NMR Spectroscopy - American Chemical Society

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NMR Spectroscopy: A Critical Piece of the Spectroscopy-Centered Synthetic Curriculum John J. Esteb, LuAnne M. McNulty,* Stacy A. O’Reilly, and Anne M. Wilson Clowes Department of Chemistry, Butler University, 4600 Sunset Avenue, Indianapolis, Indiana 46208, United States *E-mail: [email protected]

Spectroscopic characterization at Butler University spans the undergraduate synthetic curriculum. Students learn basic spectroscopic techniques in organic chemistry, and then learn more advanced methods in later synthetic courses and undergraduate research. The curriculum follows a four phase plan that transitions students from an introductory phase that focuses on a single spectroscopic technique to an integrative phase where students use multiple spectroscopic methods to piece together unknown structures. NMR spectroscopic analysis is critical for students when they transition to the integrative phase.

Introduction Spectroscopy can be an important component of a comprehensive approach for teaching problem solving skills, including the development of understanding what is or is not relevant data, the enhancement of student confidence by enabling students to identify reaction outcomes, and the empowerment of students to build connections in their own knowledge. At Butler University, we value the skills that students develop by learning spectroscopy, but have found students unable to apply these skills independently in advanced classes and undergraduate research. We have worked over the course of many years to improve how we cover spectroscopy and the related skills in our classes. It is well known that frequent exposure to a topic progressively deepens understanding. Thus, structure elucidation using spectroscopic methods must © 2016 American Chemical Society

Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

be introduced and reintroduced with increased complexity from introductory organic chemistry through undergraduate research. Our approach involves the implementation of a four phase plan that starts with a very basic understanding of spectroscopy and progresses to an understanding of how spectroscopy is used to elucidate structure. The primary emphasis of this chapter is to describe how we teach Nuclear Magnetic Resonance (NMR) spectroscopy using a four phase plan. We also include a brief description of how other spectroscopic techniques are covered in our curriculum.


Background For many years at Butler University the bulk of instruction in spectroscopy occurred exclusively during the second semester of organic chemistry. Students learned mass spectrometry (MS), infrared spectroscopy (IR), 1H NMR and 13C NMR spectroscopy in the lecture portion of Organic Chemistry II and utilized the techniques during a four week unknown laboratory. In the unknown laboratory, students used the reference book, The Systematic Identification of Organic Compounds (1) to identify solid and liquid unknowns from a list of possible compounds based upon melting and boiling points. The list of possible compounds had varied molecular weights and functional groups, with the breadth of functional groups in the unknowns narrowed down after solubility testing. After obtaining the list of possible compounds, students then acquired or were given spectroscopic data that included MS, IR, 1H NMR and 13C NMR to identify their solid and liquid unknowns. This approach had limitations. First, the ready accessibility of spectroscopic data on the Internet through searchable databases reduced the need for students to struggle with their data. They searched for the spectral data based on the names of the compounds on their lists to eliminate those compounds whose data did not match, circumventing the reinforcement of spectral problem solving skills and of concepts covered in class. Second, the breadth of compounds used for unknowns was limited to those within the reference book. Although many of those compounds were useful unknown candidates, some of them had limited structural complexity resulting in students having drastically different experiences in identifying their unknowns depending on the difficulty of the unknown that they had selected. Third, the reference book identified many compounds by their common names instead of their IUPAC names. While this minimized students’ ability to easily search for those compounds online, students were often confused even when they got their structures correct. Furthermore, since IUPAC nomenclature establishes a connection between the name and structure, students are unable to identify the correlation of the expected spectral data to the functional groups contained within their compound. After the four week laboratory, students still struggled with linking lecture and laboratory material and with structure determination due to a lack of proficiency in problem solving skills. In terms of spectroscopic instruction, students did not connect the material covered in the organic chemistry course with spectroscopic experiences in subsequent courses. In order to address the multiple problems in 128 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

the instruction of spectroscopy we developed a comprehensive four phase plan supported by a CCLI grant from the National Science Foundation to integrate spectroscopy throughout the synthetic curriculum.


