1,1.1-Trihalides carboxylic acids

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... 

Hell-Volhard-Zelinsky reaction (Section 19.16) The phosphorus trihalide-catalyzed a halogenation of a carboxylic acid ... 

The formulated mechanism is supported by the finding that no halogen from the phosphorus trihalide is transferred to the a-carbon of the carboxylic acid. For instance, the reaction of a carboxylic acid with phosphorus tribromide and chlorine yields exclusively an a-chlorinated carboxylic acid. In addition, carboxylic acid derivatives that enolize easily—e.g. acyl halides and anhydrides—do react without a catalyst present. 

The preparation of a-iodocarboxylic acids is of particular interest, since iodide is a better leaving group as is chloride or bromide. A similar a-iodination with a phosphorus trihalide as catalyst is not known. However the iodination can be achieved in the presence of chlorosulfonic acid mechanistically the intermediate formation of a ketene 10 by dehydration of the carboxylic acid is assumed ... 

A methyl ester was formed by methanolysis of a trihalide (Equation 32) <2007S225>. Decarboxylation of the /3-ketoacid resulting from hydrolysis has also been reported (Equation 33) <1980LA1917>. A carboxylic acid substituent was reduced to aldehyde with LAH (Equation 34) <1974J(P1)2092>. Thiazine nitrogen probably participates in this reaction. 

Alcoholysis of trihalides 0-6 Hydrolysis of ortho esters 0-20 Alcoholysis of acyl halides 0-21 Alcoholysis of anhydrides 0-22 Esterification of carboxylic acids 0-23 Transesterification 0-24 Alkylation of carboxylic acid salts 0-25 Cleavage of ethers with anhydrides 0-26 Alkylation of carboxylic acids with diazo compounds... 

Dr L.Deffet, Bruxelles private communication, March 10,1954 Alkenyl Aromatics of the general formula Ar. CH, CHa. C CH2, were prepd by reacting aruEliatic nyuiocarbons (at moderate temp and press) with 1,3 diolefins in the presence of a catalyst(such as boron trihalide satd with an organic carboxylic acid). The purified alkenyl aromatics can be nitrated to yield expl derivs... 

The reaction of chromone-2-carboxylic acid with thionyl chloride or phosphorus halides gives the trihalide (400). This compound readily loses one of its geminal chlorine atoms and with water, for example, affords 4-chlorocoumarin through the simultaneous loss of carbon monoxide (Scheme 131) (63JGU1806). 

Chlorine is introduced at the a-carbon atom of a carboxylic acid. The reaction is catalyzed by a small amount of phosphorus or a phosphorus trihalide and is called the Hell-Volhard-Zelinsky reaction. 

Methyl groups in nitromethane5 and dimethyl sulfite6 are sufficiently activated to condense with tellurium tetrachloride5,6 and tellurium tetrabromide6 to give organo tellurium trihalides. For condensation reactions with carboxylic acid anhydrides see Vol. IX, p. 1152. 

Tris(organoamino)boranes have been utilized to prepare, in reasonable yields,4,5 mono- and dihalo(organoamino)boranes which are often difficult to obtain by direct amination of the boron trihalides. Carboxylic acids, 1,3-diketones, ketones, and /3-ketoesters have been converted into carboxamides, enamino-ketones, enamines, and j -enamino-amides, respectively, by reaction with an appropriate tris(organoamino)borane under very mild conditions.6 Sulfenamides (R2NSC6H5) have also been prepared in high yield from selected tris(organoamino)boranes and sulfenic esters under relatively mild conditions.7... 

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

The first part of the mechanism includes the conversion of the carboxylic acid functionality to the acyl halide by the phosphorous trihalide. The acyl halide easily tautomerizes to the corresponding enol in the presence of a catalytic... 

Finally, phosphorus acid chlorides or bromides containing organic groups can be used for replacing the OH of carboxylic acids by Cl or Br. Carboxylic acids or their anhydrides afford the acid chlorides or bromides when heated for 30-60 minutes at 100° with 2,2,2-trichloro-1127 or 2,2,2-tribromo-l,3,2-benzodioxaphosph(v)ole (pyrocatechylphosphorus trihalides),1022,1128 yields being good. This method has the advantages that these trihalides have... 

The halogen of trihalides may be replaced analogously to that of mono- and gew-di-halides, no new considerations being involved. The usual reagents are slaked lime at 50°, alcoholic alkali hydroxides, acids, or iron(m) chloride in aqueous solution. Some trichloromethyl compounds are converted into carboxylic acids in excellent yield by heating them in chloroform in the presence of anhydrous iron(m) chloride whilst the appropriate amount of water is dropped in.549... 

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,... 

Examination indicates that the carbon skeleton remains intact in this synthesis. All that must be done is to alter the carboxylic acid to the alkyl bromide of the same carbon number. Now, if one had n-Ci1H23CH2OH (the corresponding alcohol), 1-bromododecane could be produced by reaction with the phosphorus trihalide PBr3. To obtain the alcohol, use the fact that lithium aluminum hydride, LiAli, is one of the few reagents that reduce a carboxylic acid to an alcohol of the same carbon length. Overall, then, the synthesis becomes ... 

Hell-Volhard-Zelinsky reaction (Section 20.15) Carboxylic acids undergo a-halogenation on reaction with CI2 or Br2 in the presence of phosphorus or a phosphorus trihalide as a catalyst. 

Phosphorus trihalides can in some cases be used to halogenate alcohols (12.282) and to convert nitro compounds into cyanides (12.283). Carboxylic acids are converted to acyl halides (12.284) and deoxygenations can sometimes be effected (12.285). The triiodide is a useful deoxygenating agent. 

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. ... 

---