Synthesis of Aspirin by Green Chemistry Methods

Microwave irradiation method with base catalyst

A 30 mL test tube was used as reaction vessel for this reaction. Salicylic acid (1.3905 g, 0.0101 mol), acetic anhydride (3.80 mL, 0.0403 mol), and sodium carbonate, a white powder (0.2801 g, 0.00260 mol) were added to the reaction vessel. The test tube vessel was placed inside an empty beaker and heated inside a regular microwave oven four times for 30 seconds at 10% power. The crystallization and recrystallization of product was carried out the same way as it was for the conventional heating method. Interestingly, the crystallization of the crude product was very slow and required overnight formation inside a refrigerator.

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RESULTS

Reaction raw data

Salicylic acid:                 3.0367 g * (138.12 g / mol)-1 = 0.0220 mol         (Conv.)

        

                        1.3905 g * (138.12 g / mol)-1 = 0.0101 mol         (Micr.)

Acetic anhydride:        5.00 mL * (1.082 g / mL)*(102.09 g / mol)-1 = 0.0529 mol        (Conv.)

                        

                        3.80 mL * (1.082 g / mL)*(102.09 g / mol)-1 = 0.0403 mol        (Micr.)

Sodium carbonate:        0.2801 g * (105.9884 g /mol)-1 = 0.0026 mol

Sulphuric acid (97%):        8 drops (no exact knowledge of volume)

Table of reactions (units are all in moles)

Conventional method

Microwave method

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Acetyl salicylic acid (conventional heating method)

Theoretical

Mass of product:        3.96 g

Molar mass:                180.157 g/ mol

Moles of product        0.0220 mol

Melting point:                135°C

Experimental

Mass of product:         2.0761 g

Molar mass:                180.157 g / mol

Moles of product:        0.0115 mol

Melting point:         126-129°C

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Yield:                        Exp. moles (product) / Theo. moles (product) = 52.4 %

Acetyl salicylic acid (Microwave oven heating method)

Theoretical

Mass of product:        1.820 g

Molar mass:                180.157 g/ mol

Moles of product        0.0101 mol

Melting point:                135°C

Experimental

Mass of product:         1.5184 g

Molar mass:                180.157 g / mol

Moles of product:        0.00840 mol

Melting point:         128-132°C

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Yield:                        Exp. moles (product) / Theo. moles (product) = 83.5 %

DISCUSSION

Mechanisms

In the experiment, two different routes were used to achieve the final product. One route utilizes an acid catalyst, while the other route uses a base catalysis. It is good to start the discussion with the acid-catalyzed reaction because this method is the conventional way of synthesizing aspirin. It is also reputed as being higher yielding [3].

Fig. 1 – Protonation of acetic anhydride

The goal of adding a strong (mineral) acid is to protonate the acetic anhydride (see fig. 1) at one of its carbonyl groups. By doing so, a positive charge results on the carbonyl carbon.

Fig. 2 – Hydroxyl oxygen attacks carbocation

        The acid is said to be a catalyst because the oxygen on the phenol can more easily attack a carbocation than a partially positive carbon. The reaction between salicylic acid and the protonated acetyl anhydride results in a charged intermediate compound. From a kinetic point of view, this first unstable species is short-lived. It is clear that the anhydride wants to hydrolyze very readily.

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Fig. 3 – Final product formation

        The proton transfer in figure 3 sets up an intermediate that looks like the desired final product bonded to acetic acid (center). This is exactly what is desired because the acetic acid will favourably leave, forming a the final product (right).

Fig. 4 – All three species produced by the reaction

        As catalyst, the sulphuric acid regenerates itself to complete the synthesis of aspirin. As shown, the two products of the reaction are aspirin and acetic acid. The ASA is characterized as white crystals with the smell of vinegar caused by the acetic acid. Given that both sulphuric acid and acetic acid are highly soluble in water, the crude mixture was washed and vacuum filtered using water, and then recrystallized in water and ethanol to improve purity. Despite the efforts, the final product still possesses a vinegar smell. The characterization by spectroscopy, chromatography, and physical means will be discussed later to assess the purity of the crystals.

