Chemical Education Today edited by Susan H. Hixson
NSF Highlights Projects Supported by the NSF Division of Undergraduate Education
National Science Foundation Arlington, VA 22230
Richard F. Jones
Introducing Chiroscience into the Organic Laboratory Curriculum
Sinclair Community College Dayton, OH 45402-1460
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by Kenny B. Lipkowitz,* Tim Naylor, and Keith S. Anliker*
large numbers of student samples. Several new laboratory experiments are currently under development and will be reported on at a later time. Here we describe briefly one new laboratory experiment that has been conceived, tested, implemented, and assessed for suitability in our first-semester organic chemistry laboratory. The Experiment The new experiment is an asymmetric reduction of a ketone followed by an assessment of the enantiomeric excess (ee) by gas chromatography using a chiral stationary phase (CSP). The goal of this laboratory is to show that functional group transformations can be readily accomplished and that they can also be done stereoselectively. The concept of host– guest complexation along with the ensuing stereofacial selectivity of borohydride addition is summarized in Figure 1. This stereoselective borohydride reduction, mediated by a cyclodextrin, was first reported by Deratani and Renard in their study of asymmetric acetophenone reductions (9). Their original conditions were modified by us so that the experiment could be carried out by sophomore-level organic chemistry students within a fixed time period using microscale methodology (copies of the laboratory experiment can be downloaded from http://JChemEd.chem.wisc.edu/Journal/issues/ 2000/Mar/abs305.html or obtained from the authors directly). The one-week exercise (two 3-hour sessions) involves performing a non-stereoselective reduction of the ketone on the first day, followed by gas chromatographic analysis of the product to demonstrate that chiral separation is possible and -
BH4 Na+
BH3
1
O
O
Chirality transcends traditional boundaries separating subdisciplines of the chemical sciences. The large number of scientific studies focusing on the topic of chirality has now thrust it into the scientific forefront, especially in biological and organic chemistry but more recently in inorganic and organometallic chemistry. Reflecting this interest are new journals dedicated to this topic, including: Tetrahedron: Asymmetry, Enantiomer, Chirality, and Molecular Asymmetry, all of which complement existing journals that are themselves replete with papers on chirality. When our proposal to the National Science Foundation was written, we looked at the 1996 Journal of Organic Chemistry and found that 23% of all papers focused explicitly on chirality, with an additional 27% involving stereochemistry. For Tetrahedron Letters, the numbers were 18% and 29% respectively. Workshops, symposia and conferences dedicated to chirality are now common and popular. Further attesting to the significance of this topic was a series of feature articles in C&E News laying bare the fact that a whole new industry based on chirality now exists (1). This industry, designated as “chiroscience”, is a young but robust industry linking science and technology with chemistry and biology. In contrast to all of this is the fact that most undergraduate curricula do not bring aspects of chirality to their students in a well-planned and integrated way. Few textbooks in organic chemistry describe asymmetric synthesis even though the literature in that area is dominated by this topic (2). Almost nothing is said about chirality issues in laboratory textbooks. Contrarily, the Journal of Chemical Education, a frontrunner in the modernization of curricula, contains some papers focusing on chirality (during the 7-year period from 1993–1999, 36 papers dedicated to some aspect of chirality have been published; 12 involved stereochemical nomenclature and concepts (3); 12 focused on asymmetric synthesis using nonnatural reagents (4) or enzymes (5); six papers addressed chiral separations (6) and were mostly by chromatography; five used NMR or chiroptical measurements (7); and one involved extraction of a chiral natural product (8)). All of this, however, is in stark contrast to the importance placed on chirality issues in many academic and industrial laboratories nowadays. We have been funded to redesign our undergraduate organic chemistry laboratory curriculum with a focus on chiroscience. The idea is to replace existing experiments without regard to stereochemistry with those containing some element of chiroscience. The grant allowed for the purchase of gas and liquid chromatographs with automated samplers, permitting high throughput and unattended operation, to support our need to perform a variety of chiral separations on
3
H
Na+
2
R
Figure 1. Schematic of a host–guest inclusion complex formed between β-cyclodextrin and 1´-acetonaphthone and the subsequent facial selectivity leading to the R enantiomer.
