N-Heterocyclic Carbene-Catalyzed Reaction of Chalcone and

Jun 15, 2015 - The aliphatic protons form a somewhat complex pattern due to allylic and homoallylic coupling, but with no overlap, so that students ca...
5 downloads 14 Views 297KB Size
Laboratory Experiment pubs.acs.org/jchemeduc

N‑Heterocyclic Carbene-Catalyzed Reaction of Chalcone and Cinnamaldehyde To Give 1,3,4-Triphenylcyclopentene Using Organocatalysis To Form a Homoenolate Equivalent Barry B. Snider* Department of Chemistry MS 015, Brandeis University, Waltham, Massachusetts 02454-9110, United States S Supporting Information *

ABSTRACT: In this experiment, students carry out a modern organocatalytic reaction using IMes·HCl and NaOH to catalyze the formation of 1,3,4-triphenylcyclopentene from cinnamaldehyde and chalcone in water. Deprotonation of IMes·HCl with NaOH forms the N-heterocyclic carbene IMes that reacts with cinnamaldehyde to form a homoenolate equivalent of cinnamate, which undergoes a conjugate addition to chalcone followed by an intramolecular aldol reaction to form a cyclopentane. Formation of a β-lactone and decarboxylation leads to 1,3,4-triphenylcyclopentene. This reaction introduces students to both organocatalysis and the use of carbonyl anion and homoenolate equivalents in synthesis. This novel and interesting chemistry was first reported in 2006, and the reaction was modified to be carried out in water under an air atmosphere in 2013. The very nonpolar product is easily purified chromatographically. The aliphatic protons form a somewhat complex pattern due to allylic and homoallylic coupling, but with no overlap, so that students can simulate the spectrum perfectly using Web-based software. This experiment can be combined with one of the four preparations of IMes·HCl reported in this Journal, which all use IMes as a ligand rather than an organocatalyst. KEYWORDS: Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Catalysis, Green Chemistry, Chromatography, NMR Spectroscopy, Computer-Based Learning Scheme 1. Formation of N-Heterocyclic Carbene 2 from Thiamine Pyrophosphate (1)

he field of organocatalysis has undergone a remarkable expansion over the past 20 years with the development of new reagents that catalyze reactions that cannot be achieved with typical basic, acidic, or metal-based catalysts. NHeterocyclic carbenes (NHCs) were originally developed as ligands for organometallic chemistry, but have since been shown to be powerful organocatalysts.1 Thiamine pyrophosphate (1, vitamin B1) was shown to function as an NHC precursor by Breslow in the 1950s.2 Deprotonation of 1 gives 2, which can be drawn as the zwitterion 2a or the N-heterocyclic carbene resonance structure 2b (Scheme 1). Organic chemists were slow to use this idea in developing synthetically useful reactions, and the only example for many years was the Stetter reaction, the NHC-catalyzed conversion of an aldehyde to a carbonyl anion equivalent that undergoes conjugate addition to an α,β-unsaturated ketone to give a 1,4diketone (see Supporting Information).3 In 2006, Nair reported that IMes·HCl (1,3-bis(2,4,6trimethylphenyl)imidazolium chloride, 3, 6 mol %) and DBU (an amidine base, 12 mol %) catalyze the reaction of cinnamaldehyde (PhCHCHCHO, 5) with chalcone (PhCHCHCOPh, 8) in anhydrous THF for 8 h to give trans-1,3,4-triphenylcyclopentene (14) in 78% yield (Scheme 2).4a In this reaction, IMes·HCl (3) is deprotonated to give IMes (4), which adds to the aldehyde of cinnamaldehyde (5) to form alkoxide 6. Proton transfer gives 7a, which can also be

T

© 2015 American Chemical Society and Division of Chemical Education, Inc.

drawn as resonance structures 7b and 7c. Because of the steric bulk of the two mesitylene groups, conjugate addition cannot occur from the α-carbon of 7b, but occurs from the γ-carbon of 7c to chalcone (8) to give enolate 9. In this reaction, 7 functions as an equivalent of the homoenolate of cinnamate (PhCH⊖ CH2 COX), which cannot be prepared in the Published: June 15, 2015 1394

