Benzocaine synthesis

Objective

To provide an example of multi-step synthesis (using protecting groups) by preparing an organic compound, benzocaine, that is present in many consumer products.

Background

Benzocaine (ethyl 4-aminobenzoate) is an anesthetic that is also used to relieve the pain of injuries and burns. Benzocaine is the derivative of p-aminobenzoic acid and can be synthesized via the Fischer esterification reaction. It can be prepared from p-toluidine by a four-step synthesis. The problem of a synthesis of this type is that the overall yield of the final product is usually quite low.

Experimental procedure

A) Synthesis of 4′-methylacetanilide: 

Place 4 g of p-toluidine in a 100 ml Erlenmeyer flask. Then, in a fume hood, add 10 ml of acetic anhydride and slowly stir. The reaction is highly exothermic. Allow the reaction mixture to stand for 10 min and then pour the reaction crude onto 50 ml of water/ice. If the reaction mixture crystallizes in the flask, drag the solid with a small amount of cold water. Stir the suspension of the product in water with a rod, and then collect the resulting solid by vacuum filtration. Keep the product  (4′-methylacetanilide or N-acetyl-p-toluidine) to carry out the next stage of the synthesis.

B) Synthesis of p-acetamidobenzoic acid:

In a 400 ml beaker place 4′-methylacetanilide (N-acetyl-p-toluidine), 200 ml of water, and an amount of 1.8 g KMnO₄ per gram of N -acetyl-p-toluidine. In a water bath with magnetic stirring, heat the mixture until it acquires a distinct brown (approximately 30 min). Vacuum filter the resulting hot solution. If the filtered solution has a violet color, add EtOH dropwise, and heat gently until the color disappears. When the filtrate is colorless or slightly yellow, allow to cool and acidify with H₂SO₄ (20%). Vacuum filter the resulting white solid.

C)  Synthesis of p-aminobenzoic acid hydrochloride:

Assemble the reflux in a flask of 100 ml and provide with a gas outlet to a trap with a diluted NaOH solution. Heat the flask for 30 min with a mixture of 2.5 g of p-acetamidobenzoic acid and 25 ml of HCl (conc.). Cool and collect the precipitate of p-aminobenzoic acid hydrochloride by vacuum filtration.

D)  Synthesis of benzocaine:

Into a 100 ml flask, mix 1.25 g of p-aminobenzoic acid hydrochloride, 10 ml of EtOH, and 0.5 ml H₂SO₄ (conc.). Heat the mixture at reflux for 2 h. After cooling the mixture, neutralize with an aqueous sodium carbonate solution (10%). Extract with CH₂Cl₂ (3 × 5 ml), dry the organic layer with anhydrous sodium sulfate, and evaporate in a rotary evaporator. Recrystallize the solid resulting from the EtOH/water.

Physico-chemical properties

This table collects data for the molecular weight (M_w), melting point (M.p.) boiling point (B.p.) and density of the reactives and compounds used in this laboratory experiment.

GHS pictograms

Hazard pictograms form part of the international Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and are collected in the followinf Table for the chemical compounds used in this experiment.

Name	GHS
4'-Methylacetanilide
Acetic anhydride
Benzocaine	Non-hazardous
CaCO3	Non-hazardous
CH2Cl2
EtOH
H2SO4
HCl
KMnO4
Na2SO4	Non-hazardous
NaOH
p-Acetamidobenzoic acid	Non-hazardous
p-Aminobenzoic acid
p-Aminobenzoic acid hydrochloride
p-Toluidine

International Chemical Identifier

The IUPAC InChI key identifiers for the main compounds used in this experiment are provided to facilitate the nomenclature and formulation of chemical compounds and the search for information on the Internet for these compounds.

References

• Isac-García, J.; Dobado, J. A.; Calvo-Flores, F. G.; and Martínez-García, H. (2015). Experimental Organic Chemistry Laboratory Manual. Elsevier Science & Technology. ISBN: 978-0-12-803893-2
• P. Demare and I. Regla, Synthesis of two local anesthetics from toluene: an organic mul- tistep synthesis in a project-oriented laboratory course, Journal of Chemical Education 89 (2012), no. 1, 147–149, DOI: 10.1021/ed100838a

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