RESUMEN
Hydrogen/deuterium (H/D) isotope effects are not unusual in chromatography and such phenomena have been observed in both gas- and liquid-phase separations. Despite the numerous reports on this topic, the understanding of mechanisms and the underlying noncovalent interactions at play remains rather challenging. In our recent study, we reported baseline separation of isotopologoues of some amphetamine (AMP) derivatives on achiral and polysaccharide-based chiral columns, as well as some correlations between the degree of separation of enantiomers and isotopologues on (the same) polysaccharide-based chiral column(s). Following our previous findings on isotope effects in high-performance liquid chromatography, we report herein a comparative study on the isotope effects observed with AMP and methamphetamine (MET). The impact of some pivotal factors such as the number of deuterium atoms part of AMP isotopologues, the structure of its isotopomers, the chemical structure of the achiral and chiral stationary phases used in this study, and the use of methanol- vs acetonitrile-containing mobile phases on the isotope effects was examined and discussed. Quantitative correlations between the observed isotope effects and the enantioselectivity of the chiral columns used are also shortly discussed. Furthermore, considering the chromatographic results as benchmark experimental data, we attempted to elucidate the molecular bases of the observed phenomena using quantum mechanics calculations.
Asunto(s)
Anfetamina , Deuterio , Polisacáridos , Cromatografía Líquida de Alta Presión/métodos , Estereoisomerismo , Deuterio/química , Anfetamina/química , Anfetamina/aislamiento & purificación , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Metanfetamina/química , Metanfetamina/aislamiento & purificación , Acetonitrilos/química , Metanol/químicaRESUMEN
In the last decade, biological processes involving halogen bond (HaB) as a leading interaction attracted great interest. However, although bound iodine atoms are considered powerful HaB donors, few iodinated new drugs were reported so far. Recently, iodinated 4,4'-bipyridines showed interesting properties as HaB donors in solution and in the solid state. In this paper, a study on the inhibition activity of seven halogenated 4,4'-bipyridines against malignant melanoma (MM) cell proliferation is described. Explorative dose/response proliferation assays were first performed with three 4,4'-bipyridines by using four MM cell lines and the normal BJ fibroblast cell line as control. Among them, the A375 MM cell line was the most sensitive, as determined by MTT assays, which was selected to evaluate the antiproliferative activity of all 4,4'-bipyridines. Significantly, the presence of an electrophilic iodine impacted the biological activity of the corresponding compounds. The 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridine showed significant antiproliferation activity against the A375â cell line, and lower toxicity on BJ fibroblasts. Through in silico studies, the stereoelectronic features of possible sites determining the bioactivity were explored. These results pave the way for the utilization of iodinated 4,4'-bipyridines as templates to design new promising HaB-enabled inhibitors of MM cell proliferation.
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Melanoma , Humanos , Proliferación Celular/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Halogenación , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Línea Celular TumoralRESUMEN
The different behavior of enantiomers of chiral compounds in non-isotropic environments (among them in living organism) is well known. On the other hand, the importance of a kinetic isotope effect in the biomedical field has become evident during past few decades. Thus, separation of both, enantiomers and isotopologues is now critical. Only very few published studies have attempted the simultaneous separation of enantioisotopologues. In this article we report baseline separation of partially deuterated isotopologues of a few amphetamine derivatives in high-performance liquid chromatography (HPLC) using achiral columns. In addition, the simultaneous separations of enantiomers and isotopologues (i.e. enantioisotopologues) were attempted on polysaccharide-based chiral columns. For several compounds the isotope effect was tunable and could be switched from a "normal" to "inverse" by making changes to the mobile-phase composition. A stronger isotope effect was observed in acetonitrile-containing mobile phases compared to methanol-containing ones with both chiral and achiral columns. In a separation system where both "normal" and "inverse" isotope effects were observed the "normal" isotope effect was favored in polar organic solvents while increasing content of the aqueous component in the reversed-phase (RP) mobile phase favored an "inverse" isotope effect. This observation indicates that polar, hydrogen bonding-type noncovalent interactions are involved in the "normal" isotope effect, while apolar hydrophobic-type interactions are mostly responsible for the "inverse" isotope effect.
