Absolute configuration direct assignment

Addadi, L., A Link Between Macroscopic Phenomena and Molecular Chirality, Crystals as Probes for the Direct Assignment of Absolute Configuration of Chiral Molecules, 16, 1. 

Crystals as Probes for the Direct Assignment of Absolute Configuration of Chiral Molecules... 

Having established the basic mechanism of interaction between tailor-made additives and crystal surfaces, we return now to the original problem of direct assignment of the absolute configuration of a chiral molecule. We shall first examine how to establish by such means the orientation of a chiral molecule in a chiral crystal. 

The morphological differences between crystals grown in the presence and absence of the additive would then indicate the direction of the substrate molecule W-Y with respect to the polar axis. Consequently, the absolute configuration of the crystal and of the chiral molecular constituents can be derived. The additive need not be chiral, and even if it is, the assignment of the absolute configuration... 

In principle, an anisotropic reaction performed on a crystal of polar symmetry may fix the absolute direction of the polar axis. In the case of an asymmetric reaction carried out in a centrosymmetric (enantiopolar) crystal, one may establish the absolute configuration of the chiral product. The degree of reliability of the assignment will depend on knowledge of the various states of the reaction pathway. Here we briefly describe some heterogeneous reactions in polar and enantiopolar crystals that illustrate this approach. 

In this study, an important piece of information was gleaned regarding the mechanism of the reaction from the assignment of the absolute sign of the polar axis. Of course, in transformations of this type, if the reaction mechanisms are well established, one may proceed in a reverse manner and assign the absolute polarity of the crystal (and therefore the absolute configuration of the chiral molecules) by determining the preferential direction of the attack. 

The simplest way to assign the absolute configuration of a chiral molecule would certainly be by direct inspection of the molecule itself. Were the technical means at hand powerful enough to allow it, no other technique could compete with one providing a direct three-dimensional photograph of the molecule in question. Since at present, electron microscopes can achieve resolutions as low as 3 A, we are indeed not far from this goal. 

Not every molecular crystal can be resolved at 3A resolution, especially not ones built of aliphatic nonconjugated molecules, which have lower electron densities and are more subject to radiation damage. The final aim of obtaining a direct three-dimensional picture of the chiral molecule itself thus cannot yet be pursued. Assignment of absolute configuration by lattice imaging, however, may be achieved even at lower resolutions (129). 

The purpose of this review is two pronged. We have discussed the far-reaching manifestations of molecular chirality in crystals on the macroscopic scale, and have described the various direct methods for the assignment of absolute configuration of chiral molecules in solids. Our analysis has been confined to the solid state, because of the difficulties associated with the direct assignment of absolute configuration in the dispersed phase (12). 

A LINK BETWEEN MACROSCOPIC PHENOMENA AND MOLECULAR CHIRALITY CRYSTALS AS PROBES FOR THE DIRECT ASSIGNMENT OF ABSOLUTE CONFIGURATION OF CHIRAL MOLECULES... 

Shortly after the first announcement of optical resolution of ( )-cyclooctene, Moscowitz and Mislow 13) published a communication in which, on the basis of their MO calculation/they assigned the (S)-configuration to the (—)-enantiomer. Eventually, this conclusion was proved wrong 14,15) and the opposite configuration was assigned when the absolute configuration of (—)-( )-cyclooctene was shown to be directly correlated with that of (+)-tartaric acid 16a,b). 

Osmium tetroxide oxidation of (- )-( )-cyclooctene (6) afforded the ( + )-diol 7 whose absolute configuration was related to that of (+ )-tartaric acid (9) via the (+)-dimethoxy derivative 8. The (R)-configuration assigned by this correlation has been confirmed by a number of direct or indirect approaches. 

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