Compared to any other analytical technique, the main advantage of using capillary electrophoresis (CE) for studying enantioselective recognition mechanisms in intermolecular interaction is its higher sensitivity to detect weak noncovalent interactions. Furthermore, nuclear magnetic resonance (NMR) and molecular modeling proved to be very effective to complement CE for mechanistic purposes. On the other hand, multiple factors may impact selector-selectand geometries and binding energies affecting the overall enantiorecognition process. In this regard, the validation of computational tools to verify the reliability of proposed models is still a critical issue, and suitable experimental data sets are necessary for this purpose. In this study, we combined CE, NMR spectroscopy and molecular modeling with the aim of investigating the molecular bases of the enantioseparations of metofoline (MF) with β-cyclodextrin (CD), γ-CD, and heptakis(2,3-di-O-acetyl)-β-CD (HDA-β-CD). Based on this strategy and focusing on the reversal of migration order observed by using γ-CD [(R)-(S)] in place of β-CD [(S)-(R)], good agreement between experimental and theoretical data was obtained. The absolute configuration of MF enantiomers was assigned by comparison of experimental and computed chiroptical spectra.

In the last decade, the contribution of halogen bond (HaB) in liquid phase enantioseparation of halogenated analytes was demonstrated by using polysaccharide-based chiral stationary phases (CSPs) and n-hexane-containing mixtures as mobile phases. On the other hand, it was also shown that polar organic solvents (POSs) like methanol and ethanol weaken or suppress the contribution of HaB to binding and recognition, whereas hydrophobic mechanisms become dominant by using alcohol-based mobile phases. Although some recent studies demonstrated that HaB-based systems exhibit an improved water resistance compared to the analogous hydrogen bond (HB)-based systems, currently no information is available in the literature about the effect of using aqueous organic mobile phases on the enantioseparations of halogenated compounds driven by HaB in normal phase mode. With the aim to gain information about this topic, we investigated the effect of adding water to the mobile phase on the enantioseparation of four hexahalogenated 4,4’-bipyridines by using amylose and cellulose tris(3,5-dimethylphenylcarbamate)-based chiral columns. As a result, chromatographic behaviours dependent on the distinctive halogen atom featuring the analytes were observed. The study confirmed that, when polar organic solvents and aqueous organic mixtures were used as mobile phase, both iodine-dependent and hydrophobic noncovalent interactions contributed to the enantioseparation of iodinated 4,4’-bipyridines.

Computational chemistry has evolved into a powerful and increasingly reliable tool for elucidating chemical phenomena and predicting molecular properties. Nevertheless, accurately modeling enantioselective recognition remains one of the most demanding challenges in separation science. The fundamental obstacle lies in the exceptionally small free-energy differences that distinguish competing enantioselective pathways, typically ranging from only 0.01 to 1 kcal·mol-1. Such subtle energetic variations push current theoretical approaches to their limits, making experimental validation indispensable for assessing and refining computational models. Considering this, we investigated the enantioselective recognition of erythro-mefloquine (MQ) by β-cyclodextrin (β-CD) and heptakis(2,3-di-O-acetyl)-β-cyclodextrin (HDA-β-CD) through an integrated strategy combining capillary electrophoresis (CE), nuclear magnetic resonance (NMR) spectroscopy, and quantum mechanics (QM)-based molecular modeling. This multidisciplinary approach serves a dual purpose: first, to critically evaluate the consistency and complementarity of results obtained from experimental and theoretical methodologies; second, to identify possible existing limitations in our understanding of the molecular mechanisms and noncovalent interactions governing enantioselective recognition. The long-term goal of this work is to establish a robust and systematic framework that integrates orthogonal experimental and computational techniques, providing a more reliable protocol for explaining, validating, and ultimately predicting enantioselective recognition processes.

