Brominating agents

A white solid, m.p. 178 C. Primarily of interest as a brominaling agent which will replace activated hydrogen atoms in benzylic or allylic positions, and also those on a carbon atom a to a carbonyl group. Activating influences can produce nuclear substitution in a benzene ring and certain heterocyclic compounds also used in the oxidation of secondary alcohols to ketones. 

Bromination has been described using brominating agents such as N-bromosuccinimide in carbon tetrachloride (418. 420) bromine in either chloroform, acetic acid, or hydrochloric acid (414. 418, 421-423) bromine in sulfuric acid (415-417) and enzymatic catalysis (424, 425). 

Acetamidothiazole (203) gives, according to the brominating agent, either 4-bromo- (204) or 2,4-dibromo-5-acetamidothiazole (205) (Scheme 129) (388). 

The first pubHshed information on the halogenation of butyl mbber was provided by B. F. Goodrich Co. (2). Brominating agents such as /V-bromosuccinimide were used the bromination occurred ia a bulk reaction. This technology was commercialized ia 1954, but withdrawn ia 1969 (3). Exxon Chemical researchers pursued the chlorination of butyl mbber ia hexane solution usiag elemental chlorine, and a continuous process was commercialized ia 1961 (4). Currentiy, both chlorination and bromination are carried out ia continuous-solution processes. 

Pyridine hydrobromide perbromide (pyridinium bromide perbromide) [39416-48-3] M 319.9, m 130 (dec), 132-134 (dec). It is a very good brominating agent - liberating one mol. of Br2. Purified by recrystn from glacial acetic acid (33g from lOOmL of AcOH). [Fieser and Fieser Reagents for Organic Chemistry Vol 1 967 1967.]... 

As with addition of other electrophiles, halogenation of conjugated dienes can give 1,2- or 1,4-addition products. When molecular bromine is used as the brominating agent in chlorinated hydrocarbon solvent, the 1,4-addition product dominates by 7 1 in the case of butadiene. ... 

The product distribution can be shifted to favor the 1 -product by use of such milder brominating agents as the pyridine-bromine complex or the tribromide ion, Br3. It is believed that molecular bromine reacts through a cationic intermediate, whereas the less reactive brominating agents involve a process more like the AdgS and-addition mechanism. 

Molecular bromine is believed to be the reactive brominating agent in uncatalyzed brominations. The brominations of benzene and toluene are first-order in both bromine and the aromatic substrate in trifluoroacetic acid solution, but the rate expressions become more complicated when these reactions take place in the presence of water. " The bromination of benzene in aqueous acetic acid exhibits a first-order dependence on bromine concentration when bromide ion is present. The observed rate is dependent on bromide ion concentration, decreasing with increasing bromide ion concentration. The detailed kinetics are consistent with a rate-determining formation of the n-complex when bromide ion concentration is low, but with a shift to reversible formation of the n-complex... 

It should be noted that although BrCl is mainly a brominating agent that is eompetitive with bromine, its ehemieal reaetivity makes its action similar to that of ehlorine (that is, disinfection, oxidation, and a bleaching agent). BrCl hydrolyzes exelusively to hypobromous aeid, and if any hydrobromie aeid (HBr) is formed by hydrolysis of the dissociated bromine, it quickly oxidizes to hydrobromous acid via hypochlorous acid. 

A French patent claims the successful use of methanol for the 21-bromination of 17a-hydroxy-20-ketopregnanes as well as 21-bromination of 17-desoxy-20-ketopregnanes. This solvent has been successfully employed with dioxane dibromide as the brominating agent. 

As we saw when discussing allylic bromination in Section 10.4, A-bromosuccin-imide (NBS) is a convenient free-radical brominating agent. Benzylic brominations with NBS are nonnally perfonned in carbon tetrachloride as the solvent in the presence of peroxides, which are added as initiators. As the exanple illustrates, free-radical bromination is selective for substitution of benzylic hydrogens. 

Procedures have been worked out which increased the yield of 2-bromothiophene to 78% on direct bromination in acetic acid-ether mixtures and to 67% in carbon tetraehlorided With the mild brominating agent, dioxane dibromide, quantitative yields of 2-bromothiophene are obtained. A very convenient procedure for the iodination of thiophenes consists of the acid-catalyzed (HzSOi) reaction with iodine and HIO3, giving 2-iodothiophene in 75% yieldd In contrast to the HgO method, all the iodine is utilized. 

Current views (100) on the mechanism of bromination by NBS invoke the formation of molecular bromine and bromine atoms in low concentration, which subsequently act as the brominating agent. The bromination reaction was studied in detail in this laboratory under a variety of conditions using 93 (R = Ms) as a model. The product 94 (R = Ms) was indeed formed (42%) when NBS was substituted by 1.1 equivalents of bromine which was added at a slow rate to the reaction mixture. The yield was 68% when benzoyl peroxide was used as a catalyst. Using NBS alone or in the presence of reagents such as barium carbonate, pyridine, or s-trinitrobenzene, the yield was 60-70%. 

Attempts to brominate cyclopent[/>]azepine (10) with bromine failed, as did nitration with copper(II) nitrate in acetic anhydride 2 however, with one equivalent of A -bromosuccinimide in acetic acid a separable mixture of the unstable 8-bromo 11 and 6-bromo 12 derivatives, along with the stable 6,8-dibromo derivative 13, is formed. An excess of brominating agent yields the dibromo compound as the sole product. 

Since treatment of bromine as a brominating agent is not always ease because of its volatile and toxic characters, many attempts to develop a stable solid agent in place of liquid bromine have been undertaken. 

As these solid agents, some quaternary ammonium tribromides such as pyridinium hydrobromide perbromide (ref. 1), phenyltrimethylammonium tribromide (ref. 2), tetramethylammonium tribromide (ref. 3), and tetrabutyl-ammonium tribromide (ref. 4) have already been reported as mild and selective brominating agents (Fig. 1). 

With 3-methylphenol (meto-cresol), around 8 % of dibromo products result when one equivalent of brominating agent is used, and this rises to 23 % of dibromo products on attempted monobromination of 3,5-dimethylphenol with 1 molar equivalent of resin. Nevertheless, the good yields of products obtained from the mono-substituted phenols tried demonstrate that this is a powerful new synthetic method for the organic chemist. 

Brominating agent Reaction condition Yield of 2 (reproduction) Reference... 

The effect of added [Br ] on the bromination reaction is such as to retard the rate. This phenomenon is attributable to a competing equilibrium,Br" + Br2 Br3 that decreases the available free [Br2]. In HOAc, the accepted value for the tribromide equilibrium constant is Kgq = 92 M-1 (ref. 11). Both Br2 and Br3 are brominating agents so that the rate of disappearance of total bromine, or [Br2]j, is... 

Al-Bromosuccinimide is also a highly regioselective brominating agent at other positions, including positions a to a carbonyl group, to a C=C triple bond, and to an aromatic ring (benzylic position). When both a double and a triple bond are in the same molecule, the preferred position is a to the triple bond. ... 

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