Synthesis of Acetylsalicylic Acid (Aspirin)

Synthesis of Acetylsalicylic Acid (Aspirin) Jamie Yeadon Shannon Land Leah Monroe April 24, 2003

Organic Chemistry Lab II Experiment performed on April 15 and 17, 2003

Abstract:
The purpose of this experiment was to synthesize acetylsalicylic acid via an esterification reaction between salicylic acid and acetic anhydride. The product was recrystallized using 95% ethanol. This percent yield of this synthesized product was 68.4%. Using ethanol again as a recrystallizing solvent, acetylsalicylic acid was also extracted from commercial aspirin tablets. This commercial product did not have a percent yield, because there was no need for it to be calculated. Both products were then analyzed via infrared spectroscopy, nuclear magnetic resonance spectroscopy, ultraviolet light visible spectroscopy, and melting point analysis. The melting point of the synthesized aspirin was 128 - 130C. The melting point of the commercial product was 127 -136C, compared with a literature value of 128 - 137C. All three values were relatively close, indicating that both products were acetylsalicylic acid. The melting point of the commercial product was lower and broader due to impurities in the product. Analysis of the infrared spectra, NMR spectra, and UV spectra of both products also indicated that they were both acetylsalicylic acid and that the reaction was successful.

Synthesis of Acetylsalicylic Acid (Aspirin) Introduction: The purpose of this experiment is to synthesize acetylsalicylic acid via an esterification
reaction between salicylic acid and acetic anhydride. The product will be recrystallized using 95% ethanol. The product will then be analyzed via infrared spectroscopy, nuclear magnetic resonance spectroscopy, ultraviolet light visible spectroscopy, and melting point analysis. It will then be compared with the IR, NMR, and UV spectra and melting point of acetylsalicylic acid isolated from commercial aspirin.

Materials Used:
400-mL filter flask Bchner funnel 400-mL beaker hot plate heavy walled tubing watch glass microspatula Pasteur pipet 125-mL Erlenmeyer flask glass stirring rod 250-mL beaker filter paper mortar & pestle

Reagents and Properties:

Substances Formula Amount Weight, Used g/mol Moles Used Mole Ratio Melting Point C Boiling Point C Density g/mL

Salicylic acid Acetic Anhydride Concentrated H2SO4 95% ethanol Acetylsalicylic acid

138.12 102.09 98.1 46.07 180.16

3.5 g 3.5 mL
4-5 drops ~0.2 mL

0.02534 0.0371
3.753 x 10
-3

1 to 1 1 to 1 N/A N/A 1 to 1

159 N/A N/A N/A 135

N/A 139.5 327 78.5 N/A

1.443 1.0820 1.841 0.791 N/A

8.0 mL product

0.8319 N/A

Reaction:
COOH O O O C CH3
H2SO4

O O C CH3 CH3 C

+
OH Salicylic Acid

+
COOH Acetylsalicylic Acid (Aspirin)

CH3COOH Acetic Acid

Acetic Anhydride

Mechanism: The limiting reagent for this reaction is salicylic acid. Please see calculations section for explanation.
COOH H O Salicylic Acid .. .. O C CH3 Acetic Anhydride COOH OH CH3 O Acetylsalicylic Acid (Aspirin) C O O CH3 C O COOH H O .. CH3 C O C CH3 O O
-

COOH -H+ O CH3 C O C CH3 O O-

C CH3

Acetic Acid

Synthesis of Acetylsalicylic Acid (Aspirin) Procedure:

