Halogenation of Carboxylic Acids

The selective a-chlorination of propionic acid was achieved by heating the acid with a mixture of chlorine, chlorosulfonic acid and oxygen in a semibatch reactor at 70-110 °C. The kinetics of the chlorination were autocatalytic, when the concentration of the chlorosulfonic acid catalyst was kept constant. The primary product was sulfopropionic acid and the autocatalytic kinetics were explained by a mechanism involving acid-catalysed enolization of the key intermediate, propanoyl chloride, as the rate-determining step. °  

Alkanoyl chlorides (R R CHCOCl) may be similarly a-chlorinated by heating them with a mixture of a food grade antioxidant, oxygen, TCNQ, chlorine and chlorosulfonic acid at 100-120 C.  

Aliphatic carboxylic acids may be similarly a-brominated in high yields (78-95%) by heating the acid with bromine and chlorosulfonic acid catalyst (0.05 equivalents) in 1,2-dichloroethane at 84 °C. No oxygen was required in the reaction. The kinetics of bromination were second order overall, first order in both bromine and the carboxylic acid, and the rate of reaction (v) is expressed by Equation 50. The rate constant (k) was proportional to the initial concentration of the chlorosulfonic acid catalyst at an early stage of the reaction. The rate of a- 

Et2CHC02H Me2CHC02H Me2CHCH2C02H MeCH2C02H decreasing reactivity of the acid 

The substituent effect and optimum conditions for the a-iodination of aliphatic acids in 1,2-dichloroethane were examined. The substituent effect on the rate displays both polar and steric factors and the reaction mechanism involves the electrophilic addition of iodine to the ketene intermediate. 

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OL HALOGENATION OF CARBOXYLIC ACIDS THE HELL-VOLHARD-ZELINSKY REACTION... 

Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) The a-halo acids obtained by halogenation of carboxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reactive substrates in nucleophilic substitution processes. A standard method for the preparation of a-amino acids is displacement of halide from a-halo acids by nucleophilic substitution using excess aqueous ammonia. 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

Halogenation of carboxylic acids (Hell-Volhard-Zelinskii) and acid... 

Halogenation of Carboxylic Acids and Acyl Halides Halogenation or Halo-de-hydrogenation... 

Perhaloalkanes serve as bromination or iodination agents in the radical decarbox-ylative halogenation of carboxylic acids. In an interesting modification of the Hunsdiecker-Bodin reaction Barton and coworkers have applied iV-hydroxypyridine-2-thione esters as nonelectrophilic intermediates for the decarboxylative bromination and iodination of primary, secondary and tertiary aliphatic and alicyclic592, as well as aroma-... 

ASYMMETRIC HALOGENATION OF CARBOXYLIC ACIDS DERIVATIVES PREPARED FROM CAMPHOR-IO-SULFONIC ACID... 

Asymmetric halogenation of carboxylic acid derivatives has also been achieved by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an N-acyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron enolate, which is added to a NBS slurry, at low temperature (Fig. 6) ... 

The reaction described below is an easy preparation of alkyl halides by a sequential radical decarboxylation-halogenation of carboxylic acid derivatives. In supplement to the example described here, other compoimds prepared by this method are shown in the table (yield in parentheses). In this work, ultrasonic waves were produced by a 250-W-high-intensity ultrasonic processor Vibracell from Sonics Materials Inc. 

Disconnection (a) corresponds to the synthesis of I, a-halogenation of carboxylic acid or its derivative followed by hydrolysis of halogen (Scheme 5.2). Disconnection (b) envisages building a carbon framework from C + Ci synthons but looks unacceptable since illogical synthon COOH with a negative charge on the carbonyl C atom appears. Let us, however, consider the next example. 

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