Applications as reaction media

Since the use of ionic liquids has become widespread, a large number of reactions previously developed in organic solvents have been attempted in these new solvents. Virtually aU known transformations can be tested in ionic liquids, leading to a plethora of publications. Some reactions are improved, but many are not. This section focuses on reactions that are improved by the use of ionic liquids as solvents, either by leading to better yield, regioselectivity or enantioselectivity or for 

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Ethylammonium nitrate (entry 18 in Table 3-1) was shown in 1914 to have m.p. 12 °C and was hence the first room temperature ionic Hquid [156] this was followed in 1967 by tetra- -hexylammonium benzoate with m.p. —50 °C (entry 26) [169], Ambient-temperature ionic liquids based on l-alkyl-3-methylimidazolium salts (entries 19-24) were first reported by Wilkes et al. in 1982 as tetrachloroaluminates [162a], Replacement of this moisture-sensitive anion by the tetrafluoroborate ion and other anions led, in 1992, to air- and water-stable, room temperature ionic liquids [162b], which have since found increasing application as reaction media for various kinds of organic reactions, mainly owing to the work of Seddon [167, 190] and Hussey [187], Suitably selected... 

In addition to fluorous solvents and ionie liquids, supercritical fluids sc-fluids, scf s), sueh as supercritical carbon dioxide (se-C02), constitute a third class of neoteric solvents that can be used as reaction media. Although sc-fluids have been known for a long time and have been advantageously used as eluants in extraction and chromatography processes (see Sections A.6 and A.7 in the Appendix), their application as reaction media for chemical processes has become more popular only during the last decade. Some of their physical properties and the supercritical conditions necessary for their existence have already been described in Section 3.2 (see Figure 3-2 and Table 3-4) see also references [209, 211-220, 224-230] to Chapter 3 for reviews on sc-fluids and their applications (particularly for SC-CO2 and SC-H2O). 

The aspects of medium engineering summarized so far were a hot topic in biocatalysis research during the 1980s and 1990s [5]. Nowadays, all of them constitute a well-established methodology that is successfully employed by chemists in synthetic applications, both in academia and industry. In turn, the main research interests of medium engineering have moved toward the use of ionic liquids as reaction media and the employment of additives. 

Apart from the cyclopropanation reaction, only one example has been published of the application of ionic liquids as reaction media for enantio-selective catalysis with bis(oxazoline) ligands. In this case, the complex 6b-ZnCl2 was used as a catalyst for the Diels-Alder reaction between cyclopen-tadiene and N-crotonyloxazolidin-2-one in dibutyUmidazoUiun tetrafluorob-orate (Scheme 9) [48]. Compared with the same process in CH2CI2, the reaction was faster and both the endofexo selectivity and the enantioselectivity in the endo product were excellent. However, experiments aimed at recovering the catalysts were not carried out. 

Whilst the first part of this book deals mainly with concepts and theories of alternatives to the use of organic solvents as reaction media, the later Chapters (Chapters 7-11) look at some applications of these methods and compare their strengths and limitations as illustrated by these case studies. 

Aminocarbonylation provides an efficient method for the synthesis of carboxamides from readily available alkenyl halides. This reaction finds many applications in organic synthesis, especially for the introduction of amides with a variety of A -substituents. For example, steroidal alkenyl iodide 137 was transformed to the corresponding amide derivative 138 in 88% yield through aminocarbonylation (Equation (10)). In this reaction, the palladium catalyst was recovered by using an ionic liquid, l-butyl-3-methylimidazolium salt 139, as reaction media, and reused five times with only a minor loss of activity. ... 

Industrial exploitation of ionic liquids is in its early days (Freemantle, 2000). The nse of ionic liquids in industry is seen as being highly speculative, but progress is being made. Room temperature ionic liquids have been stndied actively since their discovery in the 1970s, predominantly for their possible application as battery electrolytes. Work on the exploitation of ionic liquids as reaction media started in the early 1980s, but only recently has it attracted industrial interest. 

While a number of supercritical fluids (SC) are known and have been studied as reaction media, probably only SC-CO2 and water are of practical use in the synthesis of pharmaceutical intermediates. The application of SC-CO2 as a greener eluent for chromatography has been discussed in Chapter 12. This medium is also used as an extraction solvent and in API isolation, although its use at any scale... 

The application of SCF as reaction media for enzymatic synthesis has several advantages, such as the higher initial reaction rates, higher conversion, possible separation of products from unreacted substrates, over solvent-free, or solvent systems (where either water or organic solvents are used). Owing to the lower mass-transfer limitations and mild (temperature) reaction conditions, at first the reactions which were performed in non-aqueous systems will be transposed to supercritical media. An additional benefit of using SCFs as... 

The high melting points of molten salts prevent their use as reaction media for many practical and fundamental applications. For example, many organic substances have low boiling points and a low thermal stability and cannot be dissolved in molten salts. 

SC-CO2 is also becoming increasingly important as reaction media [7] for a great variety of fundamental chemical reactions ranging from catalysis to polymerization, [8,9] to synthesis and growth of inorganic materials [1,2], to nanoparticle production and preparation processes [1,2,10,11], and to biotechnological applications such as activation and deactivation of enzymes [12], biomass conversion, and biocatalysis [1,2,13],... 

