New developments in catalysis using ionic liquids

New developments in catalysis using ionic liquids

Applied Catalysis A: General 222 (2001) 101–117 New developments in catalysis using ionic liquids Charles M. Gordon∗ Department of Pure and Applied C...

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Applied Catalysis A: General 222 (2001) 101–117

New developments in catalysis using ionic liquids Charles M. Gordon∗ Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, UK

Abstract Ionic liquids are low melting point salts that represent an exciting new class of reaction solvents for catalysis. Being composed entirely of ions, they possess negligible vapour pressures, and the wide range of possible cations and anions means that other solvent properties may be easily controlled. There is currently great interest in the use of these materials as solvents for a wide range of applications, including catalysis. Many reactions show advantages when carried out in ionic liquids, either with regard to enhanced reaction rates, improved selectivity, or easier reuse of catalysts. This review is intended to bring the reader up to date on the developments involving ionic liquids in catalytic applications over the previous 18 months. Recent spectroscopic investigations into the solvent properties of ionic liquids with relevance to catalysis are discussed first, followed by a critical review of the major developments in transition metal, Lewis acid, and enzyme catalysed processes in these solvents. Particular emphasis is given to the combination of ionic liquids with supercritical fluids, Pd-based catalysts, and enzymes. Wherever possible, the results gained in ionic liquids are critically compared with those obtained using other catalytic systems. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Ionic liquids; Biphasic catalysis; Pd catalysis; Supercritical fluids; Lewis acid catalysis; Biocatalysis

1. Introduction Developments in the field of catalysis are being reported constantly, in the form of new catalysts, novel catalytic reactions, and alternative methodologies. Much of the pressure for this is driven by the economic requirement to develop systems in which easy separation of products and reuse of catalyst is possible, along with high reactivity and selectivity. A significant advance in recent years has been the advent of biphasic catalysis, where the catalyst is isolated in one phase and the product remains in another, thus allowing easy product isolation and catalyst reuse. As part of this effort, an ever-increasing degree of interest has been focussed on ionic liquids as media ∗ Tel.: +44-141-548-2285; fax: +44-141-548-4822. E-mail address: [email protected] (C.M. Gordon).

for catalysis, both biphasic and homogeneous. Ionic liquids are simply liquids that are composed entirely of ions, but they may be distinguished from classical molten salts by their low melting points: generally <100–150 ◦ C, although most described in this review are molten at room temperature. They are also generally much less corrosive than their high melting point relatives. This means that they can be conveniently used in place of conventional organic solvents, for example, in catalytic processes as will be outlined in this review. The history of ionic liquids goes back to 1914, when Walden reported the synthesis of ethylammonium nitrate (m.p. 12 ◦ C) [1]. This material is formed simply by the reaction of ethylamine with concentrated nitric acid, but its discovery did not prompt any great amount of interest at the time. In the 60 or so years that followed, although the majority of work on

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molten salts involved their use as high temperature media for electrochemical and other studies, a steady stream of work also reported the use of lower melting salts as solvents for organic reactions. Much of this work involved the use of chloroaluminate-based salts such as AlCl3 –NaCl eutectics and pyridinium hydrochloride, and is summarised in an excellent review by Pagni [2]. The use of salts based on organic cations was quite limited in this period, however. In 1967, for example, Swain et al. described the use of tetra-n-hexylammonium benzoate as a solvent for kinetic studies and electrochemical reactions [3]. Most of the salts employed still displayed melting points above room temperature, however. Probably the most significant discovery in this area, however, was by Hurley [4] and Hurley and Weir [5] in 1948, who developed room temperature liquid chloroaluminate melts for applications in aluminium electroplating. Room temperature ionic liquids only really reached a more general audience with the reopening of development in this area by the groups of Osteryoung and co-workers [6,7] and Wilkes et al. [8] in the 1970s. Through the 1980s chloroaluminate ionic liquids were studied by, especially the groups of Hussey et al. [9] and Seddon et al. [10], as solvents for transition metal complexes, mainly through electrochemical and spectroscopic investigations. The first report on the use of this type of low melting ionic liquids as reaction media for organic synthesis was in 1986, as combined solvents and catalysts for Friedel–Crafts reactions [11]. Their first applications as solvents for biphasic catalysis came in 1990 by Chauvin et al., who reported the dimerisation of propene by nickel complexes dissolved in acidic chloroaluminate melts [12] and Osteryoung who reported the polymerisation of ethylene by Ziegler–Natta catalysts [13]. The main problem with the ionic liquids based on chloroaluminate anions, however, remained their sensitivity to water and oxygen. In addition, these liquids are incompatible with many organic compounds such as alcohols and acetone. A major breakthrough occurred in 1992, with the report by Wilkes’ group of the synthesis of a series of air- and moisture stable imidazolium salts based on anions such as [BF4 ]− and [PF6 ]− [14]. Since this time, the number of different ionic liquids reported has expanded enormously. Ionic liquids have been applied to a wide range of applications, not only within the fields of biphasic catalysis and organic synthesis, but

also covering such diverse applications as separations [15] electrochemistry [16] photochemistry [17] and liquid crystals [18]. Overall, however, the potential applications in biphasic catalysis arguably show the greatest potential for finding industrial applications. The aim of this review is two-fold. Firstly, to highlight the papers that have appeared over the past 18 months or so in the area of ionic liquid based biphasic catalysis. In doing so, it is intended as a general supplement to the excellent reviews of Welton [19], Holbrey and Seddon [20], and Wasserscheid and Keim [21], to which the reader is directed for a full coverage of the earlier literature. Secondly, three areas potentially of great interest will be discussed in some detail, notably the use of supercritical fluids with ionic liquids, palladium catalysed reactions, and biocatalysis in ionic liquids. These are areas which have attracted particular interest over the last year or so, but which are also potentially very exciting areas of development for catalysis using ionic liquids as solvents. The remainder of the review will bring up to date other areas of catalysis using other transition metals and Lewis acids. Where possible, the advantages or disadvantages of the ionic liquid-based systems will be benchmarked against alternative systems to allow a true comparison to be made, and an assessment of the future potential will be assessed.

