What Is Chirality

Isomers are compounds with the same molecular formula but with a different arrangements of the atoms. Of the different types of isomers, optical isomers will be the focus of this chapter. A molecule is chiral when it cannot be superimposed upon its mirror image. Hence, a compound and its nonsuperimposable mirror image are two different isomers termed enantiomers. Optical isomerism is a result of this different spatial arrangements of atoms in a molecule. The lack of symmetry can arise from four different substitutions around a tetrahedral carbon atom (stereogenic center), although atoms such as phosphorous may also act as stereogenic centers. For example, lactic acid has a stereogenic center and therefore can exist in two enantiomeric forms. However, propanoic acid possesses a symmetry plane and so is achiral (i.e., the molecule can be superimposed on its mirror image) (Figure 5.1). Enantiomers are identical except for two properties: their optical activity and the way in which they interact with other chiral molecules. The optical activity of an enantiomer is the ability to rotate the plane of polarized light (i.e., light that oscillates in a single plane). A 50:50 mixture of two enantiomers is called a racemic mixture and its optical rotation is zero. The degree of rotation caused by a single enantiomer is measured using a polarimeter. If a molecule rotates plane polarized light anticlockwise it is labeled as laevorotatory, abbreviated "l" or (-), or if it is clockwise it is called dextrorotatory, "d" or (+).

Specific rotation is an intrinsic property of an optically active molecule that can be used to quantify the amount and purity of a single enantiomer. This value is dependent on the wavelength of light used, the length of the sample tube through which the light is passed, temperature, solvent, and sample concentration. The light source most often used for such determinations is that emitted by a sodium lamp at 589 nm (the so-called D line). In order to compare data, these parameters should be specified when quoting the specific rotation, [a]D. Optical purity (usually expressed as a percentage) can be defined as the ratio of the specific optical rotation of the enantiomeric mixture and the specific optical rotation of the pure enantiomer.

The observed optical rotation (d or l) was the earliest method of distinguishing between enantiomers, but this method gives no indication as to the actual spatial geometry of a molecule

Mirror plane

CO2H

The two enantiomers of lactic acid

Central carbon atom is the stereogenic center

CO2H

Propanoic acid—has a plane of symmetry

FIGURE 5.1 The two enantiomers of lactic acid are mirror images of each other. However, propanoic acid is achiral as it has a plane of symmetry through the center of the molecule.

Priority 2

Priority 2

FIGURE 5.2 Procedure for assigning stereogenic centers as possessing either (R) or (S) configuration. (a) Assign priorities according to the CIP rules. (b) View from opposite the group of lowest priority: Clockwise rotation (13) is (R); anticlockwise rotation is (S).

i.e., the configuration of atoms or groups about the stereogenic center. This was rectified by the introduction of the Fischer convention, which labeled such centers as having either d or l configuration based on an arbitrary standard, (+)-glyceraldehyde. However, this system has now been superseded by the Cahn-Ingold-Prelog (CIP) system that can be used to unambiguously assign any stereogenic center as possessing either (R) or (S) stereochemistry. Explanation of the CIP rules can be found in any general organic chemistry textbook. Once the priorities of the substituents have been assigned enantiomers are readily classified as being the (R) or (S) isomers. Lactic acid is again used as an example to demonstrate this (Figure 5.2).

Molecules such as lactic acid are relatively simple in that they only have one stereogenic center. But what are the implications if multiple stereogenic centers are present? As an example, the drug ephedrine has two stereogenic centers and thus there are four possible isomers (Figure 5.3). Of these, the isomers that are mirror images are enantiomers, while the nonsuperimposable nonmirror images are called diastereomers. It is important to note that diastereomers, unlike enantiomers, will (unless by coincidence) have nonidentical physical and chemical properties such as boiling point, solubility, and spectral properties. The potential applications of these differences are discussed in Sections 5.5.1 and 5.5.2.

As a general rule, the total number of isomers of any given molecule is also given by the rule:

Number of isomers = 2", where n is the total number of stereogenic centers

So, as in ephedrine, a compound with two stereogenic centers will have four isomers, three centers leads to eight isomers, and so on. However, there are exceptions to this rule, because some isomers may be meso compounds. These can be described as isomers that contain stereogenic centers but are achiral (and optically inactive) due to the presence of a symmetry plane. Figure 5.4 shows the example of tartaric acid, with two stereogenic centers and three isomers.

The definition of optical purity discussed earlier has been largely superseded by two related terms: enantiomeric excess (ee, or the proportion of the major enantiomer less that of the minor ch, ch,

Enantiomers (mirror images)

Diastereomers

Enantiomers (mirror images)

FIGURE 5.3 The relationship between enantiomers and diastereomers. The biologically active forms of ephedrine are those with the (1R, 2S)- and (1S, 2S) configurations, which are diastereomers of each other.

HO H

OH HO

OH HO

Plane of symmetry

CO2H CO2H

Achiral—meso form

FIGURE 5.4 Tartaric acid has two stereogenic centers but only three stereoisomers.

CO2H

CO2H

CO2H

CO2H

enantiomer) and diastereomeric excess (de, proportion of the major diastereomer less that of the minor one). Both ee and de are usually expressed as percentages.

If the only difference between enantiomers was their interaction with plane polarized light, then their existence would be little more than academic. However, stereochemistry has important implications in terms of biological activity as described in the following section.

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