Lecture Supplement 4B

Stereochemistry: Chirality and Enantiomers

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This section will introduce you to the following terms:

Chirality

Enantiomers

Fisher projections

Conformation versus Configuration

Stereoisomers

Stereoisomers are compounds that have their atoms connected in the same order but differ in their three-dimensional orientation. In general, there are two broad classes of stereoisomers of interest to us: geometric isomers and isomers that display chirality. We will take up the second group in this supplement.

Chirality

Our understanding of atomic and molecular orbtials give us a better understanding of bonding and the ability to predict molecular shapes. To illustrate this point, we will consider methane (CH4) in some detail.

Figure 1 shows a simple "flat" drawing of methane. We now understand that the four s molecular orbitals for each of the carbon-hydrogen bonds are the result of combinations of sp3 hybrid atomic orbitals on carbon and 1s atomic orbitals on hydrogen. The sp3 hybrid orbitals on carbon are oriented toward the corners of a tetrahedron, and Figure 1 also shows a picture of methane that displays the resulting tetrahedral arrangement of the four carbon-hydrogen bonds. (The dotted lines in this picture are not bonds but rather an effort to draw a tetrahedron on a flat piece of paper.)

Figure 1. Methane.

This tetrahedral shape has important consequences for carbon-based compounds.

Organic compounds that have sp3 hybridized carbons show a unique property called chirality. The word, chirality, comes from the Greek for "hand", and as we shall see, some compounds exhibit the same property as your left and right hands. Your hands are mirror images of one another. If you hold your left hand up to a mirror, you will see an image that is identical to your right hand. Certain molecules can display this same property and possess mirror images of one another.

When does this appear?

For carbon compounds, chirality is usually, but not always, manifest in cases where one carbon possesses four different groups. Figure 2 displays several simple compounds, but only compound A is chiral. All the others have at least two groups that are the same.

Figure 2.

Enantiomers

By definition, a chiral compound has two mirror image-related structures, called enantiomers, that are not superimposible on one another. Figure 3 shows the two enatiomers for compound A. The same atom in the structure on the left and right is an equal but opposite distance from the mirror plane, represented by the line in the center.

Figure 3.

Drawing specific chiral compounds in three dimensions can be a challenge, particularly in cases where we have a number of chiral centers. As we will see, the compounds of most interest in biochemistry often have numerous chiral centers. How can we represent a chiral compound without recourse to drawing a three-dimensional picture? Fortunately, Emil Fisher developed an approach, that still bears his name, for precisely this need. Without a molecular model in front of you, it may be difficult to envision exactly how this works, but the key notion here is that it is possible to convert the tetrahedral structures in Figure 3 into "flat" Fisher projections.

Fisher projections

How is this done? There are a few simple conventions that we need to understand. First, the two bonds in the horizontal axis of the Fisher projection are poking out of the plane of the paper; the two bonds in the vertical axis are below the plane of the paper. If we used the usual wedges to display this, we might draw a Fisher projection as shown in Figure 4. But, to keep things simple, we will draw each of these wedges as a solid line.

Figure 4.

 

 

We are now in a position where we can redraw the structures in Figure 3 as Fisher projections. These are shown in Figure 5.

Figure 5.

There a two "rules" that we need to follow in manipulating Fisher projections to see if they are the same or different. First, the projection must stay in the plane of the paper. We cannot flip it over, but we can rotate it in the plane of the paper. Second, we can move "groups of three". If you pick any three groups on a Fisher projection and move the first group to the secondís position, the secondís to the thirdís position, and the thirdís to the firstís position, you have identical Fisher projections. The structures in Figure 6 are all identical because we have moved "groups of three".

Figure 6.

How are we going to label these chiral carbons? Each enantiomer has a specific configuration at the central carbon that does not vary over time, and we need a system for specifying this configuration. A nomenclature system was developed to label any chiral carbon with either an R or S designation. This system replaced an older, less useful system of L and D designations (that are still, as we shall see in biochemistry, in common use). In this course, you will not be expected to learn the rules for labeling carbons as R or S.

Finally, it is very important to emphasize that two enantiomers of a compound do not generally interconvert under normal conditions. The only way to convert one enantiomer to another is to break bonds. Admittedly, they have similar chemical properties and differ only in their ability to rotate plane-polarized light, but, each enantiomer is a stable, identifiable compound with a specific configuration.

Why is chirality of interest to us? Many of the biologically interesting molecules that we will study are chiral. This property confers a shape on these molecules and has relevance to their recognition by other biomolecules. Changes in configuration or chirality will be important in some biochemical reactions. Conformation will also be, however, very important to us in our study of biochemistry and it is important that we understand the difference between configuration and conformation.

Conformation versus Configuration.

For carbon compounds, the overlap of certain atomic orbitals leads to s molecular orbitals and that these orbitals are associated with single covalent bonds. In a similar fashion, the overlap of other atomic orbitals leads to p molecular orbitals and that these orbitals, along with a s molecular orbital, are associated with "double" covalent bonds. What are the consequences of these single and double bonds?

Single bonds concentrate electron density, as we have seen, between the two nuclei. Rotating one atom in a single bond with respect to the other, as shown in the following diagram, does not alter the electron distribution in this bond. We indicate this by saying that free rotation about the single bond is allowed. This principle of free rotation has no particular consequences for a carbon hydrogen bond. The bond in Figure 7 looks same if we rotate the hydrogen by 60o relative to the carbon.

Figure 7.

However, if we consider a carbon carbon single bond, it is a different story. As shown in Figure 8, this same free rotation about the central carbon carbon bond, brings the attached hydrogens into close proximity. These time-variant forms of ethane are called conformations. Not all conformations have the same energy, and this free rotation about single bonds will account for much of the variation that we will see in biochemical systems.

Figure 8.

 

Finally, it is worth noting that we can also have "limited" rotation about carbon-carbon bonds in cyclic structures. The case that you are most familiar with is cyclohexane. It is rotation about carbon-carbon bonds that results in the "ring flipping" of one chair conformation to another as shown in Figure 9.

Figure 9.

 

PROBLEMS:

    1. Which, if any, of the 20 essential amino acids is achiral? (note: achiral means "not chiral".)
    2. Which of the following structures (A, B, C, and D) also represent the enantiomer of R-alanine shown below?
    3. How many chiral carbons are there in guanidylate?
    4.  

    5. Are glucose and galactose enantiomers of one another?
    6.  

    7. Which of the following molecules is chiral? Which carbons in each of these structures is chiral? (Part of the problem here is that you must recogize where there is a carbon and then decide if there are four different groups attached. It should be remembered that organic chemists have developed a (nasty) practice of not always drawing all of the carbon hydrogen bonds.)

 

ANSWERS:

1. Glycine

2. A, C and D are all R-alanine

3. Four (see stars)

4. No, they are not mirror image related. Therefore, they are diastereomers. Since they are diastereomers that differ only at one chiral center, they are also called epimers.

5. Stars identify chiral carbons and each of the molecules, as a consequence, is chiral: