In the Laboratory
A Laboratory Assignment in 1H NMR Spectroscopy: A Comparative Analysis of Calculated and Experimental 1H NMR Chemical Shifts
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Susan D. Van Arnum Protein Data Bank, Rutgers, The State University of New Jersey, Piscataway, NJ 08854;
[email protected] Spectral interpretation has been a significant focus in the undergraduate organic chemistry curriculum and many different experimental and methods have been used to foster this learning (1–5). Since this facet of an undergraduate organic chemistry course has both a problem-solving, experimental component and a theoretical basis, NMR spectroscopy offers the opportunity to reinforce concepts regarding structural features of organic molecules. One method of reinforcement would be by the use of discovery-based learning methods. As laboratory experiments in NMR spectroscopy frequently focus on actual experimentation, we describe an alternative in which experimentally determined, literature proton NMR chemical shifts of a complex molecule are compared to calculated values (4, 5). Several recent articles have appeared regarding the origin of through-space shielding and deshielding effects (6, 7), and, in particular, this work has emphasized, for example, that the traditional explanation for the downfield chemical shifts of arene hydrogens needs to be reconsidered (7). CambridgeSoft and ACDLabs offer computer programs that can calculate 1H and 13C NMR chemical shifts and splitting patterns of organic compounds. Consequently, the simulated NMR spectra for most organic compounds provide a reasonable representation of the actual NMR spectrum. The calculation of proton NMR chemical shifts using ChemNMR Pro (CambridgeSoft) is particularly informative as it provides the details by which chemical shifts are calculated. For example, for the compound 3-chloro-2-methylhexane, ChemNMR Pro predicts a chemical shift of 2.14 ppm for the methine proton that is beta to the chlorine substituent. This calculation is derived from a base chemical shift of 1.50 ppm for a methine proton and for shielding and deshielding effects owing to the presence of two alpha-carbon substituents, one beta-carbon substituent, and one beta-chlorine substituent. The magnitudes of these effects in ppm are presented and a student can understand the rationale for the predicted chemical shift. For 3-chloro-4-methylhexane, the calculated NMR chemical shift for the methine proton that is beta to the chlorine substituent is 1.96 ppm, owing again to the deshielding effect of the chlorine substituent and the presence of only one deshielding alpha carbon. The presence of two shielding beta-carbon substituents in 3-chloro-4-methylhexane as opposed to only one beta-carbon substituent in 3chloro-2-methylhexane plays a minor role. These details regarding the basis of the calculations also emphasize the significant deshielding effect of a beta-chlorine substituent of 0.31 ppm and the relatively minor shielding effect of a betamethyl substituent of ᎑0.01 ppm. Because the actual experimental shifts can differ from the calculated chemical shifts substrates, these differences can serve to reinforce the importance of other effects in proton www.JCE.DivCHED.org
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NMR spectroscopy such as through-space shielding effects, which are not considered in these calculations. Because the program offers the flexibility to determine the proton NMR chemical shifts of most organic compounds, a student can also use this feature to determine the chemical shifts of diagnostic structures. The chemical shifts of these model compounds can form the basis for the explanation of the differences in the actual and the predicted values. Hazards This dry laboratory experiment does not utilize any chemicals and as such, there are no known hazards. Previous Experiments An experiment that illustrates the predominance of endoproduct formation in a Diels–Alder reaction has been described (8). The synthesis of norbornenyl ketone 1 was straightforward and involved a Diels–Alder reaction between 1-(3,5-dimethyl-4-isoxazolyl)-2-propen-1-one (4) and cyclopentadiene (Scheme I).1 By 1H NMR analysis, the product mixture contained approximately 85% of the endo-isomer 1 and 15% of the exo-isomer 2 (8). Separation of the mixture of the endo-isomer 1 and the exo-isomer 2 was achieved by flash chromatography (8, 10).2 This operation produced fractions that were enriched in the exo-isomer 2. By additional purification of these fractions by flash chromatography, the pure exo-isomer 2 was isolated.
O 20–25 oC
+
N O 4
O
+
O
N O
O 1
N
2
Scheme I. Preparation of endo- and exo-norbornenyl ketones 1 and 2.
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In the Laboratory
hν
O
O
O
O N
N 1
3
Scheme II. Paterno–Büchi reaction of endo-norbornenyl ketone 1.
