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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

Left bundle branch area pacing (LBBAP) is a form of conduction system pacing. Long-term data on the safety and performance of LBBAP 1 year postdevice implantation has not been well described.Sixty-five patients (49% females) who received LBBAP for bradycardia indications using the SelectSecure 3830 lead (Medtronic) were retrospectively evaluated. Clinical variables were examined. Lead parameters were obtained at implant and during regular follow-up. Mean age of patients was 75.7 ± 10.1 years with left ventricular ejection fraction 59.8 ± 10.4%. Indications for pacing were atrioventricular block 55%, sinus node dysfunction 19%, tachy-brady syndrome 15%, atrioventricular node ablation 8%, and bail out cardiac resynchronization therapy 3%. Mean baseline QRS measured 120 ± 38 ms, paced QRS duration was 138 ± 22ms. Paced QRS narrowed by 24 ms in those with pre-existing left bundle branch block (BBB), increased by 1 ms in those with pre-existing right BBB, and increased by 42 ms in those with no BBB. LBBAP threshold at implant was 0.521 ± 0.153 V at 0.4 ms, and increased to 0.654 ± 0.186 V at 3 months (+26%), 0.707 ± 0.186 V at 6 months (+36%), and 0.772 ± 0.220 V at 12 months (+48%). Patients with left BBB showed the maximum benefit with QRS narrowing 24 ms. Pacing impedance remained unchanged with no procedure-related complications.LBBAP is a durable form of conduction system pacing with pacing thresholds remaining relatively stable over 12 months post device implantation. Patients with left BBB display the narrowest paced QRS.

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.

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.

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.

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.

Background Triple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing “special types” to high-grade invasive breast carcinomas of no special type (IBC-NST). Methods This study was performed on data obtained from TNBC Database, including pathological features and clinical records of 1009 TNBCs patients diagnosed between 1994 and 2015 in the four most important Oncology Units located in different hospitals in Sardinia, Italy. Kaplan-Meier analysis, log-rank test and multivariate Cox proportional-hazards regression were applied for overall survival (OS) and disease free survival (DFS) according to TNBC histologic types. Results TNBC “special types” showed significant differences for several clinico-pathological features when compared to IBC-NST. We observed that in apocrine carcinomas as tumor size increased, the number of metastatic lymph nodes manifestly increased. Adenoid cystic carcinoma showed the smallest tumor size relative to IBC-NST. At five-year follow-up, OS was 92.1, 100.0, and 94.5% for patients with apocrine, adenoid cystic and medullary carcinoma, respectively; patients with lobular and metaplastic carcinoma showed the worst OS, with 79.7 and 84.3%, respectively. At ten-years, patients with adenoid cystic (100.0%) and medullary (94.5%) carcinoma showed a favourable prognosis, whereas patients with lobular carcinoma showed the worst prognosis (73.8%). TNBC medullary type was an independent prognostic factor for DFS compared to IBC-NST. Conclusions Our study confirms that an accurate and reliable histopathologic definition of TNBC subtypes has a significant clinical utility and is effective in the therapeutic decision-making process, with the aim to develop innovative and personalized treatments.

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).

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.

In the last few years, halogen bonds have been exploited in a variety of research areas both in the solid state and in solution. Nevertheless, several factors make formation and detection of halogen bonds in solution challenging. Moreover, to date, few chiral molecules containing electrophilic halogens as recognition sites have been reported. Recently, we described the first series of halogen-bond-driven enantioseparations performed on cellulose tris(3,5-dimethylphenylcarbamate) by high-performance liquid chromatography. Herein the performances of amylose tris(3,5-dimethylphenylcarbamate) as halogen bond acceptor were also investigated and compared with respect to cellulose tris(3,5-dimethylphenylcarbamate). With the aim to explore the effect of polysaccharide backbone on the enantioseparations, the thermodynamic parameters governing the halogen-dependent enantioseparations on both cellulose and amylose polymers were determined by a study at variable temperature and compared. Molecular dynamics were performed to model the halogen bond in polysaccharide-analyte complexes. Chiral halogenated 4,4'-bipyridines were used as test compounds (halogen bond donors). On this basis, a practical method for detection of stereoselective halogen bonds in solution was developed, which is based on the unprecedented use of high-performance liquid chromatography as technical tool with polysaccharide polymers as molecular probes (halogen bond acceptors). The analytical strategy showed higher sensitivity for the detection of weak halogen bonds.

