In this chapter we will consider the stereochemistry of organic molecules, a topic that is concerned with how the atoms of a molecule are arranged in three dimensions. This is an important topic in pharmaceutical chemistry because the shape of a drug molecule affects both its desired biological activity and its potential for exhibiting undesired effects. To introduce the topic of stereochemistry, consider the three chemical drawings shown below (Figure 3.1). Each of these representations describes a six-membered carbon ring with two methyl groups attached at defined positions—all three drawings describe the molecule 1,3-dimethylcyclohexane. However, as one moves from the first to second drawing, additional important information is conveyed. Whereas the first drawing tells us only about the connectivity of carbon atoms, the second tells us about the relative orientation of the two methyl groups—one is projecting out of the plane of the paper whereas the other is receding behind it. This drawing describes a specific stereoisomer of 1,3-dimethylcyclohexane. An even more informative representation is provided in the third drawing, which tells us not only about the relative orientation of the methyl groups but also about the relative positioning of all the carbon atoms in the cyclohexane ring. This third drawing attempts to illustrate the actual three dimensional shape of 1,3-cyclohexane, including its conformation, a topic we will cover in detail in the following chapter.
Three depictions of the molecule 1,3-dimethylcyclohexane. Drawings (b) and (c) convey additional stereochemical and conformational information not provided by drawing (a).
In considering the drawings of 1,3-dimethylcyclohexane above it may have occurred to you that other stereoisomers of 1,3-dimethylcyclohexane might also exist. For example, what if both the methyl groups projected from the same side of the ring? What if the methyl groups were found on different carbons of the ring but still in a 1,3-relationship? There would appear to be many possible stereoisomers of 1,3-dimethylcyclohexane (Figure 3.2). But, are all of these molecules truly different? Are some of these not equivalent representations of the same molecule? How many unique stereoisomers of 1,3-dimethylcyclohexane exist and how are they related to each other? These are the questions we seek to answer in studying the stereochemistry of molecules.
Several different stereochemical representations of 1,3-dimethylcyclohexane. Not all of the structures shown represent distinct stereoisomers. Can you spot the duplicates? How many distinct stereoisomers are present in this set?
3.2 Chirality and the Shape of Molecules
Stereochemistry is of critical importance to drug action because the shape of a drug molecule is an important factor in determining how it interacts with the various biological molecules (enzymes, receptors, etc.) that it encounters in the body. Take, for example, the two very similar molecules shown ...