The endo-norbornenyl ketone 1 was irradiated at either 300 or 350 nm and the course of this photolysis monitored by 1H NMR. The only photoproduct of this reaction was oxetane 3 (Scheme II). This efficient photochemical reaction is characteristic of endo-norbornenyl ketones. The photochemical [2+2] cycloaddition reaction cannot occur in the exo-norbornenyl ketone 2 because the correct spatial orientation for this cycloaddition is not present (8). Calculated versus Experimental NMR Values For this dry experiment, the observed chemical shifts for the vinylic protons and isoxazole methyl groups in ketones 1 and 2 are compared to the calculated values. These values are summarized in Table 1. The endo- and exo-isomers 1 and 2 are prepared by a common synthetic transformation. They have identical molecular composition, the same connectivity, and differ only in the stereochemistry at the methine proton that is alpha to the carbonyl group. However, this subtle difference causes pronounced differences in the spectral properties of these molecules as well as the chemical characteristics of these molecules. The striking differences in the observed chemical shifts and the calculated chemical shifts for the endo- and exo-norbornenyl ketones 1 and 2 are due to the fact that the calculated chemical shifts do not consider the shielding effect of the carbonyl group in endonorbornenyl ketone 1 for the vinylic protons. This shielding effect causes the vinylic protons in endo-ketone 1 to appear as two discrete well-separated doublets of doublets. Because of the stereochemical relationship of the carbonyl group to
the norbornenyl group in exo-isomer 2, this shielding effect is not possible and the vinylic protons appear as a single multiplet. As a consequence of this, the calculated values for exoisomer 2 agree with the experimental values. These observed differences were significant as they formed the basis that the purity of the endo-isomer 1, with respect to any contaminating exo-isomer 2, could be determined. This quality assessment was important for the accurate determination of the quantum yield for the photocycloaddition reaction of ketone 1 to oxetane 3 (8, 13). For ketones 1, and 2, the isoxazole methyl groups were not differentiated in ChemNMR Pro. In this program, the specific contribution of the nature of the different alpha substituents were not considered and so the fact that the methyl group at C3 is beta to the nitrogen atom in the isoxazole ring and the methyl group at C5 is beta to the oxygen atom in the isoxazole ring was not considered in these calculations. The actual chemical shifts for these methyl groups are different and these differences are observed in the chemical shifts of the structurally related 4-acetyl-3,5-dimethylisoxazole and trideuterioacetyl-3,5-dimethylisoxazole (14). Because of these differences, a more advanced student could propose an experiment in which one of the isoxazole methyl groups on positions 3 and 5 in ketone 1 could be differentiated. As it is well-known that metallation of isoxazoles occurs preferentially on the 5-position in 3,5-dialkyl isoxazoles (15), a student proposal that would involve the spectroscopic analysis of a deuterium labeled 5-methyl isoxazole ketone would be a credible way in which to differentiate these methyl groups. The instructor could supplement this proposal by a discussion of a possible synthetic route to the deuterium labeled analogue of vinylic ketone 4. The basis of this discussion could be the different routes, which have been used to prepare heterocyclic norbornenyl ketones (8). When it was attempted to calculate the chemical shifts for oxetane 3, ChemNMR Pro did not recognize the oxetane ring when it was either fused to norbornane or as part of a bicyclic system as in oxetane 3. For these kinds of molecules, model compounds could be used as alternatives. The methine proton in 2-methyloxetane has a calculated chemical shift of 4.90 ppm, which parallels the observed chemical shift of 4.78 ppm for oxetane 3 (8). The literature values for the 1H NMR spectrum of 2-methyloxetane are 1.43 ppm, three protons; 2.00–2.90 ppm, two protons; 4.30–4.75, two protons; 4.80–
Table 1. Experimental and Calculated Proton Chemical Shifts for Norbornenyl Ketones 1 and 2 Observed Chemical Shift (ppm)
Calculated Chemical Shift (ppm)
H5 and H6 Vinylic Protons
5.60–6.26
5.60
Cyclopentene
C3 and C5 Isoxazole Methyl Protons
2.46, 2.66
2.35
Methyl group α to a heterocyclic ring
5.60
5.60
Cyclopentene
2.46, 2.67
2.35
Methyl group α to a heterocyclic ring
Proton Assignment
Endo-ketone 1
H5 and H6 Vinylic Protons Exo-ketone 2 C3 and C5 Isoxazole Methyl Protons
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Basis for Chemical Shift Calculations
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Difference (ppm) 0–0.66 0.11– 0.31 0 0.11-–0.32
In the Laboratory
