4- fluorobenzoate

A strain of Rhodococcus opacus isolated by enrichment with chlorobenzene was able to grow at the expense of a wide range of halogenated compounds. These included 1,3- and 1,4-dichlorobenzene, 1,3- and 1,4-dibromobenzene, 2-, 3-, and 4-fluorophenol, 2-, 3-, and 4-chlorophenol, 4-nitrophenol, 3- and 4-fluorobenzoate, and 3-chlorobenzoate (Zaitsev et al. 1995). 

A mutant strain of Alcaligenes eutrophus was used (Reiner and Hegeman 1971) to demonstrate that the initial step in the metabolism of 4-fluorobenzoate involves 1 2 dioxygenation to 4-fluoro-1,2-dihydrodihydroxybenzene-l-carboxylate. 4-Fluorobenzoate may be used for growth by several bacteria, and metabolites produced by a strain of Pseudomonas sp., which was also able to degrade... 

FIGURE 9.33 Alternative pathways for degradation of 4-fluorobenzoate by sp. (a) strain RH 025... 

Oltmanns RH, R Muller, MK Otto, F Lingens (1989) Evidence for a new pathway in the bacterial degradation of 4-fluorobenzoate. Appl Environ Microbiol 55 2499-2504. 

Schldmann M, P Fischer, E Schmidt, H-J Knackmuss (1990b) Enzymatic formation, stability, and spontaneous reactions of 4-fluoromuconolactone, a metabolite of the bacterial degradation of 4-fluorobenzoate. J Bacterial 172 5119-5129. 

N,N-Dimethylacetamide (DMAc), 4-fluorobenzoic acid, 4-fluorobenzoyl chloride, aluminum chloride, 1 -bromonaphthalene, nitrobenzene, ferric chloride, dimethyl sulfone, 4,4 -dihydroxybiphenyl (DHB), and potassium carbonate were obtained from Aldrich and used without purification. 4,4-(Hexafluoroiso-propylidiene)-diphenol (6F-BPA), 9,9-bis(4-hydroxyphenyl)fluorene (HPF), and l,l-bis(4-hydroxyphenyl)-l-phenylethane (Bisphenol AP) were obtained from Ken Seika Corporation and used without purification. 4,4 -Dihydroxydiphenyl sulfone (DHDS) was obtained from Nachem Incorporated and used without purification. 

Fig. 3.4 Relationship between the stability constant, Pioi, for formation of SmL and the acid constant, of HL (1) propionic acid (2) acetic acid (3) iodoacetic acid (4) chloroacetic acid (5) benzoic acid (6) 4-fluorobenzoic acid (7) 3-fluorobenzoic acid and (8) 3-nitrobenzoic acid. 

Conversion of toluenes to the benzoic acid is also accomplished by anodic oxidation in acetic acid containing some nitric acid. It is not clear if this reaction involves the aromatic radical-cation or if the oxidising agents are nitrogen oxide radicals generated by electron transfer from nitrate ions [66, 67]. Oxidation of 4-fluorotoluene at a lead dioxide anode in dilute sulphuric acid gives 4-fluorobenzoic acid in a reaction which involves loss of a proton from the aromatic radical-cation and them in further oxidation of the benzyl radical formed [68]. 

This enzyme [EC 6.2.1.25] catalyzes the reaction of benzoate with ATP and coenzyme A to produce benzoyl-CoA, AMP, and pyrophosphate (or, diphosphate). The enzyme will also use 2-, 3- and 4-fluorobenzoate as substrate. The corresponding chlorobenzoates will all serve as substrates, albeit less effectively. 

U. Sidelmann, S.H. Hansen, C. Gavaghan, A.W. Nicholls, H.A.J. Carless, J.C. Lindon, I.D. Wilson, J.K. Nicholson, Development of a simple liquid chromatographic method for the separation of mixtures of positional isomers and anom-ers of synthetic 2-, 3- and 4-fluorobenzoic acid glucuronides formed via acyl migration reactions, J. Chromatogr. B Biomed. Sci. Appl. 685 (1996) 113-122. 

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... 

An appreciable increase in the yield of some aromatic fluorides with hexafluorophosphoric acid, compared to the fluoroboric acid method, has been observed. Outstanding in this respect is the increase in yields of 2-fluorobenzoic acid (+52%), 4-fluorobenzoic acid ( + 49%),... 

The aromatic C-F bond in 4-fluorobenzoic acid (13) is readily hydrogenolyzed to yield benzoic acid (14) by Raney nickel or cobalt alloys and alkali,117 while the same bond resists hydrogenolysis over palladium on calcium carbonate in the presence of a base.118... 

Benzoic Acid (14), Selective Hydrogenolysis of 4-Fluorobenzoic Acid with Raney Nickel Typical Procedure 117... 

Fluorobenzoic acid (13 10 g, 71 mmol) was dissolved in a solution of NaOH (25 g) and H20 (200 mL) the solution was then healed on a bath to ca. 100 C and stirred vigorously during the gradual addition of small portions of Raney Ni alloy (23 g). The mixture was stirred and heated for a further 3 h, then decanted from the precipitated metal, which was washed several times by decantation with warm water. The combined decantates were cooled and acidified with HC1 and the liberated benzoic acid was extracted with Et20. The extract was dried (Na2S04) and the Et20 removed to afford benzoic acid yield 5.2g (60 %) mp 122 C (hexane). 

The requisite tricyclic 2,4-diaminoquinazoline precursor (687) was obtained in one step from 5-aminoindole hydrochloride and sodium dicyanamide [282], Subsequent alkylation of (687) with (4-bromome-thyl)benzoic acid yielded (688a). Alkylation of (687) with ethyl (4-bromome-thyl)benzoate afforded (688b), while arylation of (687) with ethyl 4-fluorobenzoate generated the A-aryl analogue (689). 

Figure 3.5 750 MHz 1 H continuous-flow HPLC-NMR spectrum of an equilibrium mixture of transacylated glucuronides of 4-fluorobenzoic acid. The nomenclature 271 -a denotes the 1 proton in the a-anomer of the 2-O-acyl glucuronide...

Potassium carbonate 2-Amino-4-fluorobenzoic acid Sodium hydride Triethyl orthoformate... 

A solution of 2-amino-4-fluorobenzoic acid (62 g) in aqueous sodium carbonate (44 g sodium carbonate in 1.6 liters water) was stirred and treated dropwise with a solution of phosgene (120 g) in toluene (500 ml) during 1.5 hours. The resulting suspension was stirred at room temperature for 24 hours. The solid product was collected by filtration, washed with water and dried to give 7-fluoro-l,2-dihydro-3,l(4H)-benzoxazine-2,4-dione melting point 217-219°C. 

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