Stereochemistry: Determining Molecular Chirality

Discussion: Chiral objects are not superposable with their mirror images. An excellent example of this is your hands. Hold your hands out in front of you, with the palms facing together. Neglecting unnatural additions such as jewelry, note that your hands are mirror images. Now turn your hands so that both palms face the same direction. Note that the thumbs now point in opposite directions. When the thumbs point in the same direction, the palms are opposite. Your hands are mirror images, but not superposable. Each hand is therefore chiral.

Achiral objects may be superposed on their mirror image. Examine two sheets of blank paper in the same way as you experimented with your hands. Notice the sheets of paper are mirror images, but superposable. The sheets of paper are therefore achiral.

All objects can be classified as chiral or achiral, including molecules. If our hands were molecules, they would be a pair of enantiomers.

We know from basic biology that interaction of molecules, such as the docking of a substrate to an enzyme, is vital to living organisms. Because enzymes and their substrates may be chiral, it is useful to understand how achiral and chiral molecules can interact. (enzymes are constructed from a group of about 20 small molecules called amino acids. All amino acids except one are chiral, so the enzymes they make are chiral as well.) The way a hand slips into a glove provides a useful way to model this effect. The glove is the enzyme, and the hand is the substrate that must fit properly into the enzyme pocket for the enzyme to be able to act upon the substrate. (Verify that a pair of gloves are chiral in the same way you explored the chirality of your hands.) Your right hand fits nicely into the right handed glove, but does not fit well into the left-handed glove. Likewise, your left hand fits well into the left-handed glove, but the right hand does not. Imagine the glove represents an enzyme and your hand the substrate. The left-handed enzyme/glove would accept the left-handed substrate/hand readily, and would be able to act upon the substrate. The left-handed enzyme/glove cannot readily accept the right hand/substrate, as so this enzyme cannot readily act upon this substrate. This simple model implies that an enzyme will act on one enantiomer more readily than another. Thus, enantiomers of drugs can have different effects in the body, because they are acted upon differently by enzymes, despite the fact that they have the same set of functional groups.

That enantiomers of drugs can have different biological effects has been demonstrated in many instances, but perhaps none so dramatically as the in the case of the drug thalidomide. In the late 1950s, the racemic form of this drug was prescribed as a sedative or hypnotic for pregnant women. Some women who took the drug delivered children with severe birth defects. A substance that causes fetal abnormalities is called a teratogen. Further research revealed that one enantiomer of thalidomide has the desired sedative effects, while the other enantiomer was teratogenic. The enantiomers of thalidomide were acting differently in the body, because they interacted differently with chiral biomolecules such as enzymes. The drug was quickly removed from the market.

Chiral molecules are nonsuperposable with their mirror images. This can be tested on paper or with molecular models using the two methods described below.

Internal mirror plane. We can look for a plane of symmetry in the molecule. Imagine this plane as a mirror through the middle of the molecule. If one half of the molecule is reflected into the other half, then the molecule is achiral. If no such mirror plane exist, the molecule is usually chiral. (There are symmetry elements other than a mirror plane that may render a molecule achiral, but these are rarely encountered and thus beyond the scope of an introductory organic chemistry course.) Molecular models can be used in the same way.

Example 1: Using the method of an internal mirror plane, determine if cyclohexanol is chiral or achiral.

Solution 1: To determine if cyclohexanol is chiral using the internal mirror method, draw a mirror plane through the middle of molecule. If there are any unique functional groups or atoms within the molecule, these must lie within the mirror plane, so that one half of the atom or functional group is reflected into the other half. In this case, there is only one alcohol functional group, so it must be contained in the mirror plane. Figure 1 shows that the mirror plane bisects the molecule into two equivalent halves, so cyclohexanol is achiral.

Figure 1. Two views of cyclohexanol showing the internal mirror plane.  The mirror plane is indicated by the dashed line.
 
 

Figure 2. Cyclohexanol molecular model.  A vertical mirror plane bisects the molecule through the middle of the picture.
Superposable models. To determine if a molecule is chiral using the superposability requirement, build a molecular model of the molecule in question, then a build a mirror image of this model. Now try to superpose the models by aligning them so that all the atoms match up. The models may be manipulated in any way, such as rotation around single bonds (changing molecular conformation) or changing perspective, but bonds cannot be broken. If all the atoms can be made to line up, the molecule is achiral. If they cannot be aligned, the molecule is chiral.
 

Example 2: Using the method of superposable molecular models, determine if cyclopentanol and 2-chlorobutane are chiral or achiral.
 

Solution 2:

Figure 3. Left: Molecular model of cyclopentanol and its mirror image.  Right: A top view showing that these cyclopentanol models can be aligned (superposed), so cyclopentanol is achiral.
 

Figure 4. Left: Molecular model of 2-chlorobutane and its mirror image.  Right: The same models stacked.  The Cl-C-H portions of the models can be made to superpose, but at the same time the methyl and ethyl groups do not.  The 2-chlorobutane models cannot be superposed, so the molecule is chiral.



Exercises: Using either method discussed above, determine if the molecules shown below are chiral or achiral.


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