A Multistep Organocatalysis Experiment for the Undergraduate

LABORATORY EXPERIMENT pubs.acs.org/jchemeduc

A Multistep Organocatalysis Experiment for the Undergraduate Organic Laboratory: An Enantioselective Aldol Reaction Catalyzed by Methyl Prolinamide Edmir O. Wade and Kenneth E. Walsh* Department of Chemistry, University of Southern Indiana, Evansville, Indiana 47712, United States

bS Supporting Information ABSTRACT: In recent years, there has been an explosion of research concerning the area of organocatalysis. A multistep capstone laboratory project that combines traditional reactions frequently found in organic laboratory curriculums with this new field of research is described. In this experiment, the students synthesize a prolinamide-based organocatalyst that is then used to perform an enantioselective aldol reaction between acetone and 4-nitrobenzaldehyde. The enantiomeric excess (ee) of the reaction is determined by chiral HPLC and polarimetry. Students obtained ee values ranging from 46 to 59%. This experiment is designed to be adaptable and can be performed with minimal equipment (glassware, IR, and polarimeter). It also provides flexibility to the instructor, due to the wide range of topics that may be emphasized in the experience. KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, HandsOn Learning/Manipulatives, Aldehydes/Ketones, Asymmetric Synthesis, Catalysis, HPLC, IR Spectroscopy nantioselective organocatalysis has become a field of central importance for the asymmetric synthesis of chiral molecules. A number of extensive reviews and books have been published in recent years that show the wide applicability of this field.1
7 Despite this explosion in organocatalysis, few articles have been published applying this new field of research in the undergraduate organic chemistry curriculum.8
10 Two of these involve the direct use of a commercially available amino acid, (S)-proline for an aldol and Robinson annulation reaction, respectively.8,9 The other example is the synthesis of warfarin using the commercially available enantiomers of 1,2-diphenylethylenediamine.10 We have developed a multistep synthesis organic chemistry capstone project, based on recent developments in this area, in which the students synthesize an organocatalyst that is then utilized in an enantioselective organocatalytic aldol reaction. The emphasis for this experiment is that the students are charged with both the synthesis of a methyl prolinamide catalyst (rather than using an off the shelf reagent) via a two-step process and employing that catalyst in an enantioselective aldol reaction between acetone and 4-nitrobenzaldehyde. The laboratory exercise affords the student with the opportunity to learn about, and the instructor the flexibility to include, topics such as enantioselectivity, organocatalysis, optical rotation, ester and amide synthesis, the aldol reaction, chiral HPLC, and the use of primary literature. A more extensive list of potential topics for emphasis can be found in the instructor notes in the Supporting Information. Because of the broad range of topics involved, the experiment can be tailored to suit the needs of the students enrolled by highlighting themes relevant to premeds, biology majors, or chemistry majors. The synthesis of the catalyst and

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subsequent aldol reaction is straightforward, requiring no special glassware or purification techniques such as column chromatography or recrystallization. It is easily monitored using IR spectroscopy by following the change in the carbonyl stretching frequency. Although we confirm the enantiomeric excess (ee) by chiral HPLC analysis, polarimetry measurements can also be used to obtain optical rotations and ee through subsequent student calculations.

’ EXPERIMENTAL OVERVIEW The laboratory exercise was performed over four, 3-h laboratory periods. It can be shortened to three laboratory periods if the commercially available proline methyl ester hydrochloride 2 is used. All reagents were used as received from Sigma-Aldrich. The proline methyl ester 2 was synthesized by heating a solution of Lproline 1 and thionyl chloride in methanol at reflux for 1 h. In the subsequent laboratory period, the methyl prolinamide 3 was synthesized by heating proline methyl ester hydrochloride 2 in a solution of 33% MeNH2 in ethanol for 1.25 h (Scheme 1). The enantioselective organocatalytic aldol reaction was performed and the resultant product was isolated and analyzed in laboratory periods three and four. A catalytic amount of methyl prolinamide catalyst 3 was dissolved in acetone and was added to a solution of 4-nitrobenzaldehyde in acetone (Scheme 2). The resulting solution was placed in a freezer at
35 °C for one week after which the aldol product 4 was isolated and samples were prepared and analyzed. All products were isolated after a brief Published: May 25, 2011 1152

dx.doi.org/10.1021/ed1006713 | J. Chem. Educ. 2011, 88, 1152–1154

Journal of Chemical Education

LABORATORY EXPERIMENT

Scheme 1. Synthesis of Methyl Prolinamide Catalyst

Scheme 2. Enantioselective Organocatalytic Aldol Reaction

Figure 1. Chiral HPLC Analysis of a racemic sample (left) and enantioselective sample (right).

