Laboratory Experiment Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX
pubs.acs.org/jchemeduc
Let There Be Light: Hypothesis-Driven Investigation of Ligand Effects in Photoredox Catalysis for the Undergraduate Organic Chemistry Laboratory Shuming Chen* Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States S Supporting Information *
ABSTRACT: An undergraduate organic chemistry laboratory experiment that provides an introduction to the concepts and practices of photoredox catalysis is reported. While undergraduate-level photochemistry experiments typically place emphasis on analytical properties of catalysts rather than synthetic applications, this experiment showcases the power and versatility of photoredox chemistry in modern organic syntheses. A hypothesis-driven approach is utilized as students apply chemical reasoning to formulate hypotheses predicting the relative catalytic activity of Ru(bpy)32+ and Ru(bpm)32+, which differ slightly in ligand structure. Students work collaboratively to obtain conversion data in [2 + 2] cycloadditions catalyzed by Ru(bpy)32+ and Ru(bpm)32+, and use the data to support or refute their hypotheses. The operationally straightforward experimental protocol has been shown to be robust and reproducible, providing unambiguous results that facilitate student interpretation. Furthermore, the experiment trains students in chemical thinking needed for conducting research. KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Interdisciplinary/Multidisciplinary, Laboratory Instruction, Collaborative/Cooperative Learning, Inquiry-Based/Discovery Learning, Catalysis, Organometallics, Photochemistry, Coordination Compounds
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INTRODUCTION The emergence of photosensitive transition-metal-based complexes as high-turnover, homogeneous catalysts for visible-light-mediated reactions has been one of the most notable developments in chemical research in the past decade.1 The ability to generate reactive radical intermediates under mild conditions makes photoredox catalysis an increasingly powerful and versatile method for the construction of carbon− carbon and carbon−heteroatom bonds.2 Despite the intense and ongoing interest that photoredox chemistry receives from the research community, there have been few attempts to incorporate it into the undergraduate chemistry curriculum.3,4 The in-depth treatment of photochemistry itself is almost always reserved for upper-division physical or inorganic chemistry lecture or laboratory courses,5 where the emphasis is typically on quantitative comparisons of photochemical properties, rather than applications to organic synthesis.3,4 No synthetic experiment utilizing photoredox catalysis has been designed for the undergraduate organic chemistry laboratory curriculum, despite the broad range of synthetically useful organic transformations achieved with photoredox catalysis. An introduction to photoredox chemistry provides students with a rich interdisciplinary learning experience, exposing them to a range of topics that are underrepresented in the undergraduate curriculum for organic (radical chemistry), inorganic (coordination compounds and ligand effects), and physical (photo© XXXX American Chemical Society and Division of Chemical Education, Inc.
chemical reactions and excited states) chemistry. In addition, the operational simplicity of photoredox experimental setups also renders them highly suitable for the undergraduate skill level. This synthetic experiment protocol has been developed specifically to introduce students to the concepts and practices of photoredox catalysis through a hypothesis-driven investigation of ligand effects in the [2 + 2] homodimerization of styrenes catalyzed by d6-ruthenium complexes (Figure 1).6,7 By encouraging students to generate hypotheses and acquire data as a team, collaborative learning and actively engagement in the scientific method is achieved.
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PEDAGOGICAL GOALS This laboratory experiment directs students to formulate hypotheses about the relative catalytic activities of two Ru complexes in a photoredox reaction, and gather experimental data as a class to support or refute their hypotheses. After completing this experiment, students should be able to (1) explain the chemical basis of photoredox reactivity; (2) design more strongly oxidizing/reducing photoredox catalysts through modifications to the ligand structure; and (3) use experimental Received: September 10, 2017 Revised: March 20, 2018
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DOI: 10.1021/acs.jchemed.7b00693 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Laboratory Experiment
techniques. The reaction mixture was stirred vigorously at 0 °C for 1.5 h under a lit desk lamp equipped with a 20 W compact fluorescent light (CFL) bulb. While the reaction was stirring, students prepared a miniature silica plug using a glass pipet. After 1.5 h of stirring, the reaction mixture was filtered through the silica plug. Students rinsed any remaining product from the silica plug by filtering diethyl ether through the plug, and the combined dichloromethane and diethyl ether washes were concentrated in vacuo to yield the crude products. Students submitted NMR and GC−MS samples of crude products at the end of the laboratory period. GC−MS and 1H NMR data were collected by a teaching assistant, although these data could also be collected by the students if facilities allow. Students used primarily 1H NMR spectroscopy to gauge conversion to the desired [2 + 2] cycloaddition product by comparing the integrations of the alkenyl proton peaks (6.06−6.16 ppm, 6.34−6.40 ppm, 1 H each) in trans-anethole to the benzylic protons (2.80 ppm, 2 H) in the product, which give rise to a diagnostic inverted doublet of doublets. Students completed a postlaboratory worksheet that included analysis of the experimental results, as well as further applications of concepts introduced in this experiment. The experimental design called for students to work collectively as a “research team”. Students were randomly assigned either Ru(bpy)32+ or Ru(bpm)32+ as their photoredox catalyst, but asked to follow identical experimental protocols to eliminate potential interference of other variables. After the analytical data was acquired, students uploaded their analysis results to a Google Document visible to the whole class. Students completed relevant analyses in postlaboratory worksheets based on the pooled data. A detailed description of the experiment is described in the Supporting Information.
