Using NMR Spectroscopy To Promote Active Learning in

Chapter 4

Downloaded by UNIV OF OKLAHOMA on March 20, 2013 | http://pubs.acs.org Publication Date (Web): March 19, 2013 | doi: 10.1021/bk-2013-1128.ch004

Using NMR Spectroscopy To Promote Active Learning in Undergraduate Organic Laboratory Courses John A. Cramer* Department of Chemistry, Seton Hill University, 1 Seton Hill Drive, Greensburg, Pennsylvania 15601-1599 *E-mail: [email protected]

This chapter describes experiments where NMR spectroscopy has been employed in undergraduate organic laboratory courses at Seton Hill University to promote student active learning. A wide range of NMR-enabled concepts can be successfully taught as the result of the robust capability of NMR spectroscopy to connect students with the molecular world. In these experiments the need to answer significant scientific questions drives the work expected of students.

Introduction Pedagogic research has demonstrated that chemistry students learn optimally when they are actively engaged in creating and interpreting knowledge as opposed to passively receiving information (1). This is especially true in laboratory courses. Active learning using NMR spectroscopy has been successfully employed in undergraduate organic laboratory courses at Seton Hill University, where students answer significant, realistic scientific questions as they engage a wide range of NMR-enabled concepts at multiple levels. One of the best strategies to engage students in the process and excitement of scientific discovery is to design laboratory experiments which are driven by the need to answer questions that students recognize as important. NMR spectroscopy is an ideal engine for driving active learning. The vast array of fruitful applications of NMR spectroscopy that have been developed in a variety of scientific disciplines is mirrored by the diverse ways in which © 2013 American Chemical Society In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


NMR can be used to enhance the education of chemistry students (2). While it is crucially important to train students in the theory of NMR for its own sake, it is also important to recognize the pedagogic role that NMR spectroscopy can have in serving as a powerful hook to actively engage and connect students with the molecular world. This chapter will describe how NMR spectroscopy has been used at Seton Hill University to promote active learning throughout a two-semester science major’s organic laboratory sequence. The experiments, employing a 60 MHz Anasazi Eft permanent magnet instrument, are performed by students in laboratory sections of approximately sixteen students. In the first semester course NMR FID data are typically obtained by students working in small groups. Later in the second semester students collect NMR data individually.

Atom Equivalency and 13C NMR Spectroscopy Comprehending structural relationships in molecules is crucial to learning organic chemistry. An effective pedagogic response to this need is the early introduction of 13C NMR spectroscopy to teach atom equivalency, and to thereby facilitate student understanding of molecular structure. In an example of such an exercise, students are asked early in the term to write structural formulas for the seventeen possible alkene isomers of molecular formula C6H12. After a brief introduction to structural equivalence in the context of 13C NMR spectroscopy, including the practical aspects of 1H decoupled 13C NMR spectroscopy, students are presented with a spectrum of 2-ethyl-1-butene which consists of four singlet signals (3). Students are asked to determine which of their isomers could produce such a spectrum. Only the two C6H12 alkene isomers in Figure 1 have four nonequivalent sets of carbon atoms.

Figure 1. C6H12 alkene isomers with four nonequivalent sets of carbon atoms.

The task of distinguishing between these two isomers provides an impetus for students to have a deeper understanding of 13C NMR spectroscopy, involving topics such as the dependence of chemical shift on chemical environment and the relatively shorter height of signals from carbon atoms with no attached hydrogen atoms. Alternatively, the need to distinguish between the two isomers can be an incentive for students to learn the principles of 1H NMR spectroscopy. Through these exercises students gain an early appreciation for the power and relevance of NMR spectroscopy to the important task of determining molecular structure. 58 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Use of Unknowns To Engage Student Learning Incorporation of unknowns into synthetic experiments is an effective active learning strategy which serves to increase both interest and level of engagement. In one experiment, students are informed of the molecular identity of only one reactant in a synthesis that involves two reactants. Upon completion of the synthesis, students determine the molecular structure of their products by 1H and 13C NMR spectra. By inference they are then able to identify the unknown reactant. A wide range of syntheses can be implemented which employ this strategy. One convenient example is the synthesis of aromatic tertiary alcohols by the reaction of phenylmagnesium bromide with unknown aliphatic ketones (Figure 2).