workup and characterized (IR and NMR for all products and HPLC and polarimetry for the aldol product).

’ HAZARDS All experiments should be performed in fume hoods with appropriate personal protective equipment. Students are required to wear safety goggles and use gloves. In addition students have to complete their own experiment risk assessment as part of the prelaboratory exercise. Potential areas of concern include the use of thionyl chloride, which reacts violently with water, is harmful by inhalation, and in contact with skin; contact with water liberates a toxic gas and causes severe burns. Methylamine in ethanol is flammable, harmful by inhalation, and causes severe burns. 4-Nitrobenzaldehyde is harmful if swallowed and irritating. A detailed list of hazards can be found in the Supporting Information. ’ DISCUSSION AND CONCLUSIONS The experiment provides a unique capstone experience for organic chemistry students by providing the opportunity to synthesize an organocatalyst and test its effectiveness in the same experiment. The laboratory exercise links various concepts from across the organic chemistry sequence. From our secondsemester organic chemistry sequence, it grants the students the opportunity to explore and understand the reactions of carboxylic acids and their derivatives, reactions of carbonyl compounds, amines, enamines, and R-carbon reactivity. The importance of analytical techniques such as NMR, IR, HPLC, and polarimetry are emphasized as the students monitor their progress through the synthetic sequence. Fundamental concepts such as enantioselectivity, stereochemistry, and optical rotation are revisited, reinforcing their importance to modern organic synthesis. The synthesis of the organocatalyst11
13 involves functional group transformations related to the interconversion of carboxylic acid derivatives and begins with proline 1 (Scheme 1). This sequence generates more than enough catalyst for analysis and the subsequent reaction. It introduces the students to multistep synthesis and its challenges. These reactions can be readily monitored using IR spectroscopy; a shift in the carbonyl

stretching frequency is observed from ∼1610 cm
1 for the starting proline, to ∼1742 cm
1 for the methyl ester and then to ∼1655 cm
1 for the amide catalyst (see Supporting Information for spectra). To the best of our knowledge, the methyl prolinamide 3 has not been used as an organocatalyst for enantioselective aldol reactions but related family members have been studied extensively.12,13 The methyl prolinamide 3 was chosen for ease of synthesis for students in the organic teaching laboratory11
13 and based on the previous research was expected to produce similar enantioselectivity.12,13 Methyl prolinamide 3 affords students’ yield of aldol product 4 between 43 and 100% with an average of 76% (Scheme 2). The enantiomeric excesses (ee) ranged from 46 to 59% with an average of 52%. The ee values obtained for the reaction using the new organocatalyst 3 are consistent with those reported in the literature for the other members of the alkyl prolinamide family.12,13 Analysis of enantioselectivity was achieved by chromatographic comparison of the enantioselective sample with a racemic sample prepared using sodium hydroxide.14 The separation of enantiomers was achieved using chiral HPLC analysis (Figure 1). Detailed information for the separation conditions and the calculation of ee are given in the Supporting Information. As a comparison for instructors and departments not equipped with chiral HPLC, polarimetry measurements were also recorded. The ee value was calculated based on the literature value of
58.8° for 4-hydroxy-4-(40 -nitrophenyl)-butan-2-one 4 as reported by Wu et al.15 The results from this method of analysis were, as expected, somewhat more variable, ranging from 12 to 68% ee with an average of 36% ee. Although using polarimetry to calculate ee is not ideal, it does not detract from the experience for the students. In fact, performing the polarimetry measurements and observing the rotation appear on the polarimeter gave the students a sense of accomplishment and provided motivation for a deeper understanding of the experiment. To avoid confusion for the students, we recommend that the ee calculations are done using chiral HPLC or polarimetry but not both. The reaction mechanism, as outlined in the literature, is believed to involve an enamine intermediate and a Zimmerman
Traxler type transition state, which determines the enantioselectivity. Students are directed toward the primary literature to aid their mechanistic discussion for the formal laboratory report.12,13,16 The laboratory described links a number of organic chemistry concepts and techniques providing a unique capstone experience for the students. Although this exercise is three or four laboratory 1153

