In the Laboratory

Synthesis and Hydrogenation of Disubstituted Chalcones A Guided-Inquiry Organic Chemistry Project

Jerry R. Mohrig* Department of Chemistry, Carleton College, Northfield, MN 55057; *jmohrig@carleton.edu Christina Noring Hammond Department of Chemistry, Vassar College, Poughkeepsie, NY 12604 Paul F. Schatz Department of Chemistry, University of WisconsinMadison, Madison, WI 53706 Tammy A. Davidson Department of Chemistry, University of Florida, Gainesville, FL 32611

Guided-inquiry laboratory experiments provide excellent opportunities for students to participate in the process of science within the structure of the organic chemistry laboratory (13). They offer many of the same opportunities for effective teaching as classical organic qualitative analysis used to do. The questiondriven, guided-inquiry approach requires students to become engaged in evaluating their experimental data to answer a question posed by the experiment. In the process, students develop critical thinking skills as they learn the art of data interpretationand when well-designed experiments are used, they enjoy doing it. This approach to laboratory teaching has been used successfully in small colleges, as well as in large universities (4). Although there are laboratory manuals that feature guidedinquiry organic chemistry experiments and projects (5, 6), as
O H R R = CH3, OCH3, Cl, or C6H5CH2O R R = CH3, OCH3, or F
NaOH H 2O

well as a number of such experiments in this Journal (7), there is still a need for creative guided-inquiry experiments that are designed for the organic lab. We have found the catalytic transfer hydrogenation of chalcones to be such an experiment. It is an effective modern version of organic qualitative analysis, which combines the practical use of spectroscopic methods with an important questionWhat is the regiochemistry of a reaction whose substrate has multiple functional groups? Determining which functional groups react in a chemical reaction is critical to the success of synthetic organic chemistry. When this project is carried out with teamwork opportunities and a post-laboratory discussion (1, 2), students rise to the challenge and achieve success. They learn how organic chemists actually do chemistry and have fun at the same time. As is the case with other guided-inquiry experiments, the chalcone project can also serve as an excellent introduction to undergraduate research. The Chalcone Synthesis Chalcones are an important class of naturally occurring compounds of interest to the pharmaceutical industry for their potential antitumor, antibacterial, antifungal, and anti-inflammatory activity (8). They are biochemical intermediates in the polyketide biosynthetic pathway, which leads to a large class of antioxidant flavonoids.
Table 1. Chalcone Selection Chalcone 1 R CH3 CH3 CH3 Cl Cl Cl OCH3 C6H5CH2O C6H5CH2O R CH3 OCH3 F CH3 OCH3 F OCH3 CH3 OCH3 mp/C 126127.5 127127.5 138139 146147.5 127128.5 136137 100101.5 108109 116117

R disubstituted chalcone

2 3 4 5 6 7 8 9

ammonium formate Pd/C methanol

hydrogenation product(s) Scheme I. Chalcone synthesis and hydrogenation.

