In the Laboratory
Use of the Chemical Literature as a Template To Probe Stereoselective Reactions by NMR Thomas P. Clausen,* Thomas K. Green, and Benjamin Steiner Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK 99775-6160; *
[email protected] The undergraduate chemistry curriculum at this university is typical of many institutions. The course sequence primarily involves two semesters of organic lecture along with an independent organic laboratory course. Students enrolled in the organic laboratory course have as a co-requisite, or prerequisite, the second semester of the lecture sequence. The laboratory course involves a one-hour lecture along with two four-hour laboratory sessions each week. Frequently, however, about one hour of laboratory time is converted to a classroom format to ensure students understand the theory and procedures associated with our more complex experiments. The above structure of the organic laboratory course has allowed us to offer students a chance to use literature procedures from this Journal as templates to further pursue topics they found challenging in the lecture portion of the sequence. These template experiments are not treated as “cookbook” experiments but rather as a starting point for new questions and hypotheses to be developed and experiments to be designed. In this manner, students gain a research experience, are exposed to the scientific literature, and gain better insights to challenging concepts. A primary theme in our organic laboratory course is stereochemistry, with a particular emphasis on approaches to determining stereochemical relationships in reaction products. We emphasize to our students that a variety of approaches may often be necessary to solve a particular stereochemical problem, including NMR spectroscopy, molecular modeling, and chiral chromatography, often in combination with reaction chemistry. With this in mind, we have led our students to develop their own set of strategies for solving questions of stereochemistry. In this article, we describe two research-type projects our students recently undertook in which published experiments from this Journal were modified to gain further understanding
of stereochemical concepts and the processes by which organic chemists solve questions of stereochemistry. While these experiments may be adapted by many organic teaching laboratories, we introduce them primarily to illustrate how feasible it is to adapt literature-based studies into a research-oriented teaching environment. Most students in introductory organic chemistry become familiar, to varying degrees, with one-dimensional (1D) 1H and 13C NMR spectroscopy, and on occasion, 2D spectroscopy such as COSY and HETCOR (or HSQC). All of these techniques rely on establishing correlations through the chemical bond to elucidate structure and are useful for establishing the gross structure of the molecule. However, these techniques are often inadequate for establishing stereochemical relationships in a molecule. For these relationships, correlations through-space (the nuclear Overhauser effect or NOE) need to be established. The importance of the NOE in structure elucidation can hardly be overstated since it is unique in its ability to provide information on the three-dimensional geometry of a molecule. From our search of the literature, we have only found two examples of undergraduate experiments that rely on NOESY NMR (1, 2). We describe two experiments where students have utilized the NOE to probe stereochemistry. The first experiment challenges the students to determine the stereochemistry of tetra hydropyranone products from the aldol–Michael condensation of 3-pentanone with p-chlorobenzaldehyde. After discovering that both molecular modeling and NOE experiments yield ambiguous results, students settled on an NMR spectroscopic analysis of reduction products to infer stereochemistry. In a second experiment, the students used NOE spectroscopy to determine the stereochemistry of a 1,2-diol product that results from a stereoselective Grignard reaction. Discussion
O H3 C Ar
O CH3
O
H3C
Ar
CH3
Ar
1
Ar 2
O H3 C Ar
CH3 O
Ar
(±)-3 Figure 1. “Expected” (2) and “unexpected” (1, 3) products from the aldol condensation of 3-pentanone with p-chlorobenzaldehyde.
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Project 1: Determination of Stereochemistry by Conversion to Either a Racemic Mixture or a Meso Product Followed by NMR Spectroscopy It was reported in this Journal (3) that the cross aldol condensation of 3-pentanone with p-chlorobenzaldehyde yielded the “unexpected” tetrahydropyranone 1 rather than the expected (4) enone 2 (Figure 1). Interestingly, the initial report of 1 failed to consider stereoisomer 3 as a possible structure. Close examination of the structures of 1 and 3 does not reveal an easy way to distinguish between them using standard spectroscopic methods since both structures have elements of symmetry and both have identical connectivities, differing only in the special arrangement of the substituents on the ring. Differences in the NMR spectra of these isomers must be based on subtle chemical shift differences that would be difficult to predict.
