A-bromocarboxylic acids

Thiazoles may be obtained starting from the imidazolicte of a-bromocarboxylic acids and thiobenzamide, as shown by the following example. 

McKillop and Ford synthesized a range of primary and secondary alkyl nitrates in excellent yields by treating alkyl bromides with mercury (I) nitrate in 1,2-dimethoxyethane at reflux (Equation 3.9). This method has been used to synthesize substituted nitrate esters from both a-bromocarboxylic acid and a-bromoketone substrates. Unlike metathesis with silver salts, which are widely known to promote SnI reactions, this method is not useful for the synthesis of nitrate esters from tertiary alkyl halides. 

Chloroacetic acid is readily converted into glycine by treatment with concentrated aqueous ammonia solution, but in general an a-bromocarboxylic acid is preferred. This can usually be prepared in good yield by a Hell-Volhard-Zelinsky bromination (Section 5.14.1, p. 720) of the corresponding carboxylic acid if the carboxylic acid is not readily available it can usually be obtained by the synthesis and bromination of the appropriate alkylmalonic, acid (see Expt 5.166). 

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.

The mechanism in Figure 12.7 implies that the stoichiometric use of phosphorus tribromide in the second variant of the Hell-Volhard-Zelinsky bromination leads to the selective formation of the a-bromocarboxylic acid bromide (Formula B in Figure 12.8). Often these compounds are hydrolyzed to give the bromocarboxylic acids C. More importantly, a-bromocarboxylic acid bromides B can also undergo alcoholysis and in this way provide access to a-brominated esters D. 

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).

Bold and Balu escu (13) found the monomeric copper(II) a-bromostearate CuA2(HA)2 in the extraction of Cu(II) with a-bromostearic acid in benzene. The bromine in the a-position was said to prevent sterically the formation of dimeric copper(II) species, a-Bromocarboxylic acid, being stronger than the nonsubstituted hom-ologues, is anticipated to form a less stable copper carboxylate dimer. 

Diorgano tellurium compounds have been reacted with methyl iodide (Vol. IX, p 1076), ethyl iodide ethyl iodoacetate, cyclohexyl iodide , methyl bromide, allyl bromide , benzyl bromide , bromoacetone , bromomethyl phenyl ketone , a-bromocarboxylic acids , a-bromocarboxylic acid esters , methyl chloride, and benzyl chloride . 

Dialkyl, diaryl, unsymmetrical dialkyl, alkyl aryl, and unsymmetrical diaryl telluriums served as the tellurium-containing starting materials (Vol. IX, p. 1075). The reactions with methyl iodide and low molecular mass organic bromides proceed at 20° in organic solvents such as chloroform and methanol or in mixtures of the neat reagents.With aryl telluriums several days are required for completion of the reaction. Diaryl telluriums with ortho-substituents react only with difficulty. Bis[2,4,6-trimethylpheny 1] tellurium did not combine with methyl iodide. The reactions with ethyl iodide and a-bromocarboxylic acids are accelerated by gentle heating. 

A number of syntheses of (V-hydroxy-a-amino acids and derivatives thereof have been reported. a-Bromocarboxylic acids or their r-butyl esters can be treated with hydroxylamine or 0-alkylated hydroxylamines to give the corresponding hydroxylamine derivatives. yV-Benzyloxy-t-alanine has been obtained by reaction of (/ )-a-bromopropionic acid with O-benzylhydroxylamine. But due to bromide exchange the optical yield was low. Anchimeric assistance of a suitable attached thio group can bring... 

This may be illustrated by the reaction of a-bromocarboxylic acids, which undergo substitution of the bromine atom by hydroxide anions with retention of configuration when the concentration of the hydroxide anions is low. Suggest what is the mechanism for the substitution reaction at low and high concentrations of hydroxide anions. 

Hell-Volhard-Zelinskii reaction The reaction in which a carboxylic acid is treated with Br2 and PBr3 (often formed in situ from red phosphorus and bromine) to give the a-bromocarboxylic acid bromide. 

Franchimont reaction. Carboxylic acid dimerization to 1,2-dicarboxylic acids by treating a-bromocarboxylic acids with potassium cyanide followed by hydrolysis and decarboxylation. 

Hydroxyurea (7.6 g, 0.1 mol) and NaOMe (8.1 g, 0.15 mol) in MeOH was treated with the ethyl ester of an a-bromocarboxylic acid (0.1 mol). After 20 h the mixture was evaporated, H20 was added and the resulting solution was neutralized with coned HC1. The mixture was extracted with EtOAc, dried (Na2S04), and evaporated. The residue was recrystallized (MeOH or CHC13). 

Optically active a-aminoalcohols from rac. a-bromocarboxylic acids s. 1, 75... 

N-Subst. a-aminocarboxylic acids from a-bromocarboxylic acids... 

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). 

This reaction was initially reported by Franchimont in 1872. It is a condensation of two a-bromocarboxylic acids in absolute alcohol in the presence of sodium cyanide to give 1,2-dicarboxylic acids after hydrolysis and decarboxylation. In the case of a-bromoketones, 1,4-diketones are produced similarly after hydrolysis with phosphoric acid. It was found that the bulky group at the ester end prevents condensation, as in the case of phenyl and naphthyl esters. Although the substituent at j0-position does not prevent such condensation, it reduces the overall yield. In addition, a compound with two ester groups at proper position will form cyclic diacid under such reaction conditions and cyclobutane, " cyclopentane and cyclohexane dicarboxylic acid have been prepared in such a way. In the case of l,4-dibromo-l,4-dibenzoylbutane, a derivative of cyclopentanone is produced after acidic hydrolysis. It should be pointed out that other common solvents—including acetone, ether, and acetonitrile- are not good for this reaction. ... 

The original condensation of two a-bromocarboxylic acids has been extended to the condensation of compounds with two a-bromocarbonyl groups. 

Bromination s. 27, 565 also chlorination and iodination s. J. Org. Chem. 40, 3420 (1975) a-bromocarboxylic acid chlorides from carboxylic acids cf. Org. Synth. 55, 27 (1976)... 

Without additional reagents a-Bromocarboxylic acid derivs. from 1-chloro-thioenolethers... 

Azetidinones from azometbines and a-bromocarboxylic acid esters... 

Racemisation via Sn2 displacement has been used for the DKR of a a-bromoester by enzymatic hydrolysis the product, a a-bromoacid, was less reactive in the Sn2 process. Investigations of the bromide source and the lipase employed led to an optimised system where an immobilised phosphonium bromide was used, together with cross-linked enzyme crystals from Candida rugosa lipase (CLEC-CRL), to afford the corresponding a-bromocarboxylic acid (Scheme 3.37). This procedure could be extended to a-chloroesters. 

---