Using Retrosynthetic Graphic Organizers and Molecule of the Week

Article Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

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Using Retrosynthetic Graphic Organizers and Molecule of the Week Activities in Organic Chemistry Tutorials Christine M. Le and Barbora Morra* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6

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S Supporting Information *

ABSTRACT: The tutorials of a second-year undergraduate organic chemistry course have been modified to include a retrosynthetic exercise in conjunction with a Molecule of the Week (MoW) challenge. In contrast to the original tutorial assignments in the course, which primarily focused on completing simple reaction roadmaps, the new tutorials place a heavier emphasis on retrosynthetic analysis and strategic synthetic design. MoW assignments are distributed to students prior to the tutorials, which progressively build on the course material and become more complex as the students’ chemical toolboxes expand over the course of the semester. During each tutorial, students work with a teaching assistant to construct a retrosynthetic graphic organizer (RGO), which is then used to design an optimal synthetic route toward the weekly target molecule. Overall, RGO/MoW tutorials encouraged students to formulate meaningful connections between course concepts. In addition, students who regularly attended these tutorials applied their knowledge toward complex synthetic problems more effectively than students without RGO/MoW experience. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Problem Solving/Decision Making, Applications of Chemistry, Student-Centered Learning, Synthesis

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INTRODUCTION Introductory organic chemistry has a long-standing reputation of being a challenging course, requiring students to comprehend and recall many concepts, reactions, mechanisms, and advanced terminology while at the same time being able to visualize and manipulate complex molecules in three dimensions.1 Within this subject, retrosynthetic analysis of complex molecules is often a unique challenge for introductory organic chemistry students, 2 who may resort to rote memorization instead of developing a deep understanding of the content.3 Consequently, when students are required to apply their basic knowledge toward a multifaceted synthetic problem, they often struggle to demonstrate how chemical transformations can be used in tactful ways.4,5 To combat this issue, many instructors have made efforts in recent years to emphasize the utility of synthetic chemistry in their classrooms through the use of journaling,6 synthetic and retrosynthetic road maps,7 in-class clicker problems,4 case studies,8 peerassisted learning,9 card games,10 web-based learning tools,11 student-directed learning,12 and curriculum redesign.1a The development and application of a retrosynthetic graphic organizer (RGO) exercise in conjunction with a Molecule of the Week (MoW) assignment in a second-year organic chemistry course is described. An RGO is a diagram that depicts a variety of possible retrosynthetic disconnections for a general class of molecules, continuously breaking down the target molecule(s) until simple, commercially available reagents are reached. In other words, an RGO can be viewed © XXXX American Chemical Society and Division of Chemical Education, Inc.

as an expanded retrosynthetic map that allows one to visualize the many synthetic pathways available when accessing a specific target. After the RGO is constructed, an efficient synthetic route for the MoW can be developed by overlaying the target molecule onto the map. Whereas a typical retrosynthetic analysis is more linear in nature, RGOs can be more elaborate, providing students with a comprehensive way to study the reactions they have learned. The six RGO/MoW exercises developed for this course, including answer keys and instructor guidelines, are enclosed in the Supporting Information and can be used directly by students, instructors, and teaching assistants (TAs) as “plug-and-play” handouts.

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TUTORIAL DESIGN

Learning Objectives

The ability to solve intricate synthetic problems represents one of the highest-level learning outcomes in organic chemistry.5 One of the key learning objectives of this new tutorial style was to improve students’ understanding of course concepts through retrosynthesis, allowing them to visualize the synthetic interrelationships among different functional groups and to apply this knowledge to complex organic molecules. In contrast to the previous tutorial format in the course, the Received: November 24, 2018 Revised: June 7, 2019

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DOI: 10.1021/acs.jchemed.8b00970 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Article

Figure 1. Example of a Molecule of the Week tutorial as presented to students.

