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

Fourier 300

Innovation with IntegrityNMR

Easy, intuitive 1H and 13C NMR spectroscopy with the Fourier 300

The synthesis of aspirin is a part of many undergraduate organic synthesis laborato-ries. These courses teach synthesis and purification skills. With the Fourier 300 spec-trometer, undergraduate students can now employ NMR to monitor the quality of their reactants and products in an easy and intui-tive way.

It is recommended to first prepare samp-les of the reactants, salicylic acid and acetic anhydride. Dissolve about 10 mg of sali-cylic acid in 1 mL deuterated dimethyl sul-foxide (DMSO-d6). Pipet about 550 µL into a 5 mm NMR tube to achieve a filling height of ideally 40 mm. The sample should be colorless and no particulates visible. For the second sample add a few droplets of acetic anhydride to DMSO in a separate NMR tube with the same filling height.

To synthesize aspirin (acetylsalicylic acid), add 1 mL of acetic anhydride 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. Swirl the flask to mix the reactants thoroughly and heat it in a water bath (70–80 ºC) for ten minutes to form the aspirin and acetic acid as a byproduct. After heating, carefully add first about 4 drops and then another 4 mL of distilled water. Afterwards cool the mixture in an ice bath. These measures are taken to destroy the excess acetic anhydride and cause the product to crystallize. About 10 mg of the unpurified aspirin can now be collected and dissolved in 1 mL deuterated DMSO to prepare a third NMR sample.

Purify the solid aspirin by filtering it through a Buchner funnel with an aspirator. Wash the crystals with 2–3 mL of chilled water. Recrystallize the impure aspirin with 10 mL of 95% ethanol and cool again in an ice bath. Collect the purified aspirin by filtration as before. Dry the crystals and dissolve another 10 mg in 1 mL DMSO-d6, so you can prepare a fourth NMR sample tube.

The Fourier 300 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.

The easiest way to run NMR spectra is in automation mode. If you have a SampleXpress Lite™ available on your Fourier spectrometer, place your samples in the holders. If not, submit the samples one by one when prompted. You can still use automation.

On the workstation begin by opening the TopSpin™ software and start the automation program “IconNMR” by clicking the “ACQUIRE” tab, then “OPTIONS” and choose “Icon NMR Automation”. Within IconNMR under “Automation” click on the respective holder number and choose a name, a solvent (DMSO), an experiment (PROTON) and type in a title. Submit the experiment, start a run using the “Start” button and submit the remaining samples. Once all experiments are finished—each one takes about two minutes—you will receive a printout on paper or via email. Alternatively you can analyze the spectra on the monitor screen within TopSpin. You can easily add further experiments, even two-dimensional ones, such as COSY, HSQC or HMBC. The latter would be one way to prove that you indeed synthesized aspirin rather than simply creating a mixture of salicylic acid and acetic anhydride.

The salicylic acid proton spectrum contains 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), as well as a solvent signal at 2.5 ppm. The carbonyl and hydroxy groups each show broad signals around 11.5 and 13 ppm. The acetic anhydride spectrum shows only one singlet at 2.2 ppm. The figure displays a spectrum of a mixture of the reactants.

Structural characterization of the familiar organic compound Aspirin, the most widely used drug in the world

ppm

2345678910111213 ppm

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1H spectra of reactants and product

Aspirin

2345678910111213 ppm

2345678910111213 ppm

11121314 ppm7.07.27.47.67.8 ppm

7.07.27.47.67.8 ppm

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The proton spectrum of aspirin shows four signals in the aromatic region—all of them clearly separable—at 7.9 (dd; 6), 7.6 (ddd; 4), 7.4 (ddd; 5) and 7.2 ppm (dd; 3). (Note the changes in chemical shift, especially for proton 5.) The hydroxy group is visible at 13 ppm and in addition the methyl group that was introduced during the reaction can be found at 2.2 ppm. A solvent signal from DMSO is visible at 2.5 ppm.

The carbon spectrum shows 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 appear at high field at 166 (8) and 170 ppm (7), whereas the aliphatic carbon can be found down field at 21 ppm. The solvent signal appears at 40 ppm. Connectivities can be deduced from the HSQC signals in the second figure.

Features and Specifications

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Fourier Console

nWeight: 42 kg (Electronic Console) plus ca. 270 kg (Superconducting Magnet)

nDimensions: 58 cm x 36 cm x 65 cm (H x W x D; Console) 72 cm diameter (Magnet)

nMinimum ceiling height required: 2.62 mnPower requirements: 300 W, 90–230 VAC, single phase 50–60 HznAcoustic Noise: < 39 dB (A) at 1.5 m distance nWorkstation: Windows 7, English, 19” MonitornNMR Software: TopSpin 3.1

Easy Probe

n1H & 13C 5 mm probehead including Z gradient (20 G/cm max.) and 2H locknVariable temperature from 5 to 65ºCn1H Sensitivity (0.1 % Ethylbenzene): 140:1n13C Sensitivity (ASTM): 90:1nLineshape (spinning, 3% Chloroform): 0.6/6/12 Hz

Optional SampleXpress Lite

n16 sample holdersnWeight: 12.6 kg (including carousel)nPower requirements: 40 W, 90–230 VAC, single phase 50–60 Hz

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Bruker BioSpin Corp.

Billerica, MA USAPhone: 978-667-9580 Fax: 978-667-0985sales@bruker-biospin.com

www.bruker-biospin.com