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A Mnemonic Device for Assignment of pro-R and pro-S Descriptors to Stereoheterotopic Ligands Dhanonjoy Nasipurl Indian Institute of Chemical Biology, 4 RaJa S.C. Mullick Road. Calcutta 700 032, India A number of simplified devices are known for assignment of the confirmrational descriotors R and S tochiral centers in molecules represented either in Fischer projection formulas (1-7) or in perspective formulas (8).No such device has so far been worked out for assignment of the relatedpro-R and pro-S descriptors (9) for stereoheterotopic ligands at a proc h i d center (10). We propose here a simple mnemonic device for assigning these descriptors to appropriate ligands in molecules with a orochiral center or centers written in Fiscber projection formulas and in molecules with a prochiral axis. Molecules with a prochiral center Camxmay be depicted bv two eauivalent Fischer oroiection formulas (1) and (2) @is. 1). 1; ia assumed that t'he iigand a has a higher priority than b while the lieands X mav havea orioritv lower (as in 3), in between (as in i),and higher (as ii5) relative to a and b. According to Hanson (9), one of the paired ligands, say XA,is arbitrarily elevated to a higher priority over the other (XB) without disturhing the priorities of a and b to create a hypothetical chiral center to which the chirality rule (11) is now applied. If the center then has R configuration (as in 1or 2 if a > b > X), XA is called pro-R and may be denoted1 by adding a subscript R as Xn. The other ligand XB is p r o 3 (desirmated Xd. a conclusion arrived at either bv default or by repeating Lidentical procedure for XR. ~ h r e esimple 1.1-dichloroethcomoounds ethanol (3). . . . 2-~rooanol(4).and ane i.5) are shown in Figure 1with theii enantiotopic ligands labeled following this convention.
A common feature is observed in these assignments (all possible priority sequences are covered in the examples), namely, when the higher ranking unpaired ligand a is at the top in the Fisher projection formula (called top-a), the righthand ligand (XAin 1) at the prochiral center is pro-R. A mnemonic may thus be worked out as "top-right" meaning that the lieand (at ~-~~~~ ~w~~ .~the same orochiral center) on the rieht of top-a ispro-R or converse1y:as "bottom-left" meaning that the lieand on the left of hottom-a is oro-R. When the lieands are placed vertically instead of horizontally, the mnemonic is changed from "too-rieht" to "rieht-too" (or converselv. . "leftlbottom") meaning that whena is on the right, the top lieand (XAin 2) is oro-R and so on. The mnemonic is valid only when'the paired ligands are written linearly in Fischer oroiection formula, i.e.. both either horizontally or verticaliy. if they are laced at a right angle to each other (as in 61, the reverse is true. The mnemonic is particularly helpful for labeling stereoheterotopic ligands in molecules with multiple prochiral centers. A case in hand is citric acid (7) (Fie. 2). which contains four stereochemically distinguishableprotons HA, Ha. Hr. and Hn at two orochiral centers. The CO?H erouD evydenzy corresponds to ligand a both at C-2 andc-4. ~ h "top-right" and the "bottom-left" mnemonics determine the labels for the four protons, directly and by default, as pro-&pro-R,pro-R, andpro-S,respectively (denoted by the first subscripts of the protons shown in 8). The middle ~~~~
~~
-
~~~
~~
~
~
~
The terms prod and prhSdo not necessarily mean that substitution of a prod(or pro-S) group would give a center of R(or S) chirality that has to be decided independentlyon the basis of the sequencerule (17). However, if the substitution is by a heavier isotope, substitution of the pro-R ligand does give the R-enantiomer and that of the pro-S ligand gives the Senantiomer. An alternative notation of stereoheterotoplc ligands using Reand St. deoendina on whether the iiaand in auestion is located over the Re i i ~ i i a c eoi the triangle des&ibed b i the other three ligands, has been proposed ( 13)and reviewed ( 10):
Figure 1. Labeling of enantiotopfc ilgands.
