Asymmetric Aldol Additions: A Guided-Inquiry Laboratory Activity on

Laboratory Experiment pubs.acs.org/jchemeduc

Asymmetric Aldol Additions: A Guided-Inquiry Laboratory Activity on Catalysis Jorge H. Torres King,† Hong Wang,‡ and Ellen J. Yezierski* †

Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States Department of Chemistry, University of North Texas, Denton, Texas 76203, United States

‡

S Supporting Information *

ABSTRACT: Despite the importance of asymmetric catalysis in both the pharmaceutical and commodity chemicals industries, asymmetric catalysis is under-represented in undergraduate chemistry laboratory curricula. A novel guided-inquiry experiment based on the asymmetric aldol addition was developed. Students conduct lab work to compare the effectiveness of different catalysts in catalyzing the asymmetric aldol addition of a ketone and an aldehyde. Working in pairs, students use a variety of analytical techniques including 1-D and 2-D NMR spectroscopy and chiral chromatography and write their final report in the format of an ACS style publication. Although this experiment was designed for an advanced undergraduate synthesis laboratory course, it can be readily adapted for use in an organic or an inorganic laboratory course. KEYWORDS: Upper-Division Undergraduate, Inorganic Chemistry, Laboratory Instruction, Inquiry-Based/Discovery Learning, Problem Solving/Decision Making, Asymmetric Synthesis, Catalysis, Chirality/Optical Activity, Synthesis, Organic Chemistry

C

laboratory experiments lead to students blindly following the laboratory procedure without truly understanding what they are doing and why they follow the steps. Therefore, this experiment was designed to follow a guided-inquiry approach in which students receive a laboratory procedure, but contrary to a verification lab, the student does not know the solution.24−26 In this experiment, students do not know beforehand which catalyst is most effective. Furthermore, students consider not only a few procedural choices, but also identify what criteria make a “good” catalyst. This experiment includes features from problem-based laboratories27−30 (PBL) and provides students with a real-world problem to make the content relevant. Students are given a problem statement to guide their choices regarding what data to collect to aid in solving the problem. Even though the students have a procedure to follow, contrary to traditional PBL experiments, they make several decisions regarding reaction time and data analysis. Furthermore, the laboratory procedure does not indicate how they should solve the problem.31 This experiment was designed for an advanced undergraduate synthesis laboratory course containing both organic and inorganic experiments and has a varied enrollment ranging from second year to fourth year undergraduate chemistry students. To address the breadth in students’ prior knowledge in the class, this experiment includes a set of prelab activities to

atalysis is an important research area in chemistry that has led to important contributions to organic synthesis and the pharmaceutical industry and is therefore commonly found in teaching laboratories.1,2 Furthermore, catalysis is one of the concepts included in the guidelines published by the Committee on Professional Training of the American Chemical Society.3 Most catalysis experiences for teaching, except for activities relating to enzyme chemistry, are found in organic and inorganic laboratory courses.4−9 For the organic course, many catalysis experiments focus almost exclusively on the uses of the catalyst for organic transformations while failing to provide the students with the opportunity to compare the effectiveness of different catalysts.5,7,9−12 On the other hand, the literature on inorganic chemistry teaching laboratories in catalysis is less extensive.6,13,14 Furthermore, laboratory activities involving enantioselective catalysis are under-represented in the literature even though enantioselective synthesis is crucial to both the pharmaceutical and commodities chemicals industries.1,15−22 We describe here a new laboratory activity, based on recent work from the Wang Research Group,23 in which students compare the performances of an organic catalyst to that of a metal catalyst for the asymmetric aldol addition of cyclohexanone to 4-nitrobenzaldehyde to make a recommendation to a fictitious pharmaceutical company about which catalyst is more suitable. Many chemistry faculty members agree that laboratory instruction is an important part of the undergraduate chemistry curriculum. However, chemistry laboratory instruction is dominated by a high number of verification and “cookbook” style experiments with low levels of inquiry.24 These types of © XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: February 20, 2017 Revised: October 30, 2017

