Utilizing NMR To Study Structure and Equilibrium in the Organic

Chapter 9

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Utilizing NMR To Study Structure and Equilibrium in the Organic Chemistry Laboratory Sherri C. Young,*,‡ Kyle T. Smith, James W. DeBlasio, and Christian S. Hamann* Department of Chemistry & Biochemistry, Albright College, 13th & Bern Streets, Reading, Pennsylvania 19612, United States ‡Current address: Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, Pennsylvania 18104, United States *E-mail: [email protected] (C.S. Hamann); E-mail: [email protected] (S.C. Young).

Nuclear magnetic resonance (NMR) spectroscopy is an integral part of the undergraduate chemistry curriculum. Although NMR is most commonly used for structure determination, it is also a valuable tool for the study of chemical reactions and equilibria in situ. In this chapter, we present two successive experiments for the undergraduate organic chemistry laboratory. The first is a student-centered approach to teaching chemical shift correlations, spin-spin splitting, and integration through the analysis of proton NMR spectra for a diverse set of esters. Then, students use NMR to assess the impact that various structural and electronic elements have on the keto-enol equilibrium for a series of 1,3-dicarbonyl compounds. Specifically, the impact of steric bulk, conjugation, electron withdrawing/donating groups, and resonance on keto-enol equilibrium is explored. Together, these experiments provide students with both a strong foundation in structure elucidation and an experience in using NMR data for the determination of equilibrium constants. In addition, the development of these experiments provided a group of students with undergraduate research and laboratory development experience and the opportunity to present their work regionally and nationally.

© 2016 American Chemical Society Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Background Rapid changes in the pharmaceutical industry during the first decade of the 21st Century made high-field Fourier transform nuclear magnetic resonance (NMR) spectrometers available for donation to small colleges in the Philadelphia region. Albright College was the recipient of several major instrument donations. Companies making donations include Bristol-Myers Squibb (formerly Merck-DuPont) and Pfizer (formerly Wyeth). Supported by members of Albright’s Department of Chemistry & Biochemistry and the division of academic affairs, the department has enjoyed the use of two high-field instruments for more than a decade. This represents unprecedented access to research-grade instruments for undergraduate students. Thus, it immediately became our priority to take full advantage of this exceptional facility. Our focus was the development of laboratories for the typical sophomore-level, two-semester organic chemistry sequence. Using organic, physical, and inorganic laboratory texts as well as the Journal of Chemical Education as resources, and building on our history of hands-on student training with state-of-the-art instrumentation, we began to assemble a list of experiments that would allow us to intentionally incorporate NMR into our curriculum and in a pedagogically appropriate and developmental way. There are many good experiments available; the experiments we describe here were designed to provide a firm foundation in structural analysis that students could then apply to more complex problems such as product characterization. In turn, those skills could be applied to physical chemistry questions of kinetic and thermodynamic analysis of dynamic systems. Additionally, we sought pedagogic methods that made effective use of student time by combining hands-on instrument time for students in pairs with classroom exercises for the students who are awaiting or have completed their turn. From the outset, students interested in undergraduate research and laboratory development were recruited to determine the scope and limitations of the experiments, to bring their first-hand experience of the courses into all considerations for future versions of the labs, and, of course, to gain valuable experience with NMR, literature research, and thesis writing. Over the course of several years and much iteration we arrived at the two experiments described herein. We selected the ester functional group as a device that allowed students to analyze the concepts of molecular structure, chemical shift, first-order coupling, and integration. Then we applied the lessons learned there to the determination of keto-enol equilibrium constants in a wide range of molecules containing the activated methylene group in a 1,3-dicarbonyl moiety. We are pleased to offer this chapter as a progress report in our ongoing development of experiments suitable for the teaching of foundational NMR concepts at the undergraduate level.