DOI: 10.1021/acs.jchemed.5b00105 J. Chem. Educ. 2015, 92, 1394−1397

Journal of Chemical Education

Laboratory Experiment

chromatography (98:2 hexanes/ethyl acetate) to obtain 40− 60% of 14 as a ∼10:1 mixture of trans- and cis-isomers. Students characterize 14 by TLC, 1H, and 13C NMR spectroscopy, and IR spectroscopy. The reaction proceeds in comparable yield in an open 18 × 150 mm disposable test tube equipped with a stirring bar in a 100 °C oil bath for 30−45 min.

Scheme 2. IMes-Catalyzed Formation of 1,3,4Triphenylcyclopentene (14) from Cinnamaldehyde (5) and Chalcone (8)



HAZARDS Eye protection and gloves should be worn throughout, and the synthesis of 1,3,4-triphenylcyclopentene (14) should be carried out within a fume hood. Handling organic solvents in open containers should be performed in a fume hood. Hexanes and ethyl acetate are highly flammable and should not be inhaled or ingested. There is a danger of serious damage to health by prolonged exposure through inhalation of n-hexane, including a possible risk of impaired fertility. n-Hexane is a neurotoxin. Dichloromethane is an irritant, sensitizer, suspected carcinogen and harmful by inhalation and if swallowed. CDCl3 is toxic; avoid inhalation, ingestion, and skin or eye contact. Silica gel is an inhalation hazard. Sodium hydroxide is caustic. IMes·HCl (3), chalcone (8), cinnamaldehyde (5), and 1,3,4-triphenylcyclopentene (14) have not been fully tested for toxicity and should therefore be handled with care avoiding inhalation or skin contact.



RESULTS AND DISCUSSION Four procedures for the preparation of IMes·HCl (3) have been reported in this Journal,6 but the IMes·HCl was used as a ligand for copper, nickel, or silver complexes, rather than as an organocatalyst. Only a few procedures using organocatalysts have been reported in this Journal, including the use of H2IMes· CHCl3 as an esterification catalyst7a and the use of chiral amines as catalysts for asymmetric aldol and Michael reactions.7b−d This experiment was carried out once as part of a multi-week project by 12 pairs of students in an upper-division undergraduate organic chemistry laboratory course. Students prepared IMes·HCl (3) by the procedure of Ison and Ison.6d At the end of the second lab period, they used their freshly prepared IMes·HCl to set up the preparation of 14, which was kept at 40 °C for 24 h, removed from heating before lab the next day, and kept until the following week at which time the students worked up the reaction, purified the product by flash chromatography, and characterized it by 1H NMR spectroscopy in about 3 h. The student yields of 14 ranged from 40 to 60% after chromatography. The procedure can be modified to be carried out in a single 4 h lab period with commercial IMes·HCl (3). Carrying out the reaction in water at 100 °C for 30−45 min gave comparable 40−60% yields of 4 after chromatography. During the first of the two laboratories sessions used for the preparation of IMes·HCl, students prepared a variety of chalcones by a solid state procedure grinding a substituted acetophenone, a substituted benzaldehyde, and sodium hydroxide with a mortar and pestle using a procedure reported in this Journal.8 This reaction works best with higher melting chalcones. Students set up two reactions at 40 °C, one with unsubstituted chalcone and one with the substituted one they synthesized. The next lab period, both reactions were treated with ethyl acetate and the ethyl acetate layer was analyzed by TLC. The reaction succeeded for all 12 pairs of students with

