Phenols ortho methylation

In the petroleum (qv) industry hydrogen bromide can serve as an alkylation catalyst. It is claimed as a catalyst in the controlled oxidation of aHphatic and ahcycHc hydrocarbons to ketones, acids, and peroxides (7,8). AppHcations of HBr with NH Br (9) or with H2S and HCl (10) as promoters for the dehydrogenation of butene to butadiene have been described, and either HBr or HCl can be used in the vapor-phase ortho methylation of phenol with methanol over alumina (11). Various patents dealing with catalytic activity of HCl also cover the use of HBr. An important reaction of HBr in organic syntheses is the replacement of aHphatic chlorine by bromine in the presence of an aluminum catalyst (12). Small quantities of hydrobromic acid are employed in analytical chemistry. 

The Simmons-Smith reaction has been used as the basis of a method for the indirect a methylation of a ketone. The ketone (illustrated for cyclohexanone) is first converted to an enol ether, an enamine (16-12) or silyl enol ether (12-22) and cyclopropanation via the Simmons-Smith reaction is followed by hydrolysis to give a methylated ketone. A related procedure using diethylzinc and diiodomethane allows ketones to be chain extended by one carbon. In another variation, phenols can be ortho methylated in one laboratory step, by treatment with Et2Zn and... 

The data in Table I are not directly comparable, since the viscosity of the 3-isomer was determined in benzene while the others were measured in DMSO. In addition, the first two polymers were prepared in bulk polymerizations, while the polymerization of methyl 3-vinylsalicylate was carried out with the monomer diluted 1 1 with benzene. Thus no certain conclusion can be drawn the data are, however, an indication of possible difficulty in radical polymerization of substituted styrenes bearing a phenol ortho to the vinyl group. 

Figure 3. Reaction mechanism of ortho methylation of phenol using methanol.

Kotanigawa and co-workers [7-9] studied the adsorption behavior of phenol and methanol on a Zn0-Fe203 system and highlighted the importance of acid-base sites for the selective ortho methylation. However, detailed studies of the adsorption behavior of possible products and reactants of phenol methylation on catalytic systems and their interaction among them are not available widely. 

On co-adsorbing phenol and methanol, the protonation of methanol occurs on the active acid sites as the labile protons released from the phenol reacted with methanol. Thus protonated methanol became electrophilic methyl species, which undergo electrophilic substitution. The ortho position of phenol, which is close to the catalyst surface, has eventually become the substitution reaction center to form the ortho methylated products (Figure 3). This mechanism was also supported by the competitive adsorption of reactants with acidity probe pyridine [79]. A sequential adsorption of phenol and pyridine has shown the formation of phenolate anion and pyridinium ion that indicated the protonation of pyridine. 

Further, adsorption of methylated phenols (o-cresol and 2,6-xylenol) has given very weak and broad spectral features that were correlated to their weak interaction with the catalyst. Among the ortho-methylated phenols, 2,6-xylenol desorbs fast from the surface at 200 C than o-cresol. These methylated phenols, unlike phenol, desorbed from the catalyst above 200°C that was well below the actual reaction temperature (350°C). Hence, the desorption susceptible nature of the methylated phenols above 200°C facilitated the efficient methylation at 350°C [74]. In contrast to the Cu-containing ferrospinels, CoFc204 shows little interaction [74] of phenol with methanol, when they are co-adsorbed and this might be a limiting factor to the overall reaction. 

In another variation, phenols can be ortho-methylated in one laboratory step, by treatment with Et2Zn and CH2l2-1067 The following mechanism was proposed ... 

In the first the mode of incorporation of the amino phenol O-methyl-norbelladine 343 into 10 was examined. Thus, tritium labels were inserted ortho and para to the phenolic hydroxy groups of 343 by base-catalyzed exchange with tritiated water under conditions ensuring equal labeling in all exchangeable positions. Norpluviine biosynthetized from multiply labeled 343 in Texas daffodil was selectively degraded to locate the tritium labels. 

