A Novel Method for Assigning R, S Labels to Enantiomers James E. Huheey University of Maryland, College Park, MD 20742
'.J funny thing happened to this manuscript on its way to THISJOURNAL. On my desk it crossed a copy of the August 1984 issue of the Journal of Chemical Education containing a similar article ( 1 ) that described how students mav use their hands as molecular models tu work out ~ o n f i ~ u r i t i o n s (rf optically ac1it.e organic molecules. In the present article a somewhat similar procedure is suggested to provide studenw with greater insight into the prq)crtiesofdissymm~tricmolecules. There is a certain amount of overlan between these two articles, but the assumptions and conventions used here differ from those of Beauchamp (I) in fundamental ways. Those practiced in the art of visualizing three-dimensional molecules as depicted by two-dimensional sketches, and also familiar with the application of the Cahn-Ingold-Prelog Rules to them, will find a comparison of our methods eutertaining. However, the studentattempting to get the geometric relationships of enantiomers in perspective for the first time will, in all probability, he confused by reading Beauchamp's article and mine a t the same time. Since the ultimate goal of this article is to help students encountering chirality for the first time, I prefer to present my model as a self-contained system and reserve a comparison with Beauchamp's article to the Appendix. For some time it has been common ~ r a c t i c eto introduce the student to optical isomerism by comparing the mirror images of common chiral items such as left and rieht hands. gloves, feet, shoes, etc. Furthermore, holding the iands wit11 each finger of the left hand touching the corresnundine finger on the right hand readily illustrates that a pair of enantiomers are mirror images of each other. MY class alwavs likes, and remembers, this mirror image when-desrribed a5a "spider doing push-ups on a mirror". Ilnforrunately, the student may fail to make the transition from the chirality of a five-fingeredhand to an asymmetric rarbon atom, and the discussion quicklv turns to subiects more difficult for nenphytes to &uali;e such as thekahn-lngold- rel log system for designating R and S enantiomers and discussions of such topics as racemates, meso isomers, and diastereomers. Somewhere along the way the chirality of the students' hands is overlooked or forgotten, and they cease to benefit from this everyday analogy. I t is a useful and interesting fact that the chirality of human hands follows the Cahn-Ingold-Prelog Rules! Consider your left hand with the ring and little finger bent down against the palm. If you turn your fingers toward your eyes and gaze along the axis of your forearm, your hand becomes the oft-used "steering wheel" analogy of a chiral center (2). Your wrist automatically assumes the lowest priority, often representing the hydrogen atom of real molecules. If you now assign priorities from the largest (second) finger through the index finger to the shortest (thumb), the movement is that for a "left turn", counter-clockwise, describing the S (L. sinister, "left") enantiomer. In the same way your right hand is a model of the R (L. rectus, "right") isomer. ~~~
The chirality of the student's handsmay beused readily to infer the correct chirality of a molecule shown in a twodimensional drawing, a task that is often difficult for students who have not yet learned to rotate these drawings mentally. As long as the student understands the various conventions for indicating which bonds are projecting toward or receding from the viewer, the assignment of the correct absolute configuration, S or R, is essentially automatic. The groups are numbered 1,2,3,4in order of priority, the wrist is aligned with the group of lowest priority and groups 1, 2, and 3 are matched by the longest finger, the index finger, and the thumb. Either the left or the right hand can be made to match the enantiomer in question, and a chirality of S or R immediately assigned:
In fact, hy being able to rotate either an S o r anR enantiomer readily by just rotating the wrist, the student more readily learns the mental "tricks of the trade" that chemists use routinely to visualize enantiomers as seen from various perspectives.
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Molecules with two chiral centers can he constructed with two hands: The two chiral centers of an S-R or meso isomer can he approximated by holding the forearms parallel and against each other. I t is easy to see that the two asymmetric carbon atoms must he of opposite chiralities in order to have the internal mirror plane demanded of a meso isomer. T o illustrate the diastereomers R-R and S-S requires two right or two left hands, respectively, and so requires two people cooperating. I t should he pointed out that the method presented here is not intended to emphasize the application of the CahnIngold-Prelog Rules hut to de-emphasize this very necessary aspect of learning the "rules of the game"as quickly and as painlessly as possible so that more time can he given to the other aspects of chiral molecules. Chirality is a pervasive quality of the universe, encountered in many different yet related ways, ranging from subatomic particles (3)to amino acids, sugars, and enzymes ( 4 ) , to left-handed people (5), each interesting in its owh way. One need not stop with the material discussed ahove hut may proceed to discuss i t further. Dissymmetry is all around us. My wife, a biochemist, and I have long joked over the fact that our cat Boudicca (named after the leader of the Iceni who rampaged against the Romans, destroying the IXth Legion and pillaging Londinium about A.D. 60) has the habit of lying inclined to one side, sort of propped up with one paw tucked under, making her dissymmetric. We noted that although her activation energy was high for most feline maneuvers, she "inverted" readily, analogous to the racemization of a statistically (and unbearably) large number of cats. By making certain assumptions (such as the priority: torso > head > extended paw > curled-under paw) one can readily assign an S or R label (Fig. 1) just as one might apply the method to a molecule of similar configuration (Fig. 2). Why do it? For the same reason that S or R are assigned to enantiomers, or cis and trans to geometric isomers of hoth alkenes and square planar coordination compounds: essentially for communication that allows ready discussion, learning, and use of concepts, a point that students often miss in the process of memorizing "the rules". The professors who teach the material are not blameless either. How often do we clearly illus-
Figure 1. Baudicca. "Queen enantiomer.
of the lceni and Slayer of Roman
Figure 2. 2.3-Dimelhylbutenal,
Senantiamer.
