Abstract
The NMR phenomenon of self-induced diastereomeric anisochronism (SIDA) was observed with an alcohol and an ester. The alcohol exhibited large concentration-dependent chemical shifts (δ’s), which initially led us to erroneously consider whether two enantiomers were in fact atropisomers. This highlights a potential complication for the analysis of chiral compounds due to SIDA, namely the misidentification of enantiomers. A heterochiral association preference for the alcohol in CDCl3 was determined by the intermolecular nuclear Overhauser effect (NOE) and diffusion measurements, the same preference as found in the solid state. The ester revealed more subtle effects, but concentration-dependent δ’s, observation of intermolecular NOE’s, as well as distinct signals for the two enantiomers in a scalemic sample all indicated the formation of associates. Intermolecular NOE and diffusion measurements indicated that homochiral association is slightly preferred over heterochiral association in CDCl3, thus masking association for enantiopure and racemic samples of equal concentration. As observed with the alcohol, heterochiral association was preferred for the ester in the solid state. The potential problems that SIDA can cause are highlighted and constitute a warning: Due care should be taken with respect to conditions, particularly the concentration, when measuring NMR spectra of chiral compounds. Scalemic samples of both the alcohol and the ester were found to exhibit the self-disproportionation of enantiomers (SDE) phenomenon by preparative TLC, the first report of SDE by preparative TLC.
Highlights
The NMR phenomenon of self-induced diastereomeric anisochronism (SIDA) occurs when chiral molecules that associate in solution in a dynamic equilibrium that is fast on the NMR timescale have significant condition-dependent NMR chemical shifts (δ’s)
In addition to the well-known complications arising from SIDA in the comparison of enantiopure and racemic samples and peak splitting in the spectra of scalemic samples, sometimes the comparison of enantiopure samples can present problems
We suggest that the sizeable ∆δ’s more often seen between enantiopure and racemic samples is because heterochiral associates (HET) is much more preferred (Khet >> Khom ), in accordance with Wallach’s rule [25] for crystal structures
Summary
The NMR phenomenon of self-induced diastereomeric anisochronism (SIDA) occurs when chiral molecules that associate in solution in a dynamic equilibrium that is fast on the NMR timescale have significant condition-dependent NMR chemical shifts (δ’s). In such systems, molecules can be present either as single molecules (SM), homochiral associates (HOM), or heterochiral associates (HET) in solution (Figure 1). The observed (KHOM), i.e., R with R or S with S, is likely to be different to the formation constant for the association chemicalofshift (δobs ) ofmolecules a nucleus(Kis the population-weighted average of the δ’s of the nucleus heterochiral. SM, HOM, and [1,2].
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