Laboratory Experiment pubs.acs.org/jchemeduc
Discovering Green, Aqueous Suzuki Coupling Reactions: Synthesis of Ethyl (4-Phenylphenyl)acetate, a Biaryl with Anti-Arthritic Potential Nancy E. Costa, Andrea L. Pelotte, Joseph M. Simard, Christopher A. Syvinski, and Amy M. Deveau* Chemistry & Physics Department, University of New England, Biddeford, Maine 04005, United States S Supporting Information *
ABSTRACT: Suzuki couplings are powerful chemical reactions commonly employed in academic and industrial research settings to generate functionalized biaryls. We have developed and implemented a discovery-based, microscale experiment for the undergraduate organic chemistry laboratory that explores green Suzuki coupling using water as the primary solvent. This experiment exposes students to the professional responsibilities of a pharmaceutical chemist and promotes a problem-solving approach toward learning green chemistry principles. Specifically, students assume the role of a medicinal chemistry researcher striving to identify the greenest and most cost-effective method out of three proposed synthetic approaches to make ethyl (4-phenylphenyl)acetate. Ethyl (4-phenylphenyl)acetate is a precursor to the drug felbinac and demonstrates promise as a lead compound in the discovery of new nonsteroidal anti-inflammatory drugs for the treatment of arthritis. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Problem Solving/Decision Making, Aqueous Solution Chemistry, Catalysis, Green Chemistry, Medicinal Chemistry, NMR Spectroscopy, Synthesis
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We developed a discovery-based experiment for the undergraduate organic chemistry laboratory employing greener SC methodology. Students function as medicinal chemistry research teams (three students per team) and are charged with the task of developing a high-yielding, green synthesis of ethyl (4-phenylphenyl)acetate 1 for their company (Scheme 2). Students learn that derivatives of 1 are already under patent by their company as novel, nonsteroidal anti-inflammatory drugs (NSAIDs) for treating arthritis, for example, felbinac (Figure 1).6 In their microscale synthesis of 1, students are required to employ a SC and use commercially available starting materials. Students are then provided, or could independently research, three aqueous SC approaches in the primary literature that employ palladium(II) acetate, Pd(OAc)2, as a catalyst and are devoid of a phosphine ligand.2b−d,5 Although all three approaches are ligandless and use water as the primary solvent, they differ by the choice of cosolvent (no cosolvent,2b,d acetone,2c or [Bmim]PF65) and the identity and amount of base used (Scheme 2). Tetrabutylammonium bromide (TBAB) is used as a phase transfer catalyst with the water-only solvent. Students are asked to determine the percent yield, intrinsic and experimental atom economies,7 overall reaction efficiency, and cost of each experiment. Working with their team, students assimilate their data, evaluate their options, and finally propose which of the three synthetic approaches should be used by their company. The green and high-throughput synthesis of biaryl molecules via a SC has previously been explored for the undergraduate laboratory.3 This recent literature activity further reinforces our
reen organic chemistry is a rapidly growing, high impact research area. Because of increasing concerns over our world’s environment, practical, green chemical reactions that minimize or eliminate the use of toxic chemicals and reduce chemical waste are driving innovation in industry and academia.1 Recently, there has been great interest in developing aqueous, organic reactions that create new carbon−carbon (C− C) bonds while applying green principles.2 The Suzuki crosscoupling is one such reaction (Scheme 1).3 Scheme 1. Basic Bond Formation Executed with a Suzuki Coupling Reaction
Suzuki cross-couplings date from 1979 and are employed in many syntheses of biologically active molecules containing a functionalized biaryl motif.4 These reactions are catalyzed by palladium (Pd0) and create a new C−C bond between an aryl halide and an aryl boronic acid (Scheme 1). Suzuki couplings (SCs) can be “greened” in several ways: (1) reusing the transition-metal catalyst thereby reducing the heavy-metal waste generated, (2) using nonvolatile solvents such as water or the ionic liquid (IL), 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim]PF6),1c,2,5 and (3) employing ligandfree2b−d conditions. © 2012 American Chemical Society and Division of Chemical Education, Inc.
