The Evolution of a Green Chemistry Laboratory Experiment: Greener

In the Laboratory edited by

Green Chemistry

Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036

The Evolution of a Green Chemistry Laboratory Experiment: Greener Brominations of Stilbene

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Lallie C. McKenzie, Lauren M. Huffman, and James E. Hutchison* Department of Chemistry and Materials Science Institute, University of Oregon, Eugene, OR 97403-1253; *[email protected]

Green chemistry—the design of chemical products and processes that reduce or eliminate the use and generation of hazardous substances—is becoming more widely incorporated into chemistry curricula. Previous work by our group and others describes experiments that can be used to “green” chemistry curricula (1–7); however, these are only starting points for continued innovation and optimization. This manuscript is concerned with the process used to assess and optimize greener laboratory experiments and provides a case study that demonstrates the need for continual evaluation and modification of experimental procedures in the pursuit of the most benign experiments for use in the teaching laboratory. Two alternative sets of reaction conditions, one involving pyridinium tribromide and the other a hydrogen peroxide– hydrogen bromide system, have been developed and compared to the traditional bromination of stilbene. All three laboratory procedures are analyzed through the application of several types of green chemistry metrics to assess their relative greenness and to guide the optimization of the bromination experiment. The resulting laboratories improve safety as well as demonstrate the effectiveness of using an iterative greening process to develop experiments that teach green principles and chemical concepts. Background The ideal attributes of experiments for use in a green organic chemistry laboratory curriculum have been previously discussed (1). These educational materials should convey important chemical concepts and laboratory techniques, be successfully completed within the constraints of a teaching lab, and modernize the curriculum using recent developments from the literature. In addition, each experiment should illustrate green principles and strategies (8), teaching students to objectively assess risk and hazard and optimize reaction conditions. The greenness of an experiment can almost always be improved, fueled by new innovations and driven by appropriate assessment metrics. One real world example of this type of iterative greening progression can be found in the evolution of refrigeration. Initial technology was based upon the use of ammonia, a very toxic and moderately flammable compound, as the refrigerant. While refrigeration improved public health because food did not spoil as quickly, ammonia’s strong smell and corrosive nature led to the search for new compounds for use in refrigerators. Chlorofluorocarbons (CFCs) were then introduced and acclaimed for their longevity, non-

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flammability, and lack of toxicity. Later, it was discovered that their use was contributing to the degradation of the ozone layer, and their use was restricted (9). Hydrofluorocarbons (HFCs) have been used in replacement and have shown no impact on the ozone layer. In the future, thermoelectric materials may take the place of chemical refrigerants. These solidstate devices are highly efficient, have no moving parts, and utilize no volatile substances. As this example illustrates, incremental improvement of technology, driven by concerns for public safety and environmental impact, leads to more sustainable practices. An analogous approach can be taken to improve the safety, efficiency, and environmental impact of laboratory experiments. Although the general approach to greening a reaction— identifying and eliminating or substituting for hazardous substances used in it—is known, a process for evaluating and optimizing laboratory experiments for use in the teaching labs has not been described. In the following section, two reactions are described that demonstrate the process for achieving progressively greener methods for bromination of stilbene. Each of these reactions possesses different hazards and efficiencies that are assessed and discussed in the next section. Because the teaching lab is an environment in which safety plays a dominant role, specific metrics are presented and evaluated for use in optimizing experiments for the teaching labs. The Laboratory Experiments: Greener Brominations Experiments demonstrating alkene bromination meet many of the criteria desired in an undergraduate laboratory exercise. Brominations are important and well-understood reactions that are covered in most organic lecture courses. Pedagogically, it is useful to discuss bromination within the context of alkene reactivity, reaction mechanisms, and chemical transformations; however, the hazards involved in traditional bromination reactions can prevent their use in the teaching laboratory. These considerations offered an opportunity to develop greener reaction conditions. Bromination of alkenes is typically carried out with liquid bromine in a non-reacting or acidic solvent, such as CCl4, CH2Cl2, or glacial acetic acid (Scheme I, Reaction I). While this type of bromination works well on most substrates and can be completed in as little as ten minutes (10), it can be dangerous to perform in an instructional laboratory setting. Carbon tetrachloride and dichloromethane are suspected carcinogens; the use of carbon tetrachloride soon will be phased out under the Montreal Protocol due to its ozone-depleting

Vol. 82 No. 2 February 2005

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properties (9). Glacial acetic acid and elemental bromine are corrosive and volatile, cause severe burns upon contact with the skin, and are extremely irritating upon inhalation. As demonstrated by the application of green metrics in the analysis section below, this reaction is efficient but involves hazards that must be addressed with a greener procedure.

