In the Laboratory
Diels–Alder Cycloadditions: A MORE Experiment W in the Organic Laboratory Including a Diene Identification Exercise Involving NMR Spectroscopy and Molecular Modeling Roosevelt Shaw,* Ashika Severin, Miguel Balfour, and Columbus Nettles Department of Chemistry, Morgan State University, Baltimore, MD 21251; *
[email protected] A database of safe, practical MORE (microwave-induced organic reaction enhancement) experiments is being compiled for incorporation into the undergraduate organic chemistry laboratory curriculum. For example, there are several excellent experiments that have appeared in this Journal (1–4). When nuclear magnetic resonance (NMR) spectroscopy and molecular modeling are added to the MORE experiment involving Diels–Alder cycloadditions, an interesting and challenging exercise of diene identification can be carried out with good results by the organic chemistry student. This article describes two Diels–Alder reactions that are suitable for a MORE experiment in the organic chemistry laboratory course. A second experiment is also described in which the splitting patterns of the vinyl protons in the NMR spectra of two MORE adducts are used in conjunction with molecular modeling to identify the MORE diene precursors. Background In the past, it has been necessary to heat mixtures of dienes and dienophiles for hours in an oil bath or with a heating mantle to carry out Diels–Alder [π2 + π4] cycloaddition reactions (5–7). By employing the MORE technique, Diels– Alder adducts are prepared in minutes, in good yields, and
C6H5OC
n
H
+ COC6H5
H
DMSO
H H
5
6
H
microwave irradiation full power, 2 min H
H
n H H 4 3 1 2
H
H
COC6H5 COC6H5
+
6
5
H
H 1 when n = 1 3 when n = 2
H
n H COC6H5 1 2 4 3
H
H H
2 when n = 1 4 when n = 2 enantiomers
Scheme I. Reaction to product the racemic mixtures of the MORE adducts.
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Experiment I: Synthesis of MORE Adducts
Preparation of Racemic exo,endo-2,3-Dibenzoylbicyclo[2.2.1]hept-5-ene Trans-1,2-dibenzoylethylene (200 mg, 0.8 mmole)1 and 1.0 mL of DMSO were placed in a 18-mm × 150-mm test tube. Cyclopentadiene (1.0 mL) was added to this mixture. The test tube was covered with a 10-mL beaker, swirled to mix the contents and then placed upright in a 800-mL beaker. The 800-mL beaker was placed in the microwave oven for 2 min at full (100%) power. After 2 min, it was removed from the microwave and its contents were allowed to cool to room temperature. Once cooled, the contents of the test tube were transferred to a 30-mL beaker. The test tube was rinsed with a small quantity of acetone, and the rinsed solution was added to the 30-mL beaker. The combined mixture was allowed to concentrate in the fume hood upon which crystals formed. Recrystallization from methanol gave a 91% yield of 12. mp 79 ⬚C (lit. (6) mp 78–79 ⬚C). FTIR (CHCl3): 1681.5 (C⫽O) cm᎑1.
COC6H5
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in high purity. For instance, conventional heating (refluxing) of trans-1,2-dibenzoylethylene (1,4-diphenyl-2-butene-1,4-dione) and cyclopentadiene in ethyl acetate gives racemic exo,endo-2,3-dibenzoylbicyclo[2.2.1]hept-5-ene, 12, in 2 h (5, 6), while microwave heating of the same reactants in DMSO (dimethylsulfoxide) produces 12 in 2 min (Scheme I). Furthermore, conventional heating of trans-1,2dibenzoylethylene and 1,3-cyclohexadiene in ethanol produces racemic exo,endo-2,3-dibenzoylbicyclo[2.2.2]octa-5-ene (3,6endoethylene-1,2-dibenzoyl-4-cyclohexene), 3/4, in 10 hr (7). Microwave heating of these same two reactants in DMSO for 2 min gives 34 as well (Scheme I). The assignment of structures for 12 and 34 obtained from microwave heating is confirmed by comparison to published melting points for these compounds and for 12 by 1H NMR data (8). Also, proof of structures of 12 and 34 is based on obtained combined high resolution 1D 1H NMR data and 2D 1H–13C HMQC (heteronuclear multiple quantum coherence) data, showing 1H–13C NMR connectivities, and also on molecular modeling calculations.