Figure 2. Synthesis of aromatic tertiary alcohols from the reaction of phenylmagnesium bromide with unknown ketones.

Structural analysis of the tertiary alcohol products by NMR spectroscopy permits students to identify the products formed, as well as the structures of the ketone reactants. In determining the identity of products from 1H NMR spectra students set the integration of the aromatic region to five hydrogen atoms, which permits the determination of the number of remaining hydrogen atoms in the product molecule. Students then assign the structure of products and ketone reactants by working in small groups. The ketones employed in this experiment (Figure 3) provide a range of difficulty level, with acetone being a significantly less challenging ketone than the five-carbon ketones.

Figure 3. Unknown ketones used in tertiary alcohol syntheses.

Figure 4 shows the 1H NMR spectrum of the alcohol product formed from the reaction of phenylmagnesium bromide with 3-methyl-2-butanone. 59 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Figure 4. 1H NMR spectrum of 3-methyl-2-phenyl-2-butanol.

In this example students initially determine that eleven aliphatic hydrogen atoms exist in the product molecule, in addition to the five aromatic hydrogen atoms. The major problem students have in assigning the spectrum is with the proper interpretation of what appears to be a triplet at 0.8 ppm. This provides an excellent opportunity to introduce the concept of diastereotopic atoms in a way that is logical, natural, and compelling for students. In this case, the apparent triplet is the result of two overlapping doublet resonances from the nonequivalent diastereotopic isopropyl methyl groups (4).

Molecular Structure of Limonene by NMR Spectroscopy One of the experiments introduced early in the first semester of organic chemistry at Seton Hill is the isolation, characterization, and structural formula determination of limonene which students isolate from orange peels by steam distillation. Students calculate the molecular formula of limonene (C10H16) from elemental composition and vapor density data which are given. After an explanation of the concept of unsaturation index, students determine that the index of unsaturation for limonene is three. Students are then introduced to the six possible combinations of rings and/or pi bonds that are consistent with that index. Students are next challenged with identifying which of the six combinations of pi bonds and/or rings is exhibited by the limonene molecule. As a response to the need to answer this question students are reintroduced to 13C NMR spectroscopy at a deeper level than that of the earlier atom equivalency exercise. The observation of ten signals in the spectrum indicates that each of the ten carbon atoms in the limonene molecule has a unique chemical environment. After a discussion of how carbon chemical shift values correlate with various types of carbon atoms, students 60 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


are able to identify the four alkene carbon peaks between 110 and 150 ppm in the 13C NMR spectrum of limonene (Figure 5). This in turn leads students to the conclusion that limonene must contain two nonequivalent carbon-carbon double bonds and one ring.

Figure 5.

13C

NMR spectrum of student isolated limonene (C10H16).

From the ozonolysis products of limonene (5), students are able to narrow the structure of limonene to the three possibilities (1, 2, and 3) shown in Figure 6, and ultimately choose the cyclic monoterpene structure 3 as the structure of limonene by comparing their experimental spectrum with spectra calculated for the three candidate molecules using ChemDraw.

Figure 6. Possible structural formulas for limonene.

Analyses of Mixtures by 1H NMR Spectroscopy The linear relationship between the area of 1H NMR signals and the number of hydrogen atoms causing that signal permits 1H NMR spectroscopy to be used in the determination of the composition of mixtures. This type of analysis requires each component of interest in a mixture to have at least one 1H NMR signal which is resolved from the signals produced by the other components. Such an analysis is easily included in experiments involving the fractional distillation of binary 61 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


mixtures, where the composition of a distillation mixture are more traditionally determined from either gas chromatographic analysis, or from a distillation curve created by students from data collected during the distillation. However, if resolved 1H NMR resonances exist for each component of the mixture, 1H NMR spectroscopy can be used as an additional independent experimental method for assessing the composition of the mixture. A mixture consisting of acetone and propyl acetate is a good example of a fractional distillation mixture which can be conveniently analyzed by 1H NMR spectroscopy. In this case the areas of the resolved methyl singlets at 2 ppm can be used to calculate the composition of the mixture. This analysis means that students must take into consideration the fact that the number of hydrogen atoms per molecule represented by the acetone peak is twice that of the methyl peak of propyl acetate. Requiring students to critically evaluate the accuracy and relative merits of multiple independent protocols is a great teaching exercise, since it requires students to think carefully about the assumptions and uncertainties of each type of analysis. Another example of the application of the quantitative properties of 1H NMR to assess the composition of a mixture is the alkene isomer analysis of the product mixture formed from the acid-catalyzed dehydration of an unsymmetrical alcohol such as 2-methylcyclohexanol. Determination of the isomer distribution with respect to 1-methylcyclohexene and 3-methylcyclohexene, as indicated in Figure 7, provides students with data that can be compared with the isomer distribution predicted by Zaitsev’s Rule.

