Synthesis of Aspirin by 4 methods-An Overview

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Chemical Structure of Aspirin:

Structure of Aspirin
Fig: Structure of Aspirin

Synonyms: Acetylsalicylic acid; Acetylin; Acetophen; Acetosal; Asatard; Caprin; Acetyl-SAL; ASA; Acylpyrin; Entrophen; Saletin; Arthrisin; Duramax; Solpyron; Xaxa. Aspirin may be prepared by any one of the following three methods:

Synthesis Of Aspirin by Method-I

It is prepared from salicylic acid, acetic anhydride and glacial acetic acid.


Synthesis of Aspirin method 1

Salicylic acid interacts with acetic anhydride in the presence of glacial acetic acid whereby the cleavage in acetic anhydride takes place with the formation of aspirin and a mole of acetic acid. The glacial acetic acid helps in the generation of excess acetate ion which carries the reaction in the forward direction. The acetic acid obtained as a product of reaction is reused in the reaction itself.

Yields Aspirin = 180 grams

Therefore, 6 grams of salicylic acid should yield Aspirin = 180/138 × 6 = 7.82 grams.

Therefore, Theoretical yield or output of Aspirin = 7.82 grams.

According Practical Yield = 7.5 grams.

Therefore, % Yield = Practical yield ÷Theoretical yield × 100

= 7.5÷7.82 × 100

= 95.90 %

Chemicals Required

(i) Take Acetic anhydride 10 ml

(ii) Salicylic acid 6 grams

(iii) Glacial acetic acid about 10 ml.

Procedure for Synthesis Of Aspirin:

The following steps may be adopted in a sequential manner:

(1) Prepare an admixture of 10 ml each of acetic anhydride and glacial acetic acid in a 100 ml clean and dry beaker.

(2) Instantly, add this mixture solution carefully to 6 grams of salicylic acid already weighed and placed in a 100 ml (RBF) round bottom flask; and fit the RBF with a reflux condenser.

(3) Now, heat and Boil the reaction mixture solution on an electric heating mantle for a time period of 35 to 45 minutes.

(4) Pour down the hot resulting mixture solution directly into 100 ml of cold water, contained in a 500 ml beaker in one batch; and then stir the content mixture rapidly with a clean glass rod until the shining tiny crystals of aspirin are separated out.

(5) Filter off the crude aspirin in a Buchner funnel fitted with an air-suction device and wash the residue with sufficient cold water, drain well and finally remove the excess of water by pressing it between the folds of filter paper and spread it in the air to allow it dry completely. However, it may also be dried expeditiously by drying it in an electric oven maintained at 100°C for about an hour. The yield of pure or crude aspirin having melting point 133.5–135°C is approximately 7.5 grams.

Precautions During Synthesis Of Aspirin :

(1) All glass apparatus to be used in the synthesis must be perfectly dried in an oven.

(2) Mild refluxing should be done to complete the acetylation of salicylic acid.

Recrystallization: Recrystallize the pure or crude product from a solution mixture of acetic acid and water (H20) in ratio(1:1). The yield of pure colourless aspirin (mp 13.4°C) is 7.25 g.

Theoretical yield/Practical yield: The theoretical yield is usually calculated from the equation under theory as stated under: 138 grams of salicylic acid on reacting with 102 g of acetic anhydride.

Physical Parameters: Aspirin is obtained as monoclinic tablets or needle like crystals, mp 135 °C (rapid heating); the melt gets solidified at 118°C; UV max (0.1 NH2SO4): 229 nm (E1 cm 1% 484) ; CHCl3: 277 nm (E1 cm 1% 68). It is usually odourless, but in moist air it gets hydrolysed slowly into salicylic acid and acetic acid, and overall acquires the odour of acetic acid. It is fairly stable in dry-air, 1 g dissolves in 300 ml water at 25°C, in 100 ml of water at 37°C, in 5 ml ethanol, 17 ml chloroform and 10–15 ml solvent ether.

Uses of Aspirin:

(1) It is used for the relief of minor aches and mild to moderate pain. (2) It is recommended for arthritis and related arthritic conditions. (3) It is also indicated for myocardial infarction prophylaxis. (4) It is employed to reduce the risk of transient ischaemic attacks in men.

