R,S Nomenclature: Help or Hindrance in Teaching Configurational Isomerism?

I have spent the last eleven years integrating configurational isomerism with the Cahn-Ingold-Prelog system of R,S nomenclature. This was influenced by my textbook that (like nearly every textbook) introduces R,S nomenclature early in the chapter devoted to this class of isomers. Primarily, though, my approach is derived from the opening vignette that I use in class for this chapter. The majority of my students are interested in the allied health sciences. Thus, I strive to link every concept that I introduce in class to a biological or biochemical application. When introducing configurational isomerism, I take my students “through the looking glass” into mirror-image land, whereupon we discuss the physiological implications of ingesting various substances that we may encounter.1

Year after year, students are noticeably drawn into the conversation once they realize that mirror-image land is a reality rather than fantasy, especially when it comes to pharmaceuticals. After learning of the differing physiological responses of configurational isomers vis-à-vis the enantiomeric forms of ketamine (anesthetic vs. hallucinogen), naproxen sodium (analgesic vs. liver toxin), and thalidomide (sedative vs. teratogen), students comprehend the importance of being able to distinguish between various configurational isomers. Furthermore, they almost immediately want to know to what the R or S in front of the names of these compounds refer.

In light of students’ curiosity and given my commitment to pedagogy, I was skeptical regarding the exclusion of R,S nomenclature from the chapter on configurational isomerism in Joel Karty’s forthcoming text. How could I illustrate the spatial relationships among various configurational isomers without R,S nomenclature embedded in the discussion? Of particular concern was examining pairs of molecules with multiple stereogenic centers. In these instances, direct comparison of the R and S designations of the centers allow for easy classification of the pairs as identical, enantiomers, or diastereomers. It wasn’t until I spoke with Joel on the phone during my ongoing class test of his text that I began to wonder (as he does) if a tool (R,S nomenclature) may in fact hinder a student’s ability to understand these spatial relationships. Were students becoming so dependent upon the tool that they were losing the big picture? I was intrigued, and I wanted to know.

To test this hypothesis, I modified my course this year to more closely follow the discussion of configurational isomers found in Joel’s text. Specifically, I delayed introduction of R,S nomenclature until after I had developed the various methods to determine whether a molecule is chiral and after full treatment of the spatial relationships among various configurational isomers. This change required some up-front investment of time. While I continued to use my opening vignette, I removed all references to R or S designations in the names of the pharmaceuticals. Where it was amenable, I redrew all of the molecules in my notes that had multiple stereogenic centers in eclipsed, rather than in staggered conformations; in my mind, in the absence of R and S designations, eclipsed conformations allow for a speedy determination if two centers are related as mirror images. In addition, I spent more time in class on the problems that I usually use to gauge whether students are able to classify pairs of molecules as being identical, enantiomers, or diastereomers. In past years, I often moved through these same problems quickly, as R and S designations made these relationships readily apparent only if one understood the conventions underlying the nomenclature. In the absence of R and S designations, as a class we had to perform more careful inspections of the configurations of each stereogenic center. When I was confident that the class grasped the big picture, I went back and re-examined these exact same problems while layering in R and S designations on the stereogenic centers of the molecules.

The result? During office hours, I noticed that students experienced the same level of difficulty assigning R and S designations. Ranking groups on a stereogenic center, especially when first points of difference are applicable, remained a challenging task for students. One important difference is that students struggled less with determining the spatial relationships among configurational isomers. On the exam for this unit, I was impressed by the performance of this class (compared to previous years) on the problem that asks if pairs of molecules are identical, enantiomers, or diastereomers. While some students utilized R and S designations for this problem, fewer did so than in the past.

In the end, despite my skepticism, I am now a convert. I’m persuaded by Joel’s thesis that students may use R and S nomenclature as a crutch when determining spatial relationships among configurational isomers. Given the continued difficulty students exhibit in properly assigning R and S designations in complex molecules, I may go further and state that R,S nomenclature may be a detriment to learning this core skill. If students look no further than R and S designations to determine whether pairs of molecules are identical, enantiomers, or diastereomers—if they neglect to directly compare the configurations of each and every stereogenic center of the molecules—then they are playing a risky game unless their skills of assigning R and S designations are above reproach.

— 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.

1This vignette is drawn from the article, “Through the Looking Glass and What Alice Ate There,” by Gordon T. Yee; see J. Chem. Ed. 2002, 79, 569-571. [Click here to return]

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