Communication Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX
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Empowering Students To Design and Evaluate Synthesis Procedures: A Sonogashira Coupling Project for Advanced Teaching Lab Jun-Yang Ong, Shang-Ce Chan, and Truong-Giang Hoang* Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 S Supporting Information *
ABSTRACT: A Sonogashira experiment was transformed into a problem-based learning platform for third-year undergraduate students. Given a target that could be synthesized in a single step, students worked in groups to investigate which method was the best for large-scale production. Through this practical scenario, students learn to conduct a literature search, select procedures, practice their synthesis skills, and evaluate their results in a real-world context. KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Collaborative/Cooperative Learning, Inquiry-Based/Discovery Learning, Problem Solving/Decision Making, Catalysis, Green Chemistry, Synthesis
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ross-coupling reactions are essential transformations in both academia and industry.1 While many cross-coupling experiments have been reported for teaching labs,2 most have been implemented as verification-style experiments, with some incorporating unknown products or starting materials.2a,g At the National University of Singapore (NUS), students used to carry out a Sonogashira experiment according to the procedure reported by Goodwin (Scheme 1, condition a).2d In 2015,
Coupling experiments in which students compare different reaction conditions, such as solvent6 or catalyst,7 have been reported. However, these experiments were restricted to the procedures provided in the lab manual. Other experiments demonstrated the use of coupling reactions in multistep syntheses.5d,7,8 Novak reported a project where students expanded the scopes of a published “green” Suzuki−Miyaura reaction.9 The experiment reported herein is unique in that students performed two procedures, one selected from the literature and the other from options given in the lab manual, and assessed their applicability for large-scale production. The design allowed students to study a coupling reaction in a research context while focusing on experimental procedures. Students learned the design aspect of an experiment,10 which is severely neglected in traditional-style experiments.11 This project has been implemented successfully over two semesters in our teaching lab with class sizes of 66 and 110 students.
Scheme 1. Traditional Sonogashira Coupling Experiments
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PEDAGOGICAL GOALS When doing the project, students 1. learn how to conduct a literature review and select experiments to solve a synthesis problem. 2. learn the Sonogashira coupling reaction and variation of reaction conditions. 3. learn to work in a group, proposing a common synthesis plan, sharing experimental findings, and evaluating the results.
inspired by the report by Vaccaro and co-workers that used γvalerolactone (GVL), a biomass-derived solvent, for Sonogashira coupling,3 we adapted the conditions and implemented the experiment in our teaching lab (Scheme 1, condition b). The new procedure introduced students to the concepts of copper-free Sonogashira reaction and renewable resources. While each experimental condition offered specific contents for student learning, a better way to introduce cross-coupling reactions would be to guide students to conduct a literature review and evaluate and select their procedures. On the basis of our preliminary research, many reaction conditions have been reported for the Sonogashira coupling reaction. Thus, given a target, students should be able to develop multiple approaches (synthetic pathways) and test their proposals using resources available in the teaching lab. This problem-based learning (PBL) approach has been shown to foster higher-order cognitive skills, increase students’ motivation,4 and gain popularity in the organic teaching lab.5 © XXXX American Chemical Society and Division of Chemical Education, Inc.
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PROJECT OVERVIEW A scenario was created where students worked as R&D chemists in a materials firm. Their task was to investigate a Received: July 15, 2017 Revised: April 26, 2018
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DOI: 10.1021/acs.jchemed.7b00522 J. Chem. Educ. XXXX, XXX, XXX−XXX
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excessive amounts. Palladium(II) acetate, copper(I) iodide, and 1,4-diazabicyclo[2.2.2]octane (DABCO) are irritants. Sodium hydroxide, 1 M hydrochloride solution, and piperazine are corrosive. All of the solvents used are flammable. n-Hexane is a neurotoxin. Methylene chloride, deuterated chloroform, silica gel, and celite are toxic when inhaled. The products have no known associated hazards but should be treated as toxic and handled with care. A list of all chemicals used, together with their CAS numbers and hazards, can be found in the Supporting Information.
small-scale synthesis of alkyne 1 and propose a method for the company to adopt in large-scale production (Scheme 2). Scheme 2. Project Overview
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RESULTS AND DISCUSSION The project was run for two semesters at NUS (CM3291 Advanced Experiments in Inorganic and Organic Chemistry). In semester 1, the target was 1a (Scheme 2, R = NO2). There were 66 students forming 17 groups. Eleven proposals were approved to be carried out in the lab (64.7%).12 The average yield of students’ proposed procedures was 64% (Table 2). In Students worked in groups of four to propose and attempt two synthetic procedures. One procedure was selected from the literature and the other was selected from the lab manual (three options available). Experimental work was carried out individually such that each procedure was tested twice by one group or modifications could be made if the first run was not satisfactory. The combined data were evaluated, and a method for large-scale production was proposed by the group. The timeline for the project is given in Table 1. Students first attended a 1.5 hour workshop on library resources. SciFinder
Table 2. Comparative Student Results
Table 1. Project Schedule Week
Activity
1 2 4 5 7−11 13
Introductory lecture Workshop on library resources and SciFinder program Submission of the group proposal Discussion with the lecturer about the synthesis plan Individual lab work (two 6 hour lab sessions) Submission of the group report
Parameter
Semester 1
Semester 2
Class size Target molecule Number of groups, N Number of groups working on their proposed literature procedure, N (%) Average yield of the students’ proposed method (%) Average yield (students following lab manual procedures) (%) Range of yields of the students’ proposed methods (%)
66 1a 17 11 (64.7)
110 1b 27 18 (66.7)
64
62
77
64
0−91
25−83
semester 2, the target was 1b (Scheme 2, R = COCH3). There were 110 students forming 27 groups (some groups with three or five students); 18 proposals were approved (66.7%), with the students’ average yield being 62%. The results were very encouraging because it was the first attempt for many students in applying a literature procedure directly in the lab. Some students encountered difficulties when working on the literature procedurestwo students collected the wrong products during flash column chromatography, resulting in no yields (semester 1 data), while some others experienced incomplete reactions. Such unexpected scenarios reflected the reality that a synthetic chemist would meet in his or her work. The results also demonstrated that the project is an excellent problem to facilitate student learning: multiple solutions can be formulated and studied in the teaching lab. Representative student 1H NMR data can be found in the Supporting Information. In the project, students went through a complete research experience, from library workshop, proposal writing, group discussion, risk assessments, and individual lab work to data evaluation. In the selection of literature procedures for their proposals, yield and reaction time were the main focuses of students. Little consideration was given to catalyst stability or workup procedure. During the proposal meeting, students were guided to discover different reaction setups when air- or moisture-sensitive catalysts were used or different workup procedures to remove high-boiling-point organic solvents such as GVL. Students were asked to consider scenarios where the literature procedure did not work well. Many students proposed to stop and redo the experiment; in these cases,
was used to find procedures to synthesize the target molecule. In the proposal, the two procedures that the group wished to investigate were discussed, taking into consideration the cost, environmental friendliness, and availability of equipment. To simplify the task, only the cost of chemicals used in the reaction setup were considered. Each group met with a lecturer to discuss their plan. If the proposed literature procedure was not suitable because of time or reagent constraints, a second procedure from the lab manual was selected by the group. All of the literature procedures were adjusted to 1 mmol of the aryl iodide. Students planned their experiments and prepared the risk assessments accordingly. Each procedure was conducted individually in two 6 hour lab sessions. The first session was used for reaction setup and workup. In the second session, the crude product was purified using flash column chromatography.
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HAZARDS A lab coat, safety goggles, and nitrile gloves are required for all personnel in the lab. All of the operations are performed in well-ventilated fume hoods. 4′-Iodoacetophenone and 1-iodo4-nitrobenzene are irritants. 1-Iodo-4-nitrobenzene is harmful if it is ingested or comes into contact with the skin. Phenylacetylene is flammable and can be fatal if ingested or inhaled in B
DOI: 10.1021/acs.jchemed.7b00522 J. Chem. Educ. XXXX, XXX, XXX−XXX
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1:14, as for usual experiments. Additional time and effort were required from the lecturer to supervise multiple groups working on the project; however, the outcome achieved in improving students’ learning was worth the time and effort.
the lecturer pointed out the additional costs and time incurred and the fact that the original problem would likely persist. He then guided students to adjust suitable reaction parameters to overcome potential problems. The final evaluation, which involved proposing a method for large-scale production, required students to evaluate their experimental results as a group. Students were required to consider not only the yield and the purity, as for a typical experiment, but also the reproducibility among group members, the cost (with their actual yields), and the environmental friendliness of the methods. Occasionally, students were forced to choose between cost effectiveness and green chemistry. Through this realistic context, students can see the importance of selecting appropriate procedures (the experimental design) and develop their critical analysis skills. Because most students had no prior research experience, the hybrid model (one procedure from the lab manual and one procedure from the literature) was selected. This design eased the hesitation when students transitioned to a PBL experiment. On the basis of our survey, this design was favored over a completely research-based project (two procedures selected from literature) by most of our students (85 and 95% in semesters 1 and 2, respectively). Two additional advantages were offered by this design. First, the number of proposals, and thus the amounts of reagents required were reduced, making it possible to implement the project in a medium-sized class. Second, it ensured that some reliable data could be obtained by each group simply by following the lab manual procedure. The choice of one lab manual procedure and one literature procedure was therefore appropriate and educational. While this experiment was designed for students without research experience, it could be applied at all levels.
