Mechanistic Aspects of Chiral Discrimination on an Amylose Tris(3,5-dimethylphenyl)carbamate

Abstract

The separation of [2R-[2alpha(R*),3alpha]]-5-[[2-[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]-3(S)-4-fluorophenyl)4-morpholinyl]-methyl]-N,N-dimethyl-1H-1,2,3-triazole-4-methanamine hydrochloride from its enantiomer was achieved on an amylose tris-3,5-dimethylphenyl carbamate stationary phase. The retention of the enantiomers is dominated by weak hydrogen bonds while the enantioselectivity is governed by other kinds of interactions, e.g., inclusion in the amylose carbamate chains. Van't Hoffplots of 1nalpha vs. reciprocal temperature were non-linear and could be divided into two linear regions. One region at low temperature (5 degrees C- approximately 20 degrees C) and another one between 25 degrees C-70 degrees C with the change in slope occurring between 16 degrees C and 20 degrees C. DSC experiments suggested that the behavior can be attributed to breakage of H-bonds triggering a conformational change. Molecular simulation indicated a correlation between the interaction energies and the elution order obtained experimentally. The most retained enantiomer (R,R,S-enantiomer) interacts with the stationary phase through a hydrogen bond between the triazole proton and the C=O groups of the stationary phase, as well as through an inclusion in the cleft of the stationary phase. The other enantiomer exhibits a bifurcated H-bond between the triazolic proton and the C=O groups of the stationary phase leading to a less stable complex.

Size‐exclusion capillary electrochromatographic separation of polysaccharides using polymeric stationary phases

“…Derivatization of polysaccharides with PIC gives the possibility for biopolymer self-interaction via hydrogen bonding through the amide bond of the carbamate under certain solvent conditions [70,71]. We next proceeded to establish that sample aggregation, which could falsely lead to high MW determinations, did not occur with our method.…”

Separation of Chiral Compounds on Polysaccharide Columns

“…Based on these spectra, they concluded that the primary interaction between the triazole and the Chiralpak AD stationary phase was a hydrogen bond between the NH group of the triazole moiety and the C=O of the carbamate group of the CSP. However, this proton is involved in a tautomerism, so it is likely that the hydrogen bond may be weaker than normal [54]. As in the case of the cellulosic phase, van't Hoff plots of the traiazole in several hexane/alcohol mobile phases showed a change in slope at about 16 to 20 • C. Also, as before, differential scanning colorimetry (DSC) traces showed an exothermic transition in this same temperature range.…”

“…In a subsequent study, Bereznitski et al made similar mechanistic studies of ADMPC (Chiralpak AD) [54]. In this case, the primary probe was a complex triazole molecule with three chiral centers, also containing two fluorinated or triflorinated aromatic groups and a teriary amine.…”

“…However, systematic studies employing supplemental techniques to chromatography have been used to improve our understanding of how these phases work. A number of reviews have covered various aspects of these studies [2][3][4][10][11][12][13][14][47][48][49][50][51][52][53][54][55][56][57].…”

“…Chiral selectivity is then controlled not only by the attractive interactions between CSP and solute, but also by the steric fit of the solute in the chiral cavities [88]. Another group of mechanistic studies has been carried out by Grinberg and co-workers [53][54][55]. In one study, the mechanism of interaction for cellulose tris(4-methylbenzoate) (Chiralcel OJ) was studied with a combination of solvent modification, temperature studies, infrared spectroscopy, differential scanning calorimetry, and molecular modeling.…”