The Synthesis of Aspirin Monitored by Thin Layer Chromatography

Alexandra Zambanini

Introduction

Chromatography is a technique that is used to separate two or more compounds. Thin

layer chromatography (TLC) is a specific type of solid-liquid chromatography, in which the

stationary phase is the solid absorbent, and typically polar, while the mobile phase is one or more

liquid solvents that are of different polarity than the stationary phase. The process of TLC

works by manipulating the equilibrium between adsorbed and free molecules of each compound.

This is done by adjusting the polarity of the mobile phase, polarity of the stationary phase or

polarity of the molecule’s groups and size of the molecules; however the stationary phase is

typically alumina or silica gel, both very polar, so in most cases the former will be the main

determinate in molecular equilibriums. Assuming a polar stationary phase and a less polar

mobile phase are used, molecules with greater polarity will have an equilibrium that lies in the

direction of adsorbed molecules, so less will be in the free state or mobile phase. The opposite

would be true for less polar molecules in this particular instance. The less polar molecules,

concentrated in the mobile phase, will elute faster and move farther on the TLC plate than the

more polar molecules, which will move more slowly and not as far up the plate.

When determining an appropriate mobile phase solvent for TLC, a trial and error method

is employed. The first trial should be done using a nonpolar solvent, and the resulting spots

should then be analyzed. If neither of the spots has moved significantly, a more polar solvent is

added to the non polar solvent. Trials with different ratios of polar and nonpolar solvents are
done. The resulting plates and their respective spots are compared to determine which solvent

mixture facilitated the best results.

The equipment specific to micro scale TLC that will be used in this particular experiment

is very basic. Two four ounce TLC jars will be used as developmental chambers, and will

contain the mobile phase, four centimeter filter paper saturated with solvent, and the spotted TLC

plate that acts at the stationary phase. TLC will be used in the synthesis of aspirin, to monitor

the reaction.

In this experiment, acetylsalicylic acid, commonly known as aspirin, will be synthesized.

The first synthesis of acetylsalicylic acid was done in 1853 by the French chemist, Charles

Frederic Gerhardt. This compound has very important medicinal purposes, including its anti-

clotting, fever reducing, anti-inflammatory and pain relieving properties. Aspirin is a universally

recognized and consumed drug; therefore it’s mechanism of synthesis is of great significance.

This synthesis occurs through acetylating the phenolic substituent of salicylic acid using acetic

anhydride, which produces an ester in place of the phenolic group:

It is to be approached with caution, because in the presence of moisture from the air, acetic

anhydride will decompose readily.

 The purpose of this experiment was to synthesize aspirin. The study employed

techniques of crude melting point and literature melting point comparison, as well as Nuclear

Magnetic Resonance spectroscopy to analyze the purity and identity of the product, respectively.

The product, acetylsalicylic acid, was purified via simple recrystallization.

Experimental

Before beginning the synthesis of aspirin, an appropriate mobile phase for TLC of

salicylic acid and acetylsalicylic acid was determined. Following the suggested trial and error

method, different ratios of the nonpolar solvent, hexanes, and more polar solvent, ethyl acetate

were tested on salicylic and acetylsalicylic acid standards to determine the ideal solvent. The

following data was obtained:

Table 1. TLC Mobile Phase Experimentation Data

Mobile Phase % Ethyl Acetate %Hexane Salicylic Acid

Mixture Acetylsalicylic

Composition # Acid

1 100 0 .52 .52

2 90 10 .71 .71

3 70 30 .636 .636

4 50 50 .537 .537

5 30 70 .417 .383

6 20 80 .263 .263

7 10 90 .22 .185
8 0 100 0 0

The synthesis of aspirin was done in the following way: Salicylic acid (.103 g, .746

mmol), acetic anhydride (250 μL, 2.64 mmol) and phosphoric acid (85%, one drop) were added

to a test tube, which was then corked and shaken gently until most of the salicylic acid was

dissolved. The test tube was then submerged in hot water.

TLC was used to monitor the reaction, using a mobile phase with a hexane: ethyl acetate

ratio of 70:30. TLC was done on the reaction solution every fifteen minutes, using salicylic and

acetylsalicylic acid as standards. Salicylic acid is more polar than acetylsalicylic acid, therefore

the latter should move farther up the plate. When two separate spots became visible, the reaction

was progressing and if the spot that has traveled farther up the TLC plate, which is

acetylsalicylic acid, was bigger than the other spot, there were more product than reactants.