1H
NMR–13C NMR (600 MHz, CDCl3, δ)2: 8.05–7.99 (2d, J = 7.8, 4H, ortho-Ar-H)-128.6; 7.56 (t, J = 7.8, 2H, para-Ar-H)-133.0; 7.47 (t, J = 7.8, 4H, meta-ArH)-128.4; 6.44 (dd, J = 5.4, 2.4, 1H, H5)-137.1; 5.95 (dd, J = 5.4, 3.0, 1H, H6)-134.5; 4.52 (t, J = 4.2, 1H, H2)-50.9; 3.98 (d, J = 4.2, 1H, H3)-48.7; 3.36 (s, 1H, H1)- 47.9; 3.16 (s, 1H, H4)- 48.7; 1.90 (d, J = 8.4, 1H, anti- H7)- 47.6; 1.50 (d, J = 8.4 1H, syn-H7)-47.6.
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In the Laboratory A
6.444
5.960
6.440 6.435
A
5.955
5.964
6.449
5.951
6.489
H5
H5 COC6H5
COC6H5
6.501
6.139
COC6H5
COC6H5
H5
6.151
6.164
6.477
H6
H6
H6
H5
6.5
6.4
6.3
6.2
6.1
6.0
6.6
5.9
H6
6.5
6.4
6.3
6.2
6.1
Chemical Shift (ppm)
Chemical Shift (ppm) B
B
9
8
7
6
5
4
3
2
1
0
8
7
6
5
4
3
2
1
0
Chemical Shift (ppm)
Chemical Shift (ppm)
Figure 1. 1H NMR spectrum of racemic exo,endo-2,3-dibenzoylbicyclo[2.2.1]hept-5-ene: (A) vinyl region and (B) entire spectrum.
Figure 2. 1H NMR spectrum of racemic exo,endo-2,3-dibenzoylbicyclo[2.2.2]octa-5-ene: (A) vinyl region and (B) entire spectrum.
Preparation of Racemic exo,endo-2,3-Dibenzoylbicyclo[2.2.2]octa-5-ene
88% yield. mp 128–129 ⬚C (lit. (7) mp 128 ⬚C). 1H
NMR–13C NMR (600 MHz, CDCl3, δ)2: 8.00–7.97 (2d, J = 7.2, 4H, ortho-Ar-H)-128.5; 7.56–7.54 (dt, J = 7.2, 2H, para-Ar-H)-133.4; 7.47–7.45 (dt, J = 6.9, 4H, meta-Ar-H)-128.4; 6.49 (t, J = 7.2, 1H, H5)-134.2; 6.15 (t, J = 7.2, 1H, H6)-132.3; 4.18 (m, 1H, H2)-47.7; 4.42 (d, J = 5.4, 1H, H3)-46.5; 3.01 (m, 1H, H1)-34.2; 2.93 (m, 1H, H4)-33.7; 1.94 (m, 1H, anti-H7)-25.1; 1.34 (m, 1H, syn-H7)-25.1; 1.55 (m, 1H, anti-H8)-20.0; 1.07 (m, 1H, syn-H8)-20.0.
0
H5
40
COC6H5
60 80
C Chemical Shift (ppm)
20
COC6H5 H6
100 120 140 160 9
8
7
1
6
5
4
3
2
1
0
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0 20 40 60 H5
COC6H5
80
COC6H5
100
H6
120 140 8
7
6
5
4
3
2
1
0
1
H Chemical Shift (ppm)
H Chemical Shift (ppm)
Figure 3. 1H–13C HMQC spectrum of racemic exo,endo-2,3-dibenzoylbicyclo[2.2.1]hept-5-ene.
626
FTIR (CHCl3 ): 1680 cm᎑1.
13
13
C Chemical Shift (ppm)
Trans-1,2-dibenzoylethylene (200 mg, 0.8 mmole) and 1.0 mL of DMSO were placed in a 18-mm × 150-mm test tube. 1,3-Cyclohexadiene (1.0 mL) was added to this mixture. The test tube was covered with a 10-mL beaker, swirled to mix the contents, and then placed in a 800-mL beaker. The 800-mL beaker was placed in the microwave oven for 2 min at full power. The reaction mixture was allowed to cool and concentrate in the fume hood upon which crystals formed (see the work up for 12 above). Recrystallization of the solid product from 95% ethanol gave a white solid in
Figure 4. 1H–13C HMQC spectrum of racemic exo,endo-2,3-dibenzoylbicyclo[2.2.2]octa-5-ene.