II. The majority of students taking this course were in their second year of a four-year Life Science undergraduate program at a large, research-intensive university in Canada after having completed a prerequisite single-semester course (Organic Chemistry I) in their first year. Organic Chemistry II is a 12-week course with 36 50-minute lectures taught by the course instructor(s) and five 3.5-hour laboratory sessions. The course curriculum consists of a thorough overview of spectroscopy followed by a comprehensive look at the nomenclature, reactivity, and synthetic applications of simple organic molecules. Students were evaluated on two term tests,

RGO exercise and MoW challenge involved greater student participation and focused on building problem solving skills, as opposed to simply providing a review of the content discussed in lectures. By the creation of more advanced synthetic problems on the MoW assignments, students were required to exercise higher-order thinking skills in their retrosynthetic planning.2,13 These important skills were primarily evaluated during the final examination of the course. Participants and Setting

The exercise described was designed for a large (100−550 students per term) single-semester course, Organic Chemistry B



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a final examination, and laboratory assessments. To reinforce the course curriculum, students were also encouraged to attend weekly 50-minute group discussion sessions (i.e., tutorials), which were led by a graduate student TA outside of regular class time. To facilitate group discussion, the tutorial class sizes were relatively small (50−100 students, depending on the class size). While the students were required to register for one tutorial section, their attendance and participation were not mandatory. This course offered a total of 11 tutorial sessions, of which the first five tutorials consisted of typical reaction roadmap, mechanism, and spectroscopy-type questions and the last six tutorials featured RGO/MoW activities. This new tutorial series was implemented over four semesters (Winter 2015, Fall 2016, Winter 2016, and Winter 2018) involving over 1400 students.

The development of retrosynthetic and forward routes toward the MoW is conducted in the last 25−30 min of the tutorial. Students carry out a retrosynthetic analysis of the MoW using the framework of the general RGO created (Scheme 2). Oftentimes, certain retrosynthetic disconnections are not suitable for the target because of inherent reactivity, chemo-, regio-, and/or stereoselectivity issues, enabling the students to identify which pathways are more suitable than others. For example, although epoxides can be synthesized from their respective bromohydrin derivatives, this would not be the best route for the MoW shown in Figure 1, as it would necessitate an SN2 reaction on a relatively hindered 2° alkyl bromide. At this point, students recognize that an electrophilic epoxidation of an alkene with a peracid (e.g., mCPBA) is the better route. Afterward, strategies for the synthesis of alkenes are discussed, including elimination of an alkyl halide versus semihydrogenation of an alkyne. A follow-up discussion on Zaitsev’s rule allows students to identify that the elimination pathway would lead to the formation of the undesired (E)alkene as the major product. On the other hand, a stereoselective cis hydrogenation of the alkyne could be achieved using Lindlar’s catalyst to give the desired Z isomer. At this point, the synthesis of the alkyne could be furnished through a double alkylation with the appropriate electrophiles, including 1-(bromomethyl)-4-chlorobenzene. This substrate could then be accessed from a benzylic halogenation of 4chlorotoluene. Finally, either starting material provided to students could be used to access 4-chlorotoluene through an electrophilic aromatic substitution reaction. However, chlorination of toluene was identified as the superior approach over a Friedel−Crafts methylation of chlorobenzene, which often suffers from overalkylation side reactions. With the guidance of the TA, the students suggest multiple “correct” answers to a synthesis problem, and the feasibility of each pathway is evaluated on the basis of selectivity, atom economy,14 efficiency,15 and green chemistry principles.16 Throughout the tutorial, the TAs are encouraged to probe the students’ knowledge by suggesting alternative pathways, reagents, and mechanistic outcomes. Some TAs even employ Socratic questioning by asking students, “What would happen if these particular reaction conditions were used?” or “What route would you take if this particular molecule was the target and not the one given in the assignment?” Next, the students choose the ideal retrosynthesis on the basis of efficiency, selectivity, and practicality. The TA then writes out the student answers at the front of the classroom, which is followed by a group discussion on the advantages and/or disadvantages of each retrosynthetic plan. At the end of the tutorial, a forward route for the target molecule is selected, and the students identify the reaction conditions required for each step of the synthesis (Scheme 3). Throughout the semester, the course instructor(s) observe the TA-guided tutorials and provide constructive feedback to each tutor afterward to promote good teaching practices and consistency across tutorial sections.