A

DOI: 10.1021/acs.jchemed.7b00147 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Both prelab activities are designed to help students connect their knowledge from general and organic chemistry to the various concepts crucial to promoting meaningful learning in the laboratory. When students face new information, they can either memorize the new information (rote learning) or connect the new information to previous knowledge (meaningful learning).32 Even though meaningful learning is desirable, students do not always have the prior knowledge needed to connect the new information. Additionally, students may not know how the new information relates to their prior knowledge. Thus, it is important for students to receive the prelab assignments as well as the problem statement at least 1 week prior to the beginning of experimental work. To address their problem, students use different catalysts for the asymmetric aldol addition of 4-nitrobenzaldehyde and cyclohexanone and use spectroscopic and chromatographic techniques to determine the effectiveness of each catalyst. Figure 1 shows

introduce students to the concepts of catalysis and asymmetric synthesis as well as the characterization techniques required. Contrary to a frequently used practice for prelaboratory assignments, the prelab material is not simply content for students to read but rather is a set of guiding questions to create a “needto-know” situation requiring students to connect their prior knowledge to new concepts relevant to the experiment. After completing the experiment, students write their report in the format of an ACS style publication to become more adept at dissemination methods akin to the chemistry community. This laboratory activity is ready to be implemented and allows students to develop a deeper understanding of enantioselective synthesis and its relevance to the pharmaceutical industry. Furthermore, to fulfill the learning objectives, students use spectroscopic techniques akin to the chemistry community (IR, 1-D and 2-D NMR techniques) and chiral chromatographic techniques to measure the selectivity of the reactions.

■

LEARNING OUTCOMES This experiment aims to help students gain an understanding of catalysis and asymmetric synthesis. Upon completing this experiment, students should be able to (1) Explain the usefulness of catalysts. (2) Interpret the scientific literature and use it to describe and explain their results. (3) Use experimental data to determine the effectiveness of a catalyst. (4) Use spectroscopic techniques to characterize organic compounds. (5) Use dissemination methods commonly used in the field.

■

PROBLEM STATEMENT Suppose you are an undergraduate research assistant in Dr. Jones’ research group at a research institution. Dr. Jones recently began collaborating with Mason Pharmaceuticals in their attempts to find efficient and highly selective routes for asymmetric syntheses. As part of Dr. Jones’ group, you have been tasked to work with the asymmetric aldol reaction. Dr. Jones is not interested in pursuing natural product synthesis but rather focuses on developing new catalysts with novel reactivity so their collaboration with Mason Pharmaceuticals consists of finding new methods that can be used for asymmetric transformations. As part of their aim toward environmental protection, Mason Pharmaceuticals aims to develop methods that encompass the principles of green chemistry and are selective and cost-effective. To help find efficient catalysts for the asymmetric aldol reaction, you will be testing the use of organocatalysis and the use of transition metal complex catalysis for the asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone.

Figure 1. Reactions set up by students during the completion of week 1.23,33 Only the main stereoisomers are shown.

the three reactions that the students set up during this experiment. Student and instructor guides for the prelab assignments and experimental work can be found in the Supporting Information. Prelab Week 1: Catalysis Prelab

A crucial element of this experiment is the guided-inquiry approach, which facilitates connections between students’ prior knowledge and new principles introduced in the experiment. The catalysis prelab does this by providing a series of guiding questions along with an introduction to the concept of catalysis and asymmetric synthesis. Scheme 1 shows an overview of the catalysis prelab activity. A sample question from the catalysis prelab can be found in Figure 2. The utility of catalysts in asymmetric synthesis and its relevance to the pharmaceutical industry are also addressed in the catalysis prelab.

■

EXPERIMENTAL OVERVIEW Students work in groups of two on the laboratory syntheses, but the prelab and the postlab assignments are designed to be completed individually. This experiment requires two laboratory periods with each period taking between three and four h. The two prelab activities are completed before week one and week two, respectively. The Week 1 Prelab introduces students to the concepts of catalysis and asymmetric synthesis, and the Week 2 Prelab introduces students to the characterization techniques they use for the completion of the activity.

