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In the last decade, planar chiral ferrocenes have attracted a growing interest in several fields, particularly in asymmetric catalysis, medicinal chemistry, chiroptical spectroscopy and electrochemistry. In this frame, the access to pure or enriched enantiomers of planar chiral ferrocenes has become essential, relying on the availability of efficient asymmetric synthesis procedures and enantioseparation methods. Despite this, in enantioseparation science, these metallocenes were not comprehensively explored, and very few systematic analytical studies were reported in this field so far. On the other hand, enantioselective high-performance liquid chromatography has been frequently used by organic and organometallic chemists in order to measure the enantiomeric purity of planar chiral ferrocenes prepared by asymmetric synthesis. On these bases, this review aims to provide the reader with a comprehensive overview on the enantioseparation of planar chiral ferrocenes by discussing liquid-phase enantioseparation methods developed over time, integrating this main topic with the most relevant aspects of ferrocene chemistry. Thus, the main structural features of ferrocenes and the methods to model this class of metallocenes will be briefly summarized. In addition, planar chiral ferrocenes of applicative interest as well as the limits of asymmetric synthesis for the preparation of some classes of planar chiral ferrocenes will also be discussed with the aim to orient analytical scientists towards 'hot topics' and issues which are still open for accessing enantiomers of ferrocenes featured by planar chirality.

It is not a coincidence that both chirality and noncovalent interactions are ubiquitous in nature and synthetic molecular systems. Noncovalent interactivity between chiral molecules underlies enantioselective recognition as a fundamental phenomenon regulating life and human activities. Thus, noncovalent interactions represent the narrative thread of a fascinating story which goes across several disciplines of medical, chemical, physical, biological, and other natural sciences. This review has been conceived with the awareness that a modern attitude toward molecular chirality and its consequences needs to be founded on multidisciplinary approaches to disclose the molecular basis of essential enantioselective phenomena in the domain of chemical, physical, and life sciences. With the primary aim of discussing this topic in an integrated way, a comprehensive pool of rational and systematic multidisciplinary information is provided, which concerns the fundamentals of chirality, a description of noncovalent interactions, and their implications in enantioselective processes occurring in different contexts. A specific focus is devoted to enantioselection in chromatography and electromigration techniques because of their unique feature as "multistep" processes. A second motivation for writing this review is to make a clear statement about the state of the art, the tools we have at our disposal, and what is still missing to fully understand the mechanisms underlying enantioselective recognition.

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 (alfa) ranging from 1.20 to 2.92. The presence of pai-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 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 (T

The σ-hole interaction represents a noncovalent interaction between atoms with σ-hole(s) on their surface (such as halogens and chalcogens) and negative sites. Over the last decade, significant developments have emerged in applications where the σ-hole interaction was demonstrated to play a key role in the control over chirality. The aim of this review is to give a comprehensive overview of the current advancements in the use of σ-hole interactions in stereoselective processes, such as formation of chiral supramolecular assemblies, separation of enantiomers, enantioselective complexation and asymmetric catalysis.

Bilateral Agreement Italy/Georgia, Consiglio Nazionale delle Ricerche/Shota Rustaveli National Science Foundation CNR/SRNSF (years 2021-2022), Project PELUSO/JIBUTI Design, preparation and applications of new halogenated polysaccharide-based chiral stationary phases for liquid-phase separation of enantiomers

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.

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 (?) 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.

In capillary electrophoresis an enantioseparation of daclatasvir (DCV) was observed in case of heptakis(2,6-di-O-methyl)-beta-CD, heptakis(2-O-methyl)-beta-CD and beta-CD, while two peaks with a plateau were noted for heptakis(2,3,6-tri-O-methyl)-beta-CD and heptakis(2,3-di-O-methyl)-beta-CD indicating a slow equilibrium. Heptakis(6-O-methyl)-beta-CD and heptakis(3-O-methyl)-beta-CD yielded broad peaks. Nuclear magnetic resonance experiments including nuclear Overhauser effect-based techniques revealed inclusion complex formation for all CDs with the biphenyl ring of DCV within the cavity and the valine-pyrrolidine moieties protruding from the torus. However, in case of heptakis(2,6-di-O-methyl)-beta-CD, heptakis(2-O-methyl)-beta-CD and beta-CD higher order structures with 1:3 stoichiometry were concluded, where the valine moieties enter additional CD molecules via the secondary side. Heptakis(2,3,6-tri-O-methyl)-beta-CD and heptakis(2,3-di-O-methyl)-beta-CD yielded primarily 1:1 complexes. Higher order complexes between DCV and heptakis(2,6-di-O-methyl)-beta-CD were corroborated by mass spectrometry. Complex stoichiometry was not the reason for the slow equilibrium yielding the plateau observed in capillary electrophoresis, but structural characteristics of the CDs especially complete methylation of the secondary rim.

