Reactions in Organic Solvents

Although other scandium salts have recently been reported in the literature, their properties are similar to Sc(OTf)3 in many respects, and so this article surveys useful synthetic reactions which employ Sc(OTf)3 as a catalyst, focusing in particular on carbon-carbon bond-forming reactions in organic solvents, aqueous media, and the solid phase. 

Although Sc(OTf)3 and other scandium salts are water-stable and used in aqueous media, they are also successfully employed in organic media. They are used catalyti-cally in many reactions and can often be recovered and reused because they are stable under usual water-quenching conditions. 

Sc(OTf)3 is an effective catalyst in aldol reactions of silyl enol ethers with aldehydes [4,5]. The activities of typical rare earth triflates [Sc, Y, Yb(OTf)3] were evaluated in the reaction of 1-trimethylsiloxycyclohexene with benzaldehyde in dichloromethane (Table 1). Although the reaction scarcely proceeded at -78 °C in the presence of Yb(OTf)3 or Y(OTf)3 [3b], the aldol adduct was obtained in 81 % yield in the presence of Sc(OTf)3. Obviously, Sc(OTf)3 was more active than Y(OTf)3 or Yb(OTf)3 in this reaction. 

Several examples of Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were been examined. Silyl enolates derived from ketones, thioesters, and esters reacted smoothly with different types of aldehyde in the presence of 5 mol % Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in aldol-type reactions of silyl enolates with acetals. The reactions proceeded smoothly at -78 °C or room temperature to give the corresponding aldol-typc adducts in high )delds without side-reaction products. It should be noted that aldehydes were more reactive than acetals. For example, while 3-phenylpropionalde-hyde reacted with the ketene silyl acetal of methyl isobutyrate at -78 °C to give the aldol adduct in 80 % yield, no aldol-type adduct was obtained at -78 °C in the reaction of the same ketene silyl acetal with 3-phenylpropionaldehyde dimethyl acetal. The acetal reacted with the ketene silyl acetal at 0 °C to room temperature to give the 

Sc(OTf)3 is more soluble in water than in organic solvents such as dichloromethane. The catalyst can be recovered almost quantitatively from the aqueous layer by simple extraction after the reaction was complete (Sch. 2), and it could be re-used. The recovered catalyst is also effective in the 2nd reaction, and the yield of the 2nd run is comparable with that of the 1st run (Eq. 1) [4], Because Sc(OTf)3 can be successfully recovered and re-used in many other reactions, it is expected to solve severe environmental problems caused by mineral acid- or Lewis acid-promoted reactions in the chemical industry. 

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This thesis describes a study of catalysis of Diels-Alder reactions in water. No studies in this field had been reported at the start of the research, despite the well known beneficial effects of acpieous solvents as well as of Lewis-add catalysts on rate and endo-exo selectivity of Diels-Alder reactions in organic solvents. We envisaged that a combination of these two effects might well result in extremely large rate enhancements and improvements of the endo-exo selectivity. 

Nitration at a rate independent of the concentration of the compound being nitrated had previously been observed in reactions in organic solvents ( 3.2.1). Such kinetics would be observed if the bulk reactivity of the aromatic towards the nitrating species exceeded that of water, and the measured rate would then be the rate of production of the nitrating species. The identification of the slow reaction with the formation of the nitronium ion followed from the fact that the initial rate under zeroth-order conditions was the same, to within experimental error, as the rate of 0-exchange in a similar solution. It was inferred that the exchange of oxygen occurred via heterolysis to the nitronium ion, and that it was the rate of this heterolysis which limited the rates of nitration of reactive aromatic compounds. 

Whether AH for a projected reaction is based on bond-energy data, tabulated thermochemical data, or MO computations, there remain some fundamental problems which prevent reaching a final conclusion about a reaction s feasibility. In the first place, most reactions of interest occur in solution, and the enthalpy, entropy, and fiee energy associated with any reaction depend strongly on the solvent medium. There is only a limited amount of tabulated thermochemical data that are directly suitable for treatment of reactions in organic solvents. Thermodynamic data usually pertain to the pure compound. MO calculations usually refer to the isolated (gas phase) molecule. Estimates of solvation effects must be made in order to apply either experimental or computational data to reactions occurring in solution. 

