Semiramis Ayral Kaloustian Lebanese University and Moses K. Kaloustian' American University of Beirut Beirut, Lebanon
Determining Homotopic, Enantiotopic, and Diastereotopic Faces in Organic Molecules
In a pioneering paper in 1966,2Hanson advanced rules for naming prochiral centers and prochiral faces of trigonal atoms. A year later, Mislow and RahanS propounded original and useful terminology for determining spatial relationships of groups and faces in organic molecules. The new nomenclature and terms have been widely accepted bv organic chemists a n d biochemists alike.4-6 - ~ c i l teh e symmetry and substitution criteria for determining spatial relationships of iigands are clearly defined, those relating t o faces need further refinement. We herebv resent a s i m ~ l eset of rules, based on considerations of symmetry (fo; the appropriate time scale of observation), t h a t would allow a succinct classification of the five types of molecular faces (I-V) of interest to the organic chemist and t h e biochemist?
Figure 1. Planar moieties in organic molecules. (0represents the first amms linked Lo the atoms shown.)
Define plane (Rule I1
I
C2 axis in plans
W
=
C+,C, O+ (W
?
Z = C:, 0, S Equiv.lsnt IIIHomotopic")
(V)
Sn1to plane 7
The following postulates form the basis of the classification of molecular faces 1) Two molecular faces are either related or unrelated to each
other. 2) If related, two faces must be equivalent, or enantiotopie, or diastereotopic.8 With respect to each other, two related faces cannot be equivalent and enantiotopic at the same time; nor can they he simultaneously enantiotopic amd diastereotopic. 3) Two molecular faces of the same functional moiety in a molecule (internal comparison) are related. ~
-
-
-
-
--
1 To whom correspondenceshould be addressed. 2Hanson, K. R., J Amer. Chem. Soe., 88, 2731 (1966): ef. also Hanson, K. R., and Hirsehmann, H., J. Org. Chem., 36, 3293 (1971),37,2784 (1972): and Eur. J. Bioehem., 22,301 (1971). 3Mislow, K., and Raban, M., in "Topics in Stereochemistry," (Editom; Allinger, N. L., and Eliel, E. L.), Wiley-Interscience Publishers, New York, 1967, vol. 1,p. 1. 4 Eliel, E. L., J. CHEM. EDUC., 48, 163 (1971). 5Bentley. R., "Molecular Asymmetry in Biology," Academic Press, Inc., NewYork, 1969, vol. 1, p. 158. 'Morrison, J . D., and Mosher, H. S., "Asymmetric Organic Reactions,'' Prentice-Hall, Englewaad Cliffs, N.J., 1971, p. 419. 7 Here the treatment of (II-IV) is similar to Hanson's; case (V) is not dealt with by Hanson. For case (I), on the other hand, the face of the double bond is treated as a unit, whereas Hanson deals with each end of the double bond separately. SEquivalent faces are designated by the letters F, F', F" . . . . Enantiotopic faces are denoted by F and '3l while diastereotopic faces are indicated by F, G,H . . . . SThese rules are applicable to faces of the same functional moiety. Faces of different functional moieties are compared by carryingout the appropriate symmetry operations.
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Figure 2. Classification of molecular faces.
4 ) ' ~ w omolecular faces of different functional moieties in the same molecule (internal comparison) or in different molecules (external comparison) may be related or unrelated to each other. On the basis of the above postulates, the new rules may b e stated a s follows~ 1) Define a plane containing the atoms directly bonded to C and
X (I), to C and Y (11). to W (IV). For (111) the plane is defined by Z and the first atoms linked to C, whereas for (V),(Z) and the atoms bonded to it define the plane in question (Fig. 1). 2) Lwk for a C2 axis (lying in the plane defined above) for the ouerall molecule. If a Cz axis exists, the two faces of the functional group are equivalent ("homotopic"). If a Cz axis is absent, proceed to Rule 3. 3) Look for en S, axis (usually SIor Sz) for the overall molecule such that the S, axis is perpendicular to the plane defined above (Rule 1). If such an alternating axis is present, the faces . are enantiotopie; if not, the faces are diostereotopie. Examples illustrating the terms equivalent, enantiotopic, and diastereotopic are given in the excellent article by Mislow and Raban.3 T h e scheme in Figure 2 summarizes the rules given above.