Background The detection of dispersion forces in enantioselective liquid chromatography (LC) is rather challenging because selectand, selector and mobile phase molecules may participate in multiple types of intra- and intermolecular noncovalent interactions of different strength. In this frame, the LC system can be used as a tool to evaluate the impact of changing the structures of selectand, chiral selector and separation medium, through fast analytical screenings. In the last few years, we studied the enantioseparations of chiral compounds containing the ethynylferrocene moiety as a test probe to identify dispersion forces in LC by using amylose carbamate-based chiral stationary phases (CSPs). Results The results of the study have been reported in a series of three papers. In Part II, we confirmed that the high affinity observed for the second eluted (Rp)-enantiomer of the 1-(iodoethynyl)-3-phenylferrocene toward amylose phenylcarbamate-based selectors could be reasonably based on dispersion forces. In the present Part III of the series, we focus on the impact of changing the 3-aryl substituent of 1-(iodoethynyl)-3-arylferrocenes on the enantioseparation, considering the 1-(iodoethynyl)-3-phenylferrocene as reference for comparison. On this basis, the enantioseparations of seven planar chiral ferrocenes were performed and compared by using amylose-based CSPs. n-Hexane-based mixtures, polar organic solvents and aqueous organic mixtures were used with the aim of evaluating the impact of mobile phases of different polarity on the enantioseparations. The results of the chromatographic analyses confirmed the high and unique affinity of the second eluted (Rp)-enantiomer of the 1-(iodoethynyl)-3-(4-t-butyl)phenylferrocene toward the amylose-based CSPs. Significance By using 1-(iodoethynyl)-3-arylferrocenes as test probes, this study confirmed that dispersion forces may turn steric repulsion into attraction with a strength depending on the structure of the 3-aryl group and on mobile phase polarizability. Furthermore, the possibility to deconvolute hydrophobic and dispersion forces in aqueous mobile phases was also demonstrated.

In the last decade, by integrating experimental and computational analyses, it was demonstrated that halogen bond (HaB) may contribute to binding and enantiorecognition mechanisms underlying the HPLC enantioseparation of halogenated chiral analytes by using cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC)-based chiral columns and n-hexane-based mixtures as mobile phases. When used as a pivotal component of the mobile phase in supercritical fluid chromatography (SFC), carbon dioxide is often considered as an n-hexane-like nonpolar solvent because of its low dielectric constant and zero molecular dipole moment. On the other hand, carbon dioxide may also serve as hydrogen bond (HB) and HaB acceptor due to the presence of nonbonding electrons on the two oxygen atoms, interacting with analyte enantiomers, chiral selectors, and co-solvents. On this basis, we report herein the results of a study aiming at evaluating the impact of using carbon dioxide in SFC in place of n-hexane in HPLC on halogen-dependent enantioseparations by using atropisomeric halogenated 4,4 '-bipyridines as analytes and Lux Cellulose-1 as CDMPC-based chiral column. The experimental investigation was complemented by a computational study performed using (a) quantum mechanics (QM) calculations to map and quantify noncovalent interactions possibly underlying the contact of the analytes with carbon dioxide and with the distinctive pendant groups of the CDMPC and (b) molecular dynamics (MD) simulations to visualize noncovalent interactions acting in the analyte 1/CDMPC chromatographic system in different media. The use of MD simulations to model enantioseparations performed in carbon dioxide-based media was not reported in the literature so far.

In the last decade, biological processes involving halogen bond (HaB) as a leading interaction attracted great interest. However, although bound iodine atoms are considered powerful HaB donors, few iodinated new drugs were reported so far. Recently, iodinated 4,4'-bipyridines showed interesting properties as HaB donors in solution and in the solid state. In this paper, a study on the inhibition activity of seven halogenated 4,4'-bipyridines against malignant melanoma (MM) cell proliferation is described. Explorative dose/response proliferation assays were first performed with three 4,4'-bipyridines by using four MM cell lines and the normal BJ fibroblast cell line as control. Among them, the A375 MM cell line was the most sensitive, as determined by MTT assays, which was selected to evaluate the antiproliferative activity of all 4,4'-bipyridines. Significantly, the presence of an electrophilic iodine impacted the biological activity of the corresponding compounds. The 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridine showed significant antiproliferation activity against the A375 cell line, and lower toxicity on BJ fibroblasts. Through in silico studies, the stereoelectronic features of possible sites determining the bioactivity were explored. These results pave the way for the utilization of iodinated 4,4'-bipyridines as templates to design new promising HaB-enabled inhibitors of MM cell proliferation. The antiproliferative activity of seven substituted 3,3',5,5'-tetrachloro-4,4'-bipyridines was evaluated against malignant melanoma (MM) cell lines. The 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridine showed high activity on A375, and very low toxicity on control BJ fibroblasts. In silico studies confirmed the highest electrophilic properties for the iodine atoms contained in the most active compounds against MM cell line proliferation. image

