Recent Progress in Green Undergraduate Organic Laboratory Design

Chapter 2

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Recent Progress in Green Undergraduate Organic Laboratory Design Barbora Morra and Andrew P. Dicks* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6 *E-mail: [email protected]

Green chemistry principles have been highlighted and incorporated into the organic classroom and laboratory for over twenty years. In order to provide educators with the tools necessary to implement environmentally conscious modules into their own courses, this chapter summarizes innovative greener experiments published in the pedagogical literature since 2012. This select collection of examples serves as an introduction to Green Chemistry Experiments in Undergraduate Laboratories by describing green organic laboratories in the following three categories: (i) teaching experimental techniques; (ii) traditional verification experiments; and (iii) guided-inquiry activities.

Introduction Green, sustainable chemistry instruction has been on the radar of educators for more than twenty years. In 1995, Terry Collins outlined efforts at Carnegie Mellon University to introduce a lecture course entitled “Introduction to Green Chemistry” to advanced undergraduates and graduate students (1). Five years later, Reed and Hutchison described the environmentally responsible preparation of adipic acid as a teaching laboratory experiment, and stated that “we know of no published green experiments designed for use in the organic teaching laboratory” (2). In one 2006 Journal of Chemical Education editorial, John Moore wrote “any change in curriculum or in our approach to teaching chemistry requires time and effort on our © 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


parts, but incorporating green chemistry is a change that needs to be made, is being made by many, and is supported by the chemical industry”, and that “students trained in green chemistry principles will be better able to carry out their duties as industrial, government, or academic scientists and engineers” (3). The increasing public profile of environmental issues has undoubtedly led to many instructors rethinking their curricula to incorporate aspects of green chemistry. In 2011, one of us (A.P.D) edited a book for university and college teachers (“Green Organic Chemistry in Lecture and Laboratory”) (4). This publication summarizes efforts made in both practical and theoretical venues to introduce green principles to students at various academic levels. It includes a description of many undergraduate laboratory tasks that showcase green chemistry concepts (either deliberately or unwittingly!). However, it should be borne in mind that there are no “perfectly green” teaching experiments, but that incremental improvements are routinely possible. The current chapter provides an update to the aforementioned book by profiling new experiments published in the pedagogical literature since 2012. While not intended to be an exhaustive review, this chapter sets the scene for the remainder of Green Chemistry Experiments in Undergraduate Laboratories by providing specific examples of greener organic laboratories in the following areas: (i) teaching experimental techniques; (ii) traditional verification experiments; and (iii) guided-inquiry activities. Several experiments devised by the authors with undergraduate and graduate support at the University of Toronto are additionally included. It is hoped that this review contributes a snapshot of the current “state of the art”, and will provide impetus for educators to consider how they might introduce such procedures or indeed design some of their own.

Experiments Illustrating Fundamental Laboratory Techniques Gaining practical experience in the laboratory is a major learning objective in undergraduate chemistry education. It is in the laboratory that students improve their understanding of chemical transformations, develop technical skills, and are first introduced to the challenges of research. Some of the most common experiments conducted by novice learners are those highlighting fundamental practical techniques. The skills and confidence gained throughout introductory laboratory experiences lay the foundation that students rely upon when engaged in independent, problem-based experiments later in their education and careers. In recent years, many instructors have designed simple experiments that highlight conventional laboratory techniques with an emphasis on green chemistry principles. The specific contributions highlighted in this section introduce students to sustainable and safe practices during the early stages of their laboratory training, which encourages them to grow into environmentally responsible chemists. Just as importantly, students who eventually pursue a myriad of other scientific careers will benefit from this exposure.

8 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Extraction Soap-making is a popular experiment in introductory undergraduate laboratories as it highlights the utility of the saponification reaction with a real-world application (5–7). Sutheimer et al. recently updated this classic experiment to include an oil extraction from fresh avocados (8). The exercise has student pairs working together to peel, pit and macerate one avocado. The flesh is then extracted with a solution of ethyl acetate and isopropyl alcohol, which are safer and less toxic alternatives to petroleum ether, hexanes, or chlorinated solvents that are typically used. The fresh avocado oil is then combined with additional vegetable oils and saponified with aqueous sodium hydroxide solution, poured into molds, and left to cure for four to six weeks until ready to use. This fun procedure allows students to visualize the concepts behind extraction while recognizing aspects of green chemistry in the real-world application of soap production. Chromatography Two of the most fundamental separation techniques used in organic chemistry are column chromatography and thin-layer chromatography (TLC). A common undergraduate chromatography exercise involving the isolation of leaf pigments provides an excellent opportunity for students to visualize the colorful separation of biologically active molecules (9–15). As these experiments traditionally use halogenated or otherwise harmful solvents, Johnston et al. have developed a greener approach that employs safer solvents and recycling to minimize waste (16). Here, students use recycled acetone from a previous experiment to extract β-carotene, xanthophyll, and chlorophyll a pigments from spinach leaves. To minimize exposure to harmful solvents and limit waste production, they then utilize recycled alumina and a non-halogenated eluent system of hexanes and acetone to complete their column chromatography separation. Students support their findings through TLC and Rf comparison in order to verify the identity of each isolated pigment. Similar TLC studies of spinach and ruccola plant pigments have recently been developed, including a comparison of normal-phase (silica gel 60 with 7:3 n-hexane:acetone eluent) and reverse-phase (RP-18 silica with 2:3:5 n-hexane:acetone:ethanol eluent) chromatography (17). These activities nicely illustrate concepts of molecular polarity and retention in various mobile and stationary phases, while also employing an alternative solvent. Ethanol is a greener option than n-hexane, which among other hazards is suspected of damaging fertility. An eco-friendly modification of column chromatography has also been established by Dias and Ferreira, where the use of baking soda and potato starch as unconventional column adsorbents (instead of expensive and potentially harmful silica gel) is described (18). In this experiment, students perform an acetone extraction of plant pigments from red and green Stromanthesanguinea leaves and adsorb the chlorophyll, anthocyanin and carotenoid-rich solution onto the surface of potato starch. They proceed to load their crude sample onto a baking soda or potato starch column and separate each bioactive pigment using petroleum ether, 9 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

