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Rapid discrimination of enantiomers by ion mobility mass spectrometry and chemical theoretical calculation: Chiral mandelic acid and its derivatives

Huanhuan Wang,Fangling Wu,Xinhua Dai,Xiang Fang,Chuan-Fan Ding

Because R/S-mandelic acids (MA) and their derivatives are critical starting materials or intermediates in the synthesis of chiral drugs, their chirality discrimination is important. In this study, R/S-MA and its derivatives, including R/S-2-phenylpropionic acid (2-PPA), R/S-methoxyphenylaceticacid (MPA), and R/S-2-hydroxy-4-phenylbutyric acid (HPBA), were accurate simultaneous mobility-discriminated by forming diastereomer complexes for the first time, which were obtained by simply mixing with cyclodextrins (α, β, γ-CD) and transition-metal ions (Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ ). The mass spectra revealed non-covalent diastereomer complexes formed by CD , enantiomers , and metal ions , and ion-mobility spectrometry (IMS) was performed for 109 pairs of complexes. Significant chiral discrimination was observed in the formed diastereomeric complexes, and their separation peak-to-peak resolution (R p−p ) for the enantiomers depended on the transition metal ion type. In most cases, the R p−p value gradually increases with CD size, with quaternary complexes having the largest R p−p value. The greatest chiral distinctions of 2-PPA, MA, MPA, and HPBA were obtained by the diastereomeric complex ions of [(2-PPA)(α) 2 +Zn 2+ -H] + , [(MA)(α) 2 +Zn 2+ -H] + , [(MPA) 2 (β)+Co 2+ -H] + , and [(HPBA)(α) 2 +Fe 2+ -H] + , with R p−p values of 1.35, 1.57, 1.70, and 0.71, respectively. Furthermore, the favorable conformation and collisional cross section (CCS) value of the different [CD + R/S-MA + Cu–H] + complexes were measured using chemical theoretical calculations to detail their intermolecular interaction , revealing that [α-CD + R/S-MA + Cu–H] + has two favored gas complexes, and the CCS calculated were consistent with the TIMS observed. In addition, R 2  > 0.99 was obtained for the relative quantification of the chiral enantiomers. Overall, the proposed method provides a promising strategy for distinguishing the enantiomers of MA and their derivatives, with the advantages of simplicity, speed, and accuracy, without the need for complex chemical derivatization or chromatographic separation.