In the Laboratory
Developing Investigation Skills in an Introductory Multistep Synthesis Using Fluorene Oxidation and Reduction
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Mark G. Stocksdale,* Steven E. S. Fletcher, Ian Henry, and Paul J. Ogren Department of Chemistry, Earlham College, Richmond, IN 47374; *
[email protected] Michael A. G. Berg, Roy D. Pointer, and Barrett W. Benson Department of Chemistry, Bloomsburg University, Bloomsburg, PA 17815
This article describes a two-step oxidation–reduction sequence (Scheme I) that incorporates several important aspects of synthesis into introductory organic chemistry laboratories. Alternative oxidations of fluorene to 9-fluorenone have been described previously (1, 2); in our programs we added a step that reduces 9-fluorenone to 9-fluorenol (3). This experiment is an excellent vehicle for introducing elements of discovery and intermediate yield improvement strategies, central considerations in designing real-world multistep syntheses of targeted quantities of final product (200 mg of 9-fluorenol in our case). Each of the alternatives for the first reaction (routes A and B) can be set up and run in parallel on a small scale in about 2 hours. Although both routes produce some fluorenone, students readily determine the best route in terms of yield, convenience, mildness of reaction conditions, and reagent hazards. Because the final step, route C, is quite efficient, the comparison of routes A and B becomes a central feature of the investigation. The entire project occurs over three lab periods.
fluorene route A
O2, NaOH(aq), ⴙ ⴚ R4N Cl , C7H16
HOAc, route B Na2Cr2O7
O
9-fluorenone
route C
1. NaBH4, CH3OH 2. H2O
OH
9-fluorenol Scheme I. Two-step oxidation–reduction synthesis of fluorenol.
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As is true of many synthesis experiments, the lab employs a number of common techniques and reinforces several aspects of class presentations regarding functional group transformations and spectral interpretations. Students learn that a single-step direct transformation to a desired functional group is often not feasible. We give this some context by pointing out that almost all of today’s interesting molecular targets require protection, deprotection, and sequential stereospecific reactions. Thin layer chromatography (TLC) plays a particularly important role in this lab. Since the relatively simple molecules in our example have IR, 1H, and 13C spectra that are readily interpreted, we have also introduced these tools for assessing the outcomes of both reaction steps. As the final aspect of the project, we ask our students to consult current issues of Journal of Organic Chemistry and then to write a formal report in that style to accompany their usual notebook records and lab summary sheets. Lab Summary Students use TLC throughout the experiment to monitor reaction progress, to evaluate column chromatography fractions, and to judge final product purities. This is done using silica gel plates with a fluorescent indicator, and UV excitation at 254 nm where the fluorene compounds have comparable strong molar absorptivities. Each student prepares 3–5 plates throughout the project. There is a noticeable improvement in the plate preparation techniques as the students learn to minimize problems associated with contamination and overloading. Most recently, we have incorporated a semiquantitative TLC method that uses a CCD camera to capture and convert plate images to printable color intensity contour or 3D projection plots (4). These provide students with particularly useful tools for estimating relative quantities of analytes in TLC work. Reaction monitoring by TLC quickly reveals clear differences in yields for routes A and B as students consider which is the better alternative for the oxidation step of Scheme I. Routes A and B are well documented in the literature, and our first versions of this lab used the chromate procedure B (2). Chromate oxidations of similar hydrocarbons to make ketones and quinones have a long history (5, 6) and our students found no difficulty in verifying the production of fluorenone though TLC. However, the isolated yields of fluorenone almost invariably provided too little material to proceed with the reduction step to the final fluorenol product. A detailed study of this problem turned into a small student research project in another course, but fluorenone yields over a range of preparation conditions never improved beyond 25%, based upon starting material.
