Communication pubs.acs.org/jchemeduc
Using Esters To Introduce Paradigms of Spin−Spin Coupling Kyle T. Smith and Christian S. Hamann* Department of Chemistry & Biochemistry, Albright College, Reading, Pennsylvania 19604, United States S Supporting Information *
ABSTRACT: Students analyzed a set of 34 carboxylic esters using 1H nuclear magnetic resonance (NMR) spectroscopy to examine paradigmatic examples of spin−spin coupling, a foundational concept used to determine molecular structure by NMR spectroscopy. The ester functional group provides excellent chemical shift dispersion so that students were able to analyze well-resolved peaks and to apply concepts of chemical shift, line shape, and integration to the analysis of molecular substructures. A laboratory activity combining molecular models, worksheets, and NMR data collection and analysis provided students with the ability to predict and to analyze spectra representing spin−spin splitting for N = 0−6 (where N is the number of three-bond neighbors that are hydrogens). KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Problem Solving/Decision Making, Constitutional Isomers, Esters, NMR Spectroscopy, Student-Centered Learning
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paper by Mann focuses on first-order coupling,5 and another by Lowry and Thoben provides a provocative analogy to help students focus on the reason for spin−spin splitting.6 The approach described herein used commercially available compounds from which students predicted NMR spectra and then tested their predictions by collecting their own data. This was accomplished by asking students to observe the chemical shift values, spin−spin splitting (multiplicity), and integral values of each resonance peak in an intentionally selected set of esters. Concurrently, students built molecular models so they could compare spectra to three-dimensional structures, practice naming ester compounds, and practice drawing line-angle structures. Importantly, this “dry lab” portion allowed students to remain engaged in the educational content of the laboratory even as they waited their turn for the spectrometer. Overall, these teaching techniques provided a firm foundation in spectra prediction and analysis that was applied to the analysis of more complicated spectra later in the organic chemistry course and then in advanced courses.
INTRODUCTION Nuclear magnetic resonance (NMR) spectroscopy is integral to the undergraduate chemistry curriculum. Concepts such as chemical shift, spin−spin splitting, and integration are learned and applied to clarifying substructures as students identify molecules and solve structures.1 However, interpreting undergraduate laboratory spectra can become complicated quickly, frustrating students and faculty alike as “work-arounds” are provided to the students so they can complete spectral and structural assignments. Ultimately, students know they did not accomplish the goal: an independent determination of their structure. We recently reported an updated experiment in which students determine the position of keto−enol equilibrium using NMR spectroscopy, including compounds containing methyl, ethyl, isopropyl, and t-butyl substructures.2 During the development of that experiment, we noticed that students could not focus on the determination of equilibrium constants when they were challenged by the interpretation of the signals correlated to these substructures. This report describes the implementation of a new approach that addresses this frustration by successfully making students more confident in their knowledge of paradigmatic structure assignments, spin−spin splitting patterns, and integral values.3 Thus, armed early in their study of organic chemistry, students solved basic and then more complex spectral assignments readily. Coupled in-class and in-laboratory exercises allowed students to make and test predictions of NMR spectra for a series of esters, a functional group that provided spectra with well-resolved signals. This Journal has several papers that provide students with the opportunity to solve structural problems and identify unknowns, two by Branz and co-workers specifically focusing on compounds containing the ester functional group.4 One © XXXX American Chemical Society and Division of Chemical Education, Inc.
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EXPERIMENTAL SECTION The handouts used for this laboratory may be found in the Supporting Information. The esters selected for this exercise are found in Tables 1 and 2. (See the Supporting Information for sources and experimental conditions.) Students collected spectra on either a 300-MHz or a 400-MHz spectrometer. The complete version of the experiment included all 34 esters and took two laboratory periods; the second week typically Received: May 28, 2016 Revised: October 28, 2016
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DOI: 10.1021/acs.jchemed.6b00397 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Table 1. 25 Nonhalogenated Esters Students Analyzed in This Exercisea
a
Black = commercially available; blue = not commercially available [synthesis accessible to undergraduates]; green = overlapping CH2 signals prevent unambiguous assignment.
Table 2. 9 Chlorinated Esters Students Analyzed in This Exercisea
a
All of the chlorinated esters used are commercially available.