Figure 7. 1H NMR spectrum of the alkene mixture formed from the acid-catalyzed dehydration of 2-methylcyclohexanol. A further advantage of this analysis is the fact that student curiosity about the small peak at 4.5 ppm can serve as an impetus for the introduction of the concept of carbocation rearrangements. 62 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Using NMR Spectroscopy To Teach Experimental Design


A guided inquiry multi-step synthesis project has been developed at Seton Hill in which NMR spectroscopy plays an important role in the structural determination of an unexpected product. This project involves the bromination of the dimethyl ester of cis-norbornene-5,6-endo-dicarboxylic acid 4 derived from the corresponding anhydride formed from the Diels-Alder addition reaction of cyclopentadiene and maleic anhydride as summarized in Figure 8.

Figure 8. Synthesis of the dimethyl ester of cis-norbornene-5,6-endo-dicarboxylic acid (4).

For the bromination reaction, students plausibly expect that anti addition of bromine to the carbon-carbon double bond of 4 will occur to give the corresponding trans-dibromide product in which the two methyl ester groups are retained. However, the integration data from the 1H NMR spectrum of the bromination product of 4 (Figure 9) indicates the presence of just one methyl ester group.

Figure 9. 1H NMR spectrum of the reaction product formed from the bromination of the dimethyl ester of cis-norbornene-5,6-endo-dicarboxylic acid. 63 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Infrared analysis of the crystallized product reveals the presence of a lactone carbonyl group and an ester carbonyl. This information, in conjunction with stereochemical insights gained from building a model of the assumed exo-bromonium ion intermediate, guides students to the conclusion that the bromolactonic ester, shown in Figure 10, is the product formed from the bromination of the cis-norbornene-5,6-endo-dicarboxylic acid (6).

Figure 10. Formation of bromolactonic ester from the bromination of the dimethyl ester of cis-norbornene-5,6-endo-dicarboxylic acid (4).

A proposed mechanism for this reaction is discussed with students in which the exo-bromonium ion undergoes nucleophilic attack from the carbonyl of the methyl ester as opposed to bromide ion, Figure 11.

Figure 11. Proposed mechanism for the formation of bromolactonic ester from the bromination of the dimethyl ester of cis-norbornene-5,6-endo-dicarboxylic acid 4.

Finally, students are asked to design an experiment which would represent a test of the proposed mechanism. Since the mechanism involves the formation of methyl bromide, which has a boiling point of 4 °C, students are encouraged to consider how the reaction could be conducted such that any methyl bromide formed could be observed by 1H NMR spectroscopy. Through a process of guided inquiry involving leading questions, students are led to an experimental 64 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


design where a solution of the dimethylester reactant (4) in carbon tetrachloride is brominated in an NMR tube fitted with the usual plastic cap to prevent the escape of methyl bromide. This microscale experiment can be conveniently performed by the addition of a 1 M solution of Br2 in CCl4 to an NMR tube containing the dimethyl ester dissolved in CCl4. Upon addition of Br2 the appearance of a sharp singlet at 2.6 ppm, as shown in the 1H NMR spectrum in Figure 12, indicates that methyl bromide is indeed formed in the reaction. This observation provides support for the proposed mechanism and is particularly effective in teaching students how experiments can be carefully designed in order to answer scientific questions.

Figure 12. 1H NMR spectrum of the product mixture formed from the bromination of the dimethyl ester of cis-norbornene-5,6-endo-dicarboxylic acid (4) in a closed NMR tube.

