Experiment 3

Hydrolysis of Methylsalicylate and Synthesis of Acetylsalicylic Acid

Background

The experiment of composed of two parts.  The first involves the hydrolysis of methylsalicylate to produce salicylic acid (day 1).  This salicylic will then be used to prepared acetylsalicylic acid, which is aspirin (day 2). The aspirin must be very pure, so you will do a second purification of the aspirin on the third day.

Day 1: Hydrolysis of Methylsalicylate

Many esters have familiar odors. Methyl salicylate, an ester derived from the combination of salicylic acid and methanol, is also known as the oil of wintergreen. Methyl salicylate was first isolated in pure form in 1843 by extraction from wintergreen plant (Gaultheria). It was soon found that this compound had analgesic and antipyretic character almost identical to that of salicylic acid when taken internally. This medicinal effect probably results from the ease with which methyl salicylate is hydrolyzed to salicylic acid under the alkaline conditions found in the intestinal tract. Methyl salicylate can be taken internally or absorbed through the skin, hence its use in some liniment preparations. When applied to the skin, it produces a mild burning or soothing sensation, which is probably due to the action of its phenolic hydroxyl group. Methyl salicylate also has a pleasant odor, and it is used as an extract for flavoring purposes.

Esters can be hydrolyzed into their carboxylic acid and alcohol components under either acidic or basic conditions in the presence of heat. In this experiment, methyl salicylate, an ester also known as oil of wintergreen because of its natural source and odor, is treated with aqueous base and heated. Since, in our experiment, hydrolysis occurs in the presence of base (instead of acid), the carboxylic acid and phenolic -OH groups on salicylic acid are ionized and this compound exists as the sodium salt of salicylic acid, sodium salicylate. The reaction mixture is subsequently acidifed using sulfuric acid, which converts this anion into the fully protonated acid, salicylic acid. The alcohol is methanol. The salicylic acid, which is mostly insoluble, is a solid and can be isolated and purified by crystallization.

The chemical equation that describes this experiment is:

As mentioned above, the phenolic hydroxyl group, which is also acidic, would be ionized and exist as the sodium salt during the basic hydrolysis, just like the carboxylic acid group, but it is not shown ionized in this figure because we are concerned with the ester hydrolysis. As the following figure shows, the phenolic -OH, as well as the carboxylic acid group, will be protonated during the acidification step following the addition of the sulfuric acid.  The following figure shows what happens during acidification:

Procedure

Obtain 25 mL of freshly prepared 5 M NaOH (or, you can dissolve 5 g of sodium hydroxide pellets in 25 mL of water). To the NaOH (which should be room temperature) add 7.5 g (0.050 mol) of methyl salicylate (a liquid), in a 100-mL round-bottomed flask. A white solid may form, but it will dissolve when the mixture is heated.  Add 3-4 boiling stones to prevent bumping or uneven boiling.  Attach a reflux condenser to the flask and turn on the cooling water.  Heat the reaction mixture to boiling and maintain under reflux conditions for 20 minutes using a heating mantel.  Maintain a constant boiling mixture for the entire reflux time.

After the 20 min reflux, transfer the reaction mixture to a 125-mL beaker, and carefully added enough 3 M H2SO4 to make the solution acidic to litmus paper (blue litmus turns red). You may need to add more than 25 mL of 3 M sulfuric acid (for example, you will need more than 20 mL just to neutralize the NaOH used in the reaction).  Solid salicylic acid will form as the neutralization proceeds. After the litmus paper turns red, add about 3 mL more 3M sulfuric acid so that all the salicylic acid precipitates, and the mixture is acidic (too much acid is not a problem). Cool the mixture in an ice-water bath to about 0oC and allow the crystals to settle.  Collect the crystals by vacuum filtration, using a Büchner funnel and filter paper. The filtration can be conducted most easily by decanting off most of the supernatant liquid through the Büchner funnel before adding the mass of crystals. Carefully wash the beaker with ice cold water, if necessary, to transfer all the crystals to the funnel.

Allow the crystals to dry in the drying oven until the next lab period. When the crystals are thoroughly dry, weigh them and determine the percent yield, based on the amount of starting material (e.g., 1 mol methyl salicylate yields 1 mol salicylic acid). Determine the melting point of your purified salicylic acid (m.p. 159-160oC) and compare it to a sample of pure salicylic acid from the stockroom.

Day 2: Synthesis of Acetylsalicylic acid, Aspirin

Aspirin is a trade name for acetylsalicylic acid, a common analgesic.  Acetylsalicylic acid is an acetic acid ester derivative of salicylic acid. The earliest known uses of the drug can be traced back to the Greek physician Hippocrates in the fifth century B.C. He used powder extracted from the bark of willows to treat pain and reduce fever. Salicin, the parent of the salicylate drug family, was successfully isolated in 1829 from willow bark. Sodium salicylate, a predecessor to aspirin, was developed along with salicylic acid in 1875 as a pain reliever.  Sodium salicylate was not often popular though, as it has a habit of irritating the stomach. However, in 1897, a man named Felix Hoffman changed the face of medicine forever. Hoffman was a German chemist working for Bayer. He had been using the common pain reliever of the time, sodium salicylate, to treat his father's arthritis.  The sodium salicylate caused his father the same stomach trouble it caused other people, so Felix decided to try and concoct a less acidic formula. His work led to the synthesis of acetylsalicylic acid, or ASA. This soon became the pain killer of choice for physicians around the globe. Scientists never really understood the inner workings of the drug however. It wasn't until the 1970's, when British pharmacologist John Vane, Ph.D. began work on aspirin that people began to understand how aspirin really works. Vane and his colleagues found that aspirin inhibited the release of a hormone like substance called prostaglandin. This chemical regulates certain body functions, such as blood vessel elasticity and changing the functions of blood platelets. Thus can aspirin affect blood clotting and ease inflammation.