Journal of Chemical Education • Vol. 85 No. 5 May 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Laboratory
Students initially attempted both molecular modeling and NOE experiments to distinguish 1 or 3 as the major product, both of which gave ambiguous results (see the Instructor Notes in the online supplement). They eventually used a combination of reaction chemistry and 1D-NMR to prove 1 as the correct product. Specifically, reduction of 1 with sodium borohydride provides a mixture of diastereomers while the reduction of 3 yields a racemic mixture (Scheme I). Consequently, reduction of 1 and 3 would yield mixtures showing 16 and 15 peaks respectively in their 13C NMR spectra. In the 1H NMR spectra, 4 and 5 (from 1) would yield two triplets of unequal intensities corresponding to CHOH hydrogen while 6 (from 3) should yield only a single doublet of doublets absorbance for this hydrogen. Finally, integration of the 1H NMR signals in the reduction of 3 should reduce to small whole numbers (2:2:1:1:1:3) while the integration of the signals arising from the reduction of 1 should yield a more complex pattern due to an unequal mixture of diastereomers. When students performed the reduction of their tetra hydropyranone, they obtained a 1.4:1 mixture of 4 and 5, which led to the assignment of 1 as the correct structure of the aldol–Michael product. Except for the aromatic 1H NMR absorbances, the peaks were well-resolved and showed nearly first-order coupling.
O H3C
CH3
Ar
O
NaBH4
Ar
1 H
HO
H3C
H3C
H
CH3
Ar O
CH3
Ar
or
O
Ar
4
Ar
5
O
OH
H3C
CH3
Ar
OH
O
H 3C
NaBH4
CH3
Ar
Ar
(±)-3
O
Ar
(±)-6
Scheme I. Expected products from the reductions of 1 and 3.
Project 2: Determination of Stereochemistry by NOESY Correlations of Acetonide Derivative In this project, we adopted a reaction from this Journal (5) involving the stereoselective attack on a prochiral carbonyl (benzoin) by a Grignard reagent (Scheme II). In the original description of this reaction, the authors proposed a bridged intermediate that resulted in one face of the carbonyl group being less sterically assessable than the other face. Details for safely carrying out the reaction with methyl magnesium iodide were provided as well as literature references for the melting points and 1H NMR absorbances of the two racemic diastereomers (5). While the authors took great care in illustrating how methyl iodide could be safely handled in an organic teaching laboratory, we remained ill at ease in having such a volatile and potent carcinogen used in a teaching laboratory. Consequently we chose to substitute n-butyl bromide in place of methyl iodide because its health hazards, as described in its MSDS, were much less severe. This substitution also gave students a chance to hypothesize whether the butyl Grignard reaction would be more stereoselective than the methyl Grignard reaction based on steric considerations. The use of butylmagnesium bromide, however, resulted in difficulties in assigning stereochemistry to the products because neither product had been previously characterized in the literature. Using the original article’s approach of comparing chemical shifts and melting points with literature values was not a practical approach, so another approach, based upon spectroscopic analyses, had to be developed. The approach we used was to form the acetonides of the crude diol products and to then use NOESY and NOE difference spectroscopies to assign stereochemistry (6). The use of acetonides to determine stereochemistry of benzoin reduction products has been described in this Journal (7), but simple inspection of the 1H NMR spectra
HO
O
H C6H5
HO
OH R C6H5
H C6H5
C6H5
(±)-7
(±)-9 RMgBr 1) RMgBr 2) H+
Mg O
O
H C6H5
C6H5 (±)-8
Scheme II. Mechanism that explains the stereochemical outcome of a Grignard attack on benzoin, 7, as described by Ciaccio et al. (5).
of the acetonides was sufficient to determine stereochemistry in that case. For the diol products described here, NOE is required to distinguish the two possible diastereomers, as outlined in Scheme III. It is clear that there are several NOE correlations that can be used to unambiguously assign the stereochemistry of each product. As anticipated, the major (and only detectable) products of the crude mixture were the (R,S) and (S,R) enantiomers in which the Grignard attacked the carbonyl from the less hindered face of the bridged intermediate.
