Greener Solutions for the Organic Chemistry Teaching Lab: Exploring

In the Laboratory edited by

Green Chemistry

Mary M. Kirchhoff

ACS Green Chemistry Institute Washington, DC 20036

Greener Solutions for the Organic Chemistry Teaching Lab: Exploring the Advantages of Alternative Reaction Media Lallie C. McKenzie, Lauren M. Huffman, and James E. Hutchison* Department of Chemistry, University of Oregon, Eugene, OR 97403; *[email protected] Courtney E. Rogers and Thomas E. Goodwin Department of Chemistry, Hendrix College, Conway, AR 72032 Gary O. Spessard Department of Chemistry, St. Olaf College, Northfield, MN 55057

Researchers in industry and academia are actively pursuing green chemistry, and greener chemical practices are increasingly being implemented in the commercial realm. At the same time, new educational materials are being developed that introduce the strategies and tools of green chemistry to students at the undergraduate level (1). These new materials teach that relevant considerations for a chemical synthesis include cost, environmental impact, and effects on personal and public health, in addition to the more traditional criteria of yield and synthetic ease (2). Chemistry majors educated within this context are developing new skills that will contribute to the success of the chemical enterprise. Both majors and non-majors, including many future health professionals, are developing an appreciation for the ways in which chemistry can improve human life and protect the environment. Several green chemistry programs have demonstrated the practical advantages of a greener curriculum (e.g., improved safety, reduced hazard, and decreased waste) and have introduced and ingrained the principles of green chemistry (1c). Along with the practical and pedagogical benefits, the implementation of a greener curriculum provides numerous opportunities for improved public relations for the participating institutions. A major strategy of green chemistry is the discovery and development of new approaches that reduce the quantity of solvent needed, eliminate it altogether, or rely on new reaction media (3). Most solvents serve important roles in synthetic transformations, including bringing reagents together within a homogeneous mixture, dissipating heat, and modulating chemical reactivity. Because of the attributes desired by chemists (e.g., that solvents be inert, non-flammable, inexpensive, volatile, and non-toxic), a relatively small number of solvents are widely used (4). Unfortunately many traditional solvents present health, environmental, or physical hazards that may be compounded by their volatility. Solvents also make up the largest volume in many organic transformations; thus, solvents can contribute significantly to the hazard and waste generated during reactions. Although the elimination of solvents or the replacement of traditional solvents with greener substitutes or alternative reaction media can eliminate waste and reduce hazard, these changes must be carefully implemented to avoid unacceptable sacrifices in performance. The wrong solvent may limit reagent solubility, reduce reactivity, or have inappropriate physical properties. The elimination of solvent may lead to deleterious, abnormal reactivity of reagents or inadequate homogeneity of the reaction 488

mixture. Finally, although a solvent may be inherently more benign than others, the manner in which it is used and disposed of after the reaction must be considered when evaluating its environmental impact. As Blackmond et al. recently discussed, careful consideration of solvent choice is important because a greener solvent often can lead to increased waste, inefficiency, or energy use (5). As opposed to reactions where performance is compromised when solvents are replaced with greener alternatives, an increasing number of examples have demonstrated that new, greener reaction solvents or media can enhance performance. Here we describe four experiments for the undergraduate organic chemistry laboratory that illustrate both enhanced performance and a greener approach.1 The first experiment is a solventless aldol condensation that involves the reaction of two solid reagents and leads to a single product. The second reaction is a rapid, solvent-free, room temperature example of the venerable Diels–Alder reaction followed by an intramolecular nucleophilic acyl substitution. The third laboratory exercise, a Diels–Alder reaction in water, illustrates how this solvent can enhance reaction rates. The fourth experiment demonstrates the use of environmentally benign polyethylene glycol (PEG) as the medium for a Diels–Alder reaction under either conventional or microwave heating. The elimination of solvent or the use of a greener solvent (e.g., water or PEG) as the reaction medium in these reactions decreases the generation of waste, reduces the hazard involved, and raises student awareness of the role that solvent plays in these reactions. Each of these experiments demonstrates the expected benefits of greener solvent replacement and shows the performance benefits of the solvent choice. The solventless aldol condensation lab presents the idea that chemical reactions can proceed without solvent and therefore provides a platform for discussion of the role of solvents in reactions. Additionally, through a visual demonstration, the laboratory teaches concepts of melting points, purity, and eutectic points. The solventless Diels–Alder experiment reinforces these concepts, can be carried out at room temperature similar to the aforementioned aldol condensation, and introduces a highly atom economical and often taught organic reaction. The Diels–Alder reaction run in water demonstrates that the particular solvent used in a reaction is just as important as whether solvent is used at all. In this reaction, water is a more environmentally benign solvent that also enhances the rate of reaction, provides for easy separation of the product,