acetone, ethanol, or saturated aqueous sodium bicarbonate solution as eluents. The experiment takes advantage of the high concentration of colorful pigments in plants to demonstrate chromatographic techniques, while simultaneously reinforcing green chemistry through use of renewable feedstocks, reduction of waste, and by employing safer solvents and column adsorbents.


Batch and Flow Methods Simeonov and Afonso have developed a modern undergraduate laboratory that introduces students to industrially useful separation technology utilized in the efficient synthesis and isolation of 5-hydroxymethylfurfural (HMF) (19). This 2,5-disubstituted furan was chosen as a target molecule in the experimental design as it is easily accessible from carbohydrates (a biorenewable resource) with potential applications in the biofuel and sustainable polymer industries (20). A key limitation in production of HMF is its efficient isolation, since it suffers from poor solubility in both aqueous and organic solvents. The experiment addresses this challenge by engaging students in batch and flow syntheses of HMF to explore the efficacy and environmental impact of each isolation method (Figure 1).

Figure 1. Green comparison of batch and flow syntheses of 5-hydroxymethylfurfural (HMF).

While working in small groups, some students perform a batch method which involves synthesis of HMF from fructose using heterogeneous acid catalysis and separation by precipitation from the reaction media. This approach also features a fully recyclable reaction medium, catalyst, and solvent while achieving a remarkable 90-97% yield of highly pure product. Other students concurrently explore the synthesis through a flow method which features homogeneous acid-catalyzed reaction conditions along with a similar precipitation method of isolating the product. This alternative protocol furnishes pure HMF with lower yields (average of 77%) compared to the batch method. After the laboratory session is complete, students evaluate class results to identify the superior method of HMF synthesis and isolation by considering the yield, purity, and E-factor for each process. This novel undergraduate experiment engages students in a synthetic challenge to prepare an industrially relevant biomolecule by comparing modern isolation techniques that stimulate discussion of green chemistry principles. 10 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Traditional Verification Laboratory Experiments


This section presents a range of activities where students primarily follow a scripted procedure to learn about greener approaches. The experiments are organized into four major categories according to several of the Twelve Principles of Green Chemistry: safer solvents and auxiliaries, design for energy efficiency, less hazardous chemical syntheses, and catalysis. Additional green aspects of each experiment are highlighted where appropriate. Safer Solvents and Auxiliaries One of the Twelve Principles of Green Chemistry states that “the use of auxiliary substances (e.g. solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used” (21). Several recent teaching experiments have focused on this principle from two different perspectives: elimination of reaction solvents (i.e. solventless transformations (22, 23) and greener solvent replacements (24). Examples in both categories will be discussed here.

Solvent-Free Syntheses Goldstein and Cross have reported a solvent-free reductive amination reaction between a range of liquid aromatic aldehydes and two liquid benzylamine derivatives (Figure 2), which is part of an introductory undergraduate organic course (25).

Figure 2. Solventless formation of dibenzylamines via reductive amination. Each student or student pair identifies their specific dibenzylamine product formed by generating the corresponding hydrochloride salt and making melting point measurements. This cost-effective and efficient experiment requires reactant grinding at room temperature for a total of 45 minutes, using a mortar and pestle. In a similar vein, synthesis of β-citronellyl tosylate (a laundry detergent additive) was described where citronellyl alcohol is briefly ground with p-toluenesulfonyl chloride under basic conditions (26) (Figure 3). 11 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 3. Solvent-free tosylation of β-citronellol.

As a third example, Patterson et al. designed the preparation of a thiol-reactive sensor via a microscale, solventless Diels-Alder reaction that does not require heating or stirring (27). Student yields of the sensor typically range from 7-16 mg (30-70%). As the work-up and purification steps of these three syntheses are not solvent-free, an important opportunity exists to point out this drawback to students and that one should consider more than just the reaction itself from a green chemistry perspective (28).

