Fluorination methods

Samples of l,l,l-trifhioro-2,2-bis(p-fluorophenyl)-ethane, and the corresponding bis-(p-chlorophenyl) derivative were obtained by applying Henne s fluorination method to DFDT and DDT, respectively. In both instances a mixture of the mono-, di-, and trifluoro compounds was obtained, but the desired trifluorinated material was separated by fractional recrystallization from methanol and cooling with a mixture of dry ice and acetone. 

The principal laws for the fluorination of polymeric hydrocarbons are the same as those described above for the simple case. Direct fluorination has been used extensively in organic chemistry (but only since the early 1970s) in low-temperature methods, where the fluorine is strongly diluted with some inert gas (helium, argon, nitrogen, krypton). One can note the La Mar, aerosol-based, and liquid-phase fluorination methods. 

Oxidation/epoxidation methods without the use of chlorinated solvents New greener fluorination methods... 

Taylor, B.E. 2004. Fluorination Methods in Stable Isotope Analysis. In DeGroot, P.A.jed.), Handbook of Stable Isotope Techniques, 1, Elsevier, Amsterdam, 400-472. 

A.D. Windhorst, R.P. Klok, C.L. Koolen, G.W.M. Visser, J.D.M. Herscheid, Labeling of [ F]flumazenil via instant fluorination, a new nucleophilic fluorination method, J. Label. Compds Radiopharm. 44 (2001) S930-S932. 

Recently, there have been a number of reports on stable fluorinated radicals, which include functionalized radicals and different fluorination methods, for example, electrochemical fluo-rination.41... 

The increasing importance of fluoroaromatics as fine chemicals and continuing research into more selective or directed fluorination methods suggests that the future may see the introduction of more industrial processes, especially for those compounds such as the 1,2-difluorobenzenes which are difficult or expensive to produce by existing technologies. 

The overall reaction in the replacement of hydrogen is exothermic enough (AG298 = -103.4 kcal mole 1) to fracture carbon--carbon bonds if it were to occur by a concerted mechanism or if it were to occur on several adjacent carbon atoms simultaneously. The comparison of 86 versus 103 kcal mole-1 has been cited in many previous discussions as an obvious basis for the prediction of the failure of direct fluorination methods. For the rapid reaction rates employed in most previous experiments, this is a valid argument. 

CF3)3CF, for which cobalt trifluoride and electrochemical-fluorination methods have not been successful, a yield of over 50% has been obtained. The direct fluorination of ethyl acetate (75), shown in Fig. 17, was the first example of conversion of a hydrocarbon ester to a perfluorocarbon ester by any fluorination technique. 

It may be true that presently the most important contribution of direct fluorination is in the preparation of fluorine compounds for which conventional fluorination methods have failed, but as direct fluorination techniques mature, they may be expected to compete in many syntheses where other techniques are also successful. Certainly the new procedures for direct fluorination discussed in this review will have a significant impact on fluorine chemistry. 

Fluorination Methods in Organic Chemistry Gerstenberger M R C Haas A Angeu, Chem 91 659-680... 

An enantioselective fluorination method with catalytic potential has not been realized until recently, when Takeuchi and Shibata and co-workers and the Cahard group independently demonstrated that asymmetric organocatalysis might be a suitable tool for catalytic enantioselective construction of C-F bonds [78-80]. This agent-controlled enantioselective fluorination concept, which requires the use of silyl enol ethers, 63, or active esters, e.g. 65, as starting material, is shown in Scheme 3.25. Cinchona alkaloids were found to be useful, re-usable organocata-lysts, although stoichiometric amounts were required. 

It is worthy of note that this practical fluorination method developed by Takeuchi and Shibata et al. is based on the use of commercially available reagents. In addi-... 

To summarise, the development of novel enantioselective fluorination methods with the aid of either chiral N-fluoro ammonium salts or transition metal catalysts has established truely practical routes towards chiral fluorinated compounds. Despite the current mechanistic uncertaincies it appears that a door has been opened for exciting and promising further development of asymmetric (catalytic) fluorination reactions in the near future [31, 32]. 

The chemistry of fluorine-18 radiopharmaceuticals, the reagents employed in electrophilic and nucleophilic fluorination methods and in aliphatic and aromatic nucleophilic substitutions, for the period 1977-1986 have been reviewed by Berridge and Tewson1. The earlier 18F-chemistry has been reviewed by Palmer, Clark and Goulding2. 

Other selected examples of this "classicar fluorination method arc summarized in Table 10. 

McConnell, D., 1962. Dating of fossil bones by the fluorine method. Science, 136 241— 244. 

Although we were able to improve the yield of fluorination with DAST, we examined other fluorination methods to develop a more economic and safer industrial process. 

The synthesis of [18F]FDG has been very well developed and refined since its introduction by Ido and co-workers in 1978 [12]. Whereas the original synthesis of [18F]FDG was done using electrophilic fluorination of an alkene precursor, yields were limited by the maximum 50% possible from an electrophilic reagent (see later discussion on electrophilic 18F-fluorinations), and much higher-yield nucleophilic fluorination methods were subsequently developed [13] and have been adopted by virtually every investigator at present. 

Applying this novel fluorination method to 18F-fluorination provides great improvement in radiochemical yields (Table 14.5) [101]. The use of a protic solvent in nucleophilic 18F-fluorination not only improved the radiochemical yield of widely used radiopharmaceuticals such as [18F]FLT (3 -deoxy-3 -[18F]fluorothymidine) [101, 102], [18F]FP-CIT (3-[18F]fluoropropyl-2-(3-carboxymethoxy-3-(3-(4-iodophenyl) nortropane) [101, 103], and [18F]FMISO ([18F]fhioromisonidazole) [101, 104], which were difficult to prepare in conventional methods under mild conditions. This method has advanced the availability of these important radiopharmaceuticals, and should help the development of new pharmaceuticals for research and clinical application in the future. 

The recent interest in electrophilic fluorination of phosphonates reflects the importance of a-fluorophosphonates as isosteres of biologically important phosphates. However, the use of electrophilic fluorination methods is increasing with the availability of safe and easy to handle fluorine sources. Several reviews of the synthesis and applications of electrophilic fluorination reagents are now available. Here only the most important of these reagents and their use in the electrophilic fluorination of phosphonates are presented. 

Time-consuming work-up procedures must be avoided in the synthesis of labeled diagnostics, but essentially the usual fluorination methods are used. [1 F]FDG can be prepared by electrophilic fluorination of a glycal with [ F acctyl hypofluorite [87] (Scheme 4.40). This reagent again is produced by reaction of F labeled fluorine gas with KOAc -2HOAc [88]. The synthesis of other [ F]fluor-odopa isomers is illustrated in Scheme 4.41. 

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