Journal of Chemical Education • Vol. 86 No. 4 April 2009 • www.JCE.DivCHED.org • © Division of Chemical Education

In the Laboratory

and can be recycled along with excess starting material. The last example shows the use of a versatile green solvent with increasing applications as a reaction medium for a variety of synthetic transformations, especially when it is employed in the context of microwave heating. Experiment 1: Solventless Aldol Condensation Summary of Reaction The aldol condensation, an oft-employed carbon–carbon bond-forming reaction, demonstrates stereo- and regioselectivity that add to the utility of this reaction (6). Many examples, therefore, have been included in organic laboratory curricula (7). Although most aldol condensation reactions are run in organic solvents at elevated temperatures, “solid-state” and solventless aldol condensations have recently been shown to be efficient and regioselective (8). The laboratory exercise described here was adapted from Rothenberg et al. (9) and was modified to run in one lab period (Scheme I). The starting materials are two low-melting solids that when mixed have a eutectic point below room temperature, and the reaction leads to a single product in good yield. The product is isolated after an acidic workup and recrystallized using a benign solvent. Although other laboratory experiments have been developed that demonstrate the utility of solvent-free aldol reactions (7a, 10), this exercise focuses on specific advantages due to the removal of solvent from the reaction and additional pedagogical opportunities that arise through the introduction of melting point concepts. Experimental Description The reagents are combined and crushed with a spatula until they form a homogeneous brown oil. Solid NaOH is added to the reaction mixture and well combined. Over the course of several minutes, the product forms and solidifies. After trituraO O

OCH3 OCH3 2 mp 42–45 pC

1 mp 40–42 pC

1. NaOH 2. H3O+ workup

O

OCH3 OCH3 3 mp 178–181 pC Scheme I. The aldol condensation reaction of 1-indanone, 1, and 3,4-dimethoxybenzaldehyde, 2. Although the reaction could yield both diastereomers, only the one shown is obtained (8a).

tion with dilute HCl, filtration, and recrystallization using 9:1 EtOH:H2O, typical student yields of the pale-yellow product (mp 178–181 °C) are 60%. (For the detailed procedure, see the online material.) Hazards A heavy-walled vessel should be used to avoid breakage when crushing together the starting materials. Solid sodium hydroxide is corrosive, causes severe burns, and is harmful by skin contact, inhalation, or ingestion. Hydrochloric acid is corrosive and may cause severe burns. All students must wear proper safety glasses and gloves at all times while in the laboratory. Green Benefits In addition to the obvious advantage of removal of the waste and hazard of traditional solvents, there are other green chemistry benefits to this experiment. Since there is no organic solvent to remove and the product is not water soluble, the isolation of the product is both energy efficient and simple. Application of green chemistry principles to compare this solventless reaction with a traditional aldol condensation provides an opportunity for students to assess reaction conditions and evaluate each part of a reaction for its impact. This reaction can be carried out in fewer than 15 minutes, occurs at room temperature, and produces a relatively pure and easily purified product. The atom economy of this reaction is high, and the only byproduct is water. This example of a “solid–solid” reaction also raises awareness of alternative approaches to chemistry that are currently being explored. Pedagogical Benefits At the University of Oregon, the solventless aldol condensation has been used as the first experiment in the organic laboratory course (~240 students/year) (1a). It can be used to introduce the relationship between melting points and compound purity and to teach techniques for determining melting points. The phase change at room temperature vividly illustrates the concept of eutectic points. Since there is no addition of solvent to the reaction, this exercise allows for the discussion of the role of solvent in chemical reactions and why it is usually necessary. Since the students’ first experience with organic reactions is conducted without a solvent, they do not assume that solvent is required but instead learn to evaluate the need for and appropriateness of solvents in subsequent reactions. Experiment 2: Solventless, Room Temperature, Tandem Diels–Alder Reaction and Nucleophilic Acyl Substitution Summary of Reaction As an experiment for the introductory organic chemistry laboratory, McDaniel and Weekly (11) reported the Diels– Alder reaction of (E,E)-2,4-hexadien-1-ol, 4, with the popular dienophile maleic anhydride, 5, in refluxing toluene to provide, after subsequent intramolecular nucleophilic acyl substitution, carboxylic acid 6. It should be noted that while the reactants are achiral, the product has four chirality centers and thus the possibility of 16 stereoisomers. Because of the inherent stereochemical requirements of a Diels–Alder reaction, however, only two isomers are produced: compound 6 and its enantiomer. A key pedagogical component of this experiment is analysis of the

© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 4 April 2009 • Journal of Chemical Education

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In the Laboratory OH

2D COSY NMR spectrum of the product. At Hendrix College, we have found that this reaction may be carried out rapidly and simply by stirring the two reactants with a spatula at room temperature in the absence of solvent (Scheme II). Experimental Description Equimolar amounts of (E,E)-2,4-hexadien-1-ol, 4, and finely powdered maleic anhydride, 5, are stirred for 10–15 min at room temperature and a white solid (compound 6) forms. The product is normally pure enough for spectroscopic evaluation by NMR and FTIR. For a solventless and reagentless reaction in which the two substrates are merely mixed at the ambient temperature, one should expect a quantitative yield. Nonetheless, the class average was 90%; presumably some product adhered to the spatula. Small portions of the product may be mixed with aqueous NaHCO3 to produce effervescence and thus evidence of the carboxylic acid functionality. (For the detailed procedure, see the online material.) Hazards (E,E)-2,4-Hexadien-1-ol and maleic anhydride are skin irritants, corrosive, and irritating to the mucous membranes. Avoid inhalation and skin contact. Wear eye protection and gloves. Green Benefits The McDaniel and Weekly procedure (11) calls for boiling the two reactants in toluene for 5 min. Although this solvent choice represents an improvement over the original methodology (12, 13) (refluxing the reactants in benzene for 48 h), our commitment to continuous greening of laboratory experiments led us to seek (unsuccessfully) a better solvent than toluene. Heating the two reagents without solvent at 90 °C for 15 min or by microwave heating at reduced power for 30 s was successful. We then discovered the reaction works well without heating. The current green experiment is run on a very small scale and requires no solvent. The only energy required is provided by 10–15 min of manual stirring by the experimentalist. As in all Diels–Alder reactions, the atom economy for this reaction is 100%. Pedagogical Benefits This experiment shares many of the benefits listed for the solventless aldol reaction discussed earlier. In addition, it illustrates a highly stereoselective reaction sequence that allows not only a discussion of Diels–Alder reaction characteristics, but also a review of nucleophilic acyl substitution. Wender and Miller stated, “The ideal synthesis may be defined as one in which the target molecule is prepared from readily available starting materials in one, simple, safe, environmentally acceptable, and resource-effective operation that proceeds quickly and in quantitative yield” (14). This experiment approaches that ideal. The facile intramolecular nucleophilic acyl substitution illustrates the relative nucleophilicity of an alcohol versus a carboxylic acid. It also exemplifies a principle enunciated by the late R. B. Woodward: “We all know that enforced propinquity often leads on to greater intimacy” (15). That is, the higher probabilities of collision and favorable entropy change for intramolecular processes lead to more favorable reactions. As additional benefits of this experiment, NMR analysis of the product 6 provides an excellent introduction to 2D COSY spectral interpretation (since the resonances of all protons are distinct at 300 MHz in acetone-d6, a greener solvent than the 490

O O

O 4

5 no heat no solvent

OH O

á O

H Oź O

O O

O

O O CO2H 6 (and enantiomer) Scheme II. The tandem Diels–Alder and intramolecular nucleophilic acyl substitution reaction of (E,E)-2,4-hexadien-1-ol, 4, with maleic anhydride, 5.

usual CDCl3), as well as an outstanding example of enantiotopic and diastereotopic hydrogens. The energy of the product structure can be minimized with molecular mechanics software such as Spartan (Wavefunction, Inc.). Measurement of the dihedral angles can facilitate a discussion of the Karplus relationship between dihedral angle and NMR coupling constant. This experiment also enables the students to learn about critical evaluation of literature methods and the evolution of an experiment in an asymptotic approach to the ideal (16). Experiment 3: Diels–Alder Reaction in Water Summary of Reaction Another example of this atom economical carbon–carbon bond-forming reaction uses water as the solvent. Because of the time constraints of teaching laboratories, traditional Diels– Alder experiments involve the use of extremely reactive reagents (e.g., cyclopentadiene or 1,3-butadiene) that require specialized preparation procedures and use of aromatic solvents (17). Recently, exciting work has been done on the rate acceleration of these reactions due to the hydrophobic effect when done in water (18). Because water increases the reaction rate, this


