CHAPTER OUTLINE
3.2 Chirality and the Shape of Molecules
3.3 Stereoisomers—Some Important Definitions
Box 3.1—Determining isomeric and stereochemical relationships between molecules
3.5 Stereoisomers of 1,3-Dimethylcyclohexane
3.7 Assigning the Configuration of Chirality Centers
Box 3.2—Cahn–Ingold–Prelog rules in brief
3.8 Configurational Assignment and Stereochemical Relationships
3.10 Chirality Centers at Non-Carbon Atoms
3.11 Other Sources of Chirality and Stereoisomerism
3.13 Case Study—Racemic and Non-Racemic Drugs
3.1 Introduction
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.
Figure 3.1 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.
Figure 3.2 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 above (Figure 3.3). At first glance they may appear to be identical but in fact they are related to one other in the same way a right hand is to a left hand. That is, each molecule is the mirror image of the other. You can see this by imagining (or actually placing) a mirror between the molecules on the page. Just as the mirror image of your right hand is a left hand, so is the mirror-image form of some molecules distinct. Objects or molecules that possess this property of being different from their mirror image are said to be chiral. Objects or molecules that are indistinguishable from their mirror image are achiral (not chiral).
Figure 3.3 An example of two mirror-image molecules (enantiomers), both of which happen to be useful drugs. The two molecules have very different biological activities however, as is often the case with enantiomers.
To understand why chirality is important in the action of drugs, consider the chiral, mirror-image drug molecules levorphanol and dextrorphan (Figure 3.3). Levorphanol activates opioid receptors and has powerful analgesic properties. However, its activity at multiple opioid receptors means that it is also a highly addictive substance and therefore is used only in the treatment of severe pain. In contrast, dextrorphan has no significant analgesic properties and is nonaddictive, but does has antitussive activity (it is the active metabolite of dextromethorphan, a widely used cough suppressant). Mirror-image molecules tend to have different pharmacological properties because biological macromolecules are themselves chiral and hence are affected differently by the mirror-image forms of a chiral drug molecule. A helpful analogy is that of hands and gloves—both chiral objects. A right-handed glove best fits a right hand so we might say that a right-handed glove can distinguish a right hand from a left. So too can biological macromolecules distinguish between the mirror-image forms of chiral drug molecules.
3.3 Stereoisomers—Some Important Definitions
It will be helpful at this stage to introduce some terms that are useful in describing relationships between stereoisomers. First, one must be clear about the distinction between constitutional isomers and stereoisomers. Constitutional isomers have a different connectivity of atoms. For example, 1,2-dimethylcyclohexane and 1,3-dimethylcyclohexane are constitutional isomers because the methyl groups on the cyclohexane ring are attached at different positions—their atom connectivity is different (Figure 3.4). Stereoisomers have identical atom connectivity but are distinct in shape (they cannot be perfectly superimposed). If two stereoisomers are also mirror-image molecules, then they are said to be enantiomers. The molecules levorphanol and dextrorphan discussed above are enantiomers because they are mirror-image stereoisomers. Since a molecule can have only a single mirror image, enantiomers always come in pairs. Any pair of stereoisomers that are not mirror-image molecules are termed diastereomers. The relationships between these various terms are summarized in the box (Box 3.1).
Figure 3.4 Constitutional isomers have different connectivity of atoms, whereas stereoisomers differ only in shape.
Box 3.1 Determining isomeric and stereochemical relationships between molecules.
The tree diagram below may be helpful in illustrating and determining the relationship between different types of isomers. Start at the top by asking the question whether the two molecules in question are actually different (we will assume that the molecular formulae are the same). If the molecules are truly different then we can say that we are dealing with isomers of one sort or another. If the atom connectivity is also the same, then we are dealing with stereoisomers that differ only in shape. The final question then is whether or not the stereoisomers are mirror image isomers. If yes, they are enantioners, if no, they are diastereomers.
