Synthesis of Aspirin (Acetylsalicylic acid)

Authors: ABESAMIS, M., ACOSTA, M., AGUSTIN, F., *AQUITANIA, M., BAGSICAN, M.

AbstractAcetylsalicylic acid , known as Aspirin, is one of the popular and

versatile medicines that cure diseases. It is considered a powerful drug for relieving pain (analgesic), reducing fever (antipyretic), and reducing swelling (anti-inflammatory). The synthesis of acetylsalicylic acid is derived from salicylic acid which can be extracted in willow trees and allowing it to react with acetic anhydride and a catalyst through the principle of crystallization.

I. IntroductionSalicylic

acid is

a fine white crystal and odorless. It is extracted in willow and poplar bark that has been used as an analgesic for centuries. The boiling point of salicylic acid is 211°C and the 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 pharmaceutical applications, including methyl salicylate.

Acetic anhydride is

a colorless liquid with a pungent vinegar-like odor when it reacts with water to form acetic acid. The boiling point of acetic anhydride is 140°C and the melting point is -73°C. It is soluble in ether, chloroform and benzene. It is soluble in water when acetic anhydride decomposes. The

density of acetic anhydride is 1.082 g/ml in liquid state and its molecular weight is 102.09 g/mol. Acetic anhydride is most widely used for the conversion of cellulose to cellulose acetate, which is a component of photographic film and other coated materials. It is also known as acetyl ether.

Crystallization is one of the most used purifying methods in organic experiments. It is a process of crystal formation in a solution. Organic compounds that are solid in room temperature are usually purified by crystallization. The substance to be purified is dependent to its solubility in change of temperature whether in a hot or cold solvent. It is the main factor that affects crystallization. The substance to be crystallized should show the ideal solubility behavior in solvent. A substance can be purified when both the

Figure 1 Structural formula of Salicylic

Acid

Figure 2 Structural formula of Acetic anhydride

desired substance and the impurity have similar solubility at its boiling point temperature, and when the impurity represents only a small fraction of total solid. The desired substance will crystallize on cooling, but the impurities will not.

The objectives obtained in this experiment are the following: (1) to be able to explore the chemical process in the synthesis of aspirin; (2) and to calculate for the percentage yield of the synthesized aspirin.

II. MethodologyTo synthesize aspirin, a 250-

ml beaker filled with three-fourths of tap water was subjected to boil. The beaker is supported by the iron ring and iron stand. A 250-ml plastic wash bottle filled with distilled water was packed ice which was placed in a larger beaker. While boiling, exactly 2.00 g salicylic acid was tared in a watch glass and it was transferred in a clean, dry 20-cm test tube. Exactly 5.00 ml acetic anhydride was dispensed to the test tube and 5 drops of concentrated sulfuric acid was added. The mixture is stirred using a stirring rod until the salicylic acid was dissolved. The burner was turned off when the water in the beaker began to boil vigorously. The test tube was placed in a hot water bath to allow the mixture the react within a temperature range of 70°C to 80°C in 20-30 minutes. The content of the test tube was stirred well in 1 minute. Then, the test tube was removed from the water bath and its contents were poured slowly and cautiously in 150-ml beaker filled with 5 ml distilled water. When the mixture subsided, the mixture was stirred in 1 minute

while a drop of room temperature water was added at a time, until it reached a maximum of 40 drops or the solution became cloudy. When the solution became clear, a few drops of water were added dropwise until crystals of aspirin reappeared. When there are no crystals found, the inner walls of the beaker was scratched gently using the stirring rod to induce crystal formation. Once the crystals of aspirin appeared, the test tube was rinsed with a small volume of ice-cold water from the wash bottle. A 20-ml of ice cold water was added into the 150-ml beaker then the beaker was packed in ice for at least 10 minutes to allow the aspirin to be crystallized. The aspirin crystals were filtered using a pre-weighed filter paper and it was dried overnight. Then, dried aspirin crystals were weighed.