5.20 ppm, one proton (16). Although it was anticipated that reasonable chemical shifts could be obtained by using this program, the observation that credible chemical shifts could not be obtained may offer the instructor the opportunity that such tools in their current state are to be used as guides in spectral interpretation and should not supplant actual experimentation. Students who recognize that the calculated chemical shifts do not agree with the values that were obtained experimentally or that would be predicted by theory may suggest other model substrates. The flexibility of these structuredrawing programs such as ChemDraw and ChemSketch in concert with their associated NMR simulation software can evaluate such alternatives and would support such independent study. Conclusion A comparison of experimentally determined values to theoretical or standard values is a typical way in which percent error values are obtained by a student. Percent yield is another example in which a student’s experimental results are different from a theoretical value. This comparison of proton chemical shifts may be different in this context as the experimental values are the standard values and the calculated values, while useful, only provide approximate values. The ChemNMR Pro program can be used in conjunction with other discourse to facilitate the understanding of concepts in NMR spectroscopy. In this context, the experimental and calculated proton chemical shifts of the endoand exo-isomers of norbornenyl ketones 1 and 2 can be used as tools to supplement a discussion of the importance of through-space shielding effects in proton NMR spectroscopy. A caveat to this methodology is presented for the specific example of the photoproduct of the endo-isomer 1, oxetane 3. For oxetane 3, the calculated proton chemical shift for the methine proton of the oxetane ring did not agree with the experimental value or for the value for a methine proton, that is adjacent to an electronegative oxygen atom. This discrepancy can be resolved by the use of model diagnostic structures and this situation offers the instructor the opportunity to suggest such alternatives as a general way to reduce complexity in experimental observations. Acknowledgments We thank Ronald R. Sauers for the initial review of this manuscript. We thank Joanna de la Cruz for helpful information about file formats. We thank the J. L. R. Morgan Fellowship Fund of Rutgers University and the Garden State Graduate Fellowship Commission for financial support. We thank Laurence S. Romsted for the use of his UV spectrophotometer. We are grateful to R. P. Gomez for the initial characterization of endo-norborneyl ketone 1.
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Supplemental Material
Background information, detailed student procedures, ChemNMR Pro spectra, questions, and instructor’s notes are available in this issue of JCE Online. Notes 1. In this experiment, the students characterized the product by spectroscopic methods. Both characterization and separation of the endo and exo products was not readily achieved; although substantive differences were observed in the spectra derived from the Diels–Alder adducts of maleic acid as opposed to fumaric acid (9). 2. As the Diels–Alder reaction invariably produces a mixture of isomers, a study of this reaction can introduce the student on a conceptual basis to some of the typical organic chemistry laboratory techniques that are used by the research chemist. A rapid and efficient way to preparatively separate compounds of very similar polarity is by radial chromatography. Separations by a Chromatotron require only a minimal quantity of solvent and this technique may also be appropriate for use in the microscale organic chemistry laboratory (11, 12).
Literature Cited 1. Benefiel, C.; Newton, R.; Crouch, G. K.; Grant, K. J. Chem. Educ. 2003, 80, 1494–1496. 2. Grant, A.; Latimer, D. J. Chem. Educ. 2003, 80, 670–672. 3. Danylec, B.; Iskander, M. N. J. Chem. Educ. 2002, 79, 1000– 1002. 4. Habata, Y.; Akabori, S. J. Chem. Educ. 2001, 78, 121–124. 5. Bosch, E. J. Chem. Educ. 2000, 77, 890–892. 6. Martin, N. H.; Brown, J. D.; Nance, H. K.; Schaefer, H. F., III; Schleyer, P. v. R.; Wang, Z.–H.; Woodcock, H. L. Org. Lett. 2001, 3, 3823–3826. 7. Wannere, C. S.; Schleyer, P. v. R. Org. Lett. 2003, 5, 605– 608. 8. Sauers, R. R.; Hagedorn, A. A., III; Van Arnum, S. D.; Gomez, R. P.; Moquin, R. V. J. Org. Chem. 1987, 52, 5501–5505. 9. Jarret, R. M.; New, J.; Hurley, R.; Gillooly, L. J. Chem. Educ. 2001, 78, 1262–1263. 10. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925. 11. Das, K. K.; Basu, M.; Basu, S. Anal. Biochem. 1984, 143, 125– 134. 12. Hostellmann, K.; Hostettmann–Kaldas, M.; Sticher, O. J. Chrom. 1980, 202, 154–156. 13. Sauers, R. R.; Van Arnum, S. D.; Scimone, A. A. Green Chem. 2004, 6, 578–582. 14. Sauers, R. R.; Hadel, L. M.; Scimone, A. A.; Stevenson, T. A. J. Org. Chem., 1990, 55, 4011–4019. 15. Iddon, B. Heterocycles 1994, 37, 1263–1320. 16. Fuijiwara, M.; Hitomi, K.; Baba, A.; Matsuda, H. Synthesis 1990, 106–108.
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