of properties which make them suitable alternatives to conventional solvents. They have very low vapour pressure and hence produce virtually no hazardous vapours; in addition they are non-explosive and thermally stable providing a relatively wide liquid range. Their polar nature means they are often immiscible with organic solvents and may therefore be used in biphasic systems. In principle this provides an easy separation of products from metal-containing catalysts and allows easy recycling of the ionic liquid phase for reuse of solvent and catalyst. The use of room temperature ionic liquids as solvents for synthesis and catalysis has recently been reviewed.¹

Diels–Alder reactions are some of the most useful carbon–carbon bond forming reactions in organic chemistry² being used in the synthesis of many natural products and physiologically active molecules. Solvent effects on the rate and selectivity of Diels–Alder reactions are well established, notably use of water as a solvent leads to dramatic enhancements of rate and stereoselectivity.³ Ionic liquids have also been used as solvents and as Lewis acid catalysts for Diels–Alder reactions. For example, the reaction between cyclopentadiene and ethyl or methyl acrylate gave a mixture of endo and exo products in a ratio of 6.7∶1 in [EtNH₃][NO₃].⁴ The same reactions have been studied in a number of 1-alkyl-3-methylimidazolium salts (alkyl = Et or Bu) with rate and selectivity being dependent on the anion chosen with endo∶exo selectivity up to 8∶1 in the best case.⁵ Chloroaluminate ionic liquids have been reported as both solvent and Lewis acid catalyst for Diels–Alder reactions.⁶ Thus, cyclopentadiene and methyl acrylate reacted to give endo and exo cycloadducts in greater than 79% combined yield; the rate and endo∶exo selectivity was dependent on the Lewis acidity of the ionic liquid. However, these ionic liquids are extremely sensitive to water and are corrosive to many materials because of the presence of aluminium chloride. Dialkylimidazolium bromide and trifluoroacetate are reported to catalyse Diels–Alder reactions of cyclopentadiene, however, the yields were rather low due to the weak Lewis acidity of the cations.⁷

We have now found that the combination of MCl₂ (M = Zn or Sn) with choline chloride, or related ammonium salts in a 2∶1 ratio leads to a range of ionic liquids of different melting points and viscosities.⁸ These are water insensitive, non-corrosive to steel, and have a wide range of applications,⁹ for example electrochemical metal deposition, as solvents, and in certain cases as catalysts. In addition, they are relatively inexpensive compared with the imidazolium based ionic liquids. We report here the use of these choline chloride–MCl₂ (M = Zn or Sn) ionic liquids as solvents and catalysts for a number of Diels–Alder reactions and investigate the ease of separation of the products, reuse of the liquids and the effect of water on the reactions.

Results and discussion

The Diels–Alder reactions of a number of dienes (1) and dienophiles (2) were attempted using the choline chloride–MCl₂ (1∶2) (M = Zn or Sn) ionic liquids as both solvent and catalyst and the results are shown in Table 1. In all cases isolated yields of about 90% or greater were obtained. Thus, 2,3-dimethylbutadiene (1a) reacts with acrolein (2a), methyl vinyl ketone (2b), or methacrolein (2c) in the zinc-containing ionic liquid (Table 1, entries 1, 3 and 4) to give products 3a–c, respectively, which exist as single isomers. The reactions occur in 2 , 1 h and 5 h, respectively, whereas the uncatalysed reactions are reported to take at least 1000 times longer.¹⁰ Isoprene (1b) reacts similarly with acrolein (entry 6) to give a 95:5 mixture of 4a∶4b. Cyclohexadiene (1c) reacts with acrolein, and cyclopentadiene (1d) reacts with methyl vinyl ketone or methyl acrylate (entries 7, 8 and 10) to give the corresponding Diels–Alder adducts 5, 6a and 6b, respectively, with very high endo selectivity, typical of Lewis acid catalysed reactions. This indicates that the ionic liquid is acting as a catalyst and not just as a polar medium.

Table 1 Diels–Alder reactions in choline chloride–MCl₂ (1:2) ionic liquids^a

Entry	Diene	Dienophile	Product	Ratio^c	M	Time	Yield (%)
a Reactions carried out at ambient temperature.b Reactions carried out in the presence of an equivalent amount of water to metal.c Refers to endo∶exo ratio.d Refers to the ratio of 4a∶4b.
1	1a	2a	3a	—	Zn	2 h	91
2^b	1a	2a	3a	—	Zn	2 h	91
3	1a	2b	3b	—	Zn	1 h	89
4	1a	2c	3c	—	Zn	5 h	91
5^b	1a	2c	3c	—	Zn	5 h	91
6	1b	2a	4ab	95∶5^d	Zn	55 min	90
7	1c	2a	5	97∶3	Zn	2 h	90
8	1d	2b	6a	96∶4	Zn	8 min	94
9^b	1d	2b	6a	92∶8	Zn	8 min	86
10	1d	2d	6b	83∶17	Zn	30 min	89
11	1a	2a	3a	—	Sn	20 h	85
12^b	1a	2a	3a	—	Sn	20 h	89
13^b	1b	2a	4ab	95∶5^d	Sn	24 h	88