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Anfetamina , Polisacáridos , Cromatografía Líquida de Alta Presión/métodos , Polisacáridos/química , Solventes/química , Isótopos , EstereoisomerismoRESUMEN
Over time, chiral organometallic compounds have attracted great interest in several fields, with applications going across several disciplines of chemical, biological, medical, and material sciences. In the last decades, due to advancements in molecular design and computational modeling, the chemistry of chiral transition metal complexes had a remarkable flowering, with the development of new structures for applications in asymmetric synthesis, bioinorganic chemistry, and molecular recognition. In these fields, fast chiral analysis to determine the enantiomeric purity of organometallic structures prepared by asymmetric synthesis, and for high-throughput screening of analytes, catalysts, and reactions, is very important. Capillary electrophoresis and related techniques proved to be extremely versatile for chiral analysis, showing unsurpassed advantages compared to chromatography like low consumption of materials, production of limited amounts of waste, fast equilibration, and possibility to replace easily type and concentration of the chiral selector, among others. Furthermore, electromigration techniques may be useful to gain details about the stereochemistry of the enantiomers of new compounds and to study analyte-selector noncovalent interactions at molecular level. On this basis, this short review aims to provide the reader with a comprehensive view on the enantioseparation of organometallic compounds by electromigration techniques, examining the topic from the historical perspective and showing what was made in this field so far, an essential know-how for developing new and advanced applications in the next future.
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Electroforesis Capilar , Compuestos Organometálicos , Estereoisomerismo , Compuestos Organometálicos/química , Electroforesis Capilar/métodosRESUMEN
In the last few decades, theoretical and technical advancements in computer facilities and computational techniques have made molecular modeling a useful tool in liquid-phase enantioseparation science for exploring enantioselective recognition mechanisms underlying enantioseparations and for identifying selector-analyte noncovalent interactions that contribute to binding and recognition. Because of the dynamic nature of the chromatographic process, molecular dynamics (MD) simulations are particularly versatile in the visualization of the three-dimensional structure of analytes and selectors and in the unravelling of mechanisms at molecular levels. In this context, MD was also used to explore enantioseparation processes promoted by amylose and cellulose-based selectors, the most popular chiral selectors for liquid-phase enantioselective chromatography. This review presents a systematic analysis of the literature published in this field, with the aim of providing the reader with a comprehensive picture about the state of the art and what is still missing for modeling cellulose benzoates and the phenylcarbamates of amylose and cellulose and related enantioseparations with MD. Furthermore, advancements and outlooks, as well as drawbacks and pitfalls still affecting the applicability of MD in this field, are also discussed. The importance of integrating theoretical and experimental approaches is highlighted as an essential strategy for profiling mechanisms and noncovalent interaction patterns.
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Amilosa , Celulosa , Celulosa/química , Amilosa/química , Simulación de Dinámica Molecular , Cromatografía Líquida de Alta Presión/métodos , Estereoisomerismo , Fenilcarbamatos/químicaRESUMEN
BACKGROUND: Highly ordered chiral secondary structures as well as multiple (tunable) recognition sites are the keys to success of polysaccharide carbamate-based chiral selectors in enantioseparation science. Hydrogen bonds (HBs), dipole-dipole, and π-π interactions are classically considered the most frequent noncovalent interactions underlying enantioselective recognition with these chiral selectors. Very recently, halogen, chalcogen and π-hole bonds were also identified as interactions working in polysaccharide carbamate-based selectors to promote enantiomer distinction. On the contrary, the function of dispersion interactions in this field was not explored so far. RESULTS: The enantioseparation of chiral ferrocenes featuring chiral axis or chiral plane as stereogenic elements was performed by comparing five polysaccharide carbamate-based chiral columns, with the aim to identify enantioseparation outcomes that could be reasonably determined by dispersion forces, making available a reliable experimental data set for future theoretical studies to confirm the heuristic hypothesis. The effects of mobile phase polarity and temperature on the enantioseparation were considered, and potential recognition sites on analytes and selectors were evaluated by electrostatic potential (V) analysis and molecular dynamics (MD). In this first part, the enantioseparation of 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-bipyridine bearing two ferrocenylethynyl units linked to an axially chiral core was performed and compared to that of the analyte featuring the same structural motif with two phenyl groups in place of the ferrocenyl moieties. The results of this study showed the superiority of the ferrocenyl compared to the phenyl group, as a structural element favouring enantiodifferentiation. SIGNIFICANCE AND NOVELTY: Even if dispersion (London) forces have been envisaged acting in liquid-phase enantioseparations, focused studies to explore possible contributions of dispersion forces with polysaccharide carbamate-based selectors are practically missing. This study allowed us to collect experimental information that support the involvement of dispersion forces as contributors to liquid-phase enantioseparation, paving the way to a new picture in this field.