120 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Part I: Esters as a Template for the First Experience in Studying of Molecular Structure


Introduction Laboratories that require active engagement may complement or supersede traditional cookbook approaches, depending on the subject matter involved and the learning goals for the laboratory exercise. The success of these experiments corroborates well with the notion that student learning and understanding are enhanced when students make the connections themselves (1–3). Several previously-reported experiments provide students with the opportunity to utilize NMR spectroscopy to explore molecular structure and identify unknowns; many of these experiments exploit the ester functional group (4, 5). NMR spectra generated by analysis of esters yield appropriate introductory yet challenging spectra for student interpretation. This moiety with its two electronegative oxygen atoms provides excellent chemical shift dispersion such that students develop foundational knowledge from cleanly resolved signals and paradigmatic splitting. A range of esters allows students to access all splitting patterns for various numbers of non-equivalent neighboring hydrogens. Esters allow students to compare and contrast predicted spectra with experimental spectra, leading to a greater appreciation of molecular structure and greater facility with foundational concepts before moving to more complicated spectra. In summary, we developed a hands-on method for teaching introductory NMR. In this experiment, students analyze the structure of a series of esters by observing chemical shift values, spin-spin splitting (multiplicity), and integral values of each resonance peak. This guided-inquiry experience provided students with a firm foundation for the analysis of more complex molecules in upper level courses (e.g., physical chemistry, analytical chemistry, advanced organic chemistry). In the context of sophomore organic, this experiment allowed students to utilize NMR to study keto-enol equilibria in a subsequent experiment (vide infra). Experimental Laboratory Details At Albright College, the organic chemistry labs are four hours long with up to fifteen students in each section. One instructor and 1-2 undergraduate lab assistants are present. The NMR of esters experiment fits into one 30-minute orientation followed by two laboratory periods. The experiment can be divided into four parts: 1) students draw line-angle structures of each ester, 2) students predict the NMR spectra for a series of esters, 3) students obtain their own NMR data, and 4) students compare their predicted data to their experimental data. The students who are not with the instructor in the NMR room work with a student assistant in a classroom on the other parts of the experiment. Our aim was to provide a large list of commercially available esters to minimize the number of repeats. 121 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Materials and Instrumentation


All of the chemicals were purchased from Sigma-Aldrich or Acrōs and were used without further purification. NMR samples were prepared in advance by the instructor using 15 μL of the ester plus 750 μL of deuterated chloroform. NMR tubes were purchased from Wilmad-LabGlass (product no. 528-PP-7). Spectra were collected at room temperature in CDCl3 using a Varian 400 MHz spectrometer; chemical shifts were referenced to residual CHCl3. For the purposes of this exercise we did not optimize relaxation time (6) or concentration (7) although we commend these approaches to faculty interested in focusing on these important features of NMR analysis.

Student Handouts and Report Students are provided with a protocol that guides them through both the “classroom” portion of the laboratory (building molecular models, predicting chemical shifts, interpreting spectra) and their turn to actually collect data on the NMR spectrometer. This was an important feature as the guided classroom exercises provided students with a constructive learning experience while they waited to use the instrument. Thus, the students are engaged in four activities as described in the Laboratory Details. Students were afforded the opportunity to make predictions for all compounds, depending on the length of the laboratory and the goals for the experiment in a given year. In practice, each student collected her or his own spectrum and interpreted all or almost all of the spectra collected by the other students (distributed as photocopies during the laboratory period).

Hazards Halogenated compounds have associated hazards (including but not limited to carcinogenicity, acute toxicity, organ toxicity with single or repeated exposure, and skin, eye, and respiratory tract irritation). Many of these compounds are flammable and should be dispensed in a fume hood while wearing appropriate personal protective equipment (gloves, goggles). Results and Discussion Use of Esters To Construct Chemical Shift Correlations The NMR spectra for 18 esters (Figure 1) were generated and/or interpreted by students. This diverse set of esters allowed students to explore the impact of the carbonyl carbon and ester oxygen on chemical shift, and the impact that degree of substitution (primary, secondary, tertiary) has on chemical shift. In addition, paradigmatic splitting patterns for various moieties were interpreted. Students began with simple esters (such as methyl acetate, ethyl acetate, and methyl propanoate) to develop a sense of correlation directly from the NMR 122

Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


spectra themselves; later in the exercise they were able to use correlation tables from their texts. Note that while in this conception students know the ester with which they are working in each sample and thus compare structure-based predictions to experimental data, it is a facile change to reverse the process and have students solve the structure from the spectrum.

Figure 1. The 18 commercially available esters used for this experiment.