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Supplemental Material
Supplemental material for this article is available in this issue of JCE Online. 306
60
Solvent
50
Starting ketone
40 30 20
15.638 15.994
to emphasize that a racemate is formed. Day one is also used by students to begin formation of the host-guest inclusion complex between the ketone and the β-cyclodextrin (the enantioselectivity depends critically upon how well this complex forms; complexation usually takes 12 hours for good results). The reduction in the presence of the cyclodextrin is performed during the second lab session using this preformed complex and chromatographic analysis is then used to determine the ee. We selected this particular experiment from the literature because: (1) the yields and ee’s are high enough to carry out an effective analysis of enantiomeric excess, but not too high to leave the impression that all asymmetric reactions give high yields and high enantioselectivities (part of the laboratory write-up involves students submitting, from a current journal, the highest reported ee in that issue for comparison with their values to put this into perspective) and (2) the products are amenable to chromatographic resolution as illustrated in Figure 2. This experiment has been developed, tested before introduction into the curriculum, and then subjected to full implementation in our undergraduate organic laboratory. As with other new experiments, we assessed the impact of the exercise by using student evaluation forms meant to probe whether or not students were able to grasp the subtleties of the concepts presented, their satisfaction with the laboratory experience, and how they perceived the experiment when compared to other experiments performed in the course (results are available from the authors). In the first year of implementation, 86 students carried out the experiment. Of those, only 5% were not able to get the experiment to work properly (the ee = zero in those instances was attributed to the poor solubility of cyclodextrin in the aqueous NaBH4 solution and inadequate stirring). All students, however, were able to perform the non-stereoselective reduction and successfully isolated and analyzed the products by chromatography. Overall, the experiment was deemed successful and has now been permanently included in our laboratory curriculum. Our goal is to expand the realm of our organic chemistry laboratory to better reflect the fact that chiroscience is a major aspect of modern science. This is being accomplished in part by replacing existing experiments with those containing elements of chirality like asymmetric induction followed by analysis of the induced asymmetry. Designing these new experiments keeps pace with what is in the modern literature. In this way, a working parlance related to chirality that exists in books and journals, but that is not well integrated into the typical undergraduate curriculum, can be effectively introduced to students in a seamless manner. In this paper we have brought to your attention the need to reformulate undergraduate laboratories in order to make them better reflect issues related to chiroscience, and we have presented information on our successful implementation of an experiment toward that goal.
S-OH
R-OH
10 0 0
5
10
15
20
Figure 2. Gas chromatogram (time versus detector response) of the alcohols on a Supelco beta-DEX 120 column (30 m, 0.25 mm ID, 0.25 µm film thickness) operating isothermally at 185° C; He flow 1.0 mL/min (19 psi). The R enantiomer is enriched, and the unreacted ketone elutes before the alcohols.