In the Laboratory

O

N O (≥ 3 equiv)

HO H2O % 1 hr

7

8

O N O

HO

9

Scheme III. The Diels–Alder reaction of 9-anthracenemethanol, 7, and N-methylmaleimide, 8.

Diels–Alder reaction (Scheme III) can be completed in an hour, even though it uses much less reactive reagents than traditional Diels–Alder experiments. This exercise allows for discussion of solvent effects and factors affecting reactivity in the Diels–Alder reaction. Experimental Description 9-Anthracenemethanol [9-(hydroxymethyl)anthracene], 7, and three molar equivalents of N-methylmaleimide, 8, are suspended in water and refluxed for an hour. Reaction progress is monitored by thin-layer chromatography, and, upon cooling, the product precipitates and is collected by vacuum filtration. The Diels–Alder adduct 9, an off-white crystalline solid (mp 237–239 °C), is isolated with typical student yields of 80%. (For the detailed procedure, see the online material.) Hazards N-Methylmaleimide is corrosive and should be handled with care. The toxicological properties of 9-anthracenemethanol have not been investigated. Students should wear gloves and safety glasses. Green Benefits As in the exercises above, this experiment offers students the opportunity to compare the reaction conditions with those of a traditional Diels–Alder reaction and to identify greener solvents and methods. Students use less reactive, safer materials, and reduce energy inputs by relying on water to enhance the reaction rate. This reaction also demonstrates a greener, straightforward, and efficient method for isolating products. The Diels–Alder adduct is not water-soluble; therefore, it precipitates at the end of the reaction and can simply be filtered. The efficiency of the reaction can be improved further by using the filtrate as the solvent in a subsequent reaction. In this case, two equivalents of N-methylmaleimide, 8, remain dissolved in the water, and the reaction will go to completion with the addition of equimolar

amounts of 9-anthracenemethanol, 7, and N-methylmaleimide, 8. Recycling the solution from the reaction reduces the quantity of waste produced. As for other Diels–Alder reactions, the atom economy for this transformation is 100%. Pedagogical Benefits At the University of Oregon, we have used this experiment (~240 students/year) as a context to discuss various concepts in physical organic chemistry. The impact of the solvent on the acceleration of the rate of the reaction can be addressed in as much depth as desired by the instructor. Primary literature contains many studies of Diels–Alder reaction kinetics between 9-anthracenemethanol and N-methylmaleimide in various solvents, including water, hydrocarbons, fluorous solvents, and supercritical CO2 (18a–c, 19). The properties of various solvents can be related to their ability to enhance the rate of the reaction through hydrophobic interactions and hydrogen bonding. Discussions of the required excess of starting material can advance students’ understanding of the role of reagent solubility in the hydrophobic effect.2 The Diels–Alder adduct synthesized in this laboratory can be characterized by 1H NMR spectroscopy. In particular, the coupling constants of the protons at the reaction site can be used to demonstrate that only one product is formed (17c, 20). This laboratory exercise also offers additional opportunities to discuss anthracene–maleimide Diels–Alder chemistry and its role in “Click Chemistry” and materials synthesis (20, 21). Experiment 4: Polyethylene Glycols as Green Solvents Summary of Reaction Polyethylene glycols (PEGs) are characterized by the general formula RO−(CH2CH2−O)nR, where R = H, alkyl, or acyl. They range in molecular weight from around 200 to well over 1000 Da. PEGs are considered to be benign solvents, finding wide use in the food, cosmetic, and pharmaceutical industries. They exhibit very low volatility and flammability and are biodegradable. PEGS are soluble in water and a variety of organic solvents, so reactions can be run readily in PEG– cosolvent mixtures. Although PEGs are produced now from polymerization of ethylene oxide, a compound produced by the petrochemical industry, the potential exists to manufacture them from non-petroleum feedstocks. PEGs have been considered as far cheaper and non-toxic alternatives to ionic liquids, which some deem to be green solvents due to their non-volatility. They have been used as solvents in several common types of organic reactions, including SN2 substitution, oxidation, and reduction. PEGs can serve as phase-transfer catalysts, and transition-metal catalysts have been covalently attached to PEGs, allowing for ease of catalyst recycling (3a, 22). At St. Olaf College, we have developed procedures for running the Diels–Alder reaction during the first semester of our organic laboratory sequence using PEG [MW = 200 (R = H) or 250 (R = CH3)] as the solvent. The procedures, which involve use of either conventional or microwave heating (23), are outlined in Scheme IV. Other dienes (furan or 1,3-cyclohexadiene) and another dienophile (diethyl fumarate) will also react with the same conditions. Our procedures are characterized by mild reaction conditions and ease of workup. Near quantitative isolation of relatively pure product is accomplished simply by pour-


