Alkaloid-Derived Thioureas in Asymmetric Organocatalysis: A

Laboratory Experiment pubs.acs.org/jchemeduc

Alkaloid-Derived Thioureas in Asymmetric Organocatalysis: A Cooperative Learning Activity in a Project-Based Laboratory Course David Monge* Departamento de Química Orgánica, Universidad de Sevilla, C/Prof. García González, 1, 41012 Sevilla, Spain S Supporting Information *

ABSTRACT: An experiment carried out by advanced undergraduate students in a projectbased laboratory course is described. Taking into account the positive effects of working in teams, which has been key for successful research in industry and academia, a cooperative learning experience in the laboratory was developed. Students working in teams of four synthesize two alkaloid-derived thioureas starting from a chiral pool (quinidine and quinine). The thioureas are used to catalyze an enantioselective Michael reaction between acetylacetone and trans-4-methyl-β-nitrostyrene, providing a platform for discussion of stereochemistry and chirality transfer events. Qualitative analysis of the reaction enantioselectivity is performed by polarimetry, which allows students to assign product optical rotations (+/−) with their absolute configurations (S/R). Students are exposed to an entire research process: analysis of primary literature, discussion with colleagues, planning laboratory schedules, and execution of experiments. KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Collaborative/Cooperative Learning, Hands-On Learning/Manipulatives, Chirality/Optical Activity, Chromatography, Enantiomers, Hydrogen Bonding, Asymmetric Synthesis

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rotation, pseudoenantiomers and to move from guided experiments to a more professional way to do chemistry.

symmetric organocatalysis is an important emerging area of organic chemistry and a number of extensive reviews and books have been published recently.1 The operational simplicity (e.g., inert atmosphere, low temperatures, absolute solvents, etc., are, in many instances, not required), relatively low cost and green character (absence of transition metals) of organocatalytic methods provide attractive features around which to design new experiences in the undergraduate organic chemistry curriculum. In this context, this new field of research has been incorporated into student laboratory experiments.2 Stereochemistry appears as one of the most challenging topics in teaching organic chemistry, and useful exercises for the classroom or the laboratory have been designed and successfully applied.3 One of the most interesting concepts behind asymmetric synthesis is the chirality transfer event from the catalyst, organocatalyst in the case of a pure organic molecule, to the synthesized product. Herein, a project-based laboratory experiment is described for an advanced organic chemistry course that combines traditional advanced organic reactions for the synthesis of targeted alkaloid-derived thioureas with their application as organocatalysts in an enantioselective benchmark Michael reaction. Qualitative analysis of the enantiomeric excess (ee) in the final product by polarimetry measurements and interpretation of the stereoinduction sense provide an attractive tool for discussing the possible bifunctional activation models (H-bonding organocatalysis/base catalysis) that account for the chirality transfer event. The laboratory experiment provides students with an opportunity to learn about topics such as organocatalysis, enantioselectivity, H-bond donor, acidity, basicity, optical © XXXX American Chemical Society and Division of Chemical Education, Inc.

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EXPERIMENTAL OVERVIEW

There are three phases for the project. In the first phase (Scheme 1), quinidine (QD) or quinine (Q) are converted to epi-quinidine azide or epi-quinine azide, respectively, with diphenylphosphoryl azide (DPPA), triphenylphosphine (PPh3), Scheme 1. Synthesis of epi-Quinidine Amine (1) and epiQuinine Amine (2)

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DOI: 10.1021/ed5008603 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

chromatography. The product identity is confirmed by 1H NMR spectroscopy (see idealized data in the Supporting Information).

and diisopropyl azodicarboxylate (DIAD) in tetrahydrofuran (THF); the azide intermediates are reduced using excess PPh3 in water to epi-quinidine amine (1) or epi-quinine amine (2), respectively.4 In the second phase (Scheme 2), the reaction of

Phase II. Synthesis of Alkaloid-Derived Thioureas 4 and 5

Students work individually. Two of the four students in the group synthesize 4 and two students synthesize 5. Two laboratory periods are required to complete phase II. In the first period, a solution of 3 (1 mmol) in THF is added to a solution of 1 or 2 (1 mmol) in THF at room temperature, and the mixture is stirred for 12 h. TLC is used to determine the completeness of the reaction. In the second period, solvent is removed in vacuo and the residue is purified by column chromatography.

