Liquid Biphasic Systems

In an aqueous system, the only possible way to suppress the unwanted chemical HCN addition to carbonyl compounds is to work at low pH to reduce the concentration of the cyanide ion-the reactive species-and at low temperature to increase the selectivity. However, in an acidic medium, most HNLs lose activity very fast [15, 16], and it is therefore necessary to find reaction conditions to avoid these problems. 

One method is to run the reaction in an aqueous buffer/organic solvent biphasic system. This makes it possible to work at high substrate and product concentrations and at the pH-optimum of the enzyme. In addition, in water-immiscible solvents the non-enzymahc addition of HCN to the carbonyl group is non-existent or extremely slow. Possible disadvantages are enzyme deactivation at the interface and the presence of organic solvent dissolved in the aqueous phase [15, 17, 18]. 

Bauer et al. [18] showed that, for HbHNL also, ethers are the solvents of choice to maintain enzyme activity. The stability in the presence of the substrates was also investigated, indicating that the enzyme is already destabilized at low 

A comparison of the qualitative results of the two mathematical models shows strong similarities between the consequences of the mass transfer limitation model and the adsorbed enzyme model [28]. Experimental findings show that the reaction mode is strongly dependent on the process conditions, and the different models cannot be adopted for other conditions [29]. 

For preparative purposes, the use of biphasic solvent systems consisting of an aqueous phase and a water-immiscible organic phase for PaHNL and llhl INI. catalysis has proven to have a broad applicability, also including, for example, pyrrole derivatives [30] (see Table 9.3, Section 9.2.2.3) and to be suitable for industrial scale. DSM established enzymatic hydrocyanation processes, e.g., for the production of (S)-m-phenoxymandelonitrile [31, 32] and large-scale production of (R) -2 - (2 -furyl) - 2 -hydroxyace tonitrile [33]. 

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Transition metal catalysis in liquid/liquid biphasic systems principally requires sufficient solubility and immobilization of the catalysts in the IL phase relative to the extraction phase. Solubilization of metal ions in ILs can be separated into processes, involving the dissolution of simple metal salts (often through coordination with anions from the ionic liquid) and the dissolution of metal coordination complexes, in which the metal coordination sphere remains intact. 

Different type of reaction system containing organic solvent can be classified in a simple way. To accomplish this we first distinguished between microaqueous organic systems with a continuous organic phase, then reversed micelles stabilized with surfactant and a liquid-liquid biphasic system in which distinct organic and aqueous phase are mixed. The latter medium is discussed in this paper. 

Recently, the fluorous biphasic separation technique has been enriched with two new developments, both of which were demonstrated in hydrogenation. The need for a fluorous solvent can be eliminated by using fluorous silica as a fluorous catalyst scavenger. In liquid-liquid biphasic systems, reversible expan-... 

To date, several reports have been published dealing with the non-stereoselec-tive hydrogenation of olefins in a liquid-liquid biphasic system containing ionic liquids [69-72]. 

The hydrogenation of arenes is industrially important, but so far has been dominated by the use of heterogeneous catalysts. In principle, ionic liquids offer the chance to use a liquid-liquid biphasic system where the homogeneous catalyst is immobilized and the ionic catalyst solution is reusable. 

Webb, P.B.and Sellin, M.F. and Kimene, T.E. and Williamson, S. and Slawin, A.M.Z. and Cole-Hamilton, D.J. (2003). Continuous Flow Hydroformylation of Alkenes in Supercritical Fluid-Ionic Liquid Biphasic System. J. Am. Chem. Soc., 125, 15577-15588. 

A butoxylcarbonylation reaction was conducted in a liquid-liquid biphasic system under process conditions, but the removal of the product was conducted in a liquid-solid biphasic system at a lower temperature (84). lodobenzene or 4-bromoacetophenone reacted with CO at a pressure of 1-8 atm in the presence of a palladium-benzothiazole complex catalyst in the ionic liquid [TBA]Br (m.p. = 110°C) in the presence of Et3N base. The catalyst/ionic liquid system was recycled by extractive removal of the butyl ester product with diethyl ether. The solid residue, containing the catalyst, [TBA]Br, and Et3N.HBr, remained effective in subsequent carbonylation tests. After each cycle, the yields were still close to the initial value. A slight decrease in yield was attributed to a loss of catalyst during handling. 

Pina, F. et al.. Thermal and photochemical properties of 4, 7-dihydroxyflavylium in water-ionic liquid biphasic systems a write-read-erase molecular switch, Angew. Chem. Int. Ed., 43,1525,2004. 

Since then, several publications dealing with liquid/liquid biphasic systems or the application of an immobilized enzyme in pure organic solvent have appeared. 

In a liquid/liquid biphasic system (Figure 9.1a), the enzyme is in the aqueous phase, whereas the hydrophobic compounds are in the organic phase. In pure organic solvent (Figure 9.1b) a solid enzyme preparation is suspended in the solvent, making it a liquid/solid biphasic system. In a micellar system, the enzyme is entrapped in a hydrated reverse micelle within a homogeneous organic solvent... 

More recent conceptual advances in the liquid/liquid biphasic systems include the novel fluorous biphase system (FBS)12-14,70-73 and the use of ionic liquids15-22... 

Catalysis in liquid-liquid biphasic systems has developed recently into a subject of great practical interest because it provides an attractive solution to the problems of separation of catalysts from products and of catalyst recycle in homogeneous transition metal complex catalysis. Two-phase systems consist of two immiscible solvents, e.g., an aqueous phase or another polar phase containing the catalyst and an organic phase containing the products. The reaction is homogeneous, and the recovery of the catalyst is facilitated by simple phase separation. 