N-(3-hydroxyacyl)glycines are compounds of remarkable interest due to their biogenic origin and bioactivity and as precursors of the corresponding 3-acyloxy derivatives which represent an important class of bioactive products of bacterial origin. Commendamide [N-(3-hydroxypalmitoyl)glycine] (1) is a gut microbiota-derived bioactive metabolite that is structurally like endogenous long-chain N-acyl-amino acids belonging to the endocannabinoidome, a complex lipid signaling system involved in several aspects of mammalian physiology and pathology. Thanks to this structural similarity, this compound and its analogues, like the N-(3-hydroxymyristoyl)glycine 2, exert a remarkable bioactivity in mammals, for instance, through activation of G-protein-coupled receptors (GPCRs). N-(3-Hydroxyacyl)glycines are chiral and the availability of their pure enantiomers may bring light to possible enantioselective pathways within the biological processes which these compounds are involved in. A sustainable synthesis of rac-1 and its analogues was recently reported, but asymmetric synthesis and enantioseparation methods to access their pure or enriched enantiomers were not reported so far. In this paper, we report the first direct separation of commendamide enantiomers by using enantioselective high-performance liquid chromatography (HPLC) with polysaccharide-based chiral columns, aqueous-organic mixtures as mobile phases and either electrospray ionization mass spectrometry (ESI-MS) or UV detection. Optimal enantioseparation was obtained by using an amylose tris(3,5-dimethylphenylcarbamate)-based chiral column and acetonitrile/water 60:40 (v/v) (0.1 % acetic acid) as mobile phase. By adopting the same method, the enantioseparation of the analogue 2 was also performed. The molecular bases of the higher retention and selectivity observed for the N-(3-hydroxyacyl)glycine 1 compared to the analogue 2 were explored by computational analysis.

Chiral organometallic compounds and metal complexes, and more recently metal clusters, have attracted great interest for applications in chemical, biological, medical, and material sciences. In these fields, liquid chromatography has been widely used for fast chiral analysis to determine the enantiomeric purity of metal-containing chiral compounds prepared by asymmetric synthesis, for quality control of commercial chiral metal catalysts, for accessing enantioenriched or pure enantiomers of metal complexes for various applications, and often as test probe analytes for screening the enantioseparation capability of newly developed chiral columns and chromatographic systems. With the aim to show what was done in this field as a useful guide for new applications, in this review the evolution of methods and approaches used to separate the enantiomers of chiral metal-containing compounds is described, showing how this field have been changed over time, from the 1970s until most recent studies. For this purpose, representative applications of enantioselective liquid chromatography for the enantioseparation of chiral organometallic compounds and metal complexes will be presented and discussed, indicating chiral columns, mobile phases, and chromatographic conditions which have been used to obtain successful enantioseparations in this field.

Background: In the first part of our study on possible contribution of dispersion forces in liquid-phase enantioseparations, the enantioseparation of the axially chiral 3,3 '-dibromo-5,5 '-bis-ferrocenylethynyl-4,4 '-bipyridine '-dibromo-5,5 '-bis-ferrocenylethynyl-4,4 '-bipyridine with an amylose tris (3,5-dimethylphenylcarbamate)-based chiral column appeared reasonably consistent with a picture of the enantioselective recognition based on the interplay between hydrogen bond (HB), it-it stacking and dispersion interactions. Results: In the second part of this study, we evaluated the impact of analyte and chiral stationary phase (CSP) structure, mobile phase and temperature on the enantioseparations of planar chiral 1-(iodoethynyl)-3 arylferrocenes (3-aryl = phenyl, 2-naphthyl, 4-methylphenyl, 4-t-butylphenyl) t-butylphenyl) with polysaccharide-based chiral columns. The main aim of the present study was to understand the molecular bases of the high affinity observed for the second eluted (Rp)-enantiomer R p )-enantiomer of some of these analytes toward amylose phenylcarbamate-based selectors when methanol-containing mixtures were used as mobile phases. Significantly, higher affinity of the second eluted (Rp)-enantiomer R p )-enantiomer toward the selector could be also observed for the sterically hindered 1-(iodoethynyl)-3-(4-t-butylphenyl)ferrocene t-butylphenyl)ferrocene (k2 k 2 = 6.21) compared to the smaller 1-(iodoethynyl)-3-(4-methylphenyl) ferrocenes (k2 k 2 = 4.07) as 2.5% methanol was added to the n-hexane-based mobile phase. Significance: This study reasonably showed that the contribution of dispersion forces may explain the unusually large retention of the second eluted enantiomers observed for the enantioseparation of some planar chiral 1(iodoethynyl)-3-arylferrocenes with amylose-based selectors. Based on the obtained results, we can conclude that in liquid-phase enantioseparation steric repulsion can be turned into attraction depending on the features of analyte, selector, and mobile phase.

