Embedded Research in a Lower-Division Organic Chemistry Lab

Chapter 5

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Embedded Research in a Lower-Division Organic Chemistry Lab Course Lee J. Silverberg,*,1 John Tierney,2 and Kevin C. Cannon3 1Pennsylvania

State University, Schuylkill Campus, 200 University Drive, Schuylkill Haven, Pennsylvania 17972, United States 2Pennsylvania State University, Brandywine Campus, 25 Yearsley Mill Road, Media, Pennsylvania 19063, United States 3Pennsylvania State University, Abington Campus, 1600 Woodland Road, Abington, Pennsylvania 19001, United States *E-mail: [email protected].

This chapter describes how research has been embedded into the second-year organic chemistry laboratory course at three satellite campuses of the Pennsylvania State University. The course, CHEM 213, is a two-credit course in the Spring semester which meets for six hours per week. Approximately the last third of the course is an original research project in synthetic organic chemistry. The projects are small pieces of larger projects, and are novel and lead to publications, particularly benefiting the undergraduates concerned. Examples of the research projects and their implementation are described here.

Introduction The value of Science, Technology, Engineering and Math (STEM) research with undergraduates has been well-documented in recent years (1–12). For example, students are more satisfied and learn more (1), they integrate knowledge learned in courses (2), minority and female students are guided towards a scientific career (1), institutions attract more students (1), and students are better prepared for (2) and more likely to enroll in graduate school (3). One way of getting students involved in research is through “Course-embedded Undergraduate Research Experiences” or “CUREs” for short (13–24). This approach has seen rapid expansion in recent years. The authors of this chapter have been collectively © 2018 American Chemical Society Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

using this approach in the sophomore organic chemistry laboratory course at smaller campuses of Pennsylvania State University (PSU) for several decades. Herein, our experiences are detailed.


Course Structure Unlike most institutions, PSU’s Organic Chemistry Lab (CHEM 213) is not offered with the first semester of Organic Chemistry lecture (CHEM 210), but is introduced as a two credit course (six lab contact hours) with the second semester of lecture (CHEM 212). This results in students with a better theoretical background when they enter the lab. In the courses run by the present authors, approximately the first third of the course is devoted to learning the essential skills in an organic chemistry lab: safety, melting points, distillations, liquid-liquid extractions, recrystallization, chromatography, and spectroscopy (when available). The second third of the course consists of standard organic reactions. These are typical “cookbook” lab procedures, which give them experience in running reactions, reinforce the techniques previously learned, and allow them to see reactions that have been discussed in the lecture course. The last third of the class, four to five weeks, is a research project. At 6 hours per week, this gives them 24-30 hours of time to do a research project, enough time to get something significant accomplished. The students’ lab notebooks now become permanent documentation of research, which emphasizes the importance of taking good notes. The unknown outcome means that a) sometimes difficulties are encountered which much be overcome through careful thought and perseverance; and b) a successful result is exciting to the students. Communication of scientific results is one of the important aspects of the course. Students write lab reports, in the format of chemistry journals, for the various experiments during the semester. At the conclusion of the semester, the students do a poster or oral presentation of their research. Thus the students get training and feedback on both written and oral communication.

Embedded Research Finding Appropriate Projects The CHEM 213 research project has to draw on the laboratory skills and techniques already learned early on in the semester. In any research synthesis, additional techniques not already learned can be introduced to the more advanced and adept students in the group. Introducing synthetic research into the organic classroom and laboratory produces excitement among the students, particularly when they realize the compounds they are preparing are novel, publishable, and possibly bioactive. Each student in a group can be given a slight variation on a synthesis with regards to a substituent in the molecule, leading to a group of related compounds in a series. The resulting compounds can then undergo further study using spectroscopic techniques or biological testing which encompasses further involvement on the part of the student with potential interdisciplinary collaborations. The project becomes shared between the students, and the students 66 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


