Phosphorus trichloride reaction with carboxylic acids

Chlorinated Fatty Acids. Chlorination of carboxylic acids is much more difficult because the contribution or the carbonyl group toward proton removal is offset by the electron donation effect from the hydroxyl group. This hindrance is obviated by reaction with the acid chloride or anhydride. Chlorination is normally accomplished hy use of n catalyst, such as phosphorus trichloride. Monochloroacelic acid is an important industrial chemical. Dichloro- and trichloroacetic acids can he produced by further chlorination, although the latter can be produced convenienlly by nitric acid oxidation of chloral. Higher chlorinalcd tally acids can be produced by treatment or the hydroxy carboxylic acid or ester with HCI ur PCL ... 

This reaction represents the best general method for amide preparation. Cold, concentrated aqueous ammonia is used as in the preparation of iso-butyramide (83%),or the reaction may be carried out by passing dry ammonia into a solution of the acyl halide in anhydrous ether as in the formation of cyclopropanecarboxamide (91%). Separation of the amide from ammonium chloride is usually accomplished by extraction of the amide by organic solvents. Aqueous sodium hydroxide is employed to take up the hydrogen chloride when amine hydrochlorides are used in place of the free amines as in the preparation of N-methylisobutyramide (75%). When phosphorus trichloride is added to a mixture of an amine and a carboxylic acid, phosphazo compounds, RN=PNHR, rather than acyl halides, are believed to be intermediates. These compounds have been shown to react with carboxylic acids to give amides. ... 

For instance, the reaction of amines with carboxylic acids occurs under appreciably milder conditions if phosphorus trichloride is added the reaction does not proceed by way of the intermediate acid chloride, as previously assumed, but the amine and phosphorus trichloride first form a phosphorazo compound (phosphoramidic imide) which in turn reacts with the carboxylic acid to give the amide 693... 

The reaction of 4-amino-5-sulfonyl-4/7-[l,2,4]triazoles (104) with carboxylic acids and phosphorus trichloride has been widely applied for the preparation of 3,6-disubstituted [l,2,4]triazolo[3,4-Zi][l,3,4]thiadiazoles (3) (Equation (27) and Table 11). 

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... 

Preparation of 6-amino-l-hydroxyhexylidenediphosphonic acid — Reaction of a carboxylic acid with phosphorous acid and phosphorus trichloride... 

The first authentic synthesis of a bisphosphonic acid, l-hydroxyethane-l,l-bisphos-phonic acid (etidronic acid), was published by von Baeyer and Hofmann in 1897 [1], although it is possible that the same compound had already been obtained in 1865 by Menschutkin [2], The synthetic approach to BPs employed today differs only little from that used over a hundred years ago, and it is still based on the reaction of a carboxylic acid with phosphorus trichloride with the addition of some water [3], (Note BPs are usually represented as the free bisphosphonic acids the generic names given refer, however, to their salt forms.)... 

Phosphorus trichloride (PC13), b.p. 74.5°, is used particularly for preparation of volatile carboxylic acid chlorides (reaction b). Usually about 1.1 moles of the carboxylic acid is allowed to react with 0.5 mole of PC13 at room temperature or with slight warming until evolution of HC1 ceases and then the acid chloride is distilled off see, for instance, the preparation of acetyl chloride from glacial acetic acid and PCl3.33b The carboxylic acid chloride can also be taken up in a solvent (benzene, light petroleum, or CS2) at the end of the reaction and used directly for further reactions ... 

The A -hydrazinotriazole (35) was also used as a starting material for the synthesis of[l,2,4]tri-azolo[3,4-Z)][l,3,4,5]thiatriazines reaction with cyanogen bromide led to the amino derivative (37), whereas aryl carboxylic acids and phosphorus trichloride afforded the aryl-substituted compound (38) <88MI 821-01 >. 

The enol content of a carboxylic acid is far less than that of an aldehyde or ketone (see Table 20.2), and introducing a halogen substituent at the a-carbon atom requires a different set of reaction conditions. Bromination is the reaction that is normally carried out, the usual procedure involving treatment of the carboxylic acid with bromine in the presence of a small amount of phosphorus trichloride as a catalyst. 

As mentioned previously, the helicene-based chlorophosphite M,M,R) 25a, which is easily prepared from the reaction ofenantiopure (M,M,R)-[5 -HELOL 24a with phosphorus trichloride, has been successfirUy used to analyze the enantiomeric compositions of a variety of chiral materials such as alcohols, amines, or carboxylic acids. The reaction is conducted in an NMR tube where the analytes are added to the chiral helicene-based chlorophosphite in CDCI3. After 2 h reaction, the diastereomers ratios generated in situ are determined by P-NMR spectroscopy. Notably, this attractive method has proved to be highly efficient for analyzing the enantiomeric purities of a wide range of molecules whose stereogenic centers are far away from functional groups that react with phosphorus atom. The authors... 

Acid chlorides are prepared by reaction of a carboxylic acid with a halogenating agent sueh as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, or oxalyl chloride. 

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