Operationally, equivalent faces F and F' are indistinguishable by achiral or chiral reagents, since attacks a t such faces lead to identical results."' For every transition state involved in the attack a t face F, there is a n energetically equivalent transition state for the attack a t face F'. In internal comparisons, faces are said to be equivalent if they are interchangeable by rotation about a C. axis of rotation (2 5 n < rn ). Thus, all four carhonyl faces of planar 1,3-cyclohutanedione are equivalent. Enantiotopic faces F and T are indistinguishable by achiral reagents;lO however, they can he distinguished by chiral reagents.ll The attack by a chiral reagent a t face F would involve a t least one transition state energetically different from a corresponding transition state involved in the attack a t face T . Faces are said to he enantiotopic by internal comparison if they are interchangeable by a n S, operation but not simply by a C, operation (n > 2). For example in tram-2,4-dimethyl-1,3-cyclohutanedione there are two (equivalent) pairs of enantiotopic faces. I n external comparisons, corresponding faces of enantiomeric molecules, e.g., of (R)- and (S)-2-methylcyclohutanone,are enantiotopic. In contradistinction, both achiral and chiral reagents can distinmish between diastereoto~icfaces F and G.ll Faces arediastereotopic by internal comparison if they have the same connectedness, reside in diastereomeric surroundings, and are not interchangeable by any symmetry operation. I n 1,3-cyclohutanedione hearing a chiral GR ligand a t position 2, there are four distinct diastereotopic there are carbonyl faces; in 2-methyl-1,3-cyclohutanedione two enantiotopic sets of diastereotopic faces. In external comparisons, corresponding faces of diastereomeric molecules are diastereotopic-e.g., in (2R)- and (2s)-cyclobutanones each with a chiral GR ligand a t position 2, there are four distinct diastereotopic carbonyl faces. The application of these rules to various alkenes (I), 'ohability to distinguish between two related faces signifies that the energy of each and every transition state involved in the reaction at faee F is equal to that of a corresponding transition state resulting from attack at equivalent face F' (or enantiotopic face?'); that is, every transition state arising from faee F is identical to or enantiomeric with that from faee F' (arT ).The overall rate of reaction at faee F is equal to the rate at face F' (oIT, for achiral reagents). "Ability to distinguish between two related faces implies that the energy of s t least one transition state involved in the reaction at face F diffen from that of a corresponding transition state involved in the attack at enantiotopic face T (or diastereotopic face G ) ; that is, at least one transition state for the attack at face F is isomeric to or diastereomeric (but not enantiomeric) with a comesoondine transition state stemmine ~.from faeev (or GI. iEnergeticnlly nonequiwlmt trnnritmn states may he diaThe uvcrall reaction rate strreomerir. iwrnertc or non~sumrric.~ at face F will hence he aiderent from the overall rate at face 7 (or G ) regardlessof the nature of the products. 12Under Hanson's definition both carbon ends in cisCHGneCHGn have diastereotopic faees, while the two faees of each carbon in cis-CHR=CHR are enantiotopic. In the present classification, in each of the two instances the complete faees of the double bond are equivalent. Deuterioboration of cisCHGn=CHG~ at one face would lead to two diastereomeric products; attack at the other face would result in the same products. The two faces are equivalent since bath would lead to identical sets of products. Furthermore, the enzymatic addition of D20 to one face of maleic acid would, in principle, pmeeed through a set of four distinct diastereomeric transition states; the addition at the other face would proceed through an identical set of four transition states. That is to say, whatever happens at the "top" face also happens at the "bottom" face; the two faces are therefore equivalent. The isolation of only threo-D-malate-3-d from the action of rabbit kidney hydratase on maleie acid in the presence of D20 indicates that the reactionlis regiospecific and stereospecific. The reaction at each faee proceeds predominantly through one transition state and the threo compound in question results from two identical transition states, one for each of the equivalent faces. n
~
Classification of Molecular Faces of Certain Alkenes, Carbonyl Compounds, and Sulfides c1-iAlkwes
C,
c1nesi-
Sn ficstion
-
Cz
S n fication
R' Gn
-
Dia
S\
-
-
Dia
/ R GR
-
\s
Eq
/ Gn
~
+
I
Es
GR
-
Dia
S \
r..
-
-
Dia
/
carbonyl compounds (III) and sulfides (V) is shown in the table. In the sequel, R represents an achiral group, GR stands for a chiral ligand and Gs is enantiomeric with G,%. Eq, En, and Dia mean equivalent, enantiotopic, and diastereotopic, respectively.12 It is to be noted that the classification of molecular faces given here is based on the symmetry of the substrate and is independent of the mechanism of the reaction and of the nature of reactants and/or products. The foregoing classification can be applied to a whole host of organk compounds. Model (I) is applicable to alkenes, immonium and amidinium salts, whereas (II) is the prototype for imines, hydrazones, oximes (and their O-alkyl and O-acyl derivatives), imino ethers, imino thioethers, amidines, azines, etc. On the other hand, aldehydes, ketones, carboxylic acids, halides, esters, amides, derivatives of carbonic acid are represented by (III).Type (IV) stands for planar Volume 52, Number 1, January 1975
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carbonium ions, free radicals, jlnd oxonium ions; model (V) represents alcohols, ethers, their sulfur and selenium analogs, carbenes, nitrenium ion, hypohalides, and halonium
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ions. A further extension of the same rules would enable classification of other molecular faces, e.g., nitro, nitroso, nitrite, sulfenate, sulfinate, isocyanate, i~othioc~anate, etc.
