Biphasic organic solvents

Development of a biphasic organic solvent system to allow for conversion of hydrophobic substrates... 

One technically important example of an oligomerization that could not be carried out in a liquid-liquid biphasic mode with polar organic solvents or water is the... 

The selective, Ni-catalyzed, biphasic dimerization of 1-butene to linear octenes has been studied in the author s group. A catalytic system well loiown for its ability to form linear dimers from 1-butene in conventional organic solvents - namely the square-planar Ni-complex (q-4-cycloocten-l-yl](l,l,l,5,5,5,-hexafluoro-2,4-pen-tanedionato-0,0 )nickel [(H-COD)Ni(hfacac)] [103] - was therefore used in chloroaluminate ionic liquids. 

However, all attempts to carry out biphasic ethylene oligomerization with this cationic catalyst in traditional organic solvents, such as 1,4-butanediol (as used in the SHOP) resulted in almost complete catalyst deactivation by the solvent. This reflects the much higher electrophilicity of the cationic complex [(mall)Ni(dppmo)] [SbFg] in relation to the neutral Ni-complexes used in the SHOP. 

Obviously, there are many good reasons to study ionic liquids as alternative solvents in transition metal-catalyzed reactions. Besides the engineering advantage of their nonvolatile natures, the investigation of new biphasic reactions with an ionic catalyst phase is of special interest. The possibility of adjusting solubility properties by different cation/anion combinations permits systematic optimization of the biphasic reaction (with regard, for example, to product selectivity). Attractive options to improve selectivity in multiphase reactions derive from the preferential solubility of only one reactant in the catalyst solvent or from the in situ extraction of reaction intermediates from the catalyst layer. Moreover, the application of an ionic liquid catalyst layer permits a biphasic reaction mode in many cases where this would not be possible with water or polar organic solvents (due to incompatibility with the catalyst or problems with substrate solubility, for example). 

In comparison with traditional biphasic catalysis using water, fluorous phases, or polar organic solvents, transition metal catalysis in ionic liquids represents a new and advanced way to combine the specific advantages of homogeneous and heterogeneous catalysis. In many applications, the use of a defined transition metal complex immobilized on a ionic liquid support has already shown its unique potential. Many more successful examples - mainly in fine chemical synthesis - can be expected in the future as our loiowledge of ionic liquids and their interactions with transition metal complexes increases. 

When either the organic solvent or the ionic liquid is used as pure solvent, proper control over the water content, or rather the water activity, is of crucial importance, as a minimum amount is necessary to maintain the enzyme s activity. For ionic liquids, a reaction can be operated at constant water activity by use of the same methods as established for organic solvents [17]. [BMIM][PFg] or [BMIM][(CF3S02)2N], for example, may be used as pure solvents and in biphasic systems. Water-miscible ionic liquids, such as [BMIM][BF4] or [MMIM][MeS04], can be used in the second case. 

Hydrolysis of substrates is performed in water, buffered aqueous solutions or biphasic mixtures of water and an organic solvent. Hydrolases tolerate low levels of polar organic solvents such as DMSO, DMF, and acetone in aqueous media. These cosolvents help to dissolve hydrophobic substrates. Although most hydrolases require soluble substrates, lipases display weak activity on soluble compounds in aqueous solutions. Their activity markedly increases when the substrate reaches the critical micellar concentration where it forms a second phase. This interfacial activation at the lipid-water interface has been explained by the presence of a... 

The most important biphasic liquid systems are probably those that combine a conventional organic phase with another type of solvent, such as water, a fluorous organic solvent, or an ionic liquid [3]. In those cases the solvent can be considered as the support for the catalyst phase and we have therefore limited the examples in this review to those where the recycled liquid catalyst phase is recovered as a whole. 

The term fluorous biphase has been proposed to cover fully fluorinated hydrocarbon solvents (or other fluorinated inert materials, for example ethers) that are immiscible with organic solvents at ambient conditions. Like ionic liquids the ideal concept is that reactants and catalysts would be soluble in the (relatively high-boiling) fluorous phase under reaction conditions but that products would readily separate into a distinct phase at ambient conditions (Figure 5.5). 

Recently, the use of ionic liquids instead of organic solvents has been published for the biphasic system. For PaHNL and SbHNL, the reaction rates are increased in comparison to organic solvents without a change of enantioselectivity. ... 

Since the beginning of the 20th century, organic solvents have been used in enzymatic reaction media [30]. Biocatalytic reactions in water-organic biphasic media were first carried out by Cremonesi et al. [31] and by Buckland et al. [32] less than 30 years ago. Their work aimed at the conversion of high concentrations of poorly water soluble components, particularly steroids. Later, biphasic systems were used for enzyme-catalyzed synthesis reactions that were unfavored in water, changing the reaction equilibrium towards the higher yield of the product, such as esters or peptides. 

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. 

The development of biphasic media requires a knowledge of general rules based on observation. The choice of the biocatalyst and the organic solvent is very important. Estimation of the biocatalyst tolerance to an organic solvent is based on various indicators, described later in this chapter. Biocatalysts are also sensitive to the process of the liquid-liquid interface. They can be used in two different forms free, soluble or immobilized. 

Several experiments using different organic solvents in different biphasic media are necessary to find the adequate distribution of the reaction components. A series of experiments are essential for the choice of a process and for scaling-up. Experiments using Lewis cells [44] may yield useful results for understanding equilibrium, kinetics, and interactions between organic solvent-substrate and/or organic solvent-biocatalyst. A study of two-liquid phase biotransformation systems is detailed below in Sections II-IX. 

TABLE 1 Effect of the Organic Solvent on Stability and/or Activity of Biocatalysts in Biphasic Media... 

Organic solvent Log P Biphasic medium Biocatalyst Reaction Biocatalyst stability Activity Reference... 

Various criteria can influence the choice of organic solvent that can be used in a biphasic bioreactor degree of solubility of substrates and/or products, inactivation effect, toxicity, flammability, and essentially reactant partition between the phases. Much research has been carried out on this topic [7,8,14,15,33,67]. 

The lipases demonstrated very high stability in media partially or totally composed of organic solvent. In such media, the lipases catalyze esterification, transesterification, and resolution of enantiomers [19,45,75,97-100]. Nevertheless, several biphasic systems (organic-aqueous) are used for hydrolysis of lipid and fats [7,34,101]. Kinetic studies in biphase media or in inverted micelles demonstrate that the lipase behavior is different... 

The ability of free or immobilized lipoxygenase to introduce oxygen derived from the air into polyunsaturated fatty acids in media containing organic solvent and aqueous buffer has been investigated [9,56]. The influence of many parameters was tested upon the degree of oxygenation in biphasic systems [36,108]. 

The use of thermomorphic systems has recently been studied as a way of achieving catalyst separation in homogeneous catalysis. For example, a biphasic hydroformylation catalyst system was developed to take advantage of the unusual solvent characteristics of perfluorocarbons combined with typical organic solvents (4). Fluorous/organic mixtures such as perfiuoromethylcyclohexane... 

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