ILs have also been used as inert additives to stabilize transition metal catalysts during evaporative workup of reactions in organic solvent systems [35,36]. The non-... 

Heitz classifies corrosion reactions in organic solvents into... 

Compared with the abundance of data on azo coupling reactions in aqueous solution, relatively few investigations deal with reactions in organic solvents. 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

Phase transfer catalysis (PTC) has been utilized in organic synthesis to perform reactions in organic solvents when some of reactants are present in the aqueous phase (e.g., the substitution reaction involving alkylchlorides RCl),... 

Potential for new synthetic methodologies. Compared to reactions in organic solvents, the use of water as a reaction solvent has... 

In the synthesis of 2,2,5-trisubstituted tetrahydrofurans, a novel class of orally active azole antifungal compounds, Saksena95 reported that the key step of Diels-Alder reaction in water led to the desired substrate virtually in quantitative yields (Eq. 12.34), while the same reaction in organic solvent resulted in a complicated mixture with only less than 10% of the desired product being isolated. This success made the target compounds readily accessible. 

Spin trapping EPR technique and UV-Vis spectroscopy have been used (Polyakov et al. 2001b) to determine the relative rates of reaction of carotenoids with OOH radicals formed by the Fenton reaction in organic solvents. The Fe3+ species generated via the Fenton reaction... 

Coupling reactions in organic solvents are occasionally carried out with masked diazonium compounds e.g., with special diazonium moieties which are incorporated into a larger organic structure [4], for instance in a diazoamino compound (15) or a benzotriazinone (16) ... 

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

Other research groups have also made significant contributions to the themes described above. Fiuorous catalysts that have been recovered from homogeneous reactions in organic solvents at elevated temperatures by simple precipitations (sequence A-I, Fig. 1) are summarized in Fig. 10 (20-25). A representative application for each is given in Scheme 4. 

As would be expected, fluorous compounds are preferentially retained on fluorous silica gel [62]. Similarly, fluorous catalysts can be adsorbed on fluorous silica gel. These materials have been applied to reactions in organic solvents and water, both at room temperature and above [63-69]. The investigators have usually interpreted the transformations as bonded fluorous phase catalysis , which corresponds to sequence B-II in Fig. 1. However, there remains the possibility that at least some catalysis proceeds under homogeneous conditions via desorbed species. To our knowledge, fish-out experiments analogous to that conducted with the Teflon tape in Fig. 8 have not been conducted. 

In many respects, aqueous organometallic hydrogenations do not differ from the analogous reactions in organic solvents. There are, however, three important points to consider. One of them concerns the activation of the hydrogen molecule [3]. The basic steps are the same in both kinds of solvents, i.e. Hi can be split either by homolysis or heterolysis, equations (3.1) and (3.2), respectively. 

Figure 13. Preparation of immobilized enzymes with different solubilities in aqueous solutions and organic solvents. Procedure A mixture of an enzyme (3 mg) and the polymer (10 mg) was incubated at pH 7.5 for 20 min. Ammonium phosphate (0.1 M, pH 7, 1 mL) was then added to react with the remaining active ester. After 20 min, the solution was ready for use, or lyophilization to give the immobilized enzyme as a powder to be used for reaction in organic solvents. Each gram of the polymer contains approximately 0.7 mmol of the active ester.

As enzymes could be used to carry out synthetic reactions in organic solvents [244-246] only under certain specific conditions, the appHcation ofRMs as enzyme hosts to perform biotransformations has attracted a great deal of research attention in the recent past. The reverse micellar environment represents a medium where the aqueous/organic interface is very large ( 100 m ml ) [247]. 

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