NMR discrimination in nonrigid prochiral solutes dissolved in chiral liquid crystals: symmetry considerations

Enantiodiscrimination in the NMR spectra of flexible prochiral solutes dissolved in chiral liquid crystals (CLCs) is reviewed and compared with the analog phenomenon in such rigid solutes. In rigid prochiral solutes, the discrimination is brought about by the cancellation of improper symmetry elements upon dissolving in CLC within the frame of solute-solvent ordering mechanisms. If this reduction in symmetry renders the ordering of enantiotopic sites dissimilar, spectral discrimination may be observed. Symmetry considerations indicate that this is only possible for improper nonaxial groups lacking inversion symmetry. Nonrigid prochiral solutes consist of rapidly (on the NMR timescale) interconverting enantiomers, in which the racemization is accompanied by exchange of nonequivalent sites. These sites become, on the average, enantiotopically related, and in CLC, they exhibit spectral discrimination. The mechanism of the effect and the symmetry selection rules are different for the two cases. Specifically, the discrimination in flexible prochiral compounds results from the different ordering of the interchanging enantiomers in CLC. Using Altman's definition of average symmetry (Proc. R. Soc. A, 1967, 298, 184), selection rules for the phenomenon are derived. It follows that chiral discrimination in nonrigid prochiral solutes is much more abundant and can occur in all symmetry types except those possessing inversion. In particular, contrary to earlier thoughts, the effect can occur in compounds with axial symmetry. Illustrative examples of such studies with particular emphasis on compounds with average axial symmetry of the type D3h, C3v and C3h are reviewed in this contribution

Conformation and dynamics of 18-membered hexathiametacyclophanes: a two step racemization as studied by deuterium NMR in chiral lyotropic liquid crystals

The conformation and interconversion dynamics of two derivatives of the 18−membered hexathia metacyclophane 1 and 2 were studied by 1H NMR spectroscopy in isotropic solvents and by 2H NMR in chiral liquid crystalline (CLC) solutions, as well as by molecular structure computations. For the analysis of the dynamic effects, we made use of the concepts of "average symmetry" and "isodynamic groups", introduced by Altmann (Altmann, Proc. R. Soc.1967, 184, A298). Compound 1, which is unsubstituted in the inner aromatic site, has, according to the NMR and molecular force field calculations, a boat shaped ground conformation with C2 symmetry. It is highly flexible and in the NMR spectrum exhibits two successive dynamic processes. There is a low temperature (170−210 K, Ea = 10.5 kcal/mol) alternate "wing flipping", which corresponds to interchange between pairs of enantiomers and results, in the fast exchange limit, in an average prochiral molecule with C2v symmetry. This process is followed, at higher temperatures (290−320 K, Ea = 28.5 kcal/mol), by an umbrella flipping type inversion with an average structure of D2h symmetry. This second process involves averaging of effective enantiotopic into homotopic sites and can only be studied in chiral solvents. The origin of the chiral discrimination and of their stepwise averaging is discussed. Compound 2, which is substituted with methoxy groups at the inner sites of the benzene rings, is much less flexible and exhibits dynamic effects in the NMR spectrum only at temperatures above 370 K. We were able to study the kinetic parameters of this process in isotropic solvents (Ea = 21.4 kcal/mol). As for 1, the detailed mechanism of this process can in principle be established using dynamic NMR in CLC; however, experimental limitation precluded us from doing so. Possible alternatives and their effect on the 1D and 2D exchange spectra in CLC are discussed in a concluding sectio

Evolution of the Saupe order parameters of enantiomers from a racemic to a non-racemic liquid crystal solvent: an original light on the absolute configuration determination problem

International audienceChiral liquid crystals used as solvents have been shown to be very powerful in giving separate nuclear magneticresonance (NMR) signals for enantiomers. However, a fundamental problem remains: how to attribute absoluteconfigurations to the various NMR responses? In this paper it is demonstrated that the absolute configurationproblem could be solved in predicting the sign of the rotation of the principal axis system of the Saupe matrix in themolecular frame when going from an achiral (racemic) to a chiral anisotropic solvent

The use of residual dipolar couplings for conformational analysis of non-steroidal anti-inflammatory drugs dissolved in weakly ordering media

The three-dimensional structure and conformational equilibrium of flexible bioactive molecules in solution are of considerable importance in clarifying their role in chemical and biological activity, since their action takes place in a liquid medium. The use of residual dipolar couplings (RDCs) recently emerged as a promising and effective method to address this kind of investigation. In this brief review, the conformational analysis of several flexible non-steroidal anti-inflammatory drugs, belonging to the class of salicylates and α-arylpropionic acids (profens), is described using the RDCs measured in weakly aligning poly-γ-benzyl-l-glutamate solutions. By combining these experimental parameters, extracted by using different mono- and bi-dimensional nuclear magnetic resonance experiments, with the theoretical additive potential-direct probability description approach, accurate descriptions of the probability distributions have been obtained for all the drug molecules selected