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.

Molecular Dynamics Simulations of Amylose- and Cellulose-Based Selectors and Related Enantioseparations in Liquid Phase Chromatography.

In the last few decades, theoretical and technical advancements in computer facilities and computational techniques have made molecular modeling a useful tool in liquid-phase enantioseparation science for exploring enantioselective recognition mechanisms underlying enantioseparations and for identifying selector-analyte noncovalent interactions that contribute to binding and recognition. Because of the dynamic nature of the chromatographic process, molecular dynamics (MD) simulations are particularly versatile in the visualization of the three-dimensional structure of analytes and selectors and in the unravelling of mechanisms at molecular levels. In this context, MD was also used to explore enantioseparation processes promoted by amylose and cellulose-based selectors, the most popular chiral selectors for liquid-phase enantioselective chromatography. This review presents a systematic analysis of the literature published in this field, with the aim of providing the reader with a comprehensive picture about the state of the art and what is still missing for modeling cellulose benzoates and the phenylcarbamates of amylose and cellulose and related enantioseparations with MD. Furthermore, advancements and outlooks, as well as drawbacks and pitfalls still affecting the applicability of MD in this field, are also discussed. The importance of integrating theoretical and experimental approaches is highlighted as an essential strategy for profiling mechanisms and noncovalent interaction patterns.

Sustainable Electropolymerization of Zingerone and Its C2 Symmetric Dimer for Amperometric Biosensor Films.

Polymeric permselective films are frequently used for amperometric biosensors to prevent electroactive interference present in the target matrix. Phenylenediamines are the most commonly used for the deposition of shielding polymeric films against interfering species; however, even phenolic monomers have been utilized in the creation of these films for microsensors and biosensors. The purpose of this paper is to evaluate the performances of electrosynthesized polymers, layered by means of constant potential amperometry (CPA), of naturally occurring compound zingerone (ZING) and its dimer dehydrozingerone (ZING DIM), which was obtained by straight oxidative coupling reaction. The polymers showed interesting shielding characteristics against the main interfering species, such as ascorbic acid (AA): actually, polyZING exhibited an AA shielding aptitude comprised between 77.6 and 99.6%, comparable to that obtained with PPD. Moreover, a marked capability of increased monitoring of hydrogen peroxide (HP), when data were compared with bare metal results, was observed. In particular, polyZING showed increases ranging between 55.6 and 85.6%. In the present work, the molecular structures of the obtained polymers have been theorized and docking analyses were performed to understand their peculiar characteristics better. The structures were docked using the Lamarckian genetic algorithm (LGA). Glutamate biosensors based on those polymers were built, and their performances were compared with biosensors based on PPD, which is the most widespread polymer for the construction of amperometric biosensors.

Enantioseparations of polyhalogenated 4,4'-bipyridines on polysaccharide-based chiral stationary phases and molecular dynamics simulations of selector-selectand interactions.

2'-(4-Pyridyl)- and 2'-(4-hydroxyphenyl)-TCIBPs (TCIBP = 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridyl) are chiral compounds that showed interesting inhibition activity against transthyretin fibrillation in vitro. We became interested in their enantioseparation since we noticed that the M-stereoisomer is more effective than the P-enantiomer. Based thereon, we recently reported the enantioseparation of 2'-substituted TCIBP derivatives with amylose-based chiral columns. Following this study, herein we describe the comparative enantioseparation of both 2'-(4-pyridyl)- and 2'-(4-hydroxyphenyl)-TCIBPs on four cellulose phenylcarbamate-based chiral columns aiming to explore the effect of the polymer backbone, as well as the nature and position of substituents on the side groups on the enantioseparability of these compounds. In the frame of this project, the impact of subtle variations of analyte and polysaccharide structures, and mobile phase (MP) polarity on retention and selectivity was evaluated. The effect of temperature on retention and selectivity was also considered, and overall thermodynamic parameters associated with the analyte adsorption onto the CSP surface were derived from van 't Hoff plots. Interesting cases of enantiomer elution order (EEO) reversal were observed. In particular, the EEO was shown to be dependent on polysaccharide backbone, the elution sequence of the two analytes being P-M and M-P on cellulose and amylose tris(3,5-dimethylphenylcarbamate), respectively. In this regard, a theoretical investigation based on molecular dynamics (MD) simulations was performed by using amylose and cellulose tris(3,5-dimethylphenylcarbamate) nonamers as virtual models of the polysaccharide-based selectors. This exploration at the molecular level shed light on the origin of the enantiodiscrimination processes.

Noncovalent interactions in high-performance liquid chromatography enantioseparations on polysaccharide-based chiral selectors.

Designed more than thirty years ago in order to improve and maximize the discrimination capability of native polysaccharides, cellulose- and amylose-based selectors have shown excellent and unequalled performances for the enantioseparation of chiral compounds. The successful story of these chiral selectors relies on a multi-site high-ordered chiral platform which is held up by intramolecular hydrogen bonds (HBs), and makes the polymer able to host and discriminate enantiomers. In this environment, both achiral and stereoselective intermolecular noncovalent interactions play a pivotal role, and HBs, halogen bonds (XBs), dipole-dipole, π-π stacking, steric repulsive, and van der Waals interactions underlie adsorption process and formation of transient diastereomeric assemblies between the polymer and the enantiomer pair. In the last decades, advances in computational chemistry and spectroscopic techniques have improved knowledge of noncovalent interactions, contributing to decode their functions in chemical systems. Significantly, over time the growing interplay between experimental and theoretical approaches has contributed to unravel intermolecular forces underlying selector-selectand association and to understand recognition patterns. On this basis, this review summarizes seminal and representative studies dealing with noncovalent interactions that function in HPLC enantioseparations promoted by cellulose benzoates and phenylcarbamates of amylose and cellulose. The importance of integrating theoretical and experimental approaches to profile mechanisms and interaction patterns is highlighted by discussing focused case studies. In particular, the advantageous utilization of electrostatic potential (V) analysis and molecular dynamics (MD) simulations in this field is evidenced. A systematic compilation of all published literature has not been attempted.