2. Synthesis and properties of ionic liquids The reviews mentioned in the previous section provide an excellent source of information for much of the background on the preparation and properties of ionic liquids, and so only more recent developments will be discussed here. Almost all of the work described in this review has been carried out in neutral ionic liquids based on 1,3-dialkylimidazolium cations (Fig. 1), with 1-butyl-3-methylimidazolium [bmim]+ being probably the most common cation. Other cations

Fig. 1. Examples of typical 1-alkyl-3-methylimidazolium cations and the abbreviations used to refer to them in this article.

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employed to a lesser extent include 1-alkylpyridinium, 1,1-dialkylpyrrollidinium, tetraalkylammonium and tetraalkylphosphonium. The most common anions are [PF6 ]− and [BF4 ]− , particularly for catalytic applications, although in principle any anion could be employed. The synthesis of these salts is described elsewhere [19,21]. Ionic liquids of this type have displayed the useful combination of low melting point, along with high thermal and chemical stability necessary for a reaction solvent. They are also generally good solvents for transition metal complexes, but poorly miscible with non-polar organics such as alkanes and ethers, allowing the formation of biphasic systems and the use of homogeneous catalysts. Some ionic liquids (for example those based on anions such as [PF6 ]− and [(CF3 SO2 )2 N]− ) are also immiscible with water, introducing the possibility of forming triphasic systems or alternative separation methods. Not all of the systems reported here are “typical” biphasic systems, where reactants and catalyst exist in two mutually immiscible layers. In many cases, the reaction mixture is homogeneous, but when the reaction is complete a biphasic system is created by the addition of an extraction solvent immiscible in the ionic liquid. The other property unique to ionic liquids as reaction solvents is their lack of measurable vapour pressure. This means that they emit no volatile organic compounds, and also introduces the additional possibility of removal of products by distillation without contamination by the solvent. It also facilitates the recycling of ionic liquids, which is likely to be a financial necessity in any industrial application given the greater cost of these materials than conventional organic solvents. Properties such as melting point, density, viscosity and solvation ability can be finely tuned by alteration of the cation or anion [21]. In general, ionic liquids have densities >1, and thus exist as the lower phase in most biphasic systems. They are also generally quite viscous compared with conventional organic solvents, which means that phase separation from organic solvents is often more rapid than with two solvents of similar viscosity. Examples of density and viscosity for typical imidazolium-based ionic liquids are given in Table 1 [22–24]. From these data, it can be seen that the density decreases, but the viscosity increases as the length of the alkyl chain substituent on the imidazolium ring increases. When liquids formed

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Table 1 Densities and viscosities of typical ionic liquids Ionic liquid

Density at 20 ◦ C (g cm−3 )

Dynamic viscosity at 20 ◦ C (cP)

[bmim][PF6 ] [bmim][BF4 ] [emim][Tf2 N]e,f [bmim][Tf2 N] [emim][TfO] [bmim][TfO]

1.37a,b 1.24a,d 1.52g,h 1.43g 1.39g,h 1.29g

330c 154d 34g 52g 45g 90g

At 30 ◦ C. See [22]. c Our work. d See [23]. e emim = 1-ethyl-3-methylimidazolium. f Tf = CF SO . 3 2 g See [24]. h At 22 ◦ C. a

b

by the combination of organic halide salts and Lewis acids (e.g. chloroaluminate melts) are added to the equation, acidity and basicity can also be introduced. When ionic liquids are compared with other solvents widely used in biphasic catalysis, a number of clear advantages can be seen. Firstly, transition metal complexes are generally soluble in ionic liquids without chemical modification of the type that is often needed for aqueous and fluorous systems. The ionic liquids used in catalytic systems are also generally regarded as polar but weakly coordinating, a concept that will be expanded upon later in this section. This means that, although the catalysts are very soluble in the ionic liquid phase, a non-coordinating anion will mean that the active site is very accessible to organic substrates. Furthermore, ionic liquids are generally chemically inert towards both catalysts and reactive intermediates, meaning that catalyst stability is not a problem. Finally, the miscibility of ionic liquids can be controlled by altering their chemical makeup, thus allowing “tuning” of the system towards formation of a biphasic system, as well as optimisation of reaction conditions. Up until recently, little quantitative information existed regarding the nature of interactions between ionic liquids and different types of solute. Such information is obviously of great importance if we are to understand why certain types of reaction occur particularly favourably in these media. A simplistic view might be that ionic liquids are composed entirely of

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ions, and are therefore, very polar. As will be explained below, this is at best a great oversimplification, and in some cases incorrect. One of the major differences between ionic liquids and a typical organic solvent is that the former is a binary mixture of two different species, and thus is likely to engage in a much wider range of solvent–solute interactions. Recently, therefore, a number of research groups have carried out investigations using solvatochromic probes to try to gain more insight into this important area. Studies using Nile Red [25] and Reichardt’s dye [26] have suggested that ionic liquids based on 1-alkyl-3-methylimidazolium cations act as H-bond donors to the same degree as short chain alcohols, and can thus be regarded as being relatively polar. Previous studies on alkylammonium salts using Reichardt’s dye have shown that tetraalkyl derivatives are relatively non-polar, while those containing cations of the type [NHx R(4−x) ]+ (x ≥ 1) are considerably more polar. The fluorescent probes 4-aminophthalimide and 4-(N,N-dimethylamino)phthalimide have also been applied to investigations of the polarity of ionic liquids [27]. This study supported the measurements with Reichardt’s dye [26] indicating that the polarity of 1-alkyl-3-methylimidazolium based ILs was similar to that of short chain alcohols, and that the polarity decreased somewhat as the alkyl chain length increased. In these studies, changing the anion appeared to have little effect on the polarity of the ionic liquid. 1-Butylpyridinium tetrafluoroborate was also measured using these probes, and this proved to exhibit a lower polarity than the imidazolium salts. One feature highlighted in this study was the influence of water on position of λmax , of 4-(N,N-dimethylamino)phthalimide which shifted from 526 nm in water-saturated [bmim][PF6 ] (water content ∼0.324 M) to 512 nm (i.e. less polar) in [bmim][PF6 ] that had been dried by heating in vacuo for 24 h (water content ∼0.015 M). Another example of this is shown by work from the author’s own research group, where the λmax of Reichardt’s dye displayed a shift from 526 nm in water-saturated [bmim][PF6 ] to 546.5 nm in dry solvent. This clearly shows that for any physical measurements carried out in ionic liquids, the water content should be established. Clearly, the presence of water may also influence the performance of an ionic liquid in catalytic applications.