Week 1: Procedure

During the first laboratory period, students set up their three asymmetric aldol additions. Students set up two catalyzed reactions using one of two catalysts: (1) copper−amine complex; (2) L-proline. Furthermore, students set up a control reaction with no catalyst present. The students track the progress of their reactions using thin-layer chromatography (TLC). At the B




Scheme 1. Summary of Four Main Parts of Catalysis Prelab

Figure 2. Guiding questions found in the catalysis prelab.27

reactions in air using 4 dram vials so they can be left unattended for a weekly period. See page 16 of the instructor’s guide for further details about reaction setup.

end of the laboratory period, the students decide (based on TLC data) if their reaction is complete and if they will allow the reaction to proceed for an additional week. Students stir the C




Scheme 2. Summary of Four Main Parts of Characterization Prelab

Prelab Week 2: Characterization Prelab

professor and teaching assistant who were not on the author team but were briefed on the experiment several months before. Additionally, they were provided with the student and instructor guides several weeks before the experiment. Prior to the implementation of the activity, the experiment was piloted with four graduate students to ensure the suitability of the experiment for the course. The data from the pilot study are not provided; however, they guided revisions to instructions and questions to improve clarity. It is important to note that course instructors encouraged students to shorten the catalysis prelab, which did not include the introduction to catalysis, when the experiment was implemented. Nevertheless, students’ difficulties during the subsequent parts of the activity indicated that the shortened prelab did not offer enough guidance since the student prior knowledge had been overestimated. Future implementations will include the entire catalysis prelab. Students experienced some challenges in the characterization prelab, which indicated a need for extra support during the product characterization portion of the second week. The prelab activities invite instructors to provide student feedback on the different characterization techniques are used in the completion of this laboratory activity to help students meet requirements in the characterization prelab before they need to analyze their own data collected during the second experimental week. All students successfully carried out the reactions and obtained their desired products, although not all students identified their products correctly indicating the need for more guidance during data analysis. On the basis of TLC data, after 1 week of stirring, only the starting aldehyde and ketone were found when no catalyst was used; the students did not complete spectroscopic analyses for that reaction. For both the 1 L-proline and the copper-amine catalyzed reactions, IR, H, NMR, and COSY were used for product characterization in addition to chiral-HPLC to determine the enantioselectivity and diastereoselectivity of the reaction. Students ran their own IR spectra while they received assistance in collecting 1H NMR spectra for their products. Because of time and instrument availability, students were provided with stock data for their COSY and chiral-HPLC data for the product. Upon their completion of the experiment, students found that both the L-proline and the copper-amine catalyst yielded the aldol addition product; however, the copper-amine catalyzed reaction yielded higher purity and selectivity for the desired product. Figure 3 shows 1H NMR spectra for the products of all three reactions. Furthermore, the students used the chiral-HPLC data provided to find that the copper-amine catalyzed reaction yielded higher enantio- and diastereoselectivity when compared to the proline-catalyzed reaction (Table 1).

Before the second week, students complete the characterization prelab, which uses a series of guiding questions to facilitate their understanding of 2-D NMR techniques and chiral chromatographic techniques. Scheme 2 shows an overview of the characterization prelab. Week 2: Procedure

During the second laboratory period, students use TLC to determine the progress of their reactions. They use a silica plug to purify the reaction mixtures that resulted in conversion. After purification, students use 1H NMR spectroscopy, COSY, and IR spectroscopy to characterize their compounds and use chiral HPLC to determine the stereoselectivity of each catalyst. Using their experimental results as well as green chemistry and cost analysis arguments, students make a recommendation to Mason Pharmaceuticals on the appropriate catalyst. See page 20 of the instructor’s guide for more information about data analysis. Their final report is the equivalent to the results, discussion, and conclusion sections of a Journal of Inorganic Chemistry publication attending to the ACS style guidelines. Equipment

A detailed list of reagents and equipment can be found in the Supporting Information. For the characterization, a wide variety of NMR spectrometers and IR spectrometers can be used for this experiment. For the development of this laboratory activity, all NMR spectra were collected using a Bruker AV 500WB spectrometer, while all IR spectra were collected on a PerkinElmer Spectrum 100 FT-IR Spectrometer. Chiral HPLC chromatograms were collected using a Gold Nouveau Chromatography system using a Chiralpak AD-H column and the data recorded using a Shimadzu C-R6A Chromatopac integrator.