Liquid-phase enantioseparations have been fruitfully applied in several fields of science. Various applications along with technical and theoretical advancements contributed to increase significantly the knowledge in this area. Nowadays, chromatographic techniques, in particular HPLC on chiral stationary phase, are considered as mature technologies. In the last thirty years, CE has been also recognized as one of the most versatile technique for analytical scale separation of enantiomers. Despite the huge number of papers published in these fields, understanding mechanistic details of the stereoselective interaction between selector and selectand is still an open issue, in particular for high-molecular weight chiral selectors like polysaccharide derivatives. With the ever growing improvement of computer facilities, hardware and software, computational techniques have become a basic tool in enantioseparation science. In this field, molecular docking and dynamics simulations proved to be extremely adaptable to model and visualize at molecular level the spatial proximity of interacting molecules in order to predict retention, selectivity, enantiomer elution order, and profile noncovalent interactions patterns underlying the recognition process. On this basis, topics and trends in using docking and molecular dynamics as theoretical complement of experimental LC and CE chiral separations are described herein. The basic concepts of these computational strategies and seminal studies performed over time are presented, with a specific focus on literature published between 2015 and November 2018. A systematic compilation of all published literature has not been attempted.

Cyclodextrins (CD) are cyclic oligosaccharides consisting of ?-D-glucopyranosyl units linked through 1,4-linkages, which are obtained from enzymatic degradation of starch. The co-existence of hydrophilic and hydrophobic regions in the same structure makes these macrocycles extremely versatile as complexing host with application in food, cosmetics, environmental, agriculture, textile, pharmaceutical and chemical industries. Due to their inherent chirality, CDs have been also successfully used as chiral selectors in enantioseparation science, in particular for capillary electrophoresis (CE) enantioseparations. In the last decades, multidisciplinary approaches based on CE, NMR spectroscopy, X-ray crystallography, microcalorimetry, and molecular modeling have shed light on some aspects of recognition mechanisms underlying enantiodiscrimination. With the ever growing improvement of computer facilities, hardware and software, computational techniques have become a useful tool to model at molecular level the dynamics of diastereomeric associate formation to sample low-energy conformations, the binding energies between the enantiomer and the CD, and to profile noncovalent interactions contributing to the stability of CD/enantiomer association. On this basis, the aim of this review is to provide the reader with a critical overview on the applications of CDs in CE. In particular, the contemporary theory of the electrophoretic technique and the main structural features of CDs are described, with a specific focus on techniques, methods and approaches to model CE enantioseparations promoted by native and substituted CDs. A systematic compilation of all published literature has not been attempted.

International audience; 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.

Workshop "Enantioselective Chromatography and Electromigration Techniques: Theory, Mechanisms, and Applications"

Bridged polycyclic frameworks represent a unique tool to form curved units; the bicyclo[2.2.1]hepta-2,5-diene system is widely exploited to design and induce concave topologies. In particular, bridged benzocyclotrimers (BCTs) are characterized by a flat aromatic base decorated with bridged polycyclic motifs, which provide the suitable curvature underlying the concave-convex topology. In the 1960s, these molecules attracted interest for their own chemical and physical properties. Later, the improvements in synthetic procedures to produce bridged BCTs have paved the way for their utilization to design and prepare molecular containers, bowls, cages, and baskets that are able to accommodate target molecules, recognize them, and modulate their functions. In this frame, we aim to describe the historical evolution of the concept, from the first bridged BCTs explored to confirm the existence of strained alkynes, and the phenomenon of bond alternation (Mills-Nixon hypothesis), to the most recent gated molecular baskets developed as dynamic synthetic receptors for molecular delivery. The main synthetic approaches which have been used to perform cyclotrimerization of bridged polycyclic alkenes, and related mechanisms, are also examined and discussed, with a specific focus on the syn/anti stereoselectivity issue and its consequences at a mechanistic level. The present review covers literature contributions published until mid 2021.

Liquid-phase chromatography on chiral stationary phase is still the most popular and versatile technique to separate enantiomers, which is based on the ability of a chiral selector (CS) to recognize the enantiomers of a chiral compound in a solvating medium. The knowledge of the molecular bases of the enantiodiscrimination process is a basic requirement to approach rationally the enantioseparation task. Indeed, analyte, CS, and mobile phase (MP) being the pivotal components of the chromatographic system, their properties, functions and mutual noncovalent interactions determine the enantioseparation outcome. In the last few decades, focused computational methods and techniques have been integrating experimental data and applying for the comprehension of the enantiorecognition phenomenon at molecular level. In this context, for understanding of molecular mechanisms of chiral recognition in separation of enantiomers, we propose a computational procedure based on conformational and electrostatic potential (V) analysis of both analyte and selector. First, low-energy conformers of the analyte were identified by conformational search, which occurring potentially on the selector surface. Then, local electron charge density of specific molecular regions of the interacting partners were inspected in terms of calculated V. This approach was used to explore at molecular level the enantioseparation mechanism of 2-(benzylsulfinyl)benzamide on cellulose-based CSs. By correlating calculated properties with experimental chromatographic parameters available in the literature, the structural landscape of the analyte and CSs in the enantiodiscrimination event and the differences between potential competing sites were profiled. A conformational transition of analyte structure on the CS surface was found to originate the exceptional enantioseparation of the 2-(benzylsulfinyl)benzamide (α > 100). Importantly, the proposed computational analysis provides a rationale of why and how the analytical separation occurs.

