Fluorous Ether

In this short section, we focus mainly on four types of fluorinated solvents, traditional and new, which are available for ordinary organic synthesis. These are benzotrifluoride (BTF) 1, fluorous ether F-626 2, fluorous dimethylformamide (F-DMF) 3, and perfluorohexanes such as FC-72 4, whose physical properties are summarized in Table 3.5-1. The challenges to explore the green potentials of fluorous media have just begun but, no doubt, the concept is growing to constitute another important aspect of fluorous chemistry. 

An easy recycling method involving both catalyst and reaction medium was achieved in a Mizoroki-Heck arylation reaction of acrylic acid, using a fluorous carbene complex (prepared in situ fl om a fluorous ionic liquid and palladium acetate) as the catalyst and a fluorous ether solvent (F-626) as the reaction medium. Because of the very low solubility of arylated carboxylic acids in F-626, the products precipitated during the course of the reaction. After separation of the products and amine salts by filtration, the filtrate, which contained the fluorous Pd catalyst, could be recycled for several runs (Scheme 13). The Mizoroki-Heck reaction was effectively promoted by a fluorous SCS pincer palladium, which is discussed in Section 3.4.5. 

Fukuyama, T., Arai, M., Matsubara, H. and Ryu, I. (2004) Mizoroki-Heck arylation of a,fi-unsaturated acids with a hybrid fluorous ether, F-626 facile filtrative separation of products and efficient recycling of a reaction medium containing a catalyst. J. Org. Chem., 69, 8105-7. 

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). 

Wiles C, Watts P, Wiles C, Haswell S, Pombo-Villar E (2001) The Aldol Reaction of Silyl Enol Ethers within a Microreactor. Lab Chip 1 100-101 Zhang W (2004) Fluorous Synthesis of Heterocyclic Systems. Chem Rev 104 2531-2556... 

Another spacer which was used to insulate the phosphorus atom from the electron-withdrawing effect of the perfluoroalkyl tail is the -0-(CH2) - spacer that contains an electron-donating oxygen atom directly attached to the aryl ring [25]. Fluorous derivatives of triphenylphosphine containing this ether spacer (13a-c) were prepared, though the lower coupling constant of cis-... 

The term fluorous was coined as an analogy to aqueous for highly fluorinated alkanes, ethers and tertiary amines [1], These compounds differ markedly from the corresponding hydrocarbon compounds to the extent that such compounds commonly give bilayers with conventional organic solvents. In this chapter, we will discuss the different approaches towards carrying out reactions in fluorous media and describe how reactants and catalysts can be engineered to be preferentially soluble in fluorous solvents. 

As shown in Scheme 3, the PCP ligand coifld be palladated in high yield. The resulting complexes 14-Rf were very soluble in fluorous solvents, insoluble in hexane, slightly soluble in ether, and moderately soluble in THF, CH2CI2, and acetone. However, 14-Rf readily dissolved in hot hexane, and with 14-Rfs single crystals were obtained upon coohng. X-ray analysis afforded the structures shown in Fig. 6. 

C. Brornotris[2-(perfluorohexyl)ethyl]tin. The fluorous phenyltin product (17.2 g, 13.9 mmol) and dry ether (80 mL) are transferred to a 250-mL, three-necked flask that had been dried in an oven and cooled to 0°C under argon. Bromine (0.71 mL, 14 mmol) is added dropwise over 30 min to the mixture. The addition rate is adjusted to keep the temperature between 0° and 1°C. The mixture is warmed to 25°C and stirred for 7 hr. The reaction mixture is transferred to a 250-mL, round-bottomed flask. The ether and excess bromine are removed under reduced pressure to leave a yellow oil. The oil is dissolved in FC-72 (75 mL) and transferred to a 250-mL separatory funnel. The bromine and bromobenzene by-products are removed by washing three times with methylene chloride (3 x 75 mL) leaving the fluorous layer colorless. The FC-72 is removed under reduced pressure to provide 15.8 g (12.7 mmol, 92%) of a colorless oil (Note 6). 