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Although sodium carbonate does not form hydroxide anions unless dissolved in water, by Brønsted-Lowry theory, the ability to take a proton makes it a base. Furthermore, by Lewis theory, the lone pairs on the oxygen atoms also make sodium carbonate a base. In figure 5, the carbonate abstracts a proton from the carboxylic group to form bicarbonate because this functional group is the stronger acid. The topic of acidity will be discussed later.

Fig. 5 – base-catalyzed reaction with salicylic acid

        The ionic character of the sodium salicylate makes attack on the carbonyl of acetic anhydride favourable. This forms an intermediate that requires a proton to hydrolyze and form acetic acid.

Fig. 6 – Attack on acetic anhydride

        The molecule produced in figure 6 is clearly very unstable. This short-lived molecule undergoes the reaction shown in figure 7 to form the two desired function groups: carboxylic acid and an ester.

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Fig. 7 – regeneration of sodium carbonate

        In figure 7, acetic acid leaves and subsequently causes intra-molecular rearrangement. As seen, the reaction generates acetic acid and the base catalyst. The two are eventually washed out using water. Although not mentioned, another compound that remains in the reaction vessel would be unreacted salicylic acid. By TLC, it is important to evaluate the amount of salicylic acid that has not participated in the reaction as well as other compounds that were not removed during the recrystallization of aspirin.

        It is important to understand that the acidity of the carboxylic acids is much greater than that of phenols. Therefore, to esterify the phenol requires more intricacy. In the case of the acid-catalyzed reaction, a nucleophilic attack was the method for coupling. The phenol has a more nucleophilic oxygen than the carboxylic acid, which then favours the reaction. For the base-catalysis, an intra-molecular rearrangement was the method for obtaining the proper structure given that carbonate will readily deprotonate the carboxylic acid, which then favours the attack on acetic anhydride.

As observed based on results, both acid (H2SO4) and base (Na2CO3) catalysis are viable for synthesizing acetyl salicylic acid. What is important in the case of this experiment is the heating method. In terms of yield, microwave heating provides a much higher yield compared to conventional heating. The only caveat is the longer crystallization time. As noted in the experimental procedure, the reaction mixture required overnight cooling to form ASA.

Heating

The use of microwave is just as simple as conventional heating, but the steps are different. In microwave heating, the reaction vessel should provide a lot of dead-volume because the reaction mixture can bump quite a lot. The bumping is caused by hot spots, which are inevitable when using a multimode reactor. When small regions of a body of liquid are heated beyond boiling point, it superheats; this means that a liquid exists beyond its boiling point. This is caused by the lack of nucleation sites [4] [5]. A liquid requires a nucleation site such as a bubble in order to boil. When the hot spots do manage to find such a site, either on the sidewall of the test tube, or a bubble that has just formed, bumping occurs; evaporation is then allowed to happen. Because of the superheating issue, microwave heating should proceed in poly-phase rather than in one heating period. Moreover, if the reaction involves compounds with low boiling points, it is important to heat at lower power so as not to cause superheating. For compounds such as acetone, it would be ill-advised to work with a microwave because of the issues mentioned above. For the sake of this experiment, none of the compounds are low-boiling enough to be problematic during microwave irradiation.

It is important to understand that superheating does not occur in conventional heating because the hotplate supplies enough heat to the imperfect glass surface to provide nucleation sites and cause boiling. This method is very different from microwave irradiation in which an electric field causes dipole rotation of a polar molecule. In this case, energy of rotation generates heat within the system. Which is better? Based on yield and melting point for this experiment, the microwave method is definitely better. Additionally, microwave ovens are generally more energy efficient than hotplates, which makes it the greener method [6]. Nevertheless, the quality of the aspirin is best characterized by spectroscopy.