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In the Laboratory
Figure 5. Relative energies of different conformations, with best stable conformer and corresponding energy shown of 1 (calculated by AM1) vs dihedral angles defined by H2-C2-(C=0)2 and H3C3-(C=O)3.
Figure 6. Relative energies of different conformations, with best stable conformer and corresponding energy shown, of 3 ( calculated by AM1) vs dihedral angles defined by H2-C2-(C=0)2 and H3-C3-(C=O)3.
Experiment II: Diene Identification
chemical shift values corresponding to the centers of these two signals, the students determined the vinyl proton–carbon connectivities (1H–13C resonances) as shown in Figures 2 and 4.
The MORE Synthesis Students were given two 18-mm × 150-mm test tubes, labeled diene A and diene B, each containing one cyclodiene. trans-1,2-Dibenzoylethylene (200 mg, 0.8 mmole) and 1.0 ml of DMSO were added to each test tube. Both test tubes were covered with a 10-mL beaker, swirled to mix their contents, and placed upright in the same 800-mL beaker. The 800-mL beaker was placed in the microwave oven for 2 min at full power. After heating, the door to the microwave oven was opened and the reaction mixtures allowed to cool. Each mixture was transferred to separate 30-mL beakers and rinsed with a small quantity of acetone. The rinsed solutions were added to the appropriate 30-mL beakers. The combined mixtures in each beaker were allowed to concentrate in the fume hood upon which crystals formed. Students determined which MORE product could be recrystallized from methanol and which could be recrystallized from 95% ethanol. After recystallization of both products, their melting points were determined. NMR Examination and Calculations After the MORE product melting at 78–79 ⬚C was determined, it was exchanged at the prep room for its 1H NMR and 1H–13C HMQC NMR spectra (see Figures 1 and 3).3 Likewise, after the MORE product melting at 128–129 ⬚C was determined, it was exchanged for its 1 H NMR and 1H– 13 C HMQC NMR spectra (see Figures 2 and 4).3 The 5–7 ppm vinyl region was examined in the 1H NMR spectra of both MORE products (see Figures 1 and 2). Two multiple signals in this region were observed for both MORE products. Chemical shift values and the splitting patterns were noted for each signal, and the coupling constants ( J, in units of Hz) associated with each signal were computed. Using the
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Molecular Modeling Activity The students built a 3D computer-generated model of 1 in PC Spartan Pro4 and calculated the potential energy diagram of a set of conformations for 1 obtained by a 360⬚ dihedral drive around constrain dihedral angles H2-C2 -(C=O)2 and H3-C3-(C=O)3 (Figure 5 ) (9). The three dihedral angles (H4-C4-C5-H5), (H5- C5-C6-H6), and (H6C6-C1-H1) were measured in the best stable conformation of 1. Using these measured dihedral angles, the vinyl–allylic (bridgehead) proton coupling constants in 1 were calculated using the Garbish equation: J 3H-H = 6.6cos2φ + 2.6sin2φ (0⬚ ≤ φ ≤ ⬚90) (10) (Table 1). The intramolecular distances between the vinyl protons and the two carbonyl groups in this conformer were measured (Table 2). The students examined constructed handheld molecular models5 of the best stable conformer of 12 to envision more clearly both the relative sizes of the dihedral angles and the intramolecular distances under study. Students repeated the computer-building and potential energy diagram construction for 3 to obtain the desired molecular parameters for its best stable conformer (Figure 6) (9) and also examined handheld molecular models. Hazards Caution should be used in handling all chemicals. Avoid contact. Use goggles, gloves, and cover clothes with a lab apron or lab coat throughout the synthesis part of this lab. Cyclopentadiene, 1,3-cyclohexadiene, and DMSO are irritants. DMSO readily transports solutes through human skin. Chloroform-d is toxic, irritant, carcinogenic, and mutagenic.
