Developing Problem-Solving Skills through Retrosynthetic Analysis

Sep 6, 2011 - Applications of Chemistry; Computer-Based Learning; Drugs/Pharmaceuticals; First-Year Undergraduate/General; Natural Products; Organic C...
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Developing Problem-Solving Skills through Retrosynthetic Analysis and Clickers in Organic Chemistry Alison B. Flynn* Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5

bS Supporting Information ABSTRACT: A unique approach to teaching and learning problemsolving and critical-thinking skills in the context of retrosynthetic analysis is described. In this approach, introductory organic chemistry students, who typically see only simple organic structures, undertook partial retrosynthetic analyses of real and complex synthetic targets. Multiple reasonable answers were possible for the questions, which provided a basis for the development of critical-thinking skills. A numbering system, described herein, was developed that enabled students to submit numeric clicker answers to a single or to multiple questions and thereby revealed the many ways that they had devised to disconnect these complex synthetic targets. The predominant student answers were readily gauged using the histogram function of the clicker program, which provided a basis for multiple relevant retrosynthetic analyses and enabled prompt, regular, and relevant feedback to be provided to students, even in moderate to very large classes. KEYWORDS: First-Year Undergraduate/General, Second-Year Undergraduate, Organic Chemistry, Computer-Based Learning, Problem Solving/Decision Making, Testing/Assessment, Applications of Chemistry, Drugs/Pharmaceuticals, Natural Products, Synthesis tudent acquisition of problem-solving and critical-thinking skills1 is essential to achieving higher orders of thinking;2 however, students often struggle to develop these skills.3 When they are asked to solve a new problem or ones under new conditions, the lack of these two skills becomes apparent.4 A comparison of some of the problem-solving qualities demonstrated by experts and novices is shown in Table 1.3 Although experts tend to be curious and engage in complex problems, novices tend to disengage if the answer is not immediately apparent. Experts take the time to explore the problem and plan their strategy to a solution, whereas novices try to place given information into an equation or use a predetermined solution method. Whereas experts group information by principles, novices tend to see information as an unrelated set of facts and try to memorize accordingly. Once a solution has been reached, experts review, make modifications, and learn from the process, whereas novices tend to simply move on. Explicitly teaching and modeling problem-solving techniques can help students become more proficient problem-solvers.5 Prompt, regular, and relevant feedback are important elements in this learning process,6 although large classes pose particular challenges to providing students with that feedback. Personal response systems, or clickers, are being increasingly used to gauge students’ understanding and to provide that feedback to students.7 In organic chemistry, the ability to submit numerical responses has led to the development of mechanism-based clicker questions8 and to clicker questions in which students can design a synthesis9 by selecting their desired starting materials and reagents from a numbered list. These developments provide a means for the students and instructors to gauge the understanding of important concepts that were difficult to evaluate with standard multiple-choice questions.

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Copyright r 2011 American Chemical Society and Division of Chemical Education, Inc.

Table 1. A Comparison of Characteristics of Novice and Expert Problem-Solvers Novice Problem-Solvers Disengage:

Expert Problem-Solvers Engage:

This is too hard Jump to answers:

Curious Explore and plan:

Pick out an equation Brainstorm See information as a distinct set Group information by principles or of facts

patterns

Move on at the end

Review at the end: Evaluate and assess learning

Designing a synthesis requires higher-order thinking skills, including strong problem-solving and critical-thinking skills. In upper-level courses, there are many approaches to learning organic synthesis including a study of total syntheses,10 the comparison of successful published strategies for synthetic targets,11 and assignments that ask students to design their own synthesis of compounds.11,12 In some upper-level courses, there is the added benefit of smaller class sizes, which allows for greater faculty student contact. At this level, the synthetic targets are of sufficient complexity that retrosynthetic analyses are absolutely required.13 The ability to design a retrosynthesis is a valuable skill for students in organic chemistry to gain early in their studies and

