Enantiomer separation of a powerful chiral auxiliary, 2-methoxy-2-(1-naphthyl)propionic acid by liquid chromatography using chiral anion exchanger-type stationary phases in polar-organic mode; investigation of molecular recognition aspects

Abstract

The enantiodiscriminating potential of the weak anion exchange-type quinine-based chiral stationary phases (CSPs) for direct enantiomer separation of racemic 2-methoxy-2-(1-naphthyl)propionic acid (selectand, SA) was studied. The influence of structure variations of the selector (SO) in the carbamate functional group and/or in the C6' position of quinoline moiety on retention and enantioselectivity was investigated. Systematic chromatographic studies were made to gain more insight into the overall chiral recognition mechanism for a given mobile phase. In this context, the tert-butylcarbamoyl quinine and the corresponding diisopropylphenyl-derived selector provided the highest resolution and enantioselectivity under polar-organic conditions with the elution order of (R) before the (S) enantiomer. When the bulkiness of the substituents in the C6' position of the SO was increased, the selectivity was decreased in all cases. Alkylation of the nitrogen atom in the carbamate functionality of the SO resulted in the complete loss of enantiomer separation, confirming the crucial importance of the hydrogen-bond formation involved in the stereodiscriminating events. In addition, ten different mono-, bi-, or trivalent acids, necessary as competitor molecules (counter-ions) of the mobile phase, were screened to judge their influence on retention and overall enantioselectivity. Among them, acetic acid, formic acid, N-acetylglycine, and glycolic acid proved to be the most promising counter-ions with R(S) values of 6.35, 6.81, 8.19, and 7.34, respectively. On the basis of chromatographic data, a tentative molecular recognition model was proposed. Simultaneous ion-pairing and hydrogen bonding, in concert with pi-pi stacking and steric interactions, were expected to be responsible for chiral recognition mechanism. This was partially corroborated by structural and/or conformational analysis of the tert-butylcarbamoyl quinine-2-methoxy-2-(1-naphthyl)propionic acid (SO-SA) complex.

Investigations of molecular recognition aspects related to the enantiomer separation of 2‐methoxy‐2‐(1‐naphthyl)propionic acid using quinine carbamate as chiral selector: An NMR and FT‐IR spectroscopic as well as X‐ray crystallographic study†

“…When the methoxy group of quinine was replaced by a hydrogen (obtaining the corresponding cinchonidine derivative) in a previous chromatographic study, a stronger binding of the (R) enantiomer was observed (increase of k (R) ), being indicative for a better steric fit in the binding pocket also of the (R) enantiomer, which was accompanied by a lower enantioselectivity. 9 In contrast, when the methoxy group was replaced by more bulky alkoxy substituents (e.g., n-propoxy, isopropoxy, neopentoxy), the enantioselectivity was nearly lost and the lowered retention factors for both the (R) as well as the (S) enantiomers indicated that the perfect steric fit of the (S) enantiomer was lost due to steric overcrowding.…”

“…14 For the more stable SOÁ(S)-SA complex, the signal of H 8 overlapped with H 6b at 3.60 ppm, making the assignment of the conformers more complicated. Among others, intramolecular NOEs were detected between proton pairs H 3V -H 7b , H 5V -H 9 , H 5V -H 8 /H 6b , H 9 The intramolecular NOE between H 101 and H 109 , and H 101 and H 102 of the SA allow to derive information on the preferential conformational binding state of the SA. From the former NOE, it can be concluded that the 1-naphthyl ring is oriented such that the proton H 109 and the methyl group C 101 are on the same side of the C 104 -C 108 axis, i.e., in syn orientation to each other (see Fig.…”

“…1b) revealed high chiral discrimination potential for the direct enantiomer separation of the racemic MaNP acid with enantioselectivity (a) and resolution (R S ) values of 1.89 and 8.19, respectively, and an elution order of (R) before (S) enantiomer. 9 From the enantiomer separation factor a, the corresponding differential free energy of binding D S/R (DG) (i.e., for the process of the transfer from the mobile to the stationary phase) of (R) and (S) enantiomers of 1.58 kJ/mol may be calculated according to the relationship D S/R (DG) = ÀRT ln a at temperature T of 298 K (R, universal gas constant). This energy difference indicates a high level of enantiorecognition capability of the chiral selector.…”

Investigation of Novel Cinchona Alkaloid-based Zwitterionic Chiral Stationary Phases in Cation- and Zwitterion-Exchange Modes

“…The opposite trend was found for pure enantioselective cation-exchanger-type CSPs, where the retention decreased, in the order TEA < DEA < EA < NH3, and base additive served as the counter-ions [50,57,84,85] .…”

“…They act as a competitor in the ion-exchange equilibrium. The addition of acid and base to the nonaqueous polar organic solvents greatly influences the solvation of both SO and SA, and the anions and cations of acid and base additives have great effects on the elution strength of the mobile phase, inversely acting as displacers at the cation-and anion-exchanger sites of the zwitterionic CSP, as summarized in Figure 13 [57,[84][85][86] . According to literature reports in single anion-exchange mode the base additives (co-ions)…”