The R/S System: A Method for Assignment and Some Recent Modifications Ernest L. Ellel University of North Carolina, Chapel Hill, NC 27514
Not only many students but alsosome experienced chemisb still find it difficult toassign R o r S descriptors (1.2) tochiral centers bv insnection of a stereoformula. and mistakes are not infrequent. Itwill probably take some time hefore such a task can be routinely performed by a computer (3). When a chiral structure is written as a Fischer projection formula, assignment is simple. A number of recipes (4-10) have been proposed of which the "Vertical-4-Verity Rule" (7) and the equivalent "Very good Fischer projection'' (9) are probably the simplest t o use; if the lowest-priority group in the CIP sequence ( I , 2) is in the uertical axis of the Fischer projection,;he orde; of the remaining three groups in descendinr CIP sequence, clockwise for R, counterclockwise for S , givesthe correk descriptor; but, if the lowest-priority group is in the horizontal axis, the descriptor obtained in this way must be reversed. However, many stereoformulas, such as those of steroids, alkaloids.. nrostaelandins. macrolides. etc.. are commonlv . written as three-dimensional representations, with solid and dashed bonds for substituents oointine to the front or rear. respectively. No problem is encountered when the lowest: orioritv...arouo . is clearlv in back. However. seven other oossibilitics exist: the lowest-priority group may be clearly in front (as the methvl - arouw - . at C-10and C-13 in cummon steroids) or some other group, first, second, or third in sequence, may be clearly either in front or in back. I t is, of course, possible to transform the pertinent chiral center into a Fischer projection and then derive the descriptor for the latter. The necessary transformation is not always trivial, however, especially if a substituent (such as the C-10 methyl group) is in front of the molecule rather than in the hack. Two previous papers (11,12) have addressed this problem in part. In one (11) it is pointed out (on permutational principles) that if either the second or fourth group (in CIP seouence) is in the rear. the correct descriotor is found from the drder of the other th;ee, whereas the descriptor must he reversed if the rear group is 1 or 3. The other paper (12) deals with the case where the lowest-priority group is in front; once aaain the descri~~tor obtained in the wav described a h v e muit b i reversed. Presented here is a method tbat can be applied to all three-dimensional formulas. The ligands a t the chiral center to be described are ordered in the CIP sequence (1 > 2 > 3 > 4). One of the four ligands will be clearly in front or clearly in the back, let us call it the "reference ligand." The order (clockwise or counterclockwise) of the remaining three is then determined by inspection. Whether this order will give the correct descriptor (Rfor clockwise, S for counterclockwise) depends on the sequence order of the reference ligand and on whether it is in front or in the rear, as shown below. Front + - + Order 1 2 3 4 - + - + Rear The symbol + means that the descriptor obtained by the above procedure is correct; - means that it is incorrect and needs to be reversed (the reader may prefer to use some other symbol, such as c for correct, i for incorrect). One need not
remember the Scheme but can reconstmct it whenever needed hy recalling that 4Irear is the proper dispmition in the original CIP conversion iUsteerinewheel"! n ~ l e113) and hence must bear the symbol +; the regaining signs aiternate as one circles around the numbers. Examples are shown below. ~
~
~~
~~~
HOCH:,
?'3
4