The probes discussed above give little indication of the role of the anion in solvation, so an alternative probe molecule is required to quantify this effect. The square planar Cu(II) salt 1 has been shown to give a good correlation between the donor number of a solvent and the λmax value for the lowest energy d–d band [28] arising from changes in the splitting of the d-orbitals as the solvent coordinates at the axial sites on the metal centre.

It has also been shown that this salt can be used to estimate the donor number of anions in solution [29]. The position of λmax has been recorded for a range of ILs based on the [PF6 ]− , [TfO]− and [Tf2 N]− anions, and the results indicate that the strength of coordination at the Cu(II) centre is entirely anion-dependent [26]. The results gained using solvatochromic probes have recently been correlated with the reactivity of Ni-catalysed oligomerisation of ethylene carried out in ionic liquids and other solvents [30]. Details of this system are given in Section 5. Clearly our understanding of the solvent properties of ionic liquids remains quite incomplete, as only a handful of solvatochromic probes have been employed, and only for a small range of ionic liquids. The concept of “polarity” in ionic liquids must be considered carefully as the presence of both cations and anions can lead to far more possible interactions than in conventional molecular solvents. Nevertheless, the results shown above have started to give a picture of imidazolium-based ionic liquids as media which are polar, but whose basicity can be controlled by the nature of the anion present. It is this unique combination of factors that seems to make these materials so suitable for use in catalytic applications.

3. Supercritical fluids and ionic liquids One of the recurrent problems with the use of ionic liquids for organic synthesis is the extraction of products, owing to the lack of volatility of the liquids

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themselves. In biphasic systems this problem may be alleviated, as the products form a separate phase from the ionic liquid layer, which generally contains the catalyst. If a truly biphasic system cannot be achieved, organic products can usually be extracted using solvents that are immiscible with the ionic liquid (in many cases diethyl ether or an alkane). Although leaching of catalyst into the organic phase can be minimised, the small mutual solubility of the two phases means that in many cases investigated to date, a degree of catalyst loss is observed when the ionic liquid/catalyst system is recycled. One novel approach that reduces this possibility is the use of supercritical CO2 (scCO2 ) as the extractant for the organic products. Blanchard et al. first suggested the possibilities of this method [31] showing that naphthalene could be extracted quantitatively by scCO2 from [bmim][PF6 ]. Subsequent work by the same group has shown that a wide variety of solutes may be extracted in this manner, without any contamination by the ionic liquid [32]. This is a result of the observation that, although CO2 is extremely soluble in ionic liquids, the reverse is not the case, with no appreciable IL solubilisation in the CO2 phase. One important observation was that the solubility of CO2 in ILs was very dependent on the water content. Water saturated [bmim][PF6 ] can contain up to 2.3 wt.% water, and has a CO2 solubility of only 0.13 mol fraction compared with 0.54 mol fraction CO2 in dried (ca. 0.15 wt.% water) [bmim][PF6 ] at 57 bar and 40 ◦ C [33]. Thus, effective use of scCO2 as an extractant may be limited to systems that can be kept water-free. Spectroscopic evidence that CO2 dissolves in [bmim][PF6 ] and [bmim][BF4 ] was also reported recently Kazarian et al. using ATR-IR [34]. These investigations gave an estimate of 0.6 mol fraction for the solubility of CO2 in [bmim][PF6 ] at 68 bar and 40 ◦ C. The first report of an attempt to combine scCO2 (and scC2 H6 ) and [bmim][BF4 ] for Rh colloid-catalysed hydrogenation of arenes was not promising, however [35]. The authors suggested that the lack of activity towards hydrogenation might have resulted from deactivation of the catalyst by traces of Cl− in the ionic liquid. Following the studies reported above, three succesful reports of catalysis using combined IL/scCO2 systems have been reported. Asymmetric hydrogenation of tiglic acid using Ru(O2 CMe)2 ((R)-tolBINAP) proceeded with excellent yield and selectivity in [bmim][PF6 ] (Eq. (1)) [36].

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(1) The product was then extracted in an extremely pure form into scCO2 , without contamination from either the ionic liquid or the Ru complex. Conversions of up to 99% combined with ca. 90% ee were obtained, and the catalyst solution could be reused for four further cycles with no apparent decrease in catalyst activity. The influence of addition of water, propan-2-ol and AgPF6 was also investigated, along with that of higher H2 pressures. No kinetic data were recorded in this study, however. The authors also reported the asymmetric hydrogenation of isobutylatropic acid, to give the antiinflammatory drug ibuprofen (2, Eq. (2)).

(2) In this case, poor enantioselectivity was observed in wet ionic liquid, but when methanol was added an ee of 85% was observed using 100 bar H2 . This is higher than the enantioselectivity observed in aqueous/organic biphasic systems. Hydrogenation reactions have also been investigated in a combined scCO2 -ionic liquid system. Liu et al. report the hydrogenation of dec-1-ene and cyclohexene using Wilkinson’s catalyst RhCl(PPh3 )3 [37]. The system remained biphasic throughout the reaction, and for the hydrogenation of dec-1-ene a conversion of 98% after 1 h was reported, corresponding to a turnover frequency (TOF) of 410 h−1 . The results suggest, however, that there is no reactivity advantage with using scCO2 in place of hexane in biphasic reactions of this type. The same paper reports the RuCl2 (dppe)2 -catalysed (dppe = Ph2 PCH2 CH2 PPh2 ) hydrogenation of CO2 in the presence of dialkylamines to produce N,N-dialkylformamides. This

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Scheme 1.