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In the Laboratory Table 1. Dihedral Angles and Coupling Constants for Racemic exo,endo-2,3-Dibenzoylbicyclo[2.2.1]hept-5-ene and Racemic exo,endo-2,3-Dibenzoylbicyclo[2.2.2]octa-5-ene Compound
Proton H5
H4
H5
H6
Actual
H6
H4-C4-C5-H5
20.22
3.0
6.12
0.25
5.4
5.68b
H6-C6-C1-H1
20.01
2.4
6.13
H6-C6-C5-H5
0.25
5.4
5.68b
8.4
Width of multiplet, H6 = H5 H4
H5 H1
COC6H5
H6
H6
11.8
7.8
11.81
H4-C4-C5-H5
0.34
7.2
6.60
H5-C5-C6-H6
0.06
7.2
8.24c
Width of multiplet, H5 =
COC6H5
Calculateda
H5-C5-C6-H6 Width of multiplet, H5 =
COC6H5 COC6H5
H1
J/Hz
|φ|
Dihedral Angle
14.4
14.84
H6-C6-C1-H1
0.12
7.2
6.60
H6-C6-C5-H5
0.06
7.2
8.24c
Width of multiplet, H6 =
14.4
14.84
a
The Garbish equation, J3H-H = 6.6cos2φ + 2.6sin2φ (0⬚ ≤ φ ≤ 90⬚), was used to calculate vinyl–allylic proton coupling constants.
b
Reported for the parent structure, bicyclo[2.2.1]hept-2-ene (norbornene) (6, p 161).
c
Reported for the parent structure, bicyclo[2.2.2]octa-2-ene (6, p 161).
Discussion Three-dimensional computer drawings and handheld molecular models of the best stable conformers of 12 and 34 show that H4, H5, H6, and H1 are located in different chemical environments and thus experience different magnetic field strengths. In 12, dihedral angles (H4-C4-C5-H5) and (H6-C6-C1-H1) are roughly equal; both are much larger than dihedral angle (H5-C5-C6-H6) (Table 1). This means that the coupling constant, J, for the splitting of H5 by H6 is not the same as the J for the splitting of H5 by H4, and the J for the splitting of H6 by H5 is not the same as the J for the splitting of H6 by H1. Hence, two doublets of doublets are predicted for H5 and for H6 in the 5–7 ppm 1H NMR region of 12. This splitting pattern is observed for the MORE product melting 78–79 ⬚C (Figure 1) but not for the MORE product melting at 128–129 ⬚C (Figure 3). Computer drawings of 12 show that H5 is found at a distance closer to O3 than H6 is to O2 and that H5 is within the deshielding zone of the anisotropic carbonyl group at C3 (Table 2) (11). Thus, the signal for H5 should be downfield from that of H6 as observed in Figure 1. The doublet of doublets centered at δ 6.44 is assigned to H5 whose signal is predicted to be split by H6 into a doublet, and then H4 in turn should split each line of this doublet into doublets. The Table 2. Intramolecular Distances in Stable Conformers of Racemic exo,endo-2,3-Dibenzoylbicyclo[2.2.1]hept5-ene (1/2) and Racemic exo,endo-2,3Dibenzoylbicyclo[2.2.2]octa-5-ene (3/4) Atoms
628
Intramolecular Distance/nm 1/2 Products
3/4 Products
H5–O3
35.94
38.90
H6–O3
41.54
44.25
H5–O2
58.62
59.03
H6–O2
54.99
55.40
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same reasoning can also be applied to the splitting pattern for H6 whose signal is centered at 5.96 and falls well outside of the deshielding zones of both carbonyl groups (Table 2) (11). In 34, dihedral angles (H4-C4-C5-H5), (H5-C5-C6H6), and (H6-C6-C1-H1) are all ca. 0⬚ (Table 1), and hence, the J for the splitting of H5 by H6 is about the same as the J for splitting of H5 by H4. Also the J for the splitting of H6 by H5 is about the same as the J for the splitting of H6 by H1. Two triplets are therefore predicted, one triplet for H5 and one for H6 in the 5–7 ppm 1H NMR region of 34. Two triplets are observed in this region for the MORE product melting at 128–129 ⬚C, one triplet centered at δ 6.49 and a second one centered at δ 6.15. Computer drawings of 34 show that H5 is found at a distance closer to O3 than H6 is to O2 and H5 is located within the deshielding zone of the anisotropic carbonyl group at C3 (Table 2) (11). Also, the distance between H5 and O3 in 34 is less than the distance between H5 and O3 in 12 (Table 2 ). This suggests a smaller deshielding effect on H5 in 34 than on H5 in 12, which is observed as shown in Figures 1 and 3. Further evidence for the different chemical and magnetic environments of H5 and H6 in 12 and in 34 comes from 2D 1H–13C HMQC studies in CDCl3 (Figures 2 and 4, respectively), which show different cross peaks centers (vinyl proton–carbon connectivities or 1H–13C resonances) for H5 of δ 6.44–137.1 and for H6 of δ 5.95–134.5 in 12, and for H5 of δ 6.49–134.2 and for H6 of δ 6.15–132.3 in 34. Conclusion Using the splitting patterns of the signals observed in the vinyl region of the 1H NMR spectra of the two MORE products along with those predicted from molecular modeling calculations of 12 and of 34, students correctly conclude that the MORE product melting at 78–79 ⬚C is 12 and thus the test tube containing the diene that produced 12 must have contained cyclopentadiene. On the other hand