491

In the Laboratory O

ing the reaction mixture into water. Formation of white crystals occurs immediately, and these may be isolated and purified by vacuum filtration and air-drying.3 Experimental Description Conventional Heating The reactants are stirred in PEG for 60 min at 60–70 °C, and then the mixture is poured into water. The resulting white crystals are collected by vacuum filtration, giving typical student yields of 80–90% of white product 12 (mp 71–73 °C).4 (For the detailed procedure, see the online material). Microwave Heating The same reaction, as described above, was also run in a Milestone START microwave reactor (150 W of power for 100 s) (24) that was equipped with a carousel apparatus capable of holding 16 reactor vessels. Yield and quality of product were the same as obtained with conventional heating (25). (For the detailed procedure, see the online material.) Hazards Maleic anhydride is a skin irritant, corrosive, and irritating to the mucous membranes; plastic gloves should be worn. 2,3-Dimethyl-1,3-butadiene is highly flammable and volatile. When using flammable, volatile reagents or solvents, only laboratory-grade microwave devices designed specifically to run chemical reactions should be employed. Green Benefits The Diels–Alder reactions reported here and elsewhere have an atom economy of 100%. Near quantitative and easy recovery of relatively pure product mean that reaction mass efficiency is high and E-factor (26) is low, both of which are desirable in a green reaction. The PEG solvent is environmentally friendly in terms of toxicity, volatility, and biodegradability. This laboratory introduces students to another green reaction medium, which is an alternative to use of water, ethanol, or no solvent at all.5 Microwave radiation is considered a greener method of heating because reaction times tend to be shorter than those required using conventional heat sources. Since the microwave energy is directed more efficiently to the reaction vessel and because reaction times tend to be shorter, the energy cost associated with microwave heating is usually less (and sometimes significantly less) than that using conventional means (e.g., hot plate, Bunsen burner, steam bath, etc.) (27). Pedagogical Benefits Students at St. Olaf College (130/year) encounter the Diels–Alder reaction at the end of the first semester in our twosemester laboratory course sequence. Because the experiment takes place in either an hour (conventional) or 100 seconds (microwave), depending on the heating mode, and because workup is rapid and straightforward, students have plenty of time to characterize the product, wrap up previous experiments, and check out during the course of the three-hour time period we allot for organic laboratory. Students find that this lab ensures a high yield, and the appearance of the product as white, glistening crystals is aesthetically pleasing. Characterization of compound 12 is relatively straightforward by 1H NMR due to the symmetrical nature of the structure. The 13C NMR spectrum provides students with a good example of how symmetry reduces 492

O

O 10

11

PEG 50–70 pC 1h or microwave 150 W 100 s

H

O O

H

O (ca. 90% isolated yield) 12

Scheme IV. Diels–Alder reaction of 2,3-dimethyl-1,3-butadiene, 10, with maleic anhydride, 11, in PEG solvent.