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In the Laboratory
We then found that route A (1) gave a much better yield of fluorenone under milder conditions. The fluorenone yield after column chromatography increased to 60–80%, and TLC results showed that much of the conversion to product occurred within a few minutes, as demonstrated in Figure 1. In this figure, the lower surface is a contour projection of the upper 3D display. Seeing both plots helps students to correlate the spots that they actually see on a flat plate with the more quantitative information in the figure.1 The two oxidation routes each use small amounts of material and require about 1.5 hours to complete (column chromatography adds 1–2 hours). Therefore, we now ask students to run both routes and to decide for themselves which method works best. While this is most easily done by visual comparison of fluorenone and fluorene TLC spot intensities, it can also be done by comparing column chromatographic product yields. In lab settings where students work in pairs each student can explore one of the oxidation routes. The most successful results then can be used to proceed with the reduction step. With sufficient fluorenone in hand, the second step of the synthesis sequence has been straightforward for the students. The color loss as the yellow fluorenone is reduced to colorless fluorenol helps the students decide when the reaction is complete. Yields of recrystallized material for this step were in the 30–60% range for 22 students. Combined with the average yield of the first step using the basic oxidation procedure, the overall yield of fluorenol averaged 25%, with a range of 140–280 mg of product starting from 800 mg of fluorene. Although TLC and product melting points can provide students with sufficient data to evaluate the success of the transformation steps, we have also used the lab to introduce IR, 1H, and 13C NMR methods.2 Our students easily identify the distinctive carbonyl and hydroxyl stretching bands in their fluorenone and fluorenol products. Their NMR spectra are also readily interpretable and interesting. The chemical shift and integration of the benzylic proton provides quick verification of the final fluorenol product as well as detection of any substantial contamination. The dramatic chemical shift change of the benzylic carbon from alkyl to carbonyl to carbinol aids in product identification and reinforces class discussions of how functional groups affect the observed shift.
Figure 1. TLC UV absorbance results for route A (eluent: 20% CH2Cl2 in hexanes). The samples were taken directly from the heptane layer of the two-phase reaction mixture. The most mobile fluorene spots or peaks are closest to the elution solvent front (seen as a ragged edge across the left front of the image). A fluorenone standard (Std) locates the positions of the least mobile fluorenone peaks. The fluorenone:fluorene ratio is clearly increasing with time. The compound giving the smaller middle peaks in the 10 and 16 minute runs has not been identified. The relatively broad peaks indicate some plate overloading owing to fairly high analyte concentrations in the organic layer.
Procedure for Route A In this adaptation from (1), a medium size stir bar and 800 mg of fluorene dissolved in 8 mL of heptane are placed in a 125-mL Erlenmeyer flask. Aqueous NaOH (30%, 4 mL) is carefully added, followed by addition of 10 drops of the phase transfer catalyst Aliquat 336 (tricaprylmethylammonium chloride). The mixture is stirred vigorously for an hour. Reaction progress is monitored at 5–15-minute intervals by TLC, spotting directly from the organic layer and eluting with 20% dichloromethane in hexanes. The product is purified by column chromatography. Procedure for Route B The microscale procedure of (2) was scaled up slightly. Fluorene (800 mg) is dissolved in 4 mL of glacial acetic acid, www.JCE.DivCHED.org
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Figure 2. TLC UV absorbances for the crude product from acidic chromate oxidation of fluorene (eluent: 15% CH2Cl2 in hexanes). The two standard lanes are replicates of a 47:53 (w/w) fluorene:fluorenone mixture and the sample lanes are replicates for the crude product. As with Figure 1, the broader more mobile peaks are fluorene, and the sharp peaks at low Rf are fluorenone. Integrated peak intensities indicate that the product solid is 20% fluorenone and 56% fluorene, with 24% insoluble material. A comparison of this product data with the longer reaction time data of Figure 1 clearly indicates that the final fluorenone:fluorene ratio is much higher for method A.
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In the Laboratory
warming as necessary on a hot plate in a hood. A sodium dichromate solution (8.0 mL of 1 M Na2Cr2O7 in acetic acid) is then added in small portions. The resulting mixture is heated in hot water at 80 ⬚C for at least 30 minutes. After cooling, 25 mL of cold water is added with swirling, and the crude solid product is filtered. The solid is dissolved in dichloromethane and dried with anhydrous calcium chloride, followed by a TLC check of the dry solution and isolation of dry crude solid by evaporation. TLC results, shown in Figure 2, for the crude product obtained using slightly modified reaction conditions gave an overall fluorenone yield of 7%. Comparison with the 47:53 standards suggests that the crude solid retains much of the starting fluorene reagent.