Questions for Viva-Voice:

(1) Why is it necessary to recrystallize aspirin before being used as a medicine?

(2) Why aspirin must be stored in dry air or air-tight containers?

(3) What is the role of acetic acid in the reaction between salicylic acid and acetic anhydride?

Synthesis Of Aspirin by Method-II

Aspirin may also be prepared from salicylic acid, acetic anhydride and a few drops of concentrated sulphuric acid.


synthesis of aspirin method 2

Salicylic acid interacts with acetic anhydride in the presence of a few drops of concentrated sulphuric acid to produce aspirin and a molecule of acetic acid. The purpose of adding concentrated sulphuric acid is to aid and augment the process of detaching the acetate ion from acetic anhydride which ultimately gets associated with the H+ ion from the phenolic hydroxy group in salicylic acid to be eliminated as a mole of acetic acid.

Chemicals Required:

(1) Salicylic acid: 6 grams;

(2) Acetic anhydride: 8.5 ml; and

(3) concentrated Sulphuric acid: 3-4 drops.

Procedure for Synthesis of Aspirin:

The different steps concerned are:

(1) Weigh 6 grams of salicylic acid and then transfer it to a 100 ml clean and dry conical flask.

(2) Add to the flask 8.5 ml of acetic anhydride and 3–4 drops of concentrated sulphuric acid carefully.

(3) Mix the contents of the flask thoroughly; and warm the mixture on a water-bath maintained at 60°C for about 15–20 minutes with frequent stirring.

(4) Allow the contents of the flask to cool down to ambient temperature, and pour it in a thin stream into 100 ml of cold water in a 250 ml beaker with constant stirring.

(5) Filter the crude product on a Buchner funnel using suction, wash it generously with cold water, drain well and dry between the folds of filter paper or in an oven maintained at 90°C. The yield of crude aspirin (mp 133–134°C) is about 7.75 g.


(1) All glass equipments that are used in the synthesis must be perfectly dry.

(2) Concentrated sulphuric acid should be added very cautiously into the reaction mixture.

(3) The reaction mixture is to be warmed only at 60°C for 20 minutes.

Recrystallization: The same procedure as stated under above section may be adopted.

Questions for Viva-Voice :

(1) Why is the amount of acetic anhydride used in Method II for the same quantity of salicylic acid is 1.5 ml less than Method I?

(2) What is the specific role played by a few drops of concentrated sulphuric acid?

Synthesis of Aspirin by Method-III

Aspirin may also be synthesized by the interaction of salicylic acid with acetyl chloride (i.e., on acid chloride) in the presence of pyridine which being a weak base rapidly forms salts with strong acids.


synthesis of aspirin method 3

The interaction between salicylic acid and acetyl chloride gives rise to the formation of aspirin i.e., the acetylated product with the elimination of one mole of HCl.

The liberated mineral acid i.e., HCl, being a strong acid readily reacts with pyridine (a weak base) in the reaction mixture to form the corresponding salt i.e., pyridine hydrochloride.

Chemicals Required:

(1) Salicylic acid: 6 grams;

(2) Pyridine: 5 ml

(3) Acetyle chloride: 5 ml;.

Procedure for synthesis of aspirin

The following steps are to be followed sequentially:

(1) Transfer 6 g of salicylic acid in a 150 ml conical flask and add to it 5 ml of pure redistilled pyridine.

(2) Place the above conical flask in an ice-bath and chill the contents to approximately 5– 7°C.

(3) Transfer exactly 5 ml of acetyl chloride in a 50 ml dropping funnel and add it dropwise very slowly into the solution of salicylic acid with constant and vigorous stirring.

(4) After the absolute addition of acetyl chloride, the contents of the conical flask was heated over a water-bath for a duration of 5–10 minutes so as to allow the reactions (a) and (b) to near completion.

(5) Cool the contents of the flask when a semi-solid residue is obtained, to which 50 ml of water and a few chips of ice are added with frequent stirring/swirling.

(6) The crude aspirin is filtered on a Buchner funnel with suction, washed with cold water, drained well and dried either between the folds of filter paper or dried in an oven maintained below 95°C.

The yield of crude aspirin (mp 133–135.5°C) is 7.6 g.