In the greatest majority of cases, the methyl group transferred to a xenobiotic derives from the nucleotide S-adenosyl methionine ( ), but 5-methyltetrahydrofollc acid may be the methyl group donor to primary and secondary amines In the brain (49). A variety of N-methyltransferases are known (50) and thlolmethyltransferase has been the subject of much recent attention (51). Xenobiotic phenols undergoing methylation are generally either catechols or phenols with bulky ortho substituents (42). 

Acetophenetidine is an important analgesic and antipyretic that has nttMTicd widespread use in medicine. The principal series of reactions for its preparation are given above the one involving the nitration of chlorobenzene is of most value technically. These reactions are intertwined with the preparation of other products e.g., the ortho-nitration product of either chlorobenzene or of phenol is methylated to give o-nitroanisole, which is made into guaiacol or dianisidine. In general, the alkylation of nitrochlorobenzenes or of the nitrophenols is effected by use of either the alkyl halide or the alcohol—in both cases, in the presence of an alkali. Diethyl sulfate (or dimethyl sulfate) is also employed and can be handled more easily than the alkyl halide. 

Compounds Studied. Twenty Ortho-substituted phenyl N-methylcarba-mates were prepared in the conventional manner by reacting the selected phenols with methyl Isocyanate using a catalytic amount of triethylamine (14). The structures are listed in Table 1. 

In the m- and p-eresols both AH and AS are towered, as compared with phenol. A methyl group in the meia position lowers AH In 0 70 kcal and one in the para position by 1 37 kcal/niole (in contrast to the pyridine case where the AH values u< Qome more positive). These effects presumably result from the intensification of th(3 negativ( charges on tlie oxygen atom and on the ortho and para... 

Older equipment not capable of heating above 210°F may require the use of dye carriers to accelerate the rate of disperse dyeing. These carriers are emulsions of organic materials, (e.g., biphenyl, ortho phenyl phenol, trichlorobenzene, methyl naphthalene, methyl cresotinate, etc). Many of the ester-type carrier materials are by-products from fiber manufacturing. These carrier materials are rarely used in modem dyeing operations, having been eliminated due to their water and air pollution potential, safety hazard, and cost. 

Alkylation of phenol with methanol is effectively cattJyzed by calcium phosphate which is much more active than boron phosphorous oxide. The selectivity to ortho methylation products, o-cresol and 2,6-xylenol, is 88%. The high selectivity is caused by the basic properties on the surface,... 

The para and ortho positions of phenols condense at the carbonyl group of acetone to make bisphenols, eg, bisphenol A, 4,4 -(l-methylethyhdene)bisphenol [80-05-07]). If the H atom is activated, CICH— compounds add to the carbonyl group in the presence of strong base chloroform gives chloretone (l,l,l-trichloro-2-methyl-2-propanol [57-15-8]). 

Early Synthesis. Reported by Kolbe in 1859, the synthetic route for preparing the acid was by treating phenol with carbon dioxide in the presence of metallic sodium (6). During this early period, the only practical route for large quantities of sahcyhc acid was the saponification of methyl sahcylate obtained from the leaves of wintergreen or the bark of sweet bitch. The first suitable commercial synthetic process was introduced by Kolbe 15 years later in 1874 and is the route most commonly used in the 1990s. In this process, dry sodium phenate reacts with carbon dioxide under pressure at elevated (180—200°C) temperature (7). There were limitations, however not only was the reaction reversible, but the best possible yield of sahcyhc acid was 50%. An improvement by Schmitt was the control of temperature, and the separation of the reaction into two parts. At lower (120—140°C) temperatures and under pressures of 500—700 kPa (5—7 atm), the absorption of carbon dioxide forms the intermediate phenyl carbonate almost quantitatively (8,9). The sodium phenyl carbonate rearranges predominately to the ortho-isomer. sodium sahcylate (eq. 8). 

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

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