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Scheme 2. Synthesis of Ethyl (4-Phenylphenyl)acetate
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EXPERIMENTAL PROCEDURE Although this microscale experiment was originally designed for an introductory organic laboratory, it is also amenable to advanced organic and inorganic chemistry courses. In total, this laboratory takes approximately 2.5−3 h. Each team of three students completes the three reactions and share the data.8 Students first combine all reagents in a round-bottom flask equipped with a spin vane and water condenser. After the reaction is heated with stirring for 60 min, it is cooled and the crude product subsequently extracted with diethyl ether. The combined organic extracts are dried and concentrated, and the crude product is purified via microscale silica gel column chromatography using a Pasteur pipet mini-column. Students use thin-layer chromatography (TLC; eluent is 9:1 hexane/ ethyl acetate) to monitor their reaction progress and strategically track the formation and qualitative purity of their product. The purified product is subsequently analyzed via 1H and 13C nuclear magnetic resonance spectroscopy (NMR). Percent yield, atom economy, reaction efficiency, and cost of the reactions are calculated to identify the highest yielding, greenest, and most cost-effective procedure.
Figure 1. Structure of felbinac and 1.
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desire to introduce undergraduates to SCs as practical C−C bond forming reactions not typically taught in introductory organic chemistry (Scheme 2). This experiment builds upon previous research while introducing students to the concept of using water as a primary solvent with or without a cosolvent (acetone or [Bmim]PF6). Notably, ILs such as [Bmim]PF6 can be recycled and both ILs and water are attractive because they are less volatile than traditional organic solvents. Furthermore, the lab detailed herein is different from others’ work because students within one class can explore and compare three different green aqueous syntheses using team-based, collaborative problem solving. Students become chemical researchers and are asked to constructively decide which solvent system is the “greenest” by evaluating percent yield, per-experiment cost, atom economy (intrinsic versus experimental), and reaction efficiency. Because of this real-world extension to pharmaceutical research, students go beyond the hands-on synthesis, purification, and characterization, and work together during pre- and postlab to discuss the benefits and consequences of each synthetic method. Another feature of our experiment is that both the lab content and pre- and postlab exercises can be tailored to the students’ academic major and depth of experience. For example, chemistry majors and advanced undergraduates could be given greater responsibilities to further evaluate the scientific literature.
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standard organic lab techniques (synthesis, purification, qualitative analysis, structure elucidation). 2. To teach students some fundamental principles of green chemistry, including atom economy, reaction efficiency, solvent choice, and catalysis. 3. To expose students to typical experiences of pharmaceutical researchers and teach problem-solving skills so that students may gain insights into the research process and chemistry as a career. 4. To introduce students to literature searching techniques and promote exploration of current topics in the chemical literature such as green synthesis and ILs.
HAZARDS With exception to water and the IL ([Bmim]PF6), all solvents used are flammable and are potential irritants to the eyes, skin, and respiratory system. The reactions should be carried out in the absence of an open flame and in a fume hood. Appropriate safety precautions for the organic laboratory should be taken; gloves and safety goggles should be worn at all times. Please consult MSDS for additional information about the materials utilized in this lab.