Tutorial Structure

In the first 10 minutes of the tutorial, the answers to the primer questions are discussed. These questions serve as a refresher of the recent lecture material but are not the focus of the session. The remainder of the tutorial is devoted to the RGO exercise and the MoW assignment. An example of a typical tutorial assignment, as given to students, is shown in Figure 1. Additional tutorial information and examples with complete answer keys as well as instructor and TA guidelines are provided in the Supporting Information. In the next 15−20 min of the tutorial, the students help the TA construct an RGO. The RGOs are developed with the MoW in mind, focusing on the key retrosynthetic disconnections required to reach simple starting materials. As the tutorial progresses, the TA builds the RGO at the front of the classroom on the basis of the students’ recommendations for appropriate retrosynthetic disconnections and synthons. Each RGO focuses on a general class of molecules, such as alkyl halides, epoxides, amides, enamines, etc., breaking down the target molecule into simpler starting materials, thus serving as a useful reference for future use. An example of a general RGO created for the synthesis of epoxides is shown in Scheme 1. At each stage of the retrosynthesis, the TA engages the students by asking them to provide the reaction conditions for the forward transformations. This type of exercise also serves to reinforce lecture material. Scheme 1. General Retrosynthetic Graphic Organizer for the Synthesis of Epoxides

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RESULTS AND DISCUSSION In order to evaluate the overall effectiveness of this tutorial toward the main learning objective, a study was conducted during the Winter 2018 semester in which 296 of the 325 students enrolled in the course participated (29 opted out). The main objectives of the study were to determine (a) whether student performance on advanced synthesis problems C



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Scheme 2. Specific Retrosynthetic Graphic Organizer for the Molecule of the Week

Scheme 3. Forward Synthesis for the Molecule of the Week

was improved after attending RGO/MoW tutorials and (b) which students, if any, benefited the most from participating in the tutorials.17 First, students were divided into three main groups on the basis of their term test 1 grade (this test was written prior to the implementation of the six RGO/MoW tutorials): • low achievers: students who scored ≤59% • average achievers: students who scored 60−79% • high achievers: students who scored ≥80% These student populations were then further divided into subgroups on the basis of their attendance at the six RGO/ MoW tutorials offered in the course (Figure 2). Students who attended two or fewer tutorials were considered to have little or no experience with the RGO/ MoW concept, while students who attended three to six tutorials were considered to have a great deal of exposure to the RGO/MoW theory. It is interesting to note that the majority of students in both the low- and average-achieving student populations (63% and 58%, respectively) attended two or fewer tutorials, while a majority of high-achieving students (54%) attended three or more tutorials. This observation likely stems from the varied levels of course engagement and motivation of the different student populations within the course. Each student group was then evaluated on their performance on the final examination synthesis problems, which required

Figure 2. RGO/MoW tutorial attendance analysis within low-, average-, and high-achieving student populations.

students to design a retrosynthetic analysis and complete an efficient and effective forward synthesis for several target molecules. As can be seen in Table 1, students from all three populations benefited from attending RGO/MoW tutorials, with each group seeing similar increases in their mean scores D



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do not necessarily reflect their knowledge, since it is difficult to discern whether students were using retrosynthetic design when solving each problem. For example, it is possible that students adopted a means−end analysis19 by first constructing a forward route for each target molecule and then simply working backward to complete a retrosynthesis to satisfy the question requirements. The study involved a test before and after the delivery of the RGO/MoW tutorials (i.e., pretest, treatment, post-test design) in the absence of a control group. This design framework does not account for the students’ natural development over time.20 Since tutorials for this course were not mandatory, it was difficult to create a consistent control group. Additionally, students were free to attend any of the tutorial sections during the week, including ones in which they were not officially enrolled. Students could also sit in on other tutorial sections, which would have added an additional layer of complexity to the study. Since the tutorials were optional, attendance could be related to attitudinal factors.21 Students in each group (low, average, and high achievers) may have had varied goals within the course and attitudes toward the course content, which could have motivated students in each group to attend all, some, or none of the tutorials. It was also possible that student performance on synthesis problems was influenced simply by attending the tutorials where course content was discussed, as opposed to the specific RGO/MoW activity. However, anecdotal evidence (i.e., student comments) from the participant surveys seems to suggest otherwise. In the future, we plan on incorporating attitude surveys, such as the Attitude toward the Subject of Chemistry Instrument (ASCI/ASCI v2),22 and student interviews into our experimental design to deepen our understanding of these affective factors. The improved performance observed by students who attended tutorials was likely due to a combination of factors, including exposure to and performing the RGO/MoW exercise.

