Halogen Bond Formation Research Articles

Modulating the Competition between Different Atoms to Form Halogen Bonds

Modulating the Competition between Different Atoms to Form Halogen Bonds

Supramolecular Polymerization of Pseudo[2]rotaxanes Formation of per‐Imidazole Pillar[5]arene‐based Host–Guest Complexations and Halogen Bonding Interactions

AbstractIn this study, we reported the construction of 3D supramolecular polymeric networks using per‐imidazole pillar[5]arene (DIMP5) as a host and 1,4‐diiodotetrafluorobenzene (L) as a halogen bond donor in chloroform. The supramolecular polymerization process was characterized by 1H NMR, 19F NMR spectroscopy, and X‐ray single crystal analysis. The C─I⋯N distance (2.78 Å) and C─I⋯N angle (177°) clearly indicated the formation of halogen bonds in the crystal structure. Meanwhile, by introducing adiponitrile (G) as the guest, a supramolecular polymerization of pseudo[2]rotaxanes was also prepared, which was driven by DIMP5‐based host–guest complexations and halogen bonding interactions.

Crystallographic Evidence for Bi(I) as the Heaviest Halogen Bond Acceptor.

Complexation of the green bismuthinidene (RBi) with two equivalents of a highly fluorinated aryl iodide at low temperature allows the crystallographic identification of an unstable red species that can be regarded as an intermediate in an overall Bi(I) → Bi(III) oxidation process. Both C-I bonds are orientated toward the filled 6p orbital of bismuth (Bi-I distances 3.44-3.52 Å), leading to an elongation of the C-I bonds by 0.05 and 0.07 Å. Density functional theory (DFT) calculations confirm that the Bi(I) center is indeed acting as an electron donor, establishing two strong and directional halogen bonds. The color change from green to red upon halogen bond formation is a consequence of the energetic stabilization of a Bi(I) lone pair by interactions with the sigma-holes of the halogen bond donors. Overall, this study presents the first structural proof of bismuth, and more generally of heavy organopnictogen(I) compounds, acting as halogen bond acceptors.

Covalent Organic Frameworks in Computational Design of Second-Harmonic Generation Materials: Role of Tetrel Atoms and Their Interactions.

Modern approaches to the design of nonlinear optical materials often rely on computational techniques. Here, we discuss the effects of the variation in the center tetrel atoms, Tt = C, Si, or Ge, in a series of covalent organic frameworks of the COF-102 family. The effects of halogen substitution, Hal = Cl, Br, or I on intramolecular tetrel bonding are also discussed. The characteristics of the calculated electron density have been implemented to describe the features of the electron distribution around the central fragment involving a tetrahedral tetrel atom. The effect of the central Tt atom leads to a dramatic change in the character of electron delocalization on the Tt-Car bond with aromatic rings. The location of the halogen atom at the ortho-position of the aromatic ring leads to the formation of tetrel bonds, halogen bonds, or other noncovalent interactions. The changes in the second-order electric susceptibility χ(2) have been studied in order to describe the strength of nonlinear optical properties within the periodic couple-perturbed Kohn-Sham approach. A counterintuitive trend for the χ(2) decrease is observed upon substitution of H > Cl > Br > I at the ortho-position of the phenyl ring. This is due to the corresponding elongation of the Tt-Car bond.

AILDE Computer-Aided Discovery of Novel Ibuprofen-Coumarin Antitumor Lead Compounds Targeting Cyclooxygenase-2.

Starting from three ibuprofen-coumarin hit compounds, we designed 18 derivative compounds targeting cyclooxygenase-2 (COX-2) by introducing different substituents onto them by using the computational auto in silico ligand directing evolution (AILDE) method. After synthesizing and testing the activity, we found that 6 representative compounds have micromolar enzyme inhibitory activity against COX-2. Additionally, 16 compounds have shown certain inhibitory activity in cervical cancer cells. Among these compounds, 6c (IC50 = 0.606 μM, HeLa) and 7g (IC50 = 0.783 μM, HeLa) have exhibited excellent activity, which is approximately 10 times better than the commercial drug gefitinib. According to molecular simulation results, the halogen atoms of 6c and 7g on the coumarin ring can form halogen bonds with COX-2, which significantly improves their activity compared to their hit compounds 6a and 7a. However, the key interactions were lost in binding with COX-1. The calculation results revealed that the two compounds are selective COX-2 inhibitors, with potential selectivity indexes of 6-fold and 5-fold, respectively. The cell-based activity of compounds 6c and 7g toward HEK293 cells demonstrates that our compounds possess an acceptable safety toward normal cells. The results indicate that 6c and 7g can serve as potential lead compounds for further lucubrate.

Affinity of endosulfan and HCB with human serum albumin affects serum concentrations in a general population

Endosulfan and hexachlorobenzene (HCB) were previously widely used organochlorine pesticides. Much attention has been paid to trends in human exposure to endosulfan and HCB and to the transport and distribution of endosulfan and HCB within the body. We determined endosulfan I, endosulfan II, and HCB concentrations in serum samples collected from the general population of Wuxi in Jiangsu Province (China) between 2012 and 2016. The endosulfan concentrations varied little throughout the study period, but the HCB concentrations increased. The HCB concentrations were significantly higher in serum from overweight people and smokers than in serum from normal weight people (p = 0.028) and non-smokers (p = 0.011), respectively. HCB binds to human serum albumin (HSA) and can form halogen bonds to CYS-461 and ARG-484 at site II (subdomain IIIA). Fatty acids and nicotine increase the affinity between HCB and HSA, explaining the higher HCB concentrations in serum from overweight people and smokers than normal weight people and non-smokers, respectively.

Sensing diversity in halogen-bonded multi-stimuli responsive materials: Light, pH, magnetism, and electron-rich species

The present study delves into the synthesis and characterization of multi-stimuli responsive polymers, demonstrating their sensitivity towards magnetic field, pH level, light irradiation, and electron-rich species through halogen bonding (XB). Detailed X-ray analyses of two azobenzene derivatives, each incorporating a tetrafluoroiodobenzene group, provided the compelling evidence of engagement of the building blocks in the formation of halogen bonds. Interestingly, the investigation of an ammonium analog, featuring a tetrahalogenoferrate(III) anion, not only showcased a magnetic response even upheld its ability to undergo isomerization under UV irradiation. These functional properties were subsequently harnessed in the form of multi-responsive compounds through the random quaternization of poly(2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA), and by employing varying proportions of XB-donor dye (8, 11, 15, 21, and 43 %) followed by magnetic anion exchange. Leveraging the presence of free ternary amino groups and diazobenzene moieties, the resulting polymers demonstrated pronounced sensitivity towards a variation of pH and UV light stimuli, while a careful modulation of magnetic susceptibility was found to be directly proportional to the degree of quaternization. An NMR titration, conducted using a synthetic intermediate, revealed the formation of I⋯Cl‾ interactions in the solution state, thereby underscoring the materials' sensitivity to electron-rich species. Moreover, the electron microscopic analysis displayed an alteration in morphology upon the application of a magnetic field and UV irradiation. Thus, the presented strategic framework offers an avenue for the development of multi-stimuli responsive materials for remotely controlled smart devices to act in response to a diverse set of four stimuli, and heralding a significant advancement in the realm of responsive material design.

Molecular Interaction Fields Describing Halogen Bond Formable Areas on Protein Surfaces.

Molecular interaction fields (MIFs) are three-dimensional interaction maps that describe the intermolecular interactions expected to be formed around target molecules. In this paper, a method for the fast computation of MIFs using the approximation functions of quantum mechanics-level MIFs of small model molecules is proposed. MIF functions of N-methylacetamide with chlorobenzene, bromobenzene, and iodobenzene probes were precisely approximated and used to calculate the MIFs on protein surfaces. This method appropriately reproduced halogen-bond-formable areas around the ligand-binding sites of proteins, where halogen bond formation was suggested in a previous study.

