In the Laboratory edited by

Green Chemistry

Mary M. Kirchhoff

An Asymptotic Approach to the Development of a Green Organic Chemistry Laboratory

ACS Green Chemistry Institute Washington, DC 20036

Thomas E. Goodwin Department of Chemistry, Hendrix College, Conway, AR 72032; [email protected]

Green chemistry, as familiarly defined, is “the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture, and application of chemical products” (1a). From its genesis in academic research and chemical industry, the presentation and practice of green chemistry have begun to permeate undergraduate lectures and laboratories. As we read more about green chemistry (2), a thorough reexamination was begun of our introductory organic chemistry laboratory experiments. We started with a rethinking of why we have labs in the first place, followed by the evaluation of each experiment using green criteria. For those who may be involved in, or are considering, a similar journey, we present some philosophical questions and practical decisions that have guided the greening of our organic chemistry lab at Hendrix College thus far, followed by brief descriptions of three green experiments that are products of our own experience. Why Have Lab at All? Clearly, the minimal environmental impact could be achieved by canceling labs altogether, or by replacing all chemical experiments with computational analogues. Thus, we considered the reasons why we believe the laboratory experience to be a valuable component of the education of our students. An overarching objective is to teach the scientific method, obviously a primary goal of discovery labs and of undergraduate research. Experimentation can also make concrete the abstract and often nebulous concepts and images encountered in the classroom. Labs reinforce experimental techniques and theories and introduce scientific instrumentation and equipment. These skills are necessary and transferable to subsequent research, professional programs, and jobs. We also have a chance to inculcate environmentally responsible lab practices and thought processes. For these reasons we believe that future professional chemists, as well as other scientists and health care professionals, cannot be adequately educated without extensive, practical laboratory experience. Others may have additional goals; whatever the reasons for having a laboratory component to a course, however, they should be clearly thought out and discussed with the students. The Unexamined Experiment Is Not Worth Running We started with a deliberate evaluation of our current experiments to articulate exactly what we intended to teach with each of them. If we deemed the educational benefits of a particular experiment to be indispensable, then we assayed its greenness with an eye toward improving it, or replacing it with a better experiment that met the same objectives. We www.JCE.DivCHED.org

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were also cognizant that an experiment was not sufficiently justified merely because a worse alternative could be found. As part of this green evaluation, MSDSs and toxicology data (http://toxnet.nlm.nih.gov/, accessed May 2004) were examined for reagents, solvents, and products. Of course this led quickly to the realization that no experiment is risk free. For example, the natural product citral is a familiar terpene with a pleasant citrus odor that leads to its widespread use in flavors and fragrances. It is a major component of lemongrass oil, a common ingredient in some Asian foods. Citral was featured recently in an appealing experiment for the synthesis of ionones (the fragrance of violets) that proceeds via an aldol condensation and an acid-catalyzed cyclization (3). Yet when one reads the MSDS for citral, the words “sensitizer, severe irritant, and suspected teratogen” appear (4). At this point, a budding green chemist may be faced with a difficult question: is the use of citral worth the risk? Chemists may disagree on the answer to this question, as they might on any decision about, “How green is green enough?” In their seminal text on green chemistry, Anastas and Warner state, “…the goal of making a chemical product or process ‘environmentally benign’ is a mere statement of the ethic of continuous improvement more than it is a metric by which to measure improvement” (5). Obviously, all that we can do is strive to do better and make an asymptotic approach to the perfect green experiment. Discussing with students the criteria used in selecting and rejecting experiments is a valuable educational experience. Risk Assessment: Actual versus Perceived Risk Although we know that chemistry experiments, like all other activities in life, are not risk free, many of us are not adept at risk analysis (6). When we choose to use any chemical in the lab, we are making a decision for our students that the risk is acceptable. Thus, it is incumbent on us to choose experiments wisely and to take all appropriate precautions. At Hendrix College, many of our early experiments are modifications of traditional ones that teach experimental techniques via the isolation and purification of secondary metabolites from familiar natural products (nutmeg, spinach, cloves, etc.). We use common and relatively benign solvents like ethanol whenever possible. We try to provide our students with some risk perspective by reviewing the MSDSs of these solvents and those of other familiar compounds such as caffeine (“toxic if swallowed; irritating to eyes, respiratory system, and skin; target organs: central nervous system, heart”) that most of the students have consumed with no serious ill effects. The danger is that one can be led to extreme conclusions. Since our students know through personal experience that caffeine in beverages may be consumed safely,