The 3,3&prime, 5,5&prime, tetrachloro-2-iodo-4,4&prime, bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3&prime, tetrachloro-2-iodo-2&prime, substituted-4,4&prime, bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2&prime, substituent. The corresponding racemates, along with other five chiral 4,4&prime, bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4&prime, bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3&prime, tetrachloro-2&prime, (4-hydroxyphenyl)-2-iodo-4,4&prime, bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4&prime, bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4&prime, bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

International audience; The halogen bond (XB) is a noncovalent interaction involving a halogen acting as electrophile and a Lewis base. In the last decades XB has found practical application in several fields. Nevertheless, despite the pivotal role of noncovalent interactions in separation science, investigations of XB in this field are still in their infancy, and so far a limited number of studies focusing on solid phase extraction, liquid-liquid microextraction, liquid-phase chromatography, and gas chromatography separation have been published. In addition, in the last few years, our groups have been systematically studying the potentiality of XB for HPLC enantioseparations. On this basis, in the present paper up-to-date results emerging from focused experiments and theoretical analyses performed by our laboratories are integrated with a descriptive presentation of XB features and the few studies published until now in separation science. Then, the aim of this article is to provide a comprehensive and critical discussion of the topic, and account for some still open issues in the application of XB to separate chemical mixtures.

International audience; The chromatographic performances of four coated and immobilized amylose phenylcarbamate-based chiral columns were evaluated and compared under normal phase (NP) elution conditions by using chiral 4,4'-bipyri-dine derivatives as analytes. n-Hexane/2-propanol 90:10 and n-hexane/2-propanol/methanol 90:5:5 mixtures were employed as mobile phases (MPs), and the effect of adding methanol in the MP on retention and selectivity was considered. The effect of temperature on retention and selectivity was also evaluated, and overall thermo-dynamic 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, which are dependent on the nature of polar modifier, analyte structure, column-type, and temperature, were observed. The impact of substitution pattern and electronic properties of analytes and selectors on the separation behaviour was investigated by correlating chro-matographic parameters and molecular properties determined by using density functional theory (DFT) calculations. Both coated and immobilized amylose tris(3,5-dimethylphenylcarbamate) columns allowed for the baseline enantioseparation (2.0 ≤ R S ≤ 4.9) of all 4,4'-bipyridines considered in this study. These results appear particularly useful because both enantiomers of these 4,4'-bipyridine derivatives are currently under investigation as new inhibitors of transthyretin fibrillogenesis, a biochemical phenomenon which is implicated to cause amyloid diseases.

International audience; 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.

International audience; Asymmetric catalysis based on halogen and chalcogen bonds (XB and ChB) is in its infancy and the search for new chiral XB and ChB donors represents a crucial step towards its development. In this context, we designed and prepared new motifs containing three key substructures, namely regions of electron charge density depletion centred on iodine and chalcogen atoms, the ethynyl functionality and the planar chiral ferrocenyl platform. Nine ferrocenyl iodoalkynes were prepared as pure enantiomers by asymmetric synthesis. The XB donor property of racemic ferrocenyl iodoalkynes was demonstrated in solution in two benchmark reactions: the Ritter reaction and the benzoxazole synthesis from thioamides. In contrast, the ferrocenyl chalcogenoalkynes were far less active in these reactions. The potential of racemic and enantiopure ferrocenyl iodoalkynes as XB donors were also confirmed by X-ray diffraction analysis observing I···C contacts between the electropositive σ-hole of the iodine atom and electron rich π clouds for all crystal structures studied in the solid state.

The term Atropisomerism defines a type of enantiomerism that arises from hindered rotation around an axis that makes two rotational isomers enantiomers. Atropisomeric compounds are present in nature, being important building blocks of many biologically active compounds. Atropisomers have been extensively studied in environmental and toxicological chemistry and, in particular, separating them has become a need in specific fields as organic synthesis and pharmaceutical research. High-performance LC has been fruitfully applied in this context, and despite HPLC separation on chiral stationary phase is considered as mature technology nowadays, in the last years several advancements and applications contributed to study compounds where axial chirality is of utmost importance. Moreover, dynamic chromatography has been exploited as a versatile tool for kinetic studies of systems with slow internal motion gaining essential information on their stereodynamic behavior. On this basis, current topics and trends in liquid-phase chromatography enantioseparation of atropisomers are presented herein with specific focus on new representative applications with HPLC, covering years 2010-2016. Some examples concerning supercritical fluid chromatography applications are also reported. This review aims to provide the reader with a modern overview of the field to highlight the renewed interest toward the chemistry of molecules with atropisomeric properties. A systematic compilation of all published literature has not been attempted.