Overview of Approach The four phase strategy of teaching spectroscopy progresses from initial exposure in Organic Chemistry I through students’ participation in undergraduate research. The interconnectedness and complexity of tasks increases through the four phases, which includes the introductory phase, the exploratory phase, the participatory phase and the integrative phase (Table 1). In general, the introductory and exploratory phases were introduced in Organic Chemistry I, then the remainder of the exposure was dedicated to the participatory and integrative phases in Organic Chemistry II, advanced synthetic chemistry courses, and finally in undergraduate research.

Table 1. Summary of the Four Phase Plan for Spectroscopic Instruction Description

Phase Introductory

Student gains brief introduction to a single spectroscopic technique and uses data for matching purposes.

Exploratory

Student uses single technique to determine product ratios.

Participatory

Student uses multiple techniques (MS, IR, 1H NMR, 13C NMR) to determine relatively simple unknowns.

Integrative

Student uses multiple techniques (MS, IR, 1H NMR with complex splitting, 13C NMR and 2-D NMR) to determine structure of unknown reaction products and perform reaction analysis.

Introductory and Exploratory Phases The introductory and exploratory phases establish the foundation for the purpose of spectroscopic data analysis in synthetic chemistry. Both of these phases utilized gas chromatography-mass spectrometric (GC-MS) data, introducing students to the need to utilize data to determine reaction outcomes. This approach also foreshadows why an array of methods are needed to analyze products for full structure determination. In the introductory phase, students gained an understanding of how to compare data from an unknown compound with data from a known compound in order to verify experimental outcomes. This understanding came primarily from the students using GC-MS to analyze their reaction product and subsequently matching the parent ion in the mass spectrum to the molecular weight of their expected product. In the exploratory phase, students were exposed to the fact that multiple products can form during a reaction and determined product ratios using GC-MS. 129



Participatory The participatory phase requires data analysis from multiple spectroscopic techniques. By the end of the participatory phase, students will be able to use NMR, IR, and GC-MS data in order to determine chemical structure and to determine the outcome of reactions. From past experience, we know that the introduction of spectroscopy in lecture must closely align with dedicated practice on real samples in the laboratory, and every effort was made to introduce a new spectroscopic method in the lecture immediately before a laboratory experience that utilized the method. Several experiments in the second semester organic laboratory that utilize 1H NMR and/or 13C NMR spectra will be discussed in detail. For each experiment, the learning outcomes for the laboratory experience will be identified before the discussion of the laboratory.

Identification of Organic Unknowns Learning Outcomes: Students will utilize multiple forms of spectroscopy to determine the structure of two relatively simple organic unknowns. Further, students will recognize how GC-MS, IR, 1H and 13C NMR provide complementary information about a compound. In the laboratory, students determine the structure of both a solid and a liquid unknown using GC-MS, IR, 1H and 13C NMR. Students acquire the data over a period of three weeks. In the fourth week, the students present and support the structures of their unknowns. We have a list of approximately 30 solid unknowns and 30 liquid unknowns that were chosen on the basis of their relative safety and spectral data. While some of these unknowns may be in the book The Systematic Identification of Organic Compounds, many are not. Students obtain melting point and boiling point data for their unknowns along with IR spectra of their unknowns. The IR spectra allow students to narrow the list of possible functional groups in their unknowns. In order to reinforce the complementary information available from the different types of spectroscopy, students are encouraged to predict the characteristic 1H and 13C NMR signals based upon their IR data. Then, when students obtained their 1H NMR and 13C NMR data, they were then asked to confirm their suspected functional groups predicted by the IR data. In some cases, the interpretation of the 1H NMR and 13C NMR data is enough for students to determine the structures of their unknowns. However, we have deliberately chosen some unknowns that pose challenges for structure elucidation due to elements of symmetry or less straightforward data. These compounds require that students use all of the pieces of spectroscopic data in order to determine the final structures. For example, as shown in Figure 1, one of our unknowns is diethyl malonate, which has three signals in the 1H NMR spectrum. While students are able to easily identify the ethyl group based on splitting, the singlet from the methylene can be difficult for the students to interpret correctly. Frequently, students are confused by the relative integration values for the ethyl groups compared to those of the methylene group, thus, they assume one ethyl group and one CH. 130



Figure 1. 1H NMR spectrum of diethyl malonate.

