Halogen Bond Donor Research Articles

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.

Data and Molecular Fingerprint-Driven Machine Learning Approaches to Halogen Bonding.

The ability to predict the strength of halogen bonds and properties of halogen bond (XB) donors has significant utility for medicinal chemistry and materials science. XBs are typically calculated through expensive ab initio methods. Thus, the development of tools and techniques for fast, accurate, and efficient property predictions has become increasingly more important. Herein, we employ three machine learning models to classify the XB donors and complexes by their principal halogen atom as well as predict the values of the maximum point on the electrostatic potential surface (VS,max) and interaction strength of the XB complexes through a molecular fingerprint and data-based analysis. The fingerprint analysis produces a root-mean-square error of ca. 7.5 and ca. 5.5 kcal mol-1 while predicting the VS,max for the halobenzene and haloethynylbenzene systems, respectively. However, the prediction of the binding energy between the XB donors and ammonia acceptor is shown to be within 1 kcal mol-1 of the density functional theory (DFT)-calculated energy. More accurate predictions can be made from the precalculated DFT data when compared to the fingerprint analysis.

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.

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt.

Diaryliodonium(III) salts have been established as powerful halogen-bond donors in recent years. Herein, a new structural motif for this compound class was developed: iodoloisoxazolium salts, bearing a cyclic five-membered iodolium core fused with an isoxazole ring. A derivative of this class was synthesized and investigated in the solid state by X-ray crystallography. Finally, the potential as halogen-bonding activator was benchmarked in solution in the gold-catalyzed cyclization of a propargyl amide.

Illuminating the Performance of Electron Withdrawing Groups in Halogen Bonding.

Throughout the halogen bonding literature, electron withdrawing groups are relied upon heavily for tuning the in- teraction strength between the halogen bond donor and acceptor; however, the interplay of electronic effects associated with various substituents is less of a focus. This work utilizes computational techniques to study the degree ofσ- andπ- electron donating/accepting character of electron withdrawing groups in a prescribed set of halo-alkyne, halo-benzene, and halo-ethynyl benzene halogen bond donors. We examine how these factors affect theσ-hole magnitude of the donors as well as the binding strength of the corresponding complexes with an ammonia acceptor. Statistical analyses aid the interpretation of how these substituents influence the properties of the halogen bond donors and complexes, and show that the electron withdrawing groups that are bothσ- andπ-electron accepting form the strongest halogen bond complexes.

Pyrazolyliodonium platinum(II) trichloride features the highest positive electrostatic potential on the iodine atom among uncharged halogen bond donors

This study presents a new uncharged platinum(II) complex with a pyrazolyliodonium ligand, which features an exceptionally large σ-hole on the iodine atom. Single-crystal X-ray diffraction analysis reveals the structure of the [LPtCl3]·2DMF complex, highlighting two types of intermolecular halogen bonds: a C−I⋯O bond with DMF and C−I⋯Cl bonds with the platinum complex. Quantum chemical calculations confirm the high positive electrostatic potential on the iodine σ-hole, demonstrating its significant halogen bond donor ability.

Role of secondary interactions in a series of 2:1 halogen-bonded cocrystals formed between 4-(dimethylamino)pyridine and ditopic halogen-bond donors.

The structures of a series of 2:1 cocrystals formed between 4-(dimethylamino)pyridine and each of 1,2,4,5-tetrachloro-3,6-diiodobenzene, 2C7H10N2·C6Cl4I2, 1,2,4,5-tetrabromo-3,6-diiodobenzene, 2C7H10N2·C6Br4I2, 1-bromo-4-iodo-2,3,5,6-tetrafluorobenzene, 2C7H10N2·C6BrF4I, and 1,2-dibromo-4,5-difluoro-3,6-diiodobenzene, 2C7H10N2·C6Br2F2I2, are reported. In all five structures, the core halogen-bonded 2:1 trimolecular units have geometrically similar parameters, with the central halogen-bond donor flanked by two pyridine halogen-bond acceptors twisted with respect to the central halogen-bond donor at angles ranging from 76 to 86°. The I...N halogen-bond separations are all short, ranging from 73.3 to 76.7% of the sum of the van der Waals radii, while the C-I...N bond angles are essentially linear. The Br...N halogen-bond separation in the cocrystal formed with 1-bromo-4-iodo-2,3,5,6-tetrafluorobenzene is 80.4% of the sum of the van der Waals radii. Subtle differences in the crystal packings are attributed to the role of secondary C-H...π and weak π-type interactions with chloro and bromo substituents. The cocrystals 2C7H10N2·C6Cl4I2 and 2C7H10N2·C6Br4I2 are isomorphous.

Structure-based pharmacophore modeling for precision inhibition of mutant ESR2 in breast cancer: A systematic computational approach.

Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand-binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in-house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild-type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of -8.26, -5.73, -10.80, and -8.42 kcal/mol, respectively, along with the control -7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM-GBSA analysis. Based on MD simulations and MM-GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy.

Hypervalent Iodine (III)-Based Complexation for Chiroptical Supramolecular Glass, Deep Eutectic Solvent and Luminescent Switch.

Hypervalent iodine(III) have widely been utilized for organic synthetic reagents. They are also recognized as positive charge-assisted, exceptionally robust biaxial halogen bond donors, while their potential in supramolecular materials is barely explored. This work reports a cyclic diaryliodonium ion as biaxial halogen bonding donor that displays remarkable binding affinity toward phenanthroline or acridine acceptors with chiral pendants. Biaxial halogen bonding enables chiroptical evolution in solution, allowing for rational control over supramolecular chirality. Leveraging their strong binding affinity, the halogen bonding complexes manifested amorphous properties and deep eutectic behavior in the solid state. Capitalizing on these attributes, this work achieves the successful preparation of supramolecular glasses and deep eutectic solvents. Additionally, halogen bonding appended light irradiation-triggered luminescence through a hydrogen atom transfer process, showing applications in anti-counterfeit and display.

Hydrogen bonding, halogen bonding and C–H…π interactions governing the supramolecular architecture of 1-(4-(4-bromophenyl)piperazin-1-yl)-2-chloroethan-1-one: Insights from X-ray crystallography, DFT calculations and urease inhibitory assessment

The use of organic ligands for the generation of supramolecular