LABORATORY EXPERIMENT pubs.acs.org/jchemeduc
A Wet-Lab Approach to Stereochemistry Using 31P NMR Spectroscopy Owen S. Fenton and Bianca R. Sculimbrene* Department of Chemistry, College of the Holy Cross, Worcester, Massachusetts 01610, United States
bS Supporting Information ABSTRACT: Understanding stereochemistry is an important and difficult task for students to master in organic chemistry. In both introductory and advanced courses, students are encouraged to explore the spatial relationships between molecules, but this exploration is often limited either to the lecture hall or the confines of the library. As such, we sought to develop an experiment-based approach that would facilitate investigation of stereochemical principles in an organic chemistry laboratory. Herein is reported a 31P NMR-based experiment that allows students to explore the different stereochemical outcomes when enantiopure or racemic alcohols are coupled to an achiral phosphorous center. KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate Organic Chemistry, Laboratory Instruction, Hands-On Learning/Manipulatives, Stereochemistry, Enantiomers, Diastereomers, NMR Spectroscopy, Synthesis
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MR spectroscopy can be a particularly useful tool in assessing the enantiopurity or stereochemical identity of certain optically active reagents. For example, derivitizing chiral alcohols and amines with Mosher’s acid is used extensively to elucidate their enantiomeric purity or absolute configuration.1 Undergraduate-ready modifications of this same procedure have even been described within the pages of this Journal.2 These methods, which are typically analyzed using either 1H or 19F NMR spectroscopy, rely on the coupling of optically active materials with chiral auxiliaries to generate diastereomeric products whose chemical shifts are often distinguishable using conventional NMR technology. However, Mosher’s methodology is not the only procedure that has been used to assess the enantiopurity of chiral alcohols with NMR. In 1985, Feringa and co-workers demonstrated that the enantiomeric ratio of alcohols could be determined without the use of a chiral auxiliary coupling reagent.3 Their method relies on the coupling of two molecules of a chiral alcohol with PCl3, an achiral phosphorous-bearing center (Scheme 1). The resulting dialkyl phosphonate can be chiral or meso depending on the configuration of the two alcohols that reacted. The dialkyl phosphonate is then analyzed by 31P NMR to determine the number and ratio of phosphorous products present. The enantiomeric purity of each alcohol is then determined based on the integration of these diastereomeric peaks in the 31P NMR spectrum. The large spectral window in 31P NMR in comparison to 1H NMR easily facilitates resolution of diastereomeric peaks. We sought to develop a laboratory experiment that would introduce second-semester or advanced organic laboratory Copyright r 2011 American Chemical Society and Division of Chemical Education, Inc.
students to the stereochemical intricacies of coupling optically active or racemic mixtures of chiral alcohols to an achiral center. We envisioned that the synthesis of di-sec-phenethyl phosphonate from either racemic, (R)-, or (S)-sec-phenethyl alcohol depicted in Scheme 1 could successfully accomplish our goal. The laboratory begins with a modified Michaelis-Abruhov reaction for the synthesis of a dialkyl phosphite.4 The resulting dialkyl phosphite readily tautomerizes to the dialkyl phosphonate, which presents the students with an interesting tautomerization that occurs between the P(III) and P(V) phosphorous forms. This could serve as a point of departure for discussing keto-enol equilibrium concentrations: much as the keto form predominates, so too does the P(V) dialkyl phosphonate.5 After acquiring the 31P NMR spectra and making molecular models of their product, students are asked to interpret their results paying careful attention to stereochemistry.
’ SUMMARY OF PROCEDURE Di-sec-phenethyl phosphonate is synthesized according to a modified literature procedure.6 Students are divided into one of three groups, and each of these groups is assigned either racemic, (R)-, or (S)-sec-phenethyl alcohol. Students dissolve their respective sec-phenethyl alcohol (2.5 mmol, 3 equiv) in toluene (8 mL, 0.3 M) in a 25 mL flask. The dimethylaniline (DMA) (1.7 mmol, 2 equiv) and phosphorous trichloride (0.8 mmol, 1 equiv) are then added sequentially, and the reaction is allowed to stir for 1-2 h. Published: March 09, 2011 662
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Journal of Chemical Education
LABORATORY EXPERIMENT
Scheme 1. The Coupling of Two Molecules of a Chiral Alcohol with PCl3, an Achiral Phosphorus-Bearing Center
Figure 1. 31P NMR of di-sec-phenethyl phosphonate synthesized with: (A) racemic sec-phenethyl alcohol, (B) (R)-sec-phenethyl alcohol, and (C) (S)sec-phenethyl alcohol.
Scheme 2. A Redraw of Scheme 1, Highlighting the Stereochemistry of sec-Phenethyl Alcohol
The reaction mixture is washed with 10 mL of distilled H2O, 10 mL of 5 M NH4OH, and 10 mL of brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure or by distillation. Each group obtains a 31P NMR spectrum of their crude product in CDCl3. The three groups then compare their spectra and use molecular models to understand the stereochemical consequences of using either the racemic, (R)-, or (S)-sec-phenethyl alcohol for the synthesis of their dialkyl phosphonate product. The isolated yields for this procedure are low owing to short reaction times; however, there are no phosphorous byproducts in the crude NMR. Yields of 65% can be achieved if a 2-day laboratory procedure is used (detailed in the Supporting Information). If desired, students can use silica-gel flash chromatography to purify the products, which allows further stereochemical analysis with 1H NMR spectroscopy.