RESUMEN
The complex formation between daclatasvir and γ-CD or heptakis(2,3,6-tri-O-methyl)-ß-CD (TM-ß-CD) was studied by isothermal titration calorimetry and molecular modeling. Both techniques supported the predominant formation of a 2:1 complex in case of γ-CD although a 1:1 complex may be formed to a much lower extent as well. In case of TM-ß-CD the stoichiometry of the complex was exclusively 1:1. Complex formation with γ-CD did not require dissociation of the daclatasvir dimer, which is present in solution, and resulted in a complex with a binding constant of 1.67·107 M-2. In contrast, formation of the weak TM-ß-CD complex (K = 371 M-1) required dissociation of the daclatasvir dimer. This is in line with the observation that the complex formation in case of γ-CD is enthalpy-driven, while the process is entropy-driven in case of TM-ß-CD. It is concluded that the plateau observed in capillary electrophoresis is primarily based on the slow dissociation of the daclatasvir-CD complexes caused by steric constrains due to the folded terminal amino acid moieties of daclatasvir exerting a clip effect. In case γ-CD the thermodynamic stability might contribute to the overall slow dissociation.
RESUMEN
In this study, the enantioseparation of 14 planar chiral ferrocenes containing halogen atoms, and methyl, iodoethynyl, phenyl, and 2-naphthyl groups, as substituents, was explored with a cellulose tris(4-methylbenzoate) (CMB)-based chiral column under multimodal elution conditions. n-Hexane/2-propanol (2-PrOH) 95:5 v/v, pure methanol (MeOH), and MeOH/water 90:10 v/v were used as mobile phases (MPs). With CMB, baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.24 to 1.77, whereas only three analytes could be enantioseparated with 1.14 ≤ α ≤ 1.51 on a cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC)-based column, used as a reference for comparison, under the same elution conditions. Pendant group-dependent reversal of the enantiomer elution order was observed in several cases by changing CMB to CDMPC. The impact of analyte and chiral stationary phase (CSP) structure, and MP polarity on the enantioseparation, was evaluated. The two cellulose-based CSPs featured by different pendant groups were also compared in terms of thermodynamics. For this purpose, enthalpy (ΔΔH°), entropy (ΔΔS°) and free energy (ΔΔG°) differences, isoenantioselective temperatures (Tiso ), and enthalpy/entropy ratios (Q), associated with the enantioseparations, were derived from van 't Hoff plots by using n-hexane/2-PrOH 95:5 v/v and methanol/water 90:10 v/v as MPs. With the aim to disclose the functions of the different substituents in mechanisms and noncovalent interactions underlying analyte-selector complex formation at molecular level, electrostatic potential (V) analysis and molecular dynamics simulations were used as computational techniques. On this basis, enantioseparations and related mechanisms were investigated by integrating theoretical and experimental data.
Asunto(s)
Carbamatos , Metanol , Metalocenos , Cromatografía Líquida de Alta Presión/métodos , Celulosa/química , Benzoatos , Agua , EstereoisomerismoRESUMEN
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.
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Compuestos Ferrosos , Metalocenos , Compuestos Ferrosos/química , Estereoisomerismo , Cromatografía Líquida de Alta Presión/métodosRESUMEN
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.
Asunto(s)
Estereoisomerismo , HumanosRESUMEN
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.
Asunto(s)
Calcógenos , Halógenos , EstereoisomerismoRESUMEN
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 (α) 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.
Asunto(s)
Halógenos , Polisacáridos , Cromatografía Líquida de Alta Presión , Halógenos/química , Metalocenos , Polisacáridos/química , Electricidad Estática , EstereoisomerismoRESUMEN
Planar chiral ferrocenes are well-known compounds that have attracted interest for application in synthesis, catalysis, material science, and medicinal chemistry for several decades. In spite of the fact that asymmetric synthesis procedures for obtaining enantiomerically enriched ferrocenes are available, sometimes, the accessible enantiomeric excess of the chiral products is unsatisfactory. In such cases and for resolution of racemic planar chiral ferrocenes, enantioselective high-performance liquid chromatography (HPLC) on polysaccharide-based chiral stationary phases (CSPs) has been used in quite a few literature articles. However, although moderate/high enantioselectivities have been obtained for planar chiral ferrocenes bearing polar substituents, the enantioseparation of derivatives containing halogens, or exclusively alkyl groups, remains rather challenging. In this study, the enantioseparation of ten planar chiral 1,2- and 1,3-disubstituted ferrocenes was explored by using five polysaccharide-based CSPs under multimodal elution conditions. Baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.20 to 2.92. The presence of π-extended systems in the analyte structure was shown to impact affinity of the most retained enantiomer toward amylose-based selectors, observing retention times higher than 80 min with methanol-containing mobile phases (MPs). Electrostatic potential (V) analysis and molecular dynamics (MD) simulations were used in order to study interaction modes at the molecular level.