Phorone is another unknown that confounds students due to the symmetry of the molecule. Figure 2 shows the relative integration of peaks, which challenges students. Students do not immediately assume that they need to multiply the integration values by two. Nor does a simple doubling of the number of carbons and protons equal the molecular ion in the mass spectrum.

Figure 2. 1H NMR spectrum of phorone.

Salicylamide is not symmetrical, but it is a compound that has data that can be easily misinterpreted. Frequently, students identify the compound as a carboxylic acid, not an amide, which is likely due to the presence of hydrogen bonding in the molecule which impacts both the IR data and the 1H NMR data. In the 1H NMR spectrum of salicylamide, in Figure 3, there is a peak at 13 ppm. Although this peak at 13 ppm is higher than a typical carboxylic acid, many students are not proficient enough at NMR spectroscopy at this point to consider that it is anything other than a carboxylic acid.

131 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 3. 1H NMR spectrum of salicylamide. This organic unknown laboratory experience is the linchpin in the transition of students from introductory and exploratory spectroscopy experiences to participatory experiences. During the first three weeks of the four week experience, students acquire or are given one new piece of data. Throughout the first three weeks, faculty provide feedback to each student in order to point out pieces of data the students did not interpret fully and encourage each student to be more comprehensive in their data interpretation. During the final week, students present their findings to the class. In this way, students are able to analyze a single piece of data individually before combining the data to solve the structure. The oral presentation helps students organize their data and reflect on how they determined their final structure. In addition to the oral presentation, each student writes a formal laboratory report that includes all of their data as well as interpretation of each piece of data and how the data from one method supports data from a different method. For example, if a student observes a carbonyl peak in the IR spectra, then the student needs to correlate that to the peak in the 13C NMR spectrum that confirms the presence of the carbonyl carbon. The oral presentation and the formal laboratory report are critical for ensuring that students understand their data. Frequently, students become aware of their lack of understanding of the meaning of their spectral date only during the process of preparing for the oral presentation or writing their report. Acetylation of Ferrocene Learning Outcomes: Students will begin to understand the importance of using NMR for reaction analysis by comparing 1H and 13C NMR spectra of reactants and purified products. The acetylation of ferrocene is the first experiment after the determination of the unknowns where students are required to use NMR spectroscopy to confirm the identity and purity of both reactants and products. In this classic experiment, ferrocene undergoes acetylation to give acetylferrocene and in some 132



cases bisacetylferrocene as shown in Figure 4. The products are separated by column chromatography. Students are then provided the 1H NMR free induction decay (FID) data for the starting materials and purified products, which they then transform into the 1H NMR spectra using Spinworks (2). In addition, students are given the 13C NMR spectra of the starting ferrocene and the purified products. The students compare the spectra of the starting material to the products to verify the chemical transformation. Students need to understand that a synthetic chemist uses NMR analysis to probe the outcome of a reaction and to confirm the purification of a compound.

Figure 4. Acetylation of ferrocene. Students identify the changes in the NMR spectrum upon going from ferrocene to acetylferrocene and possibly to bisacetylferrocene. As shown in Figure 5, the 1H NMR of ferrocene is very simple due to the symmetry of the molecule; containing just a singlet at 4.2 ppm for the 10 equivalent protons.

