Methylation of phenols

Usually prepared from the corresponding sulphonic acids by alkali fusion, methylation of phenol or from the aminotoluene by treatment with nitrous acid followed by boiling. Both o- and p-cresol are used as end components in azo dyes. 

Dimethyl sulphate is of particular value for the methylation of phenols and sugars. The phenol is dissolved in a slight excess of sodium hydroxide solution, the theoretical quantity of dimethyl sulphate is added, and the mixture is heated on a water bath and shaken or stirred mechanically (compare Section IV, 104). Under these conditions only one of the methyl groups is utilised the methyl hydrogen sulphate formed in the reaction reacts with the alkali present. -... 

Ciesol and xylenol can be prepared by the methylation of phenol with methanol over both acid and base catalysts. It is postulated that phenol methylation on acid catalysts proceeds through the initial formation of anisole (methoxybenzene [100-66-3]) followed by intramolecular rearrangement of... 

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. 

A Comparison of the Reaction Mechanism for the Gas-Phase Methylation of Phenol with Methanol Catalyzed by Acid and by Basic... 

This chapter compares the reaction of gas-phase methylation of phenol with methanol in basic and in acid catalysis, with the aim of investigating how the transformations occurring on methanol affect the catalytic performance and the reaction mechanism. It is proposed that with the basic catalyst, Mg/Fe/0, the tme alkylating agent is formaldehyde, obtained by dehydrogenation of methanol. Formaldehyde reacts with phenol to yield salicyl alcohol, which rapidly dehydrogenates to salicyladehyde. The latter was isolated in tests made by feeding directly a formalin/phenol aqueous solution. Salicylaldehyde then transforms to o-cresol, the main product of the basic-catalyzed methylation of phenol, likely by means of an intramolecular H-transfer with formaldehyde. With an acid catalyst, H-mordenite, the main products were anisole and cresols moreover, methanol was transformed to alkylaromatics. 

Current single-mode continuous-flow microwave reactors allow the processing of comparatively small volumes. Much larger volumes can be processed in continuous-flow reactors that are housed inside a multimode microwave system. In a 2001 publication, Shieh and coworkers described the methylation of phenols, indoles, and benzimidazoles with dimethyl carbonate under continuous-flow microwave conditions using a Milestone ETHOS-CFR reactor (see Fig. 3.11) [104]. In a typical procedure, a solution containing the substrate, dimethyl carbonate, 1,8-diazabicy-clo[5.4.0]undec-7-ene (DBU) base, tetrabutylammonium iodide (TBAI), and a solvent was circulated by a pump through the microwave reactor, which was preheated to 160 °C and 20 bar by microwave irradiation (Scheme 4.31). Under these condi-... 

Scheme 4.31 Methylation of phenols, indoles, and benzimidazoles in a multimode continuous-flow microwave reactor.

Quantitative conversions are obtained from all the substrates listed in Table 4.3. Moreover, in the case of CH2 -active compounds, the reaction proceeds with a mono-methyl selectivity >99% (entries 4 and 5). An example reaction, shown in Figure 4.2, is the methylation of phenol under GL-PTC conditions. 

Figure 4.2 CF methylation of phenol in a plug-flow reactor under GL-PTC conditions. R reagent s reservoir P metering pump T thermostat C condenser P product store.

Figure 4.3 Schematic chart of a CSTR reactor for the 0-methylation of phenols with DMC. Liquid reagents are vaporized by contact with the hot slurry (mechanically stirred) and bubbled through it. Reaction takes place instantaneously and anisoles are picked up from the vapor phase.

Scheme 4.23 Methylation of phenols with mixed organic carbonates (ROCO2CH3).

Phenol methylation to 2,6-xylenol has been widely studied for the past few deeades owing to the room for improvisation from the viewpoint of product selectivity. Generally during phenol methylation to 2,6-xylenol, occurs via sequential methylation of phenol to o-cresol to 2,6-xylenol, various reaction parameters mediate the selectivity between the two. For instance, when the reaetants stoichiometry of methanol to phenol molar ratio > 2, and significant residence time of o-cresol may favor 2,6-xylenol selectivity. However, excess methanol is often used, sinee some amount of methanol tend to undergo oxidation into various reformate produets [71] under vapor phase condition. Similarly, reaction temperature, catalyst acid-base property, and space velocity of the reaetant are the parameters that govern the selectivity to 2,6-xylenol. 

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

The oldest cresol production method used in the United States is through the recovery of fractional distillates from coal tars. Most domestic cresols are formed via catalytic and thermal cracking of naphtha fractions during petroleum distillation. Since 1965, quantities of coal tar and petroleum isolates have been insufficient to meet the rising demand. Consequently, several processes for the manufacture of the various isomers have been developed. One General Electric facility produces o-cresol at an annual capacity of 10,000 tons by the methylation of phenol in the presence of catalysts. The Sherman-Williams Company uses the toluene sulfonation process and maintains an annual capacity for p-cresol of 15,000 tons. The Hercules Powder Company produced p-cresol until 1972 by the cymene- cresol process. 

Methylation of phenolic hydroxy groups (except C5-OH) generally shifts the phenolic a carbon resonance downfield ( 0.1 -3 ppm) and that of the ortho carbon signal upheld ( 1 -4 ppm). 

This reagent has proved especially important in the study of the constitution of the sugars, and of cellulose. A series of methyl-celluloses has been obtained, and by the study of their hydrolysis, or decomposition in a vacuum, some light has been thrown on the structure of the cellulose molecule. (J. S. C. I., 41, 362 R.) In the laboratory dimethyl sulphate is much employed in the methylation of phenols and naphthols. Diethyl sulphate is not so suitable for such alkylations as its lower homo-logue. 

Shieh, W.C., Dell, S. andRepic, O., l,8-Diazabicyclo[ 5.4.0] undec-7-ene (DBU) and micro wave-accelerated green chemistry in methylation of phenols, indoles, and benzimidazoles with dimethyl carbonate, Org. Lett., 2001, 3, 4279. 

Table 5.12. Methylation of Phenol, Cresols, and Anisole with Methyl Alcohol over Nafion-H Catalyst208...

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