Halogen atoms (F, Cl, Br, I) involved in covalent bonds present anisotropic distribution of the electron density with a region of depleted and often positive electrostatic potential (EP) (the 'sigma-hole') on the elongation of the corresponding covalent bond [1]. On this basis, the halogen bond (XB) is defined as the attractive interaction between the positive?sigma-hole, which serves as a XB donor (XBD) and an electron-rich nucleophile site (XB acceptor) [2]. Recently, our groups have systematically investigated halogen-dependent enantioseparations using chiral polyhalogenated heterocycles as XBD probes on polysaccharide-based chiral stationary phases (PCSPs), demonstrating that XBs can actually drive enantioseparations [3]. In this context, with the aim of gaining information on the potential effect of regions of electronic charge depletion on retention and selectivity, here we report the results of further investigations performed by using 4,4'-bipyridyl, aryl and ferrocenyl halogenated derivatives as test probes on PCSPs. In our studies, we use in parallel four different computational approaches to gain complementary information on chiral recognition mechanisms by correlating experimental and theoretical data: a) EP surface analysis [4]; b) the Bader-Gatti electron density source function approach, suitably extended to the EP field, to evaluate the atomic contributions to local EP [5]; c) molecular dynamics simulations [3b-d,6]; d) time-dependent density functional theory calculations to obtain theoretical electronic circular dichroism spectra for absolute configuration assignment [3b,7]. References [1] Cavallo, G., Metrangolo, P., Milani, R., Pilati, T., Priimagi, A., Resnati, G., Terraneo, G., Chem. Rev. 2016, 116, 2478-2601. [2] Peluso, P., Mamane, V., Cossu, S., Chirality 2015, 27, 667-684. [3] a) Peluso, P., Mamane, V., Aubert, E., Cossu, S., J. Chromatogr. A 2014, 1345, 182-192; b) Peluso, P., Mamane, V., Aubert, E., Dessì, A., Dallocchio, R., Dore, A., Pale, P., Cossu, S., J. Chromatogr. A 2016, 1467, 228-238; c) Peluso, P., Mamane, V., Dallocchio, R., Dessì, A., Villano, R., Sanna, D., Aubert, E., Pale, P., Cossu, S., J. Sep. Sci. 2018, 41, 1247-1256; d) Dallocchio, R., Dessì, A., Solinas, M., Arras, A., Cossu, S., Aubert, E., Mamane, V., Peluso, P., J. Chromatogr. A 2018, 1563, 71-81. [4] Peluso, P., Cossu, S., Chirality 2013, 25, 709-718. [5] a) Gatti, C., SF-ESI codes, 2018, Milano, Italy; b) Peluso, P., Gatti, C., Dessì, A., Dallocchio, R., Weiss, R., Aubert, E., Pale, P., Cossu, S., Mamane, V., J. Chromatogr. A 2018, 1567, 119-129. [6] Peluso, P., Dessì, A., Dallocchio, R., Mamane, V., Cossu, S., Electrophoresis 2019, in press. [7] Mamane, V., Peluso, P., Aubert, E., Cossu, S., Pale, P., J. Org. Chem. 2016, 81, 4576-4587. Acknowledgement: This work has been supported by Università Ca' Foscari Venezia, Italy (DSMN, ADIR funds). C. G. acknowledges funding from Danmarks Grundforskningsfond (award No. DNRF93).

In keeping with the importance of chirality in several fields, nowadays, high-performance liquid chromatography on chiral stationary phase (CSP) is largely used for resolving racemic mixtures of chiral compounds. In this field, polysaccharide-based CSPs (PCSPs) are the most versatile due to their polymeric structure where molecular, conformational and supramolecular chirality cooperate to determine the separation result.[1] The understanding of the chiral recognition mechanism is a basic requirement to design a successful enantioseparation. Nevertheless, this is still an unsolved problem for PCSPs because of the complexity of their structure, the presence of multiple active sites and the involvement of noncovalent interactions in the enantiorecognition process.[2] Currently, we are using in parallel four different computational approaches to gain complementary information on chiral recognition mechanisms by correlating experimental and theoretical data: a) electrostatic potential surface (EPS) analysis to investigate in detail the shape of both analyte and selector;[3] b) the Bader-Gatti electron density source function (SF) approach, suitably extended to the EP field, to evaluate the atomic contributions to local EP;[4] c) molecular dynamics to simulate the binding modes of the enantiomers with the polysaccharide-based selectors;[5] d) time-dependent density functional theory (TD-DFT) calculations to obtain theoretical electronic circular dichroism (ECD) spectra for absolute configuration assignment.[6] References [1] Chankvetadze, B., J. Chromatogr. A 2012, 1269, 26-51. [2] Lämmerhofer, M., J. Chromatogr. A 2010, 1217, 814-856. [3] Peluso, P., Cossu, S., Chirality 2013, 25, 709-718. [4] (a) Gatti, C., SF-ESI codes, 2018, Milano, Italy; (b) Peluso, P., Gatti, C., Dessì, A., Dallocchio, R., Weiss, R., Aubert, E., Pale, P., Cossu, S., Mamane, V., J. Chromatogr. A 2018, 1567, 119-129. [5] Peluso, P., Mamane, V., Dallocchio, R., Dessì, A., Villano, R., Sanna, D., Aubert, E., Pale, P., Cossu, S., J. Sep. Sci. 2018, 41, 1247-1256. [6] Mamane, V., Aubert, E., Peluso, P., Cossu, S., J. Org. Chem. 2012, 77, 2579-2583. Acknowledgement: This work has been supported by Università Ca' Foscari di Venezia, Italy (DSMN, ADIR funds). C. G. acknowledges funding from Danmarks Grundforskningsfond (award No. DNRF93).

