Experiment to Synthesize, Purify and Determine Percentage Yield of Aspirin

Introduction

Aspirin, chemically known as acetylsalicylic acid, is an over-counter pharmaceutical drug commonly used to reduce pain and inflammation. Salicylic acid, in which aspirin is organically derived from, is bitter and irritable to the stomach, so in order to form the drug, salicylic acid and acetic anhydride must be reacted in the presence of an acid based catalyst. However, this reaction is slow and has a relatively low yield. If acetic anhydride is used instead of acetic acid, the reaction is much faster and has a higher yield. “Acetylsalicylic acid does not have the bad taste and stomach problems of salicylic acid. Once acetylsalicylic acid is absorbed from the intestine, it is converted back to salicylic acid” (CHEM 322, 2013). It is an aromatic compound containing both a carboxylic acid and ester functional group. German chemist Felix Hoffman was the first to experiment in the synthesizing of aspirin and was credited with the success of the revolutionary drug. The experiment conducted in this report will synthesize, purify and determine the percentage yield of aspirin. The purity of the product formed will then be determined by a series of tests. Iron (lll) Chloride testing, melting point range and Thin Layer Chromatography tests will all be conducted.

Figure 1: Reaction produced in the forming of Aspirin.

Figure 2: Compound structure of Aspirin containing carboxylic acid and ester functional groups.

Equilibrium of Aspirin

The state in which the rate of the forward reaction equals the rate of the backward reaction can be defined as chemical equilibrium. This also means that no net change in concentrations of reactants and products. Many factors influence the state of equilibrium. Increasing the temperature will shift the equilibrium towards the endothermic reaction, whereas decreasing the temperature will shift in the direction of the exothermic reaction. As well as temperature, a catalyst can change the mechanisms of a reaction by lowering the activation energy equally for both the forward and backward reaction.

Figure 3: Equilibrium Graphed

Le Chatelier’s principle and esterification of the phenolic hydroxyl group of salicylic acid will be used to synthesize aspirin within this reaction. Le Chatelier’s principle states that if a constant, in this case a catalyst, is applied to a system in equilibrium, “the equilibrium will shift so as to tend to counteract the effect of the constraint.” (Linfield, 2015). The reaction that is used for the synthesis of aspirin shown below (Figure 4) uses an excess of acetic anhydride, sulfuric acid as a catalyst, and heat to push the equilibrium toward the products.

Figure 4: Equilibrium of Aspirin

Ferric Iron (lll) Chloride Test

Salicylic acid contains a phenol group, and phenols are known to be irritating to the stomach, in the original synthesis of aspirin, The Bayer Company this phenol group with an ester. This esterified compound, which is acetylsalicylic acid, proved to be significantly less irritating than salicylic acid. Within the process of synthesizing aspirin, the phenol group on the salicylic acid forms an ester with the carboxyl group on the acetic acid, seen below in Figure 4.

Figure 5: Carboxyl and Ester Groups forming.

Iron (lll) Chloride is known to react with phenol groups. A phenol group is distinguished as the -OH that is coming off a ring system. If iron chloride is added to a reactant containing a phenol group, the solution would turn purple. Aspirin does not contain a phenol group, however, salicylic acid, contains a phenol group. Therefore, iron chloride is added to aspirin samples to test for the presence of unreacted salicylic acid. If there is unreacted salicylic acid, the substance will turn a deep purple colour, if not the substance should show a yellow colour.

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Thin Layer Chromatography Test

Thin Layer Chromatography (TLC) is a common technique used in order to separate a mixture of compounds, as well as identifying and determining the purity of a compound. Through capillary action, “compounds can separate due to their different affinities for the mobile and stationary phases.” (Mohrig, 2012).  The stationary phase in TLC can be described as the adsorbent, coated on a sheet of metal. It is usually silica or alumina. The mobile phase is the solvent which slowly rises because of the capillary action and polarity. The polarity of a compound is determined by its functional groups and masses. Salicylic acid is more polar than aspirin. Acetylsalicylic acid contains an ester and acetyl functional groups, therefore giving it a larger mass than salicylic acid. Hydroxyl groups are more polar than acetyl groups, indicating that salicylic acid is more likely to absorb to the silica because of its hydrogen bonding. Furthermore, “the acetylsalicylic acid will be in a free state and travel further because the ester and acetyl functional groups no longer have hydrogen bonds that bond to the polar silica plate.” (ChemGuide, 2016). If an aspirin sample is completely pure, only one spot will be displayed on the TLC plate. The crude aspirin might have two different spots because it is not entirely pure. UV light is used to visualize the compounds on the plate.

