4- Methylphenol bromination

If t he directing effects of the two groups oppose each other, the more powerful activating group has the dominant influence, but mixtures of products often result. For example, bromination of p-methylphenol yields primarily 2-bromo-4-methylphenol because —OH is a more powerful activator than -CH3. 

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. 

Analogously, 5-tributylstannylimidazole 29 was easily obtained from the regioselective deprotonation of 1,2-disubstituted imidazole 28 at C(5) followed by treatment with tributyltin chloride [24]. In the presence of 2.6 equivalents of LiCl, the Stille reaction of 29 with aryl triflate 30 afforded the desired 1,2,5-trisubstituted imidazole 31 with 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger. Reversal of the nucleophile and electrophile of the Stille reaction also provided satisfactory results. For example, the coupling reaction of 5-bromoimidazole 33, derived from imidazole 32 via a regioselective bromination at C(5), and vinylstannane 34 produced adduct 35 [24],... 

This mechanism is challenged by Fischer and henderson1039, who suggest an ipso mechanism followed by 1,2 bromine shift in the bromination of methylphenols in trifluoromethanesulfonic acid (equation 156). 

A powerful oxidizer. Explosive reaction with acetaldehyde, acetic acid + heat, acetic anhydride + heat, benzaldehyde, benzene, benzylthylaniUne, butyraldehyde, 1,3-dimethylhexahydropyrimidone, diethyl ether, ethylacetate, isopropylacetate, methyl dioxane, pelargonic acid, pentyl acetate, phosphoms + heat, propionaldehyde, and other organic materials or solvents. Forms a friction- and heat-sensitive explosive mixture with potassium hexacyanoferrate. Ignites on contact with alcohols, acetic anhydride + tetrahydronaphthalene, acetone, butanol, chromium(II) sulfide, cyclohexanol, dimethyl formamide, ethanol, ethylene glycol, methanol, 2-propanol, pyridine. Violent reaction with acetic anhydride + 3-methylphenol (above 75°C), acetylene, bromine pentafluoride, glycerol, hexamethylphosphoramide, peroxyformic acid, selenium, sodium amide. Incandescent reaction with alkali metals (e.g., sodium, potassium), ammonia, arsenic, butyric acid (above 100°C), chlorine trifluoride, hydrogen sulfide + heat, sodium + heat, and sulfur. Incompatible with N,N-dimethylformamide. 

A strong base. Vigorous reaction with 1,2,4,5-tetrachlorobenzene has caused many industrial explosions and forms the extremely toxic 2,3,7,8-tetrachlorodibenzodioxin. Mixmres with aluminum + arsenic compounds form the poisonous gas arsine. Potentially explosive reaction with bromine, 4-chlorobutyronitrile, 4-chloro-2-methylphenol (in storage), nitrobenzene + heat, sodium tetrahydroborate, 2,2,2-trichloroethanol, zirconium + heat. Reacts to form explosive products with ammonia + silver nitrate (forms silver nitride), N,N -bis(trinitroethyl)urea (in storage), cyanogen... 

Oxidative coupling was used for the synthesis of some stabilizers having properties of AO or FR. Products of oxidation of 4,4 -isopropylidenebis(2-methyl-6-tert-butylphenol with pota ium ferricyanide [151] or of 4,4 -thiobis(2-rcr/-butyl-5-methylphenol) with oxygen in the presence of copper salts [152] (118) were tested as AO. Thermostable fireproofing additives containing 1 to 4 bromine atoms on a phenolic moiety and designed for the stabilization of thermoplastics, e.g. 119, were prepared by oxidative coupling of brominated phenols [153]. 

From archival enthalpies of formation and of fusion, the estimated enthalpy of formation of solid 3,5-dibromotoluene is 28 9 kJ moF. This value, combined with 5 (OH/H), gives a predicted enthalpy of formation of the corresponding phenol of —175 kJ moF. A bromine atom and methyl group crowd the intervening OH, which could account for at least some of the ca 16 kJ moF difference between the predicted and experimental values, and we don t expect 2,4-dibromo-6-methylphenol to participate in intermolecular hydrogen bonding. The remainder of the difference is accounted for by the error bars. Altogether, the value is plausible. 

Two reactions illustrate the use of air oxidation where toxic selenium dioxide or bromination followed by hydrolysis and oxidation would normally be used. The first (4.39) oxidizes a methylphenol to a phenolaldehyde in 95% yield.195 The second (4.40) uses air to oxidize a pinene to verbenone in 77% yield.196 This eliminates the need for the lead tetraacetate, sodium dichromate, sulfuric... 

Fig. 6 Mass spectra of a brominated contaminant identified in Rhine water samples (A) and of the reference substance obtained by acylation of 2-bromo-4-methylphenol.

Thus, glycosidation of 2-chloro-4-methylphenol (32) by penta-O-acetyl-D-galactose (15) in the presence of zinc chloride afforded 33, which was subsequently submitted to benzylic bromination to 34. Solvolysis of 34 to 35 was followed by activation using N, iV-disuccinimidylcarbonate (DSC) to give 36. This intermediate was in turn condensed without purification with daunorubicin (1) to yield 37. Final deprotection by transesterification afforded prodrug 29. 

Methylphenol in Hf / antimonypentafluoride treated with bromine and worked up after Ih. to give 3-bromo-4-methylphenol. 

Fig. 2 Left-. HPLC-UV chromatograms of BFRs obtained by stir bar sorptive extraction (SBSE) in (a) the original dust sample (b) the spiked dust sample (250 xg/L BHT and 50 Jtg/L for each BFR were added). 1, tetrabromobisphenol (T BBPA) 2, BHT 3, BDE-28 4, BDE-47 5, BDE-66 6, BDE-100 7, BDE-99 8, BDE-153. Right HPLC-UV chromatograms of BFRs obtained by SBSE in (a) tbe original dust sample (b) the spiked dust sample (250 Jtg/L BHT and 45 xg/L for each BFR were added). 1, T BBPA 2, BHT 3, BDE-28 4, BDE-47 5, BDE-66 6, BDE-100 7, BDE-99 8, BDE-153. BFR, brominated flame retardant BDE-28, 2,4,4-tribromodiphenyl ether BDE-47, 2,2,4,4-tetrabromodiphenylether BDE-66, 2,3,4,4-tetrabromodiphenyl ether BDE-99, 2,2, 4,4,5-pentabromodiphenylether BDE-100, 2,2,4,4,6-pentabromobromodiphenyl ether BDE-153, 2,2,4,4,5,5-hexabromodiphenylether BHT, 2,6-di-(l,l-dimethy-lethyl)-4-methylphenole.

Studies on the bromination of 3,4-dimethyl-phenols have revealed abnormal reaction paths. The compounds (60) and (61) yield the tribromo-dienone (62), which rearranges autocataljrtically (and possibly homocatalytically) to 3-bromomethyl-2,6-dibromo-4-methylphenol (63). 

---