Negli ultimi anni, le interazioni non covalenti che ricadono nella definizione di sigma-hole bonds (sigmaBs) sono state oggetto di numerosi studi volti a definirne proprietà e comportamento sia allo stato solido che in soluzione. Tali interazioni hanno anche suscitato interessi multidisciplinari per lo sviluppo di applicazioni nel settore dei materiali avanzati, in organocatalisi, molecular sensing e drug discovery. Tra le interazioni basate sul sigma-hole, il legame ad alogeno (halogen bond) è l'interazione non covalente che si instaura tra un atomo di alogeno, legato covalentemente e che agisce da elettrofilo, ed una specie nucleofila. Anche atomi del VI gruppo (S, Se, Te), opportunamente attivati, possono assumere la funzione di centri sigma-hole-attivi, comportandosi da elettrofili in chalcogen bonds. L'interesse intorno a interazioni basate su sigma-hole è piuttosto recente e alcune questioni rimangono ancora aperte. In particolare, i) fattori strutturali rendono difficile l'identificazione in soluzione di ?Bs deboli e ii) attualmente solo poche molecole chirali aventi sigma-holes come siti di riconoscimento sono state descritte. In particolare, nessun esempio di elettrofilo chirale coinvolto in chalcogen bond è stato finora riportato. Nell'ambito di una collaborazione bilaterale Italia/Francia, nuove molecole chirali alogenate sono state sviluppate per lo studio in soluzione di interazioni sigmaBs deboli, mostrando una interessante attività sigma-hole-controllata come organocatalizzatori in reazioni di hydrogen transfer su legami C=N. Nell'ambito di questi studi, il primo processo di enantiodiscriminazione controllato da chalcogen bond è stato osservato mediante studio basato su tecnologia HPLC.

The term halogen bond (XB) describes the intermolecular interaction occurring between a Lewis base and a halogen atom (in particular heavier halogens) which behaves like Lewis acid due to the electropositive sigma-hole. Indeed, the electrophilic nature of halogens is explained by the anisotropic distribution of the electron density around the halogen atoms. In the last decade, XBs occurring in solution have increasingly received attention as a tool to direct molecular recognition processes and underlie protein-ligand binding. Nevertheless, the exploration of solvent effects on XB has begun later compared to solid-state studies, and to date the application of XB in solution is still challenging. Another open issue concerns the application of XB in chiral systems, and only a few chiral molecules having sigma-holes as recognition sites were described recently. In addition, the detection of stereoselective XB-based interactions in solution requires the availability of analytical method characterized by higher sensitivity. In this study, the rational design of new atropisomeric sigma-hole (halogen and chalcogen) bond donors based on the 4,4'-bipyridyl core has been engineered by stereoelectronic activation of the heteroaromatic scaffold. On this basis, a HPLC protocol based on an orthogonal on-column screeninga,b) on polysaccharide-based polymers, as XB acceptors, was developed with the aim to detect stereoselective sigma-hole-driven interactions. Significantly, the HPLC outcomes of 5,5'-dibromo-2,2'-dichloro-3-(arylthio)-4,4'-bipyridines proved that chalcogen bond interactions involving activated sulfur sites as electrophiles can drive enantiodiscrimination processes. As a result of the HPLC study, new structures have been successfully pinpointed for further applications in catalysis and drug design.