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The chalcone project is a 3-week experiment that starts with the straightforward synthesis of a para-disubstituted chalcone, which demonstrates the important chemistry of the aldol condensation, followed by dehydration to form a conjugated ketone. The chalcone then serves as the substrate for a heterogeneous transfer hydrogenation reaction (Scheme I and Table 1). A goal of organic synthesis is the discovery of environmentally friendly reactions, where a minimum of waste is produced and the reactions have high atom economy (9). Searching for guided-inquiry projects that meet these goals, we were attracted by the solvent-free synthesis of chalcones (10). In this experiment substituted benzaldehydes and acetophenones are simply ground together along with sodium hydroxide with a mortar and pestle. For our purpose, however, we needed a clean and reliable synthetic method, whereas the solid-state synthesis often gave mixtures of chalcones, aldol, and Michael products. This problem was solved when we discovered that using water as the reaction medium (1113) leads to a much purer product. Ultimately, we found that running the synthesis in an EtOHH2O mixture gave the best results. Projects whose primary goal is the study of an interesting question, but which also require a synthetic step, fail all too often because students have difficulties in obtaining pure substrates in the allotted time. Our experience with the synthesis of paradisubstituted chalcones indicates that two-student teams almost always achieve success. This has been the case when the project was class tested at Carleton College and at the University of Florida, after being developed for a workshop on the successful use of guided-inquiry experiments (14). In the chalcone selection, we have tried to avoid compounds that give challenging purification problems. The para-disubstituted chalcones separate from water as crystalline solids and are produced in crude yields of 5095%. They can also be recrystallized easily from 95% ethanol with 8090% recovery. The selection of the substrates was based on three factors. First of all, we wanted a set of chalcones whose para-substituents might exhibit some interesting hydrogenation chemistry, as well as a list extensive enough so that a teacher would not have to select the same set every year. Second, we wanted the synthesis step to be straightforward so that every student team should be able to produce an adequate amount of pure product in one lab period. We also did not want students to face the vagaries of recrystallization from mixed solvents. The third factor was the availability and cost of the starting materials; all of the benzaldehydes and acetophenones are available from Aldrich and most of them are inexpensive. Heterogeneous Catalytic Transfer Hydrogenation Although catalytic hydrogenation is an important reaction in organic synthesis, it is not well represented in the organic laboratory, probably because of the challenges of handling gaseous hydrogen. Transfer hydrogenation avoids this problem. Many molecules can transfer a molecule of H2 to a substrate in the presence of a suitable catalyst. Ammonium formate is an efficient source of hydrogen, in that it readily decomposes into hydrogen, carbon dioxide, and

ammonia in the presence of a Pd/C catalyst (15):

O H O NH4
Pd/C

CO2

H2

NH3

Although attempts at mechanistic interpretations can only be tentative, because the reduction takes place on the surface of the heterogeneous catalyst, it is not unlikely that Pd(0) reacts either with H2 gas or directly with the ammonium formate by an oxidative addition pathway. These reactions form HPdH or HPdO2CH (HPdCO2H), which can subsequently transfer hydrogen to the substrate by a reductive elimination, thereby regenerating Pd(0). It is also possible that a molecule of H2, which is adsorbed on the surface of the insoluble catalyst, is transferred directly to the substrate. Catalytic hydrogenation could take place at a number of functional groups in a chalcone. For example, the alkene double bond could be reduced, as could the ketone carbonyl group:
H2
Pd/C

H2

Pd/C

H O

In addition to hydrogenation of double bonds, activated single bonds to heteroatoms can also be cleaved, with the heteroatom replaced by hydrogen:
C X H2
Pd/C

HX

The heteroatom (X) is usually an oxygen or a halogen atom. Benzylic CO bonds are the most likely to be cleaved owing to their relative weakness. Thus, C=C and C=O reduction to the secondary benzyl alcohol could be followed by cleavage, forming the 1,3-diarylpropane. Many aryl halides are also readily cleaved using ammonium formate and Pd/C. A possible minimal mechanism is oxidative addition followed by ligand exchange and reductive elimination (15):
Ar Cl
Pd oxidative addition

Ar

Pd

Cl

HCO2

Cl

O Ar Pd O C H

Pd
reductive elimination

Ar

CO2

One can envision a possible 5-membered cyclic transition state for the reductive elimination step, although it is not generally clear whether the aryl halide and formate are bound at a single Pd site or at contiguous sites on the heterogeneous catalyst. Thus, there are many possible functional groups of a disubstituted chalcone where hydrogenation or hydrogenolysis can occur, including the C=C, the C=O, a benzylic OH, and the R or R' substituents or moieties within them. As expected,