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 5 May 2008 • Journal of Chemical Education
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In the Laboratory
HO H C6H5
Me
OH CH2CH2CH2CH3 C6H5
acetone
O
H+
O CH2CH2CH2CH3 C6H5
H C6H5
(±)-9 “expected major product”
(±)-10
Me HO H C6H5
OH C6H5 CH2CH2CH2CH3
Me
O acetone
Me O
H C6H5
H+
(±)-11
C6H5 CH2CH2CH2CH3
(±)-12
Scheme III. Important NOESY correlations expected for the two diastereomeric acetonides.
Hazards Methanol, dichloromethane, butyl bromide, diethyl ether, acetone, ethanol, and d-chloroform should all be used in a hood with gloves to avoid inhalation of vapors and absorption through skin. Dichloromethane is a possible carcinogen and mutagen and d-chloroform is a probable human carcinogen. Sodium borohydride is a flammable solid and can cause burns when in contact with moist skin; use gloves to handle. Ethyl magnesium chloride is a flammable solution and reacts violently with water. Conclusions These two projects involved standard reactions used in many organic teaching laboratories (Grignard reagents, NaBH4 reductions, aldols, acetal formation) that run smoothly and produced crude products in yields that can be spectroscopically analyzed without further purification. In addition, the reactions were highly stereoselective, which provided students excellent exposure to stereochemical concepts. Except for the aromatic region in the 1H NMR, peaks were reasonably resolved for major analyses to be done with 1D spectra (this is particularly true in the first project). Both projects, however, benefited from 2D-NMR analyses that were not overly difficult owing to the well-resolved absorbances. Indeed, we were able to run 1D-NOE difference spectra successfully to determine the stereochemistry of the acetonide in the second project as well as the 2D-NOESY experiment. Students appeared to have little difficulty grasping the basic theory of NOE and how it is detected by 1D- and 2D-NMR. Finally, this approach allowed us to deliver to our students the experience of obtaining procedures from the literature rather than textbook media. Since the procedures were not in a “cookbook” form, students sharpened their skills in stoichiometric calculations, spectral analyses, and making experimental modifications. The research component 694
of the course was maintained because the questions posed to students were not previously addressed in the literature, which forced students to critically interpret their experimental design and results. Acknowledgments This work was supported by the National Science Foundation for the purchase of a high-field NMR (DUE9850731) and the installation of molecular modeling software and hardware (DUE-0088882) at the University of Alaska Fairbanks. Literature Cited 1. Augé, J.; Lubin-Germain, N. J. Chem. Educ. 1998, 75, 1285. 2. Keller, J. Chem. Educator 2006, 11, 1. 3. Clausen, T. P.; Johnson, B.; Wood, J. J. Chem. Educ. 1996, 73, 266. 4. Hathaway, B.A. J. Chem. Educ. 1987, 64, 367. 5. Ciaccio, J. A.; Bravo, R. P.; Drahus, A. L.; Biggins, J. B.; Concepcion, R. V.; Cabrera, D. J. Chem. Educ. 2001, 78, 531. 6. Nakanishi, K.; Schooley, D. A.; Koreeda, M.; Mirura, J. Am. Chem. Soc. 1972, 94, 2865–2867. 7. Rowland, A. J. Chem. Educ. 1983, 60, 1084–1085.
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2008/May/abs692.html Abstract and keywords Full text (PDF) Links to cited JCE articles Supplement
Student handout
Instructor notes, including spectral data
Journal of Chemical Education • Vol. 85 No. 5 May 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