Reflux

Reflux condensing is the application of heat to a reaction to overcome the issue of evaporating too much solvent and drying the reaction vessel. Reflux involves heating the chemical reaction for a specific amount of time, while continually cooling the vapor produced back into liquid form, using a condenser. Because the vapors produced above the reaction continually undergo condensation, it guarantees that the temperature of the reaction remains constant.  Reactants for reflux experiments are usually both liquids, but can be both solid and liquid. The temperature at which the reaction is heated depends on the boiling points. Whilst the reaction is taking place, the condenser is always completely filled with water to ensure efficient cooling. “The vapors, which are given off from the liquid reaction mixture, change from gas phase back to liquid phase due to heat loss. This then causes the liquid mixture to fall back into the round bottom flask.” (University of Birmingham, 2019).

Figure 6: Reflux Condenser Setup

In a reflux reaction with aspirin, the best yield should be obtained by heating the mixture of reactants around above the solvents boiling point. This will allow for optimal heat and higher rate of collisions during reaction, allowing more product to be produced. Yet if the reaction is heated at too higher temperature, the reflux can fail and gas can escape, causing loss of product.

Recrystallization

After the crude aspirin product is prepared, it is likely to be impure and needs to be purified by the process of recrystallization, the solvent used for this process is ethanol and water. In general, recrystallization is a procedure for purifying compounds. In order to recrystallized the crude product the solid must be dissolved in an appropriate solvent at a high temperature.  If a solid product is dissolved in hot solvent first, crystals should form when the hot solution begins to cool. For example, an ice-water bath is often used to cool the solution. The solid should be recovered with greater efficiency at these temperatures, provided the solvent itself does not freeze.

Melting Point Test

The Carboxylic acid group in aspirin’s structure allows molecules of aspirin to form hydrogen bonds with each other. Because of the permanent dipole bonds within the aspirin molecule. Because of such a strong attraction, it indicates that aspirin’s melting point is relatively high. However, the melting point of salicylic acid is expected to be higher than the melting point of aspirin as there are more hydrogen bonds formed which means that more energy is needed to break the bonds. So when testing the purification of aspirin, pure salicylic acid’s melting point should be higher than the aspirin sample.

Research Question:

What are the optimum conditions for the manufacture of aspirin?

Aim:

To determine the effect of a catalyst and reflux methods on the synthesis of salicylic acid and acetic anhydride.

Hypothesis:

If the variables being tested alter the manufacture conditions, in which the aspirin can be synthesized then it can be proven that they significantly affect the outcome, producing in pure aspirin.

Preliminary Experiment

Controlled Variables:

Catalyst: The purpose of a catalyst within a reaction is accelerate it. As well as speeding up the reaction, it presents an alternative way for the reaction to occur, therefore lowering the activation energy needed. Unlike other compounds within the mixture, a catalyst lasts the reaction without being changed. The two catalysts used in the following experiment are sulfuric acid and phosphoric acid.

Reflux and Non-Reflux: The aspirin sample being manufactured will be synthesized using two different methods, processed through a reflux condenser and then heated alone with a reflux condenser. The purpose of this is to test whether refluxing the product has effect on its purity.

Method:

REACTION WITH REFLUX

1. 2g of 2-hydroxybenzoic acid was weighed out and then transferred to the reflux flask.
2. 5ml of acetic anhydride was added to ensure that it would be present in excess.
3. The flask was continuously swirled after the addition of ethanoic anhydride.
4. A total of 8 drops of sulfuric acid (60% concentration) was added, the flask continued to be swirled after each drop.
5. Once the mixture was cooled two anti-bumping granules were added to help the mixture boil smoothly.
6. The mixture was then refluxed for 20 minutes.

MANUFACTURE & PURIFICATION:

Used Method A:

1. 150mL of cold distilled water and 10mL of diluted sulfuric acid (2moL) were placed in a 250mL beaker.
2. Very slowly, the reaction mixture was poured into the water.
3. The mixture was stirred and left to stand for roughly 15 minutes.  Both 2-hydroxybenzoic acid and aspirin are almost insoluble in acidic solution, and will separate as fine white crystals.
4. The filter paper was cut to shape to fit the Buchner funnel attached to the vacuum filtration equipment.
5. The watch glass and filter paper were pre-weighed.
6. The crystals were rinsed out onto the filter paper and dried through the vacuum filtrations system.
7. The crystals were then warmed in an oven roughly set to 105^oC.
8. The mass of the raw product was then determined.
9. Calculate the % yield of raw product as a % of the mass of aspirin that was theoretically possible if all of the 2-hydroxybenzoic acid was converted to aspirin.

