Bromination, of phenols

The mono-bromination of phenol at low temperatures in carbon disulphide or carbon tetrachloride solution results in almost exclusive para substitution ... 

Brominated Phenols. Tribromophenol [75-80-9] and dibromophenol [615-58-7] are both prepared through bromination of phenol. These are not actually used as reactive flame retardants, but rather as starting materials for other flame retardants such as BTBPE [37853-59-1] and epoxy oligomers. 

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. 

A hydroxyl group is a very powerful activating substituent, and electrophilic aromatic substitution in phenols occurs far- faster, and under milder conditions, than in benzene. The first entry in Table 24.4, for exfflnple, shows the monobromination of phenol in high yield at low temperature and in the absence of any catalyst. In this case, the reaction was carried out in the nonpolar- solvent 1,2-dichloroethane. In polar- solvents such as water it is difficult to limit the bromination of phenols to monosubstitution. In the following exfflnple, all three positions that are ortho or para to the hydroxyl undergo rapid substitution ... 

The bromination of phenol in acetic acid, containing lithium bromide and perchlorate at a constant total concentration of 0.2 M, gave kinetic isotope effects... 

Regioselective bromination of phenols gave 2-bromo-, 4-bromo-, 2,6-dibromo-, 2,4-dibromo, 2-bromo-6-substituted, 4-bromo-2-substituted and 2,4-dibromo-6-substitutgd phenols, respectively. Especially, 2-bromo-, 2,6-dibromo- and 2-bromo-6-substituted phenols which were prepared via long steps, were obtained in NBS-amine (primary and secondary) system in high yields under ordinary conditions. The scope and their mechanisms were discussed. 

Calo et al. (ref. 5) studied solvent effects on selective bromination of phenol with NBS and found the selectivity of bromination depended on the polarity of the solvents. But thereafter no investigation concerning the solvent effects was reported. We report the effects systematically. 

The results of the bromination of phenol with NBS compared with bromine in various solvents are shown (Fig. 1). NBS was not added as the solution in solvent but solid powder. 

Fig. 1. Plots of dielectric constant vs selectivity of bromination of phenol with Br2 (left) and NBS (solid powder) (right). ort/io-Bromophenol (A), para-Bromophenol ( ).

In Table 1 was shown the results of bromination of phenol with bromine, NBS, and AT-bromodibutylamine (NBB) (ref. 8) in dichloromethane. 

Table 1. Bromination of Phenol with Bromine, NBS, and iV-Bromodibutylamine (NBB) )...

As described above, it was shown that A,iV-dibromomethylamine was effective for orr/io-dibromination of phenol (ref. 7). We also carried out a bromination using NBB as A-bromoamine analogue. One molar amount of NBB did not give 2-bromophenol selectively, but gave a mixture of o/t/io-monobromophenol and 2,6-dibromophenol, and a considerable amount of phenol was recovered. On the other hand, 2,6-dibromophenol was obtained in an 81.7 % yield when two molar amounts of NBB were used. These results suggested that 7V-bromoamines were the best reagents for orf/io-bromination of phenol. However N-bromoamines were very unstable and decomposed explosively in less than a day at room temperature. 

The distribution of the products was only slightly influenced by the added amount of the amine in the bromination. Even a 0.1 molar amount of diisopropylamine was sufficiently effective. From these results, it was concluded that the amine worked catalytically in the selective orf/io-bromination of phenol. Regioselective bromination of phenol was summarized in Scheme 2. 

Because the tertiary amines cannot be brominated by NBS, they do not influence the o/tAo-bromination of phenols. Though the hydrogen bonding between the phenolic OH and NBS will be formed, the bonding is inferred to be weaker than that between the OH and the (V-bromoamines. The nucleophilicity (or basicity) of the nitrogen atom of A -bromoamines is stronger than that of NBS. This is why traces of A -bromoamines can react with phenols continuously. 

Hydrogen bonding between Br2 and 2-substituted phenols having electron-donating group is strong enough to orf/io-brominate these phenols. Therefore, o/t/io-bromination of phenol, o-cresol and 2-allylphenol was promoted by only NBS without amines. 

Because of its mild reaction conditions, simple experimental operations, and generally excellent yields of o/t/zo-bromophenols, our method is practical for a wide variety of bromination of phenols (Scheme 6) and expected for industrial preparation of fine chemicals. 

In general, it is difficult to carry out a step-by-step bromination of phenols with bromine, since phenols react very rapidly with bromine, which leads to the polybromo-substituted phenols. We found that the reaction of phenols with calculated amounts of tetrabutylammonium tribromide (TBA Br3) or BTMA Br3 in... 

Because the presence of methanol markedly facilitates the bromination of phenols, we decided that the active species is probably methyl hypobromite produced by the reaction of these tribromides with methanol as shown below (Fig. 5) (ref. 7). 

Fig. 7. Bromination of phenols with styrene polymer-bound BTMA Br3...

Fig. 9. Selective para-bromination of phenols with Amberlyst-A26 tribromide...

Evidence for molecular chlorine or bromine as the attacking species in these cases is that acids, bases, and other ions, especially chloride ion, accelerate the rate about equally, though if chlorine dissociated into Cl" and Cl , the addition of chloride should decrease the rate and the addition of acids should increase it. Compound 27 has been detected spectrally in the aqueous bromination of phenol. ... 

Figure 3 Bromination of phenol red by Laminaria digitata in seawater (see Wever). Beakers from left to right 1) seawater plus phenol red, 2) same as 1 plus H202, 3) same as 1 plus Laminaria 4) same as 2 plus Laminaria Phenol red is converted by the bromination.

Ionic reactions of neutral substrates can show large solvent dependence, due to the differential solvent stabilization of the ionic intermediates and their associated dipolar transition states (Reichardt, 1988). This is the case for the electrophilic addition of bromine to alkenes (Ruasse, 1990, 1992 Ruasse et al., 1991) and the bromination of phenol (Tee and Bennett, 1988a), both of which have Grunwald-Winstein m values approximately equal to 1 so that the reactions are very much slower in media less polar than water. Such processes, therefore, would be expected to be retarded or even inhibited by CDs for two reasons (a) the formation of complexes with the CD lowers the free concentrations of the reactants and (b) slower reaction within the microenvironment of the less polar CD cavity (if it were sterically possible). 

This approach has been applied (Tee, 1989) to kinetic data for the bromination of phenols and phenoxide ions catalysed by a-CD. For 15 different substrates (nine phenols and six phenoxides) Krs values vary only between 0.07 and 0.8 mM, with most being between 0.1 and 0.5 mM, indicating very similar transition state stabilization for substrates with a range of reactivity of 40 million (Table A4.2). Moreover, the values of Krs show no clear correlation with Ks- This lack of dependence of KTS on the structure of the substrate is strong evidence that the transition state for the catalysed process is one in which the phenol moiety is basically outside the CD cavity while the bromine is inside ([9]— [10]). The same conclusion was... 

Phenols undergo electrophilic substitutions. In phenol, the substitutions take place in ortho and para positions. As the —OH group is an activating group, the reaction rate is much faster than usually observed with benzene. For example, the bromination of phenol produces ort/io-bromophenol (12%) and para-bromophenol (88%). 

The unusual wiefa-bromination of phenols and their methyl ethers [9] under superacid conditions is quite expected because O-protonation inverts polarity of all the nuclear carbon atoms. This reaction is reminiscent of the better known electrophilic substitutions of aniline in acidic media. 

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