Table 1. Comparative Final Examination Scores on Synthesis Problems Student Group (No. of Tutorials Attended) Low Achievers (0−2) Low Achievers (3−6) Average achievers (0−2) Average achievers (3−6) High achievers (0−2) High achievers (3−6)

n

Mean (SD) (%)

39

46.3 (16.9)

23

58.1 (18.1)

74

56.6 (22.2)

53

70.0 (21.6)

49

71.1 (18.4)

58

84.3 (18.2)

Mean Difference (%)

pa

fb

+11.8

0.0127

0.6906

+13.4

0.0009

0.8353

+13.2

0.0003

0.9237

a

Independent-samples t test, where values are significant if p < 0.05. Values of 0.2 are considered to have a small effect size, 0.5 is considered medium, and 0.8 is considered large. b

(11.8% increase for low achievers, 13.4% for average achievers, and 13.2% for high achievers). The differences in mean scores observed between student groups that did not attend a significant number of tutorials (two or fewer) and those who regularly attended tutorials (three or more) were statistically significant according to an independent-samples t test, where the p values in all cases were significantly less than 0.05. In addition, the effect size was determined to be large in all categories by an f test. In the Supporting Information, these data are shown as a box-and-whisker plot. Students who attended the majority of RGO/MoW tutorials outperformed students who did not attend tutorials, specifically on their ability to use course content to design more efficient and effective retrosyntheses and forward syntheses on the final examination. It is notable that this trend was observed in the low-, average-, and high-achieving student groups, suggesting that the tutorials are beneficial to learners with varied skill levels. Anonymous survey data were also collected to determine the perceived pedagogical value of the RGO/MoW tutorials in the course. An overwhelmingly large proportion of students found that completing RGOs during tutorials helped them both understand the course material (91% of students) and also apply it to synthetic problems (90% of students). A large majority of students (82%) also felt as though creating RGOs during tutorials and on their own time served as a usef ul study aid while preparing for tests and the final examination, while 88% of students reported that the RGO/MoW activities assisted in their ability to design more efficient synthetic plans toward complex organic molecules. Complete student survey questions, results, and selected student comments are provided in the Supporting Information.

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CONCLUSION

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ASSOCIATED CONTENT

The use of RGOs exposes students to a variety of plausible synthetic routes toward the MoW targets. Overall, the revised tutorials provide a complementary method for students to organize the knowledge they have gained in the lectures, course notes, and textbook. Students who attended the RGO/ MoW tutorials regularly performed better on synthesis problems. In addition, these new tutorials were equally beneficial to students with diverse proficiencies in the course. On the basis of the study described, we suggest that retrosynthetic analysis be introduced at an early stage in introductory organic chemistry courses, as the value of problem solving and critical thinking skills certainly extend beyond the chemistry classroom.

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LIMITATIONS AND OTHER CONSIDERATIONS One potential limitation of this study was that we could evaluate only what students had written on the term tests and final examination, which does not consider any mental or written strategies that students may have employed while constructing their submitted answers.18 Besides student comments on the anonymous surveys, it is unknown whether students were using RGOs in their homework assignments, as study aids, or during their term tests or final examination. In addition, student scores on retrosynthesis/synthesis problems

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.8b00970. Detailed description of the course structure, six RGO/ MoW tutorials with answer keys, instructor guidelines, TA guidelines, box-and-whisker plot of student data, and student feedback (PDF, DOCX) E



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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Barbora Morra: 0000-0002-0103-2819 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Department of Chemistry at the University of Toronto for their support through the Chemistry Teaching Fellowship Program. We also thank Landon Edgar, David Petrone, Sean Liew, Anika Tarasewicz, and Graham Garrett for their help as teaching assistants to implement and provide feedback on this new tutorial. We also thank David Stone for his assistance with statistical data analysis.

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REFERENCES

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Using Retrosynthetic Graphic Organizers and Molecule of the Week

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