reaction was chosen as it involves ionic carbamate intermediates, as shown in Scheme 1, which would be expected to be much more soluble in the IL phase than in scCO2 . This proved to be the case, and the reaction of di-n-propylamine in a mixed scCO2 –IL system resulted in complete amine conversion, along with exclusive formation of N,N-di-n-propylformamide. This product was very soluble in the ionic liquid phase, partitioning only poorly into scCO2 and resulting in disappointing yields after the first reaction cycle. It was found, however, that the isolated yield of N,N-di-n-propylformamide increased from <5% in the first reaction cycle to quantitative recovery by the third and fourth cycle, suggesting that the IL phase becomes saturated with product over the first two reaction cycles. The final example reported to date describes the use of a continuous flow scCO2 /[bmim][PF6 ] system for the rhodium catalysed hydroformylation of hex-1-ene [38]. With [Rh2 (OAc)4 ]/P(OPh)3 as the catalyst source, carrying out the reaction in pure [bmim][PF6 ] resulted in high yields but a very poor aldehyde selectivity (15.7%), and a poor linear: branched (l:b) product ratio. When a combined scCO2 / [bmim][PF6 ] system was employed, the reaction rate fell, but much improved selectivity was observed (82.3% aldehyde; 6.1:1, l:b). Unfortunately, although

the reaction system could be recycled two or three times, after this time the catalyst was deactivated. Greatly improved results were observed, however, when [bmim][Ph2 PC6 H4 SO3 ] was used as the ligand in place of P(OPh)3 . In this case, the activity of the catalyst remained high over 12 runs (TON = 160–320 h−1 ), although the l:b ratio fell steadily from 3.7:1 to 2.5:1. No leaching of the rhodium was observed over the first nine cycles, but after this time it became significant owing to formation of scCO2 soluble [RhH(CO)4 ]. Finally, a continuous flow scCO2 /[bmim][PF6 ] system was used for the hydroformylation of oct-1-ene in conjunction with [pmim]2 [PhP(C6 H4 SO3 )2 ] as the ligand. In this case, the reaction was slow for the first 8 h of reaction. After this time, however, a linear plot of catalyst turnover versus time indicated that no catalyst decomposition was occurring over periods up to 72 h. The l:b ratio was reported as >3:1 over the whole reaction time, and <1 ppm Rh was identified in the product stream. The initial reports discussed above indicate that the combination of ionic liquids with supercritical fluids represents an extremely promising combination of techniques for biphasic catalysis. The problem of catalyst leaching into the product stream is clearly greatly reduced compared with traditional biphasic systems. It is likely that many more examples will be reported in the near future.

Scheme 2.

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4. Pd catalysis Some of the most promising applications of biphasic catalysis using ionic liquids have involved Pd-based catalysts. Most of the reactions studied to date have been C–C coupling reactions, and clear advantages in catalyst recycling and product separation have been previously shown to result when Heck reactions are carried out using both alkylammonium- [39–41] and imidazolium-based ionic liquids [42,43] as solvents.

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versions were obtained using a range of arenes when the quantity of dppp was doubled to 2 equiv. in the ionic liquid reactions. In addition to the Heck reaction, a number of other palladium-catalysed processes have been reported recently, principally cross-coupling reactions. Mathews et al. reported that Suzuki cross-coupling reactions using Pd(PPh3 )4 as catalyst and [bmim][BF4 ] as solvent gave excellent yields and TONs at room temperature (Eq. (3)) [47].

(3) It has been suggested that this is in part a result of the in situ formation of palladium carbene complexes in the imidazolium-based ionic liquids [44]. A recent publication has reported that the use of a Pd-benzothiazole carbene complex in combination with tetrabutylammonium bromide as solvent can result in conversion of bromobenzene to butyl cinnamate with a yield of 94% in only 10 min when sodium carbonate is used as the base [45]. Another recent report on the Heck reaction in ionic liquids describes how [bmim][BF4 ] has been successfully used for the regioselective arylation of an electron rich olefin, butyl vinyl ether [46]. Reactions of this type generally require the use of aryl triflates, silver triflate, or thallium acetate in order to obtained good yields. The active catalyst was prepared in situ from Pd(OAc)2 and 1,3-bis(diphenylphosphino)propane (dppp), and the reaction in [bmim][BF4 ] was compared with that in four conventional organic solvents. Although a conversion of only 50% was observed, the ␣-arylated product was formed regioselectively (Scheme 2). In DMF and DMSO, quantitative conversions of the starting material were observed, but a significant proportion of the ␤-arylated product was formed in each case, while toluene and acetonitrile gave both poor conversions and a mixture of products. Furthermore, after the reaction in ionic liquid palladium black was not observed, as was always the case with the conventional solvents. Finally, quantitative con-

In this system, it was found that optimum catalytic activity was achieved by pre-heating the catalyst with the aryl halide in [bmim][BF4 ] at 110 ◦ C, after which the reaction was started by addition of the arylboronic acid and Na2 CO3 at room temperature. An extremely large increase in reaction rate was observed compared with the conventional Suzuki conditions. The reaction of bromobenzene with phenylboronic acid under conventional Suzuki conditions result gave an 88% yield in 6 h (TON, 5 h−1 ), while the equivalent reaction in [bmim][BF4 ] gave 93% in 10 min (TON, 455 h−1 ). The reaction products were typically extracted using diethylether, while the by-products (NaHCO3 and NaXB(OH)2 (X = halide)) were removed using excess water. After this the ionic liquid/catalyst system was used for three further reaction cycles with no decrease in either yield or TON. Palladium catalysed Negishi cross-couplings of organozinc reagents were achieved in 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ([bdmim][BF4 ]) using a novel ionic phosphine prepared by reaction of PPh2 Cl with [bmim][PF6 ] (3) [48].

Yields of 70–92% were obtained using a variety of substrates, the fastest reactions being observed

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for aryl iodides. Recycling of the catalyst/IL system was attempted, but after the third cycle a decrease in yield and increase in reaction time was observed, suggesting that catalyst decomposition or leaching was occurring. Handy et al. have reported a range of Stille couplings using PdCl2 (PhCN)2 /Ph3 As/CuI in [bmim][BF4 ] [49]. Good yields and catalyst recyclability were reported for the reaction of ␣-iodenones with vinyl and aryl stannanes, although the reaction rates reported were considerably lower than those obtained in N-methylpyrrolidinone. The formation of diaryl compounds in good yields by the same reaction was also reported. The yields obtained in this reaction proved to be extremely dependent on the catalyst employed. For example, the reaction of p-iodoanisole and phenyl tributyltin proceeded with a yield of 82% using the PdCl2 (PhCN)2 /Ph3 As/CuI catalyst system, while Pd(PPh3 )4 gave a yield of 30%, and no product was observed with Pd(OAc)2 . With aryl bromides on the other hand, the PdCl2 (PhCN)2 /Ph3 As/CuI system gave only 35% yield, while Pd(PPh3 )4 gave the desired product in 90% yield. Competition reactions indicated that the reaction remained chemoselective to the weaker C–I bond in all cases, however, as indicated below (Eq. (4)).