Pyridinium Tribromide Used as the Bromine Source The first alternative to traditional bromination procedures is presented in Scheme I, Reaction II. Pyridinium tribromide, popularized by Djerassi and Scholz (11), is used as the bromine source. Solid pyridinium tribromide does not present the same degree of health risk as liquid bromine. In this reaction, bromine is gradually generated in the reaction medium through rapid equilibrium between pyridinium tribromide and molecular bromine. Students no longer need to handle the bromine directly and learn the concept of in situ generation of reagents. Many texts suggest the use of glacial acetic acid as the solvent for this reaction (10, 12); however, we have obtained similar yields when ethanol, a more benign solvent, is substituted for the acetic acid. High yields and stereoselectivity have also been reported with the use of this reagent in a water suspension medium (13). This experiment provides students with experience carrying out a reaction above room temperature, using vacuum filtration to isolate a solid product, and determining and comparing the melting points of the crude and purified products. By replacing liquid bromine and acetic acid with pyridinium tribromide and ethanol, the bromination of an alkene can be performed under safer conditions. The bromination with pyridinium tribromide is an example of a reaction that has been made safer, yet has considerable opportunities for improvement. Although the solvent

Br2

I

and bromination reagent are less hazardous, pyridinium tribromide is corrosive and can cause significant damage to metal equipment, especially balances. While the molecular bromine has been removed from the teaching lab, the reagent is synthesized from pyridine and bromine; therefore, the hazard is not eliminated entirely but is displaced to another site. As demonstrated through metrics in the following section, the reaction also has relatively poor atom economy; while the desired product is obtained, a quantitative amount of pyridinium bromide is produced as waste. In our search for improved methods of bromination, we aimed to find methods to increase the atom economy, use less corrosive materials, and continue to eliminate liquid bromine and chlorinated solvents. Primary literature provided some possible solutions. Ho et al. used hydrogen peroxide, hydrochloric acid, and a phase transfer catalyst as a chlorination method in water (14). Later, Barhate et al. explored methods of halogenation involving peroxides and hydrohalic acids on a variety of substrates and in a number of solvents (15). These reactions provided an excellent framework for the development of a greener laboratory, improving both safety and efficiency.

Hydrobromic Acid and Hydrogen Peroxide Used as the Bromine Source Building on the work of these researchers, we developed a greener bromination experiment using hydrobromic acid and hydrogen peroxide (see Scheme I, Reaction III). Stilbene is dissolved in ethanol and heated to reflux. Upon addition of hydrobromic acid and 30% hydrogen peroxide,1 the formerly colorless solution becomes a deep gold to orange color, indicating the oxidation of HBr to Br2 by the H2O2. Once the reaction is complete, the orange color disappears due to

Br

H H

CH2Cl2

N

H

II

+

Br

H Br3−

Br

H

EtOH

H

Br

H

+

N

+

H Br −

III HBr/H2O2

Br

H

EtOH

Br

H

+

H2O

Scheme I: Three bromination reactions of trans-stilbene considered in this paper. Reaction I, the traditional bromination reaction involving molecular bromine, is compared with two greener procedures. Reactions II and III utilize different brominating reagents and reaction solvents that offer safer reaction conditions. The relative greenness of the three procedures is discussed in the text.

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the incorporation of bromine into the product, and the product precipitates out of solution. Purification is completed by filtering the solid product and rinsing with a very small volume of cold ethanol. Student yields are typically around 70%, and we have received quite positive responses from the students to this experiment. The HBr–H2O2 reaction offers opportunities for chemical lessons that are not available through the other two reactions. The mechanism of the reaction can be explored through observation of the reaction and examination of 1H NMR of the crude product. The presence of the characteristic bromine color during the reaction and small amounts of bromo-ethoxy substituted product are indicative of molecular bromine and a bromonium ion intermediate. Chalcone and ethyl cinnamate also can be successfully brominated through this procedure, offering flexibility in substrate choice. Both of these starting materials are non-toxic and inexpensive, and the bromination of ethyl cinnamate provides the opportunity to work with a liquid reagent as well as to perform an optional ethanol–water recrystallization of the product. Although stilbene dibromide has been used as a starting material for the preparation of diphenylacetylene (12), it is typically not used and contributes to the waste stream. In an effort to continue greening this reaction, a procedure was developed that allows the product to be debrominated for recycling. After a short reflux of stilbene dibromide and zinc powder in ethanol and a hot filtration, pure trans-stilbene crystallizes, providing yields of around 70%. The zinc bromide by-product is non-toxic, and the ethanol can be recovered by distillation for reuse. This procedure is not only greener than disposing of the stilbene as waste, it is also cost-effective. Hazards Pyridinium tribromide, hydrobromic acid, 30% hydrogen peroxide, and zinc dibromide are corrosive and can cause