Halogen bond in high-performance liquid chromatography enantioseparations: Description, features and modelling.

Halogen bond (XB)-driven enantioseparations involve halogen-centred regions of electronic charge depletion (σ-hole) as electrophilic recognition sites. The knowledge in this field is still in its infancy. Indeed, although the influence of halogens on enantioseparation have been often considered, only recently the function of electrophilic halogens (Cl, Br, I) as enantioseparations 'drivers' has been demonstrated by our groups. Further to these studies, in this paper we focus on some unexplored issues. First, as XB-driven chiral recognition mechanisms are at an early stage of comprehension, a theoretical investigation based on a series of 32 molecular dynamic (MD) simulations was performed by using polyhalogenated 4,4'-bipyridines and polysaccharide-based polymers as ligands and receptors, respectively. Enantiomer elution orders (EEOs) were derived from calculations and the theoretical model accounted for some analyte- and chiral stationary phase (CSP)-dependent experimental EEO inversions. Then, the function of halogen-centred σ-holes in competitive systems, presenting also hydrogen bond (HB) centres as recognition sites, was considered. In this regard, Pirkle's enantioseparations of halogenated compounds performed on Whelk-O1 were theoretically re-examined and electrostatic potentials (EPs) associated with both σ-holes on halogens and HB centres were computed and compared. Then, the enantioseparation of halogenated 2-nitro-1-arylethanols was performed on cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) and the influence of halogen substituents on the chromatographic results was evaluated by correlating theoretical and experimental data.

Enantioseparation of fluorinated 3-arylthio-4,4'-bipyridines: Insights into chalcogen and π-hole bonds in high-performance liquid chromatography.

A chalcogen bond (ChB) is a σ-hole-based noncovalent interaction between a Lewis base and an electrophilic element of Group VI (O, S, Se, Te), which behaves as a Lewis acid. Recently, we demonstrated that halogen bond, the more familiar σ-hole-based interaction, is able to promote the enantioseparation of chiral compounds in HPLC environment. On this basis, an investigation to detect ChBs, functioning as stereoselective secondary interactions for HPLC enantioseparations, was started off and the results of this study are described herein. Our investigation also focused on the impact of the perfluorinated aromatic ring as a π-hole donor recognition site. For these purposes, seven atropisomeric fluorinated 3-arylthio-4,4'-bipyridines were designed, synthesized and used as potential ChB donors (ChBDs) with two cellulose-based chiral stationary phases (CSPs) containing carbonyl groups as ChB acceptors (ChBAs). In addition, one and two analogues lacking fluorine and sulphur, respectively, were prepared as terms of comparison. The design of the test analytes was computationally guided. In this regard, electrostatic potentials (EPs) associated with σ- and π-holes were computed and the atomic contributions to the sulphur EP maxima were derived using a molecular space partitioning in terms of Bader's atomic basins. This procedure is akin to the Bader-Gatti electron density source function (SF) decomposition, yet suitably extended to the EP field. For five 3-substituted-4,4'-bipyridines, thermodynamic parameters were derived from van't Hoff plots. Finally, the use of molecular dynamic (MD) simulation to model ChB in cellulose-analyte complexes was explored. Evidences that σ-hole and π-hole interactions can jointly drive HPLC enantioseparations through recognition sites generated by electronic charge depletion emerged from both experimental results and theoretical data.

Insights into halogen bond-driven enantioseparations.

Although the halogen bond (XB) has been so far mainly studied in silico and in the solid state, its potential impact in solution is yet to be fully understood. In this study, we describe the first systematic investigation on the halogen bond in solvated environment by high-performance liquid chromatography (HPLC). Thirty three atropisomeric polyhalogenated-4,4'-bipyridines (HBipys), containing Cl, Br and I as substituents, were selected and used as potential XB donors (XBDs) on two cellulose-based chiral stationary phases (CSPs) containing potential XB acceptors (XBAs). The impact of the halogens on the enantiodiscrimination mechanism was investigated and iodine showed a pivotal role on the enantioseparation in non-polar medium. Electrostatic potentials (EPs) were computed to understand the electrostatic component of CSP-analyte interaction. Moreover, van't Hoff studies for ten HBipys were performed and the thermodynamic parameters governing the halogen-dependent enantioseparations are discussed. Finally, a molecular dynamic (MD) simulation is proposed to model halogen bond in polysaccharide-analyte complexes by inclusion of a charged extra point to represent the positive 'σ-hole' on the halogen atom. On the basis of both experimental results and theoretical data, we have profiled the halogen bond as a chemo-, regio-, site- and stereoselective interaction which can work in HPLC environment besides other known interactions based on the complementarity between selector and selectand.