Methyl-Ester Protection and Deprotection-百灵威

Carboxylic acids can be protected by conversion to a methyl ester using diazomethane. The diazomethane abstracts a proton to make a carboxylate, which undergoes an S_N2 reaction with the methyldiazonium ion, releasing nitrogen gas to form the ester.

The carboxylic acid is regenerated when hydroxide attacks the carbonyl to release methoxide.

Lab Tips:

The main drawback to methyl-ester protection is the toxicity of diazomethane. One possible alternative is to use alkyltriazene instead ^[1], which is readily prepared from primary amines and aryldiazonium salts. ^[2]
The carboxylic acid can also be regenerated under acidic conditions (pH < 1). ^[3]

_{1. White, E. H., Maskill, H., Woodcock, D. J. Schroeder, M.A. Carbonium ions formed in the triazene method of deamination. Tetrahedron Lett. 1969, 1713.
2. White, E. H., Scherrer, H. The triazene method for the deamination of aliphatic amines. Tetrahedron Lett. 1961, 758.
3. Wuts, P. G. M. (2014). Greene’s Protective Groups in Organic Synthesis (5th ed.). Hoboken, New Jersey: John Wiley & Sons.}

Protection

Reactant: Carboxylic Acid, Diazomethane
Product: Ester
Type of Reaction: S_N2
Bond Formation: O=C-O-Me

Deprotection

Reagents: Base (Alkali Metal Hydroxides, Carbonates), Aqueous/Organic Solvent Mixture (H₂O, MeOH, THF, Dioxane)
Reactant: Ester
Product: Carboxylic Acid
Type of Reaction: Ester Hydrolysis
Bond Formation: O=C-OH