STEREOCHEMISTRY (original) (raw)

INTERSCIENTIA

INFELICITOUS STEREOCHEMICAL NOMENCLATURES

ERNEST L. ELlEL

Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina

ABSTRACT Misuse of current stereochemical terms is discussed, including terms that should be avoided altogether and replaced by other, standard ones. The reasons for using the proper terms and avoiding the infelicitous ones are pointed out.

Chemical nomenclature has always been somewhat problematic, and this seems to be particularly true when it comes to stereochemical terms. Authors tend to let their imagination run wild in the invention of new (and often unneeded!) terminology, making life difficult for the reader who, of course, is not familiar with the newly invented terms.1

This situation persists even though what we had hoped to be a "minimalist" glossary was published in 1994 in a stereochemistry treatise of which I am a coauthor2,3 Some particularly egregious slips were observed at a recent conference at which I had the honor of receiving the Chirality Medal. One of the attendants at this meeting was Professor Koji Nakanishi, a previous winner of the Chirality Medal, who shared with me his dismay with some of the nomenclature used. It, thus, seems appropriate that I should take up the subject in this article, which is dedicated to Professor Nakanishi as Chirality Medalist. Here are some examples of what I call "infelicitous nomenclature" in stereochemistry.

Asymmetric Synthesis. This term is probably too deeply embedded in the chemical nomenclature to be eradicated. Nonetheless two problems with this term should be pointed out. First of all, the term, in its most general sense, applies to dissymmetric (or, as we now say, chiral) reagents, catalysts, products, and chiral auxiliaries. In fact, some of the most effective chiral auxiliaries have C2 symmetry, i.e., they are not asymmetric at all! Secondly, of course, it is the catalysts, products, etc., that are chiral (not necessarily asymmetric!), not the syntheses as such. (We shall find this kind of wrong apposition in many of the other examples below.) The proper term to use, in lieu of "asymmetric synthesis" would be "enantioselective synthesis" (if one of two enantiomers is produced in predominance) or, in some cases, "diastereoselective synthesis" when one of two or more diastereomers is produced predominantly. (This, also, has been called an asymmetric synthesist i.e., when both starting material and product are enantiopure or enantioenriched, for example in the hydride reduction of cholestanone to 33-cholestanol where a new chiral center is introduced stereoselectively at C(3). Such dual use of "asymmetric synthesis" is, in this author's opinion, confusing.)

Chiral Chromatography. It is not the chromatography that is chiral but the material to be chromatographed. It might be objected that adjectives are often used loosely in English, for example "chiral center" is used properly for "center of chirality." [This looseness does not necessarily apply to other languages. Center of Chirality (Chiralitatszentrum) is the obligatory term used in German!] However, there is no linguistically inferrable sense for "chiral chromatography." The proper expression, "enantioselective chromatography," is just as easy to use! By the same token, the expression "chiral column" in this kind of chromatography should be avoided; it is not the column but the packing that is chiral (and, one hopes, enantioselective). In contrast, "chiral stationary phase," "chiral support," and "chiral solvent" are proper terms except possibly for the inherent ambiguity in the use of the term "chiral" (see "chiral substance").

Chiral Substance. This is an appropriate term for a compound whose molecules are chiral, i.e., not superposable with their mirror image molecules (enantiomers). However, at the level of a substance or compound (implying large numbers of constituent molecules) it is not clear whether these molecules are all homochiral (i.e., of the same sense of chirality), or heterochiral (i.e., some of one sense of chirality and some of the other). In the latter case, the substance, though chiral, might be racemic, or it might be partially racemic (i.e., an excess of one enantiomer over the other, but not to the exclusion of the minor enantiomer). Therefore, additional terminology is needed. The term "scalemic"4 has been proposed for any non-racemic chiral compound, but it leaves out the question as to whether the compound is "enantiopure" (enantiomerically pure) or "enantioenriched" (having an excess of one enantiomer but not to the exclusion of the other). The latter terminology has been favored in our textbooks It must be admitted that the definition of "enantiopure" depends on one's standards and means of analysis. Does it mean 99, 99.5, 99.9 or 99.99% pure? The first degree of purity is probably at the limit of what can be seen by nmr using chiral shift reagents but the highest limit might be accessible to analysis by enantioselective gas chromatography. (This question might assume importance both in relation to FDA approvals and patent litigation!) Where possible, the enantiomer excess or enantiomer ratio (see below) should be given as a number.

