2-Bromophenol

CeHsOH + 2H2SO4 CeH3(0H)(S03H)2(i,2,4) + 2H2O C6H3(0H)(S03H)2 + 3NaOH 

C6H2(0H)(S03Na)2(Br) + NaBr C6H2(0H)(S03Na)2(Br) + 2H2SO4 

The alkaline solution is cooled to room temperature and, with the stirrer still in constant operation, and after inserting a thermometer, r6o g. (i mole) of bromine is added from a dropping funnel in the course of twenty to thirty minutes. During this operation the temperature is allowed to rise to 40-50Stirring is continued for one-half hour after all of the bromine has been added. The solution should still be alkaline and should contain only a small amount of suspended material. 

The flask is then heated in an oil bath maintained at a temperature of 190-210° and the mixture subjected to steam distillation. The sulfonate groups are hydrolyzed in this process and the bromophenol passes over as a heavy, colorless or pale yellow oil. In about one hour the distillate is clear. The product is extracted with ether, the ether is removed by distillation from the steam bath, and the residue is distilled at atmospheric pressure (Note 3). The fraction boiling at 194-200° represents practically pure o-bromophenol. The yield is 70-75 g. (40-44 per cent of the theoretical amount) (Note 4). t -Bromophenol is a colorless liquid with a very characteristic odor. It is rather unstable and decomposes on standing, becoming brown or red in color. 

Too great an excess of water in the reaction mixture appears to result in the formation of higher bromination products. 

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Monobromination with bromine leads to exclusive 4-bromophenol, and dibromination with the same reagent gave predominant 2,4-dibromophenol. In the case of monobromination with NBS, the main product was 2-bromophenol, but no selectivity appeared in the bromination using two molar amounts of NBS. 

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. 

Our method, NBS-amine system, is applied to orf/zo-bromination of 2-substituted phenols (e.g. 2-allyIphenol, o-cresol, 2-bromophenol, and 2-chloro-phenol) (Table 4). 

Fig. 2 Selectivity of orf/io-bromide (left) and dibromide (right) depending on reaction temperature in the bromination of 2-substituted phenols with NBS (solid powder) and (/-Pr)2NH. 2-allylphenol ( ), o-cresol (A), 2-bromophenol (A), and 2-chlorophenol (O).

The mechanism of the orf/to-dibromination of phenol with NBS in the presence of amines is considered as follows. The hydrogen bonding between phenol and N-bromoamine which are generated from the reaction of NBS and amines (ref. 14), is the driving force, and causes the bromination at one o/t/io-position of phenol and regeneration of the amines. A catalytic amount of the amines is enough because of the regeneration of the amines. The repetition of the above process causes one more substitution at the other orf/io-position of 2-bromophenol. In the cases of 2-substituted phenols the orf/io-bromination can occur only once (Scheme 5). 

Evans CS, B Dellinger (2005b) Formation of bromochlorodibenzo-p-dioxins and furans from the high tempa-reture pyrolysis of a 2-chlorophenol/2-bromophenol mixture. Environ Sci Technol 39 7940-7948. 

A spore-forming strain of Desulfitobacterium chlororespirans was able to couple the dechlorination of 3-chloro-4-hydroxybenzoate to the oxidation of lactate to acetate, pyruvate, or formate (Sanford et al. 1996). Whereas 2,4,6-trichlorophenol and 2,4,6-tribro-mophenol supported growth with the production of 4-chlorophenol and 4-bromophenol, neither 2-bromophenol nor 2-iodophenol was able to do so. The membrane-bound dehalogenase contains cobalamin, iron, and acid-labile sulfur, and is apparently specific for ortho-substituted phenols (Krasotkina et al. 2001). 

The literature is replete with synthetic methods to prepare 5-bromofurans. One of the more practical syntheses [10, 11] commenced with etherification of 4-bromophenol with bromoacetaldehyde diethyl acetal using either NaH in DMF or KOH in DMSO. Treatment of the resulting aryloxyacetaldehyde acetal with polyphosphoric acid (PPA) afforded 5-bromofuran in good yield via intramolecular cyclocondensation. However, cyclization of m-aryloxyacetaldehyde acetal 1 resulted in a mixture of two regioisomers, 6-bromofuran (2) and 4-bromofiiran (3). Finally, 7-bromofuran 5 can be prepared similarly using the intramolecular cyclocondensation of aryloxyacetaldehyde acetal 4 generated from etherification of 2-bromophenol with bromoacetaldehyde diethyl acetal. 

