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Aspirin Synthesis

By Laura Burns '13

Organic Chemistry II

Students were to select a method to synthesize aspirin to test. After performing the synthesis, they were to write a formal lab report explaining their process and findings. The reason I chose Laura’s paper over some of the others in the class was twofold. For one, she had a very well-researched and detailed introduction and background that went well beyond the scope of the assignment. It really helped put the synthesis into context. Additionally, despite the fact that there were struggles during the synthesis, she was meticulous about giving detail. In the scientific world, this detail would help other scientists look at her work and overcome the challenges.

-James Shriver

Introduction

For centuries, willow and myrtle trees have been a known source of salicin. Ancient medicine recognized the herbal origins of salicin as a successful way to treat pain, inflammation, and fever. Babylonian and Assyrian civilizations were among the first to use willow bark to relieve pain. In 1300 BC, the Egyptians treated inflammation with willow leaves. Following in the footsteps of the Egyptians, the Chinese treated rheumatic fever, colds, hemorrhages, and goiter with extracts from willow and poplar tree bark. The Greek philosopher Hippocrates recommended women to drink a concoction containing willow leaves to reduce the pain of childbirth. A Greek physician named Dioscorides prescribed willow bark to patients to relieve the symptoms of inflammation in 100 AD.1

The healing effects of willow extracts were first introduced into the modern era in the mid-1700s by Reverend Edward Stone. Stone composed a letter to the Royal Society of London that described how powdered willow bark reduced fever. This letter was inspired by the Doctrine of Signatures, a document stating that the environment of plants offers clues to the types of illnesses the plants might remedy. For example, willow trees grow in moist soil, and moist soil is associated with fever.2 In 1876, the Scottish physician Thomas MacLagan conducted an investigation of willow powder and its effectiveness in treating inflammation and fever. The results of his study indicate that willow powder will completely reduce both fever and joint inflammation. The substance in willow bark that is responsible for relieving pain and fever is salicin. The French pharmacist Henri Leroux crystallized a pure form of this yellow substance in 1829. Salicin was oxidized to form salicylic acid in early 1835 by the German chemist Lowig.3 Hermann Kolbe developed a more economical and efficient method to synthesize salicylic acid in 1873 from phenol and sodium hydroxide. After partnership with Friedrich von Heyden, Kolbe established a factory to produce large quantities of salicylic acid using this method. Kolbe also discovered that salicylic acid could be used as both a food preservative and an antiseptic. However, Joseph Lister had already popularized a more potent as well as less expensive antiseptic known as carbolic acid. Although salicylic acid was not the most widely used antiseptic of the time, it did become an important intermediate in the production of other pharmaceuticals, dye, and perfumes. It was not until after the death of Hermann Kolbe that salicylic acid was used in the manufacturing process of aspirin.4

Felix Hoffmann was credited with the first synthesis of aspirin during his employment at Bayer Company. Hoffmann’s father suffered from rheumatoid arthritis, a condition often treated with salicylic acid. After several doses of salicylic acid, his father’s stomach became too irritated to continue the use of the medicine. Hoffmann hypothesized that salicylic acid would be tolerable if it were more soluble in stomach acid. To achieve this more soluble form, Hoffmann replaced the hydrogen from the hydroxy group on the benzene ring of salicylic acid with an acetyl group. This resulted in acetylsalicylic acid. The director of pharmacologic research at Bayer renamed the compound to aspirin in 1899 because it was difficult to pronounce under the chemical name. The ‘a’ in aspirin comes from acetyl, and the latter part of the word ‘spirin’ is from a historical term associated with the components of willow bark.5 It is worth noting that Arthur Eichengrun became employed by F. Bayer and Company in October 1896. Under his direction, Felix Hoffmann synthesized acetylsalicylic acid on August 10, 1897. Eichengrun never received full credit for his work in the discovery of aspirin because a footnote in an encyclopedia published in Nazi Germany in 1943 only gave credit to Hoffmann. Eichengrun was Jewish, and he could not speak out to refute the footnote. Eichengrun sent a letter from the Theriesentadt concentration camp to the management of the incorporated F. Bayer and Company. This letter detailed Eichengrun’s contributions to the synthesis of aspirin. Despite this letter, most authorities still did not recognize Eichengrun as a partner in the discovery of the drug.6 Aspirin was available without a prescription to the public in 1915.7