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the product composition varies with the reaction conditions. We found that an 1820 minute reaction at the temperature of refluxing methanol seemed to work best; this set of conditions usually led to 13 major hydrogenation products. Longer reaction times produced more complex reaction mixtures, and shorter times left a fair amount of unreacted chalcone in the reaction mixture. The activity of a Pd/C catalyst may vary somewhat from batch to batch, since the nature of the catalytic surface is important, which could also lead to some variation in the product composition. However, the use of modern spectroscopy readily leads to the determination of what reduction products are formed and their approximate relative yields. The project is most satisfying when the combined insights of IR, NMR, and GCMS are available to the students. These three spectroscopic methods complement one another in the analysis of the hydrogenation regiochemistry. GCMS is particularly useful in determining whether hydrogenolysis has occurred, because the molecular weights of hydrogenolysis products are substantially lower than those of the substrates. The molecular-ion peaks of the separated products are the most powerful part of the GCMS data, but the fragmentation patterns are also reasonably straightforward. The NMR spectra of the para-disubstituted chalcone hydrogenation products are quite revealing, with well-separated peaks whose 1H chemical shifts can easily be estimated from quantitative structurechemical shift correlations (16). Peaks due to the two methylene groups of the unconjugated ketone are very revealing as are the diastereotopic protons of benzylic alcohol products. If one wants to quantify the components in a product mixture, either NMR or GCMS can be used, but it is interesting to note that they systematically give somewhat different results, owing to either NMR integration errors or the assumption that the relative ion abundances of the MS peaks are a valid measure of relative product amounts or both. The carbonyl-stretching region of the IR spectra is particularly revealing in showing the doubly conjugated ketone stretch at 16501664 cm1, whereas the ketone conjugated only to an aromatic ring has its carbonyl stretch at 16651684 cm1. The OH stretching region is also diagnostic. If NMR or GC MS are unavailable, the chalcone project might still be useful using only IR and TLC data if an appropriate set of chalcones is used. Post-Laboratory Discussions When chemists have finished research experiments and evaluated their data, they get together to discuss the interpretation of their results and learn what others think about them. Post-laboratory discussions are an important adjunct for the development of critical thinking skills when guided-inquiry projects are used. It seems counterproductive to use guidedinquiry experiments and then deprive students of an important part of the scientific process. The chalcone project is designed for three laboratory sessions, with the third week devoted to a post-lab discussion. The process looks something like this. During week one students synthesize and purify one of nine possible disubstituted chalcones. In the second chalcone lab students carry out the transfer hydrogenation reaction on their disubstituted chalcone

and obtain the TLC and IR analyses, and perhaps the GCMS data as well. Subsequently they get their NMR spectra. When all of the data are in hand, each student team meets separately and analyzes its experimental results. To make sense of their IR and NMR spectra, students will need to use published tables of IR frequencies and NMR chemical shifts, such as those found in organic chemistry techniques manuals (16). Before the third lab session, the students prepare their brief presentations to be given to the entire lab section. These 1012 min presentations with suitable visual aids should summarize their data and their interpretations of the data. The presentations should suggest which functional groups of their disubstituted chalcones were hydrogenated by Pd/C and ammonium formate. The quality of the presentation can form part of the student lab grade. With a lab section of 24 students and a set of six different substrates, twelve presentations would be made. The hydrogenation of each chalcone would be the subject of two presentations. In our experience most students take their presentations seriously and are interested in what other student teams have discovered about their hydrogenation reactions. The teacher does not come with answers but takes the role of a research director who probes to see whether the student interpretations are consistent with the experimental data. Often students other than the presenters enter the give-and-take of the discussion. Only after the post-laboratory discussion do the student teams write up their results and interpretations and submit them. Insights that they have gained from the post-lab discussions can form part of their written work. The most important aspects of the written reports are the quality of the experimental data, how the data are marshaled to prove the point, and the conclusions that the students reach. It can also be useful if part of each teams report briefly summarizes the conclusion reached for each of the other substrates used by the class. The reports should not be graded on the basis of students getting the right answer. In the chalcone project students come to realize that they are participating in the process of science and that they are learning how organic chemists carry out research and analyze their experimental data. Gains in student learning make it well worth spending three laboratory sessions on this project. Assessment To assess the chalcone project, we used it at the University of Florida, Gainesville, during two semesters. The first class test was conducted with four graduate-student teaching assistants (TAs) and 60 undergraduate students. A larger-scale test using an expanded set of chalcones was conducted with 36 graduatestudent TAs and 550 students. In both cases each TA was responsible for 1518 students and the project was conducted as a 3-week capstone experience approximately three weeks prior to the end of the semester. The students had carried out five guidedinquiry style labs before doing the chalcone project. An anonymous online survey was used to assess the effectiveness of the chalcone project from the students perspective. Questions were structured to permit students to write free response answers. Approximately 95% of the students filled out

