Semester-Long Course-Based Research Project in Second-Semester Organic Chemistry: Synthesizing Potential Lead Compounds for the Treatment of a Neglected Tropical Disease

10 A semester-long research project for second-semester Organic Chemistry lab sections was developed. Student projects were based on preliminary data from faculty research that suggested the natural product neurolenin B to be a treatment for lymphatic filariasis. Students isolated neurolenins from the Central American plant Neurolaena lobata and proposed syntheses of previously unknown analogs using reactions learned 15 in firstand second-semester Organic Chemistry. Using literature-based procedures, students ran reactions on neurolenins and analyzed their results by TLC and NMR spectroscopy. The semester culminated with a public poster session and final report using the Organic Letters template. Students in a total of five lab sections over three different semesters of the class completed this pilot course and 15 sections in the same 20 time span conducted traditional lab experiments. Qualitative and quantitative assessment data were collected to demonstrate the efficacy of the course. Students did not self-select into the pilot sections, were demographically similar to those in the traditional lab sections, and performed at the same level in the lecture portion of the course. Survey results from all students (traditional and pilot) were compared and the 25 students in the pilot sections showed higher levels of self-reported topic understanding, general motivation, and interest in organic chemistry.


INTRODUCTION
Undergraduate research is one of the most powerful pedagogical tools to educate and inspire students, especially those from diverse backgrounds. 1 Many science faculty do an excellent job working one-on-one or with small groups of students on independent projects in their research labs. 2 Research students are often third-or 40 fourth-year students who are selected by faculty members because of top performances in advanced classes. Providing a meaningful undergraduate research experience for students enrolled in introductory courses is a more challenging prospect. 3 However, this is the time in students' educational paths when a research experience could be valuable for a variety of reasons. It is known that early research increases student 45 persistence in STEM disciplines. 4  period during undergraduate education has measurable benefits. 5 Early exposure to research fosters student ownership over the material. 6 Additionally, required coursebased research was shown to foster student diversity in senior research experiences. 7 Guided inquiry and discovery-based labs are excellent examples of implementing 50 research-type problems in introductory courses. These activities allow students freedom to experiment and even fail while trying to answer interesting questions. They are an important stepping-stone on the path from "cookbook" experiments to independent research. Incorporating actual research into undergraduate laboratory courses is a pedagogical advance aimed at improving students' learning and exposing 55 more students to research. 8 Course-based undergraduate research experiences (CUREs) vary from introductory to advanced classes, from modules over several weeks to a full semester, and from community colleges to liberal arts colleges to research universities. 9 Hallmarks of these types of courses include setting the research question in context, providing a true sense of discovery where neither students nor instructors 60 know the outcome of experiments, fostering student ownership over the research experience, and providing opportunities for experimental iteration. 9-10 Furthermore, CUREs promote scientific communication among students and between students, instructors, and other scientists, and usually incorporate presentations to an external audience, often via a poster session. 9a results are generally very positive and rely on students' attitudes and perception of their learning. [11][12][13][14] Focusing on undergraduate organic chemistry classes, there are a variety of inquirybased and simulated research experiences for introductory 15 and advanced courses. 16

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In recent years, several examples of CUREs have been reported and illustrate the viability and effectiveness as an educational tool for introductory organic chemistry education. 12, 17 Considering students' limited laboratory experience, course design for introductory labs is a major challenge. Additionally, the time constraints of lab courses and the number of students enrolled in the course pose potential obstacles. Courses 80 previously described focus on using a multicomponent reaction to make tetrahydropyrans, 12c developing green chemistry alternatives to traditional reactions, 17b synthesizing metalloprotease peptide inhibitors, 12b using solid-phase combinatorial chemistry to synthesize aromatic oligoamides, 12a and designing and synthesizing peptides with antimicrobial activity. 17a

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The challenges and previous successes of CUREs for organic labs were inspiration to design a CURE-based Organic Chemistry lab that exposed students to research in a second-semester Organic Chemistry course. There were two main goals for the course design. The first initiative was to design a course that provided a genuine independent research experience closely related to current faculty research in the department. A 90 second goal was to compare student outcomes from a CURE based lab experience versus a traditional topic-based lab course. These aims led to specific research questions: What will students gain from the research experience? How will students perform in the lecture portion of the course? How will student results impact independent research in faculty research labs? Answers to these questions could 95 motivate instructors at other institutions to adopt similar semester-long research experiments in Organic Chemistry teaching labs.

COURSE BACKGROUND AND DESIGN
Smith College is a primarily undergraduate institution for women with 2,500 100 students, and more than 40% declare a major in the sciences. The chemistry sequence involves one semester of either General or Advanced General Chemistry followed by first-semester Organic Chemistry. Students are co-enrolled in lecture and lab as one course for the General and Organic Chemistry classes. First-semester Organic Chemistry covers an introduction to organic compounds, followed by spectroscopy, then  Analysis of the demographics of enrolled students in the pilot sections vs the traditional sections verified proper similarity to enable comparisons, see Table 1.

PROJECT BACKGROUND
The research idea originated as an undergraduate honors thesis project with the 135 broad aim of addressing neglected tropical diseases. 18 The focus was on identifying new treatments for lymphatic filariasis, a disease that afflicts over 120 million people in tropical areas of Africa, Asia, and the Americas. 19    NMR spectroscopy Proposal ideas were turned in and instructor assigned a project from student ideas.

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Analysis of NMR spectra Proposal drafts were turned in. 6 Proposal Symposium Students turned in final proposals and presented a short talk on proposals.

