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Organic Chemistry: Stereoisomers

Racemic Mixtures and Enantiomeric Excess

Optical Activity

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Racemic Mixtures

A solution in which both enantiomers of a compound are present in equal amounts is called a racemic mixture, or racemate. Racemic mixtures can be symbolized by a (d/l)- or ()- prefix in front of the substance's name. Since enantiomers have equal and opposite specific rotations, a racemic mixture exhibits no optical activity. Therefore it is impossible to tell a racemic mixture apart from an achiral substance using polarimetry alone. Note that the terms chiral and optically active should not be confused. It would be incorrect to say that a racemic mixture is achiral. Chirality is a property of individual molecules. Optical activity is a property of solutions. A racemic mixture consists of chiral molecules, but it has no net optical activity.

The process by which a racemic mixture is formed from chiral materials is called racemization. One way to do this is to mix equal amounts of enantiomeric substances. From this point of view, it may be puzzling that racemic mixtures are important. After all, what are the chances of obtaining any mixture in which two enantiomers are present in exactly equal amounts? It turns out that racemic mixtures actually occur with considerable frequency. Racemic mixtures are often formed when achiral substances are converted into chiral ones. This is due to the fact that chirality can only be distinguished in a chiral environment. An achiral substance in an achiral environment has no preference to form one enantiomer over another.

Resolution of Racemates

The separation of enantiomers poses a special problem for chemists. Enantiomers have the same boiling points, melting points, solubilities, etc., so many of the techniques used to separate other compounds don't work on racemic mixtures. The answer to this problem is to separatee nantiomers in a chiral environment, where they interact differently.

One technique is to use a chiral resolving agent. This technique relies on the fact that while enantiomers have identical physical properties, diastereomers generally have different properties. For example, suppose we wanted to separate the enantiomers of 2-hydroxylpropionic acid. We add as the resolving agent an enantiomerically pure amount of (R)-2-phenyl-ethylamine. The two enantiomers interact with (R)-2-phenyl-ethylamine to form two distinct salt species that are diastereomers of each other. The diastereomers can then be crystallized separately.

Figure %: Separation via formation of diastereomeric salts

Another technique is to use chiral chromatography. In this process, the racemate is run through a column that is filled with a chiral substance. The enantiomers will interact differently with the substance and will then elute (or filter through the substance) at different rates. These techniques are also applied to mixtures of enantiomers beside racemic mixtures, for example to purify a species from small amounts of its enantiomer.

Reactions that Produce Enantiomeric Excess

How important is it for chemists to isolate pure enantiomers? In some applications, the chirality of a molecule is unimportant. In many cases, however, the chirality of a molecule is crucial to its function. This is especially true in biological systems, where a molecule might have a function vastly different from that of its enantiomer. Biological systems are chiral environments. Here are a few examples:

Figure %: Biological functions of molecules and their enantiomers

When chemists want to synthesize compounds that are important for biological usage, they almost always need one enantiomer in high purity. The degree of enantiomeric purity of a solution is measured by its enantiomeric excess, or ee. The enantiomeric excess is found by dividing the observed optical rotation by the optical rotation of the pure enantiomer and multiplying by 100 to obtain a percentage. This number represents the percentage of one enantiomer in excess of the other. For instance, a 75/25 mixture has a 75 - 25 = 50 % ee, while a 50/50 racemic mixture has a 50 - 50 = 0 % ee. One strategy to make a pure enantiomer is to produce the racemic mixture, resolve the racemate using one of the techniques above, and toss away the undesired half. However, this strategy is not viable for expensive syntheses that require multiple steps. The waste is special to the syntheses of complex molecules that have several stereocenters. If we threw away half the product at every stereogenic step, our yield would decrease exponentially!

A better solution is to employ a reagent that selectively produces one enantiomer over another. Of course such reagents must be chiral. The problem with this approach is that the precious chiral reagent is used up once the reaction is complete. An even better approach is to use a chiral catalyst that can be used over and over again. The field of chiral catalysis is a relatively new and exciting venture in organic chemistry that holds much promise for enhancing the power of organic synthesis.

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