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the survey and their feedback about the experiment was heavily favorable. Most students felt that the experiment was wellwritten with adequate background information to complete the task. A quantitative perspective of student career interests and what they liked about the project are shown in Tables 2 and 3. The data in Table 2 show that the students overwhelming career interests were in the medical sciences. The data in Table 3 show that only10% of the students did not find anything positive to say about the chalcone experiment. However, the data also show that combining the use of three different kinds of spectroscopy (IR, NMR, GCMS) to discover the hydrogenation regiochemistry was popular. This approach was effective in helping students learn spectroscopy, and it is worth pointing out that students who first carried out the chalcone project scored an average of 80% on their spectroscopy exam as compared to a 70% average for the students who did not. In addition, almost 15% of the students felt that the chalcone project was

an effective capstone to their organic chemistry lab experience; a number of students remarked on the sense of confidence they gained from it. For example, one student stated,
I truly learned how chemists fit together a puzzle of data to make conclusions, and how hard it can be to do that. It was an incredible critical thinking exercise.

Table 2. What Is Your Intended Career Path? Career Medicine Pharmacy Veterinary Med Dentistry Chemistry Other
Note: There were 385 student responses.

Response (%) 47.0 16.6 9.9 9.9 2.6 14.0

Table 3. Student Response to Question: What Did You Especially LIke About the Chalcone Experiment? Statement It used many different kinds of spectroscopy to answer a question. Its use of diverse lab skills brought the whole course together. I liked the project approach with the time to repeat a procedure. I didnt like the chalcone experiment. I liked a specific technique that we used. The experiments were easy to follow and carry out. The project was a real scientific experiment. Different students had different substrates. I liked carrying out the reactions. I liked the teamwork approach. I liked the post-laboratory discussion. Other aspects
Note: There were 547 student responses.

Response (%) 29.6 14.4 9.7 9.7 8.8 8.4 4.2 3.8 3.8 3.1 1.8 2.7

Many of the students negative comments concerned the kind of technical problems that need to be worked out when any new experiment is added to the laboratory syllabus. However, approximately a third of the 353 students responding did not like the length and complexity of the chalcone experiment, particularly the emphasis upon spectroscopy in elucidating the hydrogenation regiochemistry. Spectroscopy, which was seen as a real strength by many students, was a negative to others. One may surmise that the students who had mastered the fundamentals of spectroscopy, particularly NMR, were equipped to learn the most from and enjoy the chalcone project. Students also had some mixed feelings about the post-laboratory discussions. Almost 80% of 521 responses found them valuable in understanding their results and having interaction on a professional level with other students in their lab section. The other 20% found that the discussion was not particularly helpful, mainly because some student teams were not well-prepared for their presentations or the TA was not a good discussion moderator. Not only is it necessary that the TAs become wellacquainted with the experimental procedures and potential outcomes, they also need to be provided with guidance in the skills necessary to moderate post-lab discussions. The class testing in a large-university setting, as well as earlier class testing in a liberal-arts college, has shown that the chalcone project can be successful in a variety of educational environments and has substantial benefits for students in organic chemistry laboratory courses. In departments where undergraduate research is a strong component of the chemistry program, the chalcone project will also be an excellent preliminary taste of the research process. It will allow students to approach research with a much better idea of what it is all about. TA Training and Faculty Response To prepare the TAs to teach using a guided-inquiry style, the differences in this approach versus traditional methods were discussed during several meetings held in the first week of the semester. The TAs were asked to read a packet of articles that address different approaches to teaching and a mini-workshop was held the following afternoon. Each TA was given the opportunity to comment on his or her past experiences with teaching, and a list of pros and cons of teaching traditional labs was compiled. The TAs then discussed ways to make modifications in teaching styles to foster an atmosphere that was more conducive to guided-inquiry. Weekly TA meetings were also held throughout the rest of the semester to explore ways to make each laboratory experiment more interactive and rewarding for the students. This important training allows the TAs to learn the new way of teaching and learning. Most of the TAs who had previously taught labs in the traditional style reported their teaching to be richer and more rewarding when using the guided-inquiry approach. They found