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Independent research projects Poster drafts were due in week 12.

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Poster session Paper drafts due and final paper due two weeks after.

IMPLEMENTATION
The initial lab meeting began with an introduction to the project and a  During the second lab session, students were introduced to SciFinder Scholar and the Web of Science to help them find literature precedent for the proposals. The instructor taught strategies for efficient substructure searching, for example using a substituted cyclohexenone as a structural stand-in for the conjugated enone in neurolenin. Students were also instructed to search for cited references after a lead 185 paper was identified to check the reproducibility of an experimental procedure. 23 The first semester Organic Chemistry lab provided useful introductions to NMR, TLC, and standard techniques; however, students had much to learn to succeed in this Instructors of the pilot lab agreed that the time required to prep, teach and grade the pilot course vs the traditional course was comparable.
One key aspect of the course was the support of a student teaching assistant and a 275 student prep assistant. The prep student was critical for setting up the lab with equipment and reagents prior to each lab section. The prep assistant worked closely with the instructor to order, organize, and prepare chemicals for each student research group. Selection of a talented teaching assistant who had independent research experience and required minimal instruction was vital to the success of the lab.

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One concern about research-based labs is the potential higher costs versus The experimental lab generated enough questions and ideas to spawn several undergraduate honors research projects related to discoveries in the pilot lab section.
In the first year of the pilot lab, one group discovered that an acetylation reaction  The surveys were used as a method to address the concerns that students in the pilot lab may not get the same exposure to the lecture course material as those in the traditional course. The traditional lab provides a more direct means for students to reiterate and apply learned material from lecture. In contrast, the pilot lab involves 345 more independent work and focuses on the project goals established by the students.
The survey focused on student self-reported gains on knowledge of subject matter, course benefits, and perceptions.
Questions were developed focusing on several different outcomes: overall attitudes and confidence, general course topics, specific course content, and broader learning 350 objectives. 27 Statistically significant increases for students in the pilot lab were observed for questions related directly to research, such as exposure to novel ideas and learning about scientific research ( Figure S6). Pilot lab students reported higher ability to visualize organic molecules, identify reaction roles, and use mechanisms to describe selectivity ( Figure S7). Students in the traditional lab reported higher ability to 355 determine molecular structure from spectroscopic data, consistent with the larger emphasis on this topic in the traditional lab curriculum. Students in the pilot lab reported being more comfortable with reaction mechanisms, reactivity of alcohols, and reactivity of carbonyls ( Figure S8). Both student cohorts were equally comfortable with the reactivity of aromatic compounds even though the traditional lab contained a two- Students also reported having a stronger sense of a learning community in the pilot lab.
It is important to note the significance in self-confidence gain and presentation skills. In the pilot lab, students were required to give group presentations on their topics in a 370 symposium and a poster session. There was no significant difference in science writing skills or understanding science. responses based on the instructor (Figure S9). These results support that this type of course can be taught by instructors with varied experience and not affect the overall 385 outcomes of the course.

College-Administered Course Evaluations
Completion of the college administered course evaluations yielded interesting 390 qualitative and quantitative results. Using a 4-point scale, in response to the statement, "This course contributed significantly to my education," the average score for the pilot section with 51 student responses was 3.73 ± 0.55. The average score for the traditional lab sections with 168 student responses was 3.57 ± 0.55. This addressed a major concern expressed by many faculty thinking about teaching a course-based research 395 class, "How will it impact my teaching evaluations?". 28 Overall, the student evaluations were overwhelmingly positive.
For the qualitative questions, responding to the prompt, "How would you describe your own efforts to learn in this course?", students talked about how much effort they put into this lab section. "Wow, I think I did too much work for this, but it all paid off!" • It was really exciting to be doing reactions that weren't fully spelled out for us in a lab manual. We were able to explore reactions that were interesting to us, and I felt really invested in my group's project.
The "cons" of the course included: • Being almost completely oblivious to the work done in the regular lab sections, 425 and this may have helped understand concepts in lecture • This lab definitely took more time than a normal class lab.
• Less practice writing lab reports It was very reassuring to have the students echo our thoughts on both the pro and con sides of offering the course. We believed the pros greatly outweighed the cons and from 430 all the student feedback we received, they agreed with this opinion.
Two other open-ended questions were asked. Student responses to "Comment on the impact of investigating a novel problem versus your traditional lab experience in Organic I." and "What will you take from this experience as you move forward at Smith?" were very inspiring. Students wrote about exactly the sorts of things we 435 imagined they might when designing the course: embracing failure, learning perseverance, developing practical skills, and working with others. It was clear from their narrative responses that this pilot course had a positive impact on these students.

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The overall results of the pilot project were positive, though implementing this semester-long research project in all the second-semester Organic Chemistry lab sections will be logistically impossible. As mentioned previously, during the extraction and purification process, students regularly needed to perform lab work outside of regular class hours. Trying to accommodate these needs across all sections in only two 445 lab rooms (one that is used by the organic course every afternoon of the week) would be overwhelming. Also, beginning with impure neurolenin D made a difficult experiment too challenging for many groups. The positive student outcomes explained above are motivation to modify this idea to provide all students with a research-based laboratory experience. Therefore, current discussions have centered around how to develop a reactive functional groups. Students will be guaranteed to start with pure material and 455 known spectral data. All second-semester Organic Chemistry students, not just those in the pilot sections, will propose and carry out reactions of their own design and will hopefully gain the benefits described for the neurolenin lab.