Chromatographic and 1H NMR support for a proposed chiral recognition model

Abstract

Liquid chromatography and 1H NMR spectroscopy were used in an investigation of a chiral recognition rationale which was previously advanced to account for the resolution of naproxen (NAP-COOH) enantiomers on brush-type chiral stationary phases, CSP-1 and CSP-2, identical except for tether length. CSP-1 has recently been commercialized as the Whelk-O 1. This chiral stationary phase (CSP), basically an immobilized enantiomer of N-(3,5-dinitrobenzoyl)-4-amino-1,2,3,4-tetrahydrophenanthrene, was designed to have a cleft in which one enantiomer is preferentially bound. The cleft consists of π-acidic and π-basic aromatic systems held more or less perpendicular to each other. Aromatic substituents in the analyte were expected to be held in this cleft by simultaneous face-to-face and face-to-edge π—π interactions. To ascertain whether analytes are truely bound in this cleft, NMR studies of mixtures of several naproxen-like analytes and chiral solvating agent 3, a soluble version of the selector used in CSP-1, were undertaken. Additional motivation for the study came from the observation that the enantiomers of NAP-COOH and NAP-COOMe elute in a different order than do the enantiomers of NAP-CONHMe, and NAP-CON(Me) 2. This difference in the elution order of the amide derivatives with respect to the esters and free acid was not totally unexpected, for the chiral recognition hypothesis used in the design of the chiral selector allowed for such an eventuality. It was known from reciprocal chromatographic studies that the enantiomers of soluble analogs of the Whelk-O 1 CSP show different elution orders on naproxen-derived amide CSPs than they do on naproxen-derived esters CSPs. These data aided in formulation of the initial chiral recognition rationale. Evidence for the occurance of the specific molecular interactions suggested by this rational is provided by the presently described 1H NMR study of the enantioselective complexation of the enantiomers of NAP-COOH, NAP-COOMe, NAP-CONHMe, and NAP-CON(Me) 2 by a single enantiomer of a soluble analog of the Whelk-O 1 CSP.