Continuous Flow Science in an Undergraduate Teaching Laboratory

Communication Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

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Continuous Flow Science in an Undergraduate Teaching Laboratory: Photocatalytic Thiol−Ene Reaction Using Visible Light Jeffrey Santandrea, Vanessa Kairouz, and Shawn K. Collins* Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec H3C 3J7, Canada S Supporting Information *

ABSTRACT: An undergraduate teaching laboratory experiment involving a continuous flow, photocatalytic thiol−ene reaction using visible-light irradiation is described that allows students to explore concepts of green chemistry, photochemistry, photocatalysis, and continuous flow chemistry.

KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Photochemistry

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INTRODUCTION Synthetic photochemistry has experienced a resurgence in the past decade, driven by the development of new synthetic protocols that exploit visible light,1 and the parallel growth of continuous flow methods.2 Despite the adoption of synthetic photochemical processes in both academic and industrial laboratories, exposure of synthetic photochemistry to undergraduates is typically rare.3 In the past, synthetic photochemistry was relegated to the use of UV light, which presented significant health hazards. Although using UV light generally requires high-power lamps and expensive glassware which can be challenging in undergraduate teaching laboratories, the importance of developing photochemistry-based experiments has long been recognized.4 In the past five years, several examples of the implementation of photochemistry within an undergraduate curriculum have appeared in this Journal. The importance of heterogeneous photochemistry and photocatalysis using inexpensive TiO2 has been reported in laboratory experiments via qualitative analysis5 and for the reduction of methyl orange.6 Photochemical laboratory experiments in inorganic chemistry have been reported, typically exploring the kinetics7 and synthesis8 of polypyridyl Ru-based complexes. The development of new infrastructure to implement laboratory experiments using UV light has appeared. In one report a UV reactor was used to promote transformations such as the photodimerization of trans-cinnamic acid and the photochemical dimerization of benzophenone,9 while in another example an inexpensive and commercially available device was used for five organic photochemical laboratory experiments, several of which are synthetic in nature (several photodimerizations and the photoreduction of benzophenone).10 Last, commercially available light-emitting diode (LED)-based light sources were employed to promote a Paternò−Büchi photocycloaddition for a final-year undergraduate laboratory experiment.11 © XXXX American Chemical Society and Division of Chemical Education, Inc.

Visible-light photocatalysis presents an interesting avenue for exploring photochemistry in an undergraduate curriculum. Visible-light-mediated chemistry circumvents many of the aforementioned drawbacks of UV light by exploiting lowenergy LED lamps or even low-energy household lightbulbs that alleviate health hazards and the need for specialized equipment. However, the scalability of the photochemical transformation could still be problematic in a laboratory setting where experiments need to be completed in a specific time frame. As such, continuous flow methods offer a solution that can render synthetic photochemistry accessible to an undergraduate curriculum. Apart from the light source, only the appropriate tubing (commercially available)12 and a syringe pump are required. Planning for a synthetic photochemical experiment should take into account the scale of the reaction being performed, and the associated residence time. In an optimal setting, it would be best if students could perform both “batch” and “flow” processes in parallel to bring an appreciation for the advantages/disadvantages of each type of reaction process. In 2013, a photoinitiated thiol−ene reaction between various thiols and alkenes was reported, catalyzed by a Ru-polypyridyltype complex.13 While the reaction was not performed under continuous flow conditions, the reaction times were short enough (∼2 h) that it was estimated that, with the aid of continuous flow, the process could be adapted for conversion to an undergraduate teaching laboratory exercise.14 Where the previously reported laboratory experiments present examples of UV-light-mediated photochemistry, there is a lack of an experiment which provides students with exposure to visiblelight-mediated photocatalysis in combination with continuous flow techniques. Herein, a photochemical thiol−ene reaction Received: August 22, 2017 Revised: May 7, 2018

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DOI: 10.1021/acs.jchemed.7b00639 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