the number of signals exhibited compared to the number of carbon atoms present. The use of microwave ovens for heating organic reactions has increased significantly over the last few years in both industrial and academic venues (27). Laboratory-grade microwave reactors are superior to domestic microwave ovens in a number of ways: (i) they coherently direct powerful microwave radiation to the site of the reaction and not randomly throughout the oven cavity, (ii) they can be programmed to apply specific wattages or maintain precise reaction temperatures over defined time periods, and (iii) they are better outfitted for lab safety, particularly when volatile, flammable compounds are involved (25, 28). Conclusions The four organic laboratory experiments in this article provide an opportunity to introduce green chemistry into educational settings easily and, in so doing, reap multiple benefits. The alternative solvents or reaction media used in these experiments not only reduce the use of hazardous or volatile organic solvents but also enhance the transformations by increasing the rate of reaction or facilitating recovery of the product. In the cases where no solvent is used, recovery of the product is simplified and concomitantly minimizes the quantity of waste generated when isolating the product. Each experiment is based on a commonly taught organic reaction and involves a transformation exhibiting high atom economy. Finally, each of these experiments is convenient, inexpensive, and can be carried out rapidly and successfully in the organic teaching laboratory, contributing to student success in the lab and leaving more time in the lab for other activities such as spectroscopy and analysis. Acknowledgments This work was supported by the National Science Foundation (DUE-0443128) and the University of Oregon. G.O.S. acknowledges the W. M. Keck Foundation for the generous support of this work. L.C.M. acknowledges support from the National Science Foundation in the form of an IGERT fellowship (DGE-0549503). Notes 1. Although there are many examples where alternative reaction media do not enhance reactions or even cause deleterious effects, these four experiments were designed specifically to demonstrate additional advantages when greener solvents are used. They also are intended to provide a variety of pedagogical options and can be used individually or run as a sequence. Instructors are encouraged to choose the experiment that best meets the needs of their students and to guide them in examining limitations inherent in the use of any solvent.


In the Laboratory 2. Although the primary literature (18a) indicated that at least six molar equivalents of the maleimide were required in this reaction, we learned that three equivalents of N-methylmaleimide can result in high yields of pure product. When fewer than three equivalents of maleimide were used, unreacted 9-anthracenemethanol remained and precipitated with the product. 3. This Diels–Alder reaction has also been run in an ionic liquid consisting of a 2:1 molar ratio of ZnCl2 and choline chloride, but we found that there were problems with hydrolysis of the cyclic anhydride group in the product due to the presence of moisture in the ionic liquid. See Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.; Tambyrajah, V. Green Chem. 2002, 4, 24–26. 4. Compound 12 is sufficiently pure for NMR analysis. If desired, further purification may be accomplished by recrystallization from 1:9 hexanes:ethyl acetate, which yields white, feathery needles (mp 77–78 °C, consistent with the value previously reported: Grummitt, O.; Endrey, A. O. J. Am. Chem. Soc. 1960, 82, 3614–3619) or by sublimation using a 9 in. Petri dish with cover on a hot plate at low setting (mp 74–76 °C). 5. It should be pointed out that there are other green alternative solvents that are neither PEGs nor true ionic liquids. One example, which has been used to run Diels–Alder reactions, is a low-melting mixture of sugar, salt, and urea. See Imperato, G.; Eibler, E.; Niedermaier, J.; Konig, B. Chem. Commun. 2005, 1170.

Literature Cited 1. (a) Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments; Brooks/Cole: Pacific Grove, CA, 2004. (b) Greener Approaches to Undergraduate Chemistry Experiments; Kirchhoff, M., Ryan, M. A., Eds.; American Chemical Society: Washington, DC, 2002. (c) Reed, S. M.; Hutchison, J. E. J. Chem. Educ. 2000, 77, 1627–1629. 2. Haack, J. A.; Hutchison, J. E.; Kirchhoff, M. M.; Levy, I. J. J. Chem. Educ. 2005, 82, 974. 3. (a) Sheldon, R. A. Green Chem. 2005, 7, 267–268. (b) Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2004. (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074. (d) DeSimone, J. M. Science 2002, 297, 799–803. 4. Smallwood, I. M. Handbook of Organic Solvent Properties; Elsevier: New York, 1996. 5. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798–3800. 6. Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65–75. 7. (a) Palleros, D. R. J. Chem. Educ. 2004, 81, 1345–1347. (b) Bennett, G. D. J. Chem. Educ. 2006, 83, 1871. 8. (a) Raston, C. L.; Scott, J. L. Green Chem. 2000, 2, 49–52. (b) Toda, F. Acc. Chem. Res. 1995, 28, 480–486. 9. Rothenberg, G. D.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701–8708. 10. Cave, G. W. V.; Raston, C. L. S. J. Chem. Educ. 2005, 82, 468– 469. 11. McDaniel, K. F.; Weekly, R. M. J. Chem. Educ. 1997, 74, 1465– 1467. 12. For the original literature procedure see Brettle, R.; Cummings, D. P. J. Chem. Soc., Perkin Trans. 1, 1977, 2385–2392. 13. For related mechanistic examinations of this reaction, see Cayzer, T. N.; Lilly, M. J.; Williamson, R. M.; Paddon-Row, M. N.; Sherburn, M. S. Org. Biomol. Chem. 2005, 3, 1302–1307.