We now turn attention to a completely different kind of supercritical fluid supercritical water (SCW). Supercritical states of water provide environments with special properties where many reactive processes with important technological applications take place. Two key aspects combine to make chemical reactivity under these conditions so peculiar the solvent high compressibility, which allows for large density variations with relatively minor changes in the applied pressure and the drastic reduction of bulk polarity, clearly manifested in the drop of the macroscopic dielectric constant from e 80 at room temperature to approximately 6 at near-critical conditions. From a microscopic perspective, the unique features of supercritical fluids as reaction media are associated with density inhomogeneities present in these systems [1,4],... 

Notwithstanding the numerous advantages of ionic liquids as reaction media for catalytic processes widespread industrial application has not yet been forthcoming. The reasons for this are probably related to their relatively high prices and the paucity of data with regard to their toxicity and biodegradability. The replacement of conventional VOCs with ionic liquids is an obvious improvement with regard to atmospheric emissions but small amounts of ionic liquids will... 

For the use of sc-fluids as reaction media in synthesis, see reviews [211-217, 224, 225, 228-230] and Section 5.5.13, which describes applications of some neoteric solvents such as ionic liquids, perfluorohydrocarbons, and sc-fluids in organic synthesis and catalysis. 

The use of dipolar non-HBD instead of protic solvents as reaction media often has considerable practical synthetic advantages, which have been summarized by Parker [6], Madaule-Aubry [294], Liebig [295], and Schmid [26], A selection of common and less common dipolar non-HBD solvents is given in Table 5-18, together with some physical constants useful for their prachcal application. Reviews on particular dipolar non-HBD solvents have appeared these are included in Table 5-18 [cf. also references [75-91] in Chapter 3). 

ABSs have been used for many years in biotechnological applications as denaturing and benign separation media [82]. Recently, they have been used for metal ion separations, environmental remediation, metallurgical applications and as reaction media. 

SCCO2 is largely used to process food (extraction or fractionation), but other applications, such as the fluoropolymer synthesis by DuPont, hydrogenation or alkylation by Thomas Swan, coatings by Union Carbide, and polyurethane processing by Crain Industries, are still in development [111]. The application of supercritical fluids (SCFs) as reaction media with homogeneous catalysts has been mainly investigated on a laboratory scale. 

The lipase-catalysed enantioselective acylation of allylic alcohols in an ionic liquid solvent was demonstrated by Itoh et al. [16] (Fig. 7.7). They found that the acylation rate was strongly dependent on the counter anion of the imidazolium salt, while the lipase-catalysed acylation proceeded with high enantioseleclivity in all ionic liquid tested. Good results were obtained when the reaction was carried out in [bmimT [PFg ] or [bmun" ][BF ]. Other examples of kinetic resolution of allylic alcohols catalysed by lipases in ionic liquids were also reported by these authors [71, 72]. The transesterification of 5-phenyl-l-penten-3-ol under reduced pressure at 27 hPa and 40°C was carried out using methyl phenylthioacetate as acyl donor in [bmim+] [PF ] and [bdmim ][BF ], for obtaining the corresponding acylated compound in optically pure form [71], The acetylation of methyl mandelate catalysed by immobilised P5L in [bdmim ][BF ] is another example reported by these authors about the successful application of ionic liquids as reaction media in racemic resolutions... 

Ionic liquids have also been used as reaction media in biocatalytic esterification reactions. In this context, the enantioselective esterification of 2-substituted-pro-panoic acids with 1-butanol catalysed by CrL in ionic liquids has been carried out by Ulbert et al. [76] (Fig. 7.10). It was demonstrated that application of [hmim+] [PF ] and [onim ][PF ] ionic hquids was beneficial from not only enzyme activity... 

In order to investigate this type of binary solvent systems as reaction media, a kinetic study on the reaction between l-fluoro-2,4-dinitrobenzene (FDNB) and the primary amine -butylamine (BU) was performed [32, 33]. The selected mixtures were composed of AN and DMF as molecular solvent and [bmim][BF ] and [bmim] [PF,] as imidazolium-based ILs. It is possible to assume that the reaction proceeds by the classical two-step mechanism as shown in Fig. 13.6. The application of the steady-state approximation affords Eq. 13.3 for the second-order reaction rate k. ... 

Although perfluorinated hydrocarbons are well known, they have only recently found application in organic chemistry as a useful class of solvents. Their physical properties mice them unique for their use as reaction media. Since perfluorocarbons are immiscible with many common organic solvents, they are suitable for the formation of biphasic systems. This overview describes the utilization of perfluorocarbons as reaction media for various kinds of reaction such as oxidation, bromination, etc. In addition, a novel biphase reaction system based on perfluorinated solvents as well as its application in organic synthesis is presented. 

Thus the microemulsion field continues to be a very active field both scientifically and in applications, as is amply shown by the different contributions in this timely book. Here, several important novel aspects are discussed in depth, like effects of polymers on microemulsions and the use of microemulsions as reaction media for organic synthesis and for the preparation of nanomaterials. That microemulsions constitute just one type of self-assembled surfactant systems continues to be an important consideration. As illustrated... 

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