Water as an Alternative Solvent The properties of water as a greener solvent choice and its use as such in undergraduate laboratories has previously been reviewed (29, 30). Since then, water was utilized as the solvent for a Hantzsch dihydropyridine synthesis and as a co-solvent with acetic acid for eventual pyridine formation (31). This multicomponent reaction additionally highlights other green features: (i) an atom-economical approach to synthesis; (ii) isolation and purification of products without the use of volatile organic solvents; and (iii) benign oxidation conditions using an iron catalyst and hydrogen peroxide rather than more traditional stoichiometric oxidants (as discussed under “A Transition Metal-Catalyzed Alcohol Oxidation”) (Figure 4).

Figure 4. Aqueous Hantzsch dihydropyridine and pyridine synthesis. 12 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


In contrast, Morsch and coworkers have developed an aqueous Wittig reaction where a variety of aldehydes are stirred with benzyltriphenylphosphonium chloride (highly toxic by ingestion and inhalation) in 10 M NaOH at room temperature (32). One specific aldehyde employed is cinnamaldehyde, which generates the corresponding conjugated diene in 30 minutes (Figure 5).

Figure 5. A Wittig reaction under aqueous basic conditions. Thirdly, Marks and Levine reported student preparation of dibenzylaniline via reaction between benzyl bromide and aniline in aqueous sodium bicarbonate/catalytic sodium dodecyl sulfate (33). It should however be noted that aniline has high chronic and acute aqueous toxicity, is a skin sensitizer and also a suspected carcinogen. These last two experimental examples highlight that “greener” procedures can still have “non-green” aspects associated with them in terms of undesirable chemical properties.

PEG-400 as an Alternative Solvent Polyethylene glycol (PEG) is an intriguing alternative solvent in which to undertake organic reactivity (34, 35). As polyethers, PEG solvents have very low toxicity and volatility, and are stable under a wide variety of reaction conditions (including high temperatures). They are also potentially recyclable. The latter feature was harnessed in the context of consecutive one-pot carbonyl condensation reactions, within both introductory and advanced undergraduate courses (36). PEG with a molecular weight of 400 (PEG-400) is used as the solvent for sequential Knoevenagel and Michael reactions under mild, organocatalytic conditions (Figure 6).

Figure 6. Consecutive Knoevenagel and Michael reactions in PEG-400. 13 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Both PEG-400 and the proline organocatalyst are readily recycled and available for further reactions. The experimental atom economy of this reaction is 96%, as no reagents are used in excess. Very recently, PEG-400 has also been employed as the solvent for an aza-Michael addition between methyl acrylate and diethylamine (37) (Figure 7). In this experiment, students analyze product spectra to deduce whether conjugate addition or nucleophilic acyl substitution has taken place, thus introducing a discovery-based element.

Figure 7. An aza-Michael reaction in PEG-400.

Design for Energy Efficiency Microwave-Enhanced Reactions The benefits of microwave heating in the undergraduate organic laboratory have been highlighted by Baar and coworkers (38, 39). Lengthy reflux times for traditional reactions can be dramatically reduced to minutes (or sometimes even seconds) by using microwaves. Latimer and Wiebe described three microwave-induced nucleophilic aromatic substitution reactions of 1-bromo-2,4-dinitrobenzene that are complete in five minutes (40) (Figure 8).

Figure 8. Microwave-enhanced nucleophilic aromatic substitution reactions of 1-bromo-2,4-dinitrobenzene. Students compare these reactions with those undertaken by refluxing in toluene/water for one hour in the presence of a phase-transfer catalyst. In each case the microwave reaction gives a higher yield using a greener solvent combination (ethanol/water). Microwave electrophilic aromatic substitution has also been explored in the context of phenol nitration (41). Here, nitric acid (the source of NO2+) is generated in situ by the reaction between copper(II) nitrate and acetic acid (Figure 9). 14 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 9. Electrophilic aromatic substitution of phenol via microwave heating. This convenient approach has a reaction time of one minute and forms a mixture of ortho- and para-disubstituted products that are separated by column chromatography or steam distillation. Keuseman and Morrow reported a solvent-free Knoevenagel condensation of malonic acid with 4-methoxybenzaldehyde in the presence of ammonium acetate (42). Microwave irradiation promotes formation of trans-4-methoxycinnamic acid in five minutes (Figure 10). Two additional recent examples of undergraduate microwave experiments are in the areas of soap/biodiesel production (43) and the Suzuki reaction (44).

Figure 10. Microwave-enhanced synthesis of trans-4-methoxycinnamic acid.

A Diels-Alder Reaction under Solar Irradiation In a very unusual approach, Amin et al. have designed a solar heat source from a satellite dish and used it to harness sunlight for the Diels-Alder reaction between anthracene and maleic anhydride (45) (Figure 11).