Hydrogen/deuterium (H/D) isotope effects are not unusual in chromatography and such phenomena have been observed in both gas- and liquid-phase separations. Despite the numerous reports on this topic, the understanding of mechanisms and the underlying noncovalent interactions at play remains rather challenging. In our recent study, we reported baseline separation of isotopologoues of some amphetamine (AMP) derivatives on achiral and polysaccharide-based chiral columns, as well as some correlations between the degree of separation of enantiomers and isotopologues on (the same) polysaccharide-based chiral column(s). Following our previous findings on isotope effects in high-performance liquid chromatography, we report herein a comparative study on the isotope effects observed with AMP and methamphetamine (MET). The impact of some pivotal factors such as the number of deuterium atoms part of AMP isotopologues, the structure of its isotopomers, the chemical structure of the achiral and chiral stationary phases used in this study, and the use of methanol- vs acetonitrile-containing mobile phases on the isotope effects was examined and discussed. Quantitative correlations between the observed isotope effects and the enantioselectivity of the chiral columns used are also shortly discussed. Furthermore, considering the chromatographic results as benchmark experimental data, we attempted to elucidate the molecular bases of the observed phenomena using quantum mechanics calculations.

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.

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 (ΔΔ H °), entropy (ΔΔ S °) and free energy (ΔΔ G °) differences, isoenantioselective temperatures ( T iso ), 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.

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 & pi;-& pi; interactions are classically considered the most frequent noncovalent interactions underlying enantioselective recognition with these chiral selectors. Very recently, halogen, chalcogen and & pi;-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 & PRIME;-dibromo-5,5 & PRIME;-bis-ferrocenylethynyl-4,4 & PRIME;-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.

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.

In the last decade, the availability of new and versatile synthetic strategies for the preparation of substituted 4,4’-bipyridyl derivatives based on chemo- and regioselective functionalization of the 4,4’-bipyridine core has encouraged studies for exploring the bioactivity of these compounds in the fields of drug discovery and medicinal chemistry. In substituted 4,4’-bipyridines, chirality may emerge from restricted rotation induced by sterically hindered atoms or functional groups located around the 4,4’-biaryl bond (chiral axis). The first atropisomeric substituted 4,4’-bipyridine was prepared in 2008, and no asymmetric synthesis to produce pure atropisomers of chiral 4,4’-bipyridine derivatives has been available so far. Thus, in the last few years, our groups developed methods to separate atropisomers of a wide series of 4,4’-derivatives by high-performance liquid chromatography (HPLC) using polysaccharide-based chiral stationary phases (CSPs). In the frame of our interest in this field, we reported herein the synthesis of two new chiral carboxylic acids containing an axially chiral 4,4’-bipyridyl unit as source of chirality, and their HPLC enantioseparation on polysaccharide-based CSPs. In particular, the impact of analyte and CSP structures on the enantioseparation outcomes as well as mechanisms and noncovalent interactions underlying the enantioseparation were explored by using electrostatic potential analysis and molecular dynamics (MD) simulations.

Planar chiral ferrocenes are well-known compounds that have attracted interest for application in synthesis, catalysis, material science, and medicinal chemistry for several decades. In spite of the fact that asymmetric synthesis procedures for obtaining enantiomerically enriched ferrocenes are available, sometimes, the accessible enantiomeric excess of the chiral products is unsatisfactory. In such cases and for resolution of racemic planar chiral ferrocenes, enantioselective high-performance liquid chromatography (HPLC) on polysaccharide-based chiral stationary phases (CSPs) has been used in quite a few literature articles. However, although moderate/high enantioselectivities have been obtained for planar chiral ferrocenes bearing polar substituents, the enantioseparation of derivatives containing halogens, or exclusively alkyl groups, remains rather challenging. In this study, the enantioseparation of ten planar chiral 1,2- and 1,3-disubstituted ferrocenes was explored by using five polysaccharide-based CSPs under multimodal elution conditions. Baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.20 to 2.92. The presence of π-extended systems in the analyte structure was shown to impact affinity of the most retained enantiomer toward amylose-based selectors, observing retention times higher than 80 min with methanol-containing mobile phases (MPs). Electrostatic potential (V) analysis and molecular dynamics (MD) simulations were used in order to study interaction modes at the molecular level.