■

HAZARDS Standard laboratory safety practices should be followed including wearing typical personal protective equipment including gloves, safety goggles, and appropriate clothing. All operations should be performed using fume hoods. Cyclohexanone, ethyl acetate, hexane, N,N-diisopropylethylamine, and 1-hydroxybenzotriazole are flammable. Chloroform, dichloromethane, and N,N′-dicyclohexylcarboiimide are toxic if ingested or inhaled. Trifluoroacetic acid is corrosive. 4-Nitrobenzaldehyde and copper trifluorosulfonate are irritants and can cause allergic reactions.

■

RESULTS AND DISCUSSION This experiment was completed by six pairs of undergraduate students during a two-week period in an advanced undergraduate synthesis lab. The experiment was facilitated by a D




Figure 3. Stock 1H NMR spectroscopic data (collected in CDCl3) on all three reactions students complete in the lab. The spectra indicate that the copper-amine catalyst achieved higher purity and selectivity than L-proline, while no conversion was achieved in the absence of a catalyst.

in institutions without access to these instruments is possible. Although our implementation employed stock COSY and c-HPLC data, institutions that have these instruments available for academic laboratories may choose to have students collect these data themselves with their products obtained in the synthesis.

Table 1. Stereoselectivity of Catalysts

■

SUMMARY The guided-inquiry experiment on asymmetric aldol additions was designed and successfully implemented in an undergraduate advanced synthesis laboratory. Students were able to use IR, NMR, and chromatographic techniques to analyze the results of the catalytic reactions. This experiment includes two prelab assignments to introduce students to topics crucial to the completion of this activity. Comprehensive classroom-ready materials including student and instructor guides can be found in the Supporting Information. These guides include information about safety, ligand synthesis, grading rubrics, etc. This experiment is ready to be implemented, and any information about implementation at other institutions is welcome.

a Average values shown (N = 5). bEnantiomeric excess. cDiastereomeric ratio.

■

ADAPTABILITY OF LABORATORY ACTIVITY This experiment was implemented in an advanced synthesis laboratory, which included both inorganic and organic experiments. As such, this experiment can be readily adapted to be used in both organic and inorganic laboratory courses. In the case of organic chemistry, this experiment can be used to support curricula on chirality, bridge the importance of chirality to the pharmaceutical industry, and help students better connect concepts learned in the teaching laboratory to industries that rely on organic chemistry. On the other hand, this experiment could be readily implemented in an inorganic chemistry course if a heavier emphasis is placed upon the mechanistic aspects of the catalytic reactions. Furthermore, the experiment could be modified such that students isolate and characterize the copper-amine precatalyst. Apart from the possibility of placing the experiment in different laboratory courses in curriculum to attend to different levels of student prior knowledge, this experiment can also be adapted to match instrument availability. Both NMR and c-HPLC stock data are provided in the Supporting Information; implementation

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00147.

■

Instructor’s guide (PDF, DOCX) Catalysis prelab and student’s guide (PDF, DOCX) Characterization prelab (PDF, DOCX)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hong Wang: 0000-0001-7947-2083 Ellen J. Yezierski: 0000-0002-7067-7944 E