Part 1 Synthesizing Acetylsalicylic Acid Pre-heat 100 mL water in a 200-mL beaker. To do this, place the beaker with water on a hot plate and heat to boiling. Measure 3.5 g salicylic acid. Measure 3.5 mL acetic anhydride. Mix the salicylic acid and acetic anhydride in a 125-mL Erlenmeyer flask. Add 5 drops concentrated sulfuric acid to the flask. Heat the flask by placing it in the beaker of boiling water. Stir the solution in the flask occasionally with a glass stirring rod. Continue until everything in flask goes into solution (approximately 6-8 minutes). Remove flask from beaker. Add 15 mL ice cold distilled water to the flask. Then, allow flask to cool completely for crystallization to occur. If necessary, scratch the flask with a glass stirring rod to induce crystallization. Then, collect the crystals via suction filtration and a Bchner funnel. Transfer crystals into a clean, dry 125-mL Erlenmeyer flask using a microspatula. Add 4 mL 95% ethanol. Stir, then heat in the hot water bath until the crystals go into solution. Then, add 20 mL hot distilled water to the flask and heat flask again until solution is clear. Remove flask from beaker and cover it loosely with a watchglass. Allow flask to cool. Once tiny crystals can be seen forming in the solution, place flask in an ice bath. Allow crystallization to complete. Then, collect the crystals again via suction filtration using a Bchner funnel. Spread crystals on a watch glass and allow to dry for a couple days. Part 2 Extraction of Acetylsalicylic Acid from Commercial Aspirin Tablet Crush four commercial aspirin tablets (325 mg each) using a mortar and pestle. Place crushed tablets into a 125-mL Erlenmeyer flask. Add 4 mL 95% ethanol. Heat until contents go into solution. Allow flask to cool. Once tiny crystals can be seen forming in the solution, place flask in an ice bath. Allow crystallization to complete. Then, collect crystals via suction filtration using a Bchner funnel. Part 3 Analysis Melting Points, IR, NMR, UV Visible Spectrum Make two melting point capillaries. One contains the product from Part 1, another contains the product from Part 2. Take melting points of both products. Perform an infrared spectrum on both products. For the product from Part 1, add 100 mg KBR to approximately 1 mg of the respective product. Mix the two using a mortar and pestle, being sure to grind the two compounds into a fine powder. Place some of this mixture in a microcup, making sure the surface is smooth. Then place the pellet in the infrared spectrometer and obtain an infrared spectrum of the product. Repeat for the product from Part 2, and obtain an infrared spectrum of this product as well. Perform an NMR spectrum on both products. For each different product, take 20-40 mg of the respective products, and dissolve it in 0.7 0.9 mL of chloroform in an NMR tube. Place the NMR tube in the NMR spectrometer and obtain an infrared spectrum of each product using TMS as a reference point. Perform a UV Visible spectrum on both product. For the synthesized product from part 1, prepare an 0.1 M solution in a 10-mL volumetric flask. This is done by measuring approximately 20 mg of the product into the flask, then adding enough 95% ethanol to make 10 mL of solution. Fill a UV visible spectrum cuvette with the solution, then run the spectrum. If the spectrum doesnt turn out and the solution is still too concentrated, use a Pasteur pipet to remove 1 mL of the solution and place into a different 10-mL volumetric flask. Again, add enough 95% ethanol to make 10 mL of solution. Then, run the spectrum again. Repeat for the extraction product from part 2. Compare results of each different test between products.

Synthesis of Acetylsalicylic Acid (Aspirin) Data and Calculations:

Mass salicylic acid used: 3.501 g Mass crystals: 3.123 g Theoretical Yield: 4.565 g Percent Yield: 68.4% Observed melting point of synthesized product: 128 - 130C Observed melting point of commercial product: 127 -136C Literature value: 128 - 137C Finding Limiting Reagent Salicylic acid (3.5 g SA) (1 mol SA) (1 mol product) (180.16 g product) (138.12 g SA) (1 mol SA) (1 mol product) = 4.565 g acetylsalicylic acid Acetic Anhydride
(3.5 mL AA) (1.0820 g AA) (1 mol AA) (1 mol product) (180.16 g product) (1 mL AA) (102.9 g AA) (1 mol AA) (1 mol product)

= 6.684 g acetylsalicylic acid The limiting reagent for this reaction is salicylic acid. It yields the least amount of acetylsalicylic acid in this reaction, and therefore is the limiting reagent. Theoretical Yield Salicylic acid (3.5 g SA) (1 mol SA) (1 mol product) (180.16 g product) (138.12 g SA) (1 mol SA) (1 mol product) = 4.565 g acetylsalicylic acid

Percent Yield
(mass of acetylsalicylic acid crystals) (theoretical yield) (3.123 g acetylsalicylic acid) (4.565 g acetylsalicylic acid) x (100) =

=68.40% yield

IR Data and Interpretation:

An infrared spectrum of the product from part 1 indicated that the product was acetylsalicylic acid, as was predicted. The peak at 1605.75 cm-1 represents a benzene ring and the peak at 3016.31cm-1 indicates the presence of aromatic C-H bonds . The strong, broad peak that stretches from 2500 3100 cm-1 indicates the presence of a carboxylic acid. A peak at 755.53 cm-1 also represents an orthosubstituted benzene, which is what our product is. Overall, all these peaks combined indicate that the product is indeed acetylsalicylic acid. When compared with the library on the computer, acetylsalicylic acid was found to be a match of 86.92%. An infrared spectrum of the product from part 2 indicated that the product was acetylsalicylic acid, as was expected. The peak at 1605.67 cm-1 represents a benzene ring. The strong, broad peak that stretches from 2500 3100 cm-1 indicates the presence of a carboxylic acid. A peak at 755.88 cm-1 also represents an ortho-substituted benzene, which is what our product is. Overall, all these peaks combined indicate that the product is indeed acetylsalicylic acid. When compared with the library on the computer, acetylsalicylic acid was found to be a match of 87.68%. When the spectrum of our synthesized product was compared with the extraction product from the commercial aspirin, the two spectra were almost exactly alike, especially in the fingerprint region. This indicated that the two products were identical and were both acetylsalicylic acid.

Synthesis of Acetylsalicylic Acid (Aspirin) NMR Data and Interpretation:

Analysis of NMR spectra of the commercial product and the synthesized product revealed that they were both acetylsalicylic acid. Both spectra were compared with the NMR spectrum of acetylsalicylic acid from the Aldrich Library of NMR Spectra, and were found to be very similar, indicating that both products were acetylsalicylic acid. On the NMR spectrum of the commercial product, the singlet located at approximately 1.7 is from the CH3 (methyl) group on the product. The peak from the COOH (carboxylic acid) group is not visible on the spectrum and, should we have expanded the spectrum, would be located at approximately 11 - 12 . The signal that occurs the furthest upfield is from the hydrogen atom on the benzene ring closest to the carboxylic acid group. The next furthest downfield signal is from the hydrogen on the benzene ring closest to the ester functional group. The two other hydrogens on the benzene ring show up in the group of signals that is located just upfield from these other two signals. It is important to note that due to the simplicity of the spectrometer, a clear splitting pattern could not be obtained from these NMR spectrum, and thus, the analyses of them is not detailed. On the NMR spectrum of the synthesized product, the singlet located at approximately 2.3 is from the CH3 (methyl) group on the product. The peak from the COOH (carboxylic acid) group is not visible on the spectrum and, should we have expanded the spectrum, would be located at approximately 11 - 12 . The signal that occurs the furthest downfield is from the hydrogen atom on the benzene ring closest to the carboxylic acid group. The next furthest upfield signal is from the hydrogen on the benzene ring closest to the ester functional group. The two other hydrogens on the benzene ring show up in the group of signals that is located just upfield from these other two signals. Once again, due to the simplicity of the nuclear magnetic resonance spectrometer, a clear splitting pattern could not be obtained from these NMR spectrum, and thus, the analyses of them is not detailed. Overall, it was difficult to determine the splitting patterns from these NMR spectra and thus, obtain a detailed analysis of them. However, upon comparison with the literature NMR spectrum of acetylsalicylic acid, it could be confirmed that both the commercial and the synthesized products were acetylsalicylic acid.

Ultraviolet Visible Spectroscopy Data and Interpretation:

The UV spectrum of the commercial product contained a peak at 221.5 nm, indicating the presence of a COO group, which was located in the ester group of the product. Another peak at 233.5 nm represented a carboxylic acid group and another at 275.5 nm indicated the presence of an aromatic ring, both of which are present in the commercial product. These three peaks indicated that the commercial product was acetylsalicylic acid, as was expected. The UV spectrum of the synthesized product contained a peak at 215.5 nm which indicated a COO group, located in the ester group of the product. Another peak at 230.5 nm represented a carboxylic acid group and another at 275.5 nm indicated the presence of an aromatic ring, both of which are also present in the synthesized product. These three peaks, along with comparison of the spectrum with the UV spectrum of the commercial product, indicated that the synthesized product was also acetylsalicylic acid.