burns. Students should be careful to avoid contacting skin with these compounds, refrain from breathing them, and wipe up any spills immediately. Ethanol and methanol are volatile and highly flammable. No open flames should be used near these solvents. Although no specific health risks are associated with zinc dust, inhalation of particulate matter should be avoided. Gloves and eye protection should be worn during these procedures. Analysis During the process of greening a chemical reaction, each alternative procedure must be evaluated to identify hazardous materials or inefficient procedures so that one can identify areas for improvement and optimize procedures accordingly. Metrics allow for measured, objective analysis for comparison of competing procedures. Although many green chemistry metrics have been proposed (16), such metrics have not been specifically applied to the development of laboratory experiments. Development of widely applicable green chemistry metrics is an on-going research challenge. Here, the aim is not to develop an exhaustive set of metrics for use in evaluating new educational materials, but rather to examine the use of these metrics in the teaching lab environment, assess the reaction efficiencies of the reported bromination reactions, and present a case study that can be used to introduce metrics to students. When choosing metrics, the purposes of the evaluation must be considered. For an industrial process, useful metrics emphasize measures of efficiency and cost, in addition to the comparison of chemical hazards. In the teaching lab, on the other hand, reducing the exposure of the students to hazards is paramount. In this setting, metrics that lead to solutions that enhance personal safety, reduce the volume and hazard of the waste stream, and ease reliance on environmental controls are most important.

Table 1. Comparisons of Three Bromination Reactions Using Various Green Chemistry Metrics Reaction Type

c

Atom Economy, in Percent a

Experimental Atom Economy, in Percent b

I Bromine in methylene chloride f

100.0%

98.3%

7.46

11.8%

II Pyridinium tribromide in ethanol

168.0%

62.3%

8.96

62.3%

III HBr and H2O2 in ethanol

190.4%

71.8%

9.81

71.8%

mass reagent

mass waste

Method of calculation equations

MWproduct

∑ MWreagent

× 100%

in products

∑ mass reagent

E Factor

and byproducts

× 100%


•


mass product

mass product

mass nonbenign

× 100%

material

aIdeal is 100%; bIdeal is 100%; cIdeal is 0; dIdeal is 100%; eEtOH and H O were considered benign; 2 procedure found in Durst and Gokel was used for the analytical comparison (21).

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Effective Mass Yield, in Percent d,e

•

f

The bromination of stilbene

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A variety of green metrics has been developed and recently reviewed (16); those most applicable to the teaching laboratory appear to be atom economy (17), percent experimental atom economy (18), E factor (19), and effective mass yield (20). Atom economy, an indicator of the theoretical reaction efficiency, calculates the fraction of reactants converted to the product. Percent experimental atom economy is based upon atom economy analysis but is calculated using the actual masses of reagents and products in the reaction, thus incorporating an accounting of excess reagents into the metric. The E factor includes the mass of solvent used and by-products formed during the reaction and draws attention to the amount of waste produced during the course of the reaction. It simplifies the calculations but does not differentiate between types of waste. Effective mass yield takes into account relative toxicity, as well as reaction efficiency, by including only the hazardous components of the waste stream. Application of various metrics allows for comparison of the three bromination reactions (Table 1).2 Atom economy and percent experimental atom economy measure reaction efficiency without consideration of solvent use or inherent hazards. Reaction I is highly efficient by these two metrics, having nearly perfect atom economy. Of the safer alternatives, Reaction III demonstrates an improvement over Reaction II, although the traditional bromination reaction is still the most efficient. In E factor calculations, the masses of all chemical species are included in the calculation, but the identity of the solvent is not taken into account by the metric. Because both HBr and H2O2 are used as aqueous solutions, Reaction III is shown to be the least efficient reaction by the E factor. The calculated E factor for Reaction I shows it to produce the least amount of waste per mass of product despite the fact that the solvent used is a chlorinated hydrocarbon. Thus metrics that evaluate the effective use of materials indicate that the most efficient bromination occurs with molecular bromine, such as in Reaction I. In the undergraduate teaching lab, student safety and reduced reliance on environmental controls must be considered in parallel with the need for enhanced reaction efficiency. The greenness of these experiments is best evaluated through the use of metrics that include an evaluation of relative hazard, such as effective mass yield. Calculations of effective mass yield and the classification of ethanol and water as benign chemicals demonstrate that the HBr–H2O2 bromination of stilbene is greener (based on its higher effective mass yield) than the pyridinium tribromide reaction and much greener than the original reaction involving bromine in dichloromethane. Evaluating the relative hazards of individual reagents is an even more challenging task. In the present case, each of the reagents used in Reactions II and III pose less risk to exposure and lower hazard to students based upon vapor pressures, OSHA Personal Exposure Limits (22), NIOSH immediately dangerous to life or health concentrations (23), and practical concerns related to the difficulty that students have handling each material. Although the traditional bromination reaction might be more appropriate in an industrial setting where efficiency is of most importance and environmental controls are robust, the two alternative reactions are significantly safer and greener