Effect of a halogen bond on the crystal structure of terphenyldicarboxylic acid derivatives.

The syntheses and structures of dimethyl [11,21:24,31-terphenyl]-14,34-dicarboxylate (1), dimethyl 22,25-diiodo[11,21:24,31-terphenyl]-14,34-dicarboxylate (2), potassium [11,21:24,31-terphenyl]-14,34-dicarboxylate (3) and dimethyl [1,1'-biphenyl]-4,4'-dicarboxylate (4) are reported. Neighboring phenyl rings in compounds 1, 3 and 4 have a planar structure (torsion angles are 0.6-4.1°) and the molecules are packed into regular layers. In the structure of the iodinated derivative of terphenyldicarboxylic acid (2), the middle benzene ring of the terphenyl fragment is rotated relative to the other rings by 64° due to the repulsion between the protons and the iodine atoms of neighboring rings. The formation of halogen bonds between iodine and oxygen atoms of the carbonyl group leads to the movement of molecules of one layer into another layer and the loss of layered structure. Potassium [11,21:24,31-terphenyl]-14,34-dicarboxylate (3) forms crystals with an ionic structure. The coordination number of the potassium cation is eight and the resulting coordination polyhedron is a distorted square antiprism. Dianions in the potassium salt crystal are packed in layers similar to the layers in the dimethyl ethers 1 and 4. Salt 3 has high thermal stability to 500°C.

The dawn of hydrogen and halogen bonds and their crucial role in collisional processes probing long-range intermolecular interactions.

This perspective review focuses on the results of an internally consistent study developed in the Perugia laboratory, centered on the fundamental interaction components that, at large intermolecular distances, determine the formation of weak intermolecular hydrogen (HB) and halogen (XB) bonds. This investigation exploits old and novel molecular beam scattering experiments involving several gaseous prototypical systems. In particular, we focus on the kinetic energy dependence of the total (elastic + inelastic) integral cross-sections. Of particular interest is the measure of quantum interference patterns in the energy dependence of cross-sections of targeted systems and their shift compared to that of known reference systems. We interpreted these findings as interaction energy stabilization components, such as charge transfer, σ-hole, and polar flattening, that emerge at intermediate separation distance ranges and selectively manifest for specific geometries of collision complexes. Another significant observable we discuss is the absolute value of the cross-section and its dependence on permanent multipole moments of the collisional partners. Specifically, we show how the spontaneous orientation of rotationally cold and polar molecules, due to the electric field gradient associated with the interaction between permanent multipole moments, can significantly modify the magnitude of the total cross-section, even at high values of the impact parameter. We are confident that the present results can help extend the force field formulation to various interacting systems and carry out molecular dynamics simulations under conditions of application interest.

In vivo stability of 211At-radiopharmaceuticals: on the impact of halogen bond formation.

211At, when coupled to a targeting agent, is one of the most promising radionuclides for therapeutic applications. The main labelling approach consists in the formation of astatoaryl compounds, which often show a lack of in vivo stability. The hypothesis that halogen bond (XB) interactions with protein functional groups initiate a deastatination mechanism is investigated through radiochemical experiments and DFT modelling. Several descriptors agree on the known mechanism of iodoaryl substrates dehalogenation by iodothyronine deiodinases, supporting the higher in vivo dehalogenation of N-succinimidyl 3-[211At]astatobenzoate (SAB) conjugates in comparison with their iodinated counterparts. The guanidinium group in 3-[211At]astato-4-guanidinomethylbenzoate (SAGMB) prevents the formation of At-mediated XBs with the selenocysteine active site in iodothyronine deiodinases. The initial step of At-aryl bond dissociation is inhibited, elucidating the better in vivo stability of SAGMB conjugates compared with those of SAB. The impact of astatine's ability to form XB interactions on radiopharmaceutical degradation may not be limited to the case of aryl radiolabeling.

A comparison of structure, bonding and non-covalent interactions of aryl halide and diarylhalonium halogen-bond donors.

