In the Laboratory
Circular Dichroism Investigation of Dess–Martin Periodinane Oxidation in the Organic Chemistry Laboratory
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Nicole A. Reed, Robert D. Rapp, Christian S. Hamann, and Pamela G. Artz* Department of Chemistry and Biochemistry, Albright College, Reading, PA 19604; *
[email protected] Oxidation of alcohols to their corresponding ketones is a common experiment in the organic chemistry laboratory but is most often conducted using either chromic acid or bleach (1–7). To convert either (+)-menthol to (+)-menthone or (−)-menthol to (−)-menthone, this experiment uses Dess– Martin periodinane as the oxidizing agent, which represents a facile and nontoxic approach to the reaction (8–10). Beyond the oxidation reaction, our goal was to expose sophomore chemistry, biochemistry, and biology concentrators to the theory of circular dichroism (CD) through analysis of their oxidation products with a Jasco-810 spectropolarimeter.
chromatograph equipped with a Restek Corp. RTX-5 column (30-m length, 0.25-mm i.d., catalog number: 10223) and an HP 5970 series mass selective detector was used to obtain data. The mass spectral detector provides a positive identification of the compounds present in the product; however, other common detectors may be used while stressing the relationship between retention time and intermolecular
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The experiment was done in a two-week time frame. The first week was used for the oxidation of (+)- or (−)-menthol to (+)- or (−)-menthone, respectively (Scheme I), and the subsequent isolation of the product. In the second week, students analyzed their products using infrared (IR) spectroscopy, gas chromatography–mass spectrometry (GC– MS), and CD spectroscopy. Absolute configuration determination, polarimetry, and CD theory were discussed in the lecture portion of the class to provide background for the experiment. In the first week, students combined 2.2 mmol of either (+)- or (−)-menthol dissolved in 10 mL of CH2Cl2 with 2.5 mmol of Dess–Martin periodinane dissolved in 10 mL of CH2Cl2 in a reflux apparatus (8, 10). The reaction proceeded with stirring at room temperature for 30 min. The reaction mixture was combined with 50 mL of diethyl ether and washed successively with 2.5 g of sodium thiosulfate dissolved in 10 mL of aqueous saturated NaHCO3, 10 mL of water, and 10 mL of brine. The organic layer was dried over MgSO4 and rotary evaporated to remove the solvents. The following week was used for instrumental analysis of the products. Infrared spectra (Perkin Elmer Spectrum One FT–IR with Universal ATR Sampling Accessory) of the neat final product and the solid starting material, acquired using the attenuated total reflectance accessory, were obtained to determine the change in functional group upon oxidation. A 2% solution of the final product in hexane was prepared for GC–MS and CD analysis. In our case, an HP 5890A gas
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OAc AcO I OAc
θ / mdeg
Experimental Procedure
(+)-menthone
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(−)-menthone
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Wavelength / nm Figure 1. CD of student-prepared (+)-menthone and (−)-menthone. The Jasco-810 spectropolarimeter was used to obtain the data with a bandwidth of 1 nm and a response time of 4 s. The measurement range was from 330 to 250 nm. The scanning speed was 20 nm/min with a data pitch of 0.1 nm. A total of one accumulation was taken using a cell with a 1-mm path length. The spectra were obtained at a temperature of 25 ⬚C. 10
(−)-menthol
θ / mdeg
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(−)-menthone
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O O
H
O (ⴚ)- menthol
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O
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(ⴚ)- menthone
Scheme I. The oxidation of (−)-menthol to (−)-menthone using Dess– Martin periodinane (8, 9).
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Wavelength / nm Figure 2. CD of (−)-menthol and (−)-menthone. The instrumental conditions were identical to those in Figure 1.