Figure 5. 1H NMR spectrum of ferrocene. Upon monoacetylation, the D5h symmetry of ferrocene is disrupted, which is clear from the 1H NMR spectrum in Figure 6. One cyclopentadienyl ring contains five equivalent protons, giving a singlet at 4.2 ppm. The other cyclopentadienyl ring that bares the acetyl group, gives three signals. The singlet from the acetyl group occurs close to 2 ppm, which is clear from the integration of the peak. By comparing the 1H NMR spectra of the starting material and the product, students are able to also see the effect that symmetry has on the signals in a NMR spectrum. 133 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 6. 1H NMR spectrum of acetylferrocene. In order to determine if students are meeting the desired learning outcome for the laboratory the students must demonstrate in writing that they can assign peaks in the 1H NMR and 13C NMR spectra. The reactants and products of the reaction have readily accessible 1H NMR and 13C NMR spectra from online databases, so students also can use a basic matching of spectra to confirm their reaction outcomes. This experiment establishes the process by which reactions are analyzed by NMR spectroscopy and provides a foundation for how each subsequent experiment will be conducted in terms of spectroscopic analysis. Amide Preparation Learning Outcomes: Upon completion of this lab students will be able to explain how NMR spectra differ for closely related compounds. Amide preparation is introduced in the organic chemistry lecture, but the methods available for this important transformation in the teaching organic laboratory have been limited due to the need for stoichiometric amounts of hazardous reagents. We chose to utilize a literature procedure for the formation of amides from amines and carboxylic acids using activated silica gel. This bypasses some of the aforementioned difficulties typical in amide formation (3). We have been able to utilize this basic experiment in two different ways in order to change the emphasis of the procedure. In the first way, students choose their amine and carboxylic acid partners then compare the products with other students who have used different amine and carboxylic acid partners. In the second way, students use the spectral data from their product to determine the identity of an unknown amine starting material. The students are given a short list of amines (aniline, N-butylamine and Ndodecylamine) and carboxylic acids (benzoic acid, octanoic acid, and phenylacetic acid), and from these options they synthesize a small library of amides. Students choose their desired starting materials and assemble the reaction mixture in a sealed microwave reaction vessel. After microwave heating the reaction mixture, students are able to easily extract the product from the silica gel. Once the products 134



are isolated, students obtain GC-MS data and 1H and 13C NMR spectra of their starting materials and products to confirm product formation. The structure of the amines and carboxylic acids are relatively simple, which gives students the ability to identify differences between starting materials and products relatively easily. Students can clearly identify the disappearance of the carboxylic acid in the 1H NMR spectra and can clearly observe how the NMR of the amine changes upon conversion to the amide. Each student analyzes their own data and compares it to data obtained by students with a different amine/carboxylic acid pair to compare the impact of different amines on the chemical shifts of the amide protons. Students demonstrate the learning outcome through the submission of a laboratory report that includes target questions about the similarities and differences of the amide products. In an alternate approach to the experiment, students are given a known starting carboxylic acid but one of three unknown starting amines. The experimental procedure is the same, but students are given NMR and GC-MS data of their products. Using the data, students determine the identity of the unknown amine starting material. In this approach it is necessary for students to predict the NMR data for the known starting carboxylic acid and identify how signals differ in the amide product relative to the amine starting material. Students then use the remaining data to piece together the identity of the starting amine while taking into consideration how the structure of the amine changes as a result of the reaction. This alternate approach is intended to give a deeper understanding of the power of NMR spectroscopy. The synthesis of the amide has provided exposure to an important reaction in peptide synthesis but more importantly, provided flexibility in NMR laboratory coverage. Diels-Alder Learning Outcomes: Students will be able to analyze the outcomes of a set of related reactions and will be able to explain how small changes in structure impact chemical shifts through the comparison of the 1H NMR spectra. The Diels-Alder reaction has been used to provide access to a series of closely related, complex structures. As shown in Figure 7, the students converted an aldehyde, either trans-2-pentenal or E-2-methyl-2-pentenal, to a diene through in situ acetylation. One of two dienophiles, N-methylsuccinimide or succinic anhydride, was added and the reaction mixture was heated in a microwave reactor. The product, which was a highly substituted bicyclic product, was a more complex structure than what was observed in the amide lab.