Asunto(s)
Amilosa , Polisacáridos , Amilosa/química , Cromatografía Líquida de Alta Presión/métodos , Metalocenos , Polisacáridos/química , EstereoisomerismoRESUMEN
In capillary electrophoresis an enantioseparation of daclatasvir (DCV) was observed in case of heptakis(2,6-di-O-methyl)-ß-CD, heptakis(2-O-methyl)-ß-CD and ß-CD, while two peaks with a plateau were noted for heptakis(2,3,6-tri-O-methyl)-ß-CD and heptakis(2,3-di-O-methyl)-ß-CD indicating a slow equilibrium. Heptakis(6-O-methyl)-ß-CD and heptakis(3-O-methyl)-ß-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)-ß-CD, heptakis(2-O-methyl)-ß-CD and ß-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)-ß-CD and heptakis(2,3-di-O-methyl)-ß-CD yielded primarily 1:1 complexes. Higher order complexes between DCV and heptakis(2,6-di-O-methyl)-ß-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.
RESUMEN
CDs are cyclic oligosaccharides consisting of α-d-glucopyranosyl units linked through 1,4-linkages, which are obtained from enzymatic degradation of starch. The coexistence 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 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.
Asunto(s)
Electroforesis Capilar , Ciclodextrinas , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
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.
Asunto(s)
Simulación de Dinámica Molecular , Amilosa , Celulosa , Cromatografía Líquida de Alta Presión , Compuestos Heterocíclicos , Polisacáridos , EstereoisomerismoRESUMEN
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 ß-CD was observed here. In addition, opposite affinity pattern of THZ enantiomers was seen towards ß-CD and its acetylated derivatives, while methylation of ß-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.
Asunto(s)
Ciclodextrinas/química , Electroforesis Capilar/métodos , Imidazoles/análisis , Cromatografía Líquida de Alta Presión , Imidazoles/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Modelos Moleculares , EstereoisomerismoRESUMEN
The chalcogen bond (ChB) is a noncovalent interaction based on electrophilic features of regions of electron charge density depletion (σ-holes) located on bound atoms of group VI. The σ-holes of sulfur and heavy chalcogen atoms (Se, Te) (donors) can interact through their positive electrostatic potential (V) with nucleophilic partners such as lone pairs, π-clouds, and anions (acceptors). In the last few years, promising applications of ChBs in catalysis, crystal engineering, molecular biology, and supramolecular chemistry have been reported. Recently, we explored the high-performance liquid chromatography (HPLC) enantioseparation of fluorinated 3-arylthio-4,4'-bipyridines containing sulfur atoms as ChB donors. Following this study, herein we describe the comparative enantioseparation of three 5,5'-dibromo-2,2'-dichloro-3-selanyl-4,4'-bipyridines on polysaccharide-based chiral stationary phases (CSPs) aiming to understand function and potentialities of selenium σ-holes in the enantiodiscrimination process. The impact of the chalcogen substituent on enantioseparation was explored by using sulfur and non-chalcogen derivatives as reference substances for comparison. Our investigation also focused on the function of the perfluorinated aromatic ring as a π-hole donor recognition site. Thermodynamic quantities associated with the enantioseparation were derived from van't Hoff plots and local electron charge density of specific molecular regions of the interacting partners were inspected in terms of calculated V. On this basis, by correlating theoretical data and experimental results, the participation of ChBs and π-hole bonds in the enantiodiscrimination process was reasonably confirmed.
Asunto(s)
Calcógenos/química , Cromatografía Liquida/métodos , Compuestos Heterocíclicos/química , Polisacáridos/química , Piridinas/química , Piridinas/aislamiento & purificación , Termodinámica , Electricidad Estática , EstereoisomerismoRESUMEN
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.
RESUMEN
Positive electrostatic potential (V) values are often associated with σ- and π-holes, regions of lower electron density which can interact with electron-rich sites to form noncovalent interactions. Factors impacting σ- and π-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-Gatti source function (SF) for the electron density to V. In this article, this general methodology is applied to a series of 4,4'-bipyridine derivatives containing atoms from Groups VI (S, Se) and VII (Cl, Br), and the pentafluorophenyl group acting as a π-hole. As these molecules are characterized by a certain degree of conformational freedom due to the possibility of rotation around the two C-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 σ- and π-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 σ- and π-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 σ- and π-hole regions, aimed at affecting their potential involvement in noncovalent interactions in a desired way.