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that the types of questions posed by many students went from the superficial to those showing a deeper understanding. In addition, the attitude of the students was more relaxed in the lab since they were not pressured to verify the right result, but instead could focus on their understanding of the chemistry. The TAs had a significant influence on both the attitude and level of understanding exhibited by students in their lab sections. Students whose TAs were better prepared and more knowledgeable made comments that showed a greater degree of critical thinking and understanding. The data in Tables 4 and 5 show that many of the TAs adapted their teaching to using guided-inquiry techniques and that they cared about doing an effective job. Organic chemistry faculty members were quite receptive to the increased use of guided-inquiry experiments. Some were initially skeptical about fewer calendar days being devoted to

wet chemistry because they perceived the lab would be less rigorous. However, most faculty members saw that this was not the case. Instead, the guided-inquiry laboratory program provided students with an opportunity to perform more complex experiments and discuss the results with their peers. Experimental Summary Chalcone Synthesis The aldehyde and ketone (3.5 mmol of each), plus 2 mL of 95% ethanol, were mixed briefly in a small Erlenmeyer flask and then 0.350.40 g of sodium hydroxide, dissolved in 0.5 mL of water, was added to the mixture. The reaction was carried out by heating with stirring in a 70 C water bath for 30 min except for the synthesis of chalcones 3 and 6, which were carried out at room temperature for 30 min. After adding 23 mL of water to the reaction mixture and upon stirring and cooling using an ice-water bath, crystallization occurred within 5 min. The product was collected by vacuum filtration and washed twice with 510 mL of water to remove residual sodium hydroxide. Recrystallization was done from 95% ethanol. IR (cast film or ATR) and NMR spectra were useful for future comparison to the transfer hydrogenation products. Characterization of Previously Unknown Chalcone, 9
1H NMR (300 MHz, CDCl 3, ): 8.03 (d, 2H), 7.78 (d, 1H, 15.8 Hz), 7.61 (d, 2H), 7.477.31 (m, 6 H), 7.0 (dd, 4H), 5.2 (s, 2H), 3.9 (s, 3H).

Table 4. Student Response to Question: Did Your TA Ask You Questions To Help You Solve Your Own Problems in the Lab or Did He or She Tend To Step In and Do It for You? Statement My TA made me reason through my problems and come up with my own answers. My TA asked some questions and then guided me in the right direction. My TA answered all my questions and sometimes corrected my problem for me. My TA usually did it for me. My TA had no idea what to do with my questions.
Note: There were 540 student responses.

Response (%) 32 62 3 0 3

IR (cast film): 1656 cm1. EIMS mz: 345.1481 (MH + , 345.1486 calcd for C23H20O3H).

Table 5. Student Response to Question: Which of the Following Responses Best Describes Your TAs Preparedness To Teach the Lab and His or Her Knowledge of the Material? Statement My TA was always prepared to teach the lab and was very knowledgeable about the experiments. My TA seemed to be prepared most of the time but sometimes was confused about what we needed to do. My TA seemed to be unprepared to teach the lab and had to refer to the lab manual frequently to give us advice about what to do. My TA was usually unprepared to teach the lab and many times had very little knowledge about the experiment.
Note: There were 540 student responses.

Response (%) 64 32

Chalcone Hydrogenation The chalcone (200 mg ), solid ammonium formate (7.5 mmol per mmol of chalcone) and 0.040 0.005 g of 10% palladium on carbon were added carefully to a round-bottomed flask and the flask was swirled to coat the surface of the catalyst with the other reagents. (Safety precaution: The methanol must be added only after swirling the reagents together.) Anhydrous methanol (18 mL) was added and the reaction mixture was refluxed for 1820 min. The reaction flask was cooled in an icewater bath for 5 min and then the reaction mixture was filtered through a filter pipet packed with glass wool, with either Celite or cotton on top to ensure efficient filtration. To dispose of the palladium safely, the filter pipet was rinsed with 3 mL of water after the product filtration had been completed. After evaporation of the methanol, 5 mL of water was added and the crude product was extracted twice with ether. A back wash with water removed excess ammonium formate. After drying the ether solution (MgSO4), TLC analysis was carried out (ethyl acetate/hexane) on glass or aluminum-backed, silica gel TLC plates; visualization was with p-anisaldehyde dipping reagent. Evaporation of the ether led to the crude hydrogenation product, which was characterized directly by IR, NMR, and GCMS analysis.

