Synthesis of Aspirin Eryll Paolo Alea, Patrick Jerome Asutria, Nadine Joy Baccay, Charize Ann Buenavista, Stephanie Dawn Buted, Rafael James Cabanting Group # 1, 2F-PH, Department of Pharmacy, University of Santo Tomas
ABSTRACT Acetylsalicylic acid (C9H9O4), or most commonly known as Aspirin, is one of the most popular medicine used for it can cure many diseases. This includes its ability to be an antipyretic (reduces fever), analgesic (reduces pain without producing anesthesia or loss of consciousness), anti-inflammatory (relieve the pain and swelling with association to arthritis and rheumatism), uricosuric (enhances the elimination of uric acid), and interfere with the body’s production of prostaglandins and their products (thromboxanes), which are associated with headaches, platelet aggregation, and vasoconstriction. Aspirin was the first non-steroidal anti-inflammatory drug to be discovered and is a derivative of salicylate, which can be found in plants such as willow trees and myrtle. The synthesis of Aspirin aims to explore the chemical processes in the synthesis of aspirin and to calculate for the percentage yield of aspirin.
INTRODUCTION Salicylic acid (C7H6O3) is a fine white and odorless crystal. It is found and extracted in plants such as willow trees and myrtle and is commonly used as an analgesic and an antipyretic. It has long been used in Europe and China for the treatment of these conditions after Hippocrates, Galen, Pliny the Elder and others have discovered that willow bark could ease aches and pains and reduce fevers. The IUPAC Name of Salicylic acid is 2Hydroxybenzoic acid. Its boiling point is 211°C and its melting point is 159°C. The density of salicylic acid is 1.44 g/mol. Salicylic acid is very reactive in moisture, light, heat, and incompatibilities such as iron salts, lead acetate, iodine and nitrous ether. It is used in medicine such as making aspirin and used as constituents of rubefacient products such as methyl salicylate, used a liniment to soothe joint and
muscle pain and choline salicylate, used topically to relieve the pain of mouth ulcers. Acetic anhydride (C4H6O3) is a clear colorless liquid with a strong odor of vinegar. It is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. The boiling point of acetic anhydride is 140°C and the melting point is -73°C. Its density is 1.082 g/ml in liquid state and its molecular weight is 102.09 g/mol. It is mainly used for acetylations leading to commercially significant materials. Also, the largest application of acetic anhydride is for the conversion of cellulose to cellulose acetate, which is a component of photographic film and other coated materials. It is also used in the production of aspirin which is prepared by the acetylation of salicyclic acid.
The objective of this experiment is (1) to explore the chemical process in the synthesis of aspirin and (2) to calculate for the percentage yield of aspirin. Crystallization is a technique which is use to purify solid compounds. It is a process of crystal formation in a solution. Organic compounds that are solid in room temperature are usually purified by crystallization. Crystallization is based on the principles of solubility: compounds (solutes) tend to be more soluble in hot liquids (solvents) than they are in cold liquids. If a saturated hot solution is allowed to cool, the solute is no longer soluble in the solvent and forms crystals of pure compound. Impurities are excluded from the growing crystals and the pure solid crystals can be separated from the dissolved impurities by filtration. METHODS To synthesize aspirin, the acetic anhydride was reacted with salicylic acid. First, 2.00 g of salicylic acid was weighed out in a watch glass and transferred into a 20-cm test tube. Then, 5.00 mL of acetic anhydride was dispensed into the test tube followed by the addition of 5 drops of concentrated sulfuric acid (H2S04). The mixture was then stirred until the salicylic acid dissolved completely using a stirring rod. Then, a 250-mL beaker filled with three-fourths full of tap water was brought to boil. The beaker was heated using a Bunsen burner and is placed on top of it with the aid of a ring stand. After that, 250-mL plastic wash bottle was filled with distilled water and packed in ice contained large beaker. When the water in the beaker begun to vigorously boil, the burner was turned off and the test tube was clamped in the hot water bath with the aid of a iron clamp. Then, the contents of the test tube were stirred for about a minute. The reaction mixture was allowed to remain in
