Synthesis of ethyl salicylate using household chemicals

Abstract

The multistep synthesis of ethyl salicylate from aspirin tablets is discussed. The entire synthesis requires a minimum of two laboratory class periods.

Sally Solomon,(1) Chinhyu Hur, Alan Lee,(2) and Kurt Smith Drexel University, Philadelphia, PA 19104

This multistep organic synthesis of ethyl salicylate from aspirin tablets is intended as a laboratory activity to accompany introductory courses that devote time to topics in organic chemistry. The experiment is for high school or university students with sufficient background in organic chemistry to recognize the structures and reactions involved. At Drexel University this experiment is included in a general-chemistry sequence for science and engineering majors where topics in organic chemistry are covered.

Ethyl salicylate is synthesized, isolated, and characterized in a three-step process using simple equipment and household chemicals. The procedure can be done with a minimum of glassware, a hot plate, and a supply office. The entire synthesis requires a minimum of two laboratory class periods. The following steps are involved.

* Acetylsalicylic acid (ASA) is extracted from aspirin tablets with isopropyl alcohol.

* ASA is hydrolyzed to salicylic acid (SA) with muriatic acid.

* SA is esterified using ethanol and a boric acid catalyst.

Isolation of the ester product can be accomplished by treatment with lye solution (without saponification of the ester) to remove unreacted acid, followed by physical separation of the water-insoluble, pleasant-smelling oil of ethyl salicylate. The product is dried with dehydrated Epsom salts. For a class of 20, the table lists the chemicals; all are readily available in drugstores, supermarkets, hardware stores, or variety stores, so they require no special waste-disposal methods. The cost per pair of students is less than one dollar.

Procedure

Isolation of ASA from Aspirin Tablets

Caution: Although this experiment uses household materials, students should obey standard laboratory safety rules such as the wearing of safety glasses and careful handling of flammable liquids.

If only two lab periods are available, the second step, a hydrolysis, can be carried forth using wet product, allowing both isolation and hydrolysis to be finished in a single 2- or 3-h laboratory class. With this procedure the yield can only be estimated.

Aspirin tablets each contain 325 mg (5 gr) of ASA and about 50 mg of inactive starch and cellulose ingredients. Concentrated isopropyl alcohol (91%), is used to extract the ASA from the insoluble inactive ingredients. (Laboratory 100% isopropyl alcohol may be substituted for the 91% isopropyl alcohol, which is used to prepare skin for injection.) The procedure described below provides enough ASA to make 2-3 mL of the crude ester; half can be recovered.

Place 50 aspirin tablets and 50 mL of 91% isopropyl alcohol into a 250-mL Erlenmeyer flask or similar container. It is not necessary to crush the tablets, even if they are coated. Gently warm the flask on the low setting of a hot plate to keep the alcohol at a temperature below boiling. Swirl the flask and allow the extraction to proceed for 20 min or until the tablets have disintegrated. Into a 500-mL container, filter the mixture by gravity using either a basket-type coffee filter or laboratory filter paper. Wash the solid with 5-10 mL alcohol; then discard the filter paper and the small amount of starch and cellulose that remains. Add 250 mL of cold tap water to the alcohol filtrate. (All water used in this project came from the supply serving the City of Philadelphia.) The ASA immediately begins to crystallize. Cool in an ice bath for 5 min until crystallization is completed. Filter by gravity, using 5 mL water to wash the flask. Allow the ASA crystals to dry overnight. The yield should be about 12 g or 75% (1).

Hydrolysis of ASA with HCl(aq) To Produce SA

Caution: SA, the active ingredient in wart and corn removers, is irritating to the skin, and should be handled with gloves.

The time required is 1 h with overnight drying. The drying step is essential because the esterification step requires a dry reactant. The hydrolysis of ASA takes place so easily that the vinegary odor of acetic acid can sometimes be detected in an opened bottle of old aspirin tablets. The other hydrolysis product is SA.

The hydrolysis is conveniently carried out with 20% HCl, available in hardware stores as muriatic acid.

(Diagram omitted)

Before beginning the procedure below, reserve a small amount (about 0.5 g) of ASA product for characterization tests described later. If the ASA is wet, place in an open plastic vial to dry.

Add 10-12 g of the ASA product to 100 mL muriatic acid in a 250-mL flask. The hydrolysis requires about 30 min of gentle heating using the lowest setting of a hot plate that provides enough heat to maintain a temperature of about 50-60 degC (well below boiling). Swirl the reacting vessel periodically to mix the reactants: solid ASA and muriatic acid. (The solid ASA will not dissolve at these temperatures.)

When the hydrolysis nears completion, the vinegary odor of acetic acid develops, and the consistency of the reaction mixture changes so that the reaction mixture appears to thicken. Heat an additional 10 min. Remove from the hot plate and allow to cool. When the mixture is near room temperature, add 100 mL of cold water. Filter by gravity and wash the white solid SA several times with 5-10 mL cold water to remove the acetic acid. The product must be dried before the esterification. Typical yields are around 80% (giving about 7.5 to 8 g SA from 10 g ASA.).

A violet color may appear in the reaction vessel used for the hydrolysis because SA forms colored complexes with trace amounts of iron. (The tap water used at Drexel University in Philadelphia contains 0.050 to 0.060 mg iron/L.) This is the basis of one method that will be used to distinguish SA from ASA. Reserve 0.5 g SA for the characterization tests.

Esterification of SA with Ethanol

During the reflux, students can characterize the intermediates (ASA and SA) as described in the next section. (The required time is 2-3 h.) This procedure uses a simple refluxing apparatus made from an Erlenmeyer flask and a cold-finger condenser. The esterification step can be carried out using a round-bottom flask and condenser, if available.