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for use in the teaching laboratory. The incremental greening process demonstrates the ability to enhance reaction efficiency while continuing to eliminate hazards and improve safety. Effective mass yield appears to be a more useful metric for evaluation of student experiments than the metrics that focus solely on reaction efficiency. The hydrogen peroxide–hydrobromic acid reaction provides the optimal combination of safety, reaction efficiency, and efficacy for the teaching laboratory. There are considerable opportunities for further greening of this experiment. Incorporating research into vanadiumcatalyzed peroxidase brominations (24) or the use of poly(4-vinylpyridine–styrene)–bromine complexes as brominating agents (25) are exciting options. Another way to continue the greening process is to look at how the dibrominated product can be used in subsequent reactions. Although we showed that green debromination can be employed to regenerate trans-stilbene for reuse, further synthetic elaborations of the dibromide should be explored. Alternatively, if direct functionalization of the alkene were possible, the bromination step could be avoided altogether. Thus, future developments leading to greener synthesis routes may lead us to eliminate bromination reactions from the curriculum rather than greening the bromination reaction. Conclusion The use of green metrics to compare three bromination laboratory procedures demonstrates the effectiveness of an incremental greening process for chemistry curricula. Ongoing assessment and introduction of improved methods into the organic teaching lab leads to innovative experiments that improve safety and effectively teach green principles and applications as well as traditional chemical concepts and laboratory skills. As a result of this process, bromination of alkenes can now be introduced to students through the use of a safe, effective, modern procedure. Acknowledgment This work was supported by the University of Oregon, the National Science Foundation (DUE-0088986), and the American Chemical Society. We thank Christina Inman for helpful discussions. W

Supplemental Material

Notes for instructors, a student handout, and sample calculations are included in this issue of JCE Online. Notes 1. During the experiment development process, it was found that decreased solubility of the starting material with the addition of 7.5% or 3% hydrogen peroxide reduced the product yields to some extent. Although reaction efficiency is affected by the substitution of these hydrogen peroxide solutions, it may be preferable to do so in order to protect students from the hazards associated with 30% hydrogen peroxide. 2. Sample calculations for analysis of the different reactions are included in the supplementary materials. For brevity and sim-


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In the Laboratory plicity and given that the yields of these reactions are typically comparable, theoretical yield of product was used in calculations. Although this provides for a relative comparison of the reaction through the use of these metrics, actual comparisons of greenness depend on percentage yield as well. An opportunity to extend the metrics exercise includes comparison with actual percentage yields from each type of reaction.

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10. Fieser, L. F.; Williamson, K. L. Organic Experiments; Houghton Mifflin: New York, 1998; pp 24, 515. 11. Djerassi, C.; Scholz, C. R. J. Am. Chem. Soc. 1948, 70, 417– 418. 12. Pasto, D. J.; Johnson, C. R.; Miller, M. J. Experiments and Techniques in Organic Chemistry; Prentice Hall: Upper Saddle River, New Jersey, 1992; pp 409–410. 13. Tanaka, K.; Shiraishi, R.; Toda, F. J. Chem. Soc., Perkin Trans. 1, 1999, 21, 3069–3070. 14. Ho, T.-L.; Balaramgupta, B. G. B.; Olah, G. A. Synthesis 1977, 10, 676–677. 15. Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127–11142. 16. Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L. Green Chem. 2002, 4, 521–527. 17. Trost, B. M. Science 1991, 254, 1471–1477. 18. Cann, M. C.; Connelly, M. E. Real-World Cases in Green Chemistry; American Chemical Society: Washington, DC, 2000. 19. Sheldon, R. A. Chemtech 1994, 24, 38–47. 20. Hudlicky, T.; Frey, D. A.; Koroniak, L.; Claeboe, C. D.; Brammer, L. E. Green Chem. 1999, 1, 57–59. 21. Durst, H. D.; Gokel, G. W. Experimental Organic Chemistry; McGraw-Hill: San Francisco, CA, 1987; pp 240–241. 22. Toxnet Home Page. http://toxnet.nlm.nih.gov/ (accessed Oct 2004). 23. NIOSH documentation for immediately dangerous to life or health (IDLH) concentrations. http://www.cdc.gov/niosh/idlh/ intridl4.html (accessed Oct 2004). 24. Rothenberg, G.; Clark, J. H. Org. Proc. Res. Dev. 2000, 4, 270– 274. 25. Johar, Y.; Zupan, M.; Sˇket, B. J. Chem. Soc., Perkin Trans. 1, 1982, 9, 2059–2062.


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The Evolution of a Green Chemistry Laboratory Experiment: Greener

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