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RESULTS AND DISCUSSION The experiment may be modified to accommodate shorter laboratory periods and varying teaching goals by selecting a subset of structurally related compounds that illustrate a given point. With 34 compounds to choose from, individual instructors may preselect compounds that highlight certain structural paradigms based on their course goals; even in larger laboratory sections, all students could work with their own sample. The process of analysis may also be reversed, such that students take spectra and solve for structure knowing only the molecular formula or perhaps only that the primary functional group of their analyte is an ester (or students can take an infrared spectrum to identify the ester). This experiment has been implemented in various iterations for more than 5 years by over 150 students. They were enrolled in first- or second-semester organic chemistry, were at least in their second year, and represented a range of majors including chemistry, biology, biochemistry, and environmental science. Central to the success of this approach was its careful use of student time. During a given laboratory period students worked
focused on the effect of chlorination on chemical shift, spin− spin splitting, and integration. (Although not all 34 esters are available for analysis, predictions could still be made.)
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HAZARDS
A summary of the MSDSs for the chemicals used in this experiment (including the NMR solvent) may be found in the Supporting Information. Many of the chemicals used in this experiment are hazardous in the case of skin or eye contact, inhalation, or ingestion, especially the α-chloroesters. Sample volumes are small, reducing exposure risks. Those who prepare samples should wear goggles and gloves (nitrile) and work in a fume hood when handling these chemicals. Proper precautions should be taken when handling glass NMR tubes and when working in the NMR laboratory. Furthermore, several of the compounds are combustible and/or flammable liquids. Therefore, open flames are prohibited when this experiment is being performed. B
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primarily in the classroom executing a guided exercise in which they used molecular models and foundational NMR concepts of chemical shift to predict the NMR spectra for a series of esters. Periodically, pairs of students were brought to the NMR room where each student collected her or his own spectrum from a prepared sample (a process that took 20−30 min roundtrip). In this way, students stayed on task (rather than on line), and using the photocopier, all students had authentic NMR spectra for every compound under investigation. This approach also controlled the flow of NMR data into the classroom to a useful pace: students in the classroom were greeted by students bearing spectra in time either to confirm or correct their previous predictions, and to aid in preparing the next set of predictions. A student assistant (an upper-class student hired by the department) provided guidance in the classroom, and the faculty member shuttled students to the NMR room; at times, more experienced student assistants guided laboratory students through the operation of the NMR instrument. NMR spectra generated by analysis of the ester functional group yielded appropriately introductory, yet challenging, spectra for student interpretation. This functional group is “pedagogic gold”, spectra of molecules containing the carboxyl functional group with its two electronegative oxygen atoms at the core of the molecule show excellent chemical shift dispersion, so students developed foundational knowledge of the interpretation of NMR spectra from cleanly resolved signals and paradigmatic first-order splitting. Since esters may be synthesized from the condensation of alcohols and carboxylic acids, five simple alcohols and five simple carboxylic acids may be combined systematically to form 25 esters7 that represent five signature alkyl groups, methyl, ethyl, n-propyl, isopropyl, tbutyl, in an NMR spectrum (Table 1). Including the chlorinated esters allowed students to access all first-order splitting patters for N = 0−6 (where N is the number of threebond neighboring hydrogens to a hydrogen under investigation) and to explore the effect of this electronegative element on chemical shift.8,9 Thus, a detailed study of a preselected set of esters allowed students to connect their predicted spectra to experimental spectra, leading to a closer reading of molecules based on chemical shift, spin−spin splitting, and integration.
signature (triplet−quartet: t, N = 2, N + 1 = 3; q, N = 3, N + 1 = 4). A student’s first prediction for chemical shift (based either on a correlation table5 or previous spectra analyzed during the laboratory period) typically did not include the combined effects of electronegativity and degree of substitution. Thus, predictions for the 1H septet were typically lower than the actual chemical shift of 5.0 ppm. However, once students picked up on these concepts, they applied that knowledge to structures such as the isopropyl group in the isobutyrates: that moiety has a tertiary C−H that with a chemical shift (2.5 ppm) at the high end of the range predicted for an α-hydrogen (2− 2.6 ppm).6 During a typical laboratory period students carried this approach through the five common signatures: methyl (singlet), ethyl (quartet/triplet), n-propyl (triplet/sextet/ triplet), isopropyl (septet/doublet), and t-butyl (singlet). Students also relied on direct comparisons of chemical shift between structurally related molecules and area of the proton NMR signals (below) to complete their peak assignments. Note that students did not evaluate or compare the size of the coupling (J-values); however, instructors interested in teaching this aspect of NMR spectroscopy may find the esters presented here as an appropriate starting point for aliphatic systems.
Spin−Spin Splitting: Paradigms of First-Order Coupling
Integration
First-order coupling, arising from magnetic coupling that occurs between groups of adjacent protons, provides information on connectivity.8 The compounds for this laboratory were selected because they provided paradigmatic first-order coupling due to the ester functional group.10 These compounds provide a nearly complete set of congeners (methyl, ethyl, n-propyl, isopropyl, and t-butyl) that provide a foundation for the study of more complicated NMR spectra.11 Using the N + 1 rule, students predicted the familiar pattern of singlets, doublets, triplets, etc., with theoretical peak intensities predicted by Pascal’s Triangle.8 The esters selected for this experiment allowed students to investigate all values of N = 0−6. For example, students predicted the NMR spectrum of isopropyl propionate and then compared their predictions to their experimental data (Figure 1). Using the selected compounds students practiced identifying three-bond neighbors and familiarized themselves with the various “signatures” found in NMR spectra due to first-order coupling. In this example, students observed an isopropyl signature (doublet− septet: d, N = 1, N + 1 = 2; sep, N = 6, N + 1 = 7), and an ethyl
The area of proton NMR signals is almost always proportional to the number of protons found within that chemical environment.8 Students exploited this property by predicting the number of hydrogens in each chemical environment and then comparing those predictions to the integration data from their NMR spectra. Thus, this experiment allowed students to practice integrating well-resolved peaks and to apply this, in combination with spin−spin splitting, to identifying five paradigmatic substructures. The selection of esters allowed them to correlate the paradigmatic structures with characteristic integrals: methyl (3H, singlet), ethyl (2H, quartet/3H, triplet), n-propyl (2H, triplet/2H, sextet/3H, triplet), isopropyl (1H, septet/6H, doublet), and t-butyl (9H, singlet). Integration was particularly useful for students to clarify the difference between the spectra of methyl acetate, t-butyl acetate, methyl pivalate, and t-butyl pivalate.
Figure 1. Representative 1H NMR spectrum, structure, and assignment of protons for isopropyl propionate (d = doublet, sep = septet, q = quartet, t = triplet).
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ASSESSMENT Student learning outcomes were assessed using a pretest (47 students) and post-test (48 students), the former administered C
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Table 3. Pre- and Post-Test Summary for Isopropyl Propionate and Isopropyl 2-Chloropropionate Isopropyl Propionate
Isopropyl 2-Chloropropionate
Ability To Predict
Pretest (%)
Post-Test (%)
Ability To Predict
Pretest (%)
Post-Test (%)
Doublet 6H Septet 1H Quartet 2H Triplet 3H
0 0 0 0 0 0 0 0
75 58 69 79 75 81 75 79
Quartet 1H Doublet 3H
4 0 4 0
79 65 75 67
on the first day of the course and the latter administered after all students had completed the laboratory assignment. The assessment questions focused on isopropyl propionate, the ester presented in Table 1, and isopropyl 2-chloroprionate, an ester they did not analyze but that is related to two esters found in Table 2 (methyl 2-chloropropionate and ethyl 2chloropropionate). The assessment and the exam questions may be found in the Supporting Information. Table 3 contains a summary of the pre- and post-test data using isopropyl propionate and isopropyl 2-chlorpropionate as objects of study. Students were asked to predict both the spin− spin splitting and the integral ratio for all 4 unique hydrogen environments. In all cases, their ability to do this increased after engaging the laboratory activity. For spin−spin splitting, 0% of students were able to make accurate predictions before doing the laboratory, and 69−75% were able to after doing the laboratory. For integral ratio, 0% of students were able to make accurate predictions before, and 58−81% of students were able to do so after. The most challenging prediction seemed to be predicting the integral for the identical methyl groups of the isopropyl group, with the most common error being a prediction of 3H instead of 6H. When students were asked about the effect of chlorination at the 2-position on spin−spin splitting, 4% before and 79% after were able to accurately predict that there was no change in the spin−spin splitting for this hydrogen. Also, 4% before and 75% after were able to predict the change from a