Interpretation of Spin-Spin Splitting Patterns First-order coupling, arising from magnetic coupling that occurs between groups of non-equivalent, adjacent protons (8), provides information on connectivity. The compounds selected for this laboratory provide paradigmatic first-order coupling due to the ester functional group. Using the N + 1 rule, in which N is the number of three-bond neighboring hydrogens to a hydrogen under investigation, students predict the familiar pattern of singlets, doublets, triplets, etc., with theoretical peak intensities predicted by Pascal’s Triangle. Using the esters selected for this experiment, students investigate values of N = 0-6 (except N = 4). 123 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


For example, consider the NMR spectrum of ethyl isobutanoate (Figure 2). Using the selected compounds, students were able to practice identifying threebond neighbors and familiarize themselves with the various “signatures” found in NMR spectra due to first-order coupling. In this example, students observe a septet (environment C; N = 6), a quartet (environment B; N = 3), a triplet (environment A; N = 2), and a doublet (environment D; N = 1). Through interpretation of this spectrum, students are introduced to two common signatures, the isopropyl signature (septet/doublet) and the ethyl signature (triplet/quartet). By analyzing the rest of the esters, students are also introduced multiple times to methyl (singlet, with no neighbors), ethyl (quartet/triplet), n propyl (triplet/sextet/triplet), isopropyl (septet/doublet), and t-butyl (singlet) patterns. While many pedagogical approaches offer only a few examples of splitting, this method presents every type of splitting – from no splitting to a septet (with the exception of a quintet) – in a logical, developmental fashion.

Figure 2. 1H NMR spectrum and corresponding structure of ethyl isobutanoate. (A = triplet, B = quartet, C = septet, D = doublet).

Peak Integration In addition to gaining critical experience interpreting chemical shifts and splitting patterns, students were exposed to peak integrations in this experiment. The area under the curve of proton NMR signals is almost always directly proportional to the number of protons found within that chemical environment (8). We exploited this property for each NMR spectrum; integrations were particularly useful to clarify the difference between methyl acetate, t-butyl acetate, and methyl pivalate. (Students needed to apply their knowledge of chemical shift to 124 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

distinguish methyl acetate and t-butyl pivalate.) The ester functional group with a focused set of R-groups allows students to practice the concept of integration with well-resolved peaks.


Limitations We have focused our attention in this report on the detailed examination of first-order coupling in aliphatic systems. Of the 25 possible esters implied by Figure 1, 18 are currently commercially available. We are working toward a student-accessible synthesis of the remaining esters. One of the commercially available esters, n-propyl butanoate, suffers from accidental magnetic equivalence and could be resolved using two-dimensional techniques, which is beyond the scope of this work; others have proposed experiments to address this topic (9). The other limitation is the lack of a structure with N = 4 which we plan to address with substituted esters (e.g., dimethylglutarate).

Student Feedback and Outcomes The ester NMR experiment allowed us to incorporate a hands-on NMR experiment quickly and at low cost. We realized the benefits of this approach almost immediately when students became better able to interpret more complicated NMR spectra after they had mastered the interpretation of the substructures they encountered most frequently (methyl, ethyl, n-propyl, etc.). In their feedback students expressed both excitement about and gratitude for the ability to use research-grade instruments in the undergraduate laboratory. Over time we have noticed not only improved student learning outcomes concerning chemical shift, spin-spin correlation, and integration, but also improved long-term retention of the content and the ability to apply what was learned in subsequent courses as students moved forward in the curriculum and on to graduate school. Data supporting these outcomes include course evaluations and student personal narratives. We plan to implement these experiments at more than one institution and incorporate more detailed assessments as part of our ongoing collaboration designed to expand and improve the teaching of NMR in the undergraduate curriculum.