Scheme 2. Synthesis of Alkaloid-Derived Thioureas 4 and 5

Phase III. Study of Enantioselective Michael Addition Reaction

Students work individually using the alkaloid-derived thiourea each student synthesized. Two laboratory periods are required to complete phase III. In the first period, acetylacetone (0.4 mmol) is added to a solution of trans-4-methyl-β-nitrostyrene (0.2 mmol) and catalyst 4/5 (10 mol %) in dichloromethane at room temperature, and the mixture is stirred for 12 h. TLC is used to determine the completeness of the reaction. In the second period, the reaction is purified by flash chromatography. The enantiomeric purity of compound 6 is analyzed by polarimetry.

3,5-bis(trifluoromethyl)phenyl isothiocyanate (3) with 1 and 2 affords the desired thioureas, epi-quinidine-thiourea (4) and epiquinine-thiourea (5), respectively. In the third phase (Scheme 3), 4 and 5 are tested as organocatalysts in the enantioselective

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HAZARDS All experiments should be performed in fume hoods with appropriate protective equipment. Students are required, to wear safety coats, googles and gloves. THF, toluene, methanol, n-hexane (neurotoxic) and ethyl acetate, are flammable solvents. Dichloromethane is harmful in case of eye contact (irritant), ingestion, inhalation and skin contact. Potential areas of concern include the use of DPPA, which is toxic if swallowed or inhaled and in contact with skin. PPh3 and DIAD are irritants (skin) and may cause damage to organs through prolonged or repeated exposure. 3,5-Bis(trifluoromethyl)phenyl isothiocyanate may cause severe skin burns and eye damage. trans-4-Methyl-β-nitrostyrene may cause skin, eye, and respiratory irritation. Acetylacetone is harmful if swallowed and toxic in contact with skin and if inhaled. Products 1, 2, 4, and 5 are toxic if swallowed. Hazards for product 6 are unknown; however, it should be handled carefully. Silica gel constitutes an inhalation hazard owing to their small particle size. Ultraviolet (UV) radiation can cause severe damage to the eyes.

Scheme 3. Enantioselective Michael Addition of Acetylacetone to trans-4-Methyl-β-nitrostyrene

Michael addition of acetylacetone to trans-4-methyl-β-nitrostyrene in dichloromethane to give 3-[2-nitro-1-(p-tolyl)ethyl]pentane-2,4-dione (6).

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EXPERIMENT Students work in teams of four. The project is completed in eight, 3−5 h laboratory periods. Detailed procedures are given in the Supporting Information.

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Phase I. Synthesis of epi-Quinidine Amine (1) and epi-Quinine Amine (2)

RESULTS AND DISCUSSION

Phase I. Synthesis of epi-Quinidine Amine 1 and epi-Quinine Amine 2

Students work in groups of two; each pair of students in the group of four students synthesizes either 1 or 2. Four laboratory periods are required to complete phase I. In the first period, a solution of QD or Q (5 mmol) and PPh3 (6 mmol) in THF is cooled to 0 °C; DIAD (6 mmol) is added, followed by DPPA (6 mmol), and the reaction mixture is warmed to room temperature overnight with stirring. In the second period, the mixture is heated for 2 h, PPh3 (6.5 mmol) is added and heated until gas evolution ceases, the reaction is cooled to room temperature, water is added, and the mixture is stirred for 12 h. Thin-layer chromatograpy (TLC) is used to determine the completeness of the reaction. In the third and fourth periods, the reaction is worked up and purified by flash

The first phase of the experimental procedure, the preparation of alkaloid-derived amines 1 and 2 (Scheme 1), involved a nucleophilic substitution reaction (alcohol to azide, first step) and reduction (azide to amine, second step). The first step used a Mitsunobu reaction that enabled the alcohol functionality to serve as a leaving group. Moreover, Bose-modified Mitsunobu5 conditions conveniently employ DPPA, a safe and easy-tohandle hydrazoic acid (HN3) equivalent. Following an adapted synthesis,4 quinidine or quinine was reacted with DPPA, PPh3 and DIAD in THF to provide azide intermediates with inversion of stereochemistry (as in a common SN2 reaction). Subsequent Staudinger reduction using excess PPh3 in water B




As expected, the chirality induction event was the most difficult task, allowing high achievers with motivation to improve their level of knowledge.

