Grasping the Concepts of Stereochemistry Nancy S. Barta and John R. stillel Michigan State University, East Lansing, MI 48824 The concept of carbon as a tetrahedrally coordinated atom was fust introduced by Van't Hoff and LeBell in 1874 (I).Since that time, necessary methods for standardizing the nomenclature of chirality have emerged (2, 3) and evolved (4-7). In the 1950's,the Cahn-Ingold-Prelog (CIP) sequence rules were established to provide uniform designation of enantiomers as R or S, and are currently the primary tools for chirality description (2, 3).Although these rules have simplified stereochemical nomenclature overall. the ~rinciolesinvolving the stereochemistrv of a chiral milecufe and'the designation of R or S configuration are amone the first stumbline blocks that students encounter in organic chemistry. Failure to master these concepts can handicap a student throughout an entire course. As presented in undergraduate organic textbooks, assignment of the appropriate R o r S configuration to a given structure is a three-step process (8-11). This stepwise procedure is illustrated in Figure 1using lactic acid as an example. First, the substituents (a, b , c, and dl on a stereogenic (12) central atom (X)of a molecule Xabcd must be ranked in order of higher to lower suhstituent priority, a > b > c > d, as determined by the CIP sequence rules (2-6). The second s t e is ~ to draw the molecule in the conventional manner w ~ t hthe lower priority group, d, hehind the central atom X. The three-steo orocesi is cwnolettd bv determining the direction of sufsktuent priorit; arouna the stereogenic center (clockwise = R. counterclockwise = S). A number of other methods by which R or S wnfiguration can be determined have been developed that require differing intellectual skills as defmed by Bloom's Taxonomy (13).Based on the cognitive model of learning, students process new information by drawing on their background, abilities, and experiences (14). Because these backgrounds, experiences, and degrees of intellectual skill
-
-
a OH
a HO
I d ,X% H02C \ b CH3
\CO,H
H3C
b
C
C
(9-(+)-Lactic Acid
I
$x;
(@-(-)-Latic Acid a
I
cF+sX\
c
/I
)
a
%,! C '
b '
Figure l.Stereochemical designation of lactic acid enantiomers.
20
Journal of Chemical Education
Rotate 5s0
Figure 2. Changing stereochemicalprojections. development are as varied as the number of students in the classroom, the effectiveness of each method is dependent upon the individual student. When assigning R or S configurations, the three-dimensional translation of the molecule, from an original drawing to the conventional projection having substituent d farthest from the viewer, tends to be the most problematic step for students. The degree of success involved in simply rotating or flipping the molecule in one's mind and then drawing the compound again is proportional to the experience of the viewer; for novices, this endeavor is frequently overwhelming.Alternatively, a net rotation can be effected by two sequential substituent exchanges, the "double exchange" method (Fig. 2) (12). Modifications of this method allow any suhstituent to be directed away from the viewer (I5), and application to cyclic molecules (16).However, this procedure also can be quite confusing to the beginning organic student. In this article, we wish to provide an alternative procedure for the determination ofR or S configuration for chiral molecules. This method facilitates use of the CIP rules by employing the hand, which is the most familiar and appropriate model for illustrating the concept that molecules are chiral (Greek cheir, "hand?. Current Instructional Methods and Models When dealing with principles that are particularly difficult to visualize or conceptualize, such as stereochemistry, teaching aids and mnemonic devices have been invaluable in the learning process. Realizing, of course, that all of the different teaching devices cannot be presented by the instructor in lecture, these methods can be passed most efficiently on through teaching assistants and tutors due to the one-on-one nature of student contact time. Often these devices help individual students make a connection between the new material and their own experiences and prior knowledge base. For that reason, a variety of methods have been established that cater to the respective strengths of each individual. These methods vary from mathematical approaches to two-dimensional Fischer projection techniques to three-dimensional models. Recently, a numerical method of configuration determination was introduced that requires the advanced intellectual skills of synthesis and evaluation.. exoloits . mathematical principles, and encumpasws a variety of confi&wrations117, Howcvcr, use of this "Rule o f Mul'Author to whom correspondence should be addressed.