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CONCLUSION A Sonogashira coupling project has been developed and implemented successfully for a medium-sized class. The project provided students comprehensive training on how to tackle synthesis problems, beginning from library work all the way to implementation and evaluation. This problem-based learning project created an excellent platform for studying crosscoupling reactions and lab work. The target could be changed without additional resources, making it suitable for the teaching lab.
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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.7b00522. Notes for instructors; handout for students; student survey questions and results, sample student 1H NMR spectra and risk assessment (PDF, DOCX)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Truong-Giang Hoang: 0000-0003-4368-4142
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Notes
The authors declare no competing financial interest.
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STUDENT OPINION The project was perceived by most students as interesting and suitable for the advanced level. The student survey questions and results can be found in the Supporting Information. Here are some student comments about the project: • “Perform your own procedure based on research and choosing based on understanding. Most fun and excitement experience in lab.” • “Discovering ways to solve a problem that is relatable to real-life.” • “It gives me a chance to experience the whole procedure of working in a research project.” • “You learn failure is okay and learn to rectify possible mistakes. Encourage thinking.” • “Can try out proposed method. Sense of personal responsibility.” • “I like that we were able to work as a group and share our observations and results.”
ACKNOWLEDGMENTS We thank the Department of Chemistry of NUS and Yulin Lam for supporting this project; Shu-Sin Chng for his helpful discussion; the staffs from the General Teaching Lab, the Synthesis Lab, and the Advanced Teaching Lab for their support. NUS Science Library and ACS Singapore Division are gratefully acknowledged for conducting the library resource and SciFinder Scholar workshop. We also thank all of the students from CM3291 AY16/17 semesters 1 and 2 for participating in the project.
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REFERENCES
(1) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Palladium-catalyzed cross-coupling reactions in total synthesis. Angew. Chem., Int. Ed. 2005, 44 (29), 4442−4489. (2) For Sonogashira experiments, see: (a) Cranwell, P. B.; Peterson, A. M.; Littlefield, B. T. R.; Russell, A. T. An operationally simple Sonogashira reaction for an undergraduate organic chemistry lab class. J. Chem. Educ. 2015, 92 (6), 1110−1114 and references therein. (b) Pavia, D. L. Introduction to Organic Lab Techniques: A Microscale Approach, 5th ed.; Thomson Brooks/Cole: Belmont, CA, 2013; pp 316−325. (c) Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Lab Experiments. 1st ed.; Thomson Brooks/Cole: Belmont, CA, 2004; pp 186−196. (d) Goodwin, T. E.; Hurst, E. M.; Ross, A. S. A multistep synthesis of 4-nitro-1-ethynylbenzene involving palladium catalysis, conformational analysis, acetal hydrolysis, and oxidative decarbonylation. J. Chem. Educ. 1999, 76 (1), 74−75. (e) Brisbois, R. G.; Batterman, W. G.; Kragerud, A. R. Synthesis of 4Nitro-1-pentynylbenzene: An Example of Transitional Metal-Mediated Cross-Coupling. J. Chem. Educ. 1997, 74 (7), 832−833. For examples
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CHALLENGES More chemicals were required to prepare for the project; for example, five palladium catalysts (Pd(OAc)2, PdCl2, Pd/C, Pd(PPh3)4, and Pd(PPh3)2Cl2) were used in the first semester. For the second semester, the chemicals became regular, even though the target had changed. While the reaction setup and workup might differ, TLC analysis and flash column chromatography conditions could be applied for all procedures, making the workload manageable for the lecturer and teaching assistants. The TA:student ratio was kept between 1:10 and C
DOI: 10.1021/acs.jchemed.7b00522 J. Chem. Educ. XXXX, XXX, XXX−XXX