(1) Pyridine must be redistilled before use in this preparation.

(2) Step (3) above is exothermic in nature ; hence, the addition of acetyl chloride should be both gradual and vigorous stirring required.

(3) Subsequent heating of the reaction mixture after complete addition of acetyl chloride is an absolute necessity.

Recrystallization: The same procedure as stated under above section should be adopted.

Theoretical yield/Practical yield:

The theoretical yield is calculated from equation

(a) under theory section as given below:

138 grams of salicylic acid when reacted with 78.5 grams of acetyl chloride shall yield Aspirin = 180 grams

∴ 6 grams of salicylic acid should yield Aspirin = 180 ÷ 138 × 6 = 7.82 grams.

Hence, Theoretical yield of Aspirin = 7.82 grams obtained Practical Yield = 7.6 grams

Therefore, % Yield = Practical yield ÷ Theoretical yield × 100 = 7.6 ÷ 7.82 × 100 = 97.18 %.

However, the ‘Physical Parameters’ and the ‘Uses’ are same as stated under Method–I.

Questions for Viva-Voice:

(1) Why is the quantity of acetyl chloride just one half than the quantity of acetic anhydride used in Method–I and Method–II?

(2) What is the crucial role played by ‘pyridine’ in the method of acetylation?

(3) Why is acetyl chloride added gradually to an ice-cold mixture of salicylic acid and pyridine?

Synthesis of Aspirin by METHOD-IV



To synthesize acetylsalicylic acid from the reaction of esterification of the hydroxyl group of salicylic acid (2 hydroxybenzoic), purifying the product obtained by recrystallization.

Determining subsequently the purity of the product obtained as well as the yield achieved and comparing with a commercial product tablet.

1. Introduction.

Acetylsalicylic acid (2-acetoxybenzoic acid) is better known by its trade name “Aspirin”; its therapeutic action is like analgesic, anti-inflammatory and antipyretic agent (reduces fever).

Acetylsalicylic acid is the ester of acetic acid (ethanoic acid) and the hydroxyl group of salicylic acid.

Although esters can be obtained by direct interaction of the acid acetic acid with an alcohol or phenol, the acetylating agent is usually acetic anhydride as a substitute for acetic acid, since the reaction of esterification is much faster.

Two highly effective reagents are used for the synthesis of aspirin.


Acetic anhydride or ethanoic anhydride (C4H6O3): obtained from the reaction of ketone (C2H2O) with acetic acid.

Salicylic acid: obtained by reacting sodium phenoxide (C6H5ONa) with carbon dioxide at 125 ºC and 100 atm, to give sodium salicylate (C7HO3Na) which in an acid medium gives as an acid product salicylic (C7H6O3).

The use of phosphoric acid is to avoid losing the hydrogen ion (H+) of salicylic acid, and prevent the reaction from occurring in that point, because we want the hydroxyl group to be found.

Make the acetate that is formed as a by-product of the reaction, acetic anhydride, form acetic acid and do not intervene in the reaction.

The stoichiometry of the process is mole to mole, so for each mole of salicylic acid (140 grams), 198 grams of acid should be obtained acetylsalicylic; or what is the same, at an industrial level to obtain 1000 kilos of acetylsalicylic acid we should start from 832 kilos of acid salicylic, but given the losses (spills, impurities, volatilization, etc.) the amount obtained is between 85 and 80% of the expected amount.

2. Experimental part.

(a) Synthesis:

2.5 grams of salicylic acid are weighed into a watch glass, transferring it subsequently to a 100 ml beaker. Carefully add 10 ml of acetic anhydride and subsequently 2 ml of 85% phosphoric acid.

The The mixture is stirred whereupon the temperature rises (exothermic reaction) and all salicylic acid dissolves.

After approximately 30 minutes the solution will have cooled to room temperature,

add 50 ml of ice water in solution liquid, shake well and keep on crushed ice; the content will be a solid mass of crystals of aspirin and crystals are collected by vacuum filtration in a funnel Buchner. Weigh the amount of acetylsalicylic acid obtained after drying process.

(b) Purification.

Acetylsalicylic acid can be purified by recrystallization, for this the acetylsalicylic acid obtained is placed in a beaker of 100 ml and 10 ml of ethanol are added.