start to experience the aspect of working in the environment of a scientific team rather than as individuals. Planning and approach are very important. The students, no matter how academically talented, are not going to have the level of expertise and experience to do projects that are overly complicated and advanced. Further, they should not be entrusted with projects where the potential hazards are high. So in planning the research to be carried out, it is important to keep in mind what they are going to be able to do, and able to do safely. The research must be relatively simple to perform, and in “bite-size” chunks, giving them a chance of accomplishing something in the limited time frame during which they conduct research. The synthetic path chosen should have a reasonable degree of success regardless of a student’s lab skills in order for the student not to become frustrated by failure. Ideally, each piece becomes publishable, if not by itself, then as part of a larger effort. Collaboration The three authors of this chapter collaborate with each other and with scientists at other institutions as well. Research for us is a lesson in long-distance team building. With three synthetic organic chemistry groups, it becomes easier to effectively complete more experiments since we can combine our data for a publication. We have additional collaborators to obtain instrumental data, including NMR spectroscopy, infrared spectroscopy (IR), mass spectrometry (MS), and X-Ray crystallography. We collaborate with computational chemists on mechanistic and structural investigations. We work with biologists for biological testing (vide infra). Simply put, we reach out in many different directions to put our ideas into practice. However, it must be understood that this need for collaboration means work will not get done quickly. Patience is important. In order to advance our work at a reasonable pace, we sometimes assume that an experiment has worked based on observation, thin layer chromatography (TLC), and melting points until we eventually obtain more indicative data such as an NMR spectrum. Sometimes those assumptions are wrong and we get a surprise (vide infra). Examples During a kinetic study (25) of the formation of substituted 2,3-diaryl-1,3thiazolidin-4-ones from the reaction of imines with thioglycolic acid, a reaction originally demonstrated by Surrey (Figure 1) (26), it became apparent that there was a wide array of substituted 1,3-thiazolidin-4-ones that had not been prepared, but could be prepared by second-year organic chemistry students relatively easily. In addition, physical organic chemistry studies utilizing IR, NMR and MS data could be also be achieved – further incorporating information that the students had learned in the lecture portion of the class. The move to a synthetic project proved to be much more doable within the confines of the equipment available at the campus, and fruitful for incorporation into the organic chemistry lab course. 67 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


Figure 1. Synthetic scheme for the formation of substituted 2,3-diaryl-1,3-thiazolidin-4-ones.

The spectroscopic data that was used initially tracked the chemical shift variation of the methine proton (at C2), methylene protons (at C5) and the 13C NMR chemical shift data at C2, C4 and C5 in the 1,3-thiazolidin-4-one ring (Figure 2) based on substituents in the phenyl rings. It was in this phase of the project, in the early 1990s, that undergraduate students were incorporated into the project as part of the CHEM 213 undergraduate lab.

Figure 2. Nomenclature and atom positions in 1,3-thiazolidin-4-one ring. 68 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


The starting materials for these syntheses are relatively cheap and readily available. The one downside is that the thioglycolic acid is somewhat malodorous and has to be handled carefully. However, it is pointed out to the students that thioglycolic acid is used in permanent waving solutions in women’s hairdressing salons, and some students recognize the odor. The first publication where undergraduate students were intimately involved in the work appeared in Magnetic Resonance in Chemistry in 1996 (27). Soon after, a steady stream of published data appeared on the different series of compounds shown in Figure 3 (28–33). At the same time additional features, such as computational work (34), have further been incorporated into the research, enhancing the students’ research experience. An array of substituted 1,3-thiazolidin-4-ones were tested (R. Farrell, Penn State York; E. Dudkin, Penn State Brandywine) for biological activity against HT 1080 mice tumor cells. The data is, as yet, unpublished but enough positive activity resulted that a PSU Invention Disclosure was filed (35).