Figure 11. A Diels-Alder reaction heated by solar irradiation. Using round-bottomed flasks painted black to improve energy absorption, students obtain an average yield of 81% after solar heating in xylene for 30 minutes. This is comparable to an almost identical yield (80%) on using an electric hot plate for the same time period. From this experiment, undergraduates learn that the sun is a viable heating alternative to electrical sources which is a critical concept in the context of sustainability. 15 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


A Mechanochemical Charge Transfer Salt Synthesis Two solvent-free reactions that require mechanical grinding were previously discussed in this chapter. A third example of mechanochemistry that does feature a solvent (“liquid-assisted grinding”) concerns preparation of two polymorphs of a charge-transfer salt (46). Tetrathiafulvalene (TFF) is ground by students over 20 minutes with chloranil (CA), utilizing either water or acetone as the solvent. This approach negates any heating or stirring requirements. Water promotes formation of a black polymorph, whereas using acetone generates a green polymorph. These reactions have 100% atom economy and as essentially no waste is produced, the E-factor is very close to zero in each instance (Figure 12).

Figure 12. Polymorph synthesis via liquid-assisted grinding. Less Hazardous Chemical Syntheses Greener Reagents Significant progress has been made regarding incorporation of greener reagents into introductory and advanced organic teaching laboratories (47). In 2012, Geiger and Donohoe reported the oxidation of (–)-menthol to (–)-menthone using calcium hypochlorite as an environmentally friendly, nonhazardous and cost-effective oxidant (48) (Figure 13).

Figure 13. Alcohol oxidation using calcium hypochlorite. 16 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Advanced undergraduates isolate the ketone product in an average yield of 75%, and learn about circular dichroism spectroscopy as an analytical tool. In comparison, sodium hypochlorite was employed in conjunction with sodium bromide for the regioselective bromination of acetanilide (49). This safer reagent combination means that the typical use of molecular bromine in acetic acid is avoided (Figure 14).

Figure 14. Regioselective aromatic bromination of acetanilide. In a third publication, Lipshutz et al. discussed the use of a biodegradable and nontoxic surfactant (TPGS-750-M) to promote aqueous organic reactions within nanoscale micelles (50). One example is the highly atom-economical “click” reaction between benzyl azide and an aromatic alkyne (Figure 15). This [3 + 2] cycloaddition additionally features copper catalysis under energy-efficient reaction conditions.

Figure 15. An azide-alkyne “click” reaction profiling a biodegradable surfactant.

Sustainable Polymer Synthesis Two recent reports discuss sustainable polymer synthesis in the second-year undergraduate laboratory. Chan and coworkers described the generation of a biodegradable polycarbonate via ring-opening polymerization (ROP) of trimethylene carbonate using two organocatalysts (51) (Figure 16). Secondly, Schneiderman et al. outlined preparation of a block copolymer product as a transparent film (52). Two renewable resource monomers are used in this experiment which is run under mild, solventless and catalytic conditions. 17 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 16. Organocatalytic ROP generating a biodegradable polycarbonate. Catalysis An undergraduate catalytic chemistry course was described in 2013 where students undertake reactions under the general themes of organocatalysis, phase-transfer catalysis, transition metal catalysis and BrØnsted/Lewis acid catalysis (53). This course showcases experiments designed by undergraduates at the University of Toronto since 2001, and has been taken by over 300 students since its inception in 2008. Further aspects of the course will not be discussed in this section.

Transition Metal-Catalyzed Coupling Reactions The Suzuki reaction has recently been employed as a vehicle for teaching aspects of green chemistry (28). Hill and coworkers outlined a facile Suzuki coupling amenable to large undergraduate organic classes using an aqueous atomic absorption standard solution as the palladium source (54) (Figure 17).

Figure 17. Suzuki reaction using ultra-low Pd catalyst loading. The solution is commercially available and facilitates the reaction of three aryl boronic acids with six aryl bromides in less than 30 minutes at room temperature. A similar coupling reaction was reported to generate a biaryl under aqueous conditions utilizing catalytic Pd(OAc)2 (55). This strategy introduces 18 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


a problem-solving element as students work to identify the greenest approach given three potential reaction conditions. A traditional Suzuki reaction has even been performed by advanced high school students as part of a laboratory field trip with the goal of associating chemistry with the broader concept of sustainability (56). In 2015, a Ni-catalyzed Suzuki reaction was described for the first time from a pedagogical perspective (57). Undergraduates use inexpensive bis(tricyclohexylphosphine)nickel(II) dichloride in tert-amyl alcohol as a greener system with which to couple a heteroaryl bromide with two heteroarylboronic acids (Figure 18). Nickel has advantages over palladium for such reactions as Ni is a non-precious metal, is considerably cheaper, and is less toxic.

Figure 18. Nickel catalysis of a Suzuki reaction. The homocoupling of 1-methylimidazole under conditions of copper catalysis was disclosed by Ballard (58) and performed by introductory organic students at the University of Florida. The process employs in situ formation of a Grignard reagent which reacts with the metal catalyst (CuCl2) to form an organocopper intermediate. This intermediate subsequently reacts under aerobic conditions to form the dimerized product and regenerate the catalyst (Figure 19).

Figure 19. Dimerization of 1-methylimidazole using catalytic CuCl2.