Nowadays, high-performance liquid chromatography (HPLC) on chiral stationary phase (CSP) is the most versatile technique for the enantioseparation of chiral compounds. The basic requirement for distinction of enantiomers is the creation of a diastereomeric relationship between the enantiomers pair of a chiral analyte and an enantiopure chiral selector. In HPLC environment, multiple and well balanced noncovalent interactions underlie the enantiodiscrimination process.[1] In particular, the strength of secondary short-type interactions such as hydrogen bonds, pai-pai and dipole-dipole interactions can be significantly influenced by mobile phase (MP) polarity. In the last decades, sigma- and pai-hole bonds have been recognized as new families of noncovalent interactions. In particular, halogen and chalcogen bonds, involving atoms of group VII and VI, respectively, have found applications in several fields.[2] Despite the importance of noncovalent interactions in LC environment, sigma-hole bonds were unexplored in this field until we pointed out the contribution of halogen bond for stereorecognition of analytes by polysaccharide-based CSPs, thus expanding the range of interactions available for LC enantiodiscrimination.[3] Interestingly, we observed that halogens can switch their behaviour from sigma-hole donor to hydrophobic centre depending on sigma-hole depth and MP polarity. Currently, on the basis of a computational-guided study, we are investigating chalcogen and pai-hole bonds, so far unexplored in LC, by means of the enantioseparations of pentafluorophenyl (pai-hole) substituted analytes as probes, which contain sulphur[4] and selenium atoms as chalcogen sites. References [1] Scriba, G. K. E., J. Chromatogr. A 2016, 1467, 56-78. [2] (a) Cavallo, G., Metrangolo, P., Milani, R., Pilati, T., Priimagi, A., Resnati, G., Terraneo, G., Chem. Rev. 2016, 116, 2478-2601; (b) Bauzá, A., Mooibroek, T. J., Frontera, A., ChemPhysChem 2015, 16, 2496-2517. [3] (a) Peluso, P., Mamane, V., Aubert, E., Cossu, S., J. Chromatogr. A 2014, 1345, 182-192; (b) Peluso, P., Mamane, V., Aubert, E., Dessì, A., Dallocchio, R., Dore, A., Pale, P., Cossu, S., J. Chromatogr. A 2016, 1467, 228-238; (c) Dallocchio, R., Dessì, A., Solinas, M., Arras, A., Cossu, S., Aubert, E., Mamane, V., Peluso, P., J. Chromatogr. A 2018, 1563, 71-81. [4] Peluso, P., Gatti, C., Dessì, A., Dallocchio, R., Weiss, R., Aubert, E., Pale, P., Cossu, S., Mamane, V., J. Chromatogr. A 2018, 1567, 119-129. Acknowledgement: This work has been supported by Università Ca' Foscari di Venezia, Italy (DSMN, ADIR funds). V. M. thanks the International Center Frontier Research in Chemistry (icFRC) and the Laboratory of Excellence for Complex System Chemistry (LabEx CSC). C. G. acknowledges funding from Danmarks Grundforskningsfond (award No. DNRF93).

Thyroid hormones are well known halogen bond (XB) donors as shown by short I···O contacts that underlie the selective binding of hormone thyroxine (T4) to transthyretin (TTR).[1] This protein is composed of four subunits, which are organized into a homotetrameric quaternary structure with two dimer-dimer interfaces.Dissociation of the native tetramer and subsequent aggregation to form insoluble amyloid fibrils are involved in several TTR amyloidosis (ATTR) diseases. Over the past decade, it was observed that T4 and other small molecules could inhibit the tetramer dissociation, and therefore be efficacious against ATTR diseases.[1] However, currently, these diseases still lack an effective therapy. On this basis, we describe herein the development of new atropisomeric iodinated 4,4'-bipyridines (IBPYs)[2] as TTR misfolding inhibitors. In particular, a docking study was performed in order to inspect interactions and binding modes of the IBPYs into the TTR. The (M)-2-iodo-4,4'-bipyridyl substructure has been identified as suitable for developing the new TTR stabilizers (Figure b). Interestingly, in this case, a XB was observed between the 2-iodine of IBPY and the side chain of Ser117' with distance and angle values in accord with what is defined as XB biomolecular contacts (penetration of the van der Waals atomic spheres -2.8%, angles: C-I···O = 149.34° and I···O-C = 111.85°).[3] References [1] Johnson, S. M., Wiseman, R. L., Sekijima, Y., Green, N. S., Adamski-Weiner, S. L., Kelly, J. W., Acc. Chem. Res. 2005, 38, 911-921. [2] (a) Mamane, V., Aubert, E., Peluso, P., Cossu, S., J. Org. Chem. 2013, 78, 7683-7689; (b) Mamane, V., Peluso, P., Aubert, E., Cossu, S., Pale, P., J. Org. Chem. 2016, 81, 4576-4587. [3] Ho, P. S., Top. Curr. Chem. 2015, 358, 241-276. Acknowledgement: This work has been supported by Università Ca' Foscari di Venezia, Italy (DSMN, ADIR funds). V. M. thanks the International Center Frontier Research in Chemistry (icFRC) and the Laboratory of Excellence for Complex System Chemistry (LabEx CSC).