D. Tris[(2-peiiluorohexyl)ethyl]tin hydride (Note 7). A 1-L, three-necked flask and a stirring bar are dried in an oven. The fluorous tin bromide (13.8 g, 11.1 mmol) is dissolved in dry ether (275 mL) and transferred to the dried three-necked flask equipped with a thermometer, stirring bar, and an outlet to argon. The solution is cooled to O C. AIM solution of iithium aluminum hydride (LAH) in ether (11.1 mL, 11.1 mmol) is added dropwise over 45 min to the solution. The addition rate is adjusted to maintain a temperature between 0° and 1°C. The reaction mixture is stirred for 6 hr at 0°C. Water (75 mL) is slowly added (initially dropwise) with stirring to the ice-cold mixture. Sodium potassium tartrate (20%) (250 mL) is added and the mixture is transferred to a 1-L separatory funnel. The ethereal layer is separated and the aqueous layer is extracted three times with ether (3 x 100 mL). The combined extracts are dried with magnesium sulfate and vacuum filtered into a 1-L, round-bottomed flask. The solvent is evaporated under reduced pressure. The cmde product is distilled under a reduced pressure of 0.02 mm at 133-140°C to provide 11.3 g (9.69 mmol, 87%) of the pure product as an oil (Notes 8 and 9). 

Fluoroalkyl Glycosides (RFn-(CH2)2-n-0-sugar) and Perfluor-oalkylidene Acetals Derived from Sugars The very low nucleophilicity of fluoroalcohols makes it difficult to substitute of a hydroxyl (anomeric or not). ° This is the reason why this type of ether is not very common. Such ethers have only been isolated in very small quantities in solvolysis reactions, or in carben insertions, performed in fluorous alcohols.Preparation of these ethers has been solved by means of the Mitsunobu reaction. This reaction is known to be dependent on the pA a of the acceptor of the glycosyl the acidity of fluorous alcohols allows a much easier deprotonation than with non fluorinated alcohols." ... 

Fluorous Solvents. The fluorous phase is an alternative to the aqueous phase.26 Fluorous (perfluorinated) solvents, such as perfluoroalkanes, perfluoroalkyl ethers, and perfluorinated tertiary amines, have been recognized to be extremely stable and nontoxic and have high density, low solvent strength, and extremely low solubility in water and organic materials. 

The fluorous biphasic concept was introduced by the Hungarian chemists Istvan Horvath and Jozsef Rabai in 1994 [148], A fluorous biphasic system consists of a fluorous phase (a perfluoroalkane-, perfluorodialkyl ether-, or perfluorotrialkylamine-rich phase) containing a fluorous-soluble reagent or catalyst, and a second phase,... 

The acylation of aromatic ethers by acyl chlorides is highly regioselective in the presence of 10 mol% Sml3.53 Some aromatic compounds are efficiently acylated by acid anhydrides catalysed by niobium pentachloride with silver perchlorate.54 Arenes of a range of reactivity are acylated by acetic anhydride in a fluorous biphasic system catalysed by Hfps SCLCgFn L (1 mol%)55 The catalyst is easily recoverable and can usually be used again without decrease in activity. 

Fluorous biphasic catalysis was pioneered by Horvath and Rabai [54, 55] who coined the term fluorous , by analogy with aqueous , to describe highly fluori-nated alkanes, ethers and tertiary amines. Such fluorous compounds differ markedly from the corresponding hydrocarbon molecules and are, consequently, immiscible with many common organic solvents at ambient temperature although they can become miscible at elevated temperatures. Hence, this provides a basis for performing biphasic catalysis or, alternatively, monophasic catalysis at elevated temperatures with biphasic product/catalyst separation at lower temperatures. A number of fluorous solvents are commercially available (see Fig. 7.16 for example), albeit rather expensive compared with common organic... 

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