Transition Metal-Catalyzed Alkene Hydrogenations Fry and O’Connor have outlined the facile hydrogenation of methyl transcinnamate using 0.5% Pd/Al(O)OH as the catalyst (59). Very good student yields are possible using this method (Figure 20).



Figure 20. Catalytic hydrogenation of methyl trans-cinnamate. Two further advantages are apparent from a green perspective: firstly, this reaction is undertaken using solvent-free conditions, and secondly the catalyst is (unusually) recoverable without a reduction in activity. The catalytic transfer hydrogenation of castor oil using Pd/C in limonene also facilitates discussion of several green chemistry metrics such as atom economy, reaction mass efficiency, E-factor and CO2 emissions (60).

Organocatalytic Reactions Synthesis of 1,3,4-triphenylcyclopentene was described by Snider via the carbene-catalyzed reaction of cinnamaldehyde with a chalcone (61). This modern procedure showcases application of organocatalysis where students initially prepare 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride as a heterocyclic carbene, and then use it to generate the product in a 10:1 trans/cis ratio under aqueous conditions (Figure 21). Copper N-heterocyclic carbene complexes have also been synthesized by upper-level undergraduates and utilized to perform atom-economical 1,3-dipolar cycloaddition reactions under solventless conditions (62).

Figure 21. Carbene-catalyzed formation of 1,3,4-triphenylcyclopentene.

A Transition Metal-Catalyzed Alcohol Oxidation A copper(I)/2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) catalyst has been used to effect oxidation of five benzylic alcohols to the corresponding aldehydes (63). This approach negates the traditional use of stoichiometric Crand Mn-based oxidants routinely discussed in introductory organic textbooks. The experiment is amenable to large laboratory groups, requires standard glassware, 20 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


and highlights contemporary research as molecular oxygen is the active oxidizing agent (Figure 22).

Figure 22. Benzylic alcohol oxidation under catalytic conditions.

Guided-Inquiry Laboratory Experiments Many recent reports have highlighted the value of guided-inquiry experiments within undergraduate organic chemistry education (64, 65). These contributions share similar learning objectives that include (i) enhancing student interest and proficiency in the laboratory; (ii) introducing real-world problems in a research-focused context; (iii) encouraging development of critical thinking and problem solving skills; and (iv) incorporating green chemistry initiatives. Despite this encouraging progress, guided-inquiry experiments are not widely undertaken due to the extensive time and cost requirements that are often necessary to design and implement them in the curriculum. Even with these challenges, numerous guided-inquiry organic experiments have been featured in the recent literature that emphasize sustainable principles. These contributions are highlighted in the following three categories: student-driven decision- making in target-oriented synthesis, discovery-based experiments, and collaborative laboratory case studies. Student-Driven Decision-Making in Target-Oriented Synthesis The environmental and economic benefits of practicing sustainable chemistry in academia and industry are becoming increasingly important. Green chemistry education must play a significant role within undergraduate curricula in order to foster responsible chemists that are better prepared to prevent further environmental damage. One of the most powerful methods of training future chemists in a laboratory setting is allowing students to participate in decision-making and experimental design. Despite the increase of organic laboratory experiments highlighting green chemistry, few prepare students for the multifaceted decision-making required in a research laboratory. Edgar et al. emphasized student-driven decision-making as a primary learning objective within a target-oriented laboratory where students are engaged in every step of the research process (66). This upper-level laboratory requires students to independently execute a synthesis of a unique azlactone 21 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


derivative while incorporating green chemistry principles into their experimental design (Figure 23).

Figure 23. Incorporating green chemistry into an azlactone synthesis. Azlactones were selected as target molecules as they have utility in the preparation of medicinally significant biomolecules, and can be accessed through a variety of synthetic methods from readily available starting materials (67–69). Students are given two weeks to independently design a synthetic plan for their assigned azlactone complete with a retrosynthetic analysis, figures for all projected reactions, detailed experimental procedures with appropriate reference to the chemistry literature, a comprehensive list of reagents including a safety and cost analysis, and a discussion of how green chemistry principles are incorporated in the synthetic design. Once their proposals are approved for safety and cost by the course instructor, students independently embark on their three or four-step synthesis over two 4.5 h laboratory sessions. It is important to note that the course instructor and teaching assistants support students from a safety perspective but do not offer specific feedback on the chemical viability of their proposals or work performed in the laboratory. As some of the azlactone derivatives are not found in the literature, students find procedures based on similar target molecules and apply them appropriately. In the laboratory, students generally implement at least two green chemistry principles into their methodology. For example, some students substitute halogenated solvents with more sustainable non-halogenated options (e.g. naturally derived 2-methyltetrahydrofuran), while others exploit non-toxic reagents (e.g. NaHCO3 instead of triethylamine), catalysis, and energy efficient processes in order to limit the environmental impact of their synthesis. In general, students find this guided-inquiry activity to be a valuable learning experience as it offers insights into the challenges of conducting chemistry research while considering green principles. A similar research-based approach was outlined by Slade et al. in the development of a second-year organic chemistry laboratory that engages students in a target-based synthesis of a novel fluorous dye (70) (Figure 24).