Figure 1. Visible-light-mediated [2 + 2] homodimerization of transanethole performed in this experiment.
data to determine the effectiveness of photoredox catalysts. These pedagogical goals were evaluated from written answers to pre- and postlab assignments.
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OVERVIEW OF LABORATORY EXPERIMENT This laboratory experiment was incorporated into an organic chemistry laboratory course intended for undergraduate students in their second year and beyond. It has been carried out four times by a total of 109 third- and fourth-year students. The class size ranged from 19 to 34 students. Working individually, all students were able to carry out the experiment in 3 h in a single laboratory period. Students completed a prelaboratory assignment before performing the experiment. The prelaboratory assignment ensured that students familiarized themselves with the experiment and the safety requirements. Based on material introduced in the handout and the lecture, part of the prelaboratory assignment asked students to formulate hypotheses as to whether Ru(bpy)3(BArF)2 or Ru(bpm)3(BArF)2 would be a superior catalyst for the visible-light-mediated [2 + 2] homodimerization of trans-anethole. After the laboratory period, students performed analyses of their own NMR spectra and pooled experimental data in an online document to support or refute their hypotheses. Students also completed a postlaboratory assignment to deepen their understanding of the experiment, as well as hone their critical analysis skills.
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HAZARDS Closed-toed shoes, long pants/skirts covering the ankles, safety glasses, gloves, and flame-resistant laboratory coats must be worn at all times. Handle and dispose of all hazardous materials in accordance with the recommendations of their Material Safety Data Sheets (MSDSs). trans-Anethole is very hazardous in the case of eye contact or skin contact. The [2 + 2] cycloaddition product may be hazardous in the case of eye or skin contact. Dichloromethane (methylene chloride) is a proven carcinogen and very hazardous in the case of eye or skin contact. Silica is an inhalation hazard and may cause lung damage through prolonged or repeated exposure. Diethyl ether is an irritant and is flammable. Deuterated chloroform (CDCl3) is toxic and is a cancer suspect agent. Ru(bpy)3(BArF)2 and Ru(bpm)3(BArF)2 may be harmful if swallowed.
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RESULTS AND DISCUSSION The visible-light-mediated [2 + 2] cycloaddition of transanethole was chosen in this experimental design to demonstrate photoredox catalysis for several reasons. The reaction has a marked sensitivity to the electronic nature of the ligand on the ruthenium metal, with Ru(bpm)32+ providing good conversion into the desired product within 1.5 h, and Ru(bpy)32+ providing 0% conversion in stark contrast. After a brief lecture to introduce relevant concepts in photoredox chemistry, students usually correctly predict Ru(bpm)32+ to be a superior catalyst to Ru(bpy)32+ for this transformation. Regardless, students are
Experiment
The photoredox catalysts, Ru(bpy) 3 (BArF) 2 and Ru(bpm)3(BArF)2, were prepared beforehand from commercially available starting materials according to literature procedures6,8 and stored in a desiccator until the laboratory period. Students placed an oven-dried round-bottomed flask in an ice−water bath, and charged the flask with 0.5 mmol transanethole. Students weighed and transfered their assigned catalyst (0.2 mol %) into the round-bottomed flask, and added dichloromethane using air- and water-free transfer B
DOI: 10.1021/acs.jchemed.7b00693 J. Chem. Educ. XXXX, XXX, XXX−XXX
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typically still struck by the dramatic difference in reactivity due to a minor modification in the molecular structure of the ligands. The experimental setup is simple and straightforward, as the reaction is not sensitive to air, and excess water can easily be avoided by using predried glassware and anhydrous solvent sources. The reaction requires only 0.2 mol % catalyst loading to achieve good to excellent conversion for Ru(bpm)32+, which highlights the environmental friendliness of this transformation and allows it to be performed at a reasonable cost. The use of desk lamps equipped with CFL bulbs as the light source, a unique feature of