Notes

(15) Brooks, W. H.; Guida, W. C.; Daniel, K. G. The Significance of Chirality in Drug Design and Development. Curr. Top. Med. Chem. 2011, 11, 760−770. (16) Farina, V.; Reeves, J.; Senanayake, C. H.; Song, J. J. Asymmetric Synthesis of Active Pharmaceutical Ingredients. Chem. Rev. 2006, 106, 2734−2793. (17) Bennett, G. A Green Enantioselective Aldol Condensation for the Undergraduate Organic Laboratory. J. Chem. Educ. 2006, 83 (12), 1871−1872. (18) Betush, M. P.; Murphree, S. S. Use of Chiral Oxazolidinones for a Multi-Step Synthetic Laboratory Module. J. Chem. Educ. 2009, 86 (1), 91−93. (19) Lazarski, K. E.; Rich, A. a.; Mascarenhas, C. M. A One-Pot, Asymmetric Robinson Annulation in the Organic Chemistry Majors Laboratory. J. Chem. Educ. 2008, 85 (11), 1531−1534. (20) Snider, B. B. N-Heterocyclic Carbene-Catalyzed Reaction of Chalcone and Cinnamaldehyde To Give 1,3,4-Triphenylcyclopentene Using Organocatalysis To Form a Homoenolate Equivalent. J. Chem. Educ. 2015, 92 (8), 1394−1397. (21) Stacey, J. M.; Dicks, A. P.; Goodwin, A. A.; Rush, B. M.; Nigam, M. Green Carbonyl Condensation Reactions Demonstrating Solvent and Organocatalyst Recyclability. J. Chem. Educ. 2013, 90 (8), 1067− 1070. (22) Wade, E. O.; Walsh, K. E. A Multistep Organocatalysis Experiment for the Undergraduate Organic Laboratory: An Enantioselective Aldol Reaction Catalyzed by Methyl Prolinamide. J. Chem. Educ. 2011, 88 (8), 1152−1154. (23) Daka, P.; Xu, Z.; Alexa, A.; Wang, H. Primary Amine-Metal Lewis Acid Bifunctional Catalysts Based on a Simple Bidentate Ligand: Direct Asymmetric Aldol Reaction. Chem. Commun. (Cambridge, U. K.) 2011, 47 (1), 224−226. (24) Fay, M. E.; Grove, N. P.; Towns, M. H.; Bretz, S. L. A Rubric to Characterize Inquiry in the Undergraduate Chemistry Laboratory. Chem. Educ. Res. Pract. 2007, 8, 212−219. (25) Schoffstall, A. M.; Gaddis, B. A. Incorporating Guided-Inquiry Learning into the Organic Chemistry Laboratory. J. Chem. Educ. 2007, 84 (5), 848−851. (26) Lee, V. S. What is Inquiry-Guided Kearning. New Directions Teach. Learn. 2012, 129, 5−14. (27) 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 Laboratory Course. J. Chem. Educ. 2012, 89 (1), 52−57. (28) Hicks, R. W.; Bevsek, H. M. Utilizing Problem-Based Learning in Qualitative Analysis Lab Experiments. J. Chem. Educ. 2012, 89 (2), 254−257. (29) Mataka, L. M.; Kowalske, M. G. The Influence of PBL on Students’ Self-Efficacy Beliefs in Chemistry. Chem. Educ. Res. Pract. 2015, 16 (4), 929−938. (30) Ram, P. Problem-Based Learning in Undergraduate Instruction. A Sophomore Chemistry Laboratory. J. Chem. Educ. 1999, 76 (8), 1122−1126. (31) Patall, E. A.; Cooper, H.; Wynn, S. R. The Effectiveness and Relative Importance of Choice in the Classroom. J. Educ. Psychol. 2010, 102 (4), 896−915. (32) Bretz, S. L. Novak’s Theory of Education: Human Constructivism and Meaningful Learning. J. Chem. Educ. 2001, 78, 1107−1116. (33) List, B.; Lerner, R. A.; Barbas, C. F. Proline-Catalyzed Direct Asymmetric Aldol Reactions. J. Am. Chem. Soc. 2000, 122 (13), 2395− 2396.