dx.doi.org/10.1021/ed1006713 |J. Chem. Educ. 2011, 88, 1152–1154

Journal of Chemical Education periods long, it can replace experiments that are commonly found in the traditional organic teaching laboratory. Most laboratory experiences contain a carboxylic acid derivative and an aldol reaction experiment. The described sequence combines these two frequently occurring reactions, through the synthesis of the catalyst, which includes an ester and amide formation, and an enantioselective aldol reaction. This multistep sequence serves to reinforce these key reactions through state-of-the-art methodology from the research literature. Concepts of green chemistry can be introduced as the experiment avoids the environmentally unfriendly and difficult to handle metal-based reagents that dominated this area until recently. In addition, discussion of the mechanism of the enantioselective organocatalytic reaction, which mimics some enzyme catalyzed reactions, provides a bridge from organic chemistry to biochemistry and the opportunity to engage all students. Although the mechanism of asymmetric induction is challenging, the students showed, in their formal laboratory reports, an appreciable understanding of the mechanism and the concepts involved in an enantioselective reaction. Since the experiment provides a simulation of research level work, the students became more energetic and involved in the process. If desired, the experiment can be adapted into a group project by providing the students with a range of different amines to synthesize a number of different catalysts that can be compared in a catalyst screen or structure
activity relationship or by examining the effect of temperature on the ee obtained.

LABORATORY EXPERIMENT

(9) Lazarski, K. E.; Rich, A. A.; Mascarenhas, C. M. J. Chem. Educ. 2008, 85, 1531–1534. (10) Wong, T. C.; Sultana, C. M.; Vosburg, D. A. J. Chem. Educ. 2010, 87, 194–195. (11) (a) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431–8435. (b) Ahrendt, K. A.; Borths, C. J.; Macmillam, D. W. C. J. Am. Chem. Soc. 2000, 127, 9285–9289. (12) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285–9289. (13) Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5755–5760. (14) Wu, Y.-S.; Shao, W.-Y.; Zheng, C.-Q.; Huang, Z,-L.; Cai, J.; Deng, Q,-Y. Helv. Chim. Acta 2004, 87, 1377–1383. (15) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417–4429. (16) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H. Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558–569.

’ ASSOCIATED CONTENT

bS

Supporting Information Instructions for the students, safety information, sample spectra (IR, 1H, and 13C) and notes for instructors. This material is available via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT The authors thank the 73 University of Southern Indiana undergraduates who have performed this multistep synthesis and the University of Southern Indiana for a Faculty Research & Creative Work Award (FRCWA). We also thank the USI Chemistry department for its support of the work and Mark Krahling for his guidance with the HPLC analysis. KEW thanks the Lilly Foundation for support and EOW thanks the University of Southern Indiana for a Summer Research Fellowship. ’ REFERENCES (1) Dalko, P. I. Enantioselective Organocatlysis:Reactions and Experimental Procedures; Wiley-VCH: Weinheim, 2007. (2) Barbas, C. F., III. Angew. Chem., Int. Ed. 2008, 47, 42–47. (3) Clarke, M. L. Lett. Org. Chem. 2004, 1, 292–296. (4) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660. (5) Jaroch, S.; Weinmann, H.; Zeitler, K. ChemMedChem 2007, 2, 1261–1264. (6) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87. (7) MacMillan, D. W. C. Nature 2008, 455, 304–308. (8) Bennett, G. D. J. Chem. Educ. 2006, 83, 1871–1872. 1154

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