this experiment, also adds student interest. Both the starting material and the product (formed as a single regio- and diastereomer) give well-resolved diagnostic 1H NMR resonances, which makes the interpretation of experimental results straightforward. Additionally, trans-anethole is an inexpensive and readily available starting material. Although the reaction would be performed in a ventilated fume hood, the spice-like smell of trans-anethole is deemed a plus. All students who carried out the experimental protocol had completed a minimum of 2/3 of the introductory organic chemistry course sequence, and had been previously introduced to radical chemistry. Students were required to read a detailed laboratory handout, which consisted of the necessary theoretical background and the experimental protocol. Students also attended a lecture designed to provide a systematic introduction to the key concepts involved in photoredox catalysis, with a particular emphasis on the importance of “matching” redox potentials between the photoredox catalyst and the substrate. Of the 109 students who carried out the experiment protocol, 104 (95%) were able to successfully obtain data required to gauge the conversion into the desired product (representative student spectra are given in the Supporting Information). Accidental loss of product occurred in 5 cases that prevented acquisition of data. Of the 57 students who were assigned Ru(bpy)32+ as the photoredox catalyst, 54 students were able to acquire the required data; 51 of 54 (94%) reported 0% conversion, with 3 students reporting conversions of 44− 63%. (In at least 2 of these 3 cases, students reported nonzero conversions due to misinterpretation of NMR spectroscopy data.) Of the 52 students who were assigned Ru(bpm)32+ as the photoredox catalyst, 50 were able to obtain data for analysis, with 49 of 50 (98%) reporting nonzero conversion into the desired product; the range of reported conversions was 33− 99%. Collectively, these data suggest high reproducibility and robustness of the currently reported experimental protocol, providing clear trends that facilitate student learning. Many students noted the striking reactivity difference between the two catalyst systems, which provided excellent support for their hypotheses. In a few cases, it was noted that students had difficulty estimating conversion from NMR spectra both due to unfamiliarity with the procedure, as well as the complexity of crude NMR spectra. Although the collaborative nature of the experiment makes the qualitative trends more resistant to the errors of a few individuals, additional guidance or exercises provided by the instructor or a teaching assistant in spectral interpretation could provide a smoother learning experience. On the basis of graded pre- and postlaboratory assignments collected from a 28 student class, the following results were noted with regard to the accomplishment of the stated pedagogical goals:
(a) On a prelaboratory assignment question, students were asked to explain the chemical basis of the photoredox reactivity of Ru(bpy)32+ and Ru(bpm)32+ by showing the transformation that takes place in these catalysts upon visible-light irradiation. The average grade on this question was 3.8 out of 4 possible points. (b) On a prelaboratory assignment question, students were asked to design a more strongly oxidizing photoredox catalyst than Ru(bpm)32+ by modifying the ligand structure. The average grade on this question was 3.9 out of 4 possible points (with 2 students receiving minor deductions for proposing chemically unrealistic structures). (c) On a postlaboratory assignment question, students were asked to determine which catalyst was more effective in promoting the homodimerization of trans-anethole. All students correctly identified Ru(bpm)32+ as the more effective catalyst. In addition, conversion rates were independently calculated by the instructor using student NMR spectra. These conversion rates were then compared to those reported by the students to evaluate student success in NMR interpretation. It was noted that in 27 of 28 (96%) cases, the conversion rates calculated by the student and the instructor were within 10% of each other, indicating that the vast majority of students were able to accurately determine conversion rates based on NMR spectra. Student comments regarding the experimental design are given in the Supporting Information.
