Enantioseparation of organometallic compounds by electromigration techniques.

Over time, chiral organometallic compounds have attracted great interest in several fields, with applications going across several disciplines of chemical, biological, medical, and material sciences. In the last decades, due to advancements in molecular design and computational modeling, the chemistry of chiral transition metal complexes had a remarkable flowering, with the development of new structures for applications in asymmetric synthesis, bioinorganic chemistry, and molecular recognition. In these fields, fast chiral analysis to determine the enantiomeric purity of organometallic structures prepared by asymmetric synthesis, and for high-throughput screening of analytes, catalysts, and reactions, is very important. Capillary electrophoresis and related techniques proved to be extremely versatile for chiral analysis, showing unsurpassed advantages compared to chromatography like low consumption of materials, production of limited amounts of waste, fast equilibration, and possibility to replace easily type and concentration of the chiral selector, among others. Furthermore, electromigration techniques may be useful to gain details about the stereochemistry of the enantiomers of new compounds and to study analyte-selector noncovalent interactions at molecular level. On this basis, this short review aims to provide the reader with a comprehensive view on the enantioseparation of organometallic compounds by electromigration techniques, examining the topic from the historical perspective and showing what was made in this field so far, an essential know-how for developing new and advanced applications in the next future.

Unravelling dispersion forces in liquid-phase enantioseparation. Part I: Impact of ferrocenyl versus phenyl groups.

BACKGROUND: Highly ordered chiral secondary structures as well as multiple (tunable) recognition sites are the keys to success of polysaccharide carbamate-based chiral selectors in enantioseparation science. Hydrogen bonds (HBs), dipole-dipole, and π-π interactions are classically considered the most frequent noncovalent interactions underlying enantioselective recognition with these chiral selectors. Very recently, halogen, chalcogen and π-hole bonds were also identified as interactions working in polysaccharide carbamate-based selectors to promote enantiomer distinction. On the contrary, the function of dispersion interactions in this field was not explored so far. RESULTS: The enantioseparation of chiral ferrocenes featuring chiral axis or chiral plane as stereogenic elements was performed by comparing five polysaccharide carbamate-based chiral columns, with the aim to identify enantioseparation outcomes that could be reasonably determined by dispersion forces, making available a reliable experimental data set for future theoretical studies to confirm the heuristic hypothesis. The effects of mobile phase polarity and temperature on the enantioseparation were considered, and potential recognition sites on analytes and selectors were evaluated by electrostatic potential (V) analysis and molecular dynamics (MD). In this first part, the enantioseparation of 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-bipyridine bearing two ferrocenylethynyl units linked to an axially chiral core was performed and compared to that of the analyte featuring the same structural motif with two phenyl groups in place of the ferrocenyl moieties. The results of this study showed the superiority of the ferrocenyl compared to the phenyl group, as a structural element favouring enantiodifferentiation. SIGNIFICANCE AND NOVELTY: Even if dispersion (London) forces have been envisaged acting in liquid-phase enantioseparations, focused studies to explore possible contributions of dispersion forces with polysaccharide carbamate-based selectors are practically missing. This study allowed us to collect experimental information that support the involvement of dispersion forces as contributors to liquid-phase enantioseparation, paving the way to a new picture in this field.

Enantioseparation of planar chiral ferrocenes on cellulose-based chiral stationary phases: Benzoate versus carbamate pendant groups.

In this study, the enantioseparation of 14 planar chiral ferrocenes containing halogen atoms, and methyl, iodoethynyl, phenyl, and 2-naphthyl groups, as substituents, was explored with a cellulose tris(4-methylbenzoate) (CMB)-based chiral column under multimodal elution conditions. n-Hexane/2-propanol (2-PrOH) 95:5 v/v, pure methanol (MeOH), and MeOH/water 90:10 v/v were used as mobile phases (MPs). With CMB, baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.24 to 1.77, whereas only three analytes could be enantioseparated with 1.14 ≤ α ≤ 1.51 on a cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC)-based column, used as a reference for comparison, under the same elution conditions. Pendant group-dependent reversal of the enantiomer elution order was observed in several cases by changing CMB to CDMPC. The impact of analyte and chiral stationary phase (CSP) structure, and MP polarity on the enantioseparation, was evaluated. The two cellulose-based CSPs featured by different pendant groups were also compared in terms of thermodynamics. For this purpose, enthalpy (ΔΔH°), entropy (ΔΔS°) and free energy (ΔΔG°) differences, isoenantioselective temperatures (Tiso ), and enthalpy/entropy ratios (Q), associated with the enantioseparations, were derived from van 't Hoff plots by using n-hexane/2-PrOH 95:5 v/v and methanol/water 90:10 v/v as MPs. With the aim to disclose the functions of the different substituents in mechanisms and noncovalent interactions underlying analyte-selector complex formation at molecular level, electrostatic potential (V) analysis and molecular dynamics simulations were used as computational techniques. On this basis, enantioseparations and related mechanisms were investigated by integrating theoretical and experimental data.

The Effect of Enantiomer Elution Order on the Determination of Minor Enantiomeric Impurity in Ketoprofen and Enantiomeric Purity Evaluation of Commercially Available Dexketoprofen Formulations.

In a recent study, opposite enantiomer elution order was observed for ketoprofen enantiomers on two amylose-phenylcarbamate-based chiral columns with the same chemical composition of the chiral selector but in one case with coated while in the other with an immobilized chiral selector. In the present study, the influence of this uncommon effect on method validation parameters for the determination of minor enantiomeric impurity in dexketoprofen was studied. The validated methods with two alternative elution orders for enantiomers were applied for the evaluation of enantiomeric impurity in six marketed dexketoprofen formulations from various vendors. In most of these formulations except one the content of enantiomeric impurity exceeded 0.1% (w/w).

The effect of temperature on the separation of enantiomers with coated and covalently immobilized polysaccharide-based chiral stationary phases.

This article describes our attempt to re-visit the role of temperature in the separation of enantiomers with polysaccharide-based chiral columns in high-performance liquid chromatography (HPLC). Rarely observed increased retention and separation factors with increasing temperature, as well as temperature dependent reversal of enantiomer elution order are reported for several arylpropionic acid derivatives. Chiral columns with coated and covalently immobilized chiral selectors were compared from the viewpoint of effect of temperature on analyte retention, enantiomer separation and enantiomer elution order. Thermodynamic parameters were calculated for analyte transfer from the liquid phase to the chiral stationary phase and the effect of temperature on chiral selectors was investigated by using differential scanning calorimetry (DSC). DSC results along with chromatographic studies indicate that polysaccharide-based chiral selectors undergo some kind of transition at elevated temperature that is not reversible in the thermodynamic sense of this term.