Some Theoretical Insight Into Application Of Halogen Bonds

Halogen bonds (XB), as an important type of non-covalent action, have attracted extensive attention due to the range of potential applications in various fields as diverse as functional materials, drug discovery, crystal engineering, and supramolecular architectures. This specific binding pattern commonly consists of two interaction part, organic halogen (C-X, Lewis acids) and neutral or anionic Lewis bases (D). Its interesting strength and directionality have been rationalized by the anisotropic distribution of electron density around halogens, i.e., presence of a positive electrostatic potential cap at theσ-region and a negative electrostatic ring in theπ-region.As an extension of studies on halogen bonding, our focus was on identifying and exploring its controlling behaviors in a series of reported applications, particularly in the kinetic proceeding of halogenation reactions, polymeric self-assemblies of phosphazene and its derivatives, as well as the M-C-X…X’ synthon derived from metal-organic-supramolecular architectures, and roles of halogen bonding in regulating nucleic acid configurations. These studies, in combination to halogen-bonded analyses, not only enrich our knowledge on halogen bonding, but also would be greatly useful for design and synthesis of novel functional solid materials and desired drugs. The main calculations and results are as follows:(1) The 1:1 Hal/πcomplexes formed from dihalogen molecules with alkenes or alkynes are particularly fundamental prereactive complexes (or intermediates) in halogenation of unsaturated hydrocarbons. For this type of chemical rations, the overall third-order kinetic law with respect to the haloid concentration should be more reasonable. Herein, Theoretical calculations on halogen…πinteractions between halogen molecules and unsaturated hydrocarbons have been performed on the model system R…(XY)n (R=ethylene or ethyne; XY= Cl2, ClF, ClBr, Br2, BrF, BrCl; n=1～2). The conclusions showed that the addition of a second dihalogen acting as electron acceptors to the 1:1 Hal/πcomplexes shortens the halogen…πdistance and enhances significantly the halogen…πinteraction energy. Origin of the positively cooperative effect has been explored in terms of variation of charge transfer induced by the additional dihalogen molecule. The AIM analysis has also been made and the results revealed that the electron density and its Laplacian, especially the former, can also be used to describe the relative strength of halogen…πinteractions in the trimolecular complexes.(2) The P-bound halogen (P-X) likely plays an induction role in self-assembly process of polymeric and supramolecular architectures. We performed a theoretical study at a reliable level of DFT calculations on a series of dimeric complexes formed between hexachlorocyclotriphosphazene (HCCP) and several electron donors (NH3, H2O, SH2, SH-，OH-, Br-, Cl- and F-). In all cases, the intermolecular distances are shown to be equal to or below sums of van der Waals radii of the atoms involved. Halogen bonding energies, calculated at the B971/6-311+G (d, p) level, span over a relatively lager range, from -0.95 to -95.30 kcal/mol, which intimate that the interactions are comparable to, or even partly prevail over, the conventional hydrogen bonding. For the charge-assisted systems, calculations show that these systems can result in much stronger halogen bonding than the corresponding neutral ones. The results agree well with those of natural population analysis (NPA). Finally, the theory of atoms in molecules (AIM) was applied to provide more insight into the nature of these interactions. Also, these conclusions on P-Cl…D can extend the concept of classical halogen bonding.(3) Considering the two-or three-dimensional arrangements of C-X…X’-M synthons in polymeric metal-organic networks, one readily finds coordination of organic halogenated ligands to the adjacent metal centers, which produces a novel halogen-bonded contact, M-C-X…X’. A set of model systems, Cu-L…D, where L denotes the bromopyridine molecule, and D corresponds to electron density donors such as F-, Cl-, Br-, OH-, CN-, NH3, and H2O, was typically set up to simulate the metal-influenced halogen-bonded interaction. The optimized calculations indicate that, while coordinating to metal ions, the end-bromine of organic halide subunit exhibits better directionality and affinity to electron density donors. Halogen bonding energies are substantial and range from -2.5～-37.5 kcal/mol. These results reveal the importance of metal-influenced halogen bonding in directing supramolecular arrangements. To further study the nature of the halogen bond, the analyses of NBO and AIM were carried out. The conclusions show a considerable extent of charge transfer, complicated orbital interactions, and distinct bond critical points between interacting atoms upon halogen bonding.(4) As a part of our ongoing studies on M-C-X…X’, a detailed comparison of the properties for two series of model complexes has been performed to explore the M-C-X…X’ halogen bond. It is described here how the incorporated metallic complexes affect the electronic property of organic halide and properties of halogen-bonded interactions. A set of theoretical models, consisting of two series of complexes PyCl…X (PyCl=NC5H4Cl-4; X=F-, Cl-, or Br) and MPyCl…X (M=Cu+, Zn2+), was utilized to reveal features of M-C-X…X’. To explore the influence of metal centers, a detailed comparison of the properties in PyCl…X and MPyCl…X complexes was carried out. The results showed that, while coordinating to metals, interaction energies and charge transfers exhibit a remarkable increase, which have been rationalized by analyses of electrostatic potential and density difference function. Furthermore, the individual energy contributions were examined through the symmetry-adapted perturbation theory, and the results indicated that the dominant energy contribution emerges from the electrostatic and induction energy, and the electrostatic term presents a higher increment than other energy components.(5) Halogen bonding can direct the local stereochemical properties of nucleic acids by unique geometric preferences but has been inaccessible to most theoretical studies. Using a two-layer ONIOM method, halogen bonds buried in nucleic acid environments were studied by modeling the nucleotide C-Br…O-P contacts in nucleic acids of 1P54 and 1RLG (PDB code). The reduced density gradient (RDG) method shows that the presence of halogen bonds in large nucleic acid systems by visualizing the isosurfaces of the noncovalent interactions. Calculations performed at ONIOM(B3LYP/6-31G(d):Amber) level on the nucleic acid systems further reveal the geometrical features of these halogen bonds. The analysis of the electron location function (ELF) adopted for the complex unit indicates an anisotropic distribution of the lone-pairs on the halogens, which rationalizes directional halogen bonding by matching the core basins of halogens with the valence shells of the halogen acceptors. Moreover, the influence of halogen bonding on local conformations of nucleic acids has been detected by comparison with a hydrogen containing version of 5-bromouracil, and the results show that the flexible chains of halogenated nucleic acids are sensitive to the presence of halogen bonds.(6) Halogen bonds are being increasingly appreciated in biological systems with the development of modern analytic methods. However, present molecular dynamic simulations, which rely primarily on empirical force fields, are defective to account for halogen bonds due to a lack of consideration for polarization effects of halogens. Hence a site model, in combination to density anisotropy of halogens, has been built to parameterize atomic charges. Validation of the model was done through comparisons of dynamics and geometrical features using RESP and artificial ESP (model) charges in conjunction with the general AMBER force field. The conclusions show that such model is sensitive to binding surroudings, which is insufficient to demonstrate danymic behaviors of halogen bonding in biological systems. Even so, this treatment provides a primary clue of improving parameters of force fields, and further work will be carried out in future.