Instructor Notes In future iterations of this experiment we hope to finish synthesis and analysis of the esters in Figure 1. In addition, we plan to mine the commercial offerings for other suitable esters to complement those that work well as described here. Future versions of this experiment may also include a similar approach to introduce the effects of substitution on chemical shift and to include splitting in aromatic systems. 125 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Part II: Proton NMR as a Tool for the Study of Keto-Enol Equilibrium


Introduction Tautomers are a special case of structural isomerism in which a change in the position of one double bond (in this case, C=O vs C=C) and one hydrogen atom (C-H vs O-H) results in a pair of constitutional isomers (10, 11). An historically important example of tautomerization is that which occurs in the purine and pyrimidine bases of deoxyribonucleic acid (DNA). Knowledge of these systems was a key development in the proposal of Watson-Crick base pairs and the structure of DNA (12). Organic synthesis experiments in the Journal of Chemical Education rely on students’ knowledge of factors affecting keto-enol equilibria (13) and one author has developed a mnemonic to promote mastery of the mechanism of keto-enol tautomerization (14).

Figure 3. Tautomerization of pentane-2,4-dione (1) to 4-hydroxypent-3-en-2-one (R = R′ = -CH3). A common system for the study of tautomerism using NMR in the undergraduate laboratory is pentane-2,4-dione (Figure 3), a paradigmatic 1,3-dicarbonyl compound (15). Previous pedagogical papers on pentane-2,4-dione and related 1,3-dicarbonyls have focused on the effects of resonance (16), electron withdrawing/donating groups (17–19), solvent (6, 20–23), temperature (23, 24), and concentration effects (7, 23, 25) as well as kinetics and isotope exchange (26, 27) on keto-enol equilibria. We complement these investigations with the opportunity for students to investigate the effects on the position of equilibrium from steric bulk and lone pair electron conjugation. It is important to note that students who performed this experiment were already exposed to principles of chemical shift, integration, and spin-spin splitting in lecture and via the ester experiment (vide supra). Experimental Laboratory Details We had a similar goal for the experiment in which students determine keto-enol equilibrium constants: we selected a series of compounds that complement those already in the pedagogy literature such that faculty who implement this experiment can choose from that list to suit individual course learning objectives. We and others have accumulated a list of 16 suitable compounds, and that list is slated to grow. From these compounds students can 126



investigate the impact of structure, steric bulk, lone pair conjugation, and electron donating and withdrawing groups on the keto-enol equilibrium constant (Ke/k). This experiment fits into one 4-hour laboratory period. A typical session utilizes a classroom and the NMR laboratory. Students brought model kits to build some of the 1,3-dicarbonyl compounds and predicted the effect of different structural elements on Ke/k based on their knowledge of keto-enol equilibrium, pKa, or other chemical reactivity (e.g., aldol and Claisen condensations). In pairs, students were brought into the NMR room where they collected their own data which were photocopied and shared with the class for analysis. At the end of the period or in a different laboratory or lecture period, students accumulated their data for comparative analysis and discussion.

Materials and Instrumentation The Materials and Instrumentation section may be found in the esters section (above). When the analyte was a solid, a 15 μg sample was used to prepare the solution.

Calculation of Keto-Enol Equilibrium Constants To determine Ke/k, students integrate the NMR signals corresponding to the enol hydrogens and those corresponding to the keto hydrogens (Equation 1) for the compounds listed in Table 1. It should be noted that not all keto and enol hydrogens need to be integrated in order to obtain accurate Ke/k values. This feature becomes an asset when not all of the keto and enol hydrogens can be assigned or integrated, for example, in the compounds with phenyl groups (10, 11, 15, and 16) or, more generally, when the spectral window is not wide enough to observe the enol hydrogen. However, the central C-H is always observed in these compounds and, because of its distinctive chemical shift (4.6-6.8 ppm, well upfield of the corresponding keto methylene signal at 3.3-4.2 ppm), its normalized integral was used at times to “bootstrap” other peak assignments. In contrast, compounds substituted at the “3” position lose the enolized C-H (e.g., 5, 6, 7, 8) and so require other paired signals to be unambiguously assigned in order to calculate Ke/k accurately.


Student Handouts


In the laboratory, students are given a handout on keto-enol tautomerization and equilibrium. They then predict 1H NMR spectra for the keto forms of several 1,3-dicarbonyl compounds (e.g., pentane-2,4-dione, heptane-3,5-dione), much like they did in the ester experiment. As the students collect NMR data (and are given data from their peers), they compile tables of experimental data (for the keto and enol forms) and compare and contrast the two sets of data. Students also calculate Ke/k values for each compound. At the end of the handout, students describe the impact of various structural and electronic elements (e.g., steric bulk, lone pair conjugation) on Ke/k. This exercise is handed in at the end of the lab period and serves as the laboratory report for this experiment.