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the students and instructors of the CHM 419 Advanced Synthesis Laboratory course for their participation as well as the graduate students who piloted the laboratory activity. We also thank Bryan McLean and Theresa Ramelot for their assistance in setup and student data collection. We are grateful of the Yezierski, Bretz, and Wang Research Groups, especially to Jennifer Reeves and Dr. Chamini Karunaratne for their assistance with the experiment design. We also thank Miami University and the National Science Foundation (CHE-1056420) for funding this research. Finally, we also thank the reviewers for their helpful and insightful comments.

■

REFERENCES

(1) De Figueiredo, R. M.; Christmann, M. Organocatalytic Synthesis of Drugs and Bioactive Natural Products. Eur. J. Org. Chem. 2007, 16, 2575−2600. (2) Naota, T.; Takaya, H.; Murahashi, S.-I. Ruthenium-Catalyzed Reactions for Organic Synthesis. Chem. Rev. 1998, 98 (7), 2599−2660. (3) Committee on Professional Training. Undergraduate Professional Education in Chemistry ACS Guidelines and Evaluation Procedures for Bachelor’s Degree Programs; American Chemical Society: Washington, DC, 2015. (4) Edgar, L. J. G.; Koroluk, K. J.; Golmakani, M.; Dicks, A. P. Green Chemistry Decision-Making in an Upper-Level Undergraduate Organic Laboratory. J. Chem. Educ. 2014, 91 (7), 1040−1043. (5) O'Connor, K. J.; Zuspan, K.; Berry, L. An Undergraduate Organic Chemistry Laboratory: The Facile Hydrogenation of Methyl Trans -Cinnamate. J. Chem. Educ. 2011, 88 (3), 325−327. (6) Miecznikowski, J. R.; Caradonna, J. P.; Foley, K. M.; Kwiecien, D. J.; Lisi, G. P.; Martinez, A. M. Introduction to Homogenous Catalysis with Ruthenium-Catalyzed Oxidation of Alcohols: An Experiment for Undergraduate Advanced Inorganic Chemistry Students. J. Chem. Educ. 2011, 88 (5), 657−661. (7) Schepmann, H. G.; Mynderse, M.; Lafayette, W. Ring-Closing Metathesis: An Advanced Guided-Inquiry Experiment for the Organic Laboratory. J. Chem. Educ. 2010, 87 (7), 721−723. (8) De Vos, D.; Peeters, C. M.; Deliever, R. Microscale Synthesis of Chiral Alcohols via Asymmetric Catalytic Transfer Hydrogenation. J. Chem. Educ. 2009, 86 (1), 87−90. (9) Martin, W. B.; Kateley, L. J. The Heck Reaction: A Microscale Synthesis Using a Palladium Catalyst. J. Chem. Educ. 2000, 77 (6), 757−759. (10) Hammond, C. N.; Schatz, P. F.; Mohrig, J. R.; Davidson, T. a. Synthesis and Hydrogenation of Disubstituted Chalcones. A GuidedInquiry Organic Chemistry Project. J. Chem. Educ. 2009, 86 (2), 234− 239. (11) Hie, L.; Chang, J. J.; Garg, N. K. Nickel-Catalyzed Suzuki −Miyaura Cross-Coupling in a Green Alcohol Solvent for an Undergraduate Organic Chemistry Laboratory. J. Chem. Educ. 2015, 92, 571−574. (12) Hanson, J. Synthesis and Use of Jacobsen’s Catalyst: Enantioselective Epoxidation in the Introductory Organic Laboratory. J. Chem. Educ. 2001, 78 (9), 1266. (13) Higgins, S. J. Advanced Chemistry Classroom and Laboratory Ruthenium (II)− Dppm Coordination Chemistry An Advanced Inorganic Miniproject. J. Chem. Educ. 2001, 78 (5), 663−664. (14) Ison, E. A.; Ison, A. Synthesis of Well-Defined Copper NHeterocyclic Carbene Complexes and Their Use as Catalysts for a “Click Reaction”:A Multistep Experiment That Emphasizes the Role of Catalysis in Green Chemistry. J. Chem. Educ. 2012, 89 (4), 1575− 1577. F


Asymmetric Aldol Additions: A Guided-Inquiry Laboratory Activity on

Recommend Documents