Len Hand
j
Right Hand
Figure 4. Determining handedness of enantiomers Figure 3. The steering wheel model for R or Sdetermination.
tiplication" is quite complex, and appears to defeat the purpose of improving retention and simplifying application of stereochemical assignment by including the use of multiple configurations. Anumher of methods for assignment of R or S wnfiguration have been developed for those instances when a molecule is represented by a two-dimensional or flat Fischer projection. The first was a mathematically based method known as the 1, 2, 5 rule, which caters to those students who learn most easily when hard and fast rules of algebra or geometry can be applied to solve a given problem (181.A set of mnemonic rules was established for determination of R or S configuration, depending on the horizontal or vertical orientation of the lower priority substituent in a Fischer projection (19-22), and two strikingly similar descriptions of this methodology were reported somewhat later (23,24). Most recently, this approach has come full circle through introduction of the geometric "Triangle Method" (25) . The ability to visualize molecules in three-dimensional space is critical for the organic chemist, and in order to facilitate this understanding as well as to help the student remember the R-clockwiselS-counterclockwiserelationship, the analogy of a steering wheel is popular, and has been used in some organic texts (10, 11).After labeling each substituent according to their CIP priority, the R I S assignment can be visualized more easily using a threespoke wheel as a helpful device (Fig. 3). The utility of hands as asymmetric teaching tools was recognized as early as 1966 when Cahn, Ingold, andPrelog noted, "The model has two non-identical forms, interrelated by a reflection, that is, two enantiomeric forms; it has the topological property of handedness" (5). In fact, the hand often is used to illustrate chirality because this model is the most readily available teaching aid. Simply having students shake hands with their neighbors using their right hands to sequentially grip the right and left hands of a classmate quickly illustrates the concepts of stereochemistry and diastereomeric transition states (26). Several methods of configuration assignment employing this handy three-dimensional model have appeared in the literature over the past 20 years (27301. All of these reported techniques utilize the wrist or arm as the substituent of lower priority, differ only in the numbering of the thumb and first two finaers and are most easily applied to tetrahedral carbon cen&s. Unfonunateh, onl!, one prominent organic text has used any of these hand relationsh~p method< and this procedure Gads to the right hand modeling the S configuration and the left hand defining the R configuration (9).
The "Right-Hand Rule" of Organic Chirality This article presents an effective means of determining the R or S configuration of chiral molecules using the CIP sequence rules to establish substituent priority and use of the ultimate model for chirality, the hands, to aid in the direct correlation and assignment of relative configuration. The unique simplicity of this method allows for assignment of R or S for a variety of different structures
Left Hand
Right Hand
Lefl Hand
Right Hand
Figure 5. Use of the "Right-Hand Rule" with different stereochemical projections. Volume 71
Number 1 January 1994
21
Flscher Projection
(a-(+)-LacticAcid
[alQ+3.E0 Figure 8. Application of the "Right-HandRule'to a Fischer projection.