Chiral Synthesis. This term is even more objectionable than "asymmetric synthesis," again because it is not the synthesis that is chiral. In most cases, this term has been applied to a synthesis from a chiral, enantioenriched, or enantiopure starting material (sometimes said to belong to the "chiral pool," i.e., the inventory of readily available enantiopure or highly enantioenriched starting materials; "chiral pool" is another misnomer). The proper term here would be "stereospecific synthesis," implying a synthesis in which a starting material of a given configuration gives a product of given configuration; thus an enantiopure starting material (e.g., a natural product--though not all chiral natural products are enantiopure) would give rise to an enantiopure product in a stereospecific synthesis.

Geometrical Isomers. At one time in the past, stereoisomers were divided into "optical" and "geometrical" isomers. [We shall dispose of the term "optical isomer" in the sequel (see "optical antipode")]. The dichotomy resulted from a belief that enantiomers were topological isomers and cis-trans ("geometrical') isomers were not. In fact, however, most common enantiomers are not topological isomers either.5 In addition, it is more logical to distinguish those stereoisomers that are mirror images of each other ("enantiomers") from those that are not ("diastereomers"). The latter include not only the subclass of cis-trans isomers (which is what they should be called) but also such achiral compounds as the 1,4-dichlorocydohexanes and the two meso-2,3,4-trihydroxyglutaric acids in addition to such classical examples as the chiral and meso-tartaric acids.

Homochiral. This term has been misused to mean "chirally homogenous." In fact it means "of the same chirality." Molecules can be homochiral (or heterochiral, i.e., of opposite chirality or configuration), but to apply the term to a substance or compound is inappropriate. Recently the term "monochiral" has been suggested,6 the Greek prefix "mono" meaning "one" or "single" and this term would seem more appropriate. (A conceptual term does seem to be needed; the experimental designation "enantiopure" is not entirely synonymous, since it applies to an experimental attribute, not to a concept.)

Optical Antipodes. This archaic synonym for "enantiomers" is still occasionally used even though it is doubly flawed. When I visited Australia, my right hand remained my right hand and did not turn into my left hand a did not become an "enantio-Eliel"). Therefore, at best, antipodes are related by a C2 symmetry axis, not by a symmetry plane. Moreover, the prefix "optical" should no longer be used for enantiomers (they should not either be called "optical isomers") since optical activity - the hallmark of chirality in the first 100 years of stereochemistry - is no longer its main feature. Today that main feature is fit vs. misfit (as an enzyme with its chiral substrate or a drug with its chiral receptor).

Optical Purity. This term was appropriate when such purity was measured by polatimetry. Unfortunately, for a variety of reasons, the main one being that the maximum optical rotation of many not-so-common compounds is not firmly known, polarimetry is generally a poor method for determining enantiomeric purity. (An exception may be cases where the same measurement is carried out repeatedly and routinely on the same substance, as in the determination of purity of sugar.) Nowadays other methods, such as enantioselective chromatography, are preferred because they are more accurate. Therefore the original term should be dropped. " Enantiomeric purity" has been used but is, unfortunately, not unequivocally defined. If used, it should denote the percentage of the major enantiomer in a mixture of the two enantiomers. A more commonly used (and unequivocal) designation is that of "enantiomer(ic) excess" meaning the excess (in percent) of one enantiomer over the other; a precise definition (which applies even if there is third-body contamination) is e.e.% = (l%R - %SI)/(%R + %S). It is interesting, however, that the term "optical yield" (e.e. of product)/(e.e. of starting material) in a reaction is still used because there seems to be no better term. "Enantiomer ratio" (er) may also be used to specify enantiomeric composition; it is unequivocal.

Stereochemistry of a Compound or Reaction. This terminology is found disturbingly often but is entirely inappropriate and moreover unnecessary. What is meant in the former case is "configuration" (of a compound). In the latter case ("stereochemistry of a reaction," e.g., retention, inversion, racemization), the proper expression is "steric course" (of the reaction).