The dried SA is esterified using an excess of 100% (200-proof) ethanol or denatured alcohol, and a boric acid catalyst (2), commercially available as an antifungal agent. Sulfuric acid, usually used to catalyze esterifications, is not readily accessible to everyone and is awkward to handle (3).

(Diagram omitted)

In a 250-mL Erlenmeyer flask, mix 6.0 g dry SA with 12 mL 100% ethanol and 2-3 boiling stones or chips from a porous plate (4). The ethanol is the excess reactant and should not be scaled down. Add approximately 0.5 g boric acid to the reaction mixture. Assemble a cold-finger condenser by using a large 8-in. test tube (25 mm x 200 mm). (Check to be sure that the 8-in. test tubes fits inside the 250-mL flasks because the sizes vary somewhat.) Wrap the test tube tightly with masking tape so that the tube stays suspended about halfway down into the flask, as shown in the figure. The taped tube should rest loosely on top of the flask to prevent a tight seal. In this way, the system is still open to the atmosphere, and pressure due to vapors within the flask will not build up.

Fill the test tube with ice chips. Because the ice melts in 5-10 min, it is convenient to have a second ice-filled test tube ready to make a quick exchange. Be sure that the surface of each cold test tube is dry before putting it into place so that water will not drip into the reaction mixture. Place the flask with condenser on a hot plate and heat until the ethanol is boiling. Do not allow the mixture to heat without the condenser in place or some of the ethanol will escape, causing the product to overheat and eventually decompose. Reflux for a minimum of 1.5 h. Although esterifying SA takes as long as 6 h of reflux time (5), reasonable yields can be obtained in 2 h. Starting with 6 g of SA, refluxing for 1 h gives less than 1 mL of ester product; 1.5 h gives 2-2.5 mL, and 2 h gives 2.5-3 mL.

Isolating the Ethyl Salicylate Product

Esters are often isolated by extracting with carbon tetrachloride, dichloromethane, or ether. Without using organic solvents, the ethyl salicylate, with a density greater than that of water, can be removed by carefully drawing off the upper aqueous layer using a syringe or pipet. (The time required is 1 h.)

Cool the flask to room temperature in an ice bath. Transfer the reaction mixture to a clean, large (8-in.) test tube. A separatory funnel may be used instead but is not required. Neutralize unreacted acid by adding 10 mL 2M NaOH made from mixing lye with water (2 g lye for every 25 mL water). The mixture turns milky as approximately 2-3 mL of ester (density 1.1 g/mL) appears as the bottom layer. Wait a few minutes until the cloudy emulsion begins to clear. Occasionally this takes as long as 15 min. Draw off the bulk of the upper aqueous layer carefully using a pipet or syringe. The last of the aqueous layer is removed more easily by transferring the contents to a smaller test tube.

The volume of ester can be estimated by pouring an equivalent amount of water into another test tube. Assuming as an example that 3.0 mL ester (molar mass 166) is produced from 6.0 g SA (0.043 mol), the yield calculation is

3.0 mL/0.043 mol x 1.1g/1 mL x 1 mol/166 g x 100% = 46%

Dry the ester with anhydrous magnesium sulfate, which can be easily prepared by weighing a sample of Epsom salts (MgSO sub 4 .7H sub 2 O) and then carefully heating until it loses about 25% of its mass. Use about one spatula tip of drying agent (roughly 0.2 g). Ethyl salicylate is a clear, oily liquid with an odor similar to that of methyl salicylate (wintergreen) but more delicate.

Characterizing Intermediates and Product

Several physical and chemical methods are available to characterize the ASA, SA, and ethyl salicylate.

Melting Points

If a melting-point apparatus is available, the melting points of ASA (134-135 degC) and SA (158-160 degC) can be measured using the dried samples reserved. Without specialized equipment, the two melting temperatures can still be compared. Separate pea-sized amounts of both solids are placed on a Petri dish and gradually heated on a hot plate. The ASA melts entirely before the SA begins to melt.

Formation of Colored Complexes

SA readily forms complexes with iron, but ASA does not (6). A pea-sized amount of each solid is placed in two different test tubes. To each is added 5 mL of tapwater and 5 mL of isopropyl rubbing alcohol (70%). A few staples (check to be sure they are magnetic) are put into each tube. A violet color will appear in the tube containing SA. Gentle heating by running hot water over the tube may be needed.

Acknowledgment

We want to thank Jia Wei for providing the NMR and IR on our final product and Michael Pence for supplying information about the Philadelphia water supply, We are also grateful for helpful conversations with Anthony Addison, Robert Hutchins, and Peter Wade, Finally, we wish to thank the Drexel University general-chemistry students who helped us to test and refine our procedure,

1 Author to whom correspondence should be addressed.

2 Supported by an Academy of Applied Science REAP grant.

Literature Cited

1. Ault, A. Techniques and Experiments for Organic Chemistry, 5th ed.; Allyn and Bacon: Boston, 1987; p 325.

2. Lowrance, W. W. Tetrahedron Letters 1971, 37, 3453-3454.

3. Doyle, M.; Plummer, B. F. J. Chem. Educ. 1993, 70, 493.

4. Brewster, R. Q.; VanderWerf, C. A.; McEwen, W. E. Unitized Experiments in Organic Chemistry; Van Nostrand: New York, 1977; p 28.

5. Most, Jr., F. Experimental Organic Chemistry; Wiley: New York, 1988; p 376.

6. Comprehensive Organometallic Chemistry; Pergamon, 1982; Chapter 15.7, p 461.