(4)

Scheme 3.

Palladium-catalysed allylic substitution in ionic liquids was first reported by Chen et al. in 1999 [50]. The same group has also reported that the nature of the phosphine ligand employed can have profound effects on the activity of the palladium catalyst [51]. Electron donating phosphines such as PCy3 gave the fastest rates, while use of electron acceptors such as P(OPh)3 resulted in very low levels of conversion. A comparison between [bmim][BF4 ] and THF showed that the ionic liquid allowed the use of a wider range of phosphines for the same reaction. This was assigned to mechanistic differences between the two solvents, with the ionic liquids enhancing charge separation in the intermediate allylpalladium complex, and thus reducing the likelihood of a reverse reaction (Scheme 3). An enantioselective allylic substitution reaction between (rac)-(E)-1,3-diphenyl-3-acetoxyprop-1-ene and dimethylmalonate has also been reported, using chiral Pd0 -ferrocenylphosphine complexes in [bmim][PF6 ] (Scheme 4) [52]. The best yield (81%) and ee value (74%) were obtained in a homogeneous system using a catalyst prepared in situ from Pd2 (dba)3 ·CHCl3 and ligand 4. On recycling, this system gave a somewhat reduced yield, but a similar ee value. When the catalytic reaction was carried out in a biphasic system using toluene or cyclohexane as the second phase, similar yields and

Scheme 4.

C.M. Gordon / Applied Catalysis A: General 222 (2001) 101–117

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Scheme 5.

ee values to those from the homogeneous system were obtained from the first reaction cycles, but recycling of the IL/catalyst system resulted in much reduced enantioselectivities. Mizushima et al. have reported the palladium-catalysed carbonylation of aryl halides in [bmim][PF6 ] and [bmim][BF4 ] [53]. The reaction between a range of alcohols and bromobenzene proved to give greatly enhanced yields when [bmim][BF4 ] was present (82–91% depending on the alcohol) compared with the reaction in the absence of the IL (26–32%). Somewhat lower yields were obtained using [bmim][PF6 ]. It was found that the catalyst/IL mixture could be recycled up to four times, although with decreasing yield for each successive cycle. The recyclability of the catalyst was improved by increasing the ratio of PPh3 :Pd(OAc)2 from 4:1 to 20:1, a move that also increased the yield on the initial reaction to 99% in both ionic liquids. When the same reaction is carried out under higher pressures of CO, double carbonylation can occur, forming the ␣-ketoester (Scheme 5). With Pri OH as the nucleophile, the single carbonylation product was formed with much greater selectivity in [bmim][PF6 ] than in neat Pri OH. When the nucleophile was NEt2 H, however, little difference was observed in the presence of an ionic liquid, although the catalyst could once again be recycled. Finally, Dupont et al. have reported the use of Pd(acac)2 (acac = acetylacetonate) dissolved in [bmim][BF4 ] and [bmim][PF6 ] for the selective

biphasic hydrogenation of a range of conjugated and non-conjugated dienes to form monoenes [54]. Good selectivity for hydrogenation of only one double bond was observed in all cases, generally with trans-selectivity where applicable (Scheme 6). Turnover number values were similar for both ionic liquids (TON 982 for [bmim][BF4 ], and 885 for [bmim][PF6 ]). It should be noted, however, that for 1,3-butadiene the selectivity and TON values reported for reactions carried out in the ionic liquids differed little from those obtained in neat diene and in CH2 Cl2 solution. Set against this, separation of the products and reuse of the catalyst solution was clearly easier in the ionic liquid reaction. In the hydrogenation of 1,3-butadiene, the catalyst solution was recycled 15 times without apparent decrease in activity. The rate of conversion also showed great dependence on H2 pressures.

5. Other transition metal catalysed reactions Although ionic liquids are generally much better solvents for transition metal catalysts than the organic products in biphasic systems, catalyst leaching can still be a problem, particularly in reactions such as hydroformylation. As a result, reactions using novel cationic guanidinium-modified phosphine ligands have been reported by Wasserscheid et al. [55]. Ligand 5 has been used for the Rh-catalysed hydroformylation of oct-1-ene in [bmim][PF6 ].

Scheme 6.

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Although the conversions obtained were lower on the first cycle than those using PPh3 as the ligand, much lower levels of leaching were observed (<0.07% compared with 53%). This meant that the levels of conversion remained similar on recycling of the catalyst/IL mixture. The selectivity for the n-isomer was relatively low using 5, however. When the reaction was repeated using a specially prepared xanthene based bidentate phosphine ligand 6, the conversion steadily increased as the catalyst was reused (from 10.6% on the first run to 44.3% on the seventh run), and a much better n:iso ratio of ca. 20:1 was obtained. Once again, little catalyst leaching was observed. Alkene oligomerisation has been one of the more widely studied of transition metal catalysed reactions in ionic liquids. Recently, the oligomerisation of ethylene has been achieved using a cationic Ni-based catalyst both in a biphasic system where the catalyst was immobilised in [bmim][PF6 ], and homogeneously using CH2 Cl2 as the solvent [30]. Using the ionic liquid, a much higher selectivity for linear alk-1-enes was achieved than in any previous systems. Moreover, the rate of reaction was nearly seven times faster in [bmim][PF6 ] (TOF = 12712 h−1 ) than in CH2 Cl2 (TOF = 1852 h−1 ). Effectively no conversion was observed in butane-1,4-diol, however. This solvent gives a biphasic system, and is used successfully with neutral Ni complexes (for example the Shell SHOP ethylene oligomerisation process). Studies using solvatochromic dyes indicated that, although [bmim][PF6 ] has a polarity almost identical to butane-1,4-diol, it coordinates with Cu(II)-based

solvent probe 1 only slightly more strongly than CH2 Cl2 . Relatively few transition metal catalysed oxidation reactions have been reported in ionic liquids, the first being the epoxidation of allylic ethers and allylic arenes using a chiral Mn (III)(salen) complex [56]. More recently, Owens and Abu-Omar reported the epoxidation of alkenes and allylic alcohols using methyltrioxorhenium and urea hydrogen peroxide (UHP) in [bmim][BF4 ] [57]. In almost all cases, conversions and selectivity towards epoxide formation were excellent. When aqueous hydrogen peroxide was used in place of UHP, however, the diol was formed almost exclusively. Although no direct comparison with conventional solvents was made, reaction times were reported to be comparable. Also, no reference was made regarding whether the catalyst retained activity when recycled. Song et al. have reported the Cr(salen) catalysed asymmetric ring opening of epoxides in a range of [bmim]+ based ionic liquids [58]. Excellent yields and ee values were obtained using hydrophobic ionic liquids [bmim][PF6 ] and [bmim][SbF6 ] (see Scheme 7), while in the water miscible salts [bmim][BF4 ] and [bmim][TfO], little or no product was formed under the same conditions. This was perhaps surprising, as the authors report that the catalyst was fully dissolved in the latter solvents, while it remained as a suspension in the hydrophobic liquids. In order to aid catalyst immobilisation, the reaction was also carried out in a 5:1 mixture of [bmim][PF6 ]

Scheme 7.

