Chirality

The term "chiral" (from the Greek for "hand") is applied to molecular systems whose asymmetry results in handedness; that is, the existence of a pair of nonsuperimposable mirror-image shapes (as illustrated by the relationship between one's right and left hands). Lord Kelvin coined the term "chirality" in 1884, (Eliel, p. 4) but it did not come into common usage until the 1960s. Many macroscopic examples of handed systems exist, including any object that features an inherent spiral or twist that can exhibit a left- and right-handed form: scissors, spiral staircases, screw threads, gloves, and shoes. Some mineralogical materials exhibit handedness in the solid state. In 1801 the crystallographer René-Just Haüy (1743–1822) observed that there were right- and left-handed quartz crystals, a phenomenon known as hemihedrism. The term "enantiomorphous" ("in opposite shape") was created to describe the macroscopic relationships between nonsuperimposable, mirror-image crystalline forms.

Optical Activity

The concepts of three-dimensional isomerism, or stereochemistry, resulted from the proposition of molecular chirality. In 1812 Jean-Baptiste Biot (1774–1862), a physicist and a crystallographer, observed optical activity in mineralogical samples such as quartz, in which an asymmetrical crystalline form was macroscopically observable. In 1815 Biot also observed optical activity in samples of certain liquids, such as turpentine, various essential oils, and solutions of substances such as sugar and camphor. Because both pure liquids and solutions of organic compounds exhibit optical activity, the property could not be attributed to a characteristic of the solid state but instead had to be attributed to the molecular structure. In 1848 Louis Pasteur (1822–1895) separated an optically inactive sample of a tartaric acid salt into optically active dextrorotatory and levorotatory components by physically segregating the enantiomorphous crystalline forms. He showed that what had been thought to be a pure substance (racemic acid) was a mixture of two compounds: the natural, dextrorotatory tartaric acid and a substance that, although identical to the first compound identified in all of its other chemical properties, was yet opposite in its solid state structure and in its observed rotation of polarized light. In 1860 Pasteur proposed that molecular structural asymmetry was the basis for these observations. Jacobus van't Hoff (1852–1911) and Joseph-Achille Le Bel (1847–1930) independently proposed, in 1874, that molecular asymmetry and its consequences on isomerization could be explained if the arrangement (configuration) of the groups on a tetravalent atom was tetrahedral. Macroscopically or microscopically, a tetrahedral array of four different things gives rise to two and only two different arrangements that have a nonsuperimposable mirrorimage (enantiomorphic) relationship (see Figure 1). In the case of molecular structures, these two shapes would be examples of enantiomers.

Representing Chiral Geometry

Asymmetrical atomic centers giving rise to stereoisomers have been known as chiral centers, although the more general terms "stereocenter" and "stereogenic center" have come into common usage since the 1980s. Asymmetrical tetrahedral atoms are only one example of what is meant by a stereocenter because the definition of the term encompasses a larger territory of structural characteristics. Over the years, a variety of representations have been used to depict the three-dimensionality of stereocenters. The representations in Figure 2 all depict the same sense of chirality for one of the two mirror-image arrangements (enantiomers) of 2-bromobutane.

Molecular Chirality

Chirality is a term that can be applied to molecular mixtures as well as to individual molecular species. Mixtures of chiral molecules can range from having 100 percent of the sample representing the same sense of asymmetry

(in which case the sample is a collection of homochiral molecules) to equal representation by molecules and their mirror-image isomers (in which case the sample is heterochiral or racemic), or any distribution inbetween (heterochiral and nonracemic). Extended tetrahedra (see bottom of Figure 3) are representative of molecules with an axis of chirality rather than a center of chirality. Molecular chirality results from one degree or another of twisting within a molecular structure, whereby a "turn to the left" can be distinguished from a "turn to the right." Even a simple stereocenter or an allene, when viewed from a certain perspective, presents a molecular twist that emerges as a common theme in the three-dimensional structure of chiral geometries (see Figure 3).

Restricted rotation in biphenyls (see Figure 4) creates another example of molecular chirality, which is called atropisomerism (literally "not turning," a reference to the restricted rotation). In other cases, the overall molecular architecture causes a twist of one sense or another to form. In helicenes, the simple interconversion realized by having one end of the molecule move past the other is restricted, and this results in isolatable chiral substances (see Figure 5). Different molecular geometries resulting from the bond rotations in butane, on the other hand, interconvert on a fast timescale at extremely low temperatures. The three staggered geometrical forms for rotation about the C2–C3 bond in butane are shown in Figure 6. Two of

the conformational isomers of butane are chiral whereas the third is not. Molecular chirality can be examined by considering the definition. A molecular geometry that results in the possibility of a nonsuperimposable mirror image is chiral, but a superimposable mirror image renders the object achiral. The third conformational isomer shown in Figure 6 has a mirror plane of symmetry and a superimposable mirror image. It is achiral.