Figure 7. Multicomponent Diels-Alder reaction. 135 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


While the experiments were running in the microwave reactor, students were provided NMR spectra of their starting materials and used the Spinworks2 program to transform an FID of their likely product into a proton NMR spectrum. Although it would have been ideal to have students use their own samples, there was not enough time to perform the synthesis, work up the reaction mixture and obtain an NMR spectrum during the three hour lab period. The FIDs that were used were chosen deliberately because they had somewhat limited impurities, which in the case of the complex product structure, enabled students to more clearly interpret the peaks in the spectrum. However, the spectrum still contained peaks that were not from the pure product. Each student paired with two additional students who used a different combination of aldehyde and dienophile. During a discussion in the lab, the three students worked together to correctly identify all peaks in their starting materials. They then compared the NMR spectra from their starting materials to the NMR spectra of their products in order to assign all peaks in the product spectrum. To do this, students had to compare the peaks (chemical shift, integration, splitting) from each reactant and contrast those peaks to the chemical shifts of their products. They determined exactly what peak correlated with each proton in the product. Students had to be able to explain the difference in chemical shift, integration and the difference in splitting between the peaks in order to give full assignments. We thought there were at least three diagnostic peaks that students should identify as is seen in Figure 8. Each structure had a proton that is labeled Ha in the structure below, which is a methine carbon with an acetoxy group. Each structure contained at least one vinylic proton, which is labeled as Hb, but one product also had a second vinylic proton, which is identified as Hc. For two of the three products, the group Y was an N-methyl group. Given the distinctive shift of protons on a carbon next to the nitrogen, we considered that the protons on the methyl group would give a distinctive signal in both the 1H and the 13C NMR spectra.

Figure 8. Key protons in bicyclic Diels-Alder product. As can be seen in the 1H NMR spectra in Figure 9, the peak for Ha is close to 5.4 ppm, which is consistent for a proton on an allylic carbon that also has an electronegative atom. The peak at 5.55 ppm in RXN 1 and in RXN 2 correspond to structures where there is a single vinylic proton Hb. However, the broad peak at 5.9 ppm in RXN 3 reflects both vinylic protons. Although the integration is not shown on these spectra, the students obtain integration values that confirm the number of protons represented by the overlapping peak at 5.9 ppm. The protons 136 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


in the N-methyl group are found at 2.9 ppm in RXN 3 and RXN 1 as a singlet with integration of three protons.

Figure 9. 1H NMR spectra of various Diels-Alder adducts. The NMR portion of this experiment worked very well for improving student understanding of analyzing complex structures by NMR spectroscopy. As these were the most complex structures the students had analyzed, the students struggled at first, and required a lot of instructor prompting. Eventually the students became more comfortable with the process aided by the group analysis of similar compounds for reinforcement of chemical shifts and splitting. The students were better able to justify their assignments as a result of comparison with other related spectra. Students were also more proficient at identifying how small changes in structure impact chemical shifts. Although the spectra were relatively clean, there were solvent peaks and some minor impurities that the students had to distinguish, which better prepared them for analysis of complex structures as they continued in the course. Unfortunately, the experiment experienced challenges associated with running several different reactions simultaneously in our microwave reactor. We have been looking for an alternate reaction or a way to incorporate this as a dry exercise for students to continue to reinforce the use of NMR spectroscopy for complex analysis. Synthesis Lab Learning Outcome: Students will gain an understanding of the types of techniques involved in undergraduate research and of the development of experimental protocols that include NMR analysis. The final laboratory experience in organic chemistry was a synthesis experiment designed to provide students with a preview of the types of tasks that would be undertaken in an undergraduate research setting. Students were given a target compound and asked to identify a method for preparing the compound by using the literature to find reasonable synthetic procedures. The target compounds we have used include 1,2-diphenylethanol, trans-cinnamic acid, and 2-methyl-1-phenylpropanol. The synthetic procedures were checked 137