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The reactions catalysed by the zinc-containing ionic liquids are two phase reactions; the dienophile dissolves in the ionic liquid, however, the less polar diene forms a separate phase. At the end of the reaction the product also forms a separate phase on top of the ionic liquid and is therefore easily separated by decanting or removing by pipette; washing with a small amount of hexane, which then allows reuse of the ionic liquid catalyst. For example the reaction between 1a and 2b could be repeated at least five times with no noticeable drop in activity or yield.¹¹

The use of heterogeneous zinc-containing catalysts for Diels–Alder reactions has been described. Cyclopentadiene and methyl vinyl ketone gave cyclo-adduct 6a with high endo selectivity in 80 or 84% yield in the presence of Zn²⁺ ion-exchanged Zn²⁺–K10 or Zn²⁺–AlMCM-41, respectively, at 0 °C in 2 h.¹² In the zinc-containing ionic liquid, 6a was formed in 94% yield and 96∶4 endo∶exo selectivity at room temperature in 8 min (entry 8). Similar results were found using 5 mol% ZnI₂ dissolved in a dialkylimidazolium ionic liquid,^5b emphasising that the increased rate and selectivity are primarily due to the Lewis acidic zinc.

Since the reactions were biphasic and the ionic liquid is rather viscous at room temperature mechanical stirring was required to improve mass transport. Performing the reactions in an ultrasonic bath gave very similar results though no attempt was made to optimise the irradiation in the ultrasonic bath.

To show that the zinc-containing ionic liquid is unreactive to water some reactions were repeated in the presence of water. For example, the reaction between 2,3-dimethylbutadiene and acrolein in a mixture of zinc chloride–choline chloride–water (2∶1∶2 ratio) gave 3a in 91% yield at room temperature in 2 h (entry 2) i.e. the same as in the anhydrous melt (entry 1) (compare also entries 4 and 5, 8 and 9). The most noticeable effect of the added water is to reduce the viscosity of the ionic liquid hence these reactions can be stirred magnetically. These results also suggest that traces of moisture absorbed by the hygroscopic ionic liquids should not affect their activity as Lewis acid catalysts for Diels–Alder reactions.

Having established catalytic activity with the zinc-containing ionic liquid we tested the less Lewis acidic tin-containing liquid. Reaction of 1a with 2a gave 3a in 85% yield after 24 h (entry 11), hence the catalytic activity is somewhat less than for zinc for which the corresponding reaction took 2 h (entry 1). Similarly, reaction between 1b and 2a gave 4a and 4b in a 95∶5 ratio and 88% combined yield (entry 13) almost identical to the result in the zinc-containing liquid (entry 6) though at a slower rate. As in the case of zinc, the reactions in the tin-containing liquid can be carried out in the presence of added water with no significant effect on the course of the reaction (compare entries 11 and 12).

Conclusion

We have demonstrated that the ionic liquids formed from choline chloride and MX₂ (M = Zn or Sn) in 1∶2 ratio are effective media for some Diels–Alder reactions. In these cases the primary accelerating effect of the ionic liquids is due to their Lewis acidity. The liquid products are easily separated from the ionic liquid by decantation and washing with hexane, hence the liquids are easily recycled and can be reused at least five times. The liquids are not moisture sensitive which means that no specialist apparatus is required for their synthesis or use and aqueous work-up can be used if necessary. Further experiments to probe the effect of differently functionalised ammonium cations on catalysis and whether such groups survive recycling are under way.¹¹

Experimental

General procedure for Diels–Alder reactions

A mixture of diene (12 mmol) and dienophile (12 mmol) in zinc chloride–choline chloride (2∶1) (0.5 ml) ionic liquid was stirred mechanically (reaction time as given). Then the pure cyclo-adduct was pipetted off the top of the ionic liquid and the ionic liquid was washed with hexane (2 ml). For most of the reactions purification was not necessary and the products were analysed by ¹H NMR spectroscopy (3a–c) or gas chromatography (4–6), however, where appropriate, flash column chromatography was used for further purification. Ultrasound promoted reactions were carried out in a decon-FS100b bath.

Acknowledgement

We thank Scionix Ltd., a joint venture company between Whyte Chemicals and the University of Leicester, for financial support.

References

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11. After use, if the ionic liquid is left for a prolonged period (a week or more) it becomes yellow which may be due to impurities left after the reaction. Mass spectrometric analysis of the ionic liquid after recycling suggests that the alcohol side chain of some of the ammonium cations may have reacted with the carbonyl starting material..
12. M. Onaka and R. Yamasaki, Chem. Lett., 1998, 259.

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