Legions". S
trate the uses andapplications of these systems and conventions? One further example from common experience that the students will relate to readily illustrates perhaps the most important biological aspect of optical isomerism, the selectivitv of a narticular enzvme for a chiral suhstrate. Given the appropriate configuration of the enzyme-active site, the "correct" suhstrate enantiomer will react. Of course, this process can he matched literally by drawing a triangle on a . the a ~ i c e 1.2, s and 3, and asking a niece of ~ a n e rnumherine kudent'td set up a tripod from t h e fingersof one h&d numbered 1.2. and 3 as ahove. Ohviousls only one hand fits. However, perhaps a hetter analogy thai can readily be descril)ed verhally and visualized hv the students is simply the act of successfully shaking hands. As long as hoth handshakers use their right hands the operation proceeds rapidly and smoothlv. - - ~ ~ ,. so much so that one can he introduced to and shake hands rapidly with several people. Let just one person in the group he shaking hands with his left hand because his broken right arm is in asling, and the whole process comes to a erindine halt. as does the catalvsis of "the wrong" suhst;ate by :given enzyme. Other examples come to mind such as entropic responses by novices to "Swing your partner"! and "Allemand left"! in square dancing, or other chiralactivities. I t is hoped that the simple demonstrations given here will make it posible for students who are perplexed by twodimensional drawings to appreciate stereochemistry more readily through their use. By helping to bridge the gap between observing the obvious presence of dissymmetry on the one hand, and fluency in understanding and working with the subject on the other, i t is hoped that students will gain a better appreciation of the "why" and the "how" of optical isomerism and its importance in chemical and biological systems. ~
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Literature Clted (1) Beauchamp, P. S. J Chrm. Edue. 1984,61.666. (2) McMurry. 3. "Organic Chemistry": B~ookslCole:Mantetetey. CA. 19%pp 240-243: Monison,R.T.,Boyd,R.N."OganicChemistry",4thed.;Allynand Bacon: Boston, ,983;~ 13M39:Roberts. ~ J.D.;Csserio,M.C."BasicPrinciplesofOrganieChcmiatry", 2nd ed.;Benjamin/Cumming8: Menlo Park. CA. 1977: pp 8 7 9 w Solamans, G. "Organic Chemistry", 3rd ed.: Wiley: New York. 19W. pp 30M12:Streit%sser, A.,Jr.; Heathcock, C. H. "Introduction to Organic Chemistry". 3rd ed.;Maemillan: New York. 1985: pp 119.122 Wingrove. A. S.; Caret, R. L. "Organic Chemistry"; Harper & Row: New York, 1981: pp 201-205. (3) Gardner. M. '"The AmbiderVous Uniuerne", 2nd d.; Saibners: New York, 1979:pp 176913. (4) Ref. 3, pp 11C-124; M c M w , J. "Organic Chemietry"; BrmWole: Montemy. CA, 1984:pp83b389,10321033;Monison,R.T.:Boyd,R.N."OrganicChemiatry".4th ed.; Allyn and Bacon: Boston,1983, pp 158, 342-345, 1078-1084: Roberts, 3. D.; Caaerio, M. C. "Basic Principles of Organic Chemistry". 2nd d.; BenjaminICummings: MenloPsrk. CA. 1977:pp 1260-1262; Solomona. 0. "Organic Chemistry, 3rd ed.; Wiley: New York, 1981: pp 942-945: Wingrove, A. 8.; Ceref R. L. '"Organic Chemistry"; H a r p r & Row: NeuYork. 1981:pp 1288-1275. (5) Ref. 3, pp 57-83; Huheey, 3. E. Behou. Gen. 1977. 7,29. Appendix 'The principal difference brtwern thb methodology presented herennd that uf Beauchamp ( 1 ) is oneof the emphasisand ulrimate goal of each system. Hrauchamp'r method centers un the usefulness of matching a given configuration at a chiral center to whichever hand fits most readily. It uses the wrist that is most readily aligned with the bond to the atom of lowest priority (usually hydrogen), assignsspeeific group labels to the fingers,andthen rot& the hand in such a way as to he able to interpret the chirality of the compound in question. The hands are analogs of the molecules, and the fingers correspond to groups in an arbitrary way that simplifiesthe rotation of the molecule most readily. In fact, the strangest aspect of Beauchamp's method is that it facilitates the student's transfer of a molecule on paper to its analogous model, he the latter the left hand, the right hand, or a stick model with four different colors. In the system presented here the hands are enantiomers in and of themselves. They will always represent the same enantiomericpairs, and they have all of the symmetry properties of such pairs quite independent of chemistry. However, they are also homologs of the ehiral compounds that they represent. The chirality of each is filed and independent of the problem being presented. As a result, it is often somewhat more difficult to rotate the appropriate hand in Volume 63 Number 7 July 1986
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exactly the way necessary t o have a one-to-one homology with respect to the molecule as presented on paper. but once this h m bren done the complrte parall~listnbetween hand and n~oleculeis fixed and nor arhitrarv: Whatever the chemical nroblem, the left hand is always the S enantiomer and the right hand always the R enantiomer.
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Since the two methods use different criteria for assigning configurations LO each hand, one mrght rxpect that thry would agme and d ~ s a g r in ~ rRand Snssipnment* randomly, 50-50. Indeed thm proves to h~ trur: Of the rhrcr hands shown in Bentrhamp's art&. one (the first example) agrees and two do not, hence the caveat in the opening paragraph of this article.
