Soluble substrate

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). 

Organic solvents may improve substrate solubility, specificity of reaction and equilibrium reaction. The last two benefits are considered further in Section 2.6.2. 

Figure 4.65 Parity plot comparing the conversion of a batch and laminar flow model for five different substrates made by allyl alcohol isomerization. For calculation, the same rate law was used for all substrates. The increase in conversion is due to increased substrate solubility [112].

A very effective way of carrying out syn-dihydroxylation of alkenes is by using an osmium tetroxide-tertiary amine N-oxide system. This dihydroxylation is usually carried out in aqueous acetone in either one-or two-phase systems, but other solvents may be required to overcome problems of substrate solubility.61... 

Use of benzene suspensions containing a neutral rhodium(I)-DIOP complex supported on a cross-linked polystyrene (50) (cf. 13 in Section III,A) for hydrogenation of a-ethylstyrene (to 1.5% ee) and methyl atro-pate (2.5% ee) was less effective than the homogeneous system, as the ethanol cosolvent required for substrate solubility caused a collapse of the resin (296). 

In Section 5.03.6.2, a stereoselective synthesis of L-homophenylalanine from the racemic AAacetylated amino acid is described. The authors, however, found that substrate solubility limited the utility of this procedure. Having found an L-N-carbamoylase in Bacillus kaustophilus, they introduced the gene for this enzyme together with that for the N-acyl amino acid racemase from D. radiodurans into E. coli for coexpression. These cells, permeabilized with 0.5% toluene, were able to deliver L-homophenylalanine in 99% yield and were able to be used for multiple reaction cycles. 

A.9. Enhanced Reaction Rate Due to Increased Substrate Solubility... 

Functional P450 substrate Solubility PK/PD HERG" IC50... 

A study of substrate solubility and phase-partitioning behavior in a wide range of solvent concentrations by Truppo et al. led to a fourfold decrease in enzyme charge with an increase in product enantiomeric excess. The process was successfully run at 400-L scale yielding the desired product with 99.73%ee at 50% conversion with the optimized conditions [86]. The DP receptor antagonist 42 is being evaluated in clinical trials for the treatment of allergic rhinitis. 

Kinetic descriptions of this type of biocatalyzed system in the presence of different amounts of water [9], substrates [10], or inorganic salts [51] have been reported. In some cases, solvents ( adjuvants ) have been used to increase mass transfer [6, 7]. However, it was found that upon addition of organic co-solvents longer process times were actually required, even though the substrate solubility increased several times [54]. 

A comparison of the synthesis of Z-Phe-Leu-NH2 in ten different solvents revealed that the highest overall yields could be expected in solvents where the substrate solubility is minimized. The highest yields in terms of solid product were found in solvents where both substrate and product solubility are minimized [45]. These simple rules may not hold when special factors apply, such as the formation of solid solvates. This may account for a few apparent exceptions, such as the product precipitation in dichloromethane of both a peptide and a sugar fatty acid ester [45, 63]. 

Some literature examples of peptide synthesis in the presence of organic ( -) solvents are summarized in Table 12.4. The uncharged peptide that was not reported to precipitate in the time scale of the reaction was Ac-Phe-Ala-NH2 [65]. This was probably due to mass transfer limitations related to limited substrate solubility in the mixture of solvents used. 

The direction of a reaction can be assessed straightforwardly by comparing the equilibrium constant (Keq) and the ratio of the product solubility to the substrate solubility (Zsat) [39]. In the case of the zwitterionic product amoxicillin, the ratio of the equilibrium constant and the saturated mass action ratio for the formation of the antibiotic was evaluated [40]. It was found that, at every pH, Zsat (the ratio of solubilities, called Rs in that paper) was about one order of magnitude greater in value than the experimental equilibrium constant (Zsat > Keq), and hence product precipitation was not expected and also not observed experimentally in a reaction with suspended substrates. The pH profile of all the compounds involved in the reaction (the activated acyl substrate, the free acid by-product, the antibiotic nucleus, and the product) could be predicted with reasonable accuracy, based only on charge and mass balance equations in combination with enzyme kinetic parameters [40]. 

The reaction is usually run in aqueous acetone in either one- or two-phase systems, but substrate solubility may require the use of other solvents. Aqueous ferf-butanol, tetrahydrofuran, and mixtures of these solvents have also been used successfully. 

Applying our best conditions from this model to the real, we still could not get respectable numbers, and it was clear that the 10% cobalt catalyst being used was far too much metal for this catalytic process, especially as the final step in the synthesis. More trials and more tribulations later, eventually issues such as reagent and substrate solubilities, importance of added pyridine as well as solid Na2C03 got us to a procedure based on 5% Co(salen) which produced CoQio in 68% isolated yield (Eq. 1.5). The quality of the CoQ obtained was excellent none of the cis isomer, as expected, was present. Nonetheless, there was also no doubt that starting material had not been fully consumed, suggesting that the catalyst was dying over time. 

A minimum threshold value for reactor productivity can be set at a space-time-yield of about 100 g (L d) 1, a value which tends to be compromised more by lack of substrate solubility than by biocatalyst reactivity. Well-developed biocatalytic process often feature space-time yields of > 500 g (L d) 1 or even > 1 kg (L d) 1 (Fischer, 1994 Rozzell, 1999 Bommarius, 2001). 

The rates of asymmetric sulfoxidation of thioanisole in nearly anhydrous (99.7%) isopropyl alcohol and methanol catalyzed by horseradish peroxidase (HRP) were determined to be tens to hundreds of times faster than in water under otherwise identical conditions (Dai, 2000). Similar effects were observed with other hemo-proteins. This dramatic activation is due to a much higher substrate solubility in organic solvents than in water and occurs even though the intrinsic reactivity of HRP in isopropyl alcohol and in methanol is hundreds of times lower than in water. In addition, the rates of spontaneous oxidation of the model prochiral substrate thioanisole in several organic solvents was observed to be some 100- to 1000-fold slower than in water. This renders peroxidase-catalyzed asymmetric sulf-oxidations synthetically attractive. 

With the assumptions of second-order deactivation and first-order reaction, the regimes are characterized as follows ([A]solid 0 = initial concentration of solid substrate, [A111ril = substrate solubility) ... 

One of the most important goals is the enhancement of volumetric productivities. As high volumetric productivity correlates with high solubility of substrates (Chapter 2 Bommarius, 2001), enhancement of substrate solubility is an excellent measure for improving volumetric productivity. 

Yoon, S. H. Nakaya, H. Ito, O. Miyawaki, O. Park, K. H. Nakamura, K. Effects of Substrate Solubility in Interesterification with Riolein by Immobilized Lipase in Supercritical Carbon Dioxide. Biosci. Biotechnol. Biochem. 1998, 62, 170-172. Yu, Z. R. Rizvi, S. S. H. Zollweg, J. A. Enzymatic Esterification of Fatty Acid Mixtures from Milk Fat and Anhydrous Milk Fat with Canola Oil in Supercritical Carbon Dioxide. Biotechnol. Prog. 1992, 8, 508-513. 

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