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of Suzuki−Miyaura experiments, see: (f) Hamilton, A. E.; Buxton, A. M.; Peeples, C. J.; Chalker, J. M. An operationally simple aqueous Suzuki−Miyaura cross-coupling reaction for an undergraduate organic chemistry lab. J. Chem. Educ. 2013, 90 (11), 1509−1513. (g) Hie, L.; Chang, J. J.; Garg, N. K. Nickel-catalyzed Suzuki−Miyaura crosscoupling in a green alcohol solvent for an undergraduate organic chemistry lab. J. Chem. Educ. 2015, 92 (3), 571−574. (h) Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. P. Greening Up” the Suzuki Reaction. J. Chem. Educ. 2008, 85, 555−557. For a Heck coupling experiment, see: (i) Martin, W. B.; Kateley, L. J. The Heck Reaction: A Microscale Synthesis Using a Palladium Catalyst. J. Chem. Educ. 2000, 77 (6), 757−759. (3) Strappaveccia, G.; Luciani, L.; Bartollini, E.; Marrocchi, A.; Pizzo, F.; Vaccaro, L. γ-Valerolactone as an alternative biomass-derived medium for the Sonogashira reaction. Green Chem. 2015, 17 (2), 1071−1076. (4) (a) Kelly, O. C.; Finlayson, O. E. Providing solutions through problem-based learning for the undergraduate 1st year chemistry lab. Chem. Educ. Res. Pract. 2007, 8 (3), 347−361. (b) McDonnell, C.; O’Connor, C.; Seery, M. K. Developing practical chemistry skills by means of student-driven problem based learning mini-projects. Chem. Educ. Res. Pract. 2007, 8 (2), 130−139. (c) Cranwell, P.; Davis, F.; Elliott, J.; McKendrick, J.; Page, E.; Spillman, M. Encouraging Independent Thought and Learning in First Year Practical Classes. New Dir. Teach. Phys. Sci. 2017, DOI: 10.29311/ndtps.v0i12.674. (5) (a) Keller, V. A.; Kendall, B. L. Independent Synthesis Projects in the Organic Chemistry Teaching Laboratories: Bridging the Gap between Student and Researcher. J. Chem. Educ. 2017, 94 (10), 1450− 1457 and references therein. (b) Weaver, M. G.; Samoshin, A. V.; Lewis, R. B.; Gainer, M. J. Developing students’ critical thinking, problem-solving, and analysis skills in an inquiry-based synthetic organic lab course. J. Chem. Educ. 2016, 93 (5), 847−851. (c) Edgar, L. J. G.; Koroluk, K. J.; Golmakani, M.; Dicks, A. P. Green chemistry decision-making in an upper-level undergraduate organic lab. J. Chem. Educ. 2014, 91 (7), 1040−1043. (d) Flynn, A. B.; Biggs, R. The development and implementation of a problem-based learning format in a fourth-year undergraduate synthetic organic and medicinal chemistry lab course. J. Chem. Educ. 2012, 89 (1), 52−57. (6) Costa, N. E.; Pelotte, A. L.; Simard, J. M.; Syvinski, C. A.; Deveau, A. M. Discovering green, aqueous Suzuki coupling reactions: synthesis of ethyl acetate, a biaryl with anti-arthritic potential. J. Chem. Educ. 2012, 89 (8), 1064−1067. (7) Oliveira, D. G. M.; Rosa, C. H.; Vargas, B. P.; Rosa, D. S.; Silveira, M. V.; De Moura, N. F.; Rosa, G. R. Introducing undergraduates to research using a Suzuki−Miyaura cross-coupling organic chemistry miniproject. J. Chem. Educ. 2015, 92 (7), 1217−1220. (8) Fray, M. J.; Macdonald, S. J. F.; Baldwin, I. R.; Barton, N.; Brown, J.; Campbell, I. B.; Churcher, I.; Coe, D. M.; Cooper, A. W. J.; Craven, A. P.; Fisher, G.; Inglis, G. G. A.; Kelly, H. A.; Liddle, J.; Maxwell, A. C.; Patel, V. K.; Swanson, S.; Wellaway, N. A practical drug discovery project at the undergraduate level. Drug Discovery Today 2013, 18 (2324), 1158−1172. (9) Novak, M.; Wang, Y.-T.; Ambrogio, M. W.; Chan, C. A.; Davis, H. E.; Goodwin, K. S.; Hadley, M. A.; Hall, C. M.; Herrick, A. M.; Ivanov, A. S.; Mueller, C. M.; Oh, J. J.; Soukup, R. J.; Sullivan, T. J.; Todd, A. M. A Research Project in the Organic Instructional Laboratory Involving the Suzuki−Miyaura Cross Coupling Reaction. Chem. Educ. 2007, 12, 414−418. (10) For examples of inquiry-based experiments, see: (a) Schepmann, H. G.; Mynderse, M. Ring-closing metathesis: an advanced guidedinquiry experiment for the organic laboratory. J. Chem. Educ. 2010, 87 (7), 721. (b) Moorman, R. M.; Kasmani, M. Y.; Peeples, C. J.; Chalker, J. M. Inquiry-Driven Investigation of the Copper-Catalyzed Azide− Alkyne Cycloaddition in the Undergraduate Organic Chemistry Laboratory. Chem. Educ. 2015, 20, 214−219. (11) Horowitz, G. The state of organic teaching laboratories. J. Chem. Educ. 2007, 84 (2), 346−353.
(12) The approval of the procedures reflects only that they could be done in our teaching laboratory; it does not refer to the quality of the papers.
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DOI: 10.1021/acs.jchemed.7b00522 J. Chem. Educ. XXXX, XXX, XXX−XXX