Halogen bonding permeates many areas of chemistry. A wide range of halogen-bond donors including neutral, cationic, monovalent, and hypervalent have been developed and studied. In this work we used density functional theory (DFT), natural bond orbital (NBO) theory, and quantum theory of atoms in molecules (QTAIM) to analyze aryl halogen-bond donors that are neutral, cationic, monovalent and hypervalent and in each series we include the halogens Cl, Br, I, and At. Within this diverse set of halogen-bond donors, we have found trends that relate halogen bond length with the van der Waals radii of the halogen and the non-covalent or partial covalency of the halogen bond. We have also developed a model to calculate ΔG of halogen-bond formation by the linear combination of the % p-orbital character on the halogen and energy of the σ-hole on the halogen-bond donor.

Assessment of Halogen Off-Center Point-Charge Models Using Explicit Solvent Simulations.

Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods, allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature, and despite being efficient in reproducing protein-ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (ΔGhyd), which are often used to validate force field performance. In this work, we report the first assessment of three EP models using alchemical free energy calculations to predict ΔGhyd values. We show that describing the halogen anisotropy using some EP models can lead to a slight improvement in the prediction of the ΔGhyd when compared with the models without EP, especially for the chlorinated compounds; however, this improvement is not related to the establishment of XBs but is most likely due to the improvement of the sampling of hydrogen bonds. We also highlight the importance of the choice of the EP model, especially for the iodinated molecules, since a slight tendency to improve the prediction is observed for compounds with a larger σ-hole but significantly worse results were obtained for compounds that are weaker XB donors.

Cebranopadol: An Assessment for Its Biased Activation Potential at the Mu Opioid Receptor by DFT, Molecular Docking and Molecular Dynamic Simulation Studies

AbstractCocaine use disorder is a psychiatric condition affecting millions of people worldwide. Up till now, there are no FDA approved medications reported against this disorder. Previous pharmacological studies suggested that, simultaneously targeting all types of opioid receptors, some agonistically while others antagonistically have been proven a much useful strategy for the treatment of cocaine addiction. Recent evidence indicated that a novel agonist cebranopadol has a high binding affinity towards Nociceptin opioid receptor (NOP) and Mu opioid receptor (MOP), and partial affinity with Kappa opioid receptor (KOP) and Delta opioid receptor (DOP). Interestingly, in vivo studies revealed that cebranopadol blocked the cocaine seeking in animal models. In the present study, quantum chemical calculations were performed to calculate various thermodynamic parameters of cebranopadol using density functional theory. Flexible docking was performed to rationalize the molecular basis of cis and trans isomers of cebranopadol. Further, the atomistic description of activation mechanism of MOP receptor by cebranopadol investigated by sub‐microsecond timescale molecular dynamic (MD) simulation. Our results revealed that the operating mode of the activation switch composed of Trp2936.48 and Asn3287.45 residues, was accountable for down‐ and up‐regulation, respectively, of the β‐arrestin signaling. This particular conformational change in turn affected the G‐protein‐biased activation of MOP receptor. Cebranopadol stabilized the Asn3287.45 by mediating halogen bond formation. According to best of our knowledge, this is the first mechanistic study of cebranopadol with MOP receptor using the quantum mechanical calculations and MD simulations to explain the inhibition of cocaine addiction.

Creating an Amyloid 'Kaleidoscope' Using Short Iodinated Peptides.

