Synthesis of Aspirin with NMR - Structure Determination in Undergraduate Laboratory Courses

In most organic synthesis laboratories, synthesis of aspirin (acetylsalicylic acid) is a part of the curriculum for many undergraduate students (Figure 1). These courses are designed to teach synthesis and purification skills to the students. Using the Fourier 300 HD spectrometer, students can now apply NMR to track the quality of their products and reactants in an easy and intuitive manner (Figure 2).

Aspirin

Figure 1. Aspirin

The Fourier 300 HD spectrometer is a small footprint NMR system consisting of magnet, Fourier console and workstation. It is extremely compact, lightweight and requires only standard AC power and cryogens. The Fourier spectrometer operation is easy to comprehend and can be completely automated—from sample submission to data collection, processing and printing.

Figure 2. The Fourier 300 HD spectrometer is a small footprint NMR system consisting of magnet, Fourier console and workstation. It is extremely compact, lightweight and requires only standard AC power and cryogens. The Fourier spectrometer operation is easy to comprehend and can be completely automated—from sample submission to data collection, processing and printing.

Before checking the quality of products, it is recommended to prepare samples of the acetic anhydride, salicylic acid, and the reactants. Approximately 10 mg of salicylic acid should be dissolved in 1 mL deuterated dimethyl sulfoxide (DMSO-d6), and about 550 µL should be pipeted into a 5 mm NMR tube to establish a filling height of 40 mm. The sample has to be colorless with no visible particulates. To prepare the second sample a few drops of acetic anhydride are added to DMSO in an individual NMR tube with the same filling height. For aspirin synthesis, mL of acetic anhydride should be added to 500 mg salicylic acid in a 50 mL Erlenmeyer flask.

Be sure to take all necessary safety precautions and carefully add 1 or 2 drops of the catalyst, 85% phosphoric acid. The flask should be swirled to mix the reactants well, and then subsequently heated in a water bath (70–80ºC) for a period of 10 minutes to form the acetic acid and aspirin as a byproduct. Subsequent to heating, approximately four drops should be carefully added, followed by another 4 mL of distilled water. The mixture should be cooled in an ice bath. These procedures are performed to destroy any surplus acetic anhydride and allow the product to crystallize. Approximately 10 mg of the unpurified aspirin can be gathered and dissolved in 1 mL deuterated DMSO to set up a third NMR sample.

The solid aspirin is purified using a Buchner funnel with an aspirator to filter it. The crystals have to be washed with 2–3 mL of chilled water. The impure aspirin can be recrystallized with 10 mL of 95% ethanol and again cooled in an ice bath. The purified aspirin has to be gathered by filtration as before. The crystals are dried, and another 10 mg is dissolved in 1 mL DMSO-d6, so that a fourth NMR sample tube can be prepared.

Structural Characterization of Organic Compound Aspirin

The simplest way to operate NMR spectra is in automation mode. If the user owns a SampleXpress Lite™ on a Fourier spectrometer, then the samples can be placed in the holders. Otherwise, the samples will have to be submitted one by one when prompted. Automation can be still used.

On the workstation, the TopSpin™ software has to be opened and the automation program “IconNMR” has to be started by clicking the “ACQUIRE” tab, then “OPTIONS” and select “Icon NMR Automation”. Within IconNMR under “Automation”, the respective holder number has to be clicked and a name has to be selected, a solvent (DMSO), an experiment (PROTON), and a title has to be typed in.

The experiment is then submitted, and the “Start” button is clicked, with the remaining samples being submitted. When all experiments are completed, which takes around 2 minute per experiment, users will receive a printout through via email or paper, or they can examine the spectra on the monitor screen within the TopSpin.

Users can easily introduce more experiments, including 2D ones, such as HSQC, COSY, or HMBC. The latter would be one method to establish that aspirin has been synthesized rather than just developing a mixture of acetic anhydride and salicylic acid. The salicylic acid proton spectrum has four signals in the aromatic region at 7.8 (dd; 6), 7.5 (ddd; 4) and a multiplet at 6.9 ppm (dd / ddd; 3/5), and also a solvent signal at 2.5 ppm. The hydroxy and carbonyl groups each display wide signals of approximately 11.5 and 13 ppm, while the acetic anhydride spectrum displays only one singlet at 2.2 ppm. The figure reveals a spectrum of a mixture of the reactants.

The proton spectrum of aspirin reveals four signals in the aromatic region, with each of them visibly separable - at 7.9 (dd; 6), 7.6 (ddd; 4), 7.4 (ddd; 5) and 7.2ppm (dd; 3). The hydroxy group can be seen at 13 ppm and the methyl group, which was initiated during the reaction, can be located at 2.2 ppm. A solvent signal from DMSO can be observed at 2.5 ppm. The carbon spectrum indicates nine signals, six of them in the aromatic region at 151 (2), 134 (4), 132 (6), 127 (3), 125 ppm (1 and 5). The carboxylic carbons emerge at high field at 166 (8) and 170 ppm (7), whereas the aliphatic carbon can be located down field at 21 ppm. The solvent signal can be seen at 40 ppm. Connectivities can be interpreted from the HSQC signals (Figure 3).

1H spectra of reactants and product

Figure 3. 1H spectra of reactants and product

This information has been sourced, reviewed and adapted from materials provided by Bruker BioSpin - NMR, EPR and Imaging.

For more information on this source, please visit Bruker BioSpin - NMR, EPR and Imaging.

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