The reaction for synthesis of acetylsalicylic acid is shown in the following figure.  Salicylic acid, prepared from the hydrolysis of methylsalicylate is reacted with acetic anhydride producing the ester product, acetylsalicylic acid.

In a previous experiment, we have used the Fischer esterification reaction to produce isopentyl acetate from an acid (acetic acid) and an alcohol (isopentyl alcohol).  The current experiment uses another carboxylic acid derivative, acetic anhydride for ester formation.  The advantage of using acetic anhydride is that you do not produce water which can be used for hydrolysis of the newly formed ester.  Concentrated sulfuric acid will be used to keep everything in the protonated state.  Acetic anhydride is the preferred acid derivative to synthesize aspirin commercially because the acetic acid produced in this reaction (a reaction by-product) can be used again, by converting it back into acetic anhydride.

Procedure for the preparation of aspirin

If you recovered less than 3.5 g of salicylic acid, you will need to adjust the quantities of reagents used in this protocol.  However, if you recovered at least 3.5 g salicylic acid, use the quantities of reagents listed below (remember, if you recovered more than 3.5 g of salicylic acid, you can only use a maximum of 3.5 g in this experiment).  If you recovered less than 3.5 g salicylic acid, you will need to proportion the amounts of the other reagents for this reaction. 

Initiate the reaction.  Preheat 60-90 mL of water in a 400-mL beaker to boiling.   In a 125-mL Erlenmeyer flask, place about 3.5 g of salicylic acid (do no use more salicylic acid, even if you isolated more), 3.5 mL of acetic anhydride (density is 1.08 g/mL), and 4 or 5 drops of concentrated (18 M) sulfuric acid [or 85% phosphoric acid] to the mixture (some heat may be generated).  Heat the flask in a beaker of boiling water for five or six minutes.  Stir the mixture by gently swirling the flask.  During this time, the solid should dissolve completely.

Isolation of aspirin.  Remove the flask from the boiling water bath, and add 15 mL of ice water to it.  (The ice [water]decomposes the unreacted anhydride and keeps the mixture cool. Can you write the equation of this decomposition reaction?)  Thoroughly cool the flask to complete the initial crystallization (when a solution becomes cloudy, that is a solid and is the crystals).  If crystals are slow in forming, you may need to scratch the inside of the Erlenmeyer flask with a glass rod, which will speed up crystal formation by seeding, or initializing the formation of crystals.  After you do the following re-crystallization, collect the crystals by vacuum filtration and dry them until the next lab period in the drying oven.  You must determine your yield of dried aspirin and do a melt point analysis.

Before doing your re-crystallization, you should examine the solubility information presented below.  This solubility data is for your information, it does not describe how to do the re-crystallization, it just gives you solubility data. Apply this data, and your experience in doing re-crystallization experiments to devise a re-crystallization protocol for aspirin.

The Solubility of Aspirin: One gram of aspirin dissolves in the following solvents:

Caution: Aspirin decomposes in boiling water (therefore, do not boil the aspirin) or when dissolved in solutions of alkali hydroxides and carbonates. Inorganic salts of acetylsalicylic acid are soluble in water (especially the Calcium salt, but are decomposed quickly.

To do the re-crystallization you can follow the basic procedure listed below (similar to what we have done with other re-crystallizations).  An alternate method is also shown below.

An alternative re-crystallization procedure could include one of the following options:

  1. The purpose of re-crystallization is to get rid of contaminating chemicals, such as salts.  So, even if you do not fully dissolve all your aspirin, you could still effect a purification by adding a certain amount of water.  After adding some water (e.g., up to 100 mL water), heat the mixture up to 50-60oC and let as much aspirin dissolve as possible.  Then, cool the mixture and let the crystals form, even though not all the solid may have gone solution. This method effectively washes the crystals and lets the contaminants get diluted into the solvent.  After cooling, collect the crystals by vacuum filtration.
  2. You can take advantage of the high solubility in one solvent and the lower solubility in another.  For example, if your solid dissolves easily in ethanol, but not well in water (check the solubilities above), first dissolve your solid in as little ethanol as possible, perhaps at a slightly elevated temperature.  Then, add a large excess of water (e.g., 100 mL of water), and let your sample stand on ice for 10-15 min.  Collect the crystals as normal.

Analysis of product.  What is the yield of dry aspirin?  What is the percent yield?  What is the melt point?  (The crystals may have a wide melting range, from 125-138oC, because of potential of decomposition.  The use of a preheated melting point device (heated to about 110oC) will help to minimize this decomposition. Why do you think this could help prevent decomposition?)

Compound MW Amount Needed mmol mp bp Density ηD
Methyl salicylate  152.15 7.5 g (6.4 mL use pipettor) 49.3 110 220 1.174 ---
Salicylic acid  138.12 3.5 g 25.3 159 211 1.44 ---
Acetyl salicylic acid (aspirin)  180.16 --- --- 135 140 1.35 ---
Acetic anhydride  102.09 3.5 ml (use pipettor) --- -73.1 139.9 1.08 1.389

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Copyright © Donald L. Robertson (Modified: 03/05/2008)