Aqueous-organic two-phase reaction

Aqueous-organic two-phase reaction has been widely performed [18]. One of the purposes of using two-phase reaction system is to control the substrate concentration in aqueous phase where the biocatalysts exist. Hydrophobic substrate and products dissolve easily in the organic phase, so that the concentration in the aqueous phase decreases. The merits of controlling and decreasing the substrate concentration in the aqueous phase are as follows  

When whole cell containing plural enzymes with opposite selectivities and different (Michaelis-Menten constant) values are used, problems of low selectivities occur. If the substrate concentration is decreased, one of the enzymes with low Kra value catalyzes the reaction so that the selectivity can be improved. 

The decomposition of unstable substrate/product by aqueous buffer can be prevented by dissolving the substrate and product in the organic phase. 

Therefore, organic solvents have been widely used for biocatalytic reductions. An interesting example for stereochemical control by using organic solvents for 

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Carbonvlation of Benzyl Halides. Several organometallic reactions involving anionic species in an aqueous-organic two-phase reaction system have been effectively promoted by phase transfer catalysts(34). These include reactions of cobalt and iron complexes. A favorite model reaction is the carbonylation of benzyl halides using the cobalt tetracarbonyl anion catalyst. Numerous examples have appeared in the literature(35) on the preparation of phenylacetic acid using aqueous sodium hydroxide as the base and trialkylammonium salts (Equation 1). These reactions occur at low pressures of carbon monoxide and mild reaction temperatures. Early work on the carbonylation of alkyl halides required the use of sodium amalgam to generate the cobalt tetracarbonyl anion from the cobalt dimer(36). 

Nevertheless, for the production of the flavour-active aromatic alcohol derivatives, such as the corresponding aldehydes and acids, metabolic engineering approaches have to compete with conventional oxidative biocatalysis starting from the natural alcohol as a substrate. For instance, the whole-cell oxidation system based on Pichia pastor is AOX already described in Sect. 23.4.1.2 can also be used to convert benzyl alcohol to benzaldehyde in aqueous media although product inhibition restricted the final product concentration to about 5 g L h indicating the need for aqueous-organic two-phase reaction media [51]. Phenylacetalde-... 

Based on the inversely temperature-dependent solubility of phosphines modified with polyoxyethylene chains, TRPTC has been proposed, and applied to the aqueous/organic two-phase reaction system [11], The general principle of TRPTC is depicted in Figure 1. 

Landini, D. Maia. A. Montanari, F. Phase-transfer catalysis. Nucleophilicity of anions in aqueous organic two-phase reactions catalyzed by onium salts. A comparison with homogeneous organic systems. J. Am. Chem. Soc. 1978. 100, 2796-2801. 

Finally, Sinou el al. have employed a chiral tetrasulfonated diphosphine as a ligand in the Rh-catalysed reduction of the Schilf base depicted in Scheme 8.34. In the presence of an aqueous-organic two-phase solvent system, a quantitative yield combined with a moderate enantioselectivity of 34% ee were obtained for this reaction. 

Hydroaminomethylation of alkenes occurred to give both n- and /. so aliphatic amines catalyzed by [Rh(cod)Cl]2 and [Ir(cod)Cl]2 with TPPTS in aqueous NH3 with CO/H2 in an autoclave. The ratio of n-and /.soprimary amines ranged from 96 4 to 84 16.178 The catalytic hydroaminomethylation of long-chain alkenes with dimethylamine can be catalyzed by a water-soluble rhodium-phosphine complex, RhCl(CO) (Tppts)2 [TPPTS P(m-C6H4S03Na)3], in an aqueous-organic two-phase system in the presence of the cationic surfactant cetyltrimethy-lammonium bromide (CTAB) (Eq. 3.43). The addition of the cationic surfactant CTAB accelerated the reaction due to the micelle effect.179... 

Reaction engineering helps in characterization and application of chemical and biological catalysts. Both types of catalyst can be retained in membrane reactors, resulting in a significant reduction of the product-specific catalyst consumption. The application of membrane reactors allows the use of non-immobilized biocatalysts with high volumetric productivities. Biocatalysts can also be immobilized in the aqueous phase of an aqueous-organic two-phase system. Here the choice of the enzyme-solvent combination and the process parameters are crucial for a successful application. 

A relatively weak rate enhancement was observed in the biphasic hydroformylation of 1-octene using Rh/tppts catalysts in the presence of cosolvents such as ethanol to enhance the solubility of the olefin in the aqueous phase and with addition of buffers (Na2C03/NaHC03) to eliminate side reactions such as the formation of acetals.31,365,366 Similarly, addition of ethanol improved the yields in the hydroformylation of 1-octene catalysed by Rh2(p-S-tBu)2(CO)2(tppts)2 species in an aqueous/organic two phase system.367 However, the high selectivity to linear aldehyde observed for neat olefin in the biphasic system (97%) decreased (to 83%) in the presence of the cosolvent.367... 

Pd/PPh3 complexes catalyse the carbonylation of activated benzyl alcohols such as 4-hydroxybenzyl alcohol whereas they are inactive in the carbonylation of benzyl alcohol.463 In sharp contrast, the water soluble Pd(tppts)3 complex catalyses the carbonylation of benzyl alcohol to phenylacetic acid, equation (6), under mild reaction conditions employing an aqueous/organic two phase... 

