Carbonylation aqueous biphasic systems

The Boots Hoechst Celanese (BHC) ibuprofen process involves palladium-catalyzed carbonylation of a benzylic alcohol (IBPE). More recently, we performed this reaction in an aqueous biphasic system using Pd/tppts as the catalyst (Figure 9.6 tppts = triphenylphosphinetrisulfonate). This process has the advantage of easy removal of the catalyst, resulting in less contamination of the product. 

The salt production can be circumvented by performing the selective Pd/ tppts-catalysed carbonylation of benzyl alcohol in an acidic aqueous biphasic system (Fig. 1.36) [106]. This methodology was also applied to the synthesis of ibuprofen (see earlier) by biphasic carbonylation of l-(4-isobutylphenyl)ethanol [107] and to the biphasic hydrocarboxylation of olefins [108]. 

To determine the mode of operation (see below) it is useful to group these homogeneous catalysts into aqueous biphasic systems (see Section 3.1.1.1) and nonaqueous biphasic systems (see Section 3.1.1.2). Gas-liquid-liquid reactions are also involved in organometallic phase transfer catalysis, e. g., in biphasic carbonylation of benzyl chloride to phenylacetic acid by the catalyst system NaCo(CO)4/Bu4NBr/NaOH [21]. Here, the biphasic system consists of an organic solvent and aqueous alkali. 

Hydroformylation and Carbonylation Reactions in Aqueous Biphasic Systems... 

As an alternative to the use of fluorous tag, fluorous aqueous biphasic systems have also been explored. Recently, fluorous biphasic system composed of fluorous Lewis acid ytterbium perfluorooctanesulfonate [Yb(OPf)3], fluorous solvent perfluorocarbon has been used in the synthesis of benzodiazepines from OPD and carbonyl compounds [127]. Conceptually, the fluorous catalyst with perfluoroalkylated tails can dissolve into the fluorous phase containing the product after the reaction. The study has been extended later to the use of fluorous aqueous emulsion expecting that the organic substrate will remain in the interfacial area between a fluorous phase and aqueous media. Thus another synthesis of benzodiazepines has been reported by the same group by carrying out the reaction in a fluorous aqueous emulsion system composed of perfluorooctane and potassium perfluorooctanesulfonate at room temperature (Scheme 38) [128]. Moreover, the emulsion could be recovered and recycled without significant loss of activity. 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory dmgs (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by hydroxycarbonylation [51,53] (several more listed in [52]). The carbonylation of styrene itself serves as a useful test reaction in order to learn the properties of new catalytic systems, such as activity, selectivity to acids, regioselectivity (1/b ratio) and enantioselectivity (e.e.) in the branched product. In aqueous or in aqueous/organic biphasic systems complexes of palladium were studied exclusively, and the results are summarized in Table 5.2. 

Higher olefins have negligible solubility in water therefore their hydrocarboxylation in aqueous/organic biphasic systems needs co-solvents or phase transfer agents. With the aid of various PT catalysts 1-octene and 1-dodecene were successfully carbonylated to the corresponding carboxylic acids with good yields (< 85 %) and up to 87 % selectivity towards the formation of the linear add with a [Co2(CO)g] catalyst precursor under forcing conditions (150 °C, 200 bar CO) [57],... 

In water-heptane biphasic systems, allylic alcohols underwent rearrangement to the corresponding carbonyl compounds with a catalyst prepared in situ from RhCU.aq and TPPTS. The reactions proceeded very fast (TOP up to 2500 h ) and in most cases provided the carbonyl products quantitatively. The industrially interesting geraniol was isomerized mostly to citronelM, albeit octatrienes and tricyclene were also produced. With an increase of the pH of the aqueous phase the yield of isomerization decreased somewhat (from 48 % to 40 %), however the selectivity towards the... 

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]. 

Figure 4.11 The Montedison process for the carbonylation of benzyl chloride in a biphasic system. A phase-transfer catalyst is used to facilitate transport of Co(CO)i" and HO- from the aqueous to the organic phase.

The catalytic carbonylation of benzylic halides to arylacetic acids has been improved by using two-phase systems under phase-transfer conditions [29]. Usually the reactions were performed with an excess of base in a biphasic system with a metal catalyst in the organic phase. As phase transfer catalysts surfactants are used, which appear to play an important transport function to move the cobalt carbonyl salt from the aqueous phase to the organic droplets (cf. Section 3.2.4). While the structure of the phase transfer co-catalyst was being studied it was observed that benzyltrialkylammonium salts were easily carbonylated. In some cases the yields of arylacetic acids are higher compared with the carbonylation of the corresponding benzyl halides [30]. 

Activity and selectivity studies on the carbonylation of p-isobutyl phenylethanol using palladium catalyst has been studied in a biphasic system comprising of methyl ethyl ketone as the organic phase and 10% HCl as the aqueous phase, as well as the promoter. The effect of parameters such as catalyst precursor, types of ligand, and ligand to metal ratio were studied at a temperature of403 K. A plausible catalytic cycle is projxjsed to explain the observed results. 

It is reported that the two-phase carbonylation methodology has been used on a pilot plant scale by Montedison [31 ] for the conversion of benzyl chloride to phenylacetic acid for use in perfume constituents and pesticides (eq. (8)). The carbonylation is run in a biphasic medium employing diphenyl ether and aqueous 40 % sodium hydroxide as solvents. The catalyst system consists of a cobalt carbonyl complex and a benzyltrialkylammonium surfactant. The reaction takes place at low temperature and CO pressure, while benzyl chloride is added continuously to the reaction mixture. 

Hereby, poly(p-phenylene) polymers containing ether and carbonyl linkages in the polymer backbone are accessible. By polymerization of the AB2 monomer 3,5-dibromobenzene boronic acid in a biphasic aqueous/organic medium, Kim and Webster obtained hyperbranched polyphenylenes [233]. Suzuki polycondensation in aqueous systems has proven to be a versatile method, which has been applied to the synthesis of various polymer types ]234]. 

In the case of benzylideneacetone, the conversion of 61% was significantly lower than with a biphasic aqueous-organic catalyst system (87% conversion) or the conventional homogeneous catalyst system (100% conversion). However, the observed selectivity in the case of catalyst 22 was 96%, i.e. almost selective reduction of the olefinic moiety took place whereas the carbonyl substructure... 

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