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they may conclude from caffeine’s MSDS that all substances with a similar MSDS are equally safe, or that MSDS sheets exaggerate potential hazards and should be discounted altogether. Alternatively, they might conclude that every chemical is so risky that none can be used safely. (Admittedly, cutting back on caffeine consumption would probably be good for most students and their mentors, especially around final exam time.) As conscientious teachers, we can help our students develop a more reasonable perspective of actual versus theoretical risk (7). For example, we have found the recent controversy over the safety of chemical sunscreens to have great heuristic value for the comparison of toxicity data versus practical experience (8). One may also discuss the warning label on packets of saccharin (6h) that we blithely add to our beverages: “Use of this product may be hazardous to your health. This product contains saccharin, which has been determined to cause cancer in laboratory animals.” As laboratory supervisors, we should always try to practice good risk management. Risk has been defined as a function of hazard times exposure (9). Green chemistry is particularly effective in reducing the hazards by employing more environmentally benign reagents and solvents and producing less toxic products. When necessary we reduce exposure by proper use of gloves, eye protection, and fume hoods. The scale of our experiments has also been downsized as much as possible to minimize exposure and waste further. A strong case has been made for the synergy of microscale, green organic lab experiments (10), and we concur. Of course, smallscale reactions per se are not necessarily green. Nonetheless, it cannot be denied that green experiments that are conducted on a small scale are inherently lower in risk to individuals and the environment than the same experiments conducted on a larger scale. Searching for Green Solutions Ideally, all of our green experiments would be run without solvents or at least run in water. This will not always be feasible, so the careful choice of a reaction, chromatography, or recrystallization solvent becomes important (11). In our introductory labs, we eschew halogenated and aromatic solvents. When possible, we use acetic acid, acetone, diethyl ether, ethanol, ethyl acetate, petroleum ether, 2-propanol, or water. While none of these is perfect, we believe them to be preferable to the alternatives if used with proper caution and in the small quantities that are sufficient for microscale techniques. Although it is more expensive, we have begun using acetone-d6 as an NMR solvent whenever feasible (a reading of the MSDS of the commonly used solvent CDCl3 will explain why). Despite our best efforts to choose the safest solvent, future reevaluation will likely be necessary, owing to new toxicology data or public perceptions. For example, the gasoline additive methyl tert-butyl ether (MTBE), sometimes recommended as a good solvent for the undergraduate lab (12a), is also widely criticized as an environmental pollutant and possible health hazard (12b). In this context, MTBE makes an interesting and appropriate case study for class discussion regarding its suitability for use in a green organic chemistry lab program.

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An additional consideration for solvent use is how to remove it from the desired product(s). Among the obvious options, none of which is ideal, are water aspirators, passive evaporation, and rotary evaporators. In our opinion, water aspirators are best reserved for selected aqueous solutions, whereas passive (or nitrogen or air stream-aided) evaporation should be considered only for very small quantities of carefully selected solvents and be done only in a good fume hood. Solvent loss from rotary evaporators may be minimized by the simple insertion of a small-bore capillary glass tube in the vacuum line (13), plus recirculating ice water. For evaporation techniques that involve the use of reduced pressure, options often include the “house vacuum” or one of a variety of self-contained vacuum pumps or aspirators. With any of these, appropriate cold traps should be employed. With a house vacuum, one must be well informed about the capabilities and limitations of the local system to avoid a potentially hazardous situation. Is Green Chemistry “Real Chemistry”? In recent years, the Presidential Green Chemistry Challenge Awards have highlighted some outstanding achievements in the development of new environmentally friendly innovations in chemical industry and in the university research lab (14). However, in some circles, green chemistry in the undergraduate laboratory may be perceived as “chemistry light”, a myth that can be dispelled by the growing number of newly greened or freshly minted experiments that are every bit as educationally valid as their predecessors, yet are more environmentally benign (15). We offer three examples below from our own experience.

Example 1: Palladium-Catalyzed Cross-Coupling Reports of palladium-catalyzed carbon–carbon bond forming reactions have mushroomed in the primary literature (16) and may now be arguably viewed as at least equal in importance to the venerable Grignard reaction. Yet at this writing, to our knowledge, only two lab manuals (17) and few introductory organic chemistry textbooks include this important development in organic chemistry. Beginning with the early report of an experiment using a Heck reaction (18), a number of palladium-catalyzed cross-coupling experiments with varying degrees of greenness have been reported in this Journal for the undergraduate lab (19). In addition to the innovative procedures cited above, we reported a multistep experiment that featured a palladiumcatalyzed coupling between a terminal alkyne and an aromatic halide (20). The procedure is simple (no inert atmosphere required) and rapid (30 minute reaction time). Several steps were taken to make the procedure greener than is often encountered in the literature for such cross-couplings: 1.

95% ethanol is the solvent,

2. Solid piperazine hexahydrate is used as the base, rather than the usual malodorous and toxic tertiary or aromatic amines, and 3. No triarylphosphine was added as a solubilizing ligand.