Pd(tppts)3-catalysed carbonylation of IBPE (Figure 9) in an aqueous/organic two phase system provides for facile separation of the catalyst from reaction products as well as its quantitative recovery and recycling in an active form.451,462 Conversions up to 93% and selectivities to ibuprofen of 82% [18% linear product... 

Substituted benzyl chlorides were carbonylated using a Pd/tppts catalyst in aqueous/organic two phase systems under basic reaction conditions to afford the sodium salts of the corresponding phenylacetic acids. After acidification the phenylacetic acid dissolved in the organic phase and could be readily separated from the Pd/tppts catalyst contained in the aqueous phase (Figure 12) 466-468 TOFs up to 21 h 1 (turnover number, TON=165) and phenylacetic acid yields up to 94% were obtained at 70°C, 1 bar CO, tppts/Pd=10, NaOH/substrate=3/2 in an aqueous/toluene (1/1) two phase system in a batchwise procedure.466 The TOFs were improved to a maximum of 135 h 1 (TON=1560) in a continuous operation mode. Palladium catalysts modified with binas (Table 2 25) exhibited low catalytic activity (TONs up to 140) in the carbonylation of benzyl chloride 466 In strongly acidic media (pH=l) the Pd/25 catalyst was active and remained stable during the reaction which contrasts with Pd/tppts where palladium black was observed. However, the catalyst was completely deactivated after three cycles.466... 

Similarly, PdCl2 modified with the water soluble phosphonated phosphine 105 (Table 5) was used as catalyst in the carbonylation of benzyl chloride to afford phenylacetic acid in 91% yield in an aqueous/organic two phase system under mild reaction conditions (55°C, 8 psi CO).259... 

Hydrogenation of r/wu-cinnamaldehyde (Figure 14 I Ri=H, R2=Ph) to phenylpropanol (IV Ri=H, R2=Ph) catalysed by Ru/tppms and Ru/tppts proceeds via two different routes in an aqueous/organic two phase system.492 With HRuCl(CO)(tppms)3 the reaction proceeds exclusively via the hydro-cinnamaldehyde III whereas with HRuCl(CO)(tppts)3 both II and III are involved (Figure 14, Ri=H, R2=Ph) 492... 

Telomerization is one of the very first reactions carried out in aqueous/organic two phase systems. In 1976, Kuntz at Rhone-Poulenc518 reduced PdCl2 with NaBH4 in the presence of tppms to afford a catalyst for the telomerization of... 

Likewise, a thermoregulated phase transfer process within the aqueous/organic two-phase system has been reported by Jin and co-workers (cf. Section 3.1.1.1) [290]. A water-soluble supramolecular Rh catalyst based on functionalized /1-cyclodextrin was also described [291]. In a two-phase system this catalyst may function as a carrier for the transfer of both the starting material and the product between the different phases. As an alternative to polar media for biphasic hydroformylation, Chauvin et al., used ionic liquids based on imidazolium salts which are well known for dimerization reactions (cf. Sections 2.3.1.4 and 3.1.1.2.2) [270, 271, 292]. For introduction into technical processes the currently availability and price of ionic liquids could be a drawback, especially for bulk chemicals such as 0x0 products. 

Shin and Kim developed various methods aimed at increasing the product concentrations of transaminase catalyzed amine resolutions, through the contin uous removal of product ketone from the reactions (Figure 14.21). The application of an aqueous/organic two phase system to the co transaminase catalyzed resolution of racemic ( methylbenzylamine 1 was found to be superior to an aqueous only system in product concentration obtained [26, 27]. A drawback of the biphasic system was an increased enzyme deactivation rate compared to the aqueous only system due to the aqueous/organic emulsion. Another disadvantage was the... 

Thermoregulated phase-transfer catalysis, however, could be successfully put into effect for the hydroformylation of higher olefins in aqueous/organic two-phase media [11], As shown in Table 2, various olefins have been converted to the corresponding aldehydes in the presence of nonionic phosphine-modified rhodium complexes as catalysts. An average turnover frequency (TOF) of 250 h-1 for 1-do-decene and 470 Ir1 for styrene have been achieved. Even the hydroformylation of oleyl alcohol, an extremely hydrophobic internal olefin, would give a yield of 72% aldehyde [19]. In comparison, no reaction occurred if Rh/TPPTS complex was used as the catalyst under the same conditions. 

It has been reported that the rates of hydroformylation decrease in the order 1-hexene > 1-octene > 1-decene in the classical aqueous/organic two-phase system, whereas the rates are almost identical in the homogeneous organic system [23], Interestingly, in the hydroformylation of a mixture of equimolar 1-hexene and 1-decene in the presence of Rh/1 (N = 25) complex as the catalyst, roughly the same reaction rates at various conversion levels have been observed [19]. This phenomenon further verified the conclusion that the organic phase is the reaction site of TRPTC. 

Indeed, no substrate selectivity or increase in aldehydes ratio was observed when the reactions were conducted in the presence of a free / -CD analogous catalyst [PhN(CH2PPh2)2Rh(cod)]BF4. It must be pointed out that the reactions were performed in an aqueous organic two-phase system with an aqueous phase containing 30% DMF. The presence of an aqueous phase is supposed to force inclusion of the substrate in the cavity during the catalysis. In one-phase medium composed of DMF, the formation of transient adducts between substrate and a rhodium complex modified by a phosphinite /3-CD ligand also seems possible (Figure 19). ... 

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