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and the blue “glow” from the reactors was visually appealing to the students. In a typical experiment, the syringe pump is connected to an injection loop (5 mL), which is in turn connected to the coil reactor. Students prepared a solution of the cysteine, Ru(bpy)3(PF6)2, and p-toluidine in acetonitrile and, immediately prior to injection, added the 4-penten-1-ol to the solution and withdrew it into the syringe. Students then injected the mixture into the injection loop (Figure 1). Another syringe was filled with acetonitrile, and with the aid of a teaching assistant, the syringe was positioned on the syringe pump, connected to the injection loop, and then slowly pumped to push the reaction mixture through the irradiated coil. Students calculated the appropriate flow rate for a given residence time. The end of the tubing was placed in a vial or round-bottom flask for collection. The entire process required about 5 min. Although the elution is rapid, teaching assistants were encouraged to provide students with a short verbal “tutorial” about the influence of flow methods on photochemistry, in an effort to estimate a student’s understanding of the basis of the laboratory experiment. A further description of some of the questions that could be asked during the tutorial is included in the subsequent sections of the paper. The subsequent workup of the reaction mixtures involved concentration of the reaction mixture and purification by silica gel chromatography (ethyl acetate/ hexanes, 1:1 v/v). For the experiment, a teaching assistant with 8 students was given one continuous flow setup, so that all students could complete their flow experiments in approximately 2 h. While students waited to perform their flow experiments, they conducted the same experiment in “batch” (Figure 2). The identical reaction solution was prepared, and when the 4penten-1-ol was added, the vial (with a stirring bar) was placed inside a glass dish that had the same aluminum cylinder lined with blue LED strips in the center. The vial was stirred at room temperature, and students followed the progress of the reaction using thin layer chromatography. Typically between 1 and 3 h,

catalyzed by commercially available Ru(bpy)3 (PF 6) 2 is described under both batch and continuous flow conditions as an undergraduate-level teaching laboratory experiment.

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EXPERIMENT The photochemical thiol−ene reaction was optimized so that it could be conducted by each individual student in both “batch” and “flow” (Scheme 1, also see the Supporting Information). Scheme 1. Photochemical Thiol−Ene Reaction for the Alkylation of a Protected Cysteine Derivative

The experiment involved N-Boc L-cysteine methyl ester as the thiol component. While the solubility of thiol was an important criterion in selecting a thiol for the experiment, the fact that the protected cysteine derivative was relatively odorless was most critical. L-Cysteine methyl ester is commercially available or can be prepared by the students (a procedure is indicated in the Supporting Information). The alkene selected was 4-penten-1ol based upon the following reasons: the batch and flow reaction times were short, the yield of the product was high, and the solubility profile of the 4-penten-1-ol allowed for facile separation by chromatography at the end of the reaction. The reaction coil used commercially available PFA (perfluoroalkoxy alkane) tubing wrapped around a circular reactor whose interior diameter was designed to fit a household lightbulb (Figure 1,

Figure 1. Continuous flow setup for the photochemical thiol−ene reaction for the alkylation of a protected cysteine derivative.

also see Supporting Information for illustrations of all components). However, in place of a lightbulb, an aluminum cylinder was wrapped with commercially available blue LED strips and placed in the center of the reactor. While it may be simpler to use household lighting, it was found that the blue LEDs afforded less glare in the laboratory setting (although a box could be placed over the setup if needed). In addition, the orange color of the reaction solution was easily visible as it moves through the coil reactor against the blue background,

Figure 2. Batch setup for the photochemical thiol−ene reaction for the alkylation of a protected cysteine derivative. B



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were based on the influence of the vessel, whether another light source like a compact fluorescent lightbulb could be used and what products could be predicted to arise from a thiol−ene reaction with other types of alkenes or alkynes. Teaching assistants also “quizzed” students while they performed the experiment. Teaching assistants estimated that about 80% of students could correctly answer questions such as “What would happen if the tubing were placed farther away from the light source?”, “What would one expect to happen if the interior diameter of the tubing were increased or decreased?”, and “What would happen if the product was not soluble?” It was possible to assess whether the pedagogic goal of understanding the importance of light penetration/photon flux for photochemical reactions was achieved from the positive responses obtained from students during the laboratory period itself, as well as the questions in the laboratory report. To put the experiment within context, several important points are noteworthy: • The photochemistry experiment was performed as the third experiment in the course of a second-year undergraduate laboratory course focusing on synthetic organic chemistry. A total of four experiments were conducted in the course. Importantly, students typically performed a flow chemistry experiment prior to the photochemical experiment, so students already had some experience with flow technology. Other topics taught during the laboratory course involved multistep synthesis, catalysis, and synthesis under anhydrous/inert conditions using organometallic reagents. The photochemistry experiment took place within two, 5 h laboratory periods with typically 28−36 students and 3 teaching assistants per period. The first week, students performed both the flow and batch experiments. The second week was used for students to purify products by silica gel chromatography. Some students were able to complete one of the purifications within the first week, while about 50% performed two purifications in the period during the second week. To date, the experiment has been performed 2 times (>70 students have performed the experiment). • Both the teaching assistants and students have commented that the photochemistry experiment is unique compared to other experiments they have encountered in teaching laboratories. As mentioned above, when students perform the photochemical flow experiment, they have usually already performed a flow experiment in another laboratory period, so students are more comfortable with setting up the syringe pumps and tubing. Despite the familiarity with flow, students’ comments that clear photos of the experimental setup in the laboratory manual are extremely valuable. From the experiment, short tutorials, and questions from the teaching assistants, students were usually able to respond to all of the questions assigned in the laboratory manual about both photochemistry and flow methods. The undergraduate laboratory experiment described herein allows for many different chemical topics to be discussed by students: • The use of visible light as a reagent is noteworthy. The majority of undergraduates may have seen “hν” written above a reaction arrow in textbooks, but they will have little practical experience using light as an activation