Literature Cited 1. (a) Stinson, S. C. Chem. Eng. News 1995, 73 (41), 44. (b) Stinson, S. C. Chem. Eng. News 1994, 72 (38), 38. (c) Stinson, S. C. Chem. Eng. News 1993, 71 (39), 38. 2. The following books contain some mention of stereoselective reactions or asymmetric synthesis: (a) Wade, L. G., Jr. Organic Chemistry, 3rd ed.; Prentice Hall: Englewood Cliffs, NJ, 1995; one reference to asymmetric hydrogenation, one biological reaction, and one chemical. (b) Carey, F. A. Organic Chemistry, 3rd ed.; McGrawHill: New York, 1996; two examples of enantioselective synthesis. (c) McMurry, J. Organic Chemistry, 4th ed.; Brooks/Cole: Pacific Grove, CA, 1996; one reference to an enantioselective synthesis. (d) Solomons, T. W. G. Organic Chemistry, 5th ed.; Wiley: New York, 1992; one reference to asymmetric reduction of alkenes for amino acid synthesis. (e) Fox, M. A.; Whitesell, J. K. Organic Chemistry, 1st ed.; Jones and Bartlett: Sudbury, MA, 1994; one enzymepromoted reaction for enantioselective synthesis. The following books have no reference to asymmetric synthesis: (a) Loudon, G. M. Organic Chemistry, 3rd ed.; Benjamin/Cummings: Redwood City, CA, 1995. (b) Baker, A. D.; Engel, R. Organic Chemistry, 1st ed.; West: St. Paul, MN, 1992. (c) Oulette, R. J.; Rawn, J. D. Organic Chemistry, 1st ed.; Prentice Hall: New York, 1996. 3. (a) Siloac, E. J. Chem. Educ. 1999, 76, 798–99. (b) Zhang, Q.; Zhang, S. J. Chem. Educ. 1999, 76, 799–801. (c) Baker, R. W.; George, A.; Harding, M. M. J. Chem. Educ. 1998, 75, 853–855. (d) Neeland, E. G. J. Chem. Educ. 1998, 75, 1573. (e) Toong, Y. C.; Wang, S. Y. J. Chem. Educ. 1997, 74, 403–404. (f ) Thall, E. J. Chem. Educ. 1996, 73, 481–484. (g) Starkey, R. J. Chem. Educ. 1995, 72, 315–318. (h) Herrero, S.; Usón, M. A. J. Chem. Educ. 1995, 72, 1065–1066. (i) Barta, N. S.; Stille, J. R. J. Chem. Educ. 1994, 71, 20–23. (j) Novak, I. J. Chem. Educ. 1994, 71, 579. (k) Thall, E. J. Chem. Educ. 1994, 71, 1034–1037. (l) Caswell, L.; Garcia-Garibay, M. A.; Scheffer, J. R.; Trotter, J. J. Chem. Educ. 1993, 70, 785–787. 4. (a) Spivey, A. C.; Hanson, R.; Scorah, N.; Thorpe, S. J. J. Chem. Educ. 1999, 76, 655–658. (b) Bradley, L. M.; Springer, J. W.; Delate, G. M.; Goodman, A. J. Chem. Educ. 1997, 74, 1336– 1338. (c) Markgraf, J. H.; Fei, J. F.; Ruckman, R. E. J. Chem. Educ. 1995, 72, 270–271. (d) Scott, W. J.; Hammond, G. B.; Becicka, B. T.; Wiemer, D. F. J. Chem. Educ. 1993, 70, 951–952. 5. (a) Lee, M. J. Chem. Educ. 1998, 75, 217–219. (b) North, M. J. Chem. Educ. 1998, 75, 630–631. (c) Drouin, J.; Costante, J.; Guibé-Jampel, E. J. Chem. Educ. 1997, 74, 992–995. (d) Poiré, C.; Rabiller, C.; Chon, C.; Hudholm, P. J. Chem. Educ. 1996, 73, 93–95. (e) McClure, C. K.; Chenault, H. K. J. Chem. Educ. 1996, 73, 467–470. (f ) Besse, P.; Bolte, J.; Veschambre, H. J. Chem. Educ. 1995, 72, 277–278. (g) Lee, M.; Huntington, M. J. Chem. Educ. 1994, 71, A62–A65. (h) Lee, M. J. Chem. Educ. 1993, 70, A155–A158.
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Chemical Education Today
NSF Highlights 6. (a) LeFevre, J. W. J. Chem. Educ. 1998, 75, 1287–1290. (b) Walsh, P. J.; Smith, D. K.; Castello, C. J. Chem. Educ. 1998, 75, 1459– 1462. (c) Valenzuela, F. A.; Green, T. K.; Dahl, D. B. J. Chem. Educ. 1998, 75, 1590–1592. (d) Conradi, S.; Vogt, C.; Rohde, E. J. Chem. Educ. 1997, 74, 1122–1125. (e) Stephani, R.; Cesare, V. J. Chem. Educ. 1997, 74, 1226. (f ) Tran, C. D.; Dotlich, M. J. Chem. Educ. 1995, 72, 71–73. 7. (a) Díaz-de-Villegas, M. D.; Urriolabeitia, E. P. J. Chem. Educ. 1999, 76, 77–78. (b) Walsh, T. D.; Koontz, C. S. J. Chem. Educ. 1997, 74, 585–586. (c) Sen, S. E.; Anliker, K. S. J. Chem. Educ. 1996, 73, 569–572. (d) Gurst, J. E. J. Chem. Educ. 1995, 72, 827. (e) Viswanathan, T.; Toland, A. J. Chem. Educ. 1995,
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Kenny B. Lipkowitz, Tim Naylor, and Keith S. Anliker are in the Department of Chemistry, Indiana University-Purdue University at Indianapolis (IUPUI), 402 North Blackford Street, Indianapolis IN 46202; email:
[email protected];
[email protected].
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