Methylation: of carboxylic acids

FIGURE 15.1 Scheme showing PLC group fractionation of soluble organic matter into fractions of aliphatic hydrocarbons, aromatic compounds with application of urea clathra-tion, and methylation of carboxylic acids in polar fractions based on experimental data given in Reference 36 to Reference 52, Reference 77 to Reference 81, and Reference 88 to Reference 89. 

Another technique which has much potential in analysis, but which to date has had only limited use, is the formation of radioactive derivatives of non-radioactive compounds for quantitation by radiocounting. A radiolabeled reagent is used to form the derivative. This approach has been of use in combination with chromatography. The advantage of this technique is that it avoids problems of sample background which are often associated with spectrophotometric methods. The 14C-methylation of carboxylic acids and the 14 C-acetylation of hydroxyl groups have been studied [39,40]. These methods are quantitative and the sensitivity is dependent on the activity of the radioactive group added to the molecules. The radioactive derivatization of lipids has been reviewed [41]. 

We showed you the formation of a carbene from diazomethane to illustrate how this reaction was different from the (ionic) methylation of carboxylic acids. But this is not a very practical way of generating carbenes, not least because of the explosive nature of diazoalkanes. However, diazocarbonyl compounds are a different matter. 

Note 4. See Chapter 7.1.2.1 for alternative methods. O-Acetylation modifies both aliphatic and phenolic hydroxyl groups. In the event subsequent O-methylation of carboxylic acid groups by ethereal diazomethane is required, it is essential to carry out the O-acetylation of phenolic hydroxyl groups as completely as possible as unacetylated phenolic hydroxyl groups also undergo O-methylation with diazomethane. 

C-Methylation of carboxylic acids. Carboxylic acids can be C-methylated to f-butyl compounds by excess trimethylaluminum in benzene at about 120°. For example, benzoic acid is converted into t-butylbenzene. Adamantane-1-carboxylic acid is converted into a mixture of 1-r-butyladamantane and 1-isopropenyladamantane. 

Methylation of Heteroatoms. The most widely used feature of the chemistry of diazomethane is the methylation of carboxylic acids. Carboxylic acids are good substrates for reaction with diazomethane because the acid is capable of protonating the dia-zomethane on carbon to form a diazonium carboxylate. The car-boxylate can then attack the diazonium salt in what is most likely an Sn2 reaction to provide the ester. Species which are not acidic enough to protonate diazomethane, such as alcohols, require an additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity and facilitate the reaction. The methylation reaction proceeds under mild conditions and is highly reliable and very selective for carboxylic acids. A typical procedure is to add a yellow solution of diazomethane to the carhoxylic acid in portions. When the yellow color persists and no more gas is evolved, the reaction is deemed complete. Excess reagent can be destroyed by the addition of a few drops of acetic acid and the entire solution concentrated to provide the methyl ester. 

Interactive mechanism for methylation of carboxylic acid with diazomethane... 

N-Methylation of carboxylic acid amides CONH -> CONMe... 

Among other examples, the authors also demonstrated the synthesis of a peripheral benzodiazepine receptor (PER) ligand (62) via the C-methylation of carboxylic acid (61) (Scheme 6.21), obtaining the desired PER ligand (62) in a RCY of 65% [46]. 

A very useful reagent for methylation of carboxylic acids is diazomethane. At 0°C and within a few seconds only the carboxylic group of phenolic carboxylic acids is esterified. Alkaline saponification regenerates the carboxylic acid, but in compounds with a free hydroxyl... 

Methylation of carboxylic acids and phenolic compounds with dimethyl carbonate (DMC) in the presence of a catalytic amount of BF3-OEt2, DBU, or KOH, in good yields was reported by Rajabi and Saidi (2004) under solvent-free conditions and microwave irradiation. Guerrero and Rivero (2008) have discovered that 1,2-dimethylimidazole (DMI) can also function (like DBU) as a nucleophilic cata-... 

O-Methylatlon. Carboxylic acids can be converted to the corresponding methyl ester by stirring a mixture of the carhoxylic acid in methanol with an excess of methyl iodide and Potassium Carbonate A recent report describes the esterification of carboxylic acids using Cesium Fluoride and methyl iodide in DMF (eq 14). Dimethyl Sulfate has also been advantageously utilized to effect -methylation of carboxylic acids as well as alcohols (eq 15). These methods often serve as useful alternatives to Diazomethane for preparative scale esterification of carboxylic acids. 

Hydroxide [1899-02-1]. Trimethylanilinium hydroxide Reagent for flash methylation of carboxylic acids for gc anal. 

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