In the Classroom
The Protocenter Concept: A Method for Teaching Stereochemistry
J. Chem. Educ. 2010.87:604-607. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/12/18. For personal use only.
David E. Lewis Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin 54702
[email protected] Historically, the study of stereochemistry can be traced to the observation by Jean-Baptiste Biot that solutions of certain organic compounds rotate the plane of plane-polarized light (1). Forty-five years later, in two lectures presented before the Societe Chimique de Paris on January 20 and February 3, 1860 (2), Louis Pasteur suggested that molecules of the same substance with opposite rotations might be related to each other as mirror images. The importance of configuration was reinforced by the work of Johannes Wislicenus (3), who suggested that the differing properties of stereoisomers might be traced to differing three-dimensional arrangements of their atoms. This proposal was taken further the next year, when Jacobus Henricus van't Hoff (4) and Joseph-Achille Le Bel (5) independently proposed the concept of the tetrahedral carbon. Interestingly, although these two chemists had worked together in Charles-Adolph Wurtz's laboratory in Paris during the year before their publications, it appears that they developed their ideas independently and did not even discuss them with each other (6). The initial reception of the concept was lukewarm, at best. It sent Hermann Kolbe, editor and founder of the Journal fur Praktische Chemie and a highly respected (and conservative) chemist who deserves to be remembered for his other, more positive, contributions, into a rage in which he wrote what has become an infamous diatribe (7) against the idea. To his almost certain chagrin, the effect of his editorial may have been to give the ideas a prominence they would not otherwise have had. An excellent review of the development of modern stereochemistry is provided by the book by Ramberg (8), who traces the gradual transition of the “chemical structure” from a concept with no meaning other than to account for connectivity in molecules to a physical representation of the actual shapes and structures of molecules. Today it is well accepted that, for a molecule to exist as stereoisomers, it must have at least four groups (which may include lone pairs) that can be arranged in two or more configurationally stable, nonequivalent ways. It is not necessary that the four groups be different from each other (as is evidenced by chiral allenes and biphenyls, discussed below), but the requirement of configurational stability is absolute. Much of the introductory discussion of stereochemistry is given to describing the different types of stereoisomerism, and generally ends up treating enantiomers containing one chirality center, diastereoisomers containing two or more chirality centers, both of which are discussed when functional groups such as halides and alcohols are introduced, and geometric (E-Z) isomers, which are introduced with alkenes or cycloalkanes (although the use of the E-Z system is officially reserved to alkenes only). 604
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Both these introductions, often several weeks apart in a lecture, are accompanied by a discussion of the rules for assigning configuration. This Journal has a long history of articles suggesting useful methods and mnemonics for assigning the absolute configurations to chirality centers (9). However, except for the commonality of the sequence rules of Cahn, Ingold, and Prelog (10), students seldom see stereochemistry as a single, unified topic. More importantly, perhaps, students almost never see the relationship between chirality and geometric isomerism, and few appreciate the underlying relationships that link all types of stereoisomerism (much the same way few students see covalent and ionic bonding as two extremes of a continuum of bonding types). In addition, in my experience, the fact that we use the same set of sequence rules for assigning configuration both to enantiomers and to geometric isomers can sometimes become a source of confusion for the beginning student, and I have seen students misapply the rules to alkenes as though they were treating a single chirality center. In this article, the protocenter, defined as a point bonded to two independent, unlike groups in a nonlinear arrangement, is introduced as an adjunct to the teaching of chirality and geometric isomerism. The central point of the protocenter and the two atoms directly bonded to it define a plane. Two relatively straightforward examples of a protocenter are an sp2 carbon atom carrying two different substituent groups and an sp3 ring carbon of an alkane or cycloalkane carrying two different groups. If a molecule has fewer than two protocenters, one may make the generalization that it cannot exist as stereoisomers. It requires a minimum of two protocenters in a molecule before a molecule can exist as a stereoisomer. The one exception to this generalization occurs in molecules where the molecule as a whole has helical asymmetry (e.g., the helicenes or trans-cyclooctene). The concept becomes less useful in discussions of diastereoisomerism, where a molecule has more than two protocenters, because in such compounds the discussion is usually simpler when couched in terms of complete centers of chirality (the protocenters are still assignable in such compounds, but the discussion becomes more unwieldy when one must talk about four or more protocenters. A pair of protocenters in a molecule may be either coaxial (where the bisectors of the angles are colinear) or noncoaxial:
The discussion that follows will be largely restricted to coaxial protocenters (noncoaxial protocenters always lead to
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In the Classroom
paired protocenters or chirality centers). The spatial relationship between coaxial protocenters may be defined in terms of two parameters: the distance between the protocenters, r, and the dihedral angle, θ, between the planes defined by the two protocenters. On the basis of these two parameters, there are four ways that two coaxial protocenters may be arranged in a molecule. These are shown in Table 1. In the diagrams, the dashed line indicates the region separating the two protocenters: the intervening region may be nothing, or it may be a single bond, a double bond, a cumulene, or a cycloalkane ring.
Table 1. Possible Combinations of Two Coaxial Protocenters
Coplanar Protocenters: (E-Z) Isomers When the two protocenters are coplanar (θ = 0°), the molecule cannot be chiral, but it can exist as cis and trans (E and Z) isomers. There are two types of such compounds: compounds where the protocenters are coincident (r = 0) and share the central atom in common, and compounds where the protocenters are not coincident (r > 0) and do not have the central atom in common. Typical examples of compounds with coincident, coplanar protocenters are square planar complexes of general formula MA2B2, which can exist as both cis and trans isomers:
There are two common types of compounds with noncoincident, coplanar protocenters: alkene double bonds and symmetrically substituted (i.e., the ring retains its local mirror plane of symmetry) cycloalkane rings:
One of the problems that I find with students assigning the stereochemistry of cis-trans or (E-Z) isomers, is that the Cahn-Ingold-Prelog sequence rules used to assign the priorities of the groups are used after their application in chiral molecules, where all four groups attached to the chirality center are ranked at the same time. It is my experience that students tend to confuse the assignment of sequence rules when the configurations of cis-trans isomers are discussed after the corresponding discussion for enantiomers. In particular, the students tend to rank all four groups attached to the π bond without regard to their site of attachment (the clearly stated rules notwithstanding) and then look at the two highest groups to
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assign (E) and (Z). This misapplication of the rules can be seen in (Z)-tetrahaloethylene: simply assigning priority rankings to all four groups attached to the double bond simultaneously (i.e., I > Br > Cl > F) without regard for which groups are bonded to which carbon atom leads to the erroneous conclusion that this isomer should be labeled as (E):
The protocenter concept forestalls this. By using the protocenter concept as a basis for examining the stereochemistry of these geometrical isomers, the stereochemical assignment is now clear because the questions, “which higher priority group?” and, “where?” are now unambiguous: one ranks the groups attached to each protocenter individually and then looks at the spatial relationship between the higher-ranked groups on the two protocenters. This immediately makes the teaching of this subject easier because one can now define exactly where the sequence rules are to be applied. When the two higher priority groups are adjacent to each other in the case of coincident protocenters, the isomer is cis; where the two protocenters are not coincident, it is more usual to designate the isomer as (Z) in alkenes; this nomenclature can also be applied to cycloalkanes, although the use of cis-trans nomenclature for these compounds is still required by IUPAC. Chirality and Symmetry Elements The minimum requirement for a molecule to be able to exist as enantiomers is that it lack an improper axis of rotation, which means that it lacks reflection or inversion symmetry: a mirror plane of symmetry or an inversion center is not permitted in a chiral molecule. This does not mean that a chiral molecule must lack any symmetry: proper axes of rotation are not only permitted, but quite common in chiral molecules. A good example of this is tartaric acid, which has a 2-fold axis of symmetry, but is still chiral. In fact, the existence of a 2-fold axis of symmetry in the molecule is often a key feature of chiral
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In the Classroom Table 2. Dependence of Chirality in Organic Molecules on Protocenter Substitution
Figure 1. Typical compounds that have an axis of chirality. Note how the molecule and its mirror image are not superimposable, but how none has a chiral center.
molecules used in the synthesis of chiral catalysts, for example, BINAP (11):
Chiral Molecules Provided that there are no linkages between the groups on different protocenters, the minimum requirements for chirality can be stated in terms of r and θ (see Table 1). First, chirality in a molecule requires that the two protocenters be noncoplanar: θ > 0°. There are no known examples of chiral molecules where the protocenters are coplanar. Second, chirality is universal in systems with two noncoplanar protocenters if the two protocenters are not coincident: it is possible for both protocenters of a chiral molecule to carry the same pair of substituents provided that the two protocenters are not coincident or coplanar. The most restrictive situation for chirality occurs when the two protocenters are coincident (i.e., they share a common atom). In this type of system, it is possible to define three different pairs of protocenters (rather like noting that one may write 12 different Fischer projections for the same configuration of a center of chirality). Nevertheless, for the molecule to be chiral, neither of the protocenters, regardless of how the four substituent groups are paired to define each of them, may carry any substituent group in common with the other. In other words, the four groups around the common central atom must be different, which corresponds to the classical definition of a chirality center. These relationships are collected in Table 2. Chirality in simple molecules can be in the form of a center of chirality, an axis of chirality, or a plane of chirality. Students in introductory organic chemistry courses usually get an early, indepth introduction to centers of chirality, but seldom see other forms of chirality in other than a cursory manner. The protocenter approach, however, permits a relatively facile introduction to systems with chirality in forms other than a simple center of chirality. An axis of chirality, for example, occurs in a molecule 606
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with two noncoplanar protocenters located at opposite ends of the axis; it occurs in alkylidenecycloalkanes or substituted allenes where two mutually perpendicular protocenters are separated by two double bonds or a ring, and in molecules such as biphenyls carrying bulky ortho substituents that prevent free rotation about the σ bond between the two aromatic rings (Figure 1). In the type of biphenyl shown in Figure 1, the two protocenters are not necessarily orthogonal, as is necessarily the case in the allenes and alkylidenecycloalkanes. These isomers, which can be interconverted at temperatures high enough to permit rotation about the central σ bond, are also called atropisomers. Examples of an allene (12) and a biphenyl (13) that have been prepared in optically active form are
Assigning Configurations The application of the Cahn-Ingold-Prelog rules for (E) and (Z) isomers becomes relatively simple once the protocenters are identified. One assigns priorities to the two substituent groups on each protocenter, and the (Z) isomer has the higher (or lower) priority group of each protocenter on the same side of the double bond (or ring) and the (E) isomer has them on opposite sides of the double bond (or ring). In this case, there is no ambiguity about applying the rules because the two protocenters are treated separately. Assigning the configuration to a molecule with a chirality center is carried out as usual, although one may again use the protocenter concept to simplify this. One assigns the priorities of the four groups bonded to the chirality center in the normal manner, and then assigns the higher two priority groups to one protocenter and the lower two to the other. The molecule is now drawn with the protocenter carrying the two higher priority groups oriented toward the viewer and the protocenter with the two lower priority groups oriented away from the viewer. One then assigns the (R) configuration if the priorities of the three highest priority groups descend in a clockwise direction and the (S) configuration if this direction is counterclockwise.
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In the Classroom Table 3. Effects of Bridging Substituents on Protocenters
When assigning the configuration to an axially chiral molecule, the molecule is viewed along the axis between the protocenters (the chiral axis), and the substituents are then drawn in a Newman projection. The substituents on the closer protocenter are ranked 1 and 2 and those on the far protocenter are ranked 3 and 4; this is the same situation as just defined for assigning the configuration to a chirality center, where the two component chirality centers are oriented with the two highest priority groups toward the viewer, and the two lowest priority groups away from the viewer. Using the three highest-ranked substituent groups, the configuration of the molecule is defined as either (R) (descending priority is clockwise) or (S) (descending priority is counterclockwise). A More Complex Situation: Bridged Protocenters In the foregoing discussion, situations where the protocenters are linked by a bridging group were deliberately excluded. This type of situation occurs in molecules such as trans-cyclooctene. Assigning the configurations to such compounds is usually beyond the scope of introductory courses in organic chemistry, and this article does not seek to accomplish this (clearly a limitation of the method). However, one can use the protocenter concept to determine whether such a compound will be chiral. Compounds such as trans-cyclooctene are characterized by having two coplanar, but nonadjacent protocenters bridged by a chain that crosses the axis between the two center atoms of the protocenters. Molecules fulfilling this requirement have a plane of chirality. In molecules where the protocenters are coincident and noncoplanar, the molecule will be chiral with less than four different substituent groups bonded to the central atom if one can represent the two protocenters as rings that share a common atom—such compounds are always spirocyclic. These situations are illustrated in Table 3. Conclusion The protocenter concept can be a useful adjunct to the introduction of stereochemistry into the organic chemistry course by focusing the student's attention of the structural parts of the molecules that will determine whether the compound can exist as stereoisomers. The concept also has the advantage of treating all forms of stereoisomerism in a similar manner, so that the student sees the underlying relationships among types of stereoisomers, as well as permitting the student to determine the types of stereoisomerism that will occur in a molecule based on its structure. Literature Cited 1. (a) Biot, J. B. Bull. Soc. Philomath. Paris 1815, 190. (b) Biot, J. B. Bull. Soc. Philomath. Paris 1816, 125. (c) Biot, J. B. Mem. Acad. R. Sci. Inst. Fr. 1817, 41 (2), 114.
