Brominated carboxylic acids

Hydrodebromination. a-Brominated carboxylic acid derivatives undergo... 

In the first step of the HVZ reaction, PBr3 converts the carboxylic acid into an acyl bromide by a mechanism similar to the one by which PBr3 converts an alcohol into an alkyl bromide (Section 12.3). (Notice that in both reactions PBr3 replaces an OH with a Br.) The acyl bromide is in equilibrium with its enol. Bromination of the end forms the a-brominated acyl bromide, which is hydrolyzed to the a-brominated carboxylic acid. 

Dimethyl sulfoxide joxaly I chloride I ethyldiisopropylamine I bromine Carboxylic acid esters from prim, alcohols via hemiacetals CH2OH... 

Bromination of the enol forms a protonated a-brominated acyl bromide, which is hydrolyzed to a a-brominated carboxylic acid (Section 16.8). 

Acid-catalyzed alpha halogenation does not work for esters, amides, or carboxylic acids, but it does work for acid halides. This fact can be exploited to generate a-brominated carboxylic acid derivatives as shown in Synthetic Transformation 25.5. 

The conversion of an aliphatic carboxylic acid into the a-bromo- (or a-chloro ) acid by treatment with bromine (or chlorine) in the presence of a catal3rtic amount of phosphorus tribromide (or trichloride) or of red phosphorus is known as the Hell-Volhard-Zelinsky reaction. The procedure probably involves the intermediate formation of the acyl halide, since it is known that halogens react more rapidly with acyl haUdes than with the acids themselves ... 

This method of a bromination of carboxylic acids is called the Hell-Volhard-Zelinsky reaction This reaction is sometimes carried out by using a small amount of phosphorus instead of phosphorus trichloride Phosphorus reacts with bromine to yield phosphorus tribromide as the active catalyst under these conditions... 

Section 19 16 Halogenation at the a carbon atom of carboxylic acids can be accom plished by the Hell-Volhard-Zehnsky reaction An acid is treated with chlorine or bromine m the presence of a catalytic quantity of phospho rus or a phosphorus trihalide... 

Difluoroacetic acid undergoes reactions typical of a carboxylic acid such as forming an ester when heated with an alcohol and sulfuric acid. Typical esters are methyl difluoroacetate [433-53-4], bp, 85.2°C, and ethyl difluoroacetate [454-31-9], bp, 99.2°C. It can also be photochemicaHy chlorinated to chlorodifluoroacetic acid [76-04-0] or brominated in the presence of iron to bromodifluoroacetic acid [667-27-6] (37,38). 

Orotic acid undergoes 5-nitration, 5-bromination in hydrobromic acid with peroxide, 5,5-dibromination following decarboxylation in bromine water, esterification, methylation (rather complicated), conversion into its acid chloride (containing some anhydride) by treatment with thionyl chloride, and conversion into 2,6-dichloropyrimidine-4-carboxylic acid by phosphoryl chloride (62HC(16)422). 

Isothiazoles with electron-releasing substituents such as amino, hydroxy, or alkoxy in the 3- or 5-position are brominated in high yield in the 4-position. Alkylisothiazoles give lower yields, but 3-methylisothiazole-5-carboxylic acid has been brominated in 76% yield (72AHC(14)1). Again, thiazoles with an electron-releasing substituent in the 2- or 4-position are brominated at the 5-position (79HC(34-1)5). 

Benzo[b]furan-2-carboxylic acids bromination, 4, 602 chloromethylation, 4, 602 from coumarins, 3, 686 IR spectra, 4, 590 methyl ester... 

Furan-2-carbonyl chloride, 5-alkyl-3,4-dichloro-synthesis, 4, 690 Furancarboxamides rotational isomerism, 4, 543 Furan-2-carboxylic acid, 5-acetylamino-ethyl ester reactions, 4, 647 Furan-2-carboxylic acid, amino-properties, 4, 708 Furan-2-carboxylic acid, 5-bromo-nitration, 4, 603, 711 Furan-2-carboxylic acid, 3-methyl-methyl ester bromination, 4, 604 Furan-2-carboxylic acid, 5-methyl-nitration, 4, 602... 

