Carboxylic acids alpha-halogenation

This bromination reaction results exclusively in alpha substitution and therefore is limited to carboxylic acids with a hydrogens. Chlorine with a trace of phosphorus reacts similarily but with less overall specificity, because concurrent free-radical chlorination can occur at all positions along the chain (as in hydrocarbon halogenation see Section 4-6A). 

When a base is used with a methy] ketone, the alpha carbon will become completely halogenated. This trihalo product reacts further with the base to produce a carboxylic acid and a haloform (chloroform, CHCI j bromoform, CHBr, or iodoform, CHIj). This is called the Haloform Reaction. 

Carbonyl compounds are in a rapid equilibrium with their cnols, a process called keto-enol tautomerism. Although enol tautomers arc normally present to only a small extent at equilibrium and can t usually be isolated in pure form, they nevertheless contain a highly nucleophilic double bond and react with electrophiles. P or example, aldehydes and ketones are rapidly halogenated at the a position by reaction with CI2 Br2, or I2 in acetic acid solution. Alpha bromination of carboxylic acids can be similarly accomplished by the Hell-Volhard-Zelinskii (HVZ) reaction, in which an acid is treated with Bt2 and PBrThe a--halogenated inoducts can then undergo base-induced E2 elimination to yield a,/3-un.salurated carbonyl compounds. 

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aliphatic carboxylic acids react smoothly with chlorine or bromine to yield a compound in which a-hydrogen has been replaced by halogen.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. 

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,... 

Inductive effects are additive and increase with the number of substitutions by electron withdrawing or electron releasing groups. These effects also are sensitive to distance. Thus, substitution by a halogen on the beta carbon of a carboxylic acid is not as effective as one on the alpha - carbon. 

Alpha halogenation, as described in the previous section, occurs readily with ketones and aldehydes, but not with carboxylic acids, esters, or amides. This is likely due to the fact that these functional groups are not readily converted to their corresponding enols. Nevertheless, carboxylic acids do undergo alpha halogenation when treated with bromine in the presence of PBt3. 

In the Hell-Volhard-Zelinski reaction, a carboxylic acid undergoes alpha halogenation when treated with bromine in the presence of PBrs. 

If we want to halogenate the alpha position of a carboxylic acid, it is possible, but it will require some extra steps. First, we must convert the carboxyhc acid into an acid halide. We do this because the enol of an acid halide will rapidly attack a halogen. Then, in the end, we just convert the acid hahde back into a carboxylic acid ... 

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. 

Cellulose esters of halogenated acids are exceptionally difficult to prepare. This is particularly true if the halogen is in the alpha position to the carboxyl group. Chloroacetic anhydride in the presence of acid catalysts esterifies cellulose only after severe degradation. The use of pyridine is prohibited because of side reactions with the reagent. Mixed... 

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