Stereoisomers: Enantiomers and Diastereomers

The two categories into which stereoisomers can be placed are absolutely distinctive in definition. Two stereoisomers that have a nonsuperimposable mirror-image relationship are called enantiomers. The only other category is defined negatively. Stereoisomers that are not enantiomers are called diastereomers (see Figure 7).

Molecules with a single stereocenter as the only source of configurational stereoisomerism can exist as one of two enantiomers; no configurational diastereomers are possible. Conformational stereoisomers, on the other hand, are most commonly diastereomeric. Molecules with two dissimilar stereocenters as the source of stereoisomerism can exist as one of

four stereoisomers. Figure 8 outlines the relationships among these four stereoisomers.

As the number of stereocenters in a molecule increases, the number of possible diastereomers increases. A molecule with four dissimilar stereocenters, for example, can exist as one of sixteen stereoisomers. Of these sixteen stereoisomers there are four pairs of enantiomers, and the remaining four pairs are diastereomers. Molecules with configurational diastereomers also arise from many systems other than those with stereocenters. One of the most common examples is a double bond that is substituted in such a way that diastereomers exist. Any combination of two or more molecular features that give rise to stereoisomers will always produce diastereomers, whereas sources of chirality are needed to produce enantiomers. Because stereochemistry can have a high impact on molecular properties, diastereomers generally have easily discernable differences in their physical and chemical behaviors. Some molecules possess greater than or equal to two tetrahedral stereocenters and are nonetheless achiral. These are called meso stereoisomers. These occur when the internal symmetry of the molecule makes it superimposable on its mirror image.

Distinguishing Enantiomers

From 1874 to 1951 there was no experimental method that could be used to distinguish one enantiomeric form from the other. The physical property of optical activity formed the first basis on which labels were made. Naturally occurring (+)-glyceraldehyde [HOCH₂CH(OH)CHO] was usually used as the point of reference. Whatever its actual three-dimensional geometry, natural (+)-glyceraldehyde was assigned the designation (D), which stood for the configuration of dextrorotatory glyceraldehyde, and not for its optical rotation, which was designated as d- or (+). Optically active

molecules with single stereocenters of unknown configuration were, by precise chemical transformations, derived from or transformed into (D)-(+)-glyceraldehyde. In 1951 J. M. Bijvoet, A. F. Peerdeman, and A. J. van Bommel showed, using x-ray crystallography, that the absolute arrangement of atoms in space for sodium rubidium tartarate could be determined.

Enantiomers, and handed objects in general, can be distinguished only in a chiral environment. While a table-top (an achiral environment) interacts equally well with a left- or a right-handed glove, your own left hand (a chiral environment) can distinguish between these two chiral objects extremely easily. Plane-polarized light is comprised of equal intensities of right- and left-handed (hence, chiral) components. The interactions between these two components with inherently asymmetrical substances are unequal and give rise to the phenomenon of optical activity. In biochemical systems, enzymes represent a common chiral environment that can distinguish one enantiomeric form from another. Olfactory receptor sites and taste buds are also thought to be chiral because there are many examples of enantiomeric substances that can be distinguished by them. The two carvone enantiomers are the primary odor constituents of caraway and spearmint. Most of the naturally occurring amino acids are bitter tasting, whereas their enantiomers are sweet. In an achiral environment, the interactions and interactional energetics for enantiomers are identical and cannot be distinguished.

Separating Enantiomers

The majority of naturally occurring (plant and animal) substances for which stereoisomers are possible exist in nature as single enantiomers. The biochemical pathway used by one's body to synthesize cholesterol results in forming only a single stereoisomer, even though its connectivity represents a total of 128 possible stereoisomers. Because laboratory chemical reactions are not usually conducted in chiral environments, they will produce 1:1 (racemic) mixtures of enantiomers. Because only one enantiomer of a pharmaceutical (drug) is likely to be therapeutically active, chemists have devised strategies for preparing chemical compounds of only one enantiomer. These strategies are:(1) physical separation by temporarily converting the two enantiomers into two diastereomers (called resolution); (2) physical separation in a chiral chromatographic environment; (3) chemical discrimination in a chiral environment (using enzymes or other chiral platforms as chemical reagents ); and (4) asymmetric synthesis of one enantiomer in preference to the other. Asymmetric chemical synthesis is extremely important because it allows chemists to produce new chiral drug candidates, such as single enantiomers of nonnaturally occurring amino acids.

see also Isomerism; Le Bel, Joseph-Achille; Pasteur, Louis; van't Hoff, Jacobus.

Brian P. Coppola

Bibliography

Bonner, William A. (1988). "Origins of Chiral Homogeneity in Nature." Topics in Stereochemistry 18:1–96.

Conant, James B., and Blatt, Albert H. (1952). The Chemistry of Organic Compounds: A Year's Course in Organic Chemistry, 4th edition. New York: Macmillan.

Eliel, Ernest L., and Wilen, Samuel H. (1994). Stereochemistry of Organic Compounds. New York: Wiley.

Ihde, Aaron J. (1964). The Development of Modern Chemistry. New York: Harper & Row.