Synthesis of Acetylsalicylic Acid (Aspirin) Results and Conclusions:

The esterification reaction between salicylic acid and acetic anhydride was successful and yielded acetylsalicylic acid. The percent yield of this product was 68.4%. The extraction of acetylsalicylic acid from commercial aspirin tablets using 95% ethanol was also successful. The melting point of the synthesized aspirin (product from Part 1) was 128 - 130C. The melting point of the acetylsalicylic acid that was isolated from commercial aspirin was 127 - 136C. By comparing these observed melting points with the literature value of 128 - 137C for acetylsalicylic acid, it was found that the values were relatively close, indicating that both products were acetylsalicylic acid. The acid from the commercial aspirin had a melting point that was a little lower and broader due to impurities in the product, which may have included some starch or ethanol that did not completely separate out or evaporate, respectively. It may also be the result of binding materials in the commercial aspirin. Overall, the melting point observations proved that the synthesized product and the product obtained from commercial aspirin were both acetylsalicylic acid. An infrared spectrum of the products also confirmed their identities as acetylsalicylic acid. In the spectrum of the synthesized product, a peak at 1605.75 cm-1 represented a benzene ring and another peak at 3016.31cm-1 indicated the presence of aromatic C-H bonds . A strong, broad peak that stretched from 2500 3100 cm-1 indicated the presence of a carboxylic acid. A peak at 755.53 cm-1 also represented an ortho-substituted benzene, which is what our product was. Overall, all these peaks combined indicated that the product was indeed acetylsalicylic acid. When compared with the library on the computer, acetylsalicylic acid was found to be a match of 86.92%. An infrared spectrum of the extracted product from the commercial aspirin also proved that it was acetylsalicylic acid. A peak at 1605.67 cm-1 represented a benzene ring. A strong, broad peak that stretched from 2500 3100 cm-1 indicated the presence of a carboxylic acid. A peak at 755.88 cm-1 also represented an ortho-substituted benzene, which is what the product was. Overall, all these peaks combined indicated that the product was indeed acetylsalicylic acid. When compared with the library on the computer, acetylsalicylic acid was found to be a match of 87.68%. When compared with one another, these spectra were almost exactly alike, particularly in the fingerprint region, thus indicating that they were identical products and were both acetylsalicylic acid. Nuclear magnetic resonance spectroscopy was used to confirm the identity of both products. Due to the simplicity of the spectrometer, a distinct splitting pattern could not be obtained from the spectrum. However, by comparing the spectra with one another and with a literature NMR spectrum of acetylsalicylic acid, it could be confirmed that both the synthesized and commercial products were acetylsalicylic acid. Peaks that should be noted included a singlet located upfield, near 2.3 for the synthesized product and 1.7 for the commercial product, which was indicative of a methyl group, which is located on the product. The peaks furthest downfield on both spectra resulted from the hydrogen on the benzene ring closest to the carboxylic acid functional group. The signal just upfield from that was due to the hydrogen on the benzene ring closest to the ester functional group. The signals upfield from these were indicative of the other two hydrogens on the benzene ring. Overall, comparison of the spectra with the literature spectrum confirmed the identity of both products as acetylsalicylic acid. Ultraviolet visible spectroscopy was also used to confirm the identity of the commercial and synthesized products. On the spectrum for the commercial product, a peak at 221.5 nm indicated the presence of a COO group, which was located in the ester group of the product. Another peak at 233.5 nm represented a carboxylic acid group and another at 275.5 nm indicated the presence of an aromatic ring, On the spectrum for the synthesized product, a peak at 215.5 nm indicated a COO group, located in the ester group of the product. Another peak at 230.5 nm represented a carboxylic acid group and another at 275.5 nm indicated the presence of an aromatic ring, both of which are also present in the synthesized product. Overall, both spectra were very similar to one another and both indicated that the synthesized and commercial products were acetylsalicylic acid.

Synthesis of Acetylsalicylic Acid (Aspirin) Reference:

Campbell, Bruce and Monica McCarthy-Ali. Organic Chemistry Experiments: Micro- and Semi-microscale. Preparation of Acetylsalicylic Acid. Pacific Grove, CA: Brooks/Cole Publishing Company., 1994. p. 364 365 Fieser, Louis and Kenneth Williamson. Organic Experiments. 8th ed. Acetylsalicylic Acid (Aspirin). New York, NY: Houghten Mifflin Co., 1998. p. 392 395. Pavia, Donald, Gary Lampman and George Kriz. Introduction to Spectroscopy. New York: Sonders College Publishing, 1996. Pouchert, Charles J. The Aldrich Library of NMR Spectra. Acetylsalicylic Acid. Milwaukee, Wis.: Aldrich Chemical Co., 1983. p. 303. Weast, Robert C., ed. CRC Handbook of Chemistry and Physics. 70th ed. Boca Raton, FL: CRC Press, Inc., 1990.