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In the Laboratory
and using the same reasoning, students correctly conclude that the MORE product melting at 128–129 ⬚C is 34, and the test tube containing the diene that produced 34 must have contained 1,3-cyclohexadiene. Finally, this three-part laboratory exercise is one that captivates the interest of the organic chemistry student and challenges him or her to think logically and critically throughout the entire exercise. It is an excellent, problem-solving project that brings together microwave synthesis (MORE), structure elucidation (NMR), and structure prediction (molecular modeling). Acknowledgments We thank Hercules Incorporated for funding of this work and support of the students, AS, MB, and CN. We also thank Gregory Haynes of this department for his technical assistance and the anonymous referees for their helpful comments. W
Supplemental Material
A handout for the students, including instructions to obtain the potential energy diagrams, and notes for the instructor, including answers to the postlab questions, are available in this issue of JCE Online. Notes 1. All chemicals, except cyclopentadiene used in this experiment, are available from The Aldrich Chemical Company. See ref 6, p 488 for synthesis of cyclopentadiene. 2. 1D 1H NMR and 2D 1H–13C NMR spectra were recorded on a Varian Unity Plus 600 MHZ NMR spectrometer at the Johns Hopkins University School of Medicine, Baltimore, Maryland by Michael Massiah. 3. Product structure determination by NMR showed that the stereochemistry of the reactant trans-1,2-dibenzoylethylene in both reactions is maintained in the Diels–Alder adducts. Students were given Figures 1 and 3, and also Figures 2 and 4 without the indicated structures or names. 4. The PC Spartan Pro and Spartan’02 computer software
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packages with accompanying tutorial guides of molecular structure building and obtaining best stable conformation from a potential energy–dihedral angle diagram can be acquired from Wavefunction, Inc. (http://www.wavefun.com; accessed Jan 2005). Both software packages can be used on an 800-MHz Pentium III personal computer running Windows 98 or other compatible PCs to achieve the same results. Execution time for producing energy–dihedral angles diagrams is rapid (within minutes). A detailed step-by-step procedure for obtaining diagrams is given in the Supplemental Material.W 5. The Allyn and Bacon organic molecular model set, available from Fisher Scientific, was used to build the handheld molecular models for 12 and 34. These models were constructed well in advance of the lab experiment by the student authors of this article.
Literature Cited 1. Bari, S. S.; Bose, A. K.; Chaudhary, A. G.; Manhas, M. S.; Raju, V. S.; Robb, E. W. J. Chem. Educ. 1992, 69, 938–939. 2. Elder, J. W. J. Chem. Educ. 1994, 71, A142–A144. 3. Elder, J. W.; Holtz, K. M. J. Chem. Educ. 1996, 73, A104– A105. 4. Mirafzal, G. A.; Summer, J. M. J. Chem. Educ. 2000, 77, 356– 357. 5. Pasto, D. J.; Duncan, J. A; Silversmith, E. F. J. Chem. Educ. 1974, 51, 277–279. 6. Pasto, D.; Johnson, C.; Miller, M. Experiments and Techniques in Organic Chemistry; Prentice Hall: Upper Saddle River, NJ, 1992; pp 488–489. 7. Schenck, G. O. Chem. Ber. 1949, 82, 123–125. 8. Pasto, D.; Johnson, C.; Miller. M. Instructor’s Edition, Experiments and Techniques in Organic Chemistry; Prentice Hall: Upper Saddle River, NJ, 1992; p I-33. 9. Hehre, W. J.; Deppmeier, B. J.; Klunzinger, P. E. A PC Spartan Pro Tutorial; Wavefunction, Inc.: Irvine, CA, 1999; pp 104–106. 10. (a) Garbish, E. W. J. Am. Chem. Soc. 1964, 86, 5561–5586. (b) Gosselin, P. J. Org. Chem. 1999, 64, 9557–9565. 11. Shaw, R.; Roane, D.; Nedd, S. J. Chem. Educ. 2002, 79, 67.
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