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Hazards Palladium on activated carbon can cause fires when wet with organic solvents or in contact with combustible materials, such as filter paper. If dry Pd/C comes into contact with methanol vapor, it can ignite the methanol. Do not breathe Pd/C dust. Clean up any spilled catalyst with a wet tissue and then rinse with plenty of water before discarding (17). The aldehydes, ketones, and chalcones used in this project are skin and eye irritants. Sodium hydroxide pellets and concentrated solutions are corrosive and can cause severe burns. Hydrogen gas is flammable; no flames should be used in the laboratory. Ammonium formate and ammonia are irritants. Diethyl ether, methanol, hexane, and ethyl acetate are volatile and flammable. Methanol is toxic. The use of gloves when performing this experiment is recommended, and the experiments should be performed in a well-ventilated space. Acknowledgments We thank David G. Alberg of Carleton College for his many useful suggestions and for class testing the chalcone project and Carleton student Samuel Lemonick for determining the structures of side products in the synthesis of chalcone 6. We are indebted to Edith C. Stout of Vassar College for the acquisition of NMR and mass spectra and to Vassar students Kaysia Ludford and Samantha Greenberg for their work on synthesizing and hydrogenating some of the chalcones. Literature Cited
1. Mohrig, J. R. J. Chem. Educ. 2004, 81, 10831084. 2. Mohrig, J. R.; Hammond, C. N.; Colby, D. A. J. Chem. Educ. 2007, 84, 992998. 3. Gaddis, B. A.; Schoffstall, A. M. J. Chem. Educ. 2007, 84, 848851. 4. Bodner, G. M.; Hunter, W. J. F.; Lamba, R. S. Chem. Educator 1998, 3 (3), 121. 5. Mohrig, J. R.; Hammond, C. N.; Schatz, P. F.; Morrill, T. C. Modern Projects and Experiments in Organic Chemistry, 2nd ed.; W. H. Freeman: New York, 2003.

6. Lehman, J. W. Microscale Operational Organic Chemistry; Pearson Education, Inc.: Upper Saddle River, NJ, 2004. 7. Horowitz, G. J. Chem. Educ. 2007, 84, 346353. 8. Dimmock, J. R.; Elias, D. W.; Beazly, M. A.; Kandepu, N. M. Current Med. Chem. 1999, 6, 11251149. 9. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 2000; pp 3842. 10. Palleros, D. R. J. Chem. Educ. 2004, 81, 13451347. 11. Crouch, R. D.; Richardson, A.; Howard, J. L.; Harker, R. L.; Barker, K. H. J. Chem. Educ. 2007, 84, 475476. 12. Engberts, J. B. F. N.; Blandamer, M. J. Chem. Commun. 2001, 17011708. 13. Li, C.-J.; Chan, T.-H. Comprehensive Organic Reactions in Aqueous Media, 2nd ed.; Wiley: New York, 2007. 14. Center for Workshops in the Chemical Sciences, Georgia State University, Atlanta, GA. http://www.chemistry.gsu.edu/CWCS (accessed Oct 2008). 15. Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev. 1985, 85, 129170. 16. Mohrig, J. R.; Hammond, C. N.; Schatz, P. F. Techniques in Organic Chemistry, 2nd ed.; W. H. Freeman: New York, 2006; pp 284294. 17. Prudent Practices in the Laboratory: Handling and Disposal of Chemicals; National Research Council, National Academy Press: Washington, DC, 1995.

Supporting JCE Online Material

Abstract and keywords

http://www.jce.divched.org/Journal/Issues/2009/Feb/abs234.html

Full text (PDF) with links to cited URL and JCE articles Supplement Student handout with detailed experimental procedures Instructor notes including chemicals, equipment, and chalcone registry numbers Articles for TA training IR and NMR spectra of the disubstituted chalcones

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