Figure 24. Synthesis of a fluorous dye for use in affinity chromatography. 22 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Once synthesized, students explore the applications of the dye in fluorous affinity chromatography as a greener alternative to other solid-phase separation techniques (71). This type of affinity chromatography enables fluorous-tagged reagents and catalysts to be easily isolated in high purity for the purpose of recyclability. The main goal of this guided-inquiry project is to provide students with an authentic research experience that involves them in reaction design by adapting literature procedures. In addition, the project exposes students to a variety of advanced synthetic tools including microwave heating and Schlenk and degassing techniques. Early in the semester, students are introduced to the target molecule along with a suggested synthetic protocol which serves as a starting point from which they can begin their literature search. After several weeks, each student independently submits a proposal consisting of literature procedures for each transformation along with suggested modifications for use in the undergraduate teaching laboratory. Once each proposal is inspected for safety, cost, equipment availability, and time management considerations, students are given six consecutive laboratory sessions to execute their synthetic plan. Although students are able to complete some of the six-step synthesis, none have thus far been successful in making the final fluorous dye without any assistance. Despite this, students report having enjoyed the project as it offers a unique opportunity to make their own decisions and take ownership of their laboratory work. Multicomponent reactions are often valuable transformations from a green chemistry perspective. One such example, a Prins-Friedel-Crafts type reaction, has been implemented into a second-year undergraduate laboratory by Dintzner et al. (72) This atom-economical strategy for synthesizing a variety of tetrahydropyran derivatives showcases several green chemistry principles as it is performed using a natural and benign Montmorillonite K10 catalyst (Mont. K10) with limited waste production since the work-up is a simple filtration (Figure 25).

Figure 25. Montmorillonite K10-catalyzed multicomponent synthesis of functionalized tetrahydropyrans. This tetrahydropyran synthesis is executed in the teaching laboratory in two phases throughout the semester. The first phase (three laboratory sessions) consists of a typical verification-type experiment where students perform a Prins-Friedel-Crafts synthesis with benzene, and analyze their product using GC-MS, IR and 1H/13C NMR spectroscopy. The research component of the project takes place during the second phase (five laboratory sessions) where pairs of students use a unique aldehyde or ketone in a Prins-Friedel-Crafts reaction, applying the method from the control reaction. After independent analysis and discussion of their initial findings, students are encouraged to explore the reaction 23 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


in a direction that interests them. For example, students can decide to optimize their current reaction conditions or expand the scope of the methodology to include different arenes or carbonyl-containing starting materials, all while considering principles of green chemistry. This novel research-based laboratory exposes students to interesting multicomponent reactions and decision-making in the laboratory while developing environmentally conscious synthetic methodologies. With the intent to increase student engagement and to better prepare students for responsible chemistry research, Graham et al. designed a multiweek project as part of the second-year organic curriculum highlighting green practices within experimental design (73). This inquiry-based approach involves student pairs working collaboratively to improve a known reaction by applying green chemistry principles. Student teams begin the project by selecting a target reaction of interest from the literature and designing a modified variation that emphasizes sustainable practices. During this critical design phase, students meet with course instructors to determine whether their projected modifications demonstrate green chemistry principles, the plausibility of success, chemical and equipment availability, and safety precautions. While some students propose more ambitious changes to their reaction conditions, most suggest subtle modifications including solvent changes or omissions, employing a catalyst, or using safer reagents. Once course instructors approve the original "non-green" procedure (the control reaction) and the modified protocol, students work together to collect data for both the literature control method and the greener approach. Since each student is required to perform both reactions, teams obtain two sets of data for each protocol, which increases the reliability of the results and overall success rates. Once the experimental data is collected and analyzed, students compare the two reaction conditions based on the utility of the procedure towards product formation and reflect on the environmental implications of their modified process. This unique laboratory engages students in an independent experimental design project that reinforces the role of sustainable practices within organic synthesis. Overall, students report excellent improvement in conducting literature searches, applying knowledge to new situations, and understanding the concepts of green chemistry. A similar research-centric approach to student learning in the laboratory was implemented into the Simmons College introductory organic chemistry curriculum (74). The goal of this project is to support the development of higher-order thinking skills through a research-inspired experiment and to create a cohesive learning process from first-year introductory experiments through to fourth-year research projects. In order to engage novice learners, Lee et al. employed a green chemistry framework from which to base the experiments since students identify with sustainable principles in their own lives and are excited to extend that enthusiasm to include green chemistry research. The project involves first-year general chemistry and second-year organic chemistry students working collaboratively towards a common synthetic goal. The initial project design has first-year students working in small groups towards the development of environmentally friendly syntheses of commercially unavailable ketones. This requires extensive literature searches and student-driven decision-making to independently plan and perform a two-step protocol involving Grignard addition and oxidation reactions (Figure 26). 24 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 26. Collaborative undergraduate research projects. A unique collection of ketones is intended to serve as starting materials for the second-year organic chemistry laboratory as a method of minimizing waste, energy, and additional resources. Here, students are required to firstly identify and purify their unknown ketones and then explore the effect of chiral agents (e.g. partially-digested polylactic acid) in a reduction reaction. Similar to the first-year program, students propose purification, synthetic, and analytical methods that integrate green chemistry principles. Although the initial plan is highly collaborative, the workload is overly-ambitious for novice chemists. In most cases, first-year students are unable to complete the synthesis of their target ketones, causing students in the second-year program to use commercially available substrates. In addition, the reduction reactions performed in the second-year program are highly variable and problematic. Despite these shortcomings, the student experience and skills gained from the research project exceed instructor expectations. Throughout the process, students are immersed in every facet of conducting chemistry research which enhances their critical thinking and laboratory skills. Interestingly, the authors found that students do not explicitly comment on the “greenness” of their methods in reports or self-assessment surveys despite applying several principles of green chemistry throughout their synthetic plans. This suggests that green chemistry is seamlessly woven into the curriculum so that students do not associate organic chemistry and green chemistry as separate entities, but simply as a standard method of conducting research. Discovery-Based Experiments Advanced guided-inquiry experiments where students are required to undertake literature searches or independent experimental design may not always be suitable. This is especially the case when novice learners are involved, or due to logistical challenges associated with large classes. Discovery-based experiments offer a unique bridge between cookbook-style and advanced guided-inquiry laboratories by providing a puzzle for students to solve within a structured experimental framework. These types of laboratory activities can offer unique learning opportunities as students are exposed to the benefits and applicability of green chemistry principles in a more engaging manner. Serafin and Priest have recently implemented a green, discovery-based laboratory for second-year and upper-level organic chemistry students involving exploration of the Passerini reaction (75). This multicomponent transformation is performed with a variety of benzoic acid and benzaldehyde derivatives in water instead of typical organic solvents, which accelerates the reaction rate and allows full conversion in 25 minutes at room temperature. The experiment provides a 25 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