by instructors, then, because there are countless procedures available for many compounds, students were directed to one of a few procedures they could use. By limiting the actual procedures students could use we minimized the costs associated with running over 200 students through the lab in a semester. Each student had to identify the spectroscopic techniques that would be necessary for product determination, which was a critical part of the development process. From an instructor point of view it was expected that students recognized the need to use NMR spectroscopy to analyze their reaction outcomes. In this laboratory, NMR spectroscopy is used to confirm product formation and to determine the purity of products. Students confirm whether their reaction is successful through the identification of significant peaks in the 1H and 13C NMR spectra. Although students have been doing this throughout the semester, in this case, when the students include spectroscopic analysis in their procedure they confirm their understanding of the importance of spectroscopic data analysis of reaction outcomes. During the discussion in the laboratory they are asked to identify the purity of their compounds. The identification of the purity of their products by NMR is conceptually similar to the analysis of product mixtures by GC-MS in the first semester in order to determine product ratios. This establishes continuity in the entire lab sequence and is critical for students as they begin to transition to more research based projects. Coupled with the data analysis from the Diels-Alder lab, students are exposed to using NMR spectroscopy for routine structure confirmation, complex structure identification, and purity determination, all of which are critical skills when doing reactions with unknown outcomes that must be determined by spectroscopic evidence. For example, in the synthesis of 1,2-diphenylethanol the students can choose hydride reduction of 1,2-diphenylethanone, phenyl Grignard or benzyl Grignard addition to an aldehyde, hydration of styrene, or hydride opening of styrene oxide to prepare the target. Although all of the potential methods produce the desired product, however the ease of the reaction as well as the efficiency of the reaction relative to purity varies from procedure to procedure. By comparing the NMR spectra obtained from the different procedures, students gain a greater appreciation for the varying degree of impurities present in their product depending on the reaction pathway chosen. NMR spectroscopic analysis of the product obtained from the NaBH4 reduction of benzyl phenylketone shows that the reaction proceeds cleanly, in high yield, with minimal impurity present as seen in Figure 10.

Figure 10. 1H NMR spectrum of the product resulting from the reduction of 1,2-diphenylethanone to 1,2-diphenylethanol. 138 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Though the desired product is formed from a Grignard addition, multiple impurities can be seen in the 1H NMR spectrum of the product, particularly in the aromatic region as seen in Figure 11.

Figure 11. 1H NMR spectrum of 1,2-diphenylethanol from Grignard addition. The learning outcomes for this experiment included the development of experimental protocols and the understanding of skills involved in undergraduate research. Prior to submitting a formal experimental plan for their synthesis, students were given feedback on the feasibility of their initial plans. Each student then demonstrated their ability to develop a synthesis of the target by turning in a fully written experimental protocol including the intended analytical methods that was based on a literature procedure. After the experiment was completed, students turned in a laboratory report where the student discussed the outcome of the reaction, including how the spectroscopic data supported the formation of their product.

Integrative In the integrative phase students are able to use NMR spectroscopy to determine the structural identity of a compound and to use the analysis of NMR data to understand chemical reactivity. Students are called upon to use NMR spectroscopy as one piece of a tool kit for understanding chemical structure and reactivity. The previous phases strongly focused on how NMR is used for confirming reaction outcomes where the products are known. For example, students expected to see acetylferrocene and bisacetylferrocene before they conducted the experiment and the NMR data supported the formation of those products. Beyond the confirmation of expected reaction outcomes, in the integrative phase students deduce the structures when the product of a reaction is unknown or unexpected. Chemistry majors may elect to enroll in an advanced synthesis laboratory course, which is called Synthesis and Characterization, after completing the organic chemistry series. This course focuses on designing, executing and 139


analyzing the outcomes of synthetic reactions in order to gain insight into the reactivity of a metal complex, the mechanism of a reaction or the reactivity of a substrate. NMR spectroscopy is integral to understanding these processes. The remaining discussion will focus on three projects in the inorganic synthetic course, which emphasizes the use of main group and transition metals in organic transformations.


