In the Classroom
A Simple Method To Determine the R or S Configuration of Molecules with an Axis of Chirality Cunde Wang* School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China *
[email protected];
[email protected] Weiming Wu Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California 94132, United States,
[email protected] Chirality refers to the property of an object or molecule that is nonsuperposable on its mirror image. Such a molecule is described as “chiral”. If a molecule is superposable or identical to its mirror image, it is referred to as “achiral”. A chiral center (or stereogenic center) is the most common form of chirality in organic compounds. It is also possible for a molecule to be chiral without having a chiral center. For example, axial chirality refers to stereoisomerism of molecules with a chirality axis, an axis about which a set of substituents is arranged around in a spatial arrangement so that the compound is not superposable on its mirror image. The possible existence of two enantiomeric forms in a properly substituted allene was predicted by van't Hoff in 1875 (1). Since the 1980s, axial chirality has played an increasingly significant role in organic chemistry, especially in asymmetric catalysis (2, 3). Numerous natural products also feature axial chirality (4). Axial chirality is most commonly observed in biaryl and allene compounds, although it is also seen in other systems such as spirocyclic compounds and sterically crowded single phenyl derivatives. Examples of compounds with an axis of chirality are depicted in Figure 1. The absolute configuration of a chiral center can be easily described using the Cahn-Ingold-Prelog system. In this system, sequence rules are employed to assign priority to the four substituents on the stereogenic center. An absolute configuration of R or S is then designated based on the three-dimensional arrangement of the substituents. Two sets of stereodescriptors (Ra-Sa and M-P) are available in IUPAC nomenclature for axially chiral molecules (5-7). Two enantiomers of an axially chiral molecule are schematically shown in Figure 2 (the two small circles representing the two ends of the chirality axis). Looking along the chirality axis, the substituents are arranged in pairs (one pair on each end of the axis). For each pair of substituents (A-B and C-D), the higher ranking substituent is chosen using the Cahn-Ingold-Prelog sequence rule (A > B and C > D). In the system using stereodescriptors Ra and Sa, the chirality is described as Ra if the path from A to B to C is clockwise. A counterclockwise path is described as Sa. In the system using stereodescriptors M and P, an arrow is drawn from the higher ranking substituent in the nearer pair (i.e., A) to the higher ranking substituent in the farther away pair (i.e., C). The chirality is described as M if the arrow is counterclockwise. A clockwise arrow is described as P. Generally Ra corresponds to M and Sa to P, respectively.
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Figure 1. Examples of molecules with an axis of chirality.
Figure 2. IUPAC descriptions for molecules with axis of chirality.
Stereodescriptors Ra and Sa are preferred in IUPAC names. In this article, we describe a simple method that utilizes the same sequence rules to designate R-S configuration to molecules with an axis of chirality. R-S Designation of Molecules with a Chirality Axis In a molecule with a chirality axis as schematically represented by structure 5 in Figure 3, the only condition for it to be chiral is that A 6¼ B and A0 6¼ B0 . It should be noted that the molecule is chiral when A is the same as A0 and B is the same as B0 (such as structure 2 in Figure 1). The following rules are proposed
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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 88 No. 3 March 2011 10.1021/ed1003383 Published on Web 12/15/2010
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In the Classroom
Figure 3. Schematic representation of an axially chiral molecule and its projections.
Figure 5. Application of the method in the designation of the R-S configuration of axially chiral molecules.
Figure 4. Determination of the configuration of ethyl 4-methyl-2,3hexadienoate.
for convenient designation of the absolute configuration of these axially chiral molecules: • The chirality axis is determined. This is usually very straightforward. • The structure is simplified into a planar projection by viewing the molecule along the chirality axis from either direction. Projections 5a and 5b (Figure 3) are obtained as a result. In this projection, the direction of the lines (horizontal or vertical) that connect the substituents does not imply whether they are directed toward or pointed away from the viewer. Instead, a solid line means the two substituents are in front of the axis and the line with a circle means the two are behind the axis. • Determine the priority of the substituents on each end of the axis by comparing A with B and A0 with B0 , respectively. The sequence rules in the Cahn-Ingold-Prelog system are utilized. In this illustration, we assume A and A0 are higher than B and B0 , respectively. • Draw an arrow with the shorter path from the substituent with the higher priority on the line with a circle to the one with higher priority on the solid line. If the arrow is clockwise, the absolute configuration is Ra. Conversely, if the arrow is counterclockwise, the configuration is Sa.
The following example will demonstrate how this method is applied. As shown in Figure 4, the absolute configuration of allene 1 is determined to be Ra as reported (8). Viewing the molecule from either direction of the chirality axis (represented by the long dashed line) yields projections 1a or 1b but gives the same result, as expected. 300
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This method is also applicable to the determination of the configuration of other types of axially chiral molecules. We will use the molecules shown in Figure 1 as examples. The stereochemistry of these molecules has been discussed in some detail (6, 7, 9). The structures and their corresponding projections are depicted in Figure 5; the long dashed line represents the chirality axis. In molecules with complicated structures, it is not necessary to draw the full structures of the substituents in the projections. Only a simplified representation is required as long as a difference in priority can be seen. Conclusion A systematic method that uses a simple planar projection to determine the R-S configuration of molecules with a chirality axis is developed. It utilizes the same sequence rules in the Cahn-Ingold-Prelog system. It is easy to use and has broad applicability. Therefore, this method may be of interest to students as well as general practitioners of organic chemistry. Acknowledgment W.W. is supported by the National Institutes of Health, MBRS SCORE Program, Grant #5 S06 GM52588. We also thank Andrew Bolig, Taro Amagata, and Jane DeWitt at SFSU for helpful discussions. C. W. is supported by the NSF of Jiangsu Province (Grant BK2008216). Literature Cited 1. van't Hoff, J. H. Chimie dans l'Espace; Bazendijk: Rotterdam, 1875; p 29. 2. Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155–3212. 3. Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105, 1801–1836.
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In the Classroom 4. Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615–624. 5. Chapter 9 Specification of Configuration and Conformation. http://old.iupac.org/reports/provisional/abstract04/BB-prs310305/ Chapter9.pdf (accessed Nov 2010). 6. Krow, G. In Topics in Stereochemistry; Eliel, E. L. Allinger, N. L., Eds.; Wiley: New York, 1970; Vol. 5, pp 59-65.
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7. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994; Chapter 14. 8. (a) Bertrand, M.; Ferre, E.; Gil, G.; Le Petit, J.; Deveze, L. Tetrahedron Lett. 1980, 21, 1711. (b) Ferre, E.; Gil, G.; Bertrand, M.; Le Petit, J. Appl. Microbiol. Biotechnol. 1985, 21, 258. 9. Mannschreck, A.; von Angerer, E. J. Chem. Educ. 2009, 86, 1054–1059.
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