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In the Laboratory
forces. According to our work, the retention times of the three main peaks were generally 10.45 minutes for menthone, 10.57 minutes for isomenthone, and 10.72 minutes for menthol. It is likely that, depending on the column, gas–liquid chromatography will not resolve the menthone and isomenthone. The detection of isomenthone allows the instructor to discuss keto–enol tautomerization and its effect on the products of the oxidation. Utilizing the Jasco-810 spectropolarimeter, the 2% solution of product was used to obtain the CD spectra needed to observe the spectral change upon oxidation (Figure 1). The CD spectra of (+)-menthone and (−)-menthone were compared to observe the effect of the structural difference between the enantiomers on the absorption of circularly polarized light. Students were also provided with the CD spectra for either (+)-menthol or (−)-menthol for observation of the change in the CD data upon oxidation (Figure 2). Hazards Gloves should be worn when handling the Dess–Martin periodinane reagent and respiratory contact should be avoided. The Dess–Martin periodinane reagent must be kept dry to avoid hydrolysis to an impact-sensitive compound and should not be heated above 130 ⬚C to prevent any possibility of violent decomposition (11, 12). After the oxidation reaction, any excess periodinane is destroyed by sodium thiosulfate resulting in the conversion to 2-iodobenzoic acid. The resulting 2-iodobenzoic acid should be recovered by the instructor after acidification of the collective student thiosulfate兾bicarbonate washes and disposed of with solid organic waste. Results and Discussion As determined chromatographically, a 50–60% conversion of menthol to menthone was obtained using the Dess– Martin periodinane (8–10). This percentage was characteristic of the reaction done with either the commercial Dess–Martin periodinane (Sigma-Aldrich) or the material prepared inhouse (8, 9). Further purification of the oxidation product could be done using a Kugelrohr distillation after the extraction steps (8, 10). The chosen conditions for the reaction allow for completion of bench chemistry in the first laboratory period with the second period devoted to analytical workup of the products. Since the emphasis of the experiment is on the CD analysis of the products, complete oxidation is not necessary. The mixed product gives a massive change in the CD spectrum as a result of the presence of either (+)- or (−)menthone, which is indicative of the successful conversion of alcohol to ketone (Figure 2). Introduction of the carbonyl chromophore, containing a π system, results in a much higher molar absorptivity for the ketone. This physical property is responsible for the more intense CD spectrum in going from either (−)-menthol to (−)-menthone or (+)-menthol to (+)menthone even when the products contain a mixture of alcohol and ketone. The evidence of unreacted menthol is apparent in both the chromatographic and IR data. Conclusion This experiment provides an avenue to the introduction of CD spectroscopy in the organic chemistry curriculum as a diagnostic tool for examination of the results of a familiar 1054
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reaction and as a way to examine absolute configuration and its effect on the differential absorption of circularly polarized light. The (+) and (−) menthone enantiomers, with opposite optical activity, absorb circularly polarized light oriented in either the clockwise or counterclockwise direction depending on the particular enantiomer. As a result, the samples of similar concentration for two enantiomers produce like-shaped CD spectra of opposite sign diagnostic of the differential absorption of circularly polarized light for each enantiomer in hexane solution (Figure 1). Examination of the octant rules (13–15), which are used to relate the sign of the CD spectrum to conclusions about absolute configuration, could be included as an additional assignment for more advanced or honors students. The assessment tool, administered before and after students performed the experiment, suggests that the students increased their understanding of CD theory and practice as well as assignment of absolute stereochemistry, the behavior of optically active compounds, and alcohol oxidation through this laboratory investigation. Acknowledgments This work was supported in part by National Science Foundation, Division of Undergraduate Education (CCLIA&I #0126715) and the Camille and Henry Dreyfus Foundation Special Grant Program in the Chemical Sciences (SG-01-035). Supplemental Material Detailed student procedures (8, 10), questions, and instructor’s notes are available in this issue of JCE Online. The instructor’s notes include: the synthetic procedure for Dess–Martin periodinane (8, 9); pre- and post-evaluation questions for assessment; IR spectra for (+)-menthol, (−)menthol, and a student-produced oxidation product containing menthol and menthone; GC data for the product; chemical lists; and equipment and lab protocol notes. W
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