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DISCUSSION TOPICS A variety of topics dealing with chemistry concepts and experimental techniques were discussed. Both lecture content and the experimental design could be tailored to suit individual pedagogical needs at different knowledge and skill levels. A clear, concise introduction to the process of photoexcitation in metal coordination complexes is essential to student understanding of photoredox reactivity and successful formulation of informed hypotheses. Although students are expected to have some prior instruction in radical chemistry and reduction− oxidation processes, care should be taken to revisit these basic concepts as many students find them challenging. Cycloadditions are usually covered mid- or late-sequence in the introductory organic chemistry curriculum, and students typically only encounter the thermally promoted (e.g., Diels− Alder) varieties in the laboratory setting. Photoredox catalysis provides a unique opportunity to invoke the Woodward− Hoffmann rules to compare and contrast photochemical versus thermal conditions for pericyclic reactions, which fosters student interest in physical organic chemistry. The hypothesis-driven nature of the experiment design also lends itself to discussions of the scientific method in general. It is worth noting that the new and unfamiliar chemical situation (ligand effect in photoredox catalysis) encouraged students to rely entirely on chemical reasoning to predict reactivity, and to see their predictions verified in a gratifying fashion. Students were also encouraged to consider other examples of ligand effects in the chemical literature, as well as come up with their own “designer” ligands to fine-tune reactivity, practicing the same critical thinking skills employed in actual chemical research. As a greener alternative to more traditional methods of generating highly reactive species, photoredox catalysis also offers the opportunity to discuss the environmental impact of chemical C
DOI: 10.1021/acs.jchemed.7b00693 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Forming Reactions via Photogenerated Intermediates. Chem. Rev. 2016, 116, 9850−9913. (3) Garino, C.; Terenzi, A.; Barone, G.; Salassa, L. Teaching Inorganic Photophysics and Photochemistry with Three Ruthenium(II) Polypyridyl Complexes: A Computer-Based Exercise. J. Chem. Educ. 2016, 93, 292−298. (4) Rapp, T. L.; Phillips, S. R.; Dmochowski, I. J. Kinetics and Photochemistry of Ruthenium Bisbipyridine Diacetonitrile Complexes: An Interdisciplinary Inorganic and Physical Chemistry Laboratory Exercise. J. Chem. Educ. 2016, 93, 2101−2105. (5) For an example, see: Ma, J.; Guo, R. Engaging in Curriculum Reform of Chinese Chemistry Graduate Education: An Example from a Photocatalysis Principles and Applications Course. J. Chem. Educ. 2014, 91, 206−210. (6) Ischay, M. A.; Ament, M. S.; Yoon, T. P. Crossed Intermolecular [2 + 2] Cycloaddition of Styrenes by Visible Light Photocatalysis. Chem. Sci. 2012, 3, 2807−2811. (7) For a review on light-mediated [2 + 2] cycloadditions, see: Poplata, S.; Tröster, A.; Zou, Y.-Q.; Bach, T. Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions. Chem. Rev. 2016, 116, 9748−9815. (8) Lin, S.; Ischay, M. A.; Fry, C. G.; Yoon, T. P. Radical Cation Diels−Alder Cycloadditions by Visible Light Photocatalysis. J. Am. Chem. Soc. 2011, 133, 19350−19353.
procedures and the principles of green chemistry. Depending on its placement in the laboratory sequence, this experiment could also serve as an introduction to water-free laboratory techniques, GC−MS, or both. Due to the need to analyze challenging NMR spectra of crude reaction mixtures, this experiment is not suited to students with little or no NMR interpretation experience. However, this experiment serves as an excellent introduction to the analysis of more complex NMR spectra, which prepares students for upper-level organic chemistry laboratory coursework, as well as research.
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CONCLUSIONS An operationally straightforward experimental protocol involving the ruthenium-catalyzed [2 + 2] cycloaddition of styrene derivatives was developed to introduce students to the application of photoredox catalysis in organic synthesis. Utilizing a hypothesis-driven approach and collaborative data collection, this experiment familiarizes students with the practices of the scientific method. In addition, the experiment also offers an opportunity to expose students to a wide range of underrepresented topics in organic, inorganic, and physical chemistry, providing a rich interdisciplinary learning experience.
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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.7b00693. Detailed student handout, a prelaboratory assignment sheet, a postlaboratory assignment sheet, notes for instructors, and representative spectroscopic data from students (PDF, DOCX)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shuming Chen: 0000-0003-1897-2249 Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS Students and teaching assistants of the Chemistry 30CL organic chemistry laboratory course are gratefully acknowledged for their feedback on this experiment. S.C. thanks Hosea Nelson and Alex Bagdasarian for helpful discussions during the development phase of this experiment, as well as the University of California, Los Angeles, for financial support. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the National Center for Research Resources (S10RR025631).
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REFERENCES
(1) For a review on transition-metal-based photoredox chemistry, see: Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (2) (a) Kar̈kas̈, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis. Chem. Rev. 2016, 116, 9683−9747. (b) Ravelli, D.; Protti, S.; Fagnoni, M. Carbon−Carbon Bond D
DOI: 10.1021/acs.jchemed.7b00693 J. Chem. Educ. XXXX, XXX, XXX−XXX