In a procedure adapted from (3), a weighed quantity of fluorenone (typically 500–600 mg using all of the product from Route A) is dissolved in a minimum quantity of methanol. A 1兾3 molar equivalent of sodium borohydride is added in small portions to the stirred fluorenone solution. After the yellow color disappears (about 30 minutes), 20 mL of water is added. The resulting suspension is gently heated until it is warm to the touch. After standing for 10 minutes, 20 mL of ice water is added and the product is isolated by two extractions with ether. The combined organic layers are dried over magnesium sulfate followed by concentration of the solution on a rotovap, cooling in an ice bath, and filtration of crystals. These are further purified by recrystallization. Hazards Sodium hydroxide is a caustic strong base. Diethyl ether, ethyl acetate, hexane, heptane, and methanol are flammable liquids. Dichloromethane is a cancer suspect solvent. Sodium borohydride is a flammable, toxic solid that reacts violently with water and acids. Sodium dichromate is a toxic cancer suspect agent and a strong oxidizer. Glacial acetic acid reacts exothermically and sometimes violently with bases and oxidizing agents. Hydrochloric acid is corrosive and may cause damage to the skin. Alumina is an inhalation hazard. Aliquat 336 is toxic and a severe irritant. We recommend that all work be performed in fume hoods, with careful handling of reagents and proper disposal of wastes. More information on disposal is found in the Supplemental Material.W Conclusion We present a convenient and instructional two-step synthesis of 9-fluorenol from fluorene. This three-session lab sequence introduces students to a variety of investigation skills as well as many synthetic methods and techniques used in
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Acknowledgment This work was partially supported by a Howard Hughes Medical Institute grant.
Procedure for Route C
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real-world syntheses. Students also have the opportunity to learn and validate their modern spectroscopy interpretation skills by fully characterizing all isolated compounds using IR, 1 H, and 13C NMR. Additionally, this lab should help students learn to consider environmental hazards in making decisions about synthetic routes. The use of the small scale acidic chromate oxidation in route B provides a natural opening for further discussion. The choice of the less hazardous route A can be made on the basis of “green chemistry” goals (7) as well as on the basis of comparative yields.
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Supplemental Material
Detailed laboratory instructions for the students, notes for the instructor, additional information on the TLC product analysis for the chromate oxidation method, and NMR and IR data are available in this issue of JCE Online. Notes 1. The TLC results shown in Figures 1 and 2 were obtained at Earlham with a simple UV excitation source (UVG Inc. model UVGL-25) and a SONY XC-73 video camera interfaced to a computer using a National Instruments PCI 1407 video board. Image acquisition and processing code was written in the National Instruments LabVIEW programming environment. Further information is available in (4). 2. 1H and 13C NMR spectra for fluorene and for the 9fluorenone and 9-fluorenol products were obtained on a Bruker AC200 MHz FT-NMR. FTIR spectra were obtained on a PerkinElmer Paragon 1000 PC instrument.
Literature Cited 1. Lehman, J. W. Operational Organic Chemistry, 3rd ed.; Prentice Hall: New York, 1999; pp 510–511. 2. Williams, K. L. Macroscale and Microscale Organic Experiments, 2nd ed.; D. C. Heath: Lexington, KY, 1994; 179–181. 3. Jones, S. C. J. Chem. Educ. 1994, 71, A253. 4. Ogren, P. J.; Henry, I.; Fletcher, S. E. S.; Kelly, I. J. Chem. Educ. 2003, 80, 699–703. 5. Beilsteins Handbuch der Organischen Chemie, 4th ed.; Springer: Berlin, 1925; Vol. 7, pp 465–466. 6. Vogel, A. I. Practical Organic Chemistry, 4th ed.; Longman: Essex, U.K., 1978; pp 785–788. 7. Hjeresen, D. L.; Schutt, D. L.; Boese, J. M. J. Chem. Educ. 2000, 77, 1543–1547.
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