Positive bromination

Positive bromination was first observed by Shilov and Kaniaev189 who found that the bromination of sodium anisole-m-sulphonate by bromine-free hypo-bromous acid was accelerated by the addition of nitric or sulphuric acids, and was governed by the kinetic equation 

Derbyshire and Waters192 measured the rates of bromination of sodium toluene-m-sulphonate (in water) and of benzoic acid (in aqueous acetic acid) by hypobromous acid with sulphuric or perchloric acids as catalysts, all at 21.5 °C. No bromination occurred in the absence of mineral acid and the reaction was strictly first-order in aromatic and in hypobromous acid. The function of the catalyst was considered to be the formation of a positive brominating species, according to the equilibrium 

Addition of perchlorate ion had little kinetic effect, but addition of chloride ion decreased the rate and complicated the kinetics, probably through intervention of the equilibrium 

For the bromination of benzoic acid, the rate increased more rapidly than [H+] at high mineral acid concentrations and apparently depended on the acidity function ho rather than [H+]. Neutral salts such as disodium hydrogen phosphate, lithium and sodium sulphates also increased the rate due either to a positive salt 

The positive bromination of aromatics ethers was first studied by Bradfield et al.193 and by Branch and Jones194. The reaction of hypobromous acid in 75 % aqueous acetic acid with benzyl 4-nitrophenyl ether and 4-nitrophenetole at 20 °C was very rapid and approximately second-order193. The value of k2/[H+] remained constant in the [H+] range 0.005-0.090 M for the effect of added mineral acids on the bromination of 4-nitroanisole and 4-nitrophenetole (at 19.8 °C)194. The variation in reaction rate with the percentage of acetic acid in the medium was also studied and showed a large increase in the 0-10 % range with a levelling off at approximately 25 % acetic acid (Table 52) this was attributed 

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So if one were to replace sec-butyl alcohol in the recipe above with an equimolar amount of safrole in the above reaction, Strike will wager that a positive bromination experience will occur. And all this using the very common 48% aq. HBr The oniy difference being that once the reaction mix had cooled, one should do either of two things (1) distill as described except the bromosafrole will be the last thing to come over (not the first), or (2) flood the reaction mix with water to bring the product out of solution after which it can be physically separated by decanting or sep funnel or some such shit. 

Bromination can be conveniently effected by transfer of bromine from one nucleus to another. As the Friedel-Crafts isomerization of bromoaromatic compounds generally takes place through an intermolecular mechanism, the migrating bromine atom serves as a source of positive bromine, thus effecting ring brominations (161,162). 2,4,6-Tribromophenol, for example, has been prepared by bromination of phenol with dibromobenzene. 

Bromonium ions can be also produced by an electrophilic attack by a species that should generate a positive bromine ... 

The positive bromine which leads to bromonium ion intermediates is softer and also has unshared electron pairs which can permit a total of four electrons to participate in the bridged bromonium ion intermediate. This would be expected to lead to a more strongly bridged and more stable species than is possible in the case of the proton. The bromonium ion can be represented as having two covalent bonds to bromine and is electrophilic but not electron-deficient. 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

Whereas halogens in the a-positions are removed in the Wolff-Kishner reduction, this is not the case with /3-positioned bromine. ... 

At 0.9 °C the rate of bromination of biphenyl relative to benzene was approximately 1,270, compared to 26.9 in the presence of mineral acid, and this latter value is fairly close to that obtained with 50 % aqueous dioxan. The possibility that the positive brominating species might be protonated bromine acetate, AcOHBr+, was considered a likely one since the reaction rate is faster in aqueous acetic acid than in water, but this latter effect might be an environmental one since bromination by acidified hypobromous acid is slower in 50 % aqueous dioxan than in... 

Organic Positive Bromine Compounds , Brochure, Boulder (Co.) Arapahoe Chemicals Inc., 1962... 

A bromine molecule becomes polarized as it approaches the alkene. The polarized bromine molecule transfers a positive bromine atom (with six electrons in its valence shell) to the alkene resulting in the formation of a bromonium ion. 

The bromide ion acts as a nucleophile while the positive bromine of the bromonium ion acts as a leaving group. 