convenient method for synthesis of several α-acyloxy amide derivatives in high yield and purity while highlighting several sustainable principles including high atom economy, energy efficiency, and waste prevention. Two variations of the experiment are highlighted, which can be catered to the level of difficulty desired. In version A, students work in pairs and are provided with the identity of the benzoic acid and benzaldehyde derivatives. After synthesizing and isolating their unique α-acyloxy amide, they work together to confirm the structure of their product by applying knowledge of the transformation and a variety of spectroscopic data. Geared towards more advanced students, version B of the experiment explores the scope of the Passerini reaction with unknown starting materials. Students must perform the synthesis and analyze their product by melting point determination, MS spectrometry, and 1H NMR/IR spectroscopy. Here, students rely on their structural elucidation and problem-solving skills to determine the identity of their product. This discovery-based experiment nicely features a series of simple and environmentally friendly Passerini reactions that allow students to identify products through a variety of spectroscopic techniques and reflect on the green chemistry principles utilized in the process (Figure 27).

Figure 27. Passerini reaction scope. A second discovery-based experiment was recently developed by Morra at the University of Toronto for an introductory organic course that mimics a research environment. Students apply their chemistry knowledge to predict reaction outcomes but ultimately use a variety of spectroscopic techniques to elucidate the structure and analyze the purity of the products they obtain. The primary learning objective of this experiment is to bridge the gap between the classroom and research laboratory while introducing the role of reagent selection from a green chemistry perspective. The transformation explored is the bromination of 1,4-dimethoxybenzene with aqueous sodium bromide and Oxone®, which promotes complete conversion after 40 minutes of stirring in a fumehood at ambient temperature (Figure 28).

Figure 28. Bromination of 1,4-dimethoxybenzene. 26 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


This regioselective reaction yields pure 1,4-dibromo-2,5-dimethoxybenzene in high yield after extraction with ethyl acetate and recrystallization from 95% ethanol. In preparation for the experiment, students are instructed to review the general mechanism and regioselectivity of electrophilic aromatic substitution reactions, but the details of the reaction are not disclosed prior to the laboratory session. Since the exact transformation is not revealed, students are given the first 20-30 minutes of the laboratory session to familiarize themselves with the reaction, predict the six potential products, and discuss methods of structural elucidation. After isolation, students analyze their products by melting point determination, IR spectroscopy, 1H NMR spectroscopy, and thin layer chromatography to determine structure and purity. They are also required to consider the “greenness” of the transformation as it employs benign chemicals compared to traditional bromination protocols that use toxic and environmentally hazardous halogenated solvents and elemental bromine (Br2). A discovery-based microwave-assisted Fischer esterification experiment has been developed by Reilly et al. as an efficient method to prepare a wide variety of esters for the undergraduate organic chemistry laboratory (76) (Figure 29).

