Predicting the Enantioseparation Efficiency of Chiral Mandelic Acid in Diastereomeric Crystallization Using a Quartz Crystal Microbalance

This study uses quartz crystal microbalance (QCM) chiral recognition as a novel approach to predict the chiral recognizability of a chiral selector for a racemate. The chiral selector (L-phenylalanine, L-Phe) was immobilized on a QCM sensor surface using a two-step assembly procedure. The modification of the L-Phe on the sensor surface was then characterized using several techniques, including resonant frequency detection, the contact angle, and X-ray photoelectron spectroscopy measurements. When examining the chiral recognizability of the L-Phe-modified QCM sensor for L-mandelic acid (L-MA) using a vapor diffused molecular assembly reaction technique, the chiral discrimination factor between L- and D-MA was about 8. The practical diastereomeric crystallization resolution of a MA racemic compound was then carried out using L-Phe as the resolving agent. The different properties of the diastereomer crystals of L-Phe-L-MA and L-Phe-D-MA were confirmed using high performance liquid chromatography (HPLC) and differential scanning calorimetry (DSC) analysis, plus the factors influencing the chiral resolution, such as molar ratio of MA to L-Phe, agitation speed, pH, cooling rate, and crystallization temperature were examined. The results showed that the diastereomeric crystallization separation of racemate MA using L-Phe as the resolving agent matched well with the QCM chiral recognition results. Therefore, the proposed method using QCM chiral recognition offers a simple solution to the challenge of screening a resolving agent for diastereomeric crystallization.