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Figwe 2. Labeling of diastereotopic iigands C02H
C02H
I
H-C-OH
I
I
i
H -C-H B ,3
I
H-C-OH
H-C2-OH
A
+ HS-C-H -
I
H-C-OH
-r
i
5
CqH
CH (OH1
i
H-C-OH
i
C02H
Figure 4. Labeling of p.ochirai iigands in aiienes and biphenyls. Figwe 3. Ligands at pmstereogenlc but proachirotbpic center carbon atom (C-3) is also prochiral and the two CHzCOzH groups are enantiotopic. The hydroxyl group a t C-3 acts as the fiducial ligand a, and the "right-top" mnemonic determines the upper CHzCOzHgroup to be pro-R and the lower one p r o 3 by default. The subscripts of the groups are now added to the individual subscripts of the four protons which are thus labeled as HSR,HER,HRS, and Hss (as in 8). The oaired subscriots not onlv describe each of the four orotons ;niquely but aiso indicate their topic relationship. ~ h u HSR s isenantiotooir with Hucas also Haa with Hw while all other pairs are d&tereoto$e. The present notation is a slight modification of Hanson's (9)with the advantage of a double indexing system-first used by RBtey and Robinson (12) following Prelog-Helmchen (13) conventi~n.~ Paired ligands at a prochiral center in molecules containing one or more chiral centers are usually diastereotopic. They are first labeled with appropriate subscripts R and S following the "top-right" or "right-top" mnemonic and to these is added the configurational symbol (R and S) of the nearest chiral center with the proviso that when the two nearest chiral centen are equidistant, the one in the highest priority branch at the prochiral center is chosen. Two diastereotopic protons at C-3 of 2-R-malic acid (9) are thus designated by paired subscripts as HSRand HRR(shown in 9) which indicate their diastereotopic relati~nship.~ Two stereoheterotopic ligands at apro-pseudoasymmetric center (10) are usually designatedpro-r andpro-s in keeping with the formation of r and s pseudoasymmetric centers by aonro~riatesubstitution of the lieands one at a time.4 The ciaisiial case of 2-~,4-S-dihydrox;glutaric acid (10) (Fig. 3) orovides an examole. The two protons HAand Hn at C-3are biastere~to~ic since their substitution, s& by OH, gives two diastereomers (as 12 with H, OH at C-3 differently oriented)
It may be noted that the second subscript of the stereoheteratopic nuclei in citric acid and in malic acid has different connotations, the one in cltric acid referring to the enantiotoplcity of a grouping (of which the nuclei are parts) at a prochiral center and the other in malic acid referring to the configuration of a chiral center. Fortunately, the two situations are mutually exclusive since a chiral molecule cannot have enantiotopic groupings at a prochiral center, there being no reflection symmetry. The lower case symbols rand s refer to centers that are reflection-invariant, i.e., stereogenic but achirotopic. 484
Journal of Chemical Education
and they are not related by symmetry of any kind. Since R precedes S i n C-I-P nomenclature (11). C-2 corresponds to the fiducial ligand a so that HAis pro-r ("top-right") and HB is pro-s by default. They are shown as H, and H, in the structure (11). The central carbon atoms of 12 and 10 are called pseudoasymmetric and pro-pseudoasymmetric centen, respectively. However, according to a recent suggestion, they may preferably be called stereogenic but achirotopic and prostereogenic but proachirotopic respectively (14). The "top-right" mnemonic with slight modification may also be a .o.~ l i e dto desienate enantioto~ic in mole. lieands cules containing a chiral axis such as allenes, hiphenyls, and analomen. The molcule is first proiected on to a plane in the way i t is done for determining R and S chirality, care being taken that the front ligands (he they paired or unpaired) are on the horizontal axis (thick line):~his is shown in 14 for monochloroallene (13) (Fig. 4). In this way, the arrangement resembles a Fischer projection of a tetrahedral center (horizontal groups in front and vertical groups in the rear). The and Ha..is labeled as Ha..and "too-rieht" rule is then aoolied . ~~k (14). In order to have enantioto~iclieands in biohenvls. the two rings should he so substituted that rotation aboutthe pivotal bond is sufficientlvrestricted to oermit atro~isomerism,but one of the rings must be sym&etrically sihstituted. he biphenyl (15) provides an example in which HAand HBare enantiotopic (related by a o plane but not by a Cz axis). The projection in two dimensions (16) shows HAas Hg and He as Hs by default.
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Acknowledgment
I wish to thank E. L. Eliel of the University of North Carolina, Chapel Hill, NC, for helpful suggestions concerning the manuscript.
4, Price. H. C.B~oehem.E d u . I98O.i(, 165.
5. Idour. J. P. J . Chem. Rdue. 1982.59.553. 6. Es1mng.G. A. J . Cham. E d w . I382,59.650. 7. Kofora. M.BuN.Chem Soe. Japan. l386,59,6~. 8. Ehel. E. L. J . Chem. Educ L985.62,ZU-224,and ref- f f f cited therein. 9. Han8on.K. R. J. Am. Chem. Sac. L966,88,2131-2142: Hkchmano.H.; Haoso~aoso.K.R J. Org. Chem. l97L,36,32933306. 10. For a recent review, 88s Elid, E. L. Top. Cum. Chem. 1982,lO5,1-76. 11. Cahn. R. S.: Ineold. C. K.: Preloe. V . Amem. Cham.Int. Ed. 1%6.5.1-16.