Figure 3. Series of 1,3-thiazolidin-4-ones that have been synthesized by undergraduates. This project extended to the Penn State Abington campus in 2009 when one of the coauthors (KC) began to incorporate research into CHEM 213. Students enrolled in organic chemistry lab at Abington synthesized N-cyclohexyl 1,3-thiazolidin-4-ones (36) and 2-(o-substituted phenyl)-1,3-thiazolidin-4-ones (37) (Series 8, 9, and 10, Figure 3) as part of their practical examination for the course. Presently, six of the compounds from Series 9 are being tested at the group of Eric Ingersoll at Abington for anticancer activity against a HeLa cell line. The syntheses of novel 1,3-thiazolidin-4-ones are no longer being pursued, but the syntheses of 1,3-thiazolidin-4-ones from Series 1, 2, 8, 9, and 10 in Figure 3 are still part of the course-work since these compounds are being used in other undergraduate-based research (vide infra). On two occasions, the reaction sequence shown in Figure 1 did not go according to plan, leading to very interesting new areas of investigation. In the first instance, when, in the presence of trichloroacetaldehyde, the amine used was switched from an arylamine (Series 7, Figure 3) to cyclohexylamine, the resulting product produced was an N-formyl compound instead of the corresponding 1,3-thiazolidin-4-one (Figure 4) (38). However, use of an appropriate Lewis acid allowed for the formation of the 1,3-thiazolidin-4-one. The second reaction that gave an interesting, but yet to be characterized polymeric product, was the reaction of p-hydroxybenzaldehyde with aniline. On addition of the thioglycolic 69 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


acid a thick glassy orange mass resulted. Initial work indicates the possible coupling of imine units with the loss of the hydroxyl group as water (Figure 5) (39).

Figure 4. Reaction of chloral, cyclohexyl amine, and thioglycolic acid without a Lewis acid.

Figure 5. Possible polymerization product from the C-p-hydroxy imine. The synthesis of novel 1,3-thiazolidin-4-ones in organic chemistry lab provided a library of compounds which serve as a basis for an ongoing undergraduate research projects involving Oxone® oxidation to produce the corresponding sulfoxide or sulfone compounds (Figure 6) (37, 40, 41). This library enables a thorough investigation of substituent effects on the oxidation of these compounds.

Figure 6. Oxidation of 1,3-thiazolidin-4-ones. The 2-(m- and p-substituted phenyl)-3-cyclohexyl-1,3-thiazolidin-4-one series produced in organic lab has also been reacted with Ph3SnCl to produce 1:1 1,3-thiazolidin-4-one tin complexes (42); similar organotin complexes have demonstrated antifungal activity against Ceratocytis ulmi, the cause of Dutch Elm disease (43, 44). The 1,3-thiazolidin-4-one ligand is coordinated to the Sn metal center via the oxygen atom of the C4 carbonyl (Figure 7). Currently, studies 70 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


utilizing IR and NMR data are being conducted by undergraduate researchers to track the chemical shift variation of the methine proton (at C2), methylene protons (at C5) and the 13C NMR chemical shift data at C2, C4 and C5 in the 1,3-thiazolidin-4-one ring.

Figure 7. Preparation of organotin complexes of 1,3-thiazolidin-4-ones.

Upon joining PSU in 2009, one of the authors (LJS) opened two lines of synthetic research. The first was a progression from some research done while working as a process chemist in the pharmaceutical industry. In that work, the very reactive epoxides of (+)-2-carene had been studied (45). The goals of the new research were to study the aziridines and halonium ions of (+)-2-carene and of α- and β-pinene (Figure 8).

Figure 8. Cyclopropyl and cyclobutyl aziridines and halonium ions. X = NTs, Br+, Cl+. 71 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