Amyloid fibrils formed by peptides with different sequences exhibit diversified morphologies, material properties and activities, making them valuable for developing functional bionanomaterials. However, the molecular understanding underlying the structural diversity of peptide fibrillar assembly at atomic level is still lacking. In this study, by using cryogenic electron microscopy, we first revealed the structural basis underlying the highly reversible assembly of 1 GFGGNDNFG9 (referred to as hnRAC1) peptide fibril. Furthermore, by installing iodine at different sites of hnRAC1, we generated a collection of peptide fibrils with distinct thermostability. By determining the atomic structures of the iodinated fibrils, we discovered that iodination at different sites of the peptide facilitates the formation of diverse halogen bonds and triggers the assembly of entirely different structures of iodinated fibrils. Finally, based on this structural knowledge, we designed an iodinated peptide that assembles into new atomic structures of fibrils, exhibiting superior thermostability, that aligned with our design. Our work provides an in-depth understanding of the atomic-level processes underlying the formation of diverse peptide fibril structures, and paves the way for creating an amyloid "kaleidoscope" by employing various modifications and peptide sequences to fine-tune the atomic structure and properties of fibrillar nanostructures.

Creating an Amyloid ‘Kaleidoscope’ Using Short Iodinated Peptides

AbstractAmyloid fibrils formed by peptides with different sequences exhibit diversified morphologies, material properties and activities, making them valuable for developing functional bionanomaterials. However, the molecular understanding underlying the structural diversity of peptide fibrillar assembly at atomic level is still lacking. In this study, by using cryogenic electron microscopy, we first revealed the structural basis underlying the highly reversible assembly of 1GFGGNDNFG9 (referred to as hnRAC1) peptide fibril. Furthermore, by installing iodine at different sites of hnRAC1, we generated a collection of peptide fibrils with distinct thermostability. By determining the atomic structures of the iodinated fibrils, we discovered that iodination at different sites of the peptide facilitates the formation of diverse halogen bonds and triggers the assembly of entirely different structures of iodinated fibrils. Finally, based on this structural knowledge, we designed an iodinated peptide that assembles into new atomic structures of fibrils, exhibiting superior thermostability, that aligned with our design. Our work provides an in‐depth understanding of the atomic‐level processes underlying the formation of diverse peptide fibril structures, and paves the way for creating an amyloid “kaleidoscope” by employing various modifications and peptide sequences to fine‐tune the atomic structure and properties of fibrillar nanostructures.

Impact of Intermolecular Interactions between Halogenated Volatile Solid Additives and the Nonfullerene Acceptor in Organic Solar Cells

AbstractThe halogenated volatile solid additives can delicately optimize the active layer morphology of organic solar cells, improving the devices' performance, stability, and reproducibility. However, what type of intermolecular interaction occurs between the solid additives and the active layer and whether the interaction truly impacts the donor or acceptor remains debatable. Herein, the focus is on halogenated volatile solid additives with conjugated benzene rings and their influence on the morphology of the active layer composed of PM6:Y6 as they evaporated. The absorbance spectra exhibit apparent red‐shift features in Y6 absorption regions, while the donor part is unaffected. The theoretical calculation results reveal that the additives can stay between two Y6 molecules and form halogen bonds, affecting the π–π aggregation properties of Y6. As a result, the crystalline features of the active layer are altered, leading to increased charge carrier mobilities, extended charge carrier diffusion lengths, reduced bimolecular charge recombination, and thus the device performance. Especially when 1,3,5‐tri bromobenzene is used, a champion power conversion efficiency of 17.9% is attained, among the best‐performed organic solar cells comprising PM6:Y6. The findings shed light on theoretical and experimental guidelines for designing and developing volatile solid additives for highly efficient nonfullerene organic solar cells.

Synthesis and characterization of a new chalcone-based nonlinear optical crystal: BBC

A new chalcone-based nonlinear optical crystal BBC (C22H17BrO2) using long π-conjugated and halogen substituent, as a potential alternative to develop organic crystals, are reported. BBC was designed and synthesized by replacing benzyloxy and -Br groups on both sides of molecular framework. Flaky yellowish BBC single crystal with size of 5 × 5 × 1 mm3 was grown by solution evaporation method. BBC crystal crystallizes in the monoclinic system, Pc (NO. 7) space group, with noncentrosymmetric structure. In the BBC molecule, benzyl oxide acts as donor (D) and Br and carbonyl group act as acceptor (A), forming D - π - A - π - A structure with electron gradient. The introduction of Br group, which contributes to strong halogen bond formation, lead to the “head-to-tail” arrangement. Remarkably, BBC exhibits strong second harmonic generation (SHG) intensity (14 × KDP and 2.2 × Urea), wide transmission range (600-1600 nm, >60%), high optical energy gap (Eg=2.85 eV) and high thermal stability (Tm=106 °C). In addition, to investigate the relationships between the structure and physical properties, the electronic structure and optical properties of BBC crystal were theoretically calculated. This work not only provides a newly chalcone-based NLO crystal, but also presents a feasible molecular design approach by introducing long π-conjugated and halogen substituents.

