Self-assembled Binuclear Cu(II)−L-Histidine Complex in the Gas Phase for Chiral Differentiation of Naproxen Drug

Naproxen is one of the most consumed nonsteroidal anti-inflammatory drugs and marketed as S-naproxen as its R-enantiomer is hepatotoxic [1]. Developments of efficient and reliable methods for chiral differentiation and quantification of naproxen are thus essential [2]. In this work [3], we discovered a self-assembled binuclear Cu(II) diastereomeric complex ion in the gas phase, [(Cu^IIL-His)₂(S/R-naproxen)−3H]⁺, that can be applied to effectively determine the absolute configuration of naproxen and quantify the enantiomeric excess of S/R-naproxen mixtures using collision-induced dissociation with a tandem mass spectrometer. The key candidate structure of this gas-phase diastereomeric complex ion has an unusual self-assembled, compact geometry with the two Cu(II) ions bridged closely together by the carboxylate groups of the two histidines, proposed using density functional theory, and supported by ion-mobility spectrometry and collision cross section modeling. The difference in dissociation efficiency of the two diastereomers is attributed to the σ-π interaction between the NH₂ group of one histidine and the naphthyl ring of naproxen in the complex. The present report observes and characterizes the diastereomeric complexes of [(Cu^II)(L-His)₂] with aromatic acid, which could contribute to the recognition of chiral aromatic acids, design of catalysts based on binuclear copper-bound complex, as well as the better understanding of metal-ion complexation by His or His-containing ligands.