’ HAZARDS sec-Phenethyl alcohol, dimethylaniline, and phosphorous trichloride are all toxic, and toluene is flammable. Five molar ammonium hydroxide is corrosive, and magnesium sulfate, brine, and deuterated chloroform are irritants. Accordingly, students
should work in a hood if possible and wear appropriate eyewear and gloves.
’ RESULTS Students are divided into three groups and are assigned either racemic, (R)-, or (S)-sec-phenethyl alcohol to synthesize the corresponding dialkyl phosphonate. The crude reaction is then analyzed with 31P NMR spectroscopy. Upon collecting their respective spectra, students assigned the racemate will discover that their 31P NMR spectrum contains three distinct peaks in a 1:2:1 ratio (Figure 1A), whereas students assigned either the (R) or (S) enantiomer have identical spectra that bear only one peak (Figure 1B,C). A primary goal for the students is to determine the origin of these differences, a challenge that can only be understood through a thorough investigation of the stereochemistry of each of the products. ’ DISCUSSION To understand the stereochemistry of di-sec-phenethyl phosphonate, it is useful to redraw Scheme 1, taking into account the 663
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Journal of Chemical Education stereochemistry of the sec-phenethyl alcohol starting material and analyzing its effect on the synthesized products (Scheme 2). The group assigned racemic sec-phenethyl alcohol will synthesize equal amounts of products 1A, 1B, 1C, and 1D because the (R) and (S) alcohol enantiomers are equally reactive under achiral conditions. However, these four products are not equivalent and each has their own stereochemical identity because the phosphorus atom can become a pseudo-asymmetric center.7 Products 1A and 1D are enantiomers of each other, whereas products 1B and 1C are diastereomers of each other and also diastereomers of 1A and 1D. Because enantiomers are magnetically equivalent in the achiral environment of the NMR spectrometer, products 1A and 1D show up with identical phosphorous signals. Because 1B and 1C are diastereomers of each other (and of the 1A-1D enantiomeric pair), three distinct peaks are present in the 31P NMR. The ability to easily resolve the diastereomeric phosphorous signals highlights the advantages of the large spectral window in 31P NMR. Thus, a total of three unique phosphorous signals in a 1:2:1 ratio are observed in the synthesis of di-sec-phenethyl phosphonate from racemic starting material because the signals for 1A and 1D are additive. The groups assigned optically pure alcohol will exclusively synthesize either 1A (S,S-enantiomer) or 1D (R,R-enantiomer). Because these two products have already been established as enantiomers, it thus follows that groups assigned (R) or (S) alcohol will obtain identical spectra in this experiment.
LABORATORY EXPERIMENT
(5) (a) Pietro, W. J.; Hehre, W. J. J. Am. Chem. Soc. 1982, 104, 3594–3595. (b) Doak, G. O.; Freedman, L. D. Chem. Rev. 1961, 61, 31–44. (6) (a) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102–4103. (b) Folsch, G. Acta Chem. Scand. 1956, 10, 686. (7) Mislow, K.; Siegel, J. J. Am. Chem. Soc. 1984, 106, 3319–3328. (8) (a) Ault, A. J. Chem. Educ. 1965, 5, 269. (b) McCullagh, J. V. J. Chem. Educ. 2008, 85, 941–943.
’ NOTE ADDED AFTER ASAP PUBLICATION Due to a production error, this paper published on the web on March 9, 2011 with a misplaced hydrogen atom in the Abstract and in Scheme 2. The corrected version was published on March 14, 2011.
’ CONCLUSION The plausible initial expectation that di-sec-phenethyl phosphonate would have only one signal in the 31P NMR forces students to think more carefully about their reaction once the data are acquired. The three groups of students are challenged to use molecular models to explain why different spectra are obtained when the reaction is done with racemic versus optically pure alcohol. This helps students appreciate the often-subtle effects the 3-dimensional shape of a molecule can have on a reaction. In addition to providing students with a wet-lab approach to stereochemistry,8 undergraduates will be exposed to some of the unique benefits of heteroatom NMR spectroscopy. ’ ASSOCIATED CONTENT
bS
Supporting Information Handout for students; notes for the instructor; 1H NMR spectra; pre- and postlab questions. This material is available via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ REFERENCES (1) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90, 3732–3738. (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–2549. (c) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519. (2) Allen, D. A.; Tomaso, A. E.; Priest, O. P.; Hindson, D. F.; Hurlburt, J. L. J. Chem. Educ. 2008, 85, 698–700. (3) Feringa, B. L.; Smaardijk, A.; Wynberg, H. J. Am. Chem. Soc. 1985, 107, 4798–4799. (4) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430. 664
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