Demystifying Enolate Chemistry

In my mind, enolate chemistry is one of the highlights of the second-semester organic chemistry course. Granted, the list of named enolate-based reactions (Aldol, Claisen, Michael, Robinson, etc.) can be daunting to students. Nevertheless, the importance of enolate chemistry in biochemical processes (glycolysis, gluconeogenesis, fatty acid biosynthesis), as well as in the synthesis of compounds of interest to both the pharmaceutical (Tamoxifen, progesterone) and personal-care (jasmone, b-vetivone) industries, has in my experience been manifold in convincing students of the relevance of organic chemistry to their curricular and career plans.

Unfortunately, most texts (and by extension most courses) place enolate chemistry into a one- or two-chapter unit near the end—it’s often one of the last things that students see in the year-long organic chemistry sequence. I have two concerns with this long-standing organization. First, students often see these important reactions at a time of year when both their energy and motivation are low. Second (and worse in my opinion), students see enolate chemistry separated from other mechanistically-related reactions. Year after year, I have seen this combination work against students. Encountering disconnected enolate chemistry when they are fatigued, they rely on memorization rather than mechanism to move through the unit. The net result? Increased anxiety and lower exam scores.

When I saw the table of contents for Karty’s text, one of the first things that stood out to me was the integration of enolate chemistry into the chapters on additions to polar pi bonds. I was excited—I had wanted to try this approach for years, but I didn’t have a text that would provide pedagogical support. This year, my students saw aldol additions and Claisen condensations presented earlier and alongside other examples of nucleophilic addition and nucleophilic addition–elimination, respectively. Enolates were demystified and treated as ordinary nucleophiles. In so doing, students were liberated: I observed them focusing less on the enolates themselves and more on the fate of the tetrahedral intermediates common to both mechanism classes.

Students did well on the exam covering nucleophilic addition and nucleophilic addition–elimination (including enolate chemistry). I saw marked improvement, compared to past semesters, on questions involving enolates, both on those that asked them to draw mechanisms and those that asked them to predict the products of reactions. For example, one question asked students to draw the mechanism that accounted for the formation of a cyclic dione reported in the Journal of Organic Chemistry. The mechanism had four major parts, including an aldol condensation, a Dieckmann condesation, a Michael addition, and an acid catalyzed ester hydrolysis followed by decarboxylation. A sizeable majority of the class moved through the mechanism with ease. When students did have difficulty, it was not with the enolate chemistry, but rather with the mechanism of decarboxylation. In past years, where enolate chemistry was separated from other mechanistically-related reactions, I observed on similar questions difficulties with both decarboxylation and the enolate-based reactions. Just as pleasing was the relative calm leading up to the exam itself. This year, having been placed in context, enolate chemistry made more sense to my students, and I observed less anxiety in the class. Leading into the final exam, my students now have positive momentum, as well as an increased confidence in their abilities to use reason rather than memorization as a path to success.

— Brad Chamberlain, Luther College

Brad Chamberlain teaches at Luther College and is currently class-testing the Preliminary Edition of Joel Karty’s forthcoming textbook. Click here to learn more about Prof. Chamberlain.

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