Figure 29. Microwave-assisted Fischer esterification reactions. Students performing this experiment apply their chemistry knowledge and critical-thinking skills to design an environmentally friendly procedure to prepare unique ester derivatives. After selecting an ester, students choose one of two microwave-assisted experimental procedures (either excess alcohol or excess carboxylic acid) by considering the physical properties of their unique starting materials (boiling point, melting point, solubility, etc.), cost, and green chemistry principles. Pure esters are isolated in modest to high yields after a liquid-liquid extraction with no further purification required. Students also characterize their ester products by IR and 1H NMR spectroscopy. This work provides an opportunity for students to discover the effects of varying simple reaction conditions while utilizing modern microwave technology to achieve a greener variation of a classic transformation. Collaborative Laboratory Case Studies Conventional undergraduate experiments often expose students to a particular chemical transformation or technique but rarely provide context in which that knowledge can be applied in a research setting. Case-based laboratories furnish an innovative solution by introducing students to a real-world problem that must be solved by using chemistry knowledge and reasoning abilities, often in a collaborative manner. 27 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Schaber et al. developed a case-based laboratory that invites second-year undergraduate students to play the role of laboratory technicians tasked with evaluating the efficacy of a new supercritical fluid extraction (SFE) technique compared to a traditional liquid extraction with an organic solvent (77). This study requires students to work in pairs during a three-hour laboratory session to explore the extraction of caffeine from tea leaves. While one student in each pair conducts the SFE technique with supercritical fluid CO2 (with 10% ethanol as a modifier), the other student performs a traditional liquid extraction using dichloromethane and alkaline water. Student pairs then share results and observations before deciding which extraction method is preferred. This case-based laboratory requires undergraduates to consider several variables including the isolated caffeine purity and percentage recovery of caffeine, as well as green chemistry principles when making their choice. Almost all students (95% of the class) endorse the SFE technique over traditional liquid extraction for high-volume requirements (>1000 extractions per year). While both techniques produce caffeine of high purity, the SFE method allows for a more complete recovery of caffeine while employing a greener approach (SFE offers 34-54% recovery while liquid extraction gives 14-30% recovery). Students successfully identify the environmental benefits of SFE compared to liquid extraction, since SFE generates less waste and employs safe, naturally occurring CO2 instead of halogenated solvents. At the University of Toronto, Morra and Tsoung have recently implemented a case-study experiment into the second-year organic chemistry curriculum that effectively bridges the gap between the classroom and research laboratory. In this guided-inquiry activity, students are given the opportunity to play the role of a process chemist employed by a pharmaceutical company working towards the synthesis of lysergic acid for the treatment of Parkinson’s disease (78). Students work as a team to optimize one of the key steps in the synthesis, a Sandmeyer reaction with 2-amino-3-nitrobenzoic acid. They accomplish this task by screening several reaction parameters including varying the type of acid used, reagent equivalents, reaction temperature, and iodide source (Figure 30).

Figure 30. Unoptimized Sandmeyer reaction in the synthesis of lysergic acid. In order to generate reliable data, several students examine the same reaction parameter (7-9 students per parameter). The progress of each reaction is monitored and an approximate purity determined with an in-process check (IPC). This common technique used in the pharmaceutical industry involves running a large collection of reactions for a pre-determined amount of time, solubilizing each mixture and analyzing the solutions directly using HPLC. This type of analysis is 28 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


efficient and accurate, and highlights several green principles as it prevents waste by avoiding typical reaction work-up and purification steps while conducting optimization studies. After the experiment is complete, a comprehensive set of data is posted on the course website and students evaluate the results to select the optimal Sandmeyer reaction conditions. Students are assessed on their ability to analyze the overall data and rationalize their choice based on reaction conversion and purity, while considering green chemistry principles. The two optimal reaction conversion and purity results are observed when the Sandmeyer reaction is performed with either hydrochloric acid or p-toluenesulfonic acid with three equivalents of sodium nitrite and potassium iodide at elevated temperatures (70 °C and 90 °C compared to 50 °C). Interestingly, most students select the 70 °C reaction temperature as part of their optimal parameters despite the fact that the 90 °C reaction temperature gives slightly better results (5% higher reaction conversion and 1% higher reaction purity). Students rationalize their choice by stating the results obtained from the two elevated temperatures are similar but the 70 °C reaction temperature has the added benefit of increased energy efficiency. This activity gives students a chance to work collaboratively with their peers towards a real research problem that requires green chemistry decision-making.

Conclusion Given the various contributions made by the authors reviewed in this chapter and elsewhere, there has been a surge towards highlighting sustainability and green chemistry principles in the undergraduate organic laboratory. These publications provide educators with the resources necessary to implement creative and innovative experiments into their own teaching laboratories as they cater to a wide variety of learners. Whether technique-focused, verification-driven, or guided-inquiry, instructors are able to choose examples of greener experiments that accommodate their specific resources, time restrictions, and student learning goals. Progress has also specifically been made in the area of teaching green chemistry metrics from an organic perspective (79–82). We anticipate that this chapter serves as an introduction to the exciting modernization of undergraduate organic experiments, and recognize that our pivotal role in the laboratory is to prepare students for careers in areas including research, industry, government and teaching. Accordingly, we hope the described experiments will inspire instructors to adopt greener practices at their own institutions in order to better prepare students for the varied challenges they will undoubtedly face in their future professions.

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