Dispersion-Corrected DFT-D4 Study of the Adsorption of Halobenzenes and 1,3,5-Trihalobenzenes on the Cu(111) Surface─Effect of Sigma Hole Properties.

Halogen bonds, characterized by directionality, tunability, hydrophobicity, and variable sizes, are ideal noncovalent interactions to design and control the formation of self-assembled nanostructures. The specific self-assembly cases formed by the halogen-bonding interaction have been well studied by scanning tunneling microscopy (STM) experiments and density functional theory (DFT) calculations. However, there is a lack of systematic theoretical adsorption studies on halogenated molecules. In this work, the adsorption of halobenzenes and 1,3,5-trihalobenzenes on the Cu(111) surface was examined by dispersion-corrected DFT methods. The adsorption geometries, noncovalent molecule-surface interactions, electronic densities, and electrostatic potential maps were examined for their most stable adsorption sites using the DFT-D4 method. Our calculations revealed that the iodo compounds favor a different adsorption geometry from aryl chlorides and bromides. Down the halogen group (Cl to I), the adsorption energy increases and the distance between the halogen atom and Cu surface decreases, which indicates stronger molecule-surface interactions. This is supported by the changes in the density of states upon adsorption. Noncovalent interaction analysis was also employed to further understand the nature and relative strength of the molecule-surface interactions. Electrostatic potential maps revealed that the positive character of the halogen sigma hole becomes stronger upon adsorption. Thus, surface adsorption of the halogenated molecule will enhance the formation of intermolecular halogen bonds. The present theoretical findings are expected to contribute toward a more comprehensive understanding of halogen bonding on the Cu(111) surface.

Manipulation of the Structure and Optoelectronic Properties through Bromine Inclusion in a Layered Lead Bromide Perovskite.

One of the great advantages of organic-inorganic metal halides is that their structures and properties are highly tuneable and this is important when optimizing materials for photovoltaics or other optoelectronic devices. One of the most common and effective ways of tuning the electronic structure is through anion substitution. Here, we report the inclusion of bromine into the layered perovskite [H3N(CH2)6NH3]PbBr4 to form [H3N(CH2)6NH3]PbBr4·Br2, which contains molecular bromine (Br2) intercalated between the layers of corner-sharing PbBr6 octahedra. Bromine intercalation in [H3N(CH2)6NH3]PbBr4·Br2 results in a decrease in the band gap of 0.85 eV and induces a structural transition from a Ruddlesden-Popper-like to Dion-Jacobson-like phase, while also changing the conformation of the amine. Electronic structure calculations show that Br2 intercalation is accompanied by the formation of a new band in the electronic structure and a significant decrease in the effective masses of around two orders of magnitude. This is backed up by our resistivity measurements that show that [H3N(CH2)6NH3]PbBr4·Br2 has a resistivity value of one order of magnitude lower than [H3N(CH2)6NH3]PbBr4, suggesting that bromine inclusion significantly increases the mobility and/or carrier concentration in the material. This work highlights the possibility of using molecular inclusion as an alternative tool to tune the electronic properties of layered organic-inorganic perovskites, while also being the first example of molecular bromine inclusion in a layered lead halide perovskite. By using a combination of crystallography and computation, we show that the key to this manipulation of the electronic structure is the formation of halogen bonds between the Br2 and Br in the [PbBr4]∞ layers, which is likely to have important effects in a range of organic-inorganic metal halides.