the reaction was close to completion, and students halted the reaction and performed the workup and silica gel chromatography to obtain the pure product. The products were characterized by TLC, 1H NMR, and IR spectroscopic analyses.

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HAZARDS

All reagents and reaction products should be considered as irritants and are harmful upon skin and eye contact and if swallowed (gloves should be worn, and contact with skin, eyes, and clothing should be avoided). Acetonitrile, ethyl acetate, and hexanes are volatile and flammable organic solvents; n-hexane is a neurotoxin. p-Toluidine is light sensitive, and 4-penten-1-ol is a flammable liquid. KMnO4 is a strong oxidant and reacts violently with combustible and reducing materials. CDCl3 is toxic, and inhalation can cause coughs, dizziness, drowsiness, headache, nausea, and unconsciousness. Silica gel can irritate the digestive and respiratory tract. UV light can damage the skin and eyes, and suitable precautions should be taken to limit exposure. All solvents/solutions should be used in the hood, and gloves should be worn when working with them. Note that the blue LEDs are quite bright.15

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RESULTS AND DISCUSSION Recent reports of undergraduate-level teaching laboratory experiments designed for synthetic photochemistry exploit UV light and batch-type conditions. The laboratory experiment described herein offers the opportunity to explore synthetic photochemistry using different experimental conditions: using visible light and continuous flow methods. Consequently, in addition to pedagogy related to photochemistry, the importance of the reaction vessel and photon flux in photochemistry is explored. In general, both visible-light photocatalysis and continuous flow chemistry are rarely mentioned in the context of either physical or organic chemistry in undergraduate classes. In the laboratory experiment, the photochemical reactions proceeded to normally provided high yields (>80%), and high conversions (>99%) in the time allotted in flow (2 min) and in batch (1−3 h) (Scheme 1). Although the odor of the sulfurcontaining compound was found to be minimal and trivial, the most significant issue was students adding the alkene too early before injection in the flow apparatus (otherwise ambient light in the laboratory might promote the reaction). Another practical consideration is when students were asked to place their batch reaction in a glass dish with the blue LED light source at the center. Students would attempt to place their vial too close to the light source or in front of another student’s vial, effectively blocking another from the light source. All batch reactions contained a magnetic stirrer, and careful supervision of the stirring should be taken to ensure the vials do not move during agitation. No comparative experiment in which the vial is placed in a position with poor irradiation was performed. While TLC analysis of the reaction mixtures typically provided a very “clean” TLC plate (“spot-to-spot” conversion), the product is the most polar “spot” (Rf = 0.3), and the use of KMnO4 stain is recommended. Note that residual 4-penten-1ol and p-toluidine coelute (Rf = 0.5). In all cases purification by silica gel chromatography was necessary to remove residual Ru catalyst, 4-penten-1-ol, and p-toluidine. In addition to evaluating the quality and quantity of the product obtained by students, a series of questions were provided in the laboratory manual for students to answer that C



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ACKNOWLEDGMENTS The authors acknowledge the Natural Sciences and Engineering Research Council of Canada (NSERC), Université de Montréal, the Centre for Green Chemistry and Catalysis (CGCC), and the NSERC CREATE program in Continuous Flow Science for generous funding. The Canadian Foundation for Innovation (CFI) is acknowledged for generous funding of the flow chemistry infrastructure. Denis Deschênes is thanked for helpful suggestions.