laboratory. Proton transfer gives enolate 10, which undergoes an intramolecular aldol reaction to give cyclopentane alkoxide 11. The alkoxide adds to the carbonyl group to give tetrahedral intermediate 12, which collapses forming β-lactone 13 and regenerating the catalyst IMes (4). As expected, β-lactone 13 decarboxylates to give 1,3,4-triphenylcyclopentene (14). Although both the cis- and trans-isomers are formed, the trans isomer predominates greatly for complex reasons. This reaction was run in dry THF under argon, conditions that are difficult to achieve in a teaching laboratory. In 2013, Chi reported a version of this reaction that proceeds with catalytic IMes·HCl (3, 5%), NaOH (2 equiv), cinnamaldehyde (5), and chalcone (8) in water under an air atmosphere at 40 °C for 24 h to give 14 in 80% yield as an 11:1 mixture of transand cis-isomers.5a The reaction works equally well when carried out for 30−45 min at 100 °C.



EXPERIMENTAL PROCEDURE

1,3,4-Triphenylcyclopentene (14)

Students work in pairs. A 6-dram vial containing a stirring bar is successively charged with cinnamaldehyde (5) (1.5 mmol), chalcone (8) (1 mmol), IMes·HCl (3) (0.1 mmol), NaOH (2 mmol), and water (2 mL). The vial is capped and stirred vigorously for 24 h at 40 °C by placing it in an oil bath on a hot plate stirrer. In the next lab period the reaction is worked up using ethyl acetate for extraction to give 300−350 mg of crude product, which contains mainly 14 that can be detected as a large UV-active spot near the top of a TLC plate eluted in 95:5 to 99:1 hexanes/ethyl acetate. Students purify 14 by flash 1395

DOI: 10.1021/acs.jchemed.5b00105 J. Chem. Educ. 2015, 92, 1394−1397

Journal of Chemical Education

Laboratory Experiment

graphically. The aliphatic protons form a somewhat complex pattern, but with no overlap, so that students can simulate the spectrum perfectly using web-based software. A multi-week project can be designed by combination of this experiment with one of the four preparations of IMes·HCl reported in this Journal, which all use IMes only as a ligand.6 All students groups were able to carry out the reaction successfully, obtaining crude product that showed an intense spot for the cyclopentene by TLC analysis. The yields varied primarily as a result of students’ skills and care with flash chromatography; all groups obtained 40−60% yield of pure product. The lab reports demonstrated that students understood the details of the chemistry shown in Scheme 2. They were able to analyze the NMR spectra producing a computersimulated spectrum very similar to the observed one.

chalcone, and with two of the lower melting chalcones. The reaction failed with several higher melting chalcones, presumably because a homogeneous, gummy organic layer was not formed at 40 °C. Students completed the workup and purification only of the more promising reaction. This reaction very effectively demonstrates the power of chromatographic separation. The crude product is very dark and gummy (Supporting Information, Figure S12), but fortunately, 1,3,4-triphenylcyclopentene (14) is much less polar than the starting materials and byproducts. The success of the reaction can be easily determined by TLC analysis with UV visualization (Supporting Information, Figure S13). Flash chromatography with 98:2 hexanes/ethyl acetate affords pure 14 in early fractions. Chi and co-workers reported this as green chemistry,5a which is certainly the case for the reaction run in water and the workup using ethyl acetate. However, the required chromatographic purification is not green, so that terminology has not been used here.9 In the 1H NMR spectrum (Supporting Information, Figures S1−S5) of the major isomer trans-14, there is extensive coupling between the five nonaromatic protons on the cyclopentene ring because of geminal coupling between H-5a and H-5b; vicinal coupling between H-2 and H-3, H-3 and H-4, and H-4 and both H-5a and H-5b; allylic coupling between H-2 and both H-5a and H-5b; and homoallylic coupling between H3 and both H-5a and H-5b. The complex pattern can be simulated perfectly using Web-based software.10 All five chemical shifts and the three coupling constants between H-4 and H-5a, H-4 and H-5b, and H-5a and H-5b can be easily determined by inspection. Others can be estimated using typical values of 2 Hz for allylic and homoallylic long-range coupling and 6 Hz for vicinal coupling, and then modified by trial and error until the observed and calculated spectra match (Supporting Information, Figures S6 and S7). Geminal couplings for nonequivalent sp3 hydrogens (H-5a and H-5b) are typical (−12 to −18 Hz) and vicinal couplings (H−C−C− H) are 2−10 Hz depending on the torsion angle. In general, there is no coupling for protons separated by 4 or more bonds, but 4 bond allylic coupling H−C−CCH such as that between H-2 and H-5 is typically −1 to −2 Hz, and 5 bond homoallylic coupling H−C−CC−C−H such as that between H-3 and H-5 is also typically 1 to 2 Hz. The IR spectrum (Supporting Information, Figure S11) shows no carbonyl stretch. The 13C NMR spectrum (Supporting Information, Figures S8−S10) shows 14 different alkene or arene carbons, 3 sp3 cyclopentene carbons, and no carbonyl carbons. Pedagogically, this experiment is designed to do the following: (1) introduce students to (a) modern N-heterocyclic carbene organocatalysis, (b) carbonyl anion and homoenolate equivalents (umpolung), and (c) the power of sequential reactions to produce a complex product, 1,3,4-triphenylcylopentene (14), from simple starting materials; (2) illustrate the power of chromatography to purify compounds from a complex mixture; (3) allow students to practice assigning coupling patterns in 1H NMR spectra with the help of computer simulation; and (4) introduce the concept of green chemistry using water as a solvent and ethyl acetate for workup, even though the use of chromatography for purification is not green. This novel and interesting chemistry was first reported in 2006;4a the reaction sequence is more easily carried out under conditions reported in 2013 in water under an air atmosphere.5a The product is very nonpolar and easily purified chromato-



