Chapter 1.

Introduction

Benzocaine is the trade name for the local anesthetic known chemically as ethyl p-aminobenzoate, which is found in many creams and ointments used in the treatment of pain due to sunburn, minor burns, cuts, scrapes and insect bites. Benzocaine is structurally analogous to Cocaine, Lidocaine, and Novocaine (shown below) and is prepared by the esterification of p-aminobenzoic acid with ethanol.¹ Esterification reactions can be significantly influenced by the concentration of starting materials and products in solution, as explained by Le Châtelier’s Principle.

1. Salkowski, Ber. 1895, 28, 1921 and Adams and Cohen, Org. Syn. Coll. Vol. I, 2^nd ed., 1932, p. 240

Reaction

Lab Objective

This is a group experiment. You will work in a small group to design and carry out experiments in an attempt to answer one of the focus questions. Your objective is to form and test a hypothesis in response to the focus question. The general procedure is provided and should be adapted appropriately. Before lab discuss your focus question with your small group and answer the questions found on the group experimental design sheet, which is provided in the resources folder on CTools.

Focus Question

Choose one of the focus questions below:

Question 1: Can the concentration of para-aminobenzoic acid be increased, rather than ethanol, to increase the yield of benzocaine product obtained from the reaction?

Question 2: Will the reaction work if a sterically bulky alcohol, such as isopropanol or tert-butanol, is used rather than ethanol in the esterification reaction?

Creativity is encouraged. If you have a different idea for a focus question please discuss it with your GSI before proceeding.

Procedure

Place 0.360 g of p-aminobenzoic acid and 3.60 mL of ethanol in a 10-mL conical flask. Add a magnetic spin vane and stir the mixture to dissolve the solid acid. While stirring, add 0.30 mL of concentrated sulfuric acid dropwise (CAUTION! sulfuric acid reacts violently with water, is a corrosive, and causes severe burns). Addition of sulfuric acid causes precipitation of the hydrogen sulfate salt of p-aminobenzoic acid, however this precipitate will dissolve during the following reflux period as the hydrogen sulfate salt of the acid is converted into the hydrogen sulfate salt of the ester. Check the acidity using pH paper to ensure that the reaction mixture is acidic. To prepare for reflux, attach a water-cooled condenser and heat the mixture so that it boils gently for 60–75 minutes.

When the reaction is complete, remove the reaction apparatus from the heat and allow it to cool. Using a Pasteur pipet, transfer the solution to a small Erlenmeyer flask containing about 3 mL of water. The reaction mixture should dissolve completely in the water, since the ethyl p-aminobenzoate is in the form of the hydrogen salt. After the solution has cooled to room temperature, add the 10% sodium carbonate solution dropwise to neutralize the cooled reaction mixture. As the pH of the solution rises, carbon dioxide will be produced and evolve as gas bubbles out of the solution. Continue to add the sodium carbonate until the gas evolution ceases and the pH is above 8. At this point, the sulfuric acid is completely neutralized, and the ethyl p-aminobenozate precipitates.

Collect the precipitated crude ethyl p-aminobenzoate by vacuum filtration using a Hirsch funnel. Use additional portions of water to aid in transferring the crystals to the funnel and wash the crystals with water on the funnel. Dry the cyrstals overnight and determine the melting point. Pure Benzocaine melts at 92 °C (here you can save a small sample to dry overnight for determination of the melting point and proceed with recrystallization of the bulk of the sample immediately). The crude benzocaine product can be recrystallized from a mixture of ethanol and water. Note a modification of fthe purification procedure may be necessary when isopropanol and tertbutanol are used rather than ethonol in the esterfication reaction as the expected products will exhibit slightly different solubility than benzocaine.

Techniques

Reagents