(second step) transformed the azide group into the amine group. The yields obtained by students were acceptable (Table 1). Compounds 1 and 2 were analyzed by 1H NMR

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PLANNING AND WORKING ORGANIZATION The laboratory project was designed following cooperative learning experiences in the laboratory.7 A small class size (eight students/instructor and a technician) over eight, 3−5 h laboratory sessions (22 h in a two-week period, see Supporting Information for the detailed planning) was critically necessary to make this experiment practical and pedagogically valuable. Eight students were divided into two teams (four students as heterogeneous as possible with regard to grades). In the first session, the working spirit behind a cooperative learning experience was explained to students, highlighting the importance of helping each other to reach objectives. The fact that the final individual data reports required the analysis and discussion of all students’ data was the key to raising the level of responsibility of members of the team. The following transparent assessment system was utilized: experiment results, 40% (common team grade); role of students in the team, 10% (individual); report, 20% (individual); final oral presentation (ppt), 30% (individual). The project was started in the library (searching on SciFinder). Experimental work was planned by each team. Roles such as motivator, expert, coach, and facilitator were assumed by an instructor, who promoted discussions about reproducibility, contingency, hazards, etc. (e.g., advising on a convenient scale for each synthetic step, modifying reaction times, etc.). The experimentally recommended working organization is given in the Supporting Information.

Table 1. Literature vs Student Yields

a

Compound

Literature yields (%)a

1 2 4 5

71 77 78 81

Student yields (%) 22−45 52−60 37−79 66−75

(n (n (n (n

= = = =

2) 2) 4) 4)

Typical selected yields.

spectroscopy. The purities obtained by students were acceptable/good for the subsequent step (see representative 1H NMR spectrum of one of the synthesized amines 2 in the Supporting Information). Phase II: Synthesis of Alkaloid-Derived Thioureas 4 and 5

Amines 1 and 2 were reacted (nucleophilic addition) with commercially available 3, affording the desired thioureas 4 and 5 (Scheme 2). Students obtained satisfactory yields (Table 1). The synthesis of organocatalysts 4 and 5 (phases I and II) provided students an opportunity to plan and learn how to handle multistep synthesis. Pedagogically, these phases provided a springboard for a discussion of several outstanding organic reactions (SN2-type Mitsunobu, Staudinger reduction and nucleophilic addition). Assessment of the achievements was satisfactory, revealing that students exhibited an appreciable understanding of the different reactions and their mechanisms. Analysis of 1H NMR spectra of amines 1/2 (without instructor help) was included as an additional exercise. A survey of lab reports indicated that only 2 out of 8 students performed correct assignment of signals.

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CONCLUSION An advanced undergraduate organic chemistry, project-based laboratory experiment was developed employing asymmetric organocatalysis as a relevant topic. Students learned important standard techniques in the organic chemistry laboratory (reactions with high temperature and stirring, liquid−liquid extractions, TLC monitoring, flash chromatography, vacuum pump, rotavapor, NMR spectroscopy and polarimetry). Additionally, the organocatalytic asymmetric Michael experiment (phase III) introduced students to H-bonding organocatalysis and acidity/basicity in bifunctional catalysis, providing an attractive platform for discussion of stereochemistry and chirality. Students, exposed to an entire research process, enjoyed both the independence and peer instruction in the laboratory. Overall, experimental results obtained by students were satisfactory. Most notably, working as a team, low achievers were forced to persevere when they got stuck, while high achievers were faced with tasks of explaining, clarifying concepts and develop leadership skills; this allowed all members of a team to improve their level of knowledge and interpersonal skills. Implementation of similar experiences in the advanced organic chemistry curriculum is strongly recommended.

Phase III: Study of a Model Reaction

In the last phase of the project, the two thioureas 4 and 5 were tested as organocatalysts (10 mol %) in the benchmark enantioselective Michael addition of acetylacetone to trans-4methyl-β-nitrostyrene (Scheme 3) to provide 6 with high optical rotation values under nonoptimized conditions. After consumption of starting material (TLC monitoring), the Michael product 6 was isolated by standard chromatography techniques in high yields (75−90%, n = 8). The organocatalytic reactions (1 reaction/student) were tested in parallel to ensure acceptable reproducibility, and satisfactory optical rotation values were obtained (Table 2). Table 2. Literature vs Student-Obtained [α]D

a

Compound

Literature [α]D (27 °C)