RECRYSTALLIZATION

1. The solid was transferred from the filter paper to a clean, dry 125ml conical flask.
2. The crude product was then dissolved in 5ml of warmed (via water bath) 100% ethanol.
3. If the crystals do not all dissolve, add 2 mL more of the ethanol and continue to warm the mixture to dissolve the crystals.
4. 50ml of warm water was added to the clear alcohol solution, per 20ml. The flask continued to be heated in order to dissolve any forming crystals.  (17.5ml)
5. The flask was set aside to cool, close fully observed.
6. Once the crystals had formed, the flask was cooled with cold water. The crystals were then formed and the process went to completion.
7. After 10 minutes of cooling, the beaker was placed in an ice bath and crystals formed after 1 week.
8. The filter paper was cut to shape in order to fit the Buchner funnel.
9. The watch glass and filter paper were pre-weighed.
10. The crystals were scraped out on to the filter paper from the Buchner funnel to the watch glass, drying them through vacuum filtration.
11. The mass of the purified recrystallized product was determined and recorded. 

Purification Test Results

Melting Point Test:

Non-Reflux Sulfuric Acid

Reflux Sulfuric Acid

Non-Reflux Phosphoric Acid

Reflux Phosphoric Acid

Thin Layer Chromatography Plate Test:

Non-Reflux Sulfuric Acid                                                              Non-Reflux Phosphoric Acid

Trial 1                                                                                               Trial 1

Salicylic Acid

Store Bought Aspirin

Own Aspirin Sample

Salicylic Acid

Store Bought Aspirin

Own Aspirin Sample

Reflux Sulfuric Acid                                                                     

Trial 1                                                                                              

Salicylic Acid

Store Bought Aspirin

Own Aspirin Sample

Table 1: Synthesis of Aspirin Non-Reflux Sulfuric (Trial 1)

Table 2: Synthesis of Aspirin Non-Reflux Sulfuric (Trial 2)

Table 3: Synthesis of Aspirin Reflux Sulfuric (Trial 1)

Table 4: Synthesis of Aspirin Reflux Sulfuric (Trial 2)

Table 5: Synthesis of Aspirin Non-Reflux Phosphoric (Trial 1)

Table 6: Synthesis of Aspirin Non-Reflux Phosphoric (Trial 2)

Table 7: Synthesis of Aspirin Reflux Phosphoric (Trial 1)

Table 8: Synthesis of Aspirin Reflux Phosphoric (Trial 2)

Analysis and Discussion

The initial reaction and formation of the product produced excessive samples both raw and pure aspirin. The ‘raw’ sample, however, seemed to retain more water than the other sample and held a tackier texture. Through recrystallization of the aspirin, the pure sample turned out more like powder and much purer white in color. Once the samples were made, the tests to analyze them began. First, was the iron (III) chloride test in which each sample was combined with the iron solution to observe the color produced. The presence of salicylic acid creates a dark purple color, varying from sample to sample based on the amount contained. The raw and recrystallized samples both produce a relatively dark purple color, very different from the burnt orange colors of the store bought aspirins. The raw should have contained amounts of salicylic acid within the sample, although the recrystallized sample should have contained a smaller amount. This could have been due to a faulty recrystallization and/or the contamination of the samples. A vacuum filtration was used to filter out the crystals from the solution, which could have not completely filtered correctly. If the process was rushed, and the crystals were not let to dry long enough, the samples may have retained any bit of water and/or salicylic acid. However, pure synthesized samples produced slightly lighter purple colours, indicating the presence of salicylic acid. This proves a problem as the samples synthesized through the experiment should be pure. Whilst it is understandable that the raw sample holds hints of salicylic acid, the pure aspirin should have extracted the traces through the recrystallization process. This indicates the synthesized samples held a low percentage purity. 

When observing the given TLC plate however, the salicylic acid column contains a large spot that has travelled upwards. Suggesting the salicylic acid was completely dissolved into the sample, allowing the sample to run to the end of the plate. Yet when comparing it against the store bought aspirin, the store bought aspirin had a stronger presence. This shows that there was very few traces of salicylic acid within the store bought aspirin, being the most pure out of the three samples. In regards to the experimentally synthesized aspirin, the marks on the TLC plate fluctuate proving a presence of salicylic acid in the recrystallized samples. Finally, the melting point test proved that the synthesized samples, salicylic acid and store bought aspirin were accurate. Each sample melting under the heat fell within the normal ranges of each sample. While the melting point test proved to be the most accurate, the consistency of the other tests proved unreliable, questioning the purity of the sample synthesized.

Sample Calculations:

References

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