14. Wender, P. A.; Miller, B. L. Toward the Ideal Synthesis: Connectivity Analysis and Multibond-Forming Processes. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; Jai Press: Greenwich, CT, 1993; pp 27–66. 15. Woodward, R. B. as quoted in Sharpless, K. B. Chem. Brit. 1986, 22, 38–44. 16. Goodwin, T. E. J. Chem. Educ. 2004, 81, 1187–1190. 17. (a) Harwood, L. M.; Moody, C. J.; Percy, J. M. Experimental Organic Chemistry, 2nd ed.; Blackwell Science: Malden, MA, 1999. (b) Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry, A Miniscale and Microscale Approach, 4th ed.; Thomson Brooks/ Cole: Belmont, CA, 2006. (c) Jarret, R. M.; New, J.; Hurley, R.; Gillooly, L. J. Chem. Educ. 2001, 78, 1262–1263. (d) Lee, M.; Garbiras, B.; Preti, C. J. Chem. Educ. 1995, 72, 378–380. 18. (a) Breslow, R.; Zhu, Z. J. Am. Chem. Soc. 1995, 117, 9923–9924 and references therein (b) Breslow, R.; Groves, K.; Mayer, M. U. Pure and Applied Chemistry 1998, 70, 1933–1938. (c) Meyers, K. E.; Kumar, K. J. Am. Chem. Soc. 2000, 122, 12025–12026. (d) Breslow, R.; Maitra, U.; Rideout, D. Tetrahedron Lett. 1983, 24, 1901–1904. 19. Qian, J. T.; Timko, M. T.; Allen, A. J.; Russell, C. J.; Winnik, B.; Buckley, B.; Steinfeld, J. I.; Tester, J. W. J. Am. Chem. Soc. 2004, 126, 5465–5474. 20. Kim, C.; Kim, H.; Park, K. J. Organometal. Chem. 2003, 667, 96–102. 21. (a) Gacal, B.; Durmaz, H.; Tasdelen, M. A.; Hizal, G.; Tunca, U.; Yagci, Y.; Demirel, A. L. Macromolecules 2006, 39, 5330–5336. (b) Kolb, H.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. 22. (a) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green Chem. 2005, 7, 64–82. (b) Leininger, N. F.; Clontz, R.; Gainer, J. L.; Kirwin, D. J. Chem. Eng. Comm. 2003, 200, 431–444. 23. For other articles describing the use of microwave ovens in the undergraduate organic laboratory, see (a) Parquet, E.; Lin, Q. J. Chem. Educ. 1997, 75, 1225. (b) Dintzner, M. R.; Wucka, P. R.; Lyons, T. W. J. Chem. Educ. 2006, 83, 270–272. (c) Musiol, R.; Tyman-Szram, B.; Polanski, J. J. Chem. Educ. 2006, 83, 632–633. (d) Montes, I.; Sanabria, D.; Garcia, M.; Castro, J.; Fajardo, J. J. Chem. Educ. 2006, 83, 628–631. (e) Crouch, R. D.; Howard, J. L.; Zile, J. L.; Barker, K. H. J. Chem. Educ. 2006, 83, 1658–1660. 24. For a description of the capabilities of the Milestone START system, see Schoenfeld, C.; Loechner, M.; Favretto, L. Amer. Lab. 2003, 22–27. 25. For a recent report describing the Diels–Alder reaction of 10 and 11 using microwave heating without solvent, see Katritzky, A. R.; Cai, C.; Collins, M. D.; Scriven, E. F. V.; Singh, S. K.; Barnhardt, E. K. J. Chem. Educ. 2006, 83, 634–636. 26. Sheldon, R. A. ChemTech 1994, 24, 38–47. 27. Kappe, C. O. Angew. Chem,. Int. Ed. 2004, 43, 6250–6284. 28. �� For information about the theory of microwave heating, see Cresswell, S. L.; Haswell, S. J. J. Chem. Educ. 2001, 78, 900–904.

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Greener Solutions for the Organic Chemistry Teaching Lab: Exploring

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