3.4 Avoiding Confusion
It is very important to avoid confusing the property of chirality with descriptive terms like enantiomer and diastereomer. Intermingling of these terms and concepts is often a source of confusion for students of stereochemistry. First, note that all chiral molecules will have exactly one enantiomer (the mirror-image molecule). Note also that the mirror image of an achiral molecule will be the same molecule and so an achiral molecule can never have an enantiomer. However, some achiral molecules do have stereoisomers. This may seem surprising since chirality seems so closely tied to stereoisomerism. Consider however the “cis” and “trans” isomers of 1,4-dimethylcyclohexane shown below (Figure 3.5). Both molecules are achiral and neither has an enantiomer since both are identical to their mirror image. The two molecules have the same connectivity of atoms but are clearly different, thus meeting our definition of stereoisomers. Since they are not mirror-image isomers, cis– and trans-1,4-dimethylcyclohexane must be diastereomers.
Figure 3.5 An example of stereoisomers that are achiral (not chiral). The cis and trans isomers of 1,4-dimethylcyclohexane are diastereomers since they are nonsuperimposable stereoisomers but are not mirror-image isomers.
3.5 Stereoisomers of 1,3-Dimethylcyclohexane
Now let us reconsider all the possible stereoisomers of 1,3-dimethylcyclohexane. It is possible to imagine many possibilities (Figure 3.2) but closer inspection reveals that many of these structures are the same molecule drawn in a different orientation (e.g., upside down, or rotated on the plane of the paper). Since each methyl group can be found in one of two configurations (pointing up or down) we need only consider the four structures shown below (Figure 3.6). Inspection of the first two structures reveals them to be the same molecule—a rotation of 180° through the plane of this page will convert one into the other. It is also apparent that this stereoisomer is achiral since it is identical to its mirror image. One way to see this is to recognize that a mirror plane can be placed within the molecule. Any molecule (or object) that can be bisected by a mirror plane will be identical to its mirror image and thus, is achiral. Now consider the second (lower) pair of isomers in Figure 3.6. In this case, no internal mirror plane is present and no amount of rotation through space will serve to superimpose the two molecules—thus, they are stereoisomers. By reorienting this pair of molecules in space we can show that they are in fact mirror-image stereoisomers and therefore must be enantiomers. In summary, we can conclude that there are only three unique stereoisomeric forms of 1,3-dimethylcyclohexane—one symmetrical (achiral) stereoisomer and a pair of chiral enantiomers. The relationship between the achiral stereoisomer and the enantiomers is that of diastereomers—distinct stereoisomers but not mirror-image isomers.
Figure 3.6 Only three distinct stereoisomers of 1,3-dimethylcyclohexane are possible. These include a pair of enantiomers (bottom) and a single achiral stereoisomer (top) that is diastereomeric with each of the chiral stereoisomers.
3.6 Chirality Centers
When considering molecules more complex than 1,3-dimethylcyclohexane, it can be challenging to correctly identify stereoisomeric relationships by performing rotations and translations in three dimensional space. We need another way to rapidly identify the stereochemical relationships between molecules. One helpful approach is to first identify any chirality centers in a molecule and assign their configuration. As the name implies, chirality centers are centers within a molecule from which chirality originates. The most typical source of chirality centers in drug molecules are tetrahedral sp3 hybridized carbon atoms attached to four different substituents. Consider for example the pair of enantiomers shown above in which a carbon atom is attached to four substituents, generically denoted A, B, C, and D (Figure 3.7). The central carbon atom in each enantiomer is a chirality center. It will always be the case that a molecule with a single chirality center will be chiral and will have a single enantiomer. Molecules with more than one chirality center will typically have both an enantiomer and one or more diastereomers. There are special cases however when a molecule with two or more chirality centers is achiral on the whole. This occurs when multiple chirality centers are related by a symmetry element such as a mirror plane. These special cases will be covered later in the chapter.
Figure 3.7 A hypothetical pair of enantiomers based on tetrahedral carbon with four different groups attached. The hashed line indicates a mirror that relates the two enantiomers. The sense of rotation moving from A to B to C is indicated on the drawings at bottom, and is opposite in the two enantiomers.