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and [bmim][TfO], giving a good combination of catalyst activity and immobilisation (68% yield, 94% ee). This system allowed reuse of the catalyst over five cycles with no loss of activity or ee and with little leaching of catalyst. Unfortunately no comparison with the reaction yield, rate or stereoselectivity in conventional media was reported in this paper. In a final example of oxidation, Howarth has reported the first example of conversion of aromatic aldehydes to aromatic alcohols in an ionic liquid [59]. The catalyst used was [Ni(acac)2 ] (3 mol%), with O2 at atmospheric pressure the oxidant. The yields obtained were in the range 47–66%, lower than those obtained using perfluorinated solvents, possibly because of the higher solubility of O2 in these media. In the latter system, however, it was necessary to modify the catalyst with perfluorinated tails, thus adding to the cost and complexity of the process. Recycling of the catalyst/IL system for three further cycles without diminution of the yield was also reported. Moving on to other classes of reaction, the cyclodimerisation of 1,3-butadiene by iron complexes in [bmim][BF4 ] and [bmim][PF6 ] has been reported [60]. In the latter solvent, a TOF of up to 1404 h−1 was obtained, with 100% selectivity for 4-vinyl1-cyclohexene. The catalyst, prepared by reduction of [Fe(NO)2 Cl]2 by Zn, Et2 AlCl or n-BuLi in situ, could be reused several times without affecting performance. The same reaction with isoprene gave rise to a mixture of cyclic dimers. There have been few reports of transition metal catalysed polymerisation reactions in ionic liquids, but Carmichael et al. have recently reported the Cu(I) mediated living radical polymerisation of methylmethacrylate (MMA) in [bmim][PF6 ] [61]. The catalyst is based on a mixture of CuBr and N-propyl2-pyridylmethanimine, which form a homogeneous

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mixture in the ionic liquid at room temperature, unlike the same system in toluene. Polymerisation with excellent levels of conversion occurred at temperatures down to 30 ◦ C, giving products of relatively low polydispersity and molecular mass. The high solubility of the catalyst in the ionic liquid meant that separation of the polymer could be achieved simply and efficiently by washing with toluene (in which PMMA is soluble but [bmim][PF6 ] immiscible), leaving the ionic liquid/catalyst solution available for reuse. No indication was given of the activity of the recycled catalyst, however.

6. Lewis acid catalysis Ionic liquids based on Lewis acids such as AlCl3 have been applied to a number of Lewis acid catalysed organic transformations, for example Friedel–Crafts reactions [11,62]. More recently, there have been a number of reports of reactions utilising neutral ionic liquids in combination with Lewis acids, in some cases with extremely large effects on reactivity and selectivity. One of these reports that 20 mol% Sc(OTf)3 can catalyse the Friedel–Crafts alkylation of aromatic compounds in a range of hydrophobic 1-alkyl-3methylimidazolium [PF6 ]− and [SbF6 ]− ionic liquids [63]. Conversions were reported to be effectively quantitative, with isolated yields also high (65–93%). Considerable isomerisation of the hex-1-ene starting material was observed in these reactions, as indicated by the formation of two different isomeric products in solvent-dependent ratios of between 1.5:1 and 2:1 for products 7 and 8, respectively (Scheme 8). Surprisingly, in water miscible ionic liquids based on the [BF4 ]− and [TfO]− anions, as well as a range of conventional solvents, no reaction was observed at all. The reaction between cyclohexene and benzene

Scheme 8.

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Scheme 9.

was carried out using the same ionic liquid/Sc(OTf)3 system three times, with no decrease in yield. Zulfiqar and Kitazume have reported the formation of 2-methyl-2,3-dihydrobenzo[b]furan in 62% yield via the Sc(OTf)3 -catalysed Claisen rearrangement/cyclisation sequential reaction of allyl phenyl ether in 8-ethyl-1,8-diazabicyclo[5,4,0]-7-undecenium trifluoromethanesulfonate ([EtDBU][TfO]) (Scheme 9) [64]. Similar results were gained using o- and p-tolyl analogues. When the reaction was carried out in [bmim][PF6 ] and [bmim][BF4 ] much lower yields were obtained, indicating that the nature of the cation has a pronounced effect on the reaction rate in this system. No indication was given regarding how the reaction progressed in the absence of ionic liquid, however. The reaction mechanism was confirmed by showing that 2-allylphenol also formed the same product when heated in a mixture of Sc(OTf)3 in [EtDBU][TfO]. Reuse of the catalyst/ionic liquid mixture was achieved with no apparent decrease in activity over three cycles. There have been a number of reports on the use of ionic liquids as solvents for Diels–Alder reactions [65–68]. One of these [66] noted that the use of BF3 ·OEt2 and ZnI2 as Lewis acid catalysts resulted in faster reaction rates and greatly enhanced stereoselectivities. A recent report has shown that when Diels–Alder reactions are carried out in ionic liquids