A cyclic complex derivable by addition of positive bromine to a double bond has already been discussed as an example of the neighboring group effect. The same intermediate, except perhaps for the nature of the bonds to bromine, is formed in the addition of bromine to olefins and is responsible for the stereochemistry of the addition reaction and the nature of the by-products.232... 

If the above assumptions are correct, initial attack by positive bromine must occur on the olefin in accord with Markownikov s rule. The bromine is thus placed as required by the structure of the product, at the end of the side chain in both the vinylphenyl and allyl compounds. 

When there is an electron-releasing substituent in the 4-position, the electrophile attacks the 1-position. This has been used as a convenient way of preparing 1-substituted dibenzofurans by removal of an amino group at the 4-position. Bromination, chlorination, and diazo coupling of 4-dibenzofuranol occur at the 1-position. Bromination and Vilsmeier-Haack formylation of 4-methoxydibenzofuran provide the 1-substituted derivatives. Nitration and bromination of 4-acetylaminodibenzofuran take a similar course. ... 

If the 5-position is occupied, halogenation takes place in the 7-position. Bromination of 5-chloro or 5-methylisatin leads to the corresponding 7-bromo compounds,21,209 and reaction of 4-chloro-5-methoxyisatin with AT,AT-dichlorourethane in refluxing acetic acid gave 4,7-dichloro-5-methoxyisatin.138 In aqueous acetic acid these latter reactants gave 1,4-dichloro-5-methoxyisatin.136 Attempts to introduce a second iodine in 5-iodoisatin led to the isolation of 51, which could be... 

In the case of amines and phenols, bromine enters the ring in the ortho- or para- position if there is no unoccupied ortho- or para-position bromination does not take place except when this position is occupied by a carboxyl or sulphonic group, and in such case the group is split off and replaced by bromine. 

Bromination of 2-methyl-,447, 481 7-methyl-,78,478 5-bromo-,76 2-fluoro-,482 or 2-phenylbenzo[6]thiophene483 in either chloroform or carbon tetrachloride gives the 3-bromo compound in each case. 2-(2-Naphthyl )benzo[6]thiophene is brominated,54 chlorinated, and iodinated484 in the 3-position. In the cases of 3-methyl-485 and 3-bromobenzo[6]thiophene,107 bromination takes place in the 2-position. Bromination of 2,3-dimethylbenzo[6]thiophene in dilute chloroform solution at 0° gives mainly nuclear substitution in the 6-position,81 but chlorination in acetic acid causes substitution in the 2-methyl group, to give 2-chloromethyl-3-methvlbenzo[6]thiophene.419... 

N-Bromoacetamide (NBA) is also a useful positive bromine equivalent Thus NBA in the presence of H2O or LiOAc/HOAc has resulted in the functionalization of 11,12-dihydrobenzo[e]pyrene (Scheme 69).135 NBA has also been employed in conjunction with H2O for the regio- and stereo-selective hydro-bromination of the 10,11 double bond of avermectin Bla, a complex antibiotic containing five double bonds.136... 

Pyridines react quite readily with bromine to give crystalline derivatives that have some N-bromo characteristics, but that are related to the tribromide anion. In nonpolar solvents the species are largely undissociated. Positive bromine gives stable 1 2 salts and 1 1 complexes with pyridine [74HC(14-S2)416 86TL3271], but, in contrast to the chloro derivatives, N-bromo-2-pyridones are not known (82JA4142 84JOC4784). 

Electrophiles such as bromine and chlorine will, however, react with 1,2,6-thiadiazine 1,1-dioxides to give 4-halogeno derivatives [74JCS(P1)2050], and the related thiadiazinone (66) also reacted in the 4-position with bromine in carbon tetrachloride to give a product that is a potent source of positive bromine (80JHC977). 

The limiting reaction rate does not arise from the rate of formation of the electrophile since the reactions remain first-order with respect to the aromatic substrate. The limiting rate does not arise from a general breakdown in the additivity principle, e.g. as a result of the saturation of substituent effects, since the limiting rate is not found in some related reactions in which the substituent effects in deactivated systems are similar to those in nitration. This is illustrated by the results for bromination by positive bromine discussed in Section 5. Coombes et al. suggest that the limit arises from rate-determining formation of an encounter pair (ArH.NOJ between the nitronium ion and the aromatic substrate (Scheme 5). 

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