Fluorine substitution ratio

Table 1 Modulation of the pKa and P-gp ratios of ORL1 antagonists through fluorine substitution ... 

Fluoroaromatic compounds react with nucleophilic sulfur species, resulting in single, multiple, or complete replacement of fluorine, to form C —S bonds. The extent of fluorine substitution depends on (1) the solvent used, (2) the nature of the sulfur reagent, (3) the ratio RS / ArF, (4) the reaction time and temperature, and (5) the nature of the fluoroaromatic compound. 

Norrish Type I fission of the side chain carbonyl group again at C-4. - Laser flash irradiation has been used as a aethod for the production of n-butylkotene from cyclohexanone. The chemistry of this ketene was studied in detail. The cyclohexanones (9a) undergo both Norrish Type I and II processes on irradiation. The fluorinated compounds (9b) showed a preference for Norrish Type II behaviour. Within the Norrish Type II biradical fluorine substitution leads to a preference for cyclization rather than cleavage. The Norrish Type I biradical afforded a ketene rather than an alkenal. A study of the photochemical reactivity of the diones (10) has shown that both Norrish Typo I and Type II reactivity can take place. The Typo I Type II product ratio is dependent upon ring size. Thus dione (10a) affords the Type II products (11) and (12) while dione (10c) yields the Norrish type I products (I3c-15c) and low yields of the Norrish Type II products (11) and (12). Compound (10b) is intermediate between these results affording a Type I Type II ratio of 0.3. A mechanistic study of the reactions was carried out. - ... 

Treatment of a- or P hydroxyacids with sulfur tetrafluoride leads to conver Sion of the carboxylic group into the tiifluoromethyl group, but the hydroxyl group undergoes either fluorination, fluorosulfination, esterification, or dehydration to form esters, ethers, or alkenes The ratio of the products depends on P substitution [209, 210] (equations 103 and 104)... 

For toluene fluorination, the impact of micro-reactor processing on the ratio of ortho-, meta- and para-isomers for monofluorinated toluene could be deduced and explained by a change in the type of reaction mechanism. The ortho-, meta- and para-isomer ratio was 5 1 3 for fluorination in a falling film micro reactor and a micro bubble column at a temperature of-16 °C [164,167]. This ratio is in accordance with an electrophilic substitution pathway. In contrast, radical mechanisms are strongly favored for conventional laboratory-scale processing, resulting in much more meta-substitution accompanied by imcontroUed multi-fluorination, addition and polymerization reactions. 

GL 1] [R 4] [P 2] Variation of solvent affects also the substitution pattern to a certain extent [13], A ratio of ortho-, meta- and para-isomers for mono-fluorinated toluene amounting on average to 3.5 1 2 was found in the dual-channel micro reactor at room temperature, using acetonitrile as solvent [13]. Using methanol as solvent, the ratio was on average 5.5 1 2.4. Hence more products referring to an electrophilic substitution were formed [13]. 

GL 1[ [R 1[ [R 3[[P la-d[ The fluorine content in the gas phase of a falling film micro reactor was varied at 10, 25 and 50% [38]. A nearly linear increase in conversion results at constant selectivity. The substitution pattern, i.e. the ratio of ortho-to para-isomers, is strongly affected by this. 

In the phosphates, partial substitution of oxygen by fluorine also has the effect of reducing the cation anion ratio, e.g. inK2(P03F)2 and K(P02F2) . The first compound is easily obtained by fusion of ELF and potassium metaphosphate... 

Ring fluorination is observed in reactions of protected aniline derivatives, with the ojp ratio of the products, e.g. 11-13, being dependent on the substituent 5 nitrobenzene is unreactive towards electrophilic substitution. The polymerization process may be studied by di-fluorobis(fluoroxy)methane reactions with variousfluoro-substituted benzene derivatives (hexa-... 

Trialkylaryltin derivatives 30 are converted into fluoro-substituted derivatives 31. 37-38 (4-Mcth-oxyphenyl)trimethylsilane (32) in acetonitrile gives 4-fluoroanisole and (3-fluoro-4-meth-oxyphenyl)trimethylsilane in the ratio 1 2. A -Methyldiethanol esters of arylboronic acids 33 (l-aryl-5-methyl-2,8-dioxa-5-azonia-l-boranuidabicyclo[3.3.0]octanes) are converted into tluoroaromatic compounds with cesium fluoroxysulfate in acetonitrile in the presence of 1,3-dinitrobenzene at room temperature.39-40 Regiospecific synthesis of 2-fluoro-3-0-methyles-trone in 27 % yield occurs upon fluorination of the corresponding arylboronic acid with cesium fluoroxysulfate.41... 

In general, substitution of the activated fluorine by sulfur nucleophiles proceeds smoothly under gentle conditions (Table 1). As fluorine in the ortho position to a nitro group is more activated than one in the para position, in the case of difluoronitrobenzenes a selective elimination of the ortho fluorine is possible by keeping the molar ratio of RS /RF low. The activated fluorine can be successfully replaced not only by alkane- or arenethiols, but also by the sulfide ion. giving access to substituted benzcnethiols, and by benzenesulfinate,14 giving access to... 

The reaction of perfluorobenzonitrile with carbon disulfide and anhydrous tetramethylam-monium fluoride opens a convenient route to perfluoro[3-(methylsulfanyl)bcnzonitrile].53 The reaction was carried out with a 10 17 2 ratio of perfluorobenzonitrile/ carbon disulfide/tetra-methylammonium fluoride in dimethylformamide under exclusion of water at 25 C over three days, to yield 18 % of perfluoro[3-(methylsulfanyl)benzonitrile] bp 202-204 C (note the meta-rather than the expected /wra-product). The reaction is explained by assuming the intermediate formation of the dithiofluoroformic acid anion which reacts with the perfluorobenzonitrile. The primary product of this reaction could not be isolated, because it is readily fluorinated to the (trifluoromethylsulfanyl)-substituted product. 

Multiple, but not complete, substitution of fluorine by sulfur nucleophiles proceeds under conditions rather similar to those for single elimination, i.e. generally in diethylene glycol/ pyridine mixture with sodium hydroxide as base, but with an increased molar ratio of the respective thiol, corresponding to the number of fluorines to be eliminated. On reaction in ethylene glycol/ pyridine, rather than in dimethylformamide or, particularly, in hexamethyl-phosphoric triamide, at least two fluorine atoms remain in the molecule, even under drastic... 

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