Hell-Volhard-Zelinsky reactions, bromine

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 accomplished by the Hell-Volhard-Zelinsky reaction. An acid is treated with chlorine or bromine in the presence of a catalytic quantity of phosphorus or a phosphorus trihalide ... 

Carboxylic acids having an a-hydrogen are halogenated at the a-position on treatment with chlorine or bromine in the presence of small amount of red phosphorus to give a-halocarboxylic acids. The reaction is known as Hell-Volhard-Zelinsky reaction. 

To convert 3-methylbutanoic acid to valine, a leaving group must be introduced at the a carbon prior to displacement by ammonia. This is best accomplished by bromination under the conditions of the Hell-Volhard-Zelinsky reaction. 

The reaction of aliphatic carboxylic acids with bromine in the presence of phosphorous produces a halo acids. This reaction is the Hell-Volhard-Zelinski reaction. 

Fig. 12.7. Bromination of carboxylic acids in the presence of catalytic amounts of phosphorus tribromide ("Hell-Volhard-Zelinsky reaction I") the reaction product is an a-bromocarboxylic acid.

Fig. 12.8. Bromination of carboxylic acids in the presence of stoichiometric amounts of phosphorus tribromide ("Hell-Volhard-Zelinsky reaction II"). The actual reaction product is an a-bromocarboxylic acid bromide (B), which often undergoes further in situ reaction to afford an a-bromocarboxylic acid (C) or an a-bromocarboxylic acid ester (D).

The bromine is introduced onto the a-carbon by treating the carboxylic acid with Br2 and a catalytic amount of PBr, in a process known as the Hell-Volhard-Zelinsky reaction. This reaction proceeds through an enol intermediate. Because carboxylic acids form enols only with difficulty, a catalytic amount of PBr3 is added to form a small amount of the acyl bromide, which enolizes more readily than the acid. Addition of bromine to the enol produces an a-bromoacyl bromide (see Section 20.2). This reacts with a molecule of the carboxylic acid in a process that exchanges the Br and OH groups to form the... 

The Hell-Volhard-Zelinsky reaction (Section 22-6) is an effective method for introducing bromine at the a position of a carboxylic acid. The racemic a-bromo acid is converted to a racemic a-amino acid by direct amination, using a large excess of ammonia. 

In the presence of a small amount of phosphorus, aliphatic carboxylic acids react smoothly with chlorine or bromine to yield a compound in which a-hydrogen has been replaced by halogen. This is the Hell-Volhard-Zelinsky reaction. Because of its specificity—only alpha halogenation-- the readiness with which it takes place, it is of considerable importance in synthesis. 

Hell-Volhard-Zelinsky reaction. e-Benzoylaminocaproic acid is converted into the a-bromo derivative by stirring a mixture of the acid with red phosphorus in a flask cooled in an ice bath, adding bromine dropwise, gradually increasing the temperature, and stirring on the steam bath until practical disappearance of bromine... 

COBrj is reported to be a catalyst for the cu-bromination of saturated carboxylic acids, in a modified Hell-Volhard-Zelinsky reaction [e.g. 1320b]. Thus, treatment of octadecanoic acid with bromine in the presence of catalytic amounts of COBrj gave a 99.5% yield of 2-bromooctadecanoic acid [2029]. 

Carboxylic acids can be brominated at the a-position by reaction with bromine and phosphorus tribromide (PBr3) in the Hell-Volhard-Zelinsky reaction. The reaction, which proceeds via an acid bromide, leads to the substitution of an a-hydrogen atom by a bromine atom. 

Chemists do not have to rely on nature to produce amino acids they can synthesize them in the laboratory, using a variety of methods. One of the oldest methods replaces an a-hydrogen of a carboxylic acid with a bromine in a Hell-Volhard-Zelinski reaction (Section 19.5). The resulting a-bromocarboxylic acid then undergoes an Sn2 reaction with ammonia to form the amino acid (Section 10.4). 

There are other functional group transformations that lead to alkyl halides. A classical transformation converts carboxylates to allyl bromides (C—CO2 C—Br). This transformation is called the Hunsdiecker reaction (jt jjag also been called the Borodin reaction) 3 and it is most useful for the preparation of econdary halides. The silver salt of a carboxylic acid is heated with bromine to give the bromide via decarboxylation. An example is conversion of the silver salt of cyclohexane carboxylic acid (163) to bromo-cyclohexane.1 4 Phosphorus and bromine also react with acids in the Hell-Volhard-Zelinsky reaction. 

At this point, only an amino (NH2) group need be added, alpha to the carboxyl group to obtain alanine. To do this, first add a halogen, either Br or Cl, to the alpha position. This can be accomplished using the Hell-Volhard-Zelinsky reaction. This reaction results in a-halo acids. The carboxylic acid is reacted with a halogen (bromine or chlorine) in the presence of catalytic amounts of phosphorus trihalide. Hence,... 

The mechanisms for the Grignard-epoxide reaction, and the a-carbon bromination of the carboxylic acid (an example of the Hell-Volhard-Zelinsky reaction) are illustrated below. 

The a-bromination of acids (via the acid chloride) has been achieved by the Hell-Volhard-Zelinsky reaction or its variances. However... 

An a-bromo acid is prepared by reaction of the acid with bromine and phosphorus tribromide (this is known as the Hell-Volhard-Zelinsky reaction). This reaction was named for the work of C. Hell, Nikolai D. Zelinsky (Russia 1861-1953), and J. Volhard. If 3-phenylpropanoic acid (97) is treated with these reagents, 91 is formed. If 98 is subsequently heated with ammonia (see Section 27.1.1) and the product is neutralized, amino acid 57 is formed (phenylalanine). This route was used as early as 1858, when glycine (52) was prepared by the reaction of chloroacetic acid (99) and ammonia. Amino acids formed this way are racemic. 

Scheme 8.49. A variety of possibilities to account for the formation of a-bromoacetic acid (bromoethanoic acid [BrCH2C02H]) from acetic acid (ethanoic acid [CH3CO2H]) with red phosphorus and bromine (the Hell-Volhard-Zelinsky reaction).

Alpha Bromination of Carboxylic Acids The Hell-Volhard-Zelinski Reaction... 

Carboxylic acids cannot undergo substitution reactions at the a-carbon, because a base will remove a proton from the OH group instead of from the a-carbon, since the OH group is more acidic. If, however, a carboxylic acid is treated with PBr3 and Bt2, the a-carbon can be brominated. This halogenation reaction is called the Hell-Volhard-Zelinski reaction or, more simply, the HVZ reaction. (Red phosphoms can be used in place of PBr3 since P and excess Br2 react to form PBr3.)... 

Bromine has been used for brominations a to carbonyl groups. Carboxylic acids are brominated in the presence of phosphorus or phosphorus trihalides in the classical Hell-Volhard-Zelinski reaction (eq 16). Variations on this include brominations in thionyl chloride and in polyphosphoric acid. The less reactive carboxylic esters are frequently converted to the acid halide, a-brominated, and subsequently re-esterified in one pot. ... 

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