Hazards Many of the chemicals used in this experiment are hazardous in case of skin or eye contact, inhalation, or ingestion. Sample volumes are small, reducing risks of exposure. Students who prepare samples should wear goggles and gloves (nitrile) and work in a fume hood when handling these chemicals and proper precautions should be taken when handling NMR tubes. Furthermore, many of the 1,3-dicarbonyl compounds used in this experiment are combustible and/or flammable liquids. Therefore, open flames are prohibited when this experiment is being performed. Results and Discussion Interpretation of NMR Data for Keto-Enol Tautomers In this advanced experiment, students were required to go beyond the correlation tables found in most undergraduate texts to make correct peak assignments for the keto and enol tautomers of each molecule, at times relying on relative integral values. For example, when interpreting the 1H NMR spectrum for pentane-2,4-dione (Table 1, compound 1), one of the simplest molecules in the series, students must consider the deshielding effects of the two carbonyls in the keto tautomer and the vinyl and hydroxyl group of the enol tautomer. Students also learn that the hydroxyl proton of an enol group is much more deshielded than that of a typical alcohol proton. Using integrations and chemical shifts, students can readily assign the activated methylene protons of the keto form and the vinylic and hydroxyl protons for the enol form (environments B, D, and E in Figure 4). It is more challenging to assign the methyl protons in the keto and enol forms (environments A and C) since they have very similar chemical shifts and integrations. (It is noted that students can obtain accurate Ke/k values without making assignments for these methyl protons. This demonstrates the value of the normalization factors in the Ke/k calculation; see Equation 2.) Once peak assignments are made, students calculate Ke/k values for the compound of interest. An example calculation is shown in Equation 2. 128



Table 1. 1,3-Dicarbonyl Compounds with Their Respective Ke/k Values

Figure 4. 1H NMR spectrum of pentane-2,4-dione with peak assignments. 129 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Ke/k Values for 1,3-Dicarbonyl Compounds Table 1 contains the structures and Ke/k values for a diverse set of 1,3-dicarbonyl compounds. Students can assess the impact of electron donating (e.g., methyl) and withdrawing (e.g., cyano, halogens) groups at the 1 or 3 position. In addition, students assess how increasing bulk at the 1 and 3 positions affects Ke/k. Finally, lone pair conjugation and resonance are explored by looking at esters and phenyl substituents. A more detailed discussion of the structure-property relationships of these molecules is provided below.

Impact of Steric Bulk on Ke/k Compounds 1-4 were selected to evaluate the effect of aliphatic steric bulk on Ke/k. From this set of congeners students can evaluate the effect of R = R′ = -CH3, -CH2CH3, -CH(CH3)2, and -C(CH3)3 groups on Ke/k. Note that while steric bulk increases in this series the issue is not complicated with the possibility of aromatic conjugation (see below). In the cases of 2 and 3 students rely on their knowledge of spin-spin splitting as they make their peak assignments. These data suggest that increasing aliphatic steric bulk increases stability of the enol structure ([enol]: Me ≈ Et < iPr < t-Bu) thereby increasing Ke/k. However, the dynamic range (~ 7-fold) is small compared to other effects investigated in this and other reports (6, 7, 16–27). While this effect seems counterintuitive at first, students may build models of pentane-2,4-dione and 2,2,6,6-tetramethylpentane-2,4-dione to convince themselves that the enol form relieves steric clashing between the two t-butyl groups.

Impact of Electron Withdrawing and Donating Groups on Ke/k Marsh and coworkers contributed to the panel of compounds for these studies with 3-methylpentane-2,4-dione (5), 3-chloropentane-2,4-dione (7), and 3-cyanopentane-2,4-dione (8) (17–19). We add to this list 3-ethylpentane-2,4dione (6) and 1,1,1-trifluoropentane-2,4-dione (9). For compounds 5-8, R = R′ = -CH3; for compound 9, R = -CH3 and R′ = -CF3. Electron donating groups at the 3-position (methyl and ethyl) appear to stabilize the keto tautomer. This result might be counterintuitive to students who learn that for alkenes increasing substitution results in increasing stability (as measured by heats of hydrogenation (28)). The 3-chloro- and 1,1,1-trifluoromethyl- compounds clearly show that


electron withdrawing groups increase the stability of the enol structure which is consistent with Marsh and coworkers’ result (17–19) for 8.