using Sc(OTf)3 as a catalyst extremely high yields and endo-selectivity can be obtained [69]. The use of only 0.2 mol% Sc(OTf)3 in [bmim][PF6 ] resulted in a huge increase in rate compared with that obtained with the same concentration of Lewis acid in CH2 Cl2 . Rather surprisingly, similar rate enhancements were observed even when the reaction was carried out in CD2 Cl2 with just 1 equiv. of [bmim][PF6 ] present. Isolated yields of 71–96% were obtained using a range of typical substrates, and in all cases studied, endo:exo ratios were >99:1. The ionic liquid/Sc(OTf)3 mixture was then reused for 10 subsequent reaction cycles without loss of activity. In a related study, Zulfiqar and Kitazume reported the use of microencapsulated Sc(OTf)3 for the catalysis of aza-Diels–Alder reactions in [emim][TfO] and [EtDBU][TfO] (Scheme 10) [70]. Similar yields were obtained using both ionic liquids. The reaction could be carried out using both preformed imines, and also with the imine formed in situ by the reaction of an aldehyde and an amine in the ionic liquid. Both ionic liquid/catalyst systems could be reused with no apparent decrease in activity. Rosa et al. have reported the use of ionic liquids as solvents for 1,4-diazabicyclo[2,2,2]-octane (DABCO) mediated Bayliss–Hillman reactions [71]. At room temperature, the reaction rate was enhanced by factors of 14.1 and 33.6 compared with CH3 CN for

Scheme 10.

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[bmim][BF4 ] and [bmim][PF6 ], respectively. When catalytic quantities (20 mol%) of DABCO were employed, the rate enhancement in [bmim][PF6 ] was reduced to 11.1 times faster than that in CH3 CN. Addition of a range of Lewis acids (which had previously been reported to increase the reaction rate) generally resulted in a reduction in both the rate of reaction and the yields obtained.

7. Lewis acid-based ionic liquids Although ionic liquids based on Lewis acids such as AlCl3 were the materials that really kick-started research into the area, this review clearly shows that such liquids have largely been supplanted by the neutral ionic liquids for catalytic applications (and indeed most other applications). This is largely due to the fact that this class of ionic liquids is generally much more air- and moisture-sensitive than the neutral salts, thus causing problems with handling and long-term stability. Furthermore, these liquids are often incompatible with many classes of organic compound; for example, AlCl3 -based ionic liquids react rapidly with acetone [19]. Despite this, some new applications of such liquids have been reported recently, as outlined below. Clearly the fact that the relative acidity or basicity of the reaction medium can be modified over a wide range of values is potentially a very useful for catalysis since the selectivity of reactions can be influenced by the acid strength of the catalyst. Ethylene has been efficiently polymerised using a diiminenickel complex dissolved in acidic [bmim] organochloroaluminate ionic liquids [72]. The ionic liquids were formed using a mixture of ethylaluminium dichloride, aluminium(III) chloride and 1-butyl-3-methylimidazolium chloride in a molar ratio of 0.32:1.00:1.00. The polymerisation reaction occurred efficiently at temperatures ranging from −10 to +10 ◦ C. Over this temperature range, the activity of the catalyst increased with increasing temperature, but a decrease in the Tm value of the resulting polymers with increasing reaction temperature indicated that increased chain branching was occurring. The catalyst/ionic liquid mixture could be recycled, but trimethylaluminium had to be added for each successive cycle as the organic phase extracted

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free alkylaluminium during the reaction. The most remarkable observation was the large degree of rate enhancement observed when successive reactions were carried out using the same ionic liquid/nickel complex mixture. At −10 ◦ C, the productivity increased from 5 kg mol−1 h−1 for the first reaction, to 96 kg mol−1 h−1 on the second cycle, and finally to 198 kg mol−1 h−1 on the third reaction cycle. Over the same sequence, a decrease in the average molecular weight of the polyethylene products was observed, with a bimodal distribution in runs 2 and 3. This was assigned to an increase in the quantity of amorphous product formed in successive reactions. Aluminium(III) chloride-based ionic liquids immobilised on a range of silica and alumina supports have also been used as Lewis acid catalysts for Friedel–Crafts alkylation reactions [73]. ZrO2 and TiO2 were found to immobilise the ionic liquid very poorly, and were thus unsuitable for use as catalysts. Good conversions were reported for the reaction of dodecene with a range of aromatic compounds, generally with good selectivity towards the formation of monoalkylated compounds. ICP analysis indicated that negligible amounts of ionic liquid were leaching from the support, but deactivation of the catalyst was observed when it was recycled. This was thought to result from a combination of deactivation by water, as well as adsorption of reactants onto the catalyst surface that caused blocking of the active sites. It was reported that no reaction occurred when dodecene was added to the reaction before the aromatic compound, while reversal of this order gave good levels of conversion, thus indicating that dodecene was the species causing catalyst deactivation. The reactions were also carried out in a continuous liquid-phase reactor, and a slow deactivation of the catalyst with time was observed. When the same reaction was attempted in a continuous gas-phase reactor, virtually no conversion was observed, however. Deng et al. have reported the use of acidic 1-butylpyridinium/AlCl3 -based ionic liquids as reaction media for esterification reactions [74]. In general, similar levels of conversion and selectivity were observed to those obtained under conventional conditions using concentrated sulfuric acid as the catalyst. The esters formed were generally immiscible with the ionic liquids, however, resulting in easy product isolation. The ionic liquids were recycled three times

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with some decrease in yield between the first and second reaction cycle. Aluminium(III) chloride is not the only Lewis acid used to form ionic liquids. Wasserscheid et al. have described the use of moderately Lewis acidic ionic liquids based on SnCl2 for the Pt catalysed hydroformylation of functionalised and non-functionalised olefins [75]. The Pt catalyst showed enhanced stability and selectivity in the ionic liquids for these reactions

H2 O–[bmim][PF6 ] system, allowing easier separation of the two phases when the reaction was complete. The same paper also reported the use of [bmim][PF6 ] for liquid–liquid extraction of erythromycin. Soon after the publication of this paper, Erbeldinger et al. reported the use of [bmim][PF6 ] as a solvent for the thermolysin catalysed formation of Z-aspartame from carbobenzoxy-L-aspartane and L-phenylalanine methyl ester hydrochloride (Eq. (5)) [77].

(5) compared with conventional organic solvents. The paper also reports a means for determining the Lewis acidity of chlorostannate ionic liquids using 119 Sn NMR spectroscopy.