The robust nature of the rhodium-iodide catalyst is also revealed in reactions with ortho-halo phenols that proved to be problematic with the first-generation catalyst system (Section 9.3.1). By employing the [Rh(PPF-P Bu2)I] catalyst, complete conversion is obtained with 2-bromophenol to give 6 in 94% yield, and with 95% enantiomeric excess after only 1.5 h of reaction time at 1 mol% catalyst loading (Scheme 9.3) [11]. The ready availability of these ring-opened compounds has been utilized to prepare enan-tiomerically enriched benzofurans 7. 

As well as detoxication via reaction with GSH, the reactive 3,4-epoxide can be removed by hydration to form the dihydrodiol, a reaction that is catalyzed by epoxide hydrolase (also known as epoxide hydratase). This enzyme is induced by pretreatment of animals with the polycyclic hydrocarbon 3-methylcholanthrene, as can be seen from the increased excretion of 4-bromophenyldihydrodiol (Table 7.5). This induction of a detoxication pathway offers a partial explanation for the decreased hepatotoxicity of bromobenzene observed in such animals. A further explanation, also apparent from the urinary metabolites, is the induction of the form of cytochrome P-450 that catalyzes the formation of the 2,3-epoxide. This potentially reactive metabolite readily rearranges to 2-bromophenol, and hence there is increased excretion of 2-bromophenol in these pretreated animals (Table 7.5). 

In addition to being hepatotoxic, bromobenzene is also nephrotoxic because of the production of reactive polyphenolic GSH conjugates, covalent binding to protein, and the production of ROS. 2-Bromophenol and 2-bromohydroquinone are both nephrotoxic metabolites of bromobenzene. Quinones are both oxidants and electrophiles, undergoing both one and two electron reduction and reaction with sulfydryl groups such as GSH and... 

The metabolite of bromobenzene that is believed to be responsible for the hepatic necrosis is bromobenzene 3,4-oxide. This reacts with liver cell protein, which causes cell death. The reactive metabolite can be detoxified by conjugation with glutathione or be detoxified by metabolism to a dihydrodiol by epoxide hydrolase. Pretreatment of animals with the enzyme inducer 3-methylcholanthrene decreases the toxicity. This is because it increases metabolism to the 2,3-oxide. This reactive metabolite is not as toxic as the 3,4-bromobenzene oxide readily undergoing rearrangement to 2-bromophenol. 3-Methylcholanthrene also induces epoxide hydrolase and so increases detoxication. 

In another variation the dilithium salt was obtained from 2-bromophenol and contamination with LiBr followed by Soxhlet extraction to solubilize the binuclear anionic salt and obtain crystals of LieCr -OCeH BrrhE O (Scheme 21).171... 

The oxidative coupling of 2-halo-4,6-di-t-butylphenols with potassium hexacyanofer-rate(III) in benzene was investigated the 2-bromophenol (227) yielded l,4-dihydro-4-bromo-2,4,6,8-tetra-t-butyl-l-oxodibenzofuran (228 81%) and 2,4,6,8-tetra-t-butyldiben-zofuran (229) (81JOC3784). 

With one or two exceptions, dibenzo fused derivatives require quite different synthetic strategies to those above. Dibenzo[6,e][l,4]dioxin is nowadays frequently prepared in yields of 10-20% by heating a mixture of 2-chlorophenol, potassium carbonate and copper powder to 170-180 °C (57JA1439). 2-Bromophenol can also be used as the precursor but... 

Bromo-l,4-benzoquinone-4-oxime [called 2-Brom -p-chinon-oxim-(4) or 2-Brom-4-nitroso-phenol in Ger], 0 CgH3(Br) N.OH or HO.C6H3(Br).NO-See 4-Nitroso-2-bromophenol under Bromophenol and Derivative s... 

As seen from Table 2, phenol, j>-toluene sulfonate and 2 bromophenol have similar adsorption rate characteristics. The equilibrium data for these solutes indicate that phenol and p-toluene sulfonate have similar energies of adsorption (24), as indicated by the constant b in the component isotherm (qe Qbx,ce/ (1 + bLCe) -bromophenol and dodecyl benzene sulfonate are adsorbed more strongly than phenol (22). 

In closing this section, it should be mentioned that simple bromophenols (2-bromophenol, 4-bromophenol, 2,4-dibromophenol, 2,6-dibromophenol, and 2,4,6-... 

Bromophenol blue, suggested by Durrum (D13) and Jencks (J3), is used as an aqueous solution of 0.1 g per liter containing 5 % acetic acid and 5 % zinc sulfate. Here, dye fixation affects considerably the protein factor. Heat must be applied according to the standard schedule of 30 minutes at 120°C (D15). 

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