Impact of Aromatic Bulk and Conjugation on Ke/k We selected from House (29) a commercially available compound suitable for this study, 1-phenylbutane-1,3-dione (10; R = Ph, R′ = -CH3), and complemented it with 1,3-diphenylpropane-1,3-dione (11; R = R′ = Ph). These compounds add the bulky phenyl group to a 1,3-dicarbonyl compound and complicate the analysis with the possibility of preferential enol/enolate stabilization via resonance and two possible contributing enol forms. One phenyl group (10) appears to affect the position of equilibrium consistently with the isopropyl group (3). While π-conjugation cannot be ruled out, a simple steric argument describes the behavior in this system. Two phenyl groups (11) drive the equilibrium to ~100% enol form (within the limit of detection). This reflects a much larger effect than two isopropyl groups and may involve resonance into the phenyl moiety.

Impact of Lone Pair Resonance on Ke/k Organic chemistry students study the effects of lone pair resonance on Ka when studying aldol and Claisen condensations as well as the acetoacetic ester synthesis and related reactions. Esters stabilize the carbonyl carbon by resonance (Figure 5) which has the net effect of stabilizing the keto form (30). We have selected a set of compounds representing a coordinate study of the effects of lone pair conjugation on the position of keto-enol equilibrium. Thus, we selected methyl 3-oxobutanoate (12; R = -CH3; R′ = -OCH3), methyl 3-oxopentanoate (13; R = -CH2CH3; R′ = -OCH3), and methyl 4,4-dimethyl-3-oxopentanoate (14; R = -C(CH3)3; R′ = -OCH3) for study. In this series, the methoxy group (12) shifts the position of Ke/k from favoring enol (compound 1 or 2) to favoring keto. Students also observe the competing effects of aliphatic steric bulk (that favors enol) and lone pair conjugation (that favors keto) in the values of Ke/k for compounds 13 and 14: the resonance effect trumps the steric bulk (which was not a huge effect to begin with in the aliphatic systems – 4 vs 1 – but was very large in the aromatic systems – 1 vs 10 vs 11).

Figure 5. Resonance stabilization of the keto form of methyl 3-oxobutanoate (compound 12). 131 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Cumulative Effects on Ke/k Inherent in the study of the effect of lone pair conjugation on Ke/k is an analysis of the accumulated effects of various structural elements on the position of equilibrium. From this panel of compounds students may consider and prioritize the effects of appending aromatic, aliphatic, electron donating, and electron withdrawing groups. Inspired by the pedagogic potential of such systems we added 4,4,4-trifluoro-1-phenylbutane-1,3-dione (15; R = Ph; R′ = -CF3) and ethyl 3-phenyl-3-oxopropanoate (16; R = Ph; R′ = -OCH2CH3) to our series. For 15 the two groups may reinforce each other to strongly favor the enol form, although this is beyond the limit of detection. Compound 16 favors the keto form as the resonance effect of the ethoxy group negates the steric (and/or conjugation) effect of the phenyl group (cf. 10). There are numerous other 1,3-dicarbonyl compounds which would provide students with additional opportunities to explore competing/cumulating effects.

Student Feedback and Outcomes In the beginning stages of this work, we used the determination of keto-enol equilibrium constants as our initial attempt to get students into the NMR laboratory. In our excitement we did not realize the complexities of this experiment for the novice whose foundational concepts of NMR were not sufficient to achieve the goals of the keto-enol laboratory exercise. This observation led to the concurrent development of the ester NMR laboratory as a precursor to the Ke/k laboratory. The benefits of this approach were realized almost instantaneously. As noted above, the ester laboratory provided students with a level of expertise that allowed them to approach the more complicated Ke/k experiment with confidence. The quality of the student lab reports for the Ke/k experiment increased immediately upon implementation of the ester lab (Part I). While students still find the concept of keto-enol tautomerization challenging and the determination of Ke/k somewhat frustrating, course evaluations indicated a greater level of confidence in and satisfaction with this laboratory. We look forward to incorporating the determination of Ke/k in this and perhaps other systems in a physical chemistry or instrumental analysis course to better assess the long-term benefits of this approach.