the water bath heated at a range of 70-80 degrees Celsius for 20-30 minutes. The test tube was removed from the water bath and then the contents of the test tube were cautiously poured onto 5 mL of water in a 150-mL beaker. After the reaction inside the beaker had subsided, the mixture was stirred for a minute then slowly added room temperature water, a few drops at a time, until a maximum of 40 drops had been added or until the solution became cloudy. The solution became clear again, that is why addition of water was continued until a cloud of small crystals of aspirin reappears. The crystals appeared in the beaker so the test tube was rinsed with small volumes of ice-cold water from the wash bottle, adding the rinse to the solution in the 150-mL beaker. Then 20 mL of ice cold water was measured and added into the 150-mL beaker. After which, it was stirred and then the beaker was packed in ice for at least 10 minutes to allow the aspirin to crystallize. The crystals were filtered using a pre-weighed filter paper and allowed to dry overnight. Lastly, the weight of dried aspirin was measure and the percentage yield was computed. For the ferric chloride test for salicylic acid, first 1 mL of water was added to each of 6 clean 10cm test tubes. Microspatula was used to place a crystal of salicylic acid into the first test tube, powdered commercial aspirin into the second, synthesized aspirin into the third, benzoic acid into the fourth, and 1 mL of benzyl alcohol into the fifth. Nothing is to be added to sixth test tube, which will act as the control. Then, the test tubes were shaken to dissolve the solid and 2% aqueous solution of ferric chloride was dropped with a Pasteur pipette. The colors produced were observed and then an inference was written based on the findings. For the starch test, 2 mL of water was added to each of the three 10-cm test tubes. Then, to the first test tube, a small amount of the synthesized
aspirin was added. To the second, nothing was added for it acted as a control. To each of the test tube, a drop of iodine solution was added. A blue or black color will indicated the presence of starch. The color produced was observe and an inference was written based on the findings. The last test conducted for this experiment was the preparation of methyl salicylate. Methyl salicylate was prepared in a manner similar to Weight of watch 95.0 g glass + salicylic acid Weight of empty 93.0 g watch glass Weight of salicylic 2.0 g acid Volume of acetic 5.00 mL anhydride Volume of 5 drops concentrated sulfuric acid Weight of filter 6.0 g paper + product Weight of dry 3.0 g filter paper Weight of product 3.0 g aspirin but a lower temperature. 1.00 g of salicylic acid was weighed out exactly and placed in a 20-cm test tube. Then, 5 mL of methyl alcohol was added and also 3 drops of concentrated sulfuric acid (H2S04).
MATERIALS The materials used in this experiment are the following:
In the reaction of salicylic acid and acetic anhydride, the hydroxyl group (−OH ) on the
For the reaction of acetic anhydride and salicylic acid, the materials used were 20-mL test tube, 150-mL beaker, tap water, ice, bunsen burner (for heating), iron ring and clamp, stirring rod (for stirring the mixtures and solutions), 250-mL wash bottle and lastly the two main components which are the acetic anhydride and salicylic acid. For the ferric chloride test for salicylic, the materials used were 10-cm test tubes, microspatula, salicylic acid, powdered commercial aspirin, synthesized aspirin, benzoic acid, 1 mL benzyl alcohol, 2% aqueous solution of ferric chloride and Pasteur pipette. For the starch test, the materials used were 10cm test tubes, synthesized aspirin and iodine solution. For the preparation of methyl salicylate, the materials used were salicylic acid, test tube, methyl alcohol, concentrated sulfuric acid, water, beaker and hot plate (for water bath). RESULTS AND DISCUSSIONS TABLE 1. Reaction of Acetic Anhydride and Salicylic Acid
Illustration of the Synthesis of Acetylsalicylic acid
benzene of the salicylic acid reacted with acetic anhydride to form an ester functional group. Thus, the formation of acetylsalicylic acid is called as an esterification reaction. Esterification is a reaction wherein refluxing of the carboxylic
group and the primary or secondary hydroxyl group occurs to prepare an ester. This reaction requires the presence of an acid catalyst which was is the sulfuric acid in the experiment.