CHEM 213 students in Spring 2011 did experiments involving the halonium ions. Some very interesting results were obtained with the halonium ions, which were eventually included in a paper published in 2015 (46). The second track involved the synthesis and reactivity of 2,3-diaryl-1,3thiaza-4-one heterocycles in collaboration with a coauthor (JT). The initial work (Spring 2010) was on preparation of a series of 2,3-diaryl-1,3-thiazolidin-4-ones (Figure 3, Series 3). This resulted in a publication (33). Then studies of S-oxidation of 2,3-diaryl-1,3-thiazolidin-4-ones (Figure 3, Series 3) and 3-benzyl-2-phenyl-1,3-thiazolidinones (Figure 3, Series 5) were done (Figure 9) (Spring 2012). In this project, the lack of easy access to an NMR at that time caused some surprises. Using Oxone® and judging by TLC, it was believed that by controlling the temperature (0 °C or room temp.) and the amount of Oxone® (1.5 or 3.0 equivalents) either the sulfoxide or sulfone could be produced. However, when the NMRs were eventually obtained, it turned out that all of the reactions had been highly selective towards the sulfoxide. The full series has not been published, but a paper detailing the crystal structures of one sulfide and its corresponding sulfoxide has been published (47). As discussed earlier, the work has also been extended at Penn State Abington, where it has been shown that production of the sulfone requires heating and a large excess of Oxone® (37, 40, 41).

Figure 9. S-Oxidation of 1,3-thiazolidin-4-ones.

A downturn in the number of students led to only one student doing research in Spring 2013 and the course not being offered in Spring 2014. The student in 2013 was involved in initial attempts to prepare 2,3-diaryl-2,3-dihydro-4H-1,3benzothiazin-4-ones from an imine and a thioacid. This was not successful, and it was known in the literature that the six-membered rings were more challenging to make by this method than the five-membered rings and that the N-aryl rings were more difficult to prepare than the N-alkyl rings (48, 49). During further studies in the summer of 2013, it was found that 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) (50–53) worked well (Figure 10). This procedure has proven to be very general for six- and seven-membered 2,3-diaryl-1,3-thiaza-4-ones (54, 55). Students in Spring 2015 and Spring 2016 prepared 2,3-diaryl-2,3-dihydro-4H-1,3-benzothiazin-1,3-ones (Figure 10). One student also began attempts at reducing the carbonyl in these types of compounds. 72 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


Figure 10. Synthesis of 2,3-diaryl-2,3-dihydro-4H-1,3-benzothiazin-4-ones.

The Spring 2017 class worked on several aspects. Some worked on synthesis of 2,3-diaryl-2,3-dihydro-4H-1,3-benzothiazin-1,3-ones, while others worked on the synthesis of 2,3-diaryl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-ones (Figure 11) and on the S-oxidations of previously prepared 2,3-diaryl-1,3-thiaza-4-ones, using Oxone® to prepare sulfoxides, and potassium permanganate to synthesize the sulfones.

Figure 11. Synthesis of 2,3-diaryl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-ones.

Most of the specific work done in CHEM 213 from 2013-2017 at Schuylkill has not yet been published, but it will be. It has been included in a variety of presentations (56–60) and posters (61–64). Other pieces of these projects have been completed by students not enrolled in CHEM 213. This research has been well received by the undergraduates. The chemistry is readily done using standard organic techniques. Since the interest is in the compounds themselves, yields are not critical. The compounds are novel and the data produced in these studies has continually proven to be of interest to 73 Gourley and Jones; Best Practices for Supporting and Expanding Undergraduate Research in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2018.


the scientific community, as seen by the publication record. Initial screening (H. Sobhi, Coppin State U.) of six 2,3-diphenyl-1,3-thiaza-4-ones (Figure 12) (54) has shown some to have significant activity against fungi Scedosporium (Lomenstospora) prolificans and Cryptococcus neoformans (58, 60). Knowing that their compound(s) may be of medicinal use is exciting to the students.

Figure 12. 2,3-Diphenyl-1,3-thiaza-4-ones (54) tested for antifungal activity (58, 60).

Conclusion Our collective experience with CUREs in sophomore organic chemistry laboratory has been very successful both in learning outcomes for the students and in publications, which benefit both the students and the faculty. This approach assures that every student who comes through the Organic Chemistry sequence will get a genuine research experience. Most students are grateful for this opportunity. It also happens relatively early in their college education, and may lead them to seek out other research opportunities.

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