Potentially Mistaking Enantiomers for Different Compounds Due to the Self-Induced Diastereomeric Anisochronism (SIDA) Phenomenon

Abstract

<jats:p>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.</jats:p>

Recommended Tests for the Self-Disproportionation of Enantiomers (SDE) to Ensure Accurate Reporting of the Stereochemical Outcome of Enantioselective Reactions

“…Therefore, whether compounds are crystalline or liquid, of low or high molecular weight, polar or non-polar, etc., they are likely to be amenable to chromatography. Notably, SDEvC has been observed for all manner of chromatographic techniques, such as high-pressure liquid chromatography (HPLC) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ], medium-pressure liquid chromatography (MPLC) [ 18 , 19 , 20 , 21 ], routine, gravity-driven column chromatography [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ], flash chromatography [ 35 , 38 , 39 , 40 ], preparative thin-layer chromatography (PTLC) [ 10 , 41 ], and size-exclusion chromatography [ 42 , 43 ], as well as under a variety of conditions such as normal- and reverse-phase conditions and for various stationary phases [ 37 , 38 ]. Some noteworthy theoretical studies [ 15 , 73 , 74 , 75 , 76 , 77 ] have been conducted on SDEvC to describe the process.…”

“…Over the last decade, systematic research into the phenomenon of the self-disproportionation of enantiomers (SDE) [ 5 , 6 , 7 , 8 , 9 , 10 ] has clearly revealed that the accuracy in reporting the stereochemical outcome of enantioselective reactions represents a major issue of concern in terms of data integrity and the understanding of the stereochemical mechanisms at play and the interpretation of the results. It has been unequivocally shown that any physicochemical treatment, including achiral chromatography [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ] or even rotary evaporation [ 40 , 44 ], of a scalemic sample inevitably leads to fractionation of the material into portions of variable enantiomeric excess (ee), with consequent erroneous reporting of the stereochemical outcome if due care is not taken. Yet, there is a deficiency in the general understanding and appreciation of the SDE phenomenon, even though it has been known for a considerable length of time now.…”

Flurbiprofen: A Study of the Behavior of the Scalemate by Chromatography, Sublimation, and NMR

“…Because the formation constant for the association of homochiral molecules (K hom ), i.e., R with R or S with S, is likely to be different to the formation constant for the association of heterochiral molecules (K het ), the positions of the two equilibria will likely be different. Therefore, the observed δ of a nucleus is the population-weighted average of the δ's of the nucleus in the three states SM, HOM, and HET [1][2][3]. Furthermore, as the equilibrium shifts with a change in conditions (e.g., concentration or temperature), the contributions of the δ's from the SM, HOM, and HET states to the population-weighted average δ alter accordingly.…”

“…Furthermore, as the equilibrium shifts with a change in conditions (e.g., concentration or temperature), the contributions of the δ's from the SM, HOM, and HET states to the population-weighted average δ alter accordingly. Enantiopure and racemic solutions can exhibit distinct spectra because of these dynamic effects, and even distinct signals for the two enantiomers can result in the case of scalemates [1,3,4]. The SIDA phenomenon with many fine examples in the literature [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] has been well reviewed in the past [1,19] and theoretically explained [3,20] along with its potential applications and problems.…”

“…(1) Direct measurements: diffusion coefficients (D's), longitudinal relaxation times (T 1 s), and transverse relaxation times (T 2 s) [2,3], although the differences can sometimes be quite small for these measurements and some idea of associate structure may be required if mixed results are obtained for the T 1 s and T 2 s. (2) Variation in sample conditions: plots of enantiomeric titration [2,5], serial dilution, temperature variation, and titration of cofactors (e.g., secondary solvent, acid/base, ionic strength) though some idea of associate structure may be required and care is required in the interpretation of the plots together with appreciation of the δ's [21]. (3) Other complex approaches: the interpretation of δ's and intermolecular nuclear Overhauser effects (NOE's) [3], although intimate knowledge of the structure is likely to be required for δ's, together with an appreciation of the consequences of varying relative concentrations [21]. Some general structural comprehension at least is also likely to be required in the case of intermolecular NOE's, and suitable spins are not always available for such an analysis.…”