Single Isomer N-Heterocyclic Cyclodextrin Derivatives as Chiral Selectors in Capillary Electrophoresis.

Edit Luca Kukk,Szabolcs Béni,Eszter Kalydi,Mimimorena Seggio,Ida Fejős,Milo Malanga

doi:10.3390/molecules26175271

Abstract

In order to better understand the chiral recognition mechanisms of positively charged cyclodextrin (CD) derivatives, the synthesis, the pKa determination by 1H nuclear magnetic resonance (NMR)-pH titration and a comparative chiral capillary electrophoretic (CE) study were performed with two series of mono-substituted cationic single isomer CDs. The first series of selectors were mono-(6-N-pyrrolidine-6-deoxy)-β-CD (PYR-β-CD), mono-(6-N-piperidine-6-deoxy)-β-CD (PIP-β-CD), mono-(6-N-morpholine-6-deoxy)-β-CD (MO-β-CD) and mono-(6-N-piperazine-6-deoxy)-β-CD (PIPA-β-CD), carrying a pH-adjustable moiety at the narrower rim of the cavity, while the second set represented by their quaternarized, permanently cationic counterparts: mono-(6-N-(N-methyl-pyrrolidine)-6-deoxy)-β-CD (MePYR-β-CD), mono-(6-N-(N-methyl-piperidine)-6-deoxy)-β-CD (MePIP-β-CD), mono-(6-N-(N-methyl-morpholine)-6-deoxy)-β-CD (MeMO-β-CD) and mono-(6-N-(4,4-N,N-dimethyl-piperazine)-β-CD (diMePIPA-β-CD). Based on pH-dependent and selector concentration-dependent comparative studies of these single isomer N-heterocyclic CDs presented herein, it can be concluded that all CDs could successfully be applied as chiral selectors for the enantiodiscrimination of several negatively charged and zwitterionic model racemates. The substituent-dependent enantiomer migration order reversal of dansylated-valine using PIP-β-CD contrary to PYP-β-CD, MO-β-CD and PIPA-β-CD was also studied by 1H- and 2D ROESY NMR experiments.

Highlights

Chiral recognition has undisputed importance in separation sciences due to the conceivable differences in the effect of enantiomers of biologically active molecules
As high reproducibility is essential in method development, there is an ever-growing tendency to use single isomer derivatives (SIDs) as chiral selectors [3,4], as those facilitate the understanding of the chiral recognition mechanisms
This paper reports the syntheses, the acid-base profiling and the chiral capillary electrophoretic study of single isomer N-heterocyclic CDs, that carries the positively charged functions exclusively on their primary side and are unmodified on the secondary rim

Summary

Introduction

Chiral recognition has undisputed importance in separation sciences due to the conceivable differences in the effect of enantiomers of biologically active molecules. To date, charged CD selectors are predominantly represented by anionic derivatives [4], as the majority of the analytes possess basic character, and due to the fact that cationic selectors exhibit adsorption properties to the negatively charged wall of the silica capillary This may lead to decreased resolution and result in reduced reproducibility. The protonation state of weak electrolytes depends on the BGE pH, which offers the opportunity to fine-tune the analyteselector intermolecular interactions in order to enhance separation selectivity [3,9,10] This approach is lying on the theory that by finding the optimal experimental conditions, the difference in the formation degree of diastereomeric complexes can be maximized [11]. Besides the pH-dependent enantioselectivity, their concentration-dependent chiral recognition behavior was studied and compared for the first time

Synthetic Procedures

Determination of pKa of the pH-Adjustable CD-Derivatives by 1 H NMR-Titration

CE Experiments

NMR Experiments

Materials

Conclusions