The Impact of Solvophobic Interactions on the High-performance Liquid Chromatography Enantioseparation of Planar Chiral 1,2-ferrocene Derivatives on Amylose Tris(3,5-dimethylphenylcarbamate)

Background: Planar chiral ferrocenes are well-established metallocenes that have attracted considerable attention for several decades due to their potential applications in synthesis, catalysis, materials science and medicinal chemistry. The planar stereogenicity of these compounds occurs when the symmetry plane of a single planar ring is broken by the introduction of two or more different substituents. Recently, the range of applications of planar chiral ferrocenes has been further extended by using them as model systems to investigate the enantioselective properties of inherently chiral materials incorporated into electrochemical devices and polysaccharide-based chiral stationary phases used for enantioselective HPLC.

Results: This study aimed to evaluate planar chiral ferrocenes as probe molecules for the investigation of the enantiorecognition mechanism operating on the polysaccharide-based Chiralpak AD-3 chiral stationary phase containing amylose-tris(3,5-dimethylphenylcarbamate) as selector. A set of six planar chiral 1,2-ferrocene derivatives with a phosphine or phosphine oxide moiety at position 1 and π conjugated systems at position 2 were designed for this purpose. The chromatographic performance of the Chiralpak AD-3 chiral stationary phase in achieving enantioseparation was evaluated using pure ethanol and 2-propanol as mobile phases, with temperature variation as a variable. The use of 2-propanol instead of ethanol results in optimal conditions for the entropy-driven separation of the first eluted (Sp) enantiomer and the second eluted (Rp) enantiomer of phosphine oxide ferrocenes. An unusually high chiral discrimination was observed for the ferrocene phosphine oxide bearing an (E)-buta-1,3-dienyl group at the 2-position.

Significance: A meticulous and comprehensive chromatographic investigation has revealed that pronounced chiral discrimination is driven by solvophobic interactions, which are typically underestimated in studies of this nature, particularly those involving the π-conjugated apolar fragments of the ferrocene. In principle, the modeling of the unconventional chromatographic data obtained in this study could be used to assess the predictive capability of the enantiorecognition process of in silico models of the amylose-tris(3,5-dimethylphenylcarbamate)-based chiral stationary phase.