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RESULTS AND DISCUSSION
Experiment Development
The feasibility of the synthesizing the anti-arthritic 1 via a SC reaction was demonstrated (Scheme 2; Table 1) by undergraduate research students. All three solvent systems facilitated the desired transformation within 1 h and gave good yields (Table 1). Both water and ILs are attractive solvents because they are nonvolatile; employing chemicals with low volatility is an important principle of green chemistry. On the basis of intrinsic (Table 1) and experimental atom economy (see the Supporting Information), both the aqueous IL and acetone/ water systems proved to be greener than water alone.7 Of these two approaches, the aqueous acetone solvent system provided the highest overall reaction efficiency in both the development studies and student labs. The acetone in water experiment was also the most cost-effective method (Table 1). Although the IL was the most expensive, it is also important to note that the IL
PEDAGOGICAL GOALS 1. To develop an experiment for the undergraduate organic chemistry lab employing green, aqueous SCs and 1065
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valuable opportunity to further explore the utility and power of NMR beyond their textbook and to further interpret the results from their experiment. With respect to the incomplete reactions, possibly increasing the scale from 0.060 mmol (lab development) to 0.090 mmol (student lab) caused the reaction to not complete in the 1 h allotted reaction time. Success of the reaction is also sensitive to temperature (hot plate inconsistency). Additionally, measurement error is magnified on the microscale.
Table 1. Data and Calculations from the Experimental Development Using Aqueous SC Reactions Solvent System
Yield (%)a
Reaction Temperature/ °C
Intrinsic Atom Economy (%)b
Cost per Experiment/ $c
83 90 75
90−95 40−45 100−105
28.9 51.0 51.0
0.96 0.58 2.13
74
100−105
51.0
0.48d
Water Acetone/Water Bmim[PF6]/ Water Recycled Bmim[PF6]/ Water
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CONCLUSIONS We have developed and implemented a new discovery-based microscale organic chemistry experiment that uses green, aqueous SC methodology to synthesize nonsteroidal antiinflammatory drug 1. Not only does this experiment teach students green chemistry principles through integrative problem solving, it also provides students an insight into the career of a pharmaceutical chemist and introduces them to the chemical literature. Although the lab was developed for an undergraduate organic chemistry class, the lab content and preand postlab activities can be tailored to the level of student experience, interest, and independence. Additionally, this lab employs organic laboratory techniques such as column chromatography, TLC, and NMR and provides the opportunity for students to learn advanced NMR analyses like the determination of percent yield by integration.
a
Percent yield is the average of three experiments. The scale is 0.060 mmol based on ethyl (4-bromophenyl)acetate. Experiments were completed by undergraduate research students. bExperimental atom economy and overall reaction efficiency can also be calculated for each system as noted in the Supporting Information. cCurrent prices in appropriate chemical company catalogs used for calculations. d Calculated for one recycle. However, over multiple recycles the cost would be even lower.
with catalyst can be recycled, thus, reducing costs of subsequent experiments and enhancing the procedure’s “greenness”. The recycling experiments were not attempted with the IL in student labs;9 however, there is literature precedent for reuse without loss of activity for the IL/catalyst mixture (Table 1).5 Students benefit from the recycling discussion especially when results are compared to the data on other solvent systems.10 Clearly, the global question of greenness in this experiment is not linear; a strength to this lab is that a discussion is fostered among student collaborators about prioritizing green principles. Students are challenged to apply their knowledge of green principles as they compare and contrast the three experiments. For example, students must access the negative environmental impact of acetone, a volatile organic, on the overall greenness of the procedure that also demonstrated the best reaction efficiency and lowest cost.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures; a lab handout; spectral data supporting product characterization; and data analysis methods. This material is available via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Application to the Undergraduate Lab
*E-mail:
[email protected].
Data from the successful implementation of the experiment into the second-semester organic undergraduate laboratories is provided in Table 2. Because students ran a reaction, purified it,
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the University of New England for financial support via a College of Arts and Sciences Faculty Mini-grant (2007-08; awarded to Amy Deveau) and also to the Chemistry & Physics Department for supporting conference travel to disseminate this research. Additionally, we acknowledge the efforts of the Spring 2008 organic chemistry students at UNE whose results are summarized in this manuscript.