Sir John Vane discovered how aspirin works in the body while researching at the Royal College of Surgeons of England in 1971.8 According to the Journal of Chemical Education staff, aspirin relieves pain in the peripheral parts of the body by inhibiting the synthesis of prostaglandins. Healthy tissues have a certain normal concentration level of these hormones. When a tissue becomes damaged, it synthesizes more prostaglandins. A higher concentration of prostaglandins in the damaged tissue results in a sensation of pain. Aspirin inactivates enzymes that are essential in prostaglandin synthesis; therefore, it decreases pain by reducing the sensitivity of the damaged tissue to pain stimuli. The role of aspirin in reducing inflammation is not known with certainty. Prostaglandins synthesized by bacterial toxins in the hypothalamus increase body temperature. Aspirin is an antipyretic because it reduces the amount of prostaglandins that result from bacterial toxins in the hypothalamus.9

Experimental Procedure

The synthetic scheme for aspirin is indicated above. We began by weighing out 0.529 grams of salicylic acid on a balance and placng it into a 50 mL Erlenmeyer flask. Using a 2.5 mL syringe, my partner, Kelsey, added one mL of acetic anhydride to the flask. I added two drops of phosphoric acid catalyst to the reaction flask with a plastic pipette. I carefully swirled the flask to completely mix the contents. We heated the flask over a 250 mL beaker of hot water for about ten minutes to approximately 70-80 degrees Celsius. We added four drops of de-ionized water from the plastic bottle in the lab. I measured 3 mL of de-ionized water in a 4.5 mL reaction tube and added it to the 50 mL Erlenmeyer flask. We placed the Erlenmeyer flask into a 250 mL beaker filled with ice. The flask cooled in the ice bath for 16 minutes and crystals formed. We connected the Hirsch funnel to the water aspirator located in the hood and crystals were collected via filtration. Kelsey added a small amount of de-ionized water to wash the crystals out of the flask. The crystals were allowed to dry on the Hirsch funnel for an additional 15 minutes. We placed a small amount of the crude product into a pre-weighed vial (2.404 grams) for future analysis. Kelsey labeled the vial and covered it with a watch glass to dry for a week. The contents in this vial will be used to take a melting point of the crude sample.

The remainder of the crude product into a different 50 mL Erlenmeyer flask with a spatula. Kelsey measured 2 ml of ethanol in a 4.5 mL reaction tube and added it to the 50 mL Erlenmeyer flask. We dipped the flask in a 250 mL beaker of warm water to dissolve the crystals. This only took a few seconds and no additional ethanol was needed to fully dissolve the crystals. Next, I measured 3 mL of warm de-ionized water into a 4.5 mL reaction tube and added it to the Erlenmeyer flask. We covered the flask with a watch glass and set it on the table to cool to room temperature for 18 minutes. Since no crystals had formed, Dr. Shriver tried to induce crystallization by using a spatula to scratch the inside of the flask. No crystals formed, so we placed the Erlenmeyer flask in another 250 mL beaker with ice for six minutes. The contents of the Erlenmeyer flask were milky, and crystals were not forming. Dr. Shriver reheated the flask over the hot water bath. We let it re-acclimate to room temperature. Dr. Shriver tried to induce crystals to form by adding some aspirin crystals from another lab group to the flask. He placed the flask on top of the ice in the 250 mL beaker. After a few minutes, more crystals formed than in the previous attempt, but there were still not enough crystals to collect in a funnel. Dr. Shriver again re-heated the flask over the hot water bath and added a few drops of de-ionized water to the flask. We allowed the flask to cool to room temperature for several minutes. At first, the contents of the flask continued to cloud up rather than form crystals. Once crystallization began, a large amount of crystals formed. We filtered the crystals using a Hirsch funnel as before. We placed the pure product in a pre-weighed vial (2.395 grams). We placed the vial in my drawer and covered it with a watch glass to dry for a week. The crystals looked small and white. The following week we weighed both vials containing the pure and crude crystals to calculate a percent yield. We also used the melting point apparatus to obtain a melting point for both the crude and pure crystals. We increased the temperature on the melting point apparatus 5-10 volts at a time. Finally, we took an IR of the pure crystals. This procedure was adapted from The Synthesis of Aspirin.10