It is then heated up on a hot plate, until the crystals dissolve, slowly add 15 mL of water distilled and heating is continued until the solution enters Boiling.

The beaker is then allowed to cool on ice. Chopped, and when the cloudiness begins the wall of the vessel is scratched with a glass rod until the aspirin recrystallizes.

It is then filtered again under vacuum, washing the crystals with two 3-ml portions of ice water and dry by compressing them over filter paper, once most of the water has been removed, the remaining product in the watch glass to the oven to dry for 20 Minutes.

Weigh the amount of acetylsalicylic acid obtained after the re-crystallization and drying.

(c) Determination of the purity of the synthesized acetylsalicylic acid by valuation.

To avoid errors in the determination of the acid content acetylsalicylic due to the reagents and solvents used is convenient to make a blank for the valuation.

To do this put in a glass of 100ml precipitates, 25 ml of ethanol and 4 drops of phenolphthalein. Place 0.1 N Na-OH in a burette and add it drop by drop to the point turning.

Record the ml of titrant spent. Next, to assess the purity of the acetylsalicylic acid obtained, 0.3 g of the sample is weighed (record the weight exactly) and put in a 100 ml beaker, add 25 ml of ethanol to dissolve the solid and subsequently 4 drops of phenolphthalein.

Assess immediately to the turning point of the indicator, place in a 0.1 N Na-OH burret and add the Na-OH in half a millilitre until permanent colouring of the solution.

Carry out a second assessment adding two or three times a volume somewhat smaller than necessary for the Neutralization, subsequently adding the Na-OH drop by drop until the turning point.

Record the mL of titrant spent.

(d) Determination of the acetylsalicylic acid content of aspirin commercial. Proceed as in section “c”, assessing the acid content acetylsalicylic in the synthesized product. Record the ml of titrant spent. (Drug Interaction)

3. Materials and reagents.

  • 4 beakers of 100 ml,
  • 1 pipette of 10 ml,
  • 1 pipette of 2 ml,
  • 1 test tube,
  • 1 beaker of 600 ml,
  • 1 watch glass,
  • 1 glass rod,
  • 1 heating plate,
  • 1 Buchner funnel,
  • 1 250 ml kitasate flask,
  • 2 Erlenmeyers of 100 ml,
  • 1 burette,
  • 1 mortar,
  • Vacuum horn,
  • Filter paper,
  • Salicylic acid,
  • Acetic anhydride,
  • Ethanol,
  • Na-OH 0.1N,
  • 85% phosphoric acid solution,
  • Crushed ice.

4. Security measures and waste disposal:

At all times the general indications that are comment in the annex on security.

It will be essential to wear a robe, safety glasses and calculator. Special care will be taken in handling of acid and base solutions.

Laboratory group:

Date of the practice:


Salicylic acid having molecular weight (MW) = 138.12 grams/mole.

Acetic anhydride having molecular weight (MW) = 102.09 grams/mole.

Acetylsalicylic acid molecular weight = 180.16 g / mol Acetylsalicylic acid mass obtained in: –

Synthesis of aspirin…………………………………………………….. grams – Recrystallization (before drying in the oven)………… grams –

Recrystallization (after drying in an oven)……. grams – Synthesized moles (after oven drying)…. moles 1) Determination of the humidity of the crystals without drying – Humidity ………………………………………………….% 2) Calculation of the yield of the reaction.

Theoretical acetylsalicylic acid mass (-)……………….. grams -Performance……………………………………………….% (-) Assuming that the reaction is totally displaced towards the products and that there are no losses during the reaction process. 3) Calculation of the purity of the acetylsalicylic acid obtained. – Mass of heavy acetylsalicylic acid…………………. gr – Volume of Na-OH spent……………………………… ml – Purity ………………………………………………………%

(4) Calculate the amount of acetylsalicylic acid in a tablet commercial. – Heavy aspirin mass………………………………… grams – Volume of Na-OH spent……………………………… ml – Purity………………………………………………………%


1) What role does phosphoric acid play in the reaction?

2) What type of reaction belongs to the synthesis of aspirin?

3) Why is the purity of commercial aspirin not 100%?

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