Spectroscopy

The IR spectroscopic data closely matches literature results. In this experiment, both the KBr and Nujol methods of sample preparation were used to collect data. For the purpose of characterization, the KBr results will be used because there is no interference from the potassium salt. The spectroscopic data for both heating methods appear to be closely similar. At around 3000 cm-1, there is a broad signal with weak peaks spanning a large region. This is characteristic of aromatic compounds with –OH functional groups and conjugated carbon from C-H group stretching. At 1770cm-1 and 1710cm-1, the two sharp carbonyl peaks can be observed in which the former belongs to the ester and the latter belongs to the carboxylic acid. At 1450cm-1 and 1600cm-1, two more strong peaks can be seen. These indicate aromatic C-C bond stretching. Fingerprint matching can be made from 1300cm-1 and below. Interestingly, the fingerprint region for both spectrographs appears to be nearly identical to literature values. This indicates highly pure ASA. It is not all too surprising that this is the case because no solvent or third party reactant was used, except for the catalyst.

As for the 1H-NMR spectra, it is good to start the analysis with the aromatic region (~7-8.5 ppm). Given that two functional groups are attached to the 6-carbon aryl ring, 4 peaks are expected and are found. The hydrogen closest to the carboxylic group should be the most downfield, while the one closest to the phenol should be the most upfield. Both peaks should be doublets of doublets because they each have one nearest neighbour and all four protons are in different environments. The two hydrogens located in between have their peaks in between the two previously mentioned doublets and are expected to take on the shape of triplets of doublets because they have 2 nearest neighbours. For both the conventional heating and microwave heating methods, the aromatic region shows what is expected and with proper integration. Perhaps due to the poor resolution of a 200 MHz instrument or sample preparation flaw, for the conventional synthesis of Aspirin, the doublets of doublets (dd) and triplets of doublets (ddd) are not quite visible. In the microwave synthesis spectrum, the resolution was quite good and this phenomenon can be observed. Because no other resonance is seen in the phenyl region, one can suspect that no salicylic acid is present within the white crystals. The only other peak visible is the CDCl3 solvent impurity from trace chloroform at 7.26[7].

A peak is seen at 4.9 ppm, which indicates the presence of water. Despite efforts to dry the product, some water remains as impurity. To make certain of the identity of the target compound (Aspirin), a methyl peak is seen at 2.4 ppm and is the determinant peak in characterizing ASA from salicylic acid. The large peak of the methyl group has an integration value 3 times as large as that of each aromatic hydrogen. Based on NMR spectroscopy, it is possible to confirm the presence of final product.

Fig. 10 – TLC plate results; ‘Product’ denotes the pure crystals formed, ‘SA’ denotes the salicylic acid starting material and ‘AA’ denotes the acetic anhydride

        By further analysis using TLC, it becomes clear that two compounds are present. Using hexanes and ethyl acetate (5:1), one can see that both ASA (Rf = 9) and acetic anhydride (Rf = 4) are in the final product. Given the excess of acetic anhydride used, it is not all too surprising that some amount remains. The simplest way to remove this impurity is by washing the crystals with a lot of water given that the anhydride gets hydrolyzed into acetic acid in the presence of water.

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REFERENCES

1. Lancaster, Mike. Green chemistry: an introductory text. Cambridge: The Royal Society of Chemistry, 2002.

2. Badami, Bharati. Concept of Green Chemistry, Redesigning Organic Synthesis, RESONANCE. November 2008; pp 1041–1048.

3. Montes, Ingrid et al. A Greener Approach to Aspirin Synthesis Using Microwave Irradiation. Journal of Chemical Education. Vol. 83 No. 4 April 2006; 628–631.

4. Erné B. H. Thermodynamics of Water Superheated in the Microwave Oven. Journal of Chemical Education. Vol. 77 No. 10 October 2000; 1309–1310

5. "Superheating and microwave ovens" The University of New South Wales. Sydney, Australia. Consulted on 1 Oct. 2009.

6. “Consumer Energy center” California Energy commission. Consulted on 11 Jan. 2010.

7. Gottlieb, H.E. et al. NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities. J. Org. Chem. 1997, 62, 7512-7515

8. Spectral Database for Organic Compounds SDBS. (c) National Institute of Advanced Industrial Science and Technology (AIST). Consulted on 8 Jan. 2010