Aspirin Synthesis and Analysis

Purpose: Synthesize aspirin and determine the feasibility of the synthetic methodology using percent yield. The purity of the product is made by measuring melting point range.

Introduction Salicylic acid was a key component of medical treatment throughout history, dating back to the Greeks and their use of willow tree bark. Felix Hoffman, working for Friedrich Baeyer and Company in 1893, acetylated salicyclic acid and reduced the irritating side effects of salicylic acid and made one of history's most popular drugs commonly referred to as aspirin.

The acetyl group of aspirin is transferrable to enzymes such as prostaglandin synthase. Acetylation of prostaglandin synthase inhibits its cyclooxygenase activity, decreasing the synthesis of prostaglandins and reducing inflammation. Other effects of aspirin are still not fully understood and under investigation. Because of the lower pKa of benzoic acid group, aspirin exists as a water soluble salt in the intestial tract and allows for absorption into the bloodstream. This same acidity, when released from a slowly dissolving tablet does cause local irritation to the stomach lining. Therefore, many times aspirin is administered in powder form or as a buffered tablet.

Aspirin can be made by the acid catalyzed esterification of salicylic acid, a benzene ring substituted with both a carboxylic acid and an alcohol group. We will acetylate salicyclic acid using acetic anhydride, an acid anhydride, as shown in Figure 1. After synthesizing aspirin, we will analyze our product in a semiquantitative, melting temperature by DSC (a thermal analysis), its characteristic absorbance in UV light.

Safety Considerations: This experiment uses salicylic acid, acetic anhydride and phosphoric acid. The salicylic acid and aspirin may cause irritation to your skin or eyes, but are basically not hazardous. An excess of these can be disposed of in the sink or if packaged, in the trash. If you spill some, wipe it up with a wet paper towel and throw the towel in the trash. The acetic anhydride and phosphoric acid can cause bad burns. Use them in the hood. Be sure to wear gloves and safety goggles when using these chemicals. Excess chemicals must be disposed of in the plastic tub of water. This will convert the acetic anhydride to vinegar and dilute the phosphoric acid. If you spill a lot of either of these, notify your instructor.

Experimental This laboratory experience will be done in partners and is divided into 2 major parts, synthesis and analysis.

  1. Synthesis of acetylsalicylic acid (aspirin) from salicylic acid.
  2. Analysis of the product of the conversion.
  3. Differential scanning calorimetric determination of melting point
  4. FT-IR spectroscopy: structural analysis

Part I. Synthesis of Aspirin

  1. Weigh out 3.0 g of salicylic acid and place in a 250 ml Erlenmeyer flask.
  1. Measure out 6.0 ml of acetic anhydride and add this to your flask. Be sure to do this in the hood and wear your goggles. Don't let the acetic anhydride contact your skin and don't get the vapors in your eyes.
  1. Carefully add 5 to 10 drops of 85% phosphoric acid, a catalyst, to the flask and swirl to mix everything thoroughly.
  2. Still in the hood, heat the mixture for about 10 min. in a beaker of warm water (70-80 oC).
  1. After heating, cautiously add 20 drops of distilled water.
  2. Next add 20 ml of distilled water and cool in an ice bath. You can do this at your bench. If crystals do not appear, you can scratch the walls of the flask with a stirring rod to induce crystallization.
  3. Filter the solid aspirin through a piece of pre-weighed filter paper using a Buchner funnel and the aspirator. Wash the crystals with 2-3 ml of chilled water. The liquid is mostly water and can be washed down the sink. Allow the air to be drawn through the solid and filter paper for 15 minutes. Be sure to record the filter paper weight in your notebook.
  1. Place the filter paper with the product in a watch glass and put it in the oven at 100 oC for about 30 min. until dry.
  2. Put the dry aspirin and the filter paper into a pre-weighed plastic bag and weigh again.
  1. Calculate the weight of your product by subtracting the weight of the paper and bag from the total. The theoretical (maximum) yield is 3.9 grams of pure aspirin. What percent of this amount (3.9g) did you actually prepare? This is your percent yield. Record it in your notebook and turn in your product to the Stockroom.

Part II. Isolation and Purification:

Once the aspirin is prepared it must be isolated from the reaction solution and purified. The aspirin is insoluble in cold water, and can be isolated by filtering the chilled reaction solution. Purification is necessary to remove any unreacted salicylic acid and acetic anhydride, as well as the acetic acid product and phosphoric acid. Acetic anhydride is caused to decompose by the addition of water once the formation of aspirin is complete:

The acetic acid and phosphoric acid are water soluble and can be removed by washing the aspirin with chilled water. Salicylic acid is only slightly soluble in water and is not completely removed in the washing step. Final purification is accomplished by the process of recrystallization. The impure aspirin is dissolved in warm ethanol. The solution is then cooled slowly, and the aspirin crystallizes out of solution leaving the salicylic acid and other impurities behind.

Estimation of Purity: The melting point of a compound can be used to identify it and also to estimate its purity. Generally an impure compound will exhibit a melting point which is lower than that of the pure compound. Therefore, if your aspirin melts at a temperature below the accepted melting point two possibilities exist: either your product is impure or it is not aspirin. A pure substance will melt sharply over a range of 1 or 2 degrees celcius. That is, the temperature at which melting first occurs is only 1 or 2 degree less than the temperature at which the sample is completely melted. An impure compound will melt over a wider temperature range.

Part III. Characterizations on Aspirin

Invesitgation on the melting points: Measure the melting point range with the Differential Scanning Calorimetry. Compare your value to the actual melting point range for pure aspirin, 138-140oC.

FT-IR spectroscopic studies: compress the aspirin crystals with KBr into a pellet, measure the transmittance of it.

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