Past, present, and future developments in enantioselective analysis using capillary electromigration techniques

Abstract

Enantioseparation of chiral products has become increasingly important in a large diversity of academic and industrial applications. The separation of chiral compounds is inherently challenging and thus requires a suitable analytical technique that can achieve high resolution and sensitivity. In this context, CE has shown remarkable results so far. Chiral CE offers an orthogonal enantioselectivity and is typically considered less costly than chromatographic techniques, since only minute amounts of chiral selectors are needed. Several CE approaches have been developed for chiral analysis, including chiral EKC and chiral CEC. Enantioseparations by EKC benefit from the wide variety of possible pseudostationary phases that can be employed. Chiral CEC, on the other hand, combines chromatographic separation principles with the bulk fluid movement of CE, benefitting from reduced band broadening as compared to pressure-driven systems. Although UV detection is conventionally used for these approaches, MS can also be considered. CE-MS represents a promising alternative due to the increased sensitivity and selectivity, enabling the chiral analysis of complex samples. The potential contamination of the MS ion source in EKC-MS can be overcome using partial-filling and counter-migration techniques. However, chiral analysis using monolithic and open-tubular CEC-MS awaits additional method validation and a dedicated commercial interface. Further efforts in chiral CE are expected toward the improvement of existing techniques, the development of novel pseudostationary phases, and establishing the use of chiral ionic liquids, molecular imprinted polymers, and metal-organic frameworks. These developments will certainly foster the adoption of CE(-MS) as a well-established technique in routine chiral analysis.

Keywords: CE-MS; Chiral CEC; Chiral analysis; Chiral electrokinetic chromatography; Enantioselective separation.

Figure 1

Molecular structure of a β‐CD. (A) The seven glucose units connect through ether bonds to form the β‐CD. (B) Three‐dimensional view of a CD. The cyclic structure adopts a truncated cone shape with primary and secondary hydroxyl groups presented outward. Analytes approach the CD core from beneath, where chiral recognition occurs at the cavity mouth. (C) Each hydroxyl group can be substituted for a desired functionality (R).

Figure 2

Supramolecular interaction between a crown ether, cationic analyte, and a CD. Suggestion of the molecular model (schematic) of the complexation of a 18‐crown‐6, a primary amino compound, and a β‐CD. Chiral recognition can be enhanced by using this dual selector system. Adapted from [96] with permissions.

Figure 3

Synergistic effects of β‐CD and chiral ionic liquids in a dual selector system, illustrated with the enantioseparation of chiral drugs econazole (A) and sulconazole (B). The use of a single chiral selector, (2‐hydroxypropyl)‐β‐CD shown in the bottom trace, was compared to two dual selector systems including (2‐hydroxypropyl)‐β‐CD and either the chiral ionic liquid [TBA][L‐Glu] shown in the top trace, or [TBA][L‐Lys] shown in the middle trace. Enhanced resolution was observed for both chiral drugs when using a dual selector system, compared to only employing (2‐hydroxypropyl)‐β‐CD. Rs = resolution. Adapted from [170] with permissions.

Figure 4

In situ layer‐by‐layer self‐assembly approach for the fabrication of a chiral metal‐organic framework (MOF) column. By cycling through treatments of Zn(CH₃CO₂)₂·2H₂O and 1‐HL solution, the chiral MOF column is generated at room temperature. The number of alternating cycles is used to determine layer thickness of the capillary wall. Adapted from [256] with permissions.

Figure 5

Partial‐filling technique applied to chiral separation of two enantiomers. (A) Illustration of the mechanisms observed with a selector plug with a lower mobility than the analyte. A racemic mixture of enantiomers enters the selector plug (1) where they are separated into two distinct bands (2). After passing through the selector plug, both enantiomers move with equal mobility allowing separate detection (3). (B) Illustration of the mechanisms observed with a stationary selector plug, with similar separation mechanics to schematic (A).