Supercritical fluid reaction schemes

By devising supercritical fluid based schemes to remove the byproduct from the condensation reactions, higher conversions are achievable. Even though water does not show high solubility in supercritical carbon dioxide, other condensation products (i.e., phenol, acetic acid) which may have higher solubility in carbon dioxide may be extracted from the reaction mixture with carbon dioxide and increase conversion. Removal with carbon dioxide would be a desirable path compared to vacuum methods employed in traditional condensation polymerizations. 

However this result was embraced and demonstrated to be a convenient method to prepare several trifluoromethylated isomers of Lipitor in a single reaction which could then be separated using supercritical fluid chromatography (Scheme 15.95). 

Water can be used as the solvent in the presence of added surfactants. Reactions in ionic liquids and supercritical fluids are also feasible. A variety of reagents promote cychzation, which can be achieved at room temperature. Examples of compounds that promote and accelerate the reaction include A-methyhnorphohne A-oxide, trimethylamine A-oxide, phosphine oxides, dimethylsulfoxide, alkyl methyl snlfides, molecular sieves, and lithium perchlorate. A comparison of a few promoters is seen in Scheme 246. Promoters... 

An asymmetric Mukaiyama aldol reaction in supercritical fluids using a binaphthol-based titanium complex has also been reported (Scheme 7.43) [113]. 

It is clear from the several examples cited in this chapter that supercritical fluids can be advantageously used as reaction media but many unanswered questions remain. How do near-critical or supercritical conditions affect the rates and paths of chemical reactions How is the phase behavior of the initial reactants affected by product formation Is it possible to exploit the above results to devise efficient reaction/separation schemes These questions pose considerable experimental and theoretical challenges. 

The formation of diphenylcarbene by laser flash photolysis of diphenyldiazomethane was studied in SC-CO2 and other supercritical media. [18] A laser-flash induced ring-closure reaction of a bipyridyl complex (Scheme 2) revealed solvation properties. [19] Laser-flash impact to metal carbonyl complexes activated hydrogen and simple alkanes like CH4, C2H4, C2H6, and further inorganic reactions in supercritical fluids have been reviewed. [20]... 

Scheme 1.1-1 Some of the reactions of supercritical fluids or mixtures studied by Ipatiev.

Most reactions that have been investigated using PTC in supercritical fluids have been solid-SCF systems, not liquid-SCF. The first published example of PTC in an SCF is the displacement reaction of benzyl chloride 1 with potassium bromide in supercritical carbon dioxide (SCCO2) with 5 mol % acetone, in the presence of tetraheptylammonium bromide (THAB) [19-20] (Scheme 4.10-1) to yield benzyl bromide 2. The effects on reaction rate of traditional PTC parameters, such as agitation, catalyst type, temperature, pressure, and catalyst concentration were investigated. The experimental technique is described below. PTC appeared to occur between an SCF phase and a solid salt phase, and in the absence of a catalyst the reaction did not occur. With an excess of inorganic salt, the reaction was shown to follow pseudo-first order kinetics. 

Another reaction involving an SCF/PTC system is an esterification reaction [22] where the primary role of the SCF is to solubilize an intermediate product to prevent the overreaction to an unwanted byproduct. In this system (Scheme 4.10-3) an insoluble aromatic carboxylic acid 4 with a second reactive functional group is esterified at elevated temperature in supercritical dimethyl ether (scDME) with ethylene oxide 5, which is soluble in the fluid phase, in the presence of a thermally stable and insoluble phase-transfer catalyst. When esterification occurs, the product ester 6 is then soluble in the SCF and is pulled away from the site of reaction and trapped before the second functional group can be altered. Experimental data for this work were obtained using a modified Hewlett-Packard supercritical fluid extractor. This is an example of a PTC reaction where an intermediate product is desired, and the SCF system is designed to obtain only that intermediate. 

A binaphthol-derived chiral titanium(iv) complex effectively catalyzes the Mukaiyama aldol reaction in SCCHF3 or scC02. It was found that the chemical yield and enantioselectivity of the reaction in supercritical fluids could be tuned by changing the supercritical fluids (scCHFs vs. SCCO2) and adjusting the matched polarities by varying the pressure of CHF3 (Scheme 39). 

Mikami reported that BINOL derived titanium complex efficiently catalyzed the aldol reaction of silyl enol ether with excellent control of both absolute and relative stereochemistry [106] (Scheme 14.37). The reaction was proposed to proceed via a prototropic ene reaction pathway that is different from that of Mukaiyama aldol condensation. A cyclic antiperiplanar transition-state model was proposed to explain the pref erential formation of the syn diastereomer from either (E)- or (Z)-silyl enol ethers [106]. Further modifications of the catalyst system include the use of perfluorophenols and other activating additives [107], or performing the reaction in supercritical fluids [108]. Furthermore, the nucleophile could be extended to enoxysilacyclobutane derivatives [109]. 

Reaction schemes exploiting supercritical fluid diffusivities. The dif-fusivity of a dilute solute in a supercritical fluid, somewhat removed from the critical point, is typically an order of magnitude greater than in liquid solvents at comparable temperatures. Thus, radical initiators under supercritical fluid conditions are able to escape more readily from solvent cages, and the rate coefficient for the initiation process is markedly increased. Processes propagated by free radicals, such as polymerisation, are rate enhanced for this reason, as are enzymatic reactions. 

Formation of pyrene excimer (a complex between a photoexcited and a ground-state pyrene molecule Scheme 4) is an extensively characterized and well-understood bimolecular process (35). Because the process is known to be diffusion controlled in normal liquid solutions, it serves as a relatively simple model system for studying solvent effects on bimolecular reactions. In fact, it has been widely employed in the probing of the solute-solute clustering in supercritical fluid solutions (40-42,46,47,160,166-168). (See Scheme 4.)... 

Bunker et al. studied the photodimerization reaction of anthracene in supercritical CO2 at 35°C (179). They found that the reaction quantum yields are up to an order of magnitude higher in supercritical CO2 (35 C, Pr = 1.9) than in liquid benzene at the same anthracene concentrations however, for the fluid density dependence, the yields obtained at different densities agree well with the yields calculated on the basis of experimentally determined viscosities (Figure 24). Since the results provided no evidence of solute-solute clustering effects, the higher photodimerization yields in the supercritical fluid were atttibuted to more efficient anthracene diffusion associated with the lower viscosity. (See Scheme 6.)... 

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