Many experimentalists are familiar with this principle of doping a sample with a species that couples better with the microwave irradiation and so can act as a thermal dissipater. What is often less appreciated is the general nature of this process, as not only solid/liquid interfaces but also liquid/liquid biphasic systems such as emulsions show the same effects59-63. Figure 6.2 represents the heating profiles of toluene and a perfluorinated solvent first independently and then as an emulsion. A similar trend can be seen in a hexane/acetonitrile mixture, although because of the superior heating capacity of acetonitrile the effect is less pronounced. 

Rothenberg, G., Royz, M., Arrad, O. and Sasson, Y. (1999) In situ generation and synthetic applications of anhydrous hydrogen fluoride in a solid-liquid biphasic system. J. Chem. Soc., Perkin Trans., 1, 1491. 

Thanks to their speed and relatively low computational cost, M D and MC simulations can be used for studying the physical properties of large systems. This is extremely useful in heterogeneous catalysis, e.g., for modeling the structure and the properties of the bulk and the surface of a solid catalyst, or the properties of the bulk and interface of liquid/liquid biphasic systems. However, since the number of particles modeled is still very small compared to real materials, the models are susceptible to wall effects. One neat trick for avoiding this problem is to apply periodic boundary conditions The volume containing the model is treated as the primitive cell of an... 

The chemical selectivity of reactions catalyzed by supported TEMPO closely resembles the patterns observed for homogeneous reactions. Primary alcohols are strongly preferred over secondary alcohols. Especially in liquid biphasic systems, high aldehyde yields can be achieved with as little as 0.1 mol% of the immobilized catalyst (412) ... 

Chapter 7 addresses another key topic in the context of green chemistry the replacement of traditional, environmentally unattractive organic solvents by greener alternative reaction media such as water, supercritical carbon dioxide, ionic liquids and perfluorous solvents. The use of liquid/liquid biphasic systems provides the additional benefit of facile catalyst recovery and recycling. 

Typically, the reaction is performed in a liquid-liquid biphasic system where the substrates and products (upper phase) are not miscible with the catalyst/ionic liquid solution (lower phase). The SiH-functional polydimethylsiloxane and the olefin are placed in the reaction vessel and heated up to 90 °C. Then the precious metal catalyst (20 ppm) and the ionic liquid (1 %) are added. After complete SiH conversion, the reaction mixture is cooled to room temperature and the products are removed from the reaction mixture by either simple decantation or filtration (in case of non-room-temperature ionic liquids). The recovered catalyst/ionic liquid solution can be reused several times without any significant change in catalytic activity. A treatment or workup of the ionic liquid-catalyst solution after each reaction cycle is not necessary. The metal content of the products was analyzed by ICP-OES (Inductively coupled plasma optical emission spectroscopy) and the chemical identity of the organomodified polydimethylsiloxane was verified by NMR spectroscopy. 

Sinee the formation of a liquid-liquid biphase system is due to a sufficient difference in the intermolecular forces of two liquids [2], the selection of a nonaqueous catalyst phase depends primarily on the solvent properties of the product phase at a high conversion level. For example, if the product is apolar the catalyst phase should be polar, and vice versa if the product is polar the catalyst phase should be apolar. The success of any nonaqueous biphase system depends on whether the catalyst could be designed to dissolve preferentially in the catalyst phase. Perhaps the most important rule for such design is that the catalyst has to resemble the catalyst phase, since it has been known for centuries that similia similibus solvuntur of like dissolves like [3]. 

In a first approximation, the new methods correspond to the conventional solvent techniques of supported catalysts (cf Section 3.1.1.3), liquid biphasic catalysis (cf Section 3.1.1.1), and thermomorphic ( smart ) catalysts. One major difference relates to the number of reaction phases and the mass transfer between them. Owing to their miscibility with reaction gases, the use of an SCF will reduce the number of phases and potential mass transfer barriers in processes such as hydrogenation, carbonylations, oxidation, etc. For example, hydroformylation in a conventional liquid biphasic system is in fact a three-phase reaction (g/1/1), whereas it is a two-phase process (sc/1) if an SCF is used. The resulting elimination of mass transfer limitations can lead to increased reaction rates and selectiv-ities and can also facilitate continuous flow processes. Most importantly, however, the techniques summarized in Table 2 can provide entirely new solutions to catalyst immobilization which are not available with the established set of liquid solvents. 

In the previous sections the use of catalysts dissolved in ionic liquids has been documented with a variety of examples from the most recent literature. They were classified are catalytic systems based on the adoption of Strategies A, B and C, when solvent-less conditions were not adopted. In an ideal liquid-liquid biphasic system, the IL must dissolve the catalytic intermediates and, in part, the substrate to avoid that mass transfer limits reaction rates. Moreover, products should have a limited solubility in the IL to allow a facile product removal or extraction, and, possibly, the recycle of the ionic liquid-trapped catalyst. The separation of the catalyst from the products is made easier if solid support-immobilised ILs are used. The preference for a solid catalyst is dictated not only by the easier separation but also, as outlined by Mehnert in an excellent review article, " by (i) the possible use of fixed bed reactors, and (ii) the use of a limited amount of IL, a generally expensive chemical which can limit the economic viability of the process. In this section attention will be focused only on the most recent examples of solid-phase assisted catalysis using ionic liquids, following Strategy D. Examples prior to 2006 are covered in recent reviews and will not be discussed here. " ... 

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