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2. See (a) Pasteur, L. Researches on the Molecular Asymmetry of Natural Organic Products; University of Chicago Press: Chicago, IL, 1902; Alembic Club Reprints. (b) Vallery-Radot, P. Oeuvres de Pasteur; Masson et Cie.: Paris, 1922; Vol. 1, pp 315, 329. 3. Wislicenus, J. Liebigs Ann. Chem. 1873, 167, 302. 4. (a) van't Hoff, J. A. Voorstel tot Uitbreiding der tegenwoordig in de scheikunde gebruitke Structuur-Formules in die ruimte; benevens een daarme^e samenhangende opmerkung omtrent het verband tusschen optisch actief Vermogen en Chemische Constitutie van Organsiche Verbindingen; Utrecht, The Netherlands, 1874. (b) van't Hoff, J. A. Arch. Neerland. Sci. Exactes Nat. 1874, 9, 445. (c) van't Hoff, J. H. Bull. Soc. Chim. Fr. 1875, 23 (2), 295. (d) van't Hoff, J. A. La chimie dans l'espace; Bazendijk: Rotterdam, 1875. (e) van't Hoff, J. A. Die Lagerung der Atome im Raume; Vieweg: Braunschweig, 1877; Hermann, F., translator. 5. Le Bel, J.-A. Bull. Soc. Chim. Fr. 1874, 22 (2), 337. 6. Walker, J. J. Chem. Soc. 1913, 103, 1127. 7. Kolbe, H. J. Prakt. Chem. 1877, [2] 15, 473. For an English translation of this work, see Wheland, G. W. Advanced Organic Chemistry, 3rd, ed.; John Wiley & Sons: New York, 1960; pp 197-198. 8. Ramberg, P. J. Chemical Structure, Spatial Arrangement: The Early History of Stereochemistry 1874-1914; Ashgate Publishing Company: Aldershot, U.K., 2003. 9. References in this Journal from just the past 11 years: (a) Mandal, D. K. J. Chem. Educ. 2007, 82, 274. (b) Mandal, D. K. J. Chem. Educ. 2000, 77, 866. (c) Wade, L. G., Jr. J. Chem. Educ. 2006, 83, 1793. (d) Gawley, R. E. J. Chem. Educ. 2005, 82, 1009. (e) LloydWilliams, P.; Giralt, E. J. Chem. Educ. 2005, 82, 1031. (f) LloydWilliams, P.; Giralt, E. J. Chem. Educ. 2003, 80, 1178. (g) Hart, H. J. Chem. Educ. 2001, 78, 1632. (h) Lujan-Upton, H. J. Chem. Educ. 2001, 78, 475. (i) Siloac, E. J. Chem. Educ. 1999, 76, 798. (j) Neeland, E. G. J. Chem. Educ. 1998, 75, 1573. (k) Baker, R. W.; George, A. V.; Harding, M. M. J. Chem. Educ. 1998, 75, 853. 10. (a) Cahn, R. S.; Ingold, C. K. J. Chem. Soc. 1951, 612. (b) Cahn, R. S.; Ingold, C. K.; Prelog, V. Experientia 1956, 12, 81. (c) Cahn, R. S.; Ingold, C. K.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966, 5, 385. (d) Cahn, R. S. J. Chem. Educ. 1964, 41, 116. (e) Fernelius, W. C.; Loening, K.; Adams, R. M. J. Chem. Educ. 1974, 51, 735. (f) Prelog, V.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1982, 21, 567. 11. Reviews: (a) Noyori, R. Science 1990, 248, 1194. (b) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. 12. (a) Walbrich, J. M.; Wilson, J. W.; Jones, W. M. J. Am. Chem. Soc. 1968, 90, 2895. (b) Borden, W. T.; Corey, E. J. Tetrahedron Lett. 1969, 6741. 13. (a) Christie, G. H.; Kenner, J. J. Chem. Soc. 1922, 121, 614. (b) Newman, P.; Rutkin, P.; Mislow, K. J. Am. Chem. Soc. 1958, 80, 465.
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