In the last few years, chiral 4,4′-bipyridine derivatives have been developed for different applications in catalysis, enantioseparation science, supramolecular and theoretical chemistry by modulating the activity of the molecular system through the introduction of specific substituents in the heteroaromatic scaffold. More recently, the biological activity of 2′-substituted-3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridines has been explored in the field of transthyretin (TTR) fibrillogenesis inhibition, and the anticancer cytotoxicity of some derivatives is currently under systematic investigation. In this frame, the high-performance liquid chromatography (HPLC) enantioseparation of four atropisomeric 2,2′-disubstituted-4,4′-bipyridines (R, R’ = Ar, I), which contain multiple interaction sites, such as hydrogen bonding (HB) donors and acceptors, halogen bond (XB) donors, and π-extended electronic clouds, was explored by using n-hexane (Hex)/2-propanol (2-PrOH) 90:10 v/v as a mobile phase (MP), and eight chiral columns with coated and immobilized amylose- and cellulose-based selectors. The impact of subtle structural variations of analytes and selectors on their mutual intermolecular interactivity was evaluated in terms of retention (k) and selectivity (α) factors. On this basis, chromatographic analysis based on systematic screening of analytes and selectors was integrated with electrostatic potential (V) analysis and molecular dynamics (MD) simulations as computational techniques. The effect of temperature on retention, selectivity, and enantiomer elution order (EEO) of the analytes with coated and immobilized amylose tris(3,5-dimethylphenylcarbamate) was also considered by comparing the variation of the thermodynamic profile associated with each enantioseparation. Chromatographic responses proved to be strictly dependent on specific regions within the analyte, and functions of different interactions sites of the analytes as the structure of the chiral selector changes were significantly disclosed.

Planar chiral halogenated ferrocenes have come in useful as synthetic intermediates over the years, allowing for the preparation of functionalized derivatives for catalysis, material science, optoelectronics, and medicinal chemistry. Despite their chemical interest, few halogenated planar chiral ferrocenes have been prepared in enantiopure form by asymmetric synthesis so far. Enantioselective HPLC on polysaccharide-based chiral stationary phases (CSPs) has been used for resolving planar chiral ferrocenes making both enantiomers available. However, the enantioseparation of derivatives containing halogens or alkyl groups exclusively remains rather challenging. Given this context, in this study the enantioseparation of eleven dihalogenated planar chiral ferrocenes was systematically explored by using five polysaccharide-based CSPs under multimodal elution conditions. Baseline enantioseparations were achieved for nine analytes with separation factors (alpha) ranging from 1.15 to 1.66. Thermodynamic quantities associated with the enantioseparations were derived from van't Hoff plots, and for 1-halo-2-(iodoethynyl)ferrocenes (1-halogen = F, Cl, Br) halogen-dependent thermodynamic profiles were identified on a cellulose tris(3,5-dimethylphenylcarbamate)-based column. The impact of CSP structure and mobile phase (MP) polarity on the enantioseparation was evaluated. In addition, with the aim to unravel the functions of halogen substituents in mechanisms and noncovalent interactions underlying selector-selectand complex formation at molecular level, local electron charge density of specific molecular regions of the interacting partners were evaluated in terms of calculated electrostatic potential (V) and related source function (SF) contributions. On this basis, the impact of halogen type and position on the enantioseparation was investigated by correlating theoretical and experimental data. (C) 2022 Elsevier B.V. All rights reserved.

Despite the increasing number of applications based on halogen bond (XB), asymmetric catalysis purely based on such supramolecular interactions still remains a huge challenge. The first step toward its development is the design of appropriate XB chiral donor molecules with good catalytic properties. In this context, we report the synthesis of a series of iodinated compounds based on the triazole or triazolium ring and possessing the planar chirality of ferrocene. Their XB donor property was attested by X-ray diffraction analysis, showing short I...N and I....F interactions in the triazole-based derivatives and in the tetrafluoroborate salt of a idodotriazolium, respectively. The potential of these compounds to act as XB-based catalysts was demonstrated in the aza-Diels-Alder reaction involving an imine and a diene. Whereas triazole-based derivatives were inactive in this reaction, the triflate salts of iodotriazoliums delivered the expected cycloadduct with high yield.