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

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 (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). 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 (Rp−p) for the enantiomers depended on the transition metal ion type. In most cases, the Rp−p value gradually increases with CD size, with quaternary complexes having the largest Rp−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+Zn2+-H]+, [(MA)(α)2+Zn2+-H]+, [(MPA)2(β)+Co2+-H]+, and [(HPBA)(α)2+Fe2+-H]+, with Rp−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, R2 > 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.