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Journal of Chemical Education then build upon in subsequent years; however, the concept of a retrosynthetic analysis can be difficult for beginning students to grasp as they are only just learning how reactions work in the forward direction. A higher level of comprehension and analytical ability is required for them to understand a reaction in the reverse direction. An explanation that breaks down the process as well as using analogies to nonchemistry concepts, such as the construction of a house or cooking,14 can be helpful. Students can also build their base of knowledge and understanding by creating a summary of reactions, which can be in a tabular or notebook form.15 Further, online16 or written assignments can provide practice questions that ask students to devise a synthetic strategy based on given targets. One of the key challenges remaining in teaching retrosynthesis is providing feedback to students, especially in the context of large classes. Their answers can greatly diverge from the anticipated ones, either because they have devised an unanticipated synthesis or because an error, sometimes minor, has been made that completely changes their synthetic route. Another challenge of teaching retrosynthesis is in designing problems that ensure that students learn to work truly retrosynthetically. When introductory and intermediate-level students are asked to analyze a simple compound retrosynthetically, they routinely circumvent the process of the retrosynthetic analysis. They often write down the forward synthesis and then recopy it in reverse. There is typically little evidence of brainstorming or analysis of alternate possibilities, both features observed in more advanced problem-solvers.4,17 Although a complex synthetic target requires a true retrosynthetic analysis, students in these early courses are not yet equipped to accomplish the full complex syntheses that absolutely require full retrosynthetic analyses. Herein, a unique approach to teaching and learning problemsolving and critical-thinking skills in the context of retrosynthetic analysis is described. In this approach, introductory organic chemistry students, who typically see only simple organic structures and solve problems with only a single correct answer, undertook partial retrosynthetic analyses of real and complex synthetic targets. Multiple reasonable answers were possible for most questions, which is realistic and provided a basis for the development of students’ critical-thinking skills.1 Importantly, a new method was developed to ask questions pertaining to complex synthetic targets that could be answered using clickers.18 This method provided a means for collecting and analyzing the multiple answers that students devised and allowed the instructor to provide prompt, regular, and relevant feedback to the students, notably, in large classes.6

’ IN-CLASS EXERCISES The synthetic targets had sufficient complexity that the students had to analyze the structures retrosynthetically and could not readily devise a forward synthetic strategy. They did not have to design a full retrosynthesis, but rather deconstruct parts of the target using reactions that they knew. Initially, the students did not have to consider side or competing reactions, protecting groups, or the order of the reactions. One of the first steps in being able to accomplish a retrosynthetic analysis is being able to recognize the patterns in targets that suggest a particular chemical reaction. For example, when learning the aldol reaction, the 1,3-relationship in the aldol product (1) was highlighted to students, as well as the

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Scheme 1. Retrosynthetic Disconnections for the (A) Aldol and (B) Aldol Condensation Reactions

Figure 1. Summary of student responses to the question: “Identify one possible site of an aldol product in discodermolide, 8 (answer format ###).” (N = 503).

α,β-unsaturated carbonyl (4) that results from dehydration of the aldol product (Scheme 1). Once the students had seen and had the opportunity to recognize this pattern in simple compounds, they were presented with a more complex target, such as discodermolide (8, Figure 1), a natural product found to be a potent inhibitor of tumor cell growth. The students were asked to identify one possible site of aldol reactions in this target and to enter their answers on their clickers using the format ###. For example, if a student identified a possible aldol product at carbons 1, 2, and 3, he would enter 123 as his answer. The distribution of students’ answers is shown in Figure 1. Because the settings in the clicker program could be set to display a histogram of the results (e.g., the top 10 answers), it was straightforward to visually gain a qualitative understanding of the students’ key answers and errors, even in very large classes. Interestingly, some students recognized a potential aldol product in a different oxidation state, for example in answers “345” and “567”. The possible aldol product identified by answer “789” was even more difficult to recognize, as it would be of a product of dehydration and subsequent reduction of the carbonyl and yet a few students were able to recognize that pattern. The additional advantage of the design of this clicker question was that the students could see and analyze the various answers given by their peers. Following this exercise, the students were then asked to 1497