ASSOCIATED CONTENT

S Supporting Information *

Representative student 1H NMR, 13C NMR, and IR spectral data for 1,3,4-triphenylcyclopentene (14) and chemical shifts and coupling constants for simulation; instructor notes including suggestions for other chalcones and cinnamaldehydes that can be used; details of chemicals and equipment used; editable student handout. This material is available via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS The Brandeis University Chemistry Department is thanked for funding this project. The efforts of the undergraduate students who successfully completed this experiment in CHEM 49a at Brandeis University are gratefully acknowledged, as are the helpful suggestions of the teaching assistants in the course.



REFERENCES

(1) (a) Marion, N.; Díez-González, S.; Nolan, S. P. N-Heterocyclic Carbenes as Organocatalysts. Angew. Chem., Int. Ed. 2007, 46 (17), 2988−3000. (b) Bugaut, X.; Glorius, F. Organocatalytic Umpolung: NHeterocyclic Carbenes and Beyond. Chem. Soc. Rev. 2012, 41 (9), 3511−3522. (c) Ryan, S. J.; Candish, L.; Lupton, D. W. Acyl Anion Free N-Heterocyclic Carbene Organocatalysis. Chem. Soc. Rev. 2013, 42 (12), 4906−4917. (2) Breslow, R. On the Mechanism of Thiamine Action. IV. Evidence from Studies on Model Systems. J. Am. Chem. Soc. 1958, 80 (14), 3719−3726. (3) (a) Stetter, H. Catalyzed Addition of Aldehydes to Activated Double BondsA New Synthetic Approach. Angew. Chem., Int. Ed. Engl. 1976, 15 (11), 639−647. (b) Stetter, H.; Kuhlmann, H. The Catalyzed Nucleophilic Addition of Aldehydes to Electrophilic Double Bonds. Org. React. (Hoboken, NJ, U.S.) 1991, 40, 407−96. (c) Stetter, H.; Kuhlmann, H. Addition von Aliphatischen, Heterocyclischen und Aromatischen Aldehyden an α,β-Ungesattigte Ketone, Nitrile und Ester. Chem. Ber. 1976, 109 (8), 2890−2896. (4) (a) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. N-Heterocyclic Carbene-Catalyzed Reaction of Chalcones and Enals via Homoenolate: An Efficient Synthesis of 1,3,4-Trisubstituted Cyclopentenes. J. Am. Chem. Soc. 2006, 128 (27), 8736−8737. (b) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. Enantioselective, Cyclopentene-Forming Annulations via NHC-Catalyzed Benzoin-Oxy-Cope Reactions. J. Am. 1396