Enantioseparation on chiral stationary phase (CSP) is based on the formation of transient diastereomeric selectand-selector complexes in a chiral environment generated by a chiral selector. Diverse short-range directional interactions, including hydrogen bonds, pai-pai, dipole-dipole, and van der Waals interactions, underlie complex formation and promote the enantioseparation [1]. In this context, recently, our groups discovered that sigma-hole interactions can be involved in HPLC enantioseparations, enlarging the range of interactions which are active in this environment [2]. Computational tools and studies in silico have greatly contributed to the understanding of sigma-hole interactions [3]. In particular, sigma-hole being a region of electronic charge depletion, electrostatic potentials (EPs) have been widely used as an indicator of the anisotropy of the molecular charge distribution. While it is well acknowledged that sigma-holes originate from the cylindrical symmetry of the sigma-bond and of the electron sharing along its axis, nothing is quantitatively known about the role played by the various moieties of a molecule in producing such holes. The Bader-Gatti source function [4] for the electron density (ED) was thus extended to the EP, to yield a rigorous measure of how the various pieces of a molecule determine the extent of sigma-holes as measured by the EP value at their associated EP maxima on the 0.002 au ED isosurface. A FORTRAN package was developed for such a purpose [2c]. A first application of the EPSF tool to the chalcogen bonds in HPLC enantioseparations of fluorinated 4,4'-bipyridines has been reported [2c]. Here, the EPSF method is presented in detail and new examples are discussed which concern halogenated and seleno-substituted atropisomeric 4,4'-bipyridines as sigma-hole bond donors. These compounds were enantioseparated on polysaccharide-based CSPs and used as test probes to study recognition mechanisms involving sigma-hole sites. References [1] Scriba, G. K. E., J. Chromatogr. A 2016, 1467, 56-78. [2] (a) Peluso, P., Mamane, V., Aubert, E., Dessì, A., Dallocchio, R., Dore, A., Pale, P., Cossu, S., J. Chromatogr. A 2016, 1467, 228-238; (b) Dallocchio, R., Dessì, A., Solinas, M., Arras, A., Cossu, S., Aubert, E., Mamane, V., Peluso, P., J. Chromatogr. A 2018, 1563, 71-81; c) Peluso, P., Gatti, C., Dessì, A., Dallocchio, R., Weiss, R., Aubert, E., Pale, P., Cossu, S., Mamane, V., J. Chromatogr. A 2018, 1567, 119-129. [3] Kolá?, M. H., Hobza, P., Chem. Rev. 2016, 116, 5155-5187. [4] Bader, R. F. W., Gatti, C., Chem. Phys. Lett. 1998, 287, 233-238. Acknowledgement: This work has been supported by Università Ca' Foscari Venezia, Italy (DSMN, ADIR funds). C. G. acknowledges funding from Danmarks Grundforskningsfond (award No. DNRF93).

The recognition power and affinity pattern of various cyclodextrins (CD) towards the enantiomers of tetrahydrozoline (THZ) were studied using capillary electrophoresis (CE). As expected, affinity of THZ enantiomers and selectivity of recognition towards CD derivatives was strongly dependent on the cavity size and substituent type and pattern on the CD rims. Not only were the affinity strength and selectivity of recognition affected by the size of the cavity and chemistry of the CDs but also the affinity pattern. Another interesting example of opposite affinity pattern of enantiomers towards α- and β-CD was observed here. In addition, opposite affinity pattern of THZ enantiomers was seen towards β-CD and its acetylated derivatives, while methylation of β-CD did not affect the affinity pattern of THZ enantiomers. In order to get more information about structural mechanisms of the multivariate dependences mentioned above, rotating frame Overhauser enhancement spectroscopy (ROESY) and computation techniques were used. Significant differences between the structure of THZ complexes with different CDs with both methods were encountered. Good correlations between experimentally determined and computed structure of complexes, as well as between computed complex stabilities and enantiomer migration order (EMO) in CE were observed.

Two new chiral “click BOX” ligands have been synthetised with high yields starting from commercially available dimethyl propargylmalonate and optically pure alkanolamines, followed by copper catalysed cycloaddition (CuAAC) and oxazoline ring formation. Catalytic activity of the new ligands has been tested in the copper mediated Henry addition. The model reaction between nitromethane and o-anisaldehyde affords the related 1-(2-methoxyphenyl)-2-nitroethanol in high yields (up to 92%) and moderate enantioselectivities (up to 67% e.e.) under straightforward experimental conditions.

The structure of a [Cu(SiF6)(C10H8N2)2]n coordination polymer with ordered 4,4′-bi­pyridine and water mol­ecule channels is described., The coordination polymer {[Cu(SiF6)(C10H8N2)2]·2C10H8N2·5H2O}n, systematic name: poly[[bis­(μ2-4,4′-bi­pyridine)(μ2-hexa­fluorido­silicato)copper(II)] 4,4′-bi­pyridine disolvate penta­hydrate], contains pores which are filled with water and 4,4′-bi­pyridine mol­ecules. As a result of the presence of these ordered species, the framework changes its symmetry from P4/mmm to P21/c. The 4,4′-bi­pyridine guest mol­ecules form chains inside the 6.5 × 6.9 Å pores parallel to [100] in which the mol­ecules inter­act through π–π stacking. Ordered water mol­ecules form infinite hydrogen-bonded chains inside a second pore system (1.6 × 5.3 Å free aperture) perpendicular to the 4,4′-bi­pyridine channels.