Reaction Kinetics by NMR Spectroscopy Performing microscale reactions in NMR tubes positioned in the temperature controlled probe of an NMR spectrometer provides an especially convenient way of teaching students the principles of reaction kinetics. Monitoring the progress of such reactions can be accomplished by determining the area of a resolved resonance of either a reactant or a product with respect to time. Two examples of this type of experiment are presented. The dimerization reaction of cyclopentadiene (Figure 13) is relatively slow, showing second order kinetics with a half-life at room temperature of approximately one day. Spectra of neat freshly distilled cyclopentadiene monomer can be taken serially and the progress of dimerization monitored by following the area of the resolved reactant or product peaks with respect to time. Plotting the reciprocal of cyclopentadiene concentration versus time gives a linear plot from which the rate constant for the reaction can be evaluated. 65 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Figure 13. Dimerization of cyclopentadiene. An example of a kinetic study, which is more amenable to a three or four hour undergraduate laboratory period, is the solvolysis of t-butyl bromide in methanol or aqueous methanol. Solvolysis kinetics of t-butyl halides can be conveniently studied by 1H NMR spectroscopy in ordinary (protium) aqueous methanol solvent since the 1H NMR chemical shifts of methanol and water are sufficiently removed from those of the reaction substrate and products. The fact that deuterated methanol and water solvents are not required significantly lowers the cost of these experiments. The 1H NMR spectrum shown in Figure 14 reveals that t-butyl bromide reacts with 80% aqueous methanol to form the corresponding t-butyl methyl ether and t-butyl alcohol products as a result of the SN1 reaction of the t-butyl carbocation intermediate with methanol and water. Furthermore, evidence of the competing E1 reaction to form 2-methylpropene is also indicated by the spectrum.

Figure 14. 1H NMR spectrum of the solvolysis of 1 M t-butyl bromide in 80% aqueous methanol, t = 50 minutes. Scale is from 2.0 ppm to 0 ppm. Figure 15 shows serial spectra collected at various times following the addition of t-butyl bromide to 80% aqueous methanol in an NMR tube. The plot of the natural logarithm of the area of the t-butyl bromide peak versus time gives a linear plot from which the first order rate constant can be calculated as 66 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


0.016 min-1 which corresponds to a half-life of 43 minutes. The time scale of this experiment is particularly well suited to the typical length of undergraduate laboratory periods.

Figure 15. Solvolysis of 1 M t-butyl bromide in 80% aqueous methanol, t = 7 min, t = 50min, t = 93 min. Since the 1H NMR resonances of the three products shown in Figure 14 are resolved from each other and from the reactant, a wide range of experiments can be designed to teach students the important principles of nucleophilic substitution reactions. The leaving group effect on reaction rate constants can be easily studied by comparing the rate constants for the solvolysis of t-butyl bromide and t-butyl chloride. Varying the percentage of water in the aqueous methanol solvent permits the effect of solvent polarity on rate constants to be examined. Furthermore, factors affecting the ratio of substitution to elimination can be conveniently explored as well.

Conclusions In this chapter experiments have been presented which illustrate how NMR spectroscopy can be employed in the undergraduate organic laboratory curriculum to promote active learning and to effectively introduce students to a wide range of important concepts and principles in organic chemistry. A major pedagogic strategy in this work has been to design experiments involving NMR spectroscopy where the laboratory work expected of students is in response to the need to answer important scientific questions. The significant degree to which this teaching approach has been successful in enhancing student learning is a reflection of the robust pedagogic power of NMR spectroscopy in connecting and engaging students with the molecular world. 67 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

References 1. 2.

3.


4. 5. 6.

Paulson, D. R. J. Chem. Educ. 1999, 76, 1136–1140. Modern NMR Spectroscopy in Education; Rovnyak, D., Stockland, R., Eds.; ACS Symposium Series 969; American Chemical Society: Washington, DC, 2007. http://riodb01.ibase.aist.go.jp/sdbs/cgi-bin/cre_index.cgi (accessed December 2012). Kieboom, A. P. G.; Sinnema, A. Tetrahedron 1972, 28, 2527–2532. Griesbaum, M.; Hilss, M.; Bosch, J. Tetrahedron 1996, 52, 14813–14826. Fleming, I.; Michael, J. J. Chem. Soc., Perkin Trans. 1 1981, 5, 1549–1556.

68 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Using NMR Spectroscopy To Promote Active Learning in

Recommend Documents