Theoretical yield: 2.0081 g C 7 H 6 O 3 ×
1 mol 180. × 138.12 g C7 H 6 O3 1 mol C
Percentage yield:
To calculate for the actual yield of the synthesized aspirin, the limiting reagent must first be identified. Based from the calculations made, salicylic acid was found out to be the limiting reagent for it yielded a smaller value than acetic anhydride. Thus, the theoretical yield is based from and also equal to the value of the limiting reagent. This is determine if the experiment conducted obtained a complete reaction from the acetic anhydride and salicylic acid. Based from the calculations, 115% was synthesized aspirin, thus it had slight impurities which were later on confirmed using the ferric chloride test. Calculations: Chemical reaction:
3.0 g synthesized aspirin × 100=115 2.6082 g C 9 H 9 O4
TABLE 2. Ferric Chloride Test Test Tube Salicylic Acid Commercial Aspirin Synthesized Aspirin Benzoic acid Benzyl alcohol Control
Observations Purple solution N/A
Inference Presence of Salicylic acid N/A
Purple solution Turbid white solution Colorless
Presence of Salicylic acid Absence of Salicylic acid Absence of Salicylic acid Absence of Salicylic acid
Colorless
C7 H 6 O3+C 4 H 6 O3 ⟶ C 9 H 9 O4 +CH 3 COOH Limiting reagent: Acetic anhydride: 5.00 ml C 4 H 6 O3 ×
1.082 g 1 mol 180.16 g × × =9.55 g C9 H 9 O 4 1ml 102.09 g C4 H 6 O3 1 mol C9 H 9 O 4
Illustration of the Reaction of Ferric Chloride Test for Salicylic acid wherein yellow color Salicylic acid: indicates the ferric ion and purple color 1 mol 180.16 g indicated the reacted acid. 2.0081 g C 7 H 6 O 3 × × =2.61 C 9 H 9 Osalicylic 4 138.12 g C7 H 6 O3 1 mol C 9 H 9 O4
According to the results of the test conducted Salicylic acid and Synthesized salicylic acid were found to have the presence of salicylic acid, which was indicated by the purple coloration of the solution. While the Benzoic acid, Benzyl alcohol and the control had the absence of the salicylic acid.
iodine which leaves to the inference that there is no starch present both to the synthesized aspirin and the control. However, even if we did not conduct the experiment with the commercial aspirin, the expected result was a formation of a blue-black colored solution which indicates a positive result.
Thus, this test is used for determination of purity of a substance. The purple color produced is caused by the reaction of salicylic acid with aqueous ferric
( Fe ( H 2 O )6+3 )
ion. The oxygen
atoms of the carboxylic acid group (−COOH ) and hydroxyl group (−OH ) on salicylic acid can form a complex group with ferric
( Fe ( H 2 O )6+3 )
ion which indicates the
presence of salicylic acid. . In aspirin, the hydroxyl group (−OH ) was replaced by ester
(−OCOC H 3) during the process of esterification and nucleophilic substitution which prevents the complex formation. This will yield a yellow solution. However, the synthesized aspirin reacted in ferric chloride which implies that salicylic acid is present. Thus, there are certain impurities in the obtain aspirin. TABLE 3. Starch Test Test Tube Synthesized aspirin Control
Observations Clear colorless solution Light yellow solution
Starch is one of the inert binding materials used in the production of aspirin tablets. Synthesized aspirin did not reacted with iodine that is why there was no formation of a blue-black colored solution. The control did not also reacted with
Illustration of the Preparation of Methyl Salicylate Methyl salicylate is a methyl ester of salicylic acid, commonly called “oil of wintergreen”. It has two main functional groups which is the ester and phenol. Methyl salicylate is also prepared through the process of esterification just like the acetylsalicylic acid. Thus, methyl alcohol was used to dissolve the salicylic acid and was subjected to water bath afterwards. It produced a distinct mint-like odor which confirmed the presence of methyl salicylic acid. REFERENCES 1. Aspirin: Health Benefits, Uses, and Risks (n.d.) Retrieved November 28, 2015, from http://www.medicalnewstoday.com/articl es/161255.php Crystallization.html 2. Lehman, J. (2002). Multiscale Operational Organic Chemistry: A problem Solving Approach to the Laboratory Course. New Jersey: Prentice Hall. Pg. 40-48, 257-264, 530 3. Williamson, K. (1994). Macroscale and Microscale of Organic Experiments. Canda: D.C. Health and Company. Pg. 379-384
4. Pasto, D. J., John, C. R., & Miller, M. S. (1998). Experiment and Techniques in Organic Chemistry. New Jersey: Prentice Hall. Pg. 43-46 5. Crystallization. (2015, August 31). Retrieved November 29,2015 from http://orgchem.colorado.edu/Technique/ Procedures/Crystallization/
6. Acetic Anhydride. (2005, March 26). Retrieved November 30, 2015 from http://pubchem.ncbi.nlm.nih.gov/compo und/acetic_anhydride