Students [α]D (22 °C)

(R)-6 (S)-6

−194.1a 

−167 to −169 (n = 4) +162 to +166 (n = 4)

Reported value for an enantiopure (R)-6 (97% ee).6

Observing the sign of rotation gave students a sense of accomplishment and provided enough correlation with the chirality induction event. Pedagogically, this phase provided students with an opportunity to learn important concepts in asymmetric catalysis, such as enantiomers/pseudoenantiomers, H-bonding catalysis, and base catalysis. Assessment of the achievements was satisfactory. After several discussions promoted by the instructor, students were able to propose simple bifunctional activation models for the Michael reactions.

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ASSOCIATED CONTENT

S Supporting Information *

Detailed experimental procedures, session planning, handout and instructions for the students, information for instructors including additional experiments with more focus on the C




H. Kolb for Chemists: David A. Kolb and Experiential Learning Theory. J. Chem. Educ. 2001, 78 (8), 1107.

asymmetric reaction in phase III. This material is available via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS I thank university of Sevilla and the Spanish Ministerio de Economiá y Competitividad for a “Juan de la cierva” contract. Students and laboratory technicians who participate in this project are also acknowledged.

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REFERENCES

(1) Reviews on organocatalysis: (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis, from Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005. (b) Rios, R. Stereoselective Organocatalysis; John Wiley & Sons: Hoboken, NJ, 2013. (c) Dalko, P. I.; Moisan, L. In the Golden Edge of Organocatalysis. Angew. Chem., Int. Ed. 2004, 43 (39), 5138−5175. (d) Houk, K. N.; List, B. Asymmetric Organocatalysis. Acc. Chem. Res. 2004, 37 (8), 487. H-bonding organocatalysis: (e) Taylor, M. S.; Jacobsen, E. N. Asymmetric Catalysis by Chiral Hydrogen-Bond Donors. Angew. Chem., Int. Ed. 2006, 45 (10), 1520−1543. Cinchona alkaloids in organocatalysis: (f) Song, C. E. Cinchona Alkaloids in Synthesis & Catalysis: Ligands, Immobilization and Organocatalysis; Wiley-VCH: Weinheim, 2009. (2) (a) Wong, T. C.; Sultana, C. M.; Vosburg, D. A. A Green, Enantioselective Synthesis of Warfarin for the Undergraduate Organic Laboratory. J. Chem. Educ. 2010, 87 (2), 194−195. (b) 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. (c) 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. (d) Morgan, J. P.; Shrimp, J. H. NHeterocyclic Carbene-Catalyzed Alcohol Acetylation: An Organic Experiment Using Organocatalysis. J. Chem. Educ. 2014, 91 (6), 911− 914. (3) (a) Mannschreck, A.; Kiesswetter, R. Differentiations of Enantiomers via Their Diastereomeric Association Complexes There Are Two Ways of Shaking Hands. J. Chem. Educ. 2005, 82 (7), 1034−1039. (b) Mannschreck, A. The Metolachlor Herbicide: An Exercise in Today’s Stereochemistry. J. Chem. Educ. 2009, 86 (9), 1054−1059. (c) Wagner, A. J.; Miller, S. M.; Nguyen, S.; Lee, G. Y.; Rychnovsky, S. D.; Link, R. D. Undergraduate Laboratory Experiment To Determine Absolute Configuration Using Thin-Layer Chromatography. J. Chem. Educ. 2014, 91 (5), 716−721. (4) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly Enantioselective Conjugate Addition of Nitromethane to Chalcones Using Bifunctional Cinchona Organocatalysts. Org. Lett. 2005, 7 (10), 1967−1969. (5) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. A Novel Reagent for the Stereospecific Synthesis of Azides from Alcohols. Tetrahedron Lett. 1977, 23, 1977−1980. (6) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide Derivatives Are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130 (44), 14416−14417. (7) Smith, M. E.; Hinckley, C. C. Cooperative Learning in the Undergraduate Laboratory. J. Chem. Educ. 1991, 68 (5), 413−415. (b) Hass, M. A. Student-Directed Learning in the Organic Chemistry Laboratory. J. Chem. Educ. 2000, 77 (8), 1035−1038. (c) Towns, M. D


Alkaloid-Derived Thioureas in Asymmetric Organocatalysis: A

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