Fluorine, elemental selective reactions

Jahnisch, K., Baerns, M., Hessel, V, Haverkamp, V, Lowe, H., Wille, C., Selective reactions in microreactors -fluorination of toluene using elemental fluorine in a falling film microreactor, in Proceedings of tlie 37tli ESF/EUCHEM Conference on Stereocliemistry (13-19 April 2002), BUrgenstoclc, Switzerland. 

An important special case of selective direct fluorination is the reaction of elemental fluorine with uracil to produce 5-fluorouracil in 55—80% yield, which was first reported by Schuman, Tarrant et al. (94) and also studied by Hesse et al. (95). 

Considerable insight into the future of selective reactions of elemental fluorine may be gleaned from consideration of the thermodynamics and kinetic factors of the low-temperature reactions of elemental fluorine. As is stated earlier, there is, under normal circumstances, no selectivity of the reactions of fluorine with carbon-hydrogen bonds and most other bonds at room tempera-... 

Perfluoro crown ethers have been synthetically inaccessible by conventional reactions of fluorocarbons and outside the capability of synthesis by fluorination using selective fluorination reagents. Examples of this potentially useful class of macrocycles have been prepared recently in our laboratory. These syntheses have been initially accomplished using the broadly applicable technique for controlling reactions of elemental fluorine (the La Mar process) developed in our laboratory. The reactions were conducted in the previously described cryogenic fluorination reactor (2),... 

For example, direct fluorinations with elemental fluorine are kept imder control in this way, at very low conversion and by entrapping the molecules in a molecular-sieve reactor. As with some other aromatic substitutions they can proceed by either radical or electrophilic paths, if not even more mechanisms. The products are dif ferent then this may involve position isomerism, arising from different substitution patterns, when the aromatic core already has a primary substituent further, there may be changed selectivity for imdefined addition and polymeric side products (Figure 1.31). It is justified to term this and other similar reactions new , as the reaction follows new elemental paths and creates new products or at least new... 

Elemental fluorine can be used to replace relatively electron rich C-H bonds by C-F. In particular, tertiary hydrogen atoms which are remote from electron withdrawing substituents can be selectively replaced by fluorine and, where there is more than one tertiary hydrogen atom in the substrate, that with the higher electron density is replaced (Fig. 44). In contrast, where there is an electron withdrawing group close to tertiary hydrogen, very little reaction with fluorine takes place and, consequently, when one fluorine atom has been introduced into a molecule further reaction is often inhibited. 

Many current fluorine texts contain sections on the unfavorable thermochemistry of elemental fluorine reactions. A discussion of this thermochemistry, therefore, is helpful to establish the feasibility of direct fiuorination and gain insight into reaction conditions, to select, for example, the reaction temperatures that are most likely to lead to successful results. The tables of data presented and discussed deal with the thermochemistry of fiuorination of hydrocarbons. This choice was made because such data were most readily available. Similar arguments may certainly be made for inorganic compounds or polymers. 

The fact that functionalization of polymers and small molecules is observed to occur predominately on terminal (methyl) carbon atoms does not imply that the oxyfluorination reaction is truly selective. Although the reaction mechanism has not been studied in detail, it is undoubtedly a free-radical process. Molecular oxygen reacts spontaneously with the fluorocarbon—hydrogen radicals generated by fluorine during the fluorination process. Acid fluorides are retained on terminal carbon atoms because they are stable in 1 atm of elemental fluorine. Hypofluorites, which may be short-lived intermediates of oxygen reactions with methylene radical sites along the carbon chain, are not observed in the functionalized polymers. It is probable that, if they are intermediates, they are cleaved and removed by the excess elemental fluorine. 

In view of the extremely exothermic nature of the reaction of elemental fluorine with hydrocarbons, inorganic hydrides, and so on, it might seem obvious that there should be little or no selectivity in the reactions of molecular or atomic fluorine. 

At significantly lower temperatures the prospects are completely different. Although the reasons are not well understood, there is a picture of rather amazing selectivity of the reactions of elemental fluorine below —78°C emerging in the literature. 

Reduction of the carbon-halogen bond is an important synthetic reaction in organic chemistry. The importance of the reduction has been enhanced in recent years by the application of a wide range of newly available reductants. However, in the case of fluorine, the reduction is of less importance than for the other halogens. Reviews on the reduction of fluorine bonds have appeared mainly in the more specialized literature,1 4 though some aspects of the subject have formed parts of reviews of the broader topic of hydrogenation, reduction, or substitution.5,6 This section does not include patent literature and all literature data. It is thus selective, not exhaustive, and includes representative examples of the most commonly used procedures for the reduction of C-F and element-fluorine bonds. 

Both K2MnF6 and SbF5 may be prepared without the use of elemental fluorine. The very broad potential of aHF as a reaction medium is apparent from the observation that even AgIAg1IIF4 [140] may be isolated under carefully controlled conditions, although this formal isomer is much less stable than the well-known AgF2. The method also enables the preparation of Au -compounds [141]. The compounds just mentioned are selected representatives of a large variety of mostly ternary salts (Table 5). 

Barton and cowoikers have shown how elemental fluorine can be used in nitrobenzene to obtain a selective fluorination of a steroid, a reaction of importance in drug synthesis (equation 74). A variety of transition metal fluorides, such as C0F3, are milder fluorinating agents for alkanes. 

Initial attempts at the direct fluorination of carbonyl compounds such as acetone, bulan-2-one, and butyric acid with elemental fluorine resulted in the formation of complex mixtures, with only low yields of a-monofluorinated carbonyl compounds formed. However, more recently, methyl 3-phenylpyruvate. and other pyruvate derivatives, e.g. 1," are reported to be selectively monofluorinated with dilute elemental fluorine at — lO C in moderate yield. The success of this reaction is attributed to the fact that the substrate predominantly exists in the enol form and not the keto form." Direct fluorination of acyclic 1,3-dicarbonyl compounds in formic acid or acetonitrile at room temperatures results in the formation of 2-fluoro-... 

The direct fluorination of substituted pyridines with elemental fluorine results in the selective substitution of a hydrogen in the 2-position to give 2-fluoropyridines 1. - This selectivity is explained through an addition-elimination mechanism, the first step in which is the formation of a complex of type 2 between the fluorine and the pyridine. Then there is attack of the fluoride ion at C2 to give a formal addition product 3, followed by elimination of hydrogen fluoride. The initial step in thus reaction is supported by the fact that a complex between pyridine and fluorine has been isolated and characterized at — 80 C. ... 

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