DOI: 10.1021/acs.jchemed.5b00105 J. Chem. Educ. 2015, 92, 1394−1397

Journal of Chemical Education

Laboratory Experiment

Chem. Soc. 2007, 129 (12), 3520−3521. (c) Cardinal-David, B.; Raup, D. E. A.; Scheidt, K. A. Cooperative N-Heterocyclic Carbene/Lewis Acid Catalysis for Highly Stereoselective Annulation Reactions with Homoenolates. J. Am. Chem. Soc. 2010, 132 (15), 5345−5347. (d) Nair, V.; Paul, R. R.; Padmaja, D. V. M; Aiswarya, N.; Sinu, C. R.; Jose, A. NHC-Catalyzed Annulation of Enals and Chalcones: Further Explorations on the Novel Synthesis of 1,3,4-Trisubstituted Cyclopentenes. Tetrahedron 2011, 67 (51), 9885−9889. (e) Chiang, P.-C.; Bode, J. W. On the Role of CO2 in NHC-Catalyzed Oxidation of Aldehydes. Org. Lett. 2011, 13 (9), 2422−2425. (5) (a) Leong, W. W. Y.; Chen, X.; Chi, Y. R. NHC-Catalyzed Reactions of Enals with Water as a Solvent. Green Chem. 2013, 15 (6), 1505−1508. (b) Fu, Z.; Xu, J.; Zhu, T.; Leong, W. W. Y.; Chi, Y. R. βCarbon Activation of Saturated Carboxylic Esters through NHeterocyclic Carbene Organocatalysis. Nat. Chem. 2013, 5 (10), 835−839. (6) (a) Canal, J. P.; Ramnial, T.; Langlois, L. D.; Abernethy, C. D.; Clyburne, J. A. C. A Three-Step Laboratory Sequence To Prepare a Carbene Complex of Silver(I) Chloride. J. Chem. Educ. 2008, 85 (3), 416−419. (b) Ritleng, V.; Brenner, E.; Chetcuti, M. J. Preparation of a N-Heterocyclic Carbene Nickel(II) Complex. Synthetic Experiments in Current Organic and Organometallic Chemistry. J. Chem. Educ. 2008, 85 (12), 1646−1648. (c) Cooke, J.; Lightbody, O. C. Optimized Syntheses of Cyclopentadienyl Nickel Chloride Compounds Containing N-Heterocyclic Carbene Ligands for Short Laboratory Periods. J. Chem. Educ. 2011, 88 (1), 88−91. (d) Ison, E. A.; Ison, A. Synthesis of Well-Defined Copper N-Heterocyclic 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 (12), 1575−1577. (7) (a) Morgan, J. P.; Shrimp, J. H. N-Hetereocyclic CarbeneCatalyzed Alcohol Acetylation: An Organic Experiment Using Organocatalysis. J. Chem. Educ. 2014, 91 (6), 911−914. (b) 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. (c) 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. (d) 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. (8) Palleros, D. R. Solvent-Free Synthesis of Chalcones. J. Chem. Educ. 2004, 81 (9), 1345−1347. (9) Dicks, A. P. Don’t Forget the Workup. J. Chem. Educ. 2015, 92 (3), 405−405. (10) Simulation and prediction of NMR spectra - Nuclear magnetic resonance. http://www.nmrdb.org/simulator (accessed Feb 2015). See: Castillo, A. M.; Patiny, L.; Wist, J. Fast and Accurate Algorithm for the Simulation of NMR Spectra of Large Spin Systems. J. Magn. Reson. 2011, 209 (2), 123−130.

1397

DOI: 10.1021/acs.jchemed.5b00105 J. Chem. Educ. 2015, 92, 1394−1397