Stereogenic Center. This term was coined by McCasland7and brought to wider attention by Mislow and Siegel8 who also defined the term "chirotopic." A stereogenic center is a center (usually located at an atom) in a molecule such that exchange of two ligands at the center leads to a stereoisomer of the original molecule. There may be some confusion as between "stereogenic center" and "chiral center." At least with tetrahedral atoms, such as carbon, a chiral center is necessarily stereogenic, since the interchange of two ligands at a chiral tetrahedral atom interconverts enantiomers. However, the converse is not true: not every stereogenic center is a chiral center, since one cannot define chiral centers in achiral molecules. Thus C(1) and C(3) in 1,3-dichlorocyclobutane are stereogenic, since the interchange of C1 and H at C(1) or C(3) leads to (diastereo)isomers, converting the cis isomer into the bans or vice versa. However these atoms are not chiral since the 1,3-dichlorocyHobutanes, cis or bans, are achiral. By the same token C(3) in the (meso) 2R,3,4S-trihydroxy-glutaric acids is stereogenic, since switching H(3) and OH(3) coverts one meso form (3r) into the other (3s), but neither is chiral, so C (3) is not a chiral center. Ct used to be called a "pseudoasymmetric center" and this nomenclature still persists even though it is illogical in that there is no asymmetry about such a center: it lies on a plane of symmetry and is therefore "achirotopic" in the Mislow-Siegel definition8 as are C(1) and C(3) in 1,3-dichlorocyclobutane, which are not usually called pseudoasymmetric centers).

Finally, I should like to include here a fallacy, which, while not a matter of nomenclature, is repeatedly found not only in the popular literature and in scientific magazines, but also in scientific articles. I refer to the statement that the thalidomide tragedy, i.e., the birth of babies with deformed or missing limbs, could have been prevented if the pregnant women who took this drug would have been given the one pure enantiomer pharmacologically active as sedative or anti-nausea agent ("eutomer"), free of the other enantiomer ("distomer"), which was shown to be the teratogenic one. While the pharmacology of the two enantiomers was correctly established,9 it was discovered recently10 that thalidomide is racemized not only in vitro but even more rapidly in vivo so that even if the pure eutomer had been administered, it would quickly have been partially converted into the dangerous teratogenic distomer.

LITERATURE CITED

1. See also Helmchen, G. Glossary of problematic terms in organic stereochemistry. Enantiomer 1:1996; 4 unnumbered pages following p. 84.

ELIEL

2. Ebel, E.L., Wilen, S.H. Stereochemistry of Organic Compounds. New York: W~'ley-lnterscience, 1994;1191-1210.

3. See also Gawley, RE., Aube, J. Prmciples of Asymmetric Synthesis. Oxford: Pergamon, 1996:15-40.

4. Brewster, J.H. Racemic, scalemic, holemic. Chem. Eng. News 70:1992, May 18, 3; see also Heathcock, C.H. Alternative to homochiral. Chem. Eng. News 69:1991, February 4, 3.

5. Mislow, K A commentary on the topological chirality and achirality of molecules. Croat. Chem. Acta 69:485-511,1996.

6. Cornforth, RH., Cornforth J.W. How to be right and wrong. Croat. Chem. Acta 69:427-433, 1996.

McCasland, G.E. A New General System for the Naming of Stereoisomers. Columbus, OH: Chemical Abstracts Service 1950:2-3.

8. Mislow, K, Siegel, J. Stereoisomerism and local chirality. J. Am. Chem. Soc., 106:3319-3328,1984.

9. Blaschke, G., Kratt, H.P., F~ckentscher, K, Kohler, F. Chromatographische Racemattrennung von Thalidomid und teratogene Wlrkung der Enantiomere. Arzneim. Forsch. Drug Res. 29:1640-1642, 1979.

10. Knoche, B., Blaschke, G. Investigations on the in vitro racemization of thalidomide by high-performance liquid chromatography. J. Chromatogr. A 666:235-240, 1994. The half-life for racemization at 37°C in a phosphate buffer (pH 7.4), about 4.5 hr. is reduced to about 10 min in the presence of human serum albumin.