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Figure 2. The structure of a diterpene newly isolated from Euphorbia grandicornis with several labeled bonds.19.

draw the starting materials that could be used to generate one of the aldol products identified in the previous question. The students were then asked to identify any functional groups that might be problematic if present during the desired aldol reactions and to propose solutions. In a resulting class discussion, the students identified protecting groups as one way to avoid competing reactions (e.g., with other hydroxyl moieties). They also suggested performing the required reaction before the problematic functional group was installed. Stereoand regiochemical considerations could also be discussed at this point. The students did not have the ability yet to specify exactly which functional groups to use or in which order they should perform these reactions; they were nevertheless demonstrating that they were thinking through the strategies of synthesis. Although students usually learn more advanced reactions such as the aldol reaction later in their organic chemistry course(s), introductory students can be still be asked the aforementioned type of questions early in their studies. For example, in a class in which students had learned only acid base, SN2, and SN1 reactions, the students were asked to identify, in writing, all the bonds that could be formed by SN2 reaction and all those that could be formed by an SN1 reaction in the recently discovered tigliane diterpene natural product (9) shown in Figure 2 (the atoms and bonds were not initially labeled or colored).19 They were subsequently asked how many ideas they had identified using a clicker question, which revealed that 15% had not identified any, 20% had identified 1 4 ideas, almost half (48%) had identified 5 10 ideas, and 17% had identified more than 10 ideas. The answers to this second question were used as a basis for comparison between novice and expert problem-solvers. Table 1 was explained to the students and they were challenged to write down at least 10 ideas in future questions resembling the one shown in Figure 1.20 Subsequently, the following question was presented to the students: “Identify two of the red bonds in the same natural product (9, Figure 2) that could have been formed by an SN2 reaction. Use answer format ## and write the lowest number first.” For example, if a student thought that bonds 8 and 9 could be made by SN2 reactions, she could submit 89 as her answer. Even in a large class with hundreds of students, the most popular answers could be quickly and easily gauged by reading a histogram of top results. A summary of the students’ responses is shown in Figure 3. Given that the students had just learned the fundamental criteria for an effective SN2 reaction, which was only the second reaction type they had seen in the course (the first was acid base), the predominant responses that bonds two, four, and six could be made via an SN2 reaction were very reasonable. In class, a discussion of what the appropriate reactants would have to be for bond two (i.e., an alkyl halide and not an

Figure 3. Summary of students’ responses to: “Identify two of the red bonds in natural product 9 that could have been formed by an SN2 reaction. Use answer format ## and write the lowest number first.” (N = 265).

alkenyl halide) ensued as well as discussions surrounding the unsuitability of making bond three (an ester bond) or nine (a tertiary alcohol) by SN2 reactions. It was surprising that few students had identified bond one as a suitable candidate, and so the students were asked to explain why they had not included that bond. Many students had understood it as an enol linkage (i.e., they did not realize that the hydroxyl was bound to a methylene and not directly to the double bond), and therefore, a correction or reminder regarding line structures was made. To help students achieve an even higher level of thinking,2 the students were asked to identify the appropriate reactions to make specific bonds or groups in complex molecules. Because of the complexity of the targets, they had to think retrosynthetically in addition to bringing together knowledge from different sections of their courses. For the following retrosynthetic analysis of fentanyl (10, Figure 4), the students were asked to write down the reaction that could be used to synthesize each of the indicated bonds (A, B, and C). The bond indicated in red, which could be made via an SN2 reaction, was used as an example for students. The desired reactions could be performed at any point in the synthesis. The reaction choices were then revealed and the students were asked to type in each of their responses sequentially into their clickers (format ###). For example, if a student wanted to acylate an amine to make bond A, nitrate benzene for bond B, and generate an imine for bond C (which would subsequently be reduced), he would enter 937. To give more than nine choices of reactions, the students can be asked to enter a “0” between each of their answers to differentiate between single and double-digit reactions. The summary of student responses is shown in Figure 4. Even in a large class with hundreds of students, the predominant answers could be quickly and easily gauged by reading a histogram of the most popular results. This approach was successful and truly required that students think “retrosynthetically”. By asking a few questions together, question setup time was economized. Asking this type of question also revealed common errors and misconceptions as shown in the responses in Figure 4. For instance, many students did not differentiate between a Friedel Crafts acylation and a standard acylation (bond A). Others had forgotten than an SN2 reaction could not be accomplished on an sp2 center (bond B). In an extension of this question type, students were asked to decide in which order to perform each reaction and to identify 1498