Positive electrostatic potential (V) values are often associated with &sigma, and &pi, holes, regions of lower electron density which can interact with electron-rich sites to form noncovalent interactions. Factors impacting &sigma, holes may thus be monitored in terms of the shape and values of the resulting V. Further precious insights into such factors are obtained through a rigorous decomposition of the V values in atomic or atomic group contributions, a task here achieved by extending the Bader&ndash, Gatti source function (SF) for the electron density to V. In this article, this general methodology is applied to a series of 4,4&prime, bipyridine derivatives containing atoms from Groups VI (S, Se) and VII (Cl, Br), and the pentafluorophenyl group acting as a &pi, hole. As these molecules are characterized by a certain degree of conformational freedom due to the possibility of rotation around the two C&ndash, Ch bonds, from two to four conformational motifs could be identified for each structure through conformational search. On this basis, the impact of chemical and conformational features on &sigma, hole regions could be systematically evaluated by computing the V values on electron density isosurfaces (VS) and by comparing and dissecting in atomic/atomic group contributions the VS maxima (VS,max) values calculated for different molecular patterns. The results of this study confirm that both chemical and conformational features may seriously impact &sigma, hole regions and provide a clear analysis and a rationale of why and how this influence is realized. Hence, the proposed methodology might offer precious clues for designing changes in the &sigma, hole regions, aimed at affecting their potential involvement in noncovalent interactions in a desired way.

A chalcogen bond (ChB) is a sigma-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 ?-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 -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 sigma and -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 sigma and -hole interactions can jointly drive HPLC enantioseparations through recognition sites generated by electronic charge depletion emerged from both experimental results and theoretical data.

Organocatalysis through chalcogen bonding (ChB) is in its infancy, as its proof-of-principle was only reported in 2016. Herein, we report the design and synthesis of new chiral ChB donors, as well as the catalytic activity evaluation of the 5,5&prime, dibromo-2,2&prime, dichloro-3-((perfluorophenyl)selanyl)-4,4&prime, bipyridine as organocatalyst. The latter is based on the use of two electron-withdrawing groups, a pentafluorophenyl ring and a tetrahalo-4,4&prime, bipyridine skeleton, as substituents at the selenium center. Atropisomery of the tetrahalo-4,4&prime, bipyridine motif provides a chiral environment to these new ChB donors. Their synthesis was achieved through either selective lithium exchange and trapping or a site-selective copper-mediated reaction. Pure enantiomers of the 3-selanyl-4,4&prime, bipyridine were obtained by high performance liquid chromatography enantioseparation on specific chiral stationary phase, and their absolute configuration was assigned by comparison of the measured and calculated electronic circular dichroism spectra. The capability of the selenium compound to participate in &sigma, hole-based interactions in solution was studied by 19F NMR. Even if no asymmetric induction has been observed so far, the new selenium motif proved to be catalytically active in the reduction of 2-phenylquinoline by Hantzsch ester.

Halogen bond (XB)-driven enantioseparations involve halogen-centred regions of electronic charge depletion (sigma-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 sigma-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 sigma-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.

During this last decade, halogen and chalcogen bonds (XB and ChalB) have increasingly raised interest in the scientific community. According to IUPAC, the term halogen bond describes the intermolecular interaction occurring between a halogen acting as a Lewis acid and a Lewis base[1]. XB represents one of the so-called ?-hole interactions (?hI)[2] with relevance evidence in biology, recognition processes and in crystal engineering[3]. So far studied in vacuum and in solid state, such interactions have been less investigated in solution. However, they could be useful in chiral recognition, in separation[4] and in organocatalysis. To look at this aspect, we designed atropisomeric 4,4'-bipyridyl[5],[6] with exalted ?-holes (Figure 1.). After identifying the best ?hI donors and studying them through chiral environment [7],[8] we are investigating them as organocatalyst.