3.7 Assigning the Configuration of Chirality Centers
Consider again the pair of enantiomers discussed above, each containing a single chirality center (Figure 3.7). The “handedness” of the chirality centers in these molecules can be visualized in an interesting way. If we move from A to B to C in the molecule shown at left in the figure we find we are moving in a clockwise direction. If we do the same exercise with the enantiomer of this molecule (shown at right), we find that the sense of rotation is now counterclockwise. We might say that one molecule is “right handed” while its enantiomer is “left handed” based on the direction of rotation. This difference in rotational direction forms the basis of the Cahn–Ingold–Prelog (CIP) rules for assigning the stereochemical configuration of chirality centers. To successfully employ these rules requires that we properly assign the “priority” of various groups and properly orient the chirality center prior to assessing its configuration. In the example above it was natural to proceed from A to B to C based on the order of these letters in the alphabet. When actual chemical substituents are involved we instead employ the CIP rules to determine a rank-order priority for the substituents.
The CIP rules for assigning priority are quite logical and easy to master. In the simplest case, the substituents attached to a chirality center are assigned priority based on the atomic number (Z) of the atoms directly attached to the chirality center. If the four atoms directly attached are all different, then priority is easily assigned (higher priority for higher atomic number). A more typical case is shown below, where the four atoms directly attached include one hydrogen, two carbons, and one oxygen atom (Figure 3.8). Already we can say on the basis of atomic number that the oxygen substituent (Z = 8) is afforded the highest priority and the hydrogen substituent (Z = 1) the lowest. However, to distinguish priority between the two carbon substituents we must consider the additional atoms present. Moving out one additional bond in each of these substituents we arrive at a carbon atom in one case and an oxygen atom in the other. Thus we can say that the substituent with oxygen at the second atom in the chain has higher priority (based on atomic number). Note that it does not matter that the other substituent is linked to two carbon atoms—atomic number takes priority over the number of groups attached. Thus, we have now assigned priority for all four groups attached to the chirality center. The next step is to orient the molecule such that the chirality center being analyzed has its lowest priority group (in this case hydrogen) pointing away from the perspective of the viewer. In this example the orientation needs no adjustment and we can directly consider the sense of rotation in progressing from high to lower priority (from 1 to 3). In this case the sense of rotation is clockwise and we therefore assign the configuration as R, from the Latin for “right”—rectus. It may be helpful to imagine the chirality center as a steering wheel with the lowest priority group representing the steering column, receding from view. Using this pictorial device, a “right turn” at the steering wheel (clockwise rotation) indicates the R configuration.
Figure 3.8 Assignment of configuration at a chirality center using the Cahn–Ingold–Prelog rules. Priority of substituents (1-4) is based on atomic number and the molecule is oriented such that the lowest priority group is positioned away from the viewer. A clockwise rotation in moving from 1 to 2 to 3 indicates the R configuration.
Let us now consider another molecule with a single chirality center (Figure 3.9). To assign the configuration of this center we again start by first considering the four atoms directly connected to the chirality center. Immediately we can assign the amino substituent (Z = 7) highest priority and the hydrogen substituent (Z = 1) lowest priority on the basis of atomic number. As with the previous example, we cannot immediately assign the priority of the other two substituents since both are attached via carbon atoms. We therefore consider the atoms one bond further out within each substituent and find that carbon is next in both cases. However, according to the CIP rules, a double bond is treated as two single bonds and so the substituent with a double bond to carbon takes priority over that with only a single bond. Note here that the number of carbon atoms directly attached becomes relevant only when atomic number alone is not sufficient to determine priority. Note also that the presence of higher atomic number atoms (e.g., oxygen) further out in a substituent is irrelevant if a distinction can be made nearer to the chirality center. Having fully assigned priority, we must now rotate the molecule such that the lowest priority substituent is pointing away from our point of view. After doing this we can see that the sense of rotation according to priority is counterclockwise (a left-hand rotation) and can therefore assign the configuration as S, from the Latin for “left”—sinister. Everything you need to know about assigning configuration using the CIP rules has been covered in working these two examples. A more formal presentation of the CIP rules for assigning configuration is provided in Box 3.2.
Figure 3.9 Assignment of configuration using the CIP rules. The first step is to redraw the molecule with its lowest priority substituent (H) directed away from the viewer. Note that this reorientation does not change the molecule or configuration in any way. We are simply redrawing the same molecule from a different perspective.