mode for chemical reactions. Indeed, most students are familiar with thermal activation and instinctively understand why a water condenser is necessary and the importance of the boiling point of the solvent. As students have very little experience with photochemical activation, teaching assistants would discuss the absorbance characteristics of the solvents, the importance of the thickness of the tubing, and the absorbance properties of the Ru-based catalyst. During the experiment, teaching assistants and students frequently discussed the sustainability of light as an energy source. • Cysteine functionalization plays an important role in biochemistry and biotechnology. Although these topics were not discussed in detail by teaching assistants or via problems in the laboratory manual, further discussion of the importance of such a transformation could be investigated if desired. • Radical chemistry is often introduced in early organic chemistry classes. Granted, the photocatalysis mechanism is most likely more complex than the majority of the mechanisms seen by second-year students, but the laboratory experiment described herein provides an opportunity to revisit the basics of radical mechanisms. Revisiting radical chemistry should be accorded increased importance, given the resurgence of radical chemistry in modern synthetic chemistry. • Opportunities to discuss continuous flow processes to undergraduates are usually rare, and exploiting flow techniques for photochemistry is the application that is perhaps the easiest to grasp. In general, the practical considerations for conducting synthetic photochemistry are rarely discussed in undergraduate classes.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00639. Description of the experiment, including notes for instructors, procedures and guidelines for students, and examples of results obtained by students (PDF, DOCX)

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REFERENCES

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SUMMARY An undergraduate teaching laboratory experiment involving a photochemical thiol−ene reaction under continuous flow conditions was developed where students compared both “batch” and “flow” variants. Among the valuable pedagogical opportunities afforded were a discussion of light as a sustainable reagent, photochemistry, and continuous flow chemistry. It is anticipated that the design of new photochemical teaching laboratory exercises will continue to grow due to the transformative effect photochemistry and photocatalysis have had in both academic and industrial research.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shawn K. Collins: 0000-0001-9206-5538 Notes

The authors declare no competing financial interest. D



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(12) IDEX. https://www.idex-hs.com/fluidic-connections.html (last accessed May 1, 2018). Fisher. https://www.fishersci.ca/ca/en/home. html (last accessed May 1, 2018). (13) (a) Tyson, E. L.; Ament, M. S.; Yoon, T. P. Transition Metal Photoredox Catalysis of Radical Thiol-Ene Reactions. J. Org. Chem. 2013, 78, 2046−2050. (b) Tyson, E. L.; Niemeyer, Z. L.; Yoon, T. P. Redox Mediators in Visible Light Photocatalysis: Photocatalytic Radical Thiol−Ene Additions. J. Org. Chem. 2014, 79, 1427−1436. (14) (a) Feng, Z. V.; Edelman, K. R.; Swanson, B. P. StudentFabricated Microfluidic Devices as Flow Reactors for Organic and Inorganic Synthesis. J. Chem. Educ. 2015, 92, 723−727. (b) Glinski, M.; Ulkowska, U.; Iwanek, E. Application of Heterogeneous Copper Catalyst in a Continuous Flow Process: Dehydrogenation of Cyclohexanol. J. Chem. Educ. 2016, 93, 1623−1625. (c) Simeonov, S. P.; Afonso, C. A. M. Batch and Flow Synthesis of 5Hydroxymethylfurfural (HMF) from Fructose as a Bioplatform Intermediate: An Experiment for the Organic or Analytical Laboratory. J. Chem. Educ. 2013, 90, 1373−1375. (d) Tundo, P.; Rosamilia, A. E.; Arico, F. Methylation of 2-Naphthol Using Dimethyl Carbonate under Continuous-Flow Gas-Phase Conditions. J. Chem. Educ. 2010, 87, 1233−1235. (e) König, B.; Kreitmeier, P.; Hilgers, P.; Wirth, T. Flow Chemistry in Undergraduate Organic Chemistry Education. J. Chem. Educ. 2013, 90, 934−936. (15) For some notes on the safety of blue LEDs see: http://www. pointsdevue.com/white-paper/blue-light-hazard-new-knowledge-newapproaches-maintaining-ocular-health (last accessed May 1, 2018).

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Continuous Flow Science in an Undergraduate Teaching Laboratory

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