Primary Literature Work Learning Objectives: Students will use NMR data and actual NMR spectra obtained from the primary chemical literature to learn new NMR techniques, including multinuclear NMR and 2D NMR interpretation, and to learn how to use complex splitting patterns in structural analysis. For many of the students in the Synthesis and Characterization course their last experience with NMR was in the organic chemistry laboratory, one or two years prior. To bring students to a fuller understanding of the many aspects of NMR spectroscopy not addressed in the organic chemistry series, a seminar on NMR was incorporated into the course. The approach utilized NMR data and spectra from the primary literature to illustrate more advanced aspects of NMR. The journal Organic Letters was used as an invaluable resource for the discussions. In the seminar, a specific advanced aspect of NMR that students could expect to routinely encounter, such as the coupling in a terminal alkene, was presented. A simple example, like styrene, would be discussed to explain the general idea of coupling in terminal alkenes. Then, students worked in groups to apply the idea to a more complex system obtained from a literature reference. For example, students would obtain spectroscopic data from a paper or supplementary information and work through the coupling constants to relate the J values to specific structural features. Additional topics covered in the seminar included the analysis of signals representing diastereotopic hydrogens, interpretation of 2D NMR spectra, and the use of other NMR-active nuclei. After the introduction of an advanced topic and the discussion of an example, students were given an NMR problem on the topic. Students worked together to find the solution to the problem and presented the answer to the group, reinforcing their understanding of the topic. Further, the presentation to the group confirmed that students had met the desired learning outcome for the literature project. The work not only served as a review of NMR spectroscopy, but the practice with interpreting data from more advanced NMR techniques prepared the students to more fully use the information available from modern NMR spectroscopy in the analysis of their own reaction mixtures. Ring Closing Metathesis of Dienes Learning Objectives: Students will be able to prepare NMR samples, use the NMR spectrometer to obtain an NMR spectrum, and analyze NMR data. Students will be able to calculate coupling constants and use them to make structural assignments. 140 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: Upper-Level Courses and Across the Curriculum Volume 3 ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Grubbs’ first generation catalyst can be used in the ring closing metathesis of dienes, which is an effective example that we use to reinforce complex splitting within alkenes. In the laboratory, 1,7-octadiene or 1,6-heptadiene are employed as substrates to form cyclohexene and cyclopentene, respectively. As students have not yet prepared their own NMR samples or acquired their own spectra in their previous spectroscopy experiences, a critical piece of preparing students to use NMR also included training on sample preparation and on the operation of the departmental NMR spectrometer. Students are expected to obtain and analyze the NMR spectra of the starting dienes. As the seminar portion of the class has covered the coupling patterns in terminal alkenes, the students are prepared to see the three distinctive signals of the alkenes with the characteristic terminal alkene coupling pattern. As part of the data processing of the spectrum, students determine all of coupling constants for each signal in the proton NMR spectrum and in particular for the vinylic protons of each starting material. The students also obtain the 1H and 13C NMR of their products where they are able to see that the three signals of the terminal alkene are no longer present and a single vinylic signal has appeared. In most cases, the NMR spectra are messy, and students must struggle to identify the key peaks. The vinylic hydrogen appears as a triplet due to coupling to the adjacent methylene group. Again, coupling constants are calculated for each proton in the NMR spectrum. Because the compounds are known, students can compare their spectra to NMR spectra on searchable databases. Upon completion of the experiment, students prepare a lab report that must include 1H and 13C NMR data for both the starting dienes and the final cyclic alkenes in ACS format, including coupling constants. Faculty feedback is necessary at the stage to help students work through the many mistakes that are present in the assignments and in presentation of the data. As a result of this lab, students are able to use the departmental NMR to acquire and process NMR data, as well as analyze and report NMR data. Other multi-week laboratory experiences follow that further refine students’ ability to apply NMR to understanding synthetic reactions. 1,2- and 1,4-Addition Reactions Learning Objectives: Students will use NMR to determine the outcome of a short term research project. As the culminating experience in the synthetic laboratory course we want students to design and execute a short-term research project. Rather than focusing on trying to make a specific compound, students are charged with developing a thesis dealing with the addition of organometallic nucleophiles to α, β-unsaturated carbonyl species as shown in Figure 12. The addition of nucleophiles to α,β-unsaturated carbonyl species is well known for giving mixtures of 1,2and 1,4-addition products. Based on their understanding of the addition of nucleophiles to α,β-unsaturated carbonyl species from organic chemistry, students develop a hypothesis to test. Student developed projects have included a study of the impact of temperature on the addition of lithium reagents to α,β-unsaturated ketones, a study of whether the hybridization of the carbon nucleophile changes 141