To test the purity of the synthesized aspirin, it was subjected to ferric chloride test for salicylic acid. 1 ml water was placed in 6 10-cm test tubes. A small amount of each sample was added in every test tube using a microspatula. Salicylic acid was placed in the first test tube, powdered commercial aspirin in the second test tube, synthesized aspirin in the third test tube, benzoic acid in the fourth test tube and 1 ml of benzoic acid in the fifth test tube. The sixth test tube filled with 1 ml water was the control used. The sample used was dissolved in 1 ml water then a drop of 2% aqueous solution of ferric chloride was added using a Pasteur pipette. The observed color produced was noted.

Another test of purity used was starch test. A 2 ml of water

was placed in 3 10-cm test tube. A small amount of each sample was added in every test tube. The powdered commercial aspirin was placed in the first test tube and salicylic acid in the second test tube. The third test tube with 2 ml water was the control used. A drop of iodine solution was added in each test tube. The observed color produced was noted.

Methyl salicylate was prepared in a similar manner as aspirin but at a lower temperature. Exactly 1.00 g of salicylic acid was placed in a 20-cm test tube. A 5 ml of methyl alcohol and 3 drops of concentrated sulfuric acid

was added to the test tube. The mixture is stirred until the salicylic acid is dissolved in alcohol. Then, the test tube was subjected in 70°C water bath for 15 minutes. The mint aroma produced inferred the presence of methyl salicylate.

III. Discussion

The

synthesized acetylsalicylic acid is prepared by allowing salicylic acid to react in acetic anhydride with a strong acid as a catalyst such as concentrated sulfuric acid and phosphoric acid. The principles in crystallization are applied to obtain the desired product, aspirin. The difference in solubility of the synthesized acetylsalicylic acid to its mother liquor at a lower temperature will crystallize to obtain the desired substance. In Table 1, the used materials and substances are presented with their corresponding weight or volume. The weight and volume were accurately measured using the apparatus.

Figure 3 Structural formula of Aspirin (Acetylsalicylic

acid)

Table 1. Reaction of Acetic Anhydride and Salicylic AcidWeight of watch glass + salicylic

acid…….55.9455g

Weight of empty watch glass………………....53.9374

g

Weight of salicylic acid…………...………….......2.0081

g

Volume of acetic anhydride……………………....….5.00

ml

Volume of concentrated sulfuric acid…...…….…....5

drops

Weight of filter paper + product ...…………..2.8310

g

Weight of dry filter paper....…………..…...……0.2000

g

Weight of product ...…………..…………………....2.6310

g

Figure 4 Synthesis of Acetylsalicylic acid

Salicylic acid has two important functional groups present, the carboxylic group and the phenol group. In the reaction of salicylic acid and acetic anhydride, the hydroxyl group on the benzene of the salicylic acid reacted with acetic anhydride to form an ester functional group; thus, the formation of acetylsalicylic acid is referred to 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. It can be expressed by the H+ in the equation. Acetic anhydride reacts

slowly with salicylic acid. A need for a catalyst is required to hasten the reaction. In this experiment, concentrated sulfuric acid is used as the acid catalyst. The formation of ester is also referred as a nucleophilic substitution

reaction wherein the catalyst

attracts the of hydroxyl group. The salicylic acid becomes more negative that it will attract the acyl group of the acetic

anhydride. Since acetic anhydride is polar, it has a partially positive group and a partially negative group. The partially positive acyl group attaches to the salicylic acid to synthesize acetylsalicylic acid.

The by-product of this reaction is acetic acid.

Figure 5 Hydrolysis of Aspirin (Acetylsalicylic acid)

When the reaction is completed, unreacted salicylic acid and acetic anhydride will be present with the acetylsalicylic acid, acetic acid and the catalysts. Crystallization method is used to purify the acetylsalicylic acid from other substances in the mixture. At room temperature, the acetylsalicylic acid is insoluble in water. During heating when the salicylic acid is subjected to warm water bath, it dissolves. This will let the reaction of the mixture to occur at a temperature range of 70°C to 80°C in 20-30 minutes. Acetic anhydride is used as the solvent in this experiment because it has relatively low boiling during heating. In the principle of le Chatelier, the presence of excess acetic anhydride forces the equilibrium towards the desired product. Through heating the solution, there will be acceleration of the reaction to approach equilibrium. Water is not used as a solvent for this experiment because water may hydrolyze the obtain aspirin to decompose into salicylic acid and acetic acid. After transferring the mixture in the beaker, addition of ice-cold water was done dropwise to form cloud of small crystals. This will hasten

crystallization process of acetylsalicylic acid. Upon cooling, it was packed with ice, acetylsalicylic acid became insoluble as its solubility decreased and eventually formed the crystals. The crystals were obtained in acetic anhydride, the mother liquor. Ice-cold distilled water was used in filtering to rinse the mixture to obtain the desired substance, aspirin. The aspirin was dried overnight and weighed accurately.