triplet to a doublet due to the loss of one three-bond neighboring hydrogen. Similar gains in understanding were realized for predicting the integral after chlorination at the 2-position (2H → 1H: 0% before, 65% after) and at the 3-position (3H → 3H: 0% before, 67% after). For the determination of how well students did in an examination circumstance, questions related to the assessment questions were included on an in-class, closed-book exam (50 students; see the Supporting Information). For these questions, methyl butyrate and methyl 4-chlorobutyrate were selected. These compounds were not used in the laboratory, so students were making predictions based on prior experience with other compounds. Also, note that due to the timing of the laboratory and the exam, students did not have access to graded lab reports before taking the exam (although they did have their laboratory notebooks for review). In a comparison of results from Tables 3 and 4, with a focus on the post-test (second assessment) and the graded exam, students demonstrated an improvement in their ability to predict spin−spin splitting (69−75% post-test, 83−92% exam) and relative ratio of hydrogens in each chemical environment (58−81% post-test, 91% exam) for the nonhalogenated ester. When comparing their performance at predicting the changes
Table 4. In-Class Exam Summary for Methyl Butyrate and Methyl 4-Chlorobutyrate Ability To Predict for Methyl Butyrate 4 chemical environments OCH3 is a singlet Position 2 CH2 is a triplet Position 3 CH2 is a sextet
Ratio of hydrogens in each environment
Exam (%)
Ability To Predict for Methyl 4-Chlorobutyrate
Exam (%)
94 92 90 83
91
Position 3 CH2 changes from sextet to quintet (with explanation) Position 4 CH2Cl remains a triplet (with explanation) Ratio of hydrogens at the 3position does not change
77 78
Ratio of hydrogens at the 4position changes from 3 to 2
75
69
caused by chlorination, they maintained their ability to predict the effect of chlorination on spin−spin splitting at the site of chlorination (position 4 CH2Cl remains a triplet: 79% post-test, 78% exam) and at the neighboring position (position 3 CH2 changes from sextet to quintet: 75% post-test, 77% exam). Finally, on the exam students demonstrated an understanding of the effect of chlorination on integration both at the site of chlorination (3H → 2H: 65% post-test, 75% exam) and at the neighboring position (2H → 2H: 67% post-test, 69% exam). It is noted here that it is challenging to tease apart the root causes of gains in student learning outcomes because at this institution the lecture and the laboratory are part of the same course. However, gains before and after doing the experiment are evident, and those gains did persist or in some cases improved for students as evidenced by their performance on the graded exam. Similar gains have been observed although not quantified each year the laboratory has been included in the curriculum.
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SUMMARY Using 1H NMR spectroscopy students were able to analyze and determine the structure of preselected esters, compounds that have well-resolved signals and paradigmatic spin−spin splitting patters. This is accomplished by observing the chemical shift values, multiplicity, and integral values for each resonance peak. Students worked concurrently in the classroom and laboratory, an approach that helped them maintain focus and interest. Students learned and practiced NMR concepts while simultaneously improving their facility with nomenclature and line-angle drawing. Aggregate classroom data from longitudinal exam data, course evaluations, and personal narratives D
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S. Students Using Esters to Construct for Themselves the Concepts of Chemical Shift Correlation and Spin-Spin Coupling. In Abstracts of Papers, 249th American Chemical Society National Meeting, Denver, CO, March 22−26, 2015; American Chemical Society: Washington, DC, 2015; CHED-40. (4) (a) Branz, S. E. Acetylation of an Unknown Alcohol. J. Chem. Educ. 1985, 62 (10), 899−900. (b) Branz, S. E.; Miele, R. G.; Okuda, R. K.; Straus, D. A. Double Unknown Microscale Preparation and COSY Analysis of an Unknown Ester. J. Chem. Educ. 1995, 72 (7), 659−661. (5) Mann, B. E. The Analysis of First-Order Coupling Patterns in NMR Spectra. J. Chem. Educ. 1995, 72 (7), 614−615. (6) Lowry, T. H.; Thoben, D. A. An Analogy to Assist Understanding of Splitting Patterns in NMR Spectra. J. Chem. Educ. 1997, 74 (1), 68. (7) In practice, 21 of