An investigation on the high-performance liquid chromatography enantioseparation of 12 polyhalogenated 4,4'-bipyridines on polysaccharide-based chiral stationary phases is described. The overall study was directed toward the generation of efficient separations in order to obtain pure atropisomers that will serve as ligands for building homochiral metal organic frameworks. Four coated columns--namely, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-4, and Lux Amylose-2--and two immobilized columns--namely, Chiralpak IC and IA--were used under normal, polar organic, and reversed-phase elution modes. Moreover, Chiralcel OJ was considered under normal-phase and polar organic conditions. The effect of the chiral selector and mobile phase composition on the enantioseparation, the enantiomer elution order and the beneficial effect of nonstandard solvents were studied. The effect of water in the mobile phase on the enantioselectivity and retention was investigated and retention profiles typical of hydrophilic interaction liquid chromatography were observed. Interesting phenomena of solvent-induced enantiomer elution order reversal occurred under normal-phase mode. All the considered 4,4'-bipyridines were enantioseparated at the multimilligram level.

In order to elucidate the metabolite changes associated with hepatocellular carcinoma (HCC) oncogenesis and progression, we compared the profiles obtained by 1D proton HRMAS NMR spectroscopy of 51 needle biopsies (14 primary nodules, 14 recurrent, and 23 paired cirrhotic specimens). The diagnosis of HCC was based on 2 concordant imaging techniques and was confirmed by histology in 20 cases. Spectroscopy was performed using a Bruker AVANCE II 600 spectrometer. One-dimensional proton spectra were acquired using water-suppressed (noesygppr) pulse and spin-echo CPMG sequences. Signals were assigned by BBIOREFCODE and were confirmed by HSQC. Statistics was based on the SIMCA P package. Orthogonal projection to latent structure (OPLS-DA) showed a clear separation between tumor and cirrhosis. This difference was maintained when the analysis of paired samples from primary to recurrent nodules was split. OPLS-DA of primary and recurrent nodules also showed a significant difference. The relationship between metabolite profile and HCC volume was evaluated comparing the spectra obtained in tumors ≤2 cm (n = 15) and in those larger than 2 cm (n = 11). Univariate comparison of the most relevant metabolites showed that: (1) increased choline, TMAO, and decreased saturated fatty acids differentiate HCC from the surrounding tissue; (2) increased lactate and myo-inositol differentiate recurrent from primary HCC; (3) decreased saturated fatty acids characterize large HCC nodules.

The HPLC enantioseparation of nine atropisomeric 3,3',5,5'-tetrasubstituted-4,4'-bipyridines was performed in normal and polar organic (PO) phase modes using two immobilized polysaccharide-based chiral columns, namely, Chiralpak IA and Chiralpak IC. The separation of all racemic analytes, the effect of the chiral selector, and mobile phase (MP) composition on enantioseparation and the enantiomer elution order (EEO) were studied. The beneficial effect of nonstandard solvents, such as tetrahydrofuran (THF), dichloromethane (DCM), and methyl t-butyl ether on enantioseparation was investigated. All selected 4,4'-bipyridines were successfully enantioseparated on Chiralpak IA under normal or PO MPs with separation factors from 1.14 to 1.70 and resolutions from 1.3 to 6.5. Two bipyridines were enantioseparated at the multimilligram level on Chiralpak IA. Differently, Chiralpak IC was less versatile toward the considered class of compounds and only five bipyridines out of nine could be efficiently separated. In particular, on these columns, the ternary mixture n-heptane/THF/DCM (90: 5: 5) as MP had a positive effect on enantioseparation. An interesting phenomenon of reversal of the EEO depending on the composition of the MP for the 3,3'-dibromo-5,5'-bis-(E)-phenylethenyl-4,4'-bipyridine along with an exceptional enantioseparation for the 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-bipyridine (alpha = 8.33, R-s = 30.6) were observed on Chiralpak IC.