To calculate for the actual yield of synthesized aspirin, limiting reagent should be identified first. In the calculations, the limiting reagent in the reaction is salicylic acid. The theoretical yield of acetylsalicylic acid will be based on the limiting reagent. This is to identify if the actual experiment obtain a complete reaction of salicylic acid and acetic anhydride. From the calculation, 100.45% was synthesized aspirin which presents that the demonstrated experiment has slight impurities obtain. These impurities refer to the presence of salicylic acid. Ferric chloride test clarifies the purity of the obtain substance.

Calculations:Chemical Equation:

Limiting reagent:Acetic anhydride:

Salicylic acid:

Theoretical yield:

Percentage yield:

Table 2. Ferric Chloride TestTest Tube Observations InferenceSalicylic acid Purple solution (+) Salicylic acid presentCommercial aspirin

Pink solution (–) No presence of salicylic acid

Synthesized aspirin

Purple solution (+) Salicylic acid present

Benzoic acid Light orange solution (cloudy)

(–) No presence of salicylic acid

Benzyl alcohol Yellow oily solution (–) No presence of salicylic acid

Control Light yellow solution (–) No presence of salicylic acid

Figure 6 Reaction of Ferric chloride test(Yellow – Ferric ion; Purple – Reacted salicylic acid)

Ferric chloride is used for determination of purity of a substance. The intense purple color produced is caused by the reaction of salicylic acid

with aqueous ferric ion.

The oxygen atoms of the carboxylic acid group and hydroxyl

group on salicylic acid can form

a complex group with ferric

ion. It indicates the

presence of salicylic acid. In aspirin, the hydroxyl group was replaced

by ester during

esterification and nucleophilic substitution which prevents the complex formation. This will emanate a yellow solution. However, the synthesized aspirin reacted in ferric chloride which implies that salicylic acid is present, as presented in Table 2. Thus, there are impurities in the obtain aspirin.

Table 3. Starch TestTest Tube ObservationCommercial aspirin

(+) Blue-black colored solution

Synthesized aspirin

(–) No reaction

Control (–) No reaction

Aspirin tablets are acetylsalicylic acid pressed together with a small amount of inert binding material, such as starch, methylcellulose and microcrystalline cellulose. Commercial aspirin reacted to iodine. Formation of blue-black colored solution indicates a positive result. In the synthesized aspirin, there was no reaction occurred. The control did not reacted in iodine. This infers that there is no starch present in the synthesized aspirin and control which is water.

Figure 7 Preparation of Methyl salicylate

Methyl salicylate is obtained from winter green oil, an aromatic liquid distilled from the leaves of the wintergreen plant (Gaultheria procumbens) or from the bark of sweet birch trees (Betula lenta). It has two main functional groups, the ester group and phenol group. Like, acetylsalicylic acid, methyl salicylate acid is prepared through the process of esterification. Methyl alcohol reacts with salicylic acid in the presence of an acid catalyst to form methyl salicylate and a by-product of water. This reaction occurs at a low temperature. In this experiment, methyl alcohol was used to dissolve salicylic acid. It was subjected to water bath for it to produce an odor. The presence of methyl salicylic acid was confirmed in the mixture when it produced a mint-like odor.

Methyl salicylate and acetylsalicylic acid are derivatives of salicylic acid.

IV. Reference

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ACETIC ANHYDRIDE (ACETYL ETHER). (n.d.). Retrieved October 11, 2009, from http://chemicalland21.com/petrochemical/ACETIC%20ANHYDRIDE.ht

SALICYLIC ACID. (n.d.). October 11, 2009, from http://jtbaker.com/msds/englishhtml/s0506.htm