Synthesis of benzocaine from toluene
Here is the synthetic route with more detailed reaction conditions:
The second step in the synthetic route is the oxidation of p-nitrotoluene to p-nitrobenzoic acid. There are many reactions which would be suitable for this benzylic oxidation. In the condition shown, the reaction is done using oxygen gas and acetic acid as the solvent with catalytic cobalt acetate and potassium bromide .
Next, the p-nitrobenzoic acid is esterified with ethanol by Fischer esterification to ethyl p-nitrobenzoate . This reaction is conducted in refluxing ethanol with catalytic sulfuric acid. Toluene is added as a cosolvent to improve solubility. Here is an arrow-pushing mechanism for this Fischer esterification:
The final reaction in this route is reduction of the nitro group of ethyl p-nitrobenzoate to an amine, giving the desired benzocaine. This can be accomplished by palladium on carbon-catalyzed hydrogenation .
Synthesis of benzocaine from p-xylene
The p-xylene route with detailed reaction conditions follows:
Here is an arrow-pushing mechanism for ammonolysis of the methyl ester:
In the next synthetic step, a Hoffmann rearrangement is used to convert the primary amide into an arylamine. The reaction uses stoichiometric sodium hypochlorite (bleach) and excess sodium hydroxide under aqueous conditions . An arrow-pushing diagram for the rearrangement is shown below:
The final reaction is another Fischer esterification of the p-aminobenzoic acid with ethanol and catalytic sulfuric acid, giving benzocaine. Though the aryl amine is nucleophilic, the acidic conditions and large excess of ethanol supress formation of amide side product.