The enantioseparation of chiral compounds through the direct approach is an important matter in several fields of science [1]. This approach is based on the formation of transient diastereomeric selectand-selector complexes in a chiral environment generated by a chiral selector. Understanding the recognition pattern occurring in these processes remains a demanding issue in separation science because diverse short-range directional interactions, including hydrogen bonds, p-p, dipole-dipole, and van der Waals interactions, are able to promote the enantioseparation. Recently, sigma- and p-hole bonds involving atoms of Groups III-VII have also been considered as important directional noncovalent interactions [2], which involve regions of electronic charge depletion as recognition sites. The most common and well known sigma-hole bonds are halogen bonds (XB), involving halogen atoms and various Lewis bases. Besides XBs, sigma-hole interactions involving chalcogen atoms have also been identified, leading to the so-called chalcogen bonds (ChBs). Conceptually analogous to the sigma-hole bond, a p-hole bond is a noncovalent interaction which involves an unpopulated p* orbital (p-hole), as a donor, and a Lewis basis as acceptor (anion or lone-pair). A typical p-hole is located perpendicular to the molecular framework of perfluorinated aromatic rings. Computational tools and studies in silico have greatly contributed to the understanding of sigma- and p-hole based interactions. In particular, electrostatic potentials (EPs) have been widely used as an indicator of the anisotropy of the molecular charge distribution. Indeed, EP analysis allows to achieve detailed information of depth and size of electronic charge depletion and it can rationalize interaction preferences in competitive systems. On the other hand, computational techniques have been also used as tool in chiral chromatography to predict retention, selectivity and enantiomer elution order (EEO) with the aim to understand andrationalize recognition mechanisms. In this field, EPs and related EP surfaces (EPSs) contributed to investigate in detail the shape of both analyte and selector. Moreover, chromatography discrimination is a dynamic process based on reiterative adsorptiondesorption steps involving selector surface, cavities and groove. In this perspective, molecular dynamic (MD) simulations proved to be extremely versatile, in particular for studying processes where solvent effects have remarkable influence on driving interactions. Recently, our groups discovered that XBs can drive HPLC enantioseparations of halogenated analytes [3] by using cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) as a chiral selector (XB acceptor), enlarging the range of interactions which are active in HPLC environment [4,5]. Further to our recent results on the XB interactions, currently we are studying chalcogen and ?-hole bonds in HPLC environment. In particular, some unexplored issues concerning sigma- and p-hole driven enantioseparations have been addressed by using both MD simulations and EP analysis as computational tools [6]. Atomic contributions to the EPs maxima of sulphur in a series of chalcogen bond donors were derived using a molecular space partitioning in terms of Bader's atomic basins [7]. This procedure is akin to the Bader-Gatti electron density source function (SF) approach [8], suitably extended to the EP field [9].

Non-covalent interactions play a key role in many areas of science such as crystal engineering, molecular recognition and biology. Recently, various types of the so-called s-hole bonds have been identified and studied as a new family of non-covalent interactions. A s-hole bond (sB) is a non-covalent interaction (RD···A) between a covalently-bonded atom of Groups IV-VII (D, donor), bearing a region with a positive electrostatic potential on unpopulated s* orbitals, and a negative site (A, acceptor). Among these interactions, halogen- and chalcogen-bonds involve atoms of groups VI and VII as donor sites, respectively, and, in the last years, the interest in their fundamentals and applications has been grown rapidly [1]. Moreover, in the last decade, sBs occurring in solution have received attention as a tool to direct molecular recognition processes and underlie protein-ligand binding. However some issues are still open: i) so far, the investigations on sBs have mainly been focused on their description in vacuum and in solid state, whereas the behaviour in solution has received less attention [2]; ii) another open issue concerns the application of sBs in chiral systems, and only few chiral molecules having s-holes as recognition sites were described recently [3]; iii) in particular, the detection of weak stereoselective s-hole-based interactions in solution requires the availability of analytical method characterized by high sensitivity; iv) currently, only four halogen bond-driven enantiodiscrimination processes are known [3]. Recently, we reported the first series of halogen bond-driven enantioseparations observed in High-Performance Liquid Chromatography (HPLC) environment [4]. This result is related to the ability of heavy halogens (iodine and bromine) as halogen bond donor (chiral analyte) to form linear interactions with carbonyl oxygen atoms as halogen bond acceptor (polysaccharide-based support as chiral stationary phase). On this basis, we describe herein the fundamentals of an innovative approach to detect and study weak stereoselective sBs in solution, which is based on: i) the rational design of atropisomeric sB donors based on the 4,4'-bipyridyl core, ii) the application of a HPLC protocol based on an orthogonal on-columnscreening on polysaccharide-based polymers, and iii) DFT calculations and computational simulations to study the involved mechanisms. Significantly, the enantioseparations of fluorinated 3-(arylthio)-4,4'-bipyridines proved that SoooO chalcogen bonds can drive enantiodiscrimination processes in HPLC environment. As a result of the HPLC study, new structures can be successfully pinpointed for further applications in catalysis, molecular recognition and drug design.

Halogenated chiral molecules have become important in several fields of science, industry, and society as drugs, natural compounds, agrochemicals, environmental pollutants, synthetic products, and chiral supports. Meanwhile, the perception of the halogen moiety in organic compounds and its role in recognition processes changed. Indeed, the recognition of the halogen bond as an intermolecular interaction occurring when the halogen acts as a Lewis acid had a strong impact, particularly in crystal engineering and medicinal chemistry. Due to this renewed interest in the potentialities of chiral organohalogens, here we focus on selected recent applications dealing with enantioseparations of halogenated compounds on polysaccharide-based chiral stationary phases (CSPs), widely used in liquid chromatography (LC). In particular, recently the first case of halogen bonding-driven high-performance LC (HPLC) enantioseparation was reported on a cellulose-based CSP. Along with enantioseparations performed under conventional HPLC, representative applications using supercritical fluid chromatography (SFC) are reported.