Figure 6. Application of the "Right-HandRule"to a cyclic molecule. without spatial manipulation of the molecule. At the same time, students continue to develop the three-dimensional visualization skills that are so important in organic chemistry. Application of this "Right-Hand Rule" begins by establishing CIP priorities for substituents a to d around the tetrahedral atom, X, and then the right hand is positioned so that the thumb represents the Xd bond axis and is directed toward substituent d (Fig. 4). Alternatively, substituent d can be in the plane of the paper with X (Fig. 5a), or directed out of the plane of the paper for this method (Fig. 5b). The next step is to try to curl the fingers of the right hand in the direction of decreasing substituent priority for one of the three suhstituent pairs (following the shortest path from a to b, b to c, or c to a). Typically, this process is performed on the air that is drawn so that its relative configuration around carbon can be determined most easilv: however. the assienment should be confirmed bv analIf one hand will not work for this ysis of all tkree analysis, as hands are chiral and will only curl in one direction, then the other hand should be tried. When the right hand curls in the direction of decreasing suhstituent priority, the molecule is R (Latin rectus, *right"). If this analysis works with the left hand, the stereogenic center is described a s S (Latin sinister, "left"). In order to check their assignment, students should try both hands with this method to show that one will work and the other one will not. In order to facilitate the introduction of this method, the knuckles on each index finger can be labeled a, b, and c as they decrease in prioritylsize from the direction of the wrist toward the tip of the finger. As with any other method, the use of molecular models is oRen helpful for students when beginning to visualize three-dimensional stereochemistry of asymmetric molecules.
Despite the relative simplicity of this method for undergraduate students who are just picking up stereochemical concepts, graduate students who teach this method also find themselves using their hands to assign R or S configuration to more complex molecules. The "Right-Hand Rule" also is applied easily to cyclic molecules such as steroids and alkaloids (Fia. 6).bridzed bicvclic molecules (Fia. 71,Fischer projections'i~ig,81, &d o&er compounds wi& tetrahedral atoms such as silicon. sulfur. or nitrogen. In fact, application of this method dan be extended-to any molecule exhibiting chirality that can be assigned a wnfiguration using the CIP sequence rules. The R or S configuration of allenes can easily be determined by labeling the carbon end containing the substituent of higher overall priority C1,and the attached substituents al and bl; the other end of the allene is labeled Cp with substituents az and b2 (Fig. 9). Assignment of configuration is then made by placing the thumb along the C=C=C axis from C1 toward CZ,and the fingers of the ap~ t e are then curled from b, to as.(a* . r o. ~ r i ahand .and bl.are the equivalent to c and d, respectively, on a tetrahedral atoml. Similarlv.. molecules eeometricallv rclated to the allene system, such as asymmetric bridged tricyclic compounds and exocyclic alkene structures, also can be assigned in this manner (Fig. 10). The assignment of R or S configuration to the symmetric, but chiral, non-interconvertihle enantiomers of 1,l'-hi-2-naphthol can be made as well. Assignment is determined by placing the thumb along the C-C bond connecting the two aryl groups followed by curling the fingers from the lower priority group
.
-
(1R)-(-)-lo-CamphorsuIfonIcAcid
[ a ]-21" ~ Figure 7. Application of the "Right-Hand Rule'' to a bridged bicyclic 22
Journal of Chemical Education
Top view from C, to C, Figure 9. Assigning handedness to allenes.
Geometric Representation
Viewing top to boltom
