Synthesis of aspirin

Scientific report
Synthesis of aspirin

Abstract
The aim of this experiment was to produce aspirin with an optimized level of purity. In order to get to the desired result two procedures were followed; the first being the hydrolysis of methyl salicylate yielding to the production of salicylic acid and the second being a second purification through the recrystallization of the aspirin. As a result, we obtained 6.4g of aspirin with a good purity level and a satisfying yield of 72%.

Introduction

The discovery of aspirin resulted from the work of several scientists at different moments in history. The prelude to the creation of aspirin was the discovery of the pain and fever relieving powers of salicin (contained in willow bark and leaves) by the Greek physician Hippocrates in 400 BC (Bayer Healthcare LLC, 2008). The next step was the creation of Salicylic acid, the main prerequisite to the formation of aspirin by a German scientist in 1832. It is also in Germany that aspirin was synthesized for the first time. This main scientific discovery was performed by Felix Hoffman in the city of Bayer. Afterwards, the popularity and use of aspirin increased very rapidly and this product soon became the first drug worldwide. Nowadays it can be obtained without prescription, generally under the form of tablets and is used to calm many kinds of pains (e.g. rheumatism, lumbago and neuralgia) as well as fever. During the late 20th century other beneficial effects were found in aspirin and expanded its usage to the prevention of strokes in men and heart attacks. In the experiment described here aspirin was from methyl salicylate. The experiment was formed of two parts during which we first hydrolyzed the initial product to form salicylic acid and then induced the esterification of this molecule in order to form aspirin.

Materials and Methods

Hydrolyse of methyl salicylate
Products and instruments used
· Gloves and glasses
· Reflux apparatus
· 5M NaOH
· 7.5 g methylsalicylate (liquid)
· 3M H2SO4
· Boiling stones
· Round bottom flask
· Cork holder for round bottom flask
· Heating mantle
· Reflux condenser and tubing
· Glass beaker 125 mL or more
· pH-paper
· Ice
· Büchner funnel
· Water vacuum pump
· Filter paper
· Sample container

Safety considerations

- NaOH: Sodium hydroxide can cause serious damage to the eye in case of contact (Socrates Comenius & Education and Culture, 2006). Therefore any contact should be followed by prolonged and medical help. This molecule, in its solid state or dissolved is corrosive and should be prevented from being in contact with the skin or swallowed. In case of skin contact abundant rincing and medical aid is required, the latest is also required in case of swallowing. Finally, one should be careful when sodium hydroxide solid dissolves in water as significant heat is released.
- Methyl salicylate: Ingestion of this molecule is very hazardous, it can lead to coma and requires medical aid (Sciencelab.com, 2005). Skin and eye contact should be prevented as it causes irritations. Inhalation is dangerous and must be followed by medical attention. Explosion can be provoked by mechanical impact on the product or static discharge.
- Sulfuric acid: Contact with the skin causes severe burns (General Chemical, 2003). Contact with the eyes causes irritation, corneal burns, conjunctivitis, can lead to severe injury and even blindness. Inhalation is hazardous as it can cause irritation or corrosive burns in the respiratory system. Ingestion causes burns of the mouth, throat or stomach and can lead to death.

Procedures

We first added 7.5g of methyl salicylate to a solution of 5 M NaOH contained in a round bottom flask. We then added a few boiling stones in order to create an agitation within the solution during the time it is heated. The solution was then put in a heating mantle and connected to a reflux condenser in order to avoid evaporation of the volatile products contained in the solution. After 20 min of heating we poured the solution obtained into a 125mL beaker and added 3 M H2SO4 until the pH reached 3. Then we could observe the formation of white crystals of salicylic acid. In order to let the crystallization proceed we placed the beaker containing the last solution into a container filled in with ice. After the crystallization was over we filtrated the solution using a Büchner funnel. At this point we had to be careful not to lose a part of our product in order to get the maximum yield in the end. After the salicylic acid was separated from the liquid phase of the solution we collected it and put it in the stove to let it dry.

Esterification of salicylic acid

Products and instruments used
· Gloves and glasses
· Acetic Anhydride, about 15 mL
· Ethanol, keep away from flames
· Salicylic Acid, about 10 g and/or your own produced salicylic acid, do not inhale!
· A few drops (10) concentrated sulfuric or phosphoric acid
· Distilled water (flask)
· Sample container (red) for crystals
· 1 hotplate and 1 warming mantle
· 250 mL round glass flask + cork standard
· Büchner funnel with rubber stopper and filter paper
· Suction flask and Rubber hose to filter the crystal suspension
· Weighing paper and spoon
· Thermometer
· Ice
· Clamps and aluminum bars to build experimental set-up
· Glass test tubes to test aspirin purity

Safety considerations
- Acetic anhydride: This substance is highly corrosive and may cause serious burns in case of contact with the skin of the eyes (Socrates Comenius & Education and Culture, 2005). In case of contact with any part of the body abundant rincing is required as well as medical assistance in some cases. The acetic anhydride's corrosive power also induces hazardous inhalation or swallowing. Medical assistance is compulsory in this case. Furthermore, one should be careful when mixing it with water or alcohols as it may react violently.
- Ethanol: This substance can irritate the skin and cause serious irritation in case of contact with the eyes (Socrates Comenius & Education and Culture, 2004). Ingestion of large amounts can damage the liver as well and other organs, increase the risk cancer and even be fatal. Lastly, it is a very flammable substance and therefore one should be careful not to bring it too close to a source of fire.
- Salicylic acid: See first part of the experiment.

