13.13: Carboxylic Acids to Methylesters: Alkylation using Diazomethane

Carboxylic acids react with diazomethane in an ether solvent via alkylation at the carboxylate oxygen atom to give methyl esters of the corresponding acid with excellent yields.

Diazomethane is a yellow gas having a boiling point of −23 °C. It is conveniently prepared by the action of a base on N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulphonamide.

The esterification mechanism involves the protonation of diazomethane by the carboxylic acid to yield a carboxylate salt and methyldiazonium cation. The methyldiazonium cation is highly unstable due to the presence of N≡N, which functions as an excellent leaving group.

In the final alkylation step, an S_N2 attack on the methyldiazonium ion by the carboxylate anion produces a methyl ester, along with the elimination of N₂ gas.

However, diazomethane is a potentially explosive gas and requires precautions during its handling and storage. It undergoes spontaneous detonation upon contact with rough or scratched surfaces. Therefore, flame-polished glassware and a blast shield are often recommended in reactions involving diazomethane. Moreover, diazomethane is highly toxic as well as carcinogenic.

Diazomethane decomposes in the presence of heat or light to generate carbenes and eliminate nitrogen.

Carboxylic acids, upon treatment with diazomethane, undergo alkylation to yield methyl esters.

Diazomethane, a yellow-colored gas generated from precursors such as N-methyl-N-nitrosourea and a base, is a resonance hybrid of three dipolar structures.

Mechanistically, diazomethane is protonated by carboxylic acid to generate a carboxylate anion and a methyldiazonium cation.

The methyldiazonium cation is an extremely unstable species bearing dinitrogen–an excellent leaving group.

Next, the nucleophilic carboxylate anion attacks the methyldiazonium cation via an S_N2 mechanism to yield methyl esters with the simultaneous release of nitrogen gas.

Notice that the esterification proceeds via the nucleophilic carboxylate oxygen of the carboxylic acid. In contrast, acid-catalyzed Fischer esterification involves an electrophilic carbonyl carbon that eventually reacts with the nucleophilic alkoxy group of alcohol.

One of the applications of alkylation by diazomethane is to detect cocaine in a urine sample. Here, benzoylecgonine –a urinary metabolite of cocaine, is converted to a more suitable methyl ester to be detected by mass spectrometry analysis.

Methyl ester formation – Carboxylic acids react with diazomethane to form methyl esters. Diazomethane – A yellow, explosive, carcinogenic gas used for esterification. SN2 alkylation – Carboxylate ion attacks methyldiazonium to form ester and release N₂. Methyldiazonium ion – Unstable intermediate with N≡N as a leaving group. Safety precautions – Diazomethane must be handled with flame-polished glassware and a blast shield.

Define the Reaction – Describe how diazomethane reacts with carboxylic acids to form esters (e.g., methyl ester) Identify Key Intermediates – Recognize the role of methyldiazonium and carboxylate in the mechanism (e.g., methyldiazonium) Explain Product Formation – Show SN2 attack yields methyl ester and N₂ elimination (e.g., SN2) Explain Mechanism or Process – Outline proton transfer, ion formation, and nucleophilic attack Apply in Context – Handle diazomethane with care due to its toxicity, explosiveness, and carcinogenic nature

What is the role of methanol in diazomethane-based methyl ester formation? How does SN2 alkylation with diazomethane produce methyl esters from carboxylic acids? What safety precautions are necessary when using diazomethane for ester synthesis?

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