Furan-3-carboxylic acid, 2-methyl-methyl ester bromination, 4, 604 synthesis, 4, 686 Furancarboxylic acids acidity, 4, 71... 

Isotubaic acid — see Benzofuran-5-carboxylic acid, 4-hydroxy-2-isopropyl-Isouramil occurrence, 3, 144 5-Isoxalones potentiometry, 6, 11 Isoxanthopterin, 6-acetonyl-structure, 3, 276 Isoxanthopterin, 3,8-dimethyl-rearrangements, 3, 309 Isoxanthopterin, 6-methoxy-3,8-dimethyl-synthesis, 3, 297 Isoxanthopterin, 6-methyl-bromination, 3, 301 Isoxanthopterin, 8-methyl-synthesis, 3, 319 Isoxanthopterin, 6-phenacyl-structure, 3, 276... 

Boekelheide rearrangement, 3, 303 Lumazine, 6,7,8-trimethyl-hydrogen exchange, 3, 303 Lumazine, 1,3,6-trimethyl-7-hydroxy-bromination, 3, 302 Lumazinecarboxylic acid occurence, 3, 324 Lumazine-6-carboxylic acid methylation, 3, 297... 

Phenanthridine-6-carboxylic acids synthesis, 2, 415 Phenanthridines amination, 2, 236 bromination, 2, 320 hydrogenation, 2, 328 nitration, 2, 319 nomenclature, 2, 5 5-oxides... 

Pyrrolo[2,3-d]pyrimidine, 5-cyano-bromination, 4, 506 Pyrrolo[2,3-d]pyrimidine, 5-nitroso-nucleophilic reactions, 4, 507 Pyrrolo[l, 2- c]pyrimidine-3-carboxylic acids methyl ester synthesis, 4, 293 Pyrrolopyrimidine-2,4-diones Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolopyrimidines synthesis, 4, 514, 517, 524, 527 Pyrrolopyrimidines, chloro-nucleophilic attack, S, 312 Pyrrolo[2,3-d]pyrimidines NMR, 4, 500... 

Me3SiCH2CH=CH2i TsOH, CH3CN, 70-80°, 1-2 h, 90-95% yield. This silylating reagent is stable to moisture. Allylsilanes can be used to protect alcohols, phenols, and carboxylic acids there is no reaction with thiophenol except when CF3S03H is used as a catalyst. The method is also applicable to the formation of r-butyldimethylsilyl derivatives the silyl ether of cyclohexanol was prepared in 95% yield from allyl-/-butyldi-methylsilane. Iodine, bromine, trimethylsilyl bromide, and trimethylsilyl iodide have also been used as catalysts. Nafion-H has been shown to be an effective catalyst. 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

Derivatives of aldoses in which the terminal aldehyde function is oxidized to a carboxylic acid are called aldonic acids. Aldonic acids are named by replacing the -ose ending of the aldose by -onic acid. Oxidation of aldoses with bromine is the most commonly used method for the preparation of aldonic acids and involves the furanose or pyranose form of the carbohydrate. 

Finally, certain 3-substituted compounds can be prepared by utilizing the - meta) directing powet (cf. Section IV,B) of some groups in the 2-position which afterward can be removed. 3-Nitrothiophene is prepared by nitration of 2-thiophenesulfonyl chloride and by removal of the sulfonic acid group of the 4-nitro-2-sulfonyl chloride formed with superheated steam. Another approach to 3-nitrothio-phene is to nitrate 2-cyanothiophene, separate the 4-nitro-2-cyano-thiophene from the 5-isomer, hydrolyze, and decarboxylate. A final method of preparation of 3-nitrothiophene is by simultaneous de-bromination and decarboxylation of 5-bromo-4-nitro-2-thiophene-carboxylic acid obtained through the nitration of methyl 5-bromo-2-thiophenecarboxylate. 

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