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.
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.
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 interaction 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.
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.
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, with the aims to provide a comprehensive and critical discussion of the topic, and account for some still open issues in this field.
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 toward its development. In this context, we designed and prepared new motifs containing three key substructures: namely, regions of electron charge density depletion centered 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 was also confirmed by X-ray diffraction analysis, showing 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.
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