Diazomethane reaction with phenol

Methylation. The reaction with diazomethane has often been used for differentiating the acidic groups (28, 35, 38, 45, 46, 69). Diazomethane reacts, in general, with carboxylic acids, forming methyl esters which are easily hydrolyzed by dilute hydrochloric acid. With phenols, ethers are formed which are stable to hydrolysis. Alcohols are methylated only if catalysts are present, e.g., BF, ZnClj (70), or HjO (71). As Garten et al. 

For GC analysis, the salts of the lowest molecular weight acids present in ozonation products subjected to base-promoted hydrolysis have been converted to their benzyl esters by reaction with benzyl bromide (Bonnet et al. 1989). The salts of all acids produced have commonly been converted to the free acids, usually with the aid of a cation exchange resin. The acids have then been converted to methyl esters by reaction with diazomethane (Bonnet et al. 1989) or, more often, have been converted to trimethylsilyl (TMS) esters (Matsumoto et al. 1986, Taneda et al. 1989, Habu et al. 1990). Trimethylsilylation has the major advantage that alcoholic and phenolic hydroxyl groups are simultaneously converted to TMS ethers, thus greatly facilitating GC analysis. 

These surface states affect the chemical and electrochemical properties of carbon surface [24]. The amount of carboxylic and phenolic groups can be determined from the amount of nitrogen produced by their reaction with diazomethanes... 

Methoxymethyl aryl ethers, Ar0CH20CH3. These ethers can be prepared by treatment of phenols with NaH in ether-DMF followed by chloromethyl methyl ether. Ronald reports that these ethers show enhanced susceptibility at the orfho-position to halogen-metal exchange, particularly with f-butyllith-ium. Thus (1) can be converted into (2) in high yield by metalation, reaction with CO2, and then reaction with diazomethane. In contrast, the methyl ether of OT-cresol under similar conditions gives less than 1% yield of carboxylic acids. 

Upon reaction with diazomethane or dichloromethane, the phenols can be reetherified. Alkaline isomerization affords the corresponding C-9 epimers (Scheme 47) (704, 70S). 

Other acidic functional groups will also undergo reaction with diazomethane. Thus phosphonic acids (eq 5) and phenols (eq 6) are methylated in high yields, as are hydroxytropolones (eq 7) and vinylogous carboxylic acids (eq 8). The origin of the selectivity in eq 6 is due to the greater acidity of the A-ring phenol. 

In addition, phenolic hydroxyl adjacent to a carboxyl group on an aromatic ring constitutes the major entity responsible for the chelation of metals in coal, particularly in the lower-rank coals. Phenolic hydroxyl is also determined by reaction with diazomethane (CH2N2) to form the methoxyl group (-OCH3) with the release of elemental nitrogen. 

Reaction with alcohols is general for diazo compounds, but it is most often performed with diazomethane to produce methyl ethers or with diazo ketones to produce ot-keto ethers, since these kinds of diazo compounds are most readily available. With diazomethane the method is expensive and requires great caution. It is used chiefly to methylate alcohols and phenols that are expensive or available in small amounts, since the conditions are mild and high yields are obtained. Hydroxy compounds react better as their acidity increases ordinary alcohols do not react at... 

In other reactions also the OH-group of the phenols shows itself to be more reactive than that of the aliphatic alcohols. Phenols, but not alcohols, react easily with diazomethane. With other alkylating agents also, such as alkyl halides, and dialkyl sulphates, the phenols react even in aqueous alkaline solution whilst the alcohols do not react under such conditions. Benzoyl derivatives, most of which crystallise readily, are excellently adapted for the characterisation of phenols (Schotten-Baumann reaction). 

In ethereal solution diazomethane can he preserved for a long time. Information about its numerous reactions (with hydrogen cyanide, acetylene, quinone, etc.) can he found in the special literature of the subject. As has already been mentioned, it is an important methylating agent, especially for phenols. With them it reacts in such a way that the two nitrogen atoms are eliminated as elementary nitrogen, and the two valencies which thus become free are occupied by H and OR. 

The BBrs reaction with 1. l-dimethoxy-2.4.6-di-tert-butyl-4-(4 -methoxyphenyl)-X -phosphorin 200 leads to cleavage of both methoxy groups in addition to the methoxy group at the phosphorus, the 4 -methoxy group is attacked. The 2-hydro-4-(4 -hydroxyphenyl)-phosphinic acid methyl ester 201 can be methylated with methyl iodide in methanol/sodium methylate at the phenolic group, leading to 202, which can also be prepared by hydrogen peroxide oxidation of 2.6-di-tert-butyl-4-(4 -methoxy phenyl)-X -phosphorin 204 to 203, followed by diazomethane methylation (see Table 13, p. 61). 

However, the reactivity of phenolic hydroxy groups can be modified by a fused heterocyclic ring. Thus, hydroxy groups peri to a carbonyl group, e.g. (600), are hydrogen bonded they do not react with diazomethane, and are difficult to acylate. This allows selective reactions in polyhydroxychromones. 

General methylation procedure with diazomethane. The reaction must be carried out in the fume cupboard. Dissolve 2-3 g of the compound (say, a phenol or a carboxylic acid) in a little anhydrous ether or absolute methanol, cool in ice and add the ethereal solution of diazomethane in small portions until gas evolution ceases and the solution acquires a pale yellow colour. Test the coloured solution for the presence of excess of diazomethane by removing a few drops into a test tube and introducing a glass rod moistened with glacial acetic acid immediate evolution of gas should occur. Evaporate the solvent, and purify the product by distillation or crystallisation. 

Phenolic methyl ethers were usually prepared by treatment of the alkaloid with dimethyl sulfate and sodium hydroxide or with diazomethane 17). In the first case a side reaction was N-methylation or even cleavage of the lactone (3). In decodine (6) the C-17 OH group was methylated on treatment with ethereal diazomethane. The hindered C-21 OH group was alkylated with methanolic CH2N2 (77). 

The reactions illustrated in equations (62-64) are each catalyzed by rhodium acetate. Diazo compounds, especially diazoalkanes, can also react by a simple ionic mechanism. The esterification of a carboxylic acid with diazomethane is a familiar example. The ionic pathway is especially likely when the intermediate carbocation would be stabilized. Thus, diazine (158) couples smoothly with phenols, presumably by thermal rearrangement to the corresponding diazo sugar, followed by acid-catalyzed N2 loss... 

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