Fluorobenzoic acids fluorination

In one of his papers [180] Gilman reports on the metallation of fluorobenzene. Interaction at — 50 °C between this compound and BuLi in THF for 7 hours, followed by carboxylation gave a reasonable yield of fluorobenzoic acid. Fluorine activates vicinal protons exclusively by its (strong) -I effect, and it should be possible to shorten the reaction time by using more strongly basic systems. Indeed, if the reaction in THF is carried out with BuLi TMEDA, the formation of... 

Goldman P, GWA Milne, MT Pignataro (1967) Fluorine containing metabolites formed from 2-fluorobenzoic acid by Pseudomonas species. Arch Biochem Biophys 118 178-184. 

J. D. Cox, H. A. Gundry, A. J. Head. Thermodynamic Properties of Fluorine Compounds. Part 1. Heats of Combustion ofp-Fluorobenzoic Acid, Pentafluorobenzoic Acid, Hexafluorobenzene, and Decafluorocyclohexene. Trans. Faraday Soc. 1964, 60, 653-665. 

The new method of Yoneda s group132 is also a one-pot diazotization-fluoro-de-diazoniation in a liquid-liquid two-phase mixture of pyridine and hydrogen fluoride. Yields for 25 aromatic amines and diamines are 50-100%, except for 2-and 3-fluorobenzoic acid, the three nitroanilines, 3- and 4-diaminobenzene and 4,4 -diaminodiphenyl-oxide (10-50%). In their 1994 paper the authors demonstrate that, in the same system, the photochemical decomposition gives in many cases significantly higher yields than the thermal reaction. The most spectacular increase in yield was found for the fluorination of 2-fluoroaniline where o-difluorobenzene was obtained photochemically in 80.2% yield, but thermally only in 0.6% ... 

The acidity and dielectric constant of the reaction media can have a profound effect on the fluorination process. Studies concerning the fluorination of a model substrate, 4-fluorobenzoic acid, in a variety of solvents showed that conversion of the substrate to 3,4-difluorobenzoic acid (Table 5) rose as the acidity of the solvent increased, due to the increased interaction between fluorine and the reaction medium (Fig. 56) [147]. 

Table 5. Fluorination of 4-Fluorobenzoic Acid in Various Solvents [147]...

Direct fluorination, therefore, is not particularly effective for the preparation of mono-fluorinated aromatic compounds from monosubstituted precursors since, in these cases, electrophilic fluorination gives mixtures of isomeric products. However, when there are two or more groups in the aromatic substrate which activate the same carbon atom towards electrophilic attack, as in the case of 4-fluorobenzoic acid (Table 5), then direct fluorination is an efficient method for the preparation of fluoroaromatic compounds (Fig. 57) [148]. 

However, this achievement was then marred by an unfortunate error. The calcium salt of 4-fluorobenzoic acid was heated in admixture with calcium hydroxide, and fluorobenzene was claimed to be formed by decarboxylation. Later, it was shown16 that the product, a solid, was phenol. It had been analyzed only for carbon and hydrogen content an early warning to all workers in fluorine chemistry of the need for quantitative assays for fluorine in their products. Being more activated than fluorobenzene towards nucleophilic attack, the fluorobenzoate anion itself probably lost fluorine before decarboxylation occurred. A benzyne-type process seems to be a less likely reaction pathway. 

The influence of strong Lewis acids, such as aluminum trichloride and boron trichloride, on similar reactions has been studied but it was found that they did not have a significant role.50 However, it is reported that using strong acidic reaction media is very helpful and the fluorination proceeds very favorably. 4-Nitroanisole and 4-fluorobenzoic acid arc thus converted into 2-fluoro-4-nitroanisole (6) and 3,4-difluorobenzoic acid (7), respectively, in good yields.51... 

The cleavage of C —F bonds by enzymes is very interesting. Flaloacetate halidohydrolase substitutes the hydroxy group for fluorine in fluoroacetates,28,29 and enzymes from the Pseudomonas microorganism convert 2-fluorobenzoic acid into pyrocatechol.30,31... 

Why was it that only the fluorobenzoic acids and the thiophenes were apparently incorporated In the case of the former, this may reflect the probability that fluorobenzoic acid is structurally the most similar of the analogs to the natural substrate. Fluorine is a fairly inert atom and isosteric with hydrogen. It is not so clear why the thiophenes should have been incorporated. 

N-1 substituents [12,13, 37, 39]. The starting 2,4-dichloro-5-fluorobenzoic acid can be replaced advantageously by the 2-chloro-4,5-difluoro- or 2,4,5-trifluoro-benzoic acids the fluorine atom at C-7 position of the nucleus of the quinolones is more reactive than the chlorine atom and the regioselectivity of nucleophilic displacements is enhanced. 

Among fluorinated LCs, the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles by cyclocondensation of amidoximes with trifluoroacetic anhydride or fluorobenzoic acid derivatives has been reported. In these... 

The van der Waals radii of fluorine and hydrogen atoms arc similar. The pAT values of o-, m-, and /-fluorobenzoic acids are 4.1, 3.9, and 3.3, respectively. The pAT value of benzoic acid is 4.2. Explain the order of the pA values of the fluorobenzoic acids. Estimate the contribution of fluorine as an electron donor in terms of resonance. 

As an alternative to fluoride displacements directly on the compound of interest, many researchers opt for the development of molecules that have the ability be linked to a molecule that has efficiently been labeled with fluorine-18. Probably the most well known example of this class of fluorine-18 labeled linker capable molecules is the N-succinimidyl-4-[ F]fluorobenzoate ([ F]SFB). The prepa-ration of this reagent comprises a total of three steps beginning with the initial two step preparation of 4-[ F]fluorobenzoic acid ([ F]FBA) [9] and then finished off with the formation of the desireci succinimidyl ester (Figure 2) [10]. 

Very little work has been done on fluoro derivatives of thiophenes. 2-Fluorothiophene was obtained in low yield from treatment of 2-iodothiophene with arsenic trifluoride. The action of fluoroboric acid on thiophenediazonium salts was unsuccessful. It may be useful for the preparation of 4-, 5-, 6- or 7-fluorobenzo[6]thiophenes from the appropriate amines. However, these are more conveniently prepared from fluorine-substituted benzenethiols by ring-closure reactions. For example 4,5,6,7-tetrafluorobenzo[6 Jthiophene was obtained by decarboxylation of the corresponding 2,3-dicarboxylic acid (equation 99) prepared by condensation of pentafluorobenzenethiol with diethyl acetylenedicarboxylate (Section 3.15.3.4.1). 2-Fluorothiophene has been prepared from 2-thienyllithium using perchloryl fluoride, and 2-fluorobenzo[ Jthiophene from the 2-lithio derivative in a similar manner (Section 3.14.3.9.1). 

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