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Figure 4. Summary of student responses to the question: “Identify the reaction that could be used to make bond A in fentanyl (10) at any point in the synthesis, and then repeat for bonds B and C. Answer format ###.” (N = 523).

possible problems that might arise. For example, those who wanted to perform an SN2 reaction to install bond C would have to consider the decreased nucleophilic ability of an aniline or an amide nitrogen. In class, this was an opportune moment to review the advantages of reductive amination. Students can also be asked questions that require a retrosynthetic analysis using clickers or an online assignment or exam. When designing questions using an online homework program, the students can either be asked to identify the atoms involved in a given reaction type as in the above example (this would be a mapping question on an online homework program such as ACE16a), they can be asked to draw the starting materials for a given compound, or they can be asked to identify an appropriate reaction that could be used to synthesize a specific functional group or bond. On an exam, the students can be asked to determine appropriate retrosynthetic disconnections for complex targets. They can additionally be asked to include their analysis, brainstorming, and an explanation of the decisions taken to arrive at a final synthetic route, which are important components of the problem-solving and critical-thinking processes.1,17

’ DISCUSSION The use of real and relevant synthetic targets was particularly exciting because it provided an opportunity to discuss aspects of each compound including its discovery, its medicinal value, aspects of existing syntheses, and the considerations for a large-scale synthesis. In fact, the discussion of discodermolide incited such interest that a few students designed their own full synthesis after class. The challenges experienced by students demonstrated to them first-hand why so much time, money, and effort is required for the development of new and improved products and methods. Studies are currently underway to measure the impact of this method on students’ problem-solving and critical-thinking skills. The students’ abilities to design organic syntheses and retrosyntheses will be compared between groups that use this method and groups that do not. An analysis of students’ problem-

solving and critical-thinking skills on other types of questions will be undertaken, again making a comparison between the aforementioned groups. The results of these studies will be released in due course.

’ SUMMARY A unique approach to teaching and learning problem-solving and critical-thinking skills in the context of retrosynthetic analysis was described. In this approach, introductory organic chemistry students, who typically see only simple organic structures and problems with a single correct answer, undertook partial retrosynthetic analyses of real and complex synthetic targets. The synthetic targets had sufficient complexity that the students had to analyze the structures retrosynthetically. Multiple reasonable answers were possible for most questions, which provided a basis for the development of critical-thinking skills.1 Importantly, a new method was described for students to answer the questions involving these complex synthetic targets. A numbering system was developed that enabled students to submit numeric clicker answers to a single or to multiple questions simultaneously. The predominant student answers were easily gauged using the histogram function of the clicker program and this provided a basis for multiple relevant retrosynthetic analyses that were based on the students’ own responses. The students could also benefit from seeing and analyzing the varied responses of their peers. In this way, prompt, regular, and relevant feedback was provided to students, notably, in large classes.6 By engaging in the process of retrosynthetic analysis of these complex targets, the students practiced problem-solving and critical thinking, which are important in many facets of life. They were explicitly encouraged and given the opportunities to brainstorm, to recognize patterns, to generalize facts and principles and to bring together knowledge from different sections of the course(s). By developing stronger problem-solving and criticalthinking skills,3,5b,17,21 students can move beyond remembering, 1499

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Journal of Chemical Education understanding, and application toward analysis, evaluation, and synthesis.2

’ ASSOCIATED CONTENT

bS

Supporting Information ChemDraw files for the compounds described, including atom or bond numbering, are provided. This material is available via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: alison.fl[email protected].

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