Discussion and Conclusion

The IR spectrum confirms the formation of aspirin as the product. The IR spectrum is appended. The absorption at 1750.1 cm-1 indicates the carbonyl stretch of the ester. A second absorption at 1684.0 cm-1 indicates the carbonyl stretch of a benzoic acid derivative. There is also absorption consistent with a hydroxyl group, indicating consumption of salicylic acid. A broad carboxylic acid absorption appears between 2588.7 cm-1 and 3000 cm-1. The melting point of the pure crystals was 133-134 degrees Celsius. The melting point of the crude crystals was 122-123 degrees Celsius. Our procedure stated that the melting point of pure aspirin is 138-140 degrees Celsius.11 This suggests that the pure crystals still contained some impurities. One possible reason for this impurity is that we had difficulty recrystallizing the crude product. We added too much ethanol to dissolve the crude product. Our calculation of the amount of ethanol needed could have been overestimated because we had to scale the procedure down to one sixth of the original amounts of chemicals. During recrystallization, the contents of the flask continued to cloud up, and crystals would not form. There was a small amount of clear recrystallization in the flask despite the persistent cloudiness. This suggests that there was a small amount of starting material in the flask. The cloudiness could have been caused by this impurity. The percent yield of this reaction was 44.9 percent. One contributing factor for the low yield is that some crystals were lost during the filtration process. There was also a small amount of crystals lost when the crude product was transferred to the new 50 mL Erlenmeyer flask. Another source of error is that we may not have heated the flask for a long enough time period to allow the reaction to proceed to completion. This could be why a small amount of starting material was in the flask during recrystallization.

Future Directions

Recent research has indicated that aspirin has the potential to protect against specific types of cancer, such as colorectal cancer. Aspirin has been shown to stimulate apoptosis and protect cells from oxidative damage. Several studies have shown that aspirin has impeded cell division in human colorectal tumor cells, gastric cancer cells, myeloid leukemia cell lines, and vascular smooth muscle cells.12 Perhaps aspirin could be used to prevent the re-occurrence of breast cancer in the future.

Works Cited

  1. J.G. Mahdi, A.J. Mahdi, and I.D. Bowen, “The Historical Analysis of Aspirin Discovery, its Relation to the Willow Tree and Antiproliferative and Anticancer Potential,” Cell Proliferation 39, no. 2 (2006): 148, http://proxy.central.edu:2273/ehost.
  2. Aalok Mehta, “Aspirin,” Chemical Engineering News 83, no. 25 (2005): 47.
  3. Mahdi, Mahdi, and Bowen, “The Historical Analysis of Aspirin Discovery,” 149.
  4. Alan J. Rocke, “ From Kolbe, Hermann,” in New Dictionary of Scientific Biography vol. 4, ed. Noretta Koertge (Missouri: Gale Group, 2008), 149-150.
  5. Journal of Chemical Education Staff, “Medicinal Chemistry of Aspirin and Related Drugs,” Journal of Chemical Education 56, no. 5 (1979): 332.
  6. Walter Sneader, “ From Eichengrun, Arthur,” in New Dictionary of Scientific Biography vol. 2, ed. Noretta Koertge (Missouri: Gale Group, 2008), 358-359.
  7. Mahdi, Mahdi, and Bowen, “The Historical Analysis of Aspirin Discovery,” 149.
  8. Mehta, “Aspirin,” 46.
  9. Journal of Chemical Education Staff, “Medicinal Chemistry of Aspirin,” 332-333.
  10. California State University Stanislaus, The Synthesis of Aspirin, https://chem.csustan.edu/consumer/aspirincons/aspirincons.htm.
  11. California State University Stanislaus, The Synthesis of Aspirin.
  12. Mahdi, Mahdi, and Bowen, “The Historical Analysis of Aspirin Discovery,” 151.