Geometric Representation Figure 10. Assigning handedness to asymmetric bridged compounds and exocyclic alkenes. on one end of the aryl group toward the higher priority group on the other aryl end (Fig. 11). In this system, the direction of the thumb along the bond axis is inconsequential because both directions of this symmetrical molecule produce the same result. In many cases, application of the right hand in this manner comes with a certain d e a e e of familiaritv to students. Mathematical sciences emGoy the "~ight- and Rule" to determine the direction of the cross ~ r o d u cof t two vectors (31).This information also becomes important when working in physics, where the thumb shows the perpendicular direction of angular velocity when curling the fmgers of the right hand from one vector to the other (32, 33). In addition, the direction ofthe magnetic field generated by a w r e is determined by the way in which the fingers ofthe right hand, with the thumb in the direction of the eiectr~calcurrent, wrap around the wlre These principles are already found in organicchcm~stry;the "Rlght-Hand Rule" 1s used to dctermmc the direction of the KMR sh~clding effects in alkynes, carbonyls, and aromatic rings relative 6 the direction of the ring current (34).Similarly, application of this method to the three-dimensional features of chiral molecules has the potential for widespread acceptance amone the varietvof students and their manv different experiences in today's undergraduate organic classroom. This "hands on" approach to configuration determination has been well received bv undereraduate and a a d u ate students from a variety "of educational backgrknds and has met with excellent success in h e l ~ i n estudents grasp the concept of chirality. There are ma& akributes of this method that are advantageous to students. In part, the success of this method is due to the constant availabilitv of the hands as tools. the accuracv with which the method can be carried out,'and the minimal memorization required for its a~ulicationdirect correlation of the R = right-hand and s-: left-hand relationships are recalled easily by the student. Because confirmrational analysis requires only a minor amount of manual dexterity, and not the manipulation of drawings to specific representations, any convenient stereochemical drawing can be used and
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Figure 11.Assigning handedness to 1,l'-bi-2-naphthol. need not be drawn again in a conventional perspective. Another advantage in the learning process is t h a t this method reinforces the three-dimensional concept of "handedness" of molecules, which ties into the most commonlv used example of chirality in organic chemistry-the hand. Finally, through the rotational aspects involved in the use ofthe '.Right-Hand Rule", a knowledge base is estahlished fbr further elaboration to concepts such as the rotation of plane polarized light by optically active molrculrs. Acknowledgment The authors wish to thank the reviewer for many helpful comments and suggestions for revision of this manuscript, including the idea for labeling the knuckles of the index fingers. Literature Cited 1. Hlrshmann, H.:Hanaon, K R. Top. S&nochem. 19% 14,183. 2. Cahn. R.S.;Ingold,C. K. J. Cham. S o c 1951,612-622. 3. Cahn. R. S.:l n d d . C. K.: Relm V. Ernorientlo 1956.12 81-94.
9. Vo1lhardf.K. P C. Organic Ckemisfv;W R.Freeman:New YorL. 1987:pp 156161. 10. M c M w , J. Organic ChamYfry; BmoksiCole: Patifie Gmw. CA, 1992;pp 29F-299. 11. Wade, L.G., Jr Orgonie Chedry: Pmtiee-Hall: Englewmd Cllffa, NJ, 1991;pp 23LL233. 12. Mislow, K:Siegel,J. J A m . Chpm Soc 1984,IW,33193328. ofEdmofio~IO b j e d i m ~ 13. Krathwohl, D. R.: Blmm, B. S.:Masla, B. B. To*~o*~o*omy The Classifimfion ofEdumfiona1 &Ls, Langman: New York. 1964;pp 186193. 14. Nekh1eh.M.B.J. Chem. Educ. 1992,69,191-196. 15. Cod, 0. J.ChemEduc. 197Z,49,461. 16. Eliel, E. L.J Cham. Educ 1985,62,221-224. 17. Wang J-X;Yang,C. J Cham Educ 1982,69,373-375. 18. Dietzel, R. A. J. Chem. Educ 1979,56,451. 19. Idoux, J.P. J Chem. Edue. lssZ.59.553. 20. Ep1ing.G.A. J. C h m . Edvc 1982.59.650. 21. Brun,Y.; lablanc, P J.Cham Educ 1983,60,40&404. 22. Ayodnde,F. 0.J. Cham. Educ 1988.60.928-929. 23. Ruekberg, B. J. Cham. Edvc 1981.64,1034. 24. Reddy, K R.N. J Chem. Educ 1989.66.480, 25. Yongsheng,H.:Cailan,W.J. Ckem Edue. 1992.69.273, 26. Richardson, W. S. J. Cham Educ 1982.59.649, 27. Thornan, C.J.. S. J. J. Cham. Educ 1916.53,502503. 28. Garrett, J.M.J. Cham. Educ. 1918.55.493. 29. Beauchamo.P. S. J. Chem Educ 1984.61.666661.
.., . ... 34. Siuerstein, R. M.;Basler, G. C.; Marrill, T C. Spoctmmtrie In&nlific&m ~ z n i Compounds c Wiley: New Yark. 1991: pp 176175.
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