Procedure

Fig1: Production of aspirin from salicylic acid.
We removed the 7.1g of dry salicylic acid from the stove and added it to a solution of acetic anhydride in a 250mL round flask under the hood in order to avoid inhalation of dangerous products. Then we added a few drops of H3PO4, an oxidant necessary for the esterification. We chose this oxidant instead of a stronger one in order to produce aspirin of white colour. Then we heated the flask in a water bath until 80 Celsius degrees in order to trigger the complete dissolution of the salicylic acid. Once there was no solid remaining in the solution we let it cool down by slowly adding fresh water. At this point we tried to add water progressively in order to make the temperature of the solution decrease slowly and the crystallization proceed in an optimal way in order to form large crystals of aspirin. We washed and filtered the solution in a Büchner funnel in order to separate the solid product. The objective of washing the crystals was to remove the acetic and phosphoric acids (molecules soluble in water). Once the solid was collected we added a pinch of crystals in a bit of FeCl3 in order to test purity. As the slight colouration of the solution indicated that there was some salicylic acid left in the aspirin, we performed a purification and recrystallisation of our product. This operation was done by adding boiling ethanol to the impure product. Ethanol dissolves aspirin but not salicylic acid. Then the solution was let to cool down slowly in order to induce recrystallization of aspirin. The cooling down was induced by a progressive addition of fresh water. Afterwards we filtered and washed the solution obtained through the Büchner funnel, collected the crystals and performed a new purity test. Finally we put the total yield of aspirin in the stove in order to let it dry.

Results and Discussion
Results during the experiment
After we let the aspirin form, crystallize and being filtered we tested its purity using FeCl3. The observation was that after having added a few drops of the test substance to the aspirin crystals the solution obtained was very slightly violet. This means that even though the purity was high at this stage there was still some salicylic acid left among the aspirin crystals. Nevertheless, after purification of aspirin we reproduced the test and observed the formation of a colourless solution, which meant that the amount of salicylic acid left in the aspirin was negligible. In the final aspirin obtained we could observe the presence of large crystals, which signified that the crystallization process had been slow enough. Furthermore, after a time spent in the stove the product had a flaky appearance.
Moreover, we can note that the induction time for crystallization was 1min 55s.

Calculation of the yield

Theoretical mass of aspirin obtained derived from the amount of salicylic acid:
The mass of salicylic acid obtained was 7.1g. As the molar mass of this molecule is 138.123g/mol we can conclude that we had 0.0514 moles of salicylic acid. As the esterification of one mole of salicylic acid yields one mole of aspirin we can conclude that the amount of aspirin obtained, derived from the amount of salicylic acid, is 0.0514 moles. This equals to 0.0514*180.2g or 9.01g of aspirin. These results are surprizing considering the amount of methyl salicylate we started with. We can assume that there was a surrestimation of the mass of salicylic acid collected, this might be due to the fact that there was still some water or other products present in it when it was weighted.
Theoretical mass of aspirin derived from the mass of methyl salicylate we started with:
7.5g of methyl salicylate were used in the beginning of the experiment. As the molar mass of this molecule is 152.1494 g/mol we can conclude that there were 0.0493 moles of methyl salicylate. According to this the theoretical mass of aspirin obtained is 0.0493*180.2g or 8.88g. The mass of aspirin obtained was 6.4g, which means that the yield of the reaction was 72% ((6.4/8.88)*100).

Discussion

The results obtained are satisfying as the recovery is 72% and the purity was high. However it would be possible to improve them by finding ways to get a higher yield. It may be possible to get a higher recovery if the equilibrium of a reaction is moved by removing the products obtained. Practically, this could be performed during the second part of the experiment; when the esterification proceeds. At this point water is formed and can be removed if let to evaporate. Therefore, in order to improve the yield of aspirin synthesis it would be an interesting idea to find a way to let the water evaporate from the solution without loosing other products. Moreover, it may be possible to get more aspirin in the end by reducing the amount of water when washing the crystals. Indeed, when the solid aspirin is being washed it is possible that abundant amounts of water cause the crystals to go through the filter, thereby reducing the yield.

Conclusion

During this experiment we managed to produce aspirin with a good level of purity and little loss of reactive (satisfying yield). In the industrial sector economical aspects of production are of first importance and therefore it is important to be aware of the rules and methods that could lead to a higher yield. As we explained before, this can be performed by removing products during the different parts of aspirin synthesis or by limiting the amount of water used to wash the aspirin before and after purification and recrystallisation.

References

Bayer HealthCare LLC. (2008). The History of Aspirin. Retrieved April 4, 2008, from http://www.bayeraspirin.com/pain/asp_history.htm
General Chemical. (2003). Material Safety Data Sheet Sulfuric Acid. Retrieved April 5, 2008, from http://www.genchemcorp.com/pdf/msds/Sulfuric%20Acid%20-%203-01.pdf
Sciencelab.com. (2005). Material Safety Data Sheet Methyl salicylate MSDS. Retrieved April 5, 2008, from http://www.sciencelab.com/xMSDSMethyl_salicylate-9927362
Socrates Comenius & Education and Culture. (2004). Chemical Safety Data: Ethyl alcohol. Retrieved April 6, 2008, from http://ptcl.chem.ox.ac.uk/~hmc/hsci/chemicals/ethyl_alcohol.html
Socrates Comenius & Education and Culture. (2005). Chemical Safety Data: Acetic Anhydryde. Retrieved April 6, 2008, from http://ptcl.chem.ox.ac.uk/~hmc/hsci/chemicals/acetic_anhydride.html
Socrates Comenius & Education and Culture. (2006). Sodium Hydroxyde. Retrieved April 5, 2008, from http://ptcl.chem.ox.ac.uk/~hmc/hsci/chemicals/sodium_hydroxide.html