Instructor Notes Our group continues to increase the number of compounds suitable for study in the undergraduate laboratory, such that faculty and students will have a broader range of established compounds from which to develop new experiments. While others are working on compounds substituted at the central “2” position of the 1,3-dicarbonyl moiety (17–19), we plan to continue our exploration of the “terminal” positions. We are also investigating the behavior of cyclic 1,3-dicarbonyl compounds to evaluate their suitability for student analysis. 132 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Finally, we are looking to develop a laboratory exploring the limits of detection for semi-quantitative NMR analysis based on our observations for compounds 9, 11, and 15.


Conclusions The complementary experiments presented herein allow students to build a foundation in NMR spectroscopy and then explore a less traditional use of NMR. The ester experiment provides a student-centered approach to teaching chemical shift correlations, spin-spin splitting, and integrations, and it reinforces student understanding of the basic structural groups – methyl, ethyl, n-propyl, isopropyl, and t-butyl – that comprise many molecules. With this foundation in hand students embark on a more advanced experiment that allows them to utilize proton NMR to study keto-enol equilibrium in 1,3-dicarbonyl compounds. Both experiments, and particularly the keto-enol experiment, may be tailored for use in various chemistry courses including introductory and advanced organic chemistry, instrumental analysis, and physical chemistry. They also set the stage for students to use NMR for evaluation of rate constants, an area explored by others (24, 30). We encourage faculty interested in implementing these experiments to find more details, including classroom handouts, in our upcoming publications.

Coda Another benefit provided by this work was the transformational undergraduate research and laboratory development experiences of the three (former) student co-authors. Sherri Young pioneered the keto-enol experiment with salary and supplies support from the Merck Summer Undergraduate Research Fellowship (SURF; with room and board covered by the Provost’s Office through the Albright Creative & Research Experience (ACRE)). One motivation for her project was to develop a laboratory experience for undergraduates focusing on structure-function relationships in 1,3-dicarbonyl compounds. She presented her work at several regional and national conferences (including the National Conference for Undergraduate Research and the National Organic Chemistry Symposium (31–33)) and the experience was invaluable as she was discerning a career in academic chemistry. As an assistant professor, Sherri has continued to make intellectual contributions to this work and explore these and other NMR experiments for the undergraduate organic chemistry laboratory. Kyle Smith was a chemistry-secondary education student until his senior year when he decided to pursue doctoral studies in chemistry. Kyle combined his passion for chemistry with his gift for teaching by working to develop the keto-enol laboratory. His senior thesis (a requirement for the Albright Honors Program) focused in part on polishing the protocols for the ester/correlation laboratory and the keto-enol laboratory, including the implementation of real-time student feedback (that is, between two lab sections during the same semester) to generate publication-quality protocols suitable for implementation or adaptation by faculty here or at other institutions. He, too, was able to present his work regionally 133


and nationally (34, 35), and his experience paved the way to becoming an award-winning teaching assistant in graduate school. James DeBlasio continued this work, supported by the ACRE program, and is co-author on several of the presentations mentioned above. He credits his experience with an increased facility with problem-solving and method development, skills that help him in his current position as a senior chemist and laboratory supervisor in industry.


Acknowledgments We thank Michele Cramer, Christopher Graves, Stephen Paterno, Ian Rhile, and Eileen Walker, as well as the organic chemistry students at Albright over the past several years, for providing constructive feedback during the development of these experiments. We thank the Department of Chemistry & Biochemistry, the ACRE program, the SURF program, and the American Chemical Society Division of Organic Chemistry for support of this work. We are grateful to Andrea Chapdelaine, Provost, and Frieda Texter, Director of Undergraduate Research, for their unwavering support of student-faculty collaborative research; to Teresa Palazzo for assistance with preparing Figures 2 and 4; and to Nancy Kerper for secretarial support. Finally, this work would not be possible without the support of Pamela Artz who maintains the NMR facility at Albright College.

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