In the steroid, A above, the methyl group (lowest in priority) a t C-10 is forward, so a reversal of the initial descriptor to S is called for. (It must also be recognized tbat C-9 has precedence over (2-5.) In the decalone, B (above), the reference ligand at C-4a is NH2 (priority 1, in the rear) whereas that a t C-8a is CHzOH (priority 2, in rear). Hence reversal of descriptor occurs a t C-4a but not a t C-8a; the compound is (4aS,8aR)-4a-amino-8a-hydroxymetbyl-l-decalone (the cis iuncture of the ring is imolicit in the absolute stereochemisiry). In 1:2-dimelh;lcyclohexane ( C ,above) one may consider the methvl erouos (3 in or~oritv,as the refrrcnce lironds; inspection b f t h e sequence order given above shows that the descriptor should then be correct a t C-2 (3 forward) but reversed a t C-1 (3 backward). Taking into account that there is a hydrogen atom a t each position (eclipsed with methyl), the order of the other three groups (CH-CH3, CH2, H) is clockwise a t C-1, counterclockwise a t C-2 and the compound is thus (lS,2S)-1,2-dimethylcyclohexane.In this case, it would probably be easier to draw in the backward hydrogen at C-2 and note directly that this center is S; the configuration at C-l may be deduced from the fact that the compound is chiral and therefore cannot be (1R.2S). . . . This is perhaps a suitahle place to draw attention, also, to recent chanaesin theCIP swtem 121.Mmiv of the chaneesare esoteric and unlikely to be encountered in practice, so only three of them will be mentioned here. (1) Treatment of rings, chiral center in ring. An example is
S
Each cyclic ligand is detached at the distal end, where it doubles back upon the chiral center; the c h i d center is placed as a phantom atom (with no further ligands) a t the end of the chain so generated. The process is carried out as often as necessary to produce four acyclic ligands (twice for a monocyclic system, three times for a bicyclic one, etc.). The acyclic Volume 62 Number 3 March 1985
223
ligands so created are then ordered in the usual way (see above). The ~rocedureis effective for s ~ i r ocom~oundsas well. (2) Treatment of rings, chiral center outside of ring. The same procedure as in (1) is followed to open up the ring, except that the ring atom ligated to the chiral center now takes the place of the c h i d center in (1). An example is
The case for benzene is
(3) Treatment of cis-trans isomeric groups. In the 1966 system, if two ligands were cis-trans isomeric, the rule was seqcis > seqtrans (I) or, as we would now say (14), Z > E. This rule has been changed in the 1982 system: precedence goes to the ligand in which the (distal) olefinic suhstituent of higher sequence is on the same side as the (proximal) ligand connected to the chiral center. Thus the (Z)-l-propenyl-(E)-l-
224
Journal of Chemical Education
propenylcarbinol (A, below) is S both under the new rule (2) and the old (1); hut the more complex olefin B (helow) which was S under the old rule (1) is now R. for while the rieht 2,3-dichlorohutenyl is E and the left 2, it is the right s;hstituent which has C1 (nreferred over methvl) on the same side as the methylene lin!&e to the c h i d cent&. The subscript n is used with the descriptor to denote that it conforms to the new, 1982 (2) nomenclature.
Literature Cited (1) Cahn,R.S.,Ingold, C.,aod Prelap, V.,Angew. Chem Int. Ed., 5,385 (19661. (2) Prelog, V., and Helmehen, G., Angsw. Chem. Inl. Ed., 21,567 11982). (3) Cf.:Meyer, E. P., J. CHBM.EDUC., 55,780 119181. 14) ELiel. E L.,"Smhemistry of Carbon Compounds,"MeCraw-Hill,New York, 1%2, p. 92. (5) Fmeudenberg. K..Naluruiaa.,64,3 11977). (61 Dietzel, R. A,, J. CHUI. EDuC., 56,451 (1919). (7) Price, H. C.,Bimhem. Edue, 8.105 11980). 18) 1doux.J. P., J. CHSM.EDUC., 59,553 11982). 19) Epling,G.A.. J . C ~ ~ . . E D U C . . 5 9 . 6 5 0 1 1 9 8 2 ) . 110) Ayorindc. F. O..J. CHM. E?UC., 60.928 (1983). (11) Cori. 0.. J. CHBM.EDUC., 49,461 (1972). (121 Brun, Y.,and hblane, P., J. CHEM. EDuc., 60,403 11981). (131 Cehn, R. S.,and Ingold, C. K., J. Cham. Sm., 612 11951). L E., J (14) Blackood. J. E., Gladys. C. L.,Loening. K. L., Petrarea, A Chem. Soc,90,509 11968).
