Synthesis of Salicylic Acid and Acetyl Salicylic Acid (Aspirin)

ONa O
C

Aska Firmansyah.,S.Si.,Apt and + pH 1-2 H 2+ SO 4 Development Department ONa Research

Na O

O
C

H 2 SO

24

Introduction

Na

Methyl salicylate is naturally occurring compound to produce salicylic acid, which than be used Sodium Salicylate to make acetyl salicylic acid (Aspirin). Two mechanism reaction needed. First is hydrolysis, which is the OH breakingO of a bond with water. Esters are quite hydrolyzed into their two starting
C an alcohol. Then, an ester synthesis for the formation of aspirin. Using component, an acid and OH

acetic acid anhydride as the acid source prevent this backward reaction, since water is not produced during ester formation.
Salicylic acid

Na 2 SO 4

Hydrolysis occurs in the presence of base (instead of acid), the carboxylic acid and phenolic Mechanism Hydrolysis Methyl salicylate (OH- ) groups on salicylic acid are ionized and this cimpound exists as the sodium salt of salicylic Methyl salicylate can be hydrolyzed to produce salicylic acid. First the free carboxylic acid acid. The reaction mixture is subsequently acidified using sulfuric acid, which convert this anion groups will be produced when hydrolysis methyl salicylate. Methanol is the alcohol which is into fully protonated acid produce salicylic acid. released by hydrolysis. Mechanism Esterification Salicylic acid
3

OH

ONa

Salicylic acid made fromOChydrolysis of Methyl salicylate, and Salicylic acid is reacted with H ON a Acetic anhydride producing the ester product, Acetylsalicylic acid (Aspirin).
2-Hydroxy-benzoic ac id methyl ester OH OH O
C OH

+ 2 NaOH

OO H3C OH C O C CH O
3

O
C OC H
3

OH + 2 Na OO C O C CH OH H 2 SO
3

OC H

OH
4

+ Na O

+ OH Salicylic acid OO OH H 3C C O C CH ONa OH O

C 3

H 3C

C OH

O Acetic anhydride
C O
-

HO Na

O
C

+ Na

CH O O C O
2

ON a

OH

H3C O
OC Na

CO
3

++

CH

OHH H

O
C

O +
OH

CH 3COOH

OH

Sodium Salicylate

Acetyl-salicylic acid

Esterification prosess used concentrated sulfuric acid to make condition in the protonated state. The atomic hydrogen in phenolic hydroxyl group will replaced by a ester group, as result ion hydrogen will be the free electron. Because of atomic carbon bonded in atomic oxygen in phenolic group, finally the state of imbalance. For back to ground, the atomic carbon will release the carboxylic acid group, and the Acety-salicylic acid form. Using acetic anhydride as the acid sources prevent this backward reaction, since water is not produced during ester formation. Compound MW Mp C Bp C Density g/mL Solubility Methyl salicylate 152.15 -8 224-226 1.174 Ethanol, Chloroform Sodium hydroxide 40.0 318.4 1390 2.130 Water Sulfuric acid 98.07 3 280 1.841 Water Salicylic acid 138.12 159 211 1.1443 Water, Etoh Acetic anhydride 102.09 73.1 139.9 1.08 Water Aspirin 180.16 135 140 1.35 Ethanol Experimental Hydrolysis Methyl salicylic Materials and Metods R/ Methyl salicylate Sulfuric acid 3 M Aquadest 1. Prepared 25 mL NaOH 5 M, pour into a 100 mL round bottom flask. 2. Add 15 gr of methyl salicylic to the around bottom flask containing the NaOH (white solid may form, but it will dissolve quickly when the mixture is heated). 3. Heat the reaction mixture to boiling and reflux for 30 minute. 4. After 30 minute reflux, transfer the reaction mixture to a 125 mL beaker glass and let the solution cool to room temperature. 5. Than carefully add H 2 SO4 3 M to make solution acidic (Add more acid until the pH is 1-2). 15 g Sodium hydroxide 5 M 25 mL

6. Cool the mixture in an ice water bath to about 0-5C (crystallization appears). 7. After crystallization appears complete, collect the crystals by vacuum filtration. 8. Wash the crystals with a small amount of ice cold water. 9. Place product in the oven for drying. And than after the crystals dry, weight them and determine the percent yield, based on the starting material. Calculation Theoretical yield : (
) ( ) ( )

Actual yield : 12.85 g Percent yield :

Aspirin is a trade mark for Acetyl-salicylic Acid. Aspirin is most widely used OTC drug in the world as Analgesic. The earliest known uses of the drud can be traced back to the Greek Phycisian Hipprocrates in the fifth century B.C. he used powder extracted from the bark of willows to treat pain and reduced fever. Salicin, the parent of the salicylate drug family, was successfully isolated in 1829 from willow bark. Sodium salicylate, a predecessor to Aspirin, was developed along with salicylic acid in 1875 as a pain reliever. Sodium salicylate was not often popular though, as it has a habit of irritation in stomach. In 1897, Felix Hoffman a German Chemist working for Bayer and Arthur Eichengrun the first synthesized the active ingredient in Aspirin, Acetyl-salicylic Acid in 1893. Synthesis Aspirin Materials and Metods R/ Salicylic acid 5 g Acetic anhydride 5 mL Sulfuric acid 18 M 4-5 drop Aquadest

1. Preheat 60 mL water in beaker glass 250 mL to boiling. 2. In Erlenmeyer 125 mL, place about 5 g salicylic acid, 5 mL of acetic anhydride, and 5 drop of H2 SO4 18 M (some heat may be generated). 3. Heat the flask ina beaker glass of boiling water for 10 minutes, stir the mixture by gently swirling the flask. 4. During the time, the solid should dissolve completely. 5. Remove the flask from the boiling water bath, and add 25 mL of ice water to the flask (the ice water decomposed the unreacted anhydride and keeps the mixture cool). 6. Thoroughly cool the flask to complete the initial crystallization. 7. If crystals are slow in forming, you may need to scratch the inside of Erlenmeyer flask with glass rod, which will speed up crystal forming by seeding. 8. Collect the crystals by vacuum filtration and dry crystals in the drying oven. 9. Than after the cr ystals dry, weight them and determine the percent yield, based on the starting material. 10. Analysis the product. Calculation Theoretical yield : (
) ( ) ( )

Actual yield : 5.5 g Percent yield :