Table 2. Student Data from Second-Semester Organic Chemistry Labs No. of Students Obtainingb
a
Solvent
Average Yield (%)
Water Bmim[PF6]/Water Acetone/Water
39.1 38.7 48.6
a
Mixed Product
Pure Product
6 17 23
9 5 2
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Percent yield listed was determined after purification. bSee ref 8.
REFERENCES
(1) (a) Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments; Thomson Brooks/Cole Publishers: Pacific Grove, CA, 2004. (b) The Greening of Industry Resource Guide and Bibliography, 1st ed.; Groenewegen, P., Fischer, K., Schot, J., Eds.; In The Greening of Industry Network Series; Island Press: Washington, D.C., 1995. (c) ILs in Synthesis (2 Vol. Set, 2nd ed.); Wasserscheid, P., Welton, T., Eds.; In Green Chemistry Series; Wiley-VCH Verlag: Weinheim, 2007. (d) Greener Approaches to Undergraduate Chemistry Experiments; Kirchhoff, M., Ryan, M. A., Eds.; American Chemical Society: Washington, DC, 2002. (2) (a) Li, C. J. Chem. Rev. 2005, 105 (8), 3095−3166. (b) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org. Chem. 1997, 62 (21), 7170−7173. (c) Liu, L.; Zhang, Y.; Xin, B. J. Org. Chem.
and assimilated their TLC data with their NMR at the end of the experiment, students gained perspective on the aggregate value of these techniques toward problem solving in pharmaceutical research. Whereas some students achieved 100% conversion of ethyl (4-bromophenyl)acetate into 1, some had starting material left. Although incomplete reactions are generally undesirable, students can use the integration of the methylene singlet on proton NMR (found at 3.55 ppm in the starting material and at 3.65 ppm in product 1) to determine the percent starting material that remains (see the Supporting Information). This analysis provides students a 1066
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2006, 71 (10), 3994−3997. (d) Deveau, A. M.; Macdonald, T. L. Tetrahedron Lett. 2004, 45, 803−807. (e) Franzén, R.; Xu, Y. Can. J. Chem. 2005, 83 (3), 266−272. (f) Hidehiro Sakurai, H.; Tsukuda, T.; Hirao., T. J. Org. Chem. 2002, 67, 2721−2722. (3) (a) Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. P. J. Chem. Educ. 2008, 85 (4), 555−557. (b) Novak, M.; Wang, Y.-T.; Ambrogio, Michael, W. Chem. Educator 2007, 12 (6), 414−418. (c) Callam, C. S.; Lowary, T. L. J. Chem. Educ. 2001, 78, 947. (d) Hoogenboom, R.; Meier, M.A. R.; Schubert, U. S. J. Chem. Educ. 2005, 82, 1693. (e) Dicks, A. P. Green Chem. Lett. Rev. 2009, 2, 9−21. (4) (a) Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866−867. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1979, 95, 2457−2483. (5) Zhang, Y.; Liu, L.; Wang, Y. Synlett 2005, 20, 3083−3086. (6) American Cyanamid Co., United States Patent 3784701, 1974. (7) (a) Trost, B. M. Science 1991, 254, 1471−1477. (b) Cann, M. C.; Dickneider, T. A. J. Chem. Educ 2004, 81, 977−980. (8) The experiment was conducted with three different lab sections of approximately 20 students (15, 22, and 25 students). All of the students in a section did one of the three experiments and then were paired in teams with students from different sections and data was shared. There are different models to use for splitting the students into teams and this can be done based on instructor preference. (9) In subsequent semesters we plan to further explore whether it is feasible to recycle the IL/catalyst system in the undergraduate organic labs at our University. (10) Students are also encouraged to see the “big picture” of this experiment with respect to green chemistry principles (see the Supporting Information), including the impact and significance of the workup (using diethyl ether) and the purification conditions (microscale column chromatography). These two issues were not included in the overall “green” analysis described herein because all three experiments utilized the same workup and purification conditions. Temperature is also a factor that could be further analyzed and considered as a part of the “green” analyses.
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