the reactivity of Grignard reagents, a study of whether a bulky Grignard reagent will still behave as a nucleophile when added to substituted α,β-unsaturated system, and others. Possible nucleophiles that are commercially available include alkyl lithium reagents, hydride reagents, Grignard reagents, or student prepared Gilman reagents. The substrates that are commercially available include α,β-unsaturated ketones, aldehydes and esters.

Figure 12. 1,2- vs. 1,4- addition student driven projects. Students research the reaction conditions and identify experimental protocols for their reactions. The faculty member approves the plans to ensure student safety, but does not correct planning errors such as a student deciding to use a large excess of the α,β-unsaturated system or choosing an electrophile with an acidic proton. After the reactions are complete, the products are isolated but not purified. Students then collect NMR spectra on the crude reaction products. Based on their previous experience of using NMR, students expect to see the clean formation of a single product with very little else in the spectrum. However, since reaction conditions are not optimized, a single product is rarely observed. The NMR spectra that students obtain are typically complex mixtures of the expected 1,2- and 1,4-addition products, starting material, byproducts from coupling or decomposition of the nucleophiles, and other unexpected species. Signals due to starting material and solvent can easily be identified. Since many of the spectra contain too many components to allow for full peak identification, this is an ideal situation for students to identify and interpret distinctive signals from each of the components. For example, the conjugate addition of a methyl group to cyclohexenone gives a distinctive doublet for the methyl group, while addition of the methyl group to the carbonyl carbon gives a singlet for the methyl group in the 1H NMR. In order to determine if students are meeting the desired learning outcome for the experiments, students are required to submit a laboratory report. In the report, based on the NMR analysis of reaction outcomes, students explain what species formed, draw mechanisms to explain the product formation and discuss whether or not their observations coincide with their predictions. The lab is an excellent precursor to independent research since students have developed their own hypothesis, conducted the necessary experiments and analyzed their data to support or disprove their hypothesis.


Undergraduate Research


Some students move directly from the synthetic laboratories into synthetic research, but other students engage in undergraduate research without taking an advanced synthetic laboratory course. These students also experience gains in understanding spectroscopy since they have the opportunity to use spectroscopy and apply problem solving to new and different systems beyond those observed in organic chemistry. Undergraduate research is inherently integrative, as students must fully understand reaction outcomes in order to further their projects, thus, more practice analyzing unexpected results in beneficial. This is especially true when we consider that many reactions do not always give the desired outcomes, which can lead to interesting discoveries in the laboratory.

Summary The use of NMR spectroscopy in the undergraduate curriculum at Butler University has been deliberately designed to be very highly integrated into a general spectroscopy program that spans multiple disciplines and multiple courses. Further, a funded CCLI grant that provided Butler University with a GC-MS for organic chemistry and advanced synthetic inorganic chemistry was the impetus behind the integration of spectroscopy instruction throughout the synthetic courses at Butler. The four-phase approach starts with an introduction to using a single spectroscopic method to support the identity of an unknown. The students further explore the single technique for the analysis of a product mixture. Students then use the combination of multiple spectroscopic techniques to discover basic structures of unknown compounds and confirm expected product formation in organic reactions during the participatory phase. Finally, students deepen their knowledge of diastereotopic protons, coupling constants, two-dimensional techniques and other nuclei to determine structures from reactions whose outcomes are unknown at the outset. Throughout this process, a spiral approach is taken, where the material increases in complexity, and time is taken to review and reinforce prior concepts for maximum understanding.

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NMR Spectroscopy - American Chemical Society

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