Diazomethane makes methyl esters from carboxylic acids

In 1981, some chemists in Pennsylvania needed to convert this carboxylic acid into its methyl ester as part of the synthesis of an antibiotic compound. What reagent did they choose to do the reaction?

You remember, of course, that esters can be made from carboxylic acids and alcohols under acid catalysis, so you might expect them to use this type of method. On a small scale, it’s usually better to convert the acid to an acyl chloride before coupling with an alcohol, using pyridine (or DMAP) as a base; this type of reaction might have been a reasonable choice too.

But, in fact, they chose neither of these methods. Instead, they simply treated the carboxylic acid with a compound called diazomethane, CH₂N₂, and isolated the methyl ester.

Diazomethane, CH₂N₂, is a rather curious compound that has to be drawn as a dipole. There are several different ways of expressing its structure.

Diazomethane methylates carboxylic acids because carboxylic acids readily protonate it, giving an extremely unstable diazonium cation. This compound is desperate to lose N2, the world’s best leaving group, and so it does, with the N2 being substituted by the carboxylate anion. The carboxylate anion is in exactly the right position to carry out the SN2 reaction shown below.

Diazomethane methylation is a good way of making methyl esters from carboxylic acids on a small scale because yields are excellent and the only by-product is nitrogen. However, there is a drawback: diazomethane has a boiling point of –24 °C, and it is a toxic and highly explosive gas. It therefore has to be used in solution, usually in ether; the solution must be dilute, because concentrated solutions of diazomethane are also explosive. It is usually produced by reaction of N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulfonamide with base, and distilled out of that reaction mixture as an azeotrope with ether, straight into a solution of the carboxylic acid.

The mechanism of the reaction that forms diazomethane is shown below. The key step is base-catalysed elimination, although the curly arrows we have to draw to represent this are rather tortuous!

Diazomethane will also methylate phenols because they too are acidic enough to protonate it. Ordinary alcohols, though, are not methylated because they are not strong enough acids to protonate diazomethane.

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قسم الشؤون الفكرية يبحث التعاون في مجال البحث مع كلية التقنيات المتعددة في نيجيريا

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مواضيع ذات صلة

Attack of carbenes on lone pairs

Nitrenes are the nitrogen analogues of carbenes

Rearrangement reactions

Insertion into C–H bondsInsertion into C–H bonds

Making cyclopropanes

Carbenes react with alkenes to give cyclopropanes

The structure of carbenes depends on how they are made

Carbenes can be divided into two types

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العناصر

Intramolecular radical reactions are more efficient than intermolecular ones

Alkyl radicals from boranes and oxygen