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Example 2 : Stereochemistry of Reduction Garner has reported a beautiful “ultra-microscale” experiment in which 1 µL of 2,6-dimethylcyclohexanone (as a mixture of cis and trans isomers) is reduced with NaBH4 in CH3OH to a corresponding mixture of alcohols and analyzed by capillary GC (21). We and others have scaled up the reaction (in our case, to 89 µL) to facilitate conformational analysis and structure assignments on the product mixture of 2,6-dimethylcyclohexanols using 1H NMR spectroscopy (22, 23). The stereochemical outcome is surprising and the isomer ratio is solvent dependent. The reaction can be run in ethanol (or ethanol
water mixtures; we have used vodka), 2-propanol (or 2-propanol
water mixtures; we have used commercial “rubbing alcohol”), or even water. Small quantities, reaction at room temperature, relatively nontoxic wastes, plus familiar and safe solvents earn the green appellation for this experiment. Example 3: A Novel Epoxidation Epoxides are a versatile class of organic compounds that may be prepared by treatment of alkenes with a variety of reagents (24), one of the more popular having traditionally been m-chloroperoxybenzoic acid (MCPBA). Since only one oxygen atom per MCPBA molecule is used in the epoxidation, the atom economy for this reaction is not good (25). Alternatively, hydrogen peroxide may be used for alkene epoxidation under catalysis by methyl trioxorhenium (MTO; CH3ReO3) (26). The atom economy is good and the byproduct is water, clearly an improvement over MCPBA and most alternative procedures. A portion of our research on possible pheromones in elephant secretions and excretions has utilized this environmentally friendly reaction in the preparation of novel farnesol analogues (27). Since we always seek ways to integrate research with teaching labs, a microscale experiment based upon this methodology has been developed and will be reported in detail in a separate article. The experiment is greened by substitution of ethanol for the usual solvents (CH3CN, CH2Cl2), employing over-the-counter 3% hydrogen peroxide rather than the usual 30%, and using water-soluble, solid nicotinamide (derived from a commercial vitamin tablet) to replace pyridine as the activating base. We chose the terpene geraniol, 1, as the alkene substrate (Scheme I). The Sharpless asymmetric epoxidation of geraniol at the double bond proximal to the hydroxyl group has been reported as an advanced organic laboratory experiment (24e).

Our procedure is complementary in that epoxidation occurs at the double bond of geraniol that is distal to the hydroxyl to provide epoxide 2. An enlightening comparison may be made between geraniol’s MSDS (which as usual is a bit frightening) and some of its common uses, for example as an environmentally benign and safe alternative to DEET as a mosquito repellant (28). Can We Really Make a Difference? A 2002 Presidential Green Chemistry Challenge Award was presented to Pfizer, Inc. for improvements in the manufacturing process for sertraline, the active ingredient in its popular antidepressant drug Zoloft. Chemists at Pfizer were able to “reduce the solvent requirement to 6000 gal from 60,000 gal per ton of sertraline” (29). In addition, “the changes eliminate 440 metric tons of titanium dioxide-methylamine hydrochloride salt waste, and 100 metric tons of 50% sodium hydroxide waste” annually (29). These are impressive numbers and represent quantities far larger than our undergraduate organic laboratories will deal with during an instructor’s lifetime. So we may wonder then whether we can really make a difference. Why worry about undergraduate green chemistry experiments at all? There are several reasons. First, it is just the right thing to do, since even small improvements will help the local and global environment. Second, it can make us and our students feel good about doing chemistry in an environmentally responsible way. It is important that their peers and ours see that science students and scientists are active participants in sustainability issues. Our students may sometimes experience a cognitive dissonance between their fascination and respect for the beauty and power of chemistry, as in the development of a new HIV protease inhibitor, when contrasted to disturbing accounts of human and environmental tragedies such as those at Bhopal, India. An active effort on our part to practice green chemistry can help restore a healthy and realistic perspective, while not glossing over real and potential problems. Third, green chemistry can lead to great public relations, both on campus and beyond. Maybe that is not pure altruism, but it is important. Finally, the major difference that we will likely make is in the education of our students to be good environmental stewards. We will then send forth future teachers, industrial scientists, government and community leaders, and so forth who are imbued with a sensitivity to green issues. This student “biomagnification” will be our major and long-lasting accomplishment. Three Simple Questions and a Warning In closing, a suggestion is proffered. Regardless of the specific green experiments that are carried out, lab reports should include answers to three simple questions:

OH 1 3% H2O2, EtOH

1. What was green about the experiment?

CH3ReO3

2. What was not green?

O

nicotinamide

OH Scheme I. Epoxidation of geraniol.

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3. How could the experiment be made greener?

Not only will the thought process be educational, but also we can learn a lot from the answers that may lead to improve-

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ments. Now a warning: as the green mindset kicks in, be prepared to be criticized for such things as wasting wash solvents, Pasteur pipets, disposable gloves, and so forth. We must remember and remind our students that we cannot be perfect, but can only commit to continual improvement, that is, an asymptotic approach to green organic chemistry. We must not become complacent or sanctimonious, for there is always room for improvement. We should feel good about such student critiques, however, since they are clear evidence that the development of new green chemists has really begun. Acknowledgments

12.

13. 14. 15.

16.

We are grateful to our many talented students (particularly Cortney Higgins), both past and present, and for the able assistance of Shelly Bradley and Mark Smith. We acknowledge with gratitude the exchange of ideas fostered by participation in three Green Chemistry in Education Workshops led by Ken Doxsee and Jim Hutchison at the University of Oregon. Finally, we are most appreciative for a generous donation from an anonymous alumnus to help with the initiation of our lab development.

17.

18. 19.

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