When there was only one spot observed on the plate, that matched that of the acetylsalicylic acid

standard, the reaction was finished.

When TLC determined the reaction was finished, the test tube was removed from the hot

water and water (700 μL) was added to the solution. The solution was cooled to room

temperature then placed in an ice bath to induce recrystallization of the product. The crystals

were isolated using vacuum filtration with a Hirsch funnel apparatus, then allowed to dry for

approximately one week on a piece of filter paper. Aspirin was isolated as a white, crystalline

solid (.080 g, 61.3% yield); melting point is 134-136℃ (uncorrected, as observed from

recrystallization product) and 1H-NMR spectrum was obtained.

Table 2: 1H-NMR Data, Obtained with Deuterated Chloroform Solvent on a 60 MHz NMR
 Significant Signals

Integration Value Splitting Pattern Position (ppm)

A 3H Singlet 2.4

C 1H Doublet 8.1

D/E 5H Complex multiplet 7-7.7.8

Results, Discussion and Conclusion

The data in Table 1 shows that the ratio of 70:30, hexanes to ethyl acetate led to the best

separation of the compounds salicylic and acetylsalicylic acid. It proved to be a good choice of

solvent system because the spots corresponding with each compound were clearly separated and

visible on the plates. This method was successful in monitoring the reaction because it showed

the acetylsalicylic acid spot, assumedly the one that traveled further up the plate because it is less

polar than salicylic acid, gradually getting bigger until the spot finally began to remain the same,

indicating the reaction had gone almost to completion.

The synthesis of aspirin proceeded accordingly, proving this method of synthesis is very

useful. The compounds, salicylic acid and acetic anhydride, reacted to produce acetylsalicylic

acid in solution. The yield for the reaction was 61.3%. This yield seems justifiable due to the

fact that it is unlikely for reactions to go to completion, it is difficult to get all the starting

material to react and there was insufficient time to allow for complete recrystallization. Also,

transfer of the product may have resulted in a lower yield because this is a microscale experiment.
 The melting point range of the crude product was 134-136℃. This melting point is the

exact literature melting point range for acetylsalicylic acid. This result indicated that the product

was pure enough for further spectral analysis.

The obtained 1H-NMR data in Figure 1 (appendix) produced three significant peaks.

Peak A indicated the presence of a methyl group attached to a carbonyl, which signifies the

probability of the sample being acetylsalicylic acid. Peaks C, D and E all indicated the presence

of the aromatic ring. One important signal was absent from the data, and that is the theoretical

broad singlet at approximately 11.0-12.0 ppm, indicating the presence of the alcohol attached to

a carbonyl; however, this does not suggest that the product is not acetylsalicylic acid, rather it is

an indicator that perhaps the product still contained traces of water, which would cause rapid

transfer of the proton on the carboxylic acid, inhibiting production of a signal. So, the results of

this data confirm the results of the melting point and TLC data, in verifying that the product

obtained was acetylsalicylic acid.

In conclusion, TLC was very valuable in monitoring the reaction of salicylic acid and

acetic anhydride. Techniques of analysis, namely melting point comparison and 1H-NMR,

served their purpose in determining the purity and identity of the product; however for future

experimentation, enhanced drying techniques should be used to ensure an even more desirable
1
H-NMR spectrum. These methods of analysis concluded that the reaction confirmed the

predicted results and produced a reasonable amount of the desired product, aspirin.

References

Adams, Candace. Chapter 7, TLC as a Method to Monitor the Synthesis of Aspirin Data.

October 5, 2009.
Anderson, Adam. Chapter 7, TLC as a Method to Monitor the Synthesis of Aspirin Data.

October 5, 2009.

Bolinski, Cara. Chapter 7, TLC as a Method to Monitor the Synthesis of Aspirin Data,

October 5, 2009.

Minard, B.; Masters, K.M.; Bortiatinski, J.; Halmi, T.; Williamson, K. “Lab Guide For

Chemistry 203 & 213B”, 2009-2010 pp.165-183