8. Biocatalysis One of the most exciting recent developments in the use of ionic liquids for catalytic systems is the application of biocatalysis in these solvents. Only a small range of reactions has been reported to date, but the results reported suggest that this area could yield some exciting developments in the near future. The first report was by Cull et al. in 2000 [76], who reported the use of [bmim][PF6 ] as a solvent for the biphasic hydration of 1,3-dicyanobenzene using Rhodococcus 312. The reaction has been carried out in toluene solution, but this solvent can have a damaging effect on the cell wall of the biological catalyst, as well as the known problems with toxicity and flammability. The reaction was carried out in a biphasic H2 O–[bmim][PF6 ] system, and showed a lower initial rate of reaction than in an equivalent H2 O–toluene system, but a slightly higher final yield. In the former system, the ionic liquid effectively acts as a reservoir for the organic substrate, while the cells are present in the aqueous phase. The authors also indicated that less cell aggregation was observed in the

Effectively quantitative conversions were reported after 50 h reaction, and rates of reaction were comparable to those observed in conventional organic solvents such as ethyl acetate. After reaction, the ionic liquid could be successfully recycled for further reactions without affecting the rate of yield of the process. Two features of this reaction should be noted. The first is that the addition of a small (5% v/v) quantity of water was required for efficient reaction. Secondly, the thermolysin was observed to dissolve in the ionic liquid at concentrations up to 3.2 mg ml−1 , but was completely inactive at these concentrations. This suggests that the enzyme is only active in suspension. The first anhydrous system was reported by Madeira Lau et al., who described the use of candida arctica lipase B (CaLB) for transesterification, ammoniolysis, and epoxidation reactions [78]. In this case, the reaction solvents were pure [bmim][PF6 ] or [bmim][BF4 ], with no added water as in the previous two cases. The transesterification of ethyl butanoate with butan-1-ol occurred in 81% yield after 4 h in both ionic liquids using a supported CaLB catalyst. This reaction was slightly faster than that observed in tert-butanol or 1-butanol solution. The reaction using free CaLB in ionic liquids was much slower, but after 24 h conversions around 80% were achieved. CaLB showed lower activity in [bmim][BF4 ] than in tert-butanol for the ammoniolysis of ethyl octanoate, however. Finally, CaLB catalysed epoxidation of cyclohexene

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gave yields only slightly lower than those obtained in acetonitrile, previously identified as the optimum organic solvent for this process. The first example of enantioselective biocatalysis in ionic liquids was reported by Sch¨ofer et al. [79]. This paper reports the screening of nine lipase systems against ten different ionic liquids for the kinetic resolution of rac-1-phenylethanol by transesterification with vinyl acetate. The results gained were compared with those obtained in methyl tert-butyl ether (MTBE), a widely used solvent for transesterification reactions. Quite different reactivity patterns were observed in different ionic liquids, and these were different again from MTBE in many cases. As a result, no “best ionic liquid” was identified, but [bmim][Tf2 N] appeared to give some useful behaviour. Most notably, it gave excellent ee values (>98%) for five of the enzyme systems, and high conversion (but little or no chiral resolution) with two others. Possibly the most significant observation, however, was the observation that using this ionic liquid it was possible to remove the products by distillation under reduced pressure, after which the enzyme-IL system could be reused three times with a loss in activity of <10% per cycle. In a similar study, Kim et al. reported some transesterification reactions of vinyl acetate with four different alcohol substrates in [bmim][BF4 ] and [bmim][PF6 ] [80]. The lipases employed were CaLB (immobilised), and Pseudomonas cepacia (PCL, native). The reactions were found to proceed with higher enantioselectivities than in THF and toluene in all cases, with the hydrophobic [PF6 ]− salt usually giving the best values. The PCL-catalysed reaction of 1-chloro-3-phenoxypropan-2-ol with vinyl acetate (Eq. (6)) was scaled up to a preparative level. Reactions were carried out to just over 50% completion (48 h reaction time), giving unreacted substrates of >99.5% ee in 43% yield, and to 46% completion (36 h) giving the acetylated product with >99.5% ee in 42% yield.

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solvents. Recycling studies on the CaLB-catalysed reaction showed that the ionic liquid and enzyme could be recycled twice without loss of enantioselectivity or reactivity. The area of biocatalysis combined with ionic liquids is clearly still in its infancy, with only a small range of reactions and enzymes investigated to date. Probably the most important finding of the preliminary reports is the fact that many enzymes retain their activity in ionic liquids. As yet, no significant examples of rate enhancement in ionic liquids have been reported, but the final two papers mentioned above clearly indicate that advantages may be gained over reactions in organic solvents with regard to improvements in enantioselectivity and reusability of the solvent-enzyme systems. It is likely that many more examples will be reported in the near future. As the range of examples studied becomes greater, it will become necessary to investigate the nature of solvation of enzymes in ionic liquids.

9. Summary and conclusions This review shows that ionic liquids show great promise as reaction media for many types of catalysis. The ability to control their properties very precisely sets them apart from other approaches such as aqueous or fluorous systems, although all of the techniques remain complementary. Clearly ionic liquids remain relatively costly compared with conventional organic solvents or water, but this must be set against the fact that they are generally used in much smaller quantities, and are likely to be reused in most applications. Furthermore, there remains a distinct lack of information regarding the role played by the ionic liquid in many of the reactions discussed here. For example, why does Sc(OTf)3 display such different levels of reactivity in different types of ionic liquids? Also, many of the

(6) In general, reaction rates were equivalent to, or slightly lower than those observed in the organic

reactions have been tested with only a small number of ionic liquids, where there are clearly many different

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combinations of cation and anion that could be tested. Further information on the solvent properties of ionic liquids is required, as are detailed mechanistic studies, particularly where unexpected reactivity patterns are observed. Ionic liquids will clearly not provide advantages in all systems, but improvements in reactivity or selectivity are observed in many of the cases discussed above when the appropriate combination of cation and anion are selected. Despite this, the two factors that will ultimately decide whether these systems are viable on a larger scale are likely to be the ability to reuse the catalyst without a decrease in activity, and whether the products can be separated efficiently without contamination from the ionic liquid or catalyst. The combination of supercritical CO2 and ionic liquids looks like one very promising approach to attain this goal. Finally, the recent work with enzymic catalysts in ionic liquids has presented an entirely new range of possibilities. While the success of transition metal and Lewis acid catalysed processes in ionic liquids might not seem too surprising, the very promising results gained to date in biocatalysis are possibly somewhat counterintuitive. It is hoped that developments like these will attract further interest from scientists in even more diverse disciplines into this exciting area.

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