The Right Time for Synthesis?

At Butler, we have four learning goals for our students in organic chemistry: to learn the language, drawing style, and three-dimensional structure of organic molecules; to know and apply organic reactions; to demonstrate understanding of reaction mechanisms; and to integrate this knowledge through synthesis. Of these learning objectives, the most difficult for students to embrace is synthesis. For many of them, this is the first time they have been asked to apply new knowledge at the college level. While we recognize that very few of our students are likely to become synthetic chemists, we feel that synthesis is a valuable intellectual tool to facilitate creative problem solving.

In our adoption of Karty, a significant point of discussion was the placement of complex synthesis late in the text (Chapter 13). As that would be our last chapter of the fall semester, was it appropriate to leave what was, for us, such a critical item until then? Each of our faculty members has solved this differently. I chose to introduce synthesis very early, right after the discussion of SN2 chemistry (Chapter 7).

While I support Karty’s premise that synthesis works well with a solid foundation in mechanism, I also recognize the needs of my student population. The majority of my class is made up of students from our College of Pharmacy and Health Sciences. These students respond well to an applied approach to their education. By introducing synthesis earlier, they see application of reactions in addition to classification by mechanism. This synergy works well for most of this student population.

The initial syntheses I introduced were ether, thioether, and internal alkyne syntheses starting from alkyl halides. In this way, I could reinforce the importance of SN2 reactions as excellent ways to make new and larger molecules, as well as review acid/base chemistry as a way to make “good” nucleophiles. While the syntheses were straightforward, the ideas of starting material choice (on what carbon should the leaving group be attached?), what the nucleophiles should be, choice of reaction conditions to foster the appropriate reactivity (solvent choice, what other reactions could take place?), and placing reaction steps in the correct sequence were entirely new concepts.

This early introduction allowed me to continue to review and reinforce synthesis as we learned new reactions. In addition, it allowed me to gently ramp up the synthetic complexity as we learned these new reactions. I integrated sections of Chapter 13 into my coverage of Chapters 10, 11, and 12.

After completing Chapter 10, students were no longer allowed to use alkyl halides as starting materials and had to utilize alcohol reagents, taking them one step back from where they were in Chapter 7. I brought retrosynthesis forward at this point (Section 13.3) so they could identify the alcohol they needed to carry forward the synthesis. After discussion of epoxide reactivity, we discussed many ways of forming desired bonds and covered the concepts in Section 13.2. The coverage of synthetic traps (Section 13.4) provided an excellent opportunity to highlight the advantage of using epoxides as reagents in order to avoid some of these traps. Discussion of stereospecific reactions in Chapters 10 and 12 (opening of epoxides, halogenation of alkenes, hydroboration of alkenes, etc.) were woven throughout our conversations, so Section 13.6 was entirely review by the time we got to it. By integrating this information throughout the semester, it allowed me time to incorporate full class period conversations on synthesis.

Students were given synthetic targets ahead of time and encouraged to present synthetic routes on the board for their peers. For each example during these synthesis days, there were multiple routes possible. Students were encouraged to present these different, but equally correct, ways of getting to the target. Early discussions were synthetic targets that had the same basic building blocks and the reactions could be performed in different sequences to get to the final target. Later synthesis discussions had targets which could be made from different starting materials and utilized different sets of reaction sequences to get to the target.

By the end of this semester, I anticipate that synthesis will be something that the majority of my students can approach. Most of them will be able to make appropriate starting material choices and choose good reactions to bring their pieces together. A few of the more creative students will be able to envision two to three synthetic routes to form a given synthetic target.

Karty’s chapter on synthesis is excellent and very adaptable to earlier introduction in the semester. In addition, concepts like retrosynthesis and synthetic traps could be reevaluated after each new reaction type was introduced. This allowed for students to develop their own nuanced understanding of how synthesis is a creative problem-solving endeavor. I am hopeful that these skills are helpful for them as they move on to other coursework and other arenas where problem-solving is at a premium.

-Anne Wilson, Butler University

Click here to learn more about Prof. Wilson.

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