With the aim to define a combined computational/chromatographic empirical approach useful for the high-performance liquid chromatography (HPLC) method development of new chiral compounds, 36 racemic aromatic compounds with different chemical structures were used as test probes on four polysaccharide-based chiral stationary phases (CSPs) of the Lux series, namely Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-4, and Lux Amylose-2, using classical n-hexane/2-propanol mixtures as mobile phase. Electrostatic potential surfaces (EPSs) determined using Density Functional Theory (DFT) calculations were used to derive size, shape, and electronic properties of each analyte. Then a comparative HPLC screening was carried out in order to evaluate the impact of substituents, shapes, and electronic properties of the analytes on the chromatographic behavior as the column changes. The four CSPs showed good complementary recognition ability. The elution sequence was determined in 30 cases out of 36. The success rate to afford baseline separations (Rs ≥ 1.5) was estimated: 29 compounds out of 36 showed baseline enantioseparation on at least one of the four selected CSPs. The combined computational-chromatographic screening furnished useful collective structure-chromatographic behavior relationships and a map of the chiral discrimination abilities of the considered CSPs towards the analytes. On this basis, the chromatographic behavior of new analytes on a set of polysaccharide-based CSPs can be mapped through the qualitative correlation of chromatographic parameters (k, α, Rs) to computed molecular properties of the analytes. Chirality 25:709–718, 2013. © 2013 Wiley Periodicals, Inc.

International audience; Lithiation of the achiral tetrahalogenated 4,4'-bipyridine 1 with alkyllithiums was investigated. n-BuLi was found to induce either the chlorine-directed deprotolithiation reaction alone or with a concomitant halogen-lithium exchange furnishing after iodine trapping chiral 4,4'-bipyridines 2 and 6, respectively. The role of n-BuLi in the deprotolithiation process of 1 was elucidated on the basis of isolated secondary derivatives. After deprotolithiation, the lithiated species could be trapped by different electrophiles such as MeI, TMSCl, MeSSMe, R3SnCl (R = Me or n-Bu), and PPh2Cl. Moreover, 4,4'-bipyridine 2 was submitted to cross-coupling reactions (Suzuki and Sonogashira) which occurred selectively at the carbon-iodine bond. All compounds of this new family of atropisomeric 4,4'-bipyridines were separated by chiral HPLC (high-performance liquid chromatography), and the absolute configurations of obtained enantiomers were mainly assigned by XRD (X-ray diffraction) using anomalous dispersion.

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.

The preparation of 27 isomers of chiral hexahalogeno-4,4′-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.

The preparation of 27 isomers of chiral hexahalogeno-4,4'-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4'-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4'-bipyridine-2,2'-diones. Iodine in 2,2'-positions of the 4,4'-bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2'-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4'-bipyridines were enantioseparated by High Performance Liquid Chromatography (HPLC) on chiral stationary phases and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction (XRD) analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.

The high performance liquid chromatography (HPLC) enantioseparation of eleven atropisomeric 4,4′-bipyridines was performed in the normal and polar organic phase mode using three cellulose-based chiral stationary phases (CSPs), namely Lux ® Cellulose-1, Lux ® Cellulose-2, Lux ® Cellulose-4, and two amylose-based CSPs, Chiralpak ® AD-H and Lux ® Amylose-2. n -Hexane/2-propanol mixtures and pure ethanol were employed as mobile phases. The combined use of Chiralpak ® AD-H and Lux ® Cellulose-2 allowed to enantioseparate all the considered bipyridines. Ten bipyridines were enantioseparated at the multimilligram level allowing the elution sequence determination of the enantiomers as well as their future use for the preparation of homochiral metal organic frameworks (MOFs). Moreover, the performance of the CSPs regarding the same bipyridine was different and dependent on the backbone as well as on the side chain of the polymer. The impact of substitution pattern, shape and electronic properties of the molecules on the separation behavior was investigated through the evaluation of retention factors ( k ), separation factors ( α ), resolution ( R s ) and molecular properties determined using density functional theory (DFT) calculations. In this regard, the substituents at the 3,3′,5,5′ positions of the 4,4′-bipyridyl rings exhibited a pivotal role on the enantioseparation.