these 25 esters are commercially available. Four more were synthesized from the corresponding alcohol and acid chloride (see Supporting Information). Thankfully only one of these compounds, n-propyl butyrate, suffers from accidental magnetic equivalence (the two internal CH2 groups are nearly equivalent, as are the two terminal CH3 groups), which may be explored as a topic at the instructor’s discretion. (8) Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry: A Miniscale and Microscale Approach, 6th ed.; Cengage Learning: Boston, 2016; pp 260−261; 264−268, 270−271. (9) We note that for N = 4 and N = 5 there is multiplicative splitting that behaves as first-order. That is, we rely on a case of accidental magnetic equivalence (isochromism). Those who adopt this approach may wish to highlight this with the appropriate student audience. Alternatively, for N = 4, one could analyze 3-pentyl acetate, in which the methine hydrogen is split by 4 equivalent hydrogens. While 3pentyl acetate is not readily commercially available, it may be synthesized by the procedure found in the Supporting Information. Alternatively, dimethyl glutarate is commercially available (ACROS AC11623) and may be included as its central methylene (CH2) group serves as a paradigm of N = 4. (10) The differential effects of the chloro group and the carbonyl group are not detected at this level of analysis, so first-order line shapes are consistently observed. This topic might be further explored in an advanced course. (11) Angelin, M.; Ramstrom, O. Where’s Ester? A Game That Seeks the Structures Hiding Behind the Trivial Names. J. Chem. Educ. 2010, 87 (4), 406−407.
demonstrated that this technique improved students’ skills with interpretation of NMR spectra in class, in lab reports, and on exams. They also reported satisfaction with their ability to carry these concepts into later portions of the organic chemistry curriculum where they were expected to interpret more complicated spectra from their synthesis products. Further, students reported a positive effect from this exercise on their abilities in later courses (undergraduate and graduate) in which they were required to apply or extend their knowledge of NMR spectroscopy. (This evaluation is based on student narratives, not numerical assessments.) Of particular note was a benefit in instrumental analysis, advanced organic chemistry, and undergraduate research; several students also reported a positive impact from this experiment in their workplace. While many pedagogical approaches offer only a few examples of splitting, in this approach students analyzed examples from singlets (no splitting) to a septet in a logical, developmental fashion.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00397. Notes for the instructor (including a list of chemicals and suppliers), a protocol for the synthesis of esters from the corresponding alcohols and acid chlorides, 1H NMR data for all compounds, and the laboratory protocol for students (PDF, DOCX) NMR spectra (PDF) Assessment questions and exam questions (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the laboratory students and faculty whose feedback during the development and implementation of this laboratory was invaluable to the outcome. We thank the Undergraduate Research Committee and the Albright Creative & Research Experience program, the Professional Council of Albright College, and the Division of Organic Chemistry of the American Chemical Society for partial funding of this work. Special thanks are due to Pamela Artz who maintains the NMR facility.
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REFERENCES
(1) See, for example: (a) McClusky, J. V. A New Tool to Aid Students in NMR Interpretation. J. Chem. Educ. 2007, 84 (6), 983− 986. (b) Flynn, A. B. NMR Interpretation: Getting from Spectrum to Structure. J. Chem. Educ. 2012, 89 (9), 1210−1212. (2) Smith, K. T.; Young, S. C.; DeBlasio, J. W.; Hamann, C. S. Measuring Structural and Electronic Effects on Keto−Enol Equilibrium in 1,3-Dicarbonyl Compounds. J. Chem. Educ. 2016, 93 (4), 790−794. (3) Developments in the progress of this collaborative student− faculty project have been presented: (a) Smith, K. T.; Hamann, C. S. Probing New Approaches for Teaching Nuclear Magnetic Resonance Spectroscopy. In Abstracts of Papers, 43rd National Organic Chemistry Symposium, Seattle, WA, June 23−27, 2013; American Chemical Society: Washington, DC, 2013; W-76. (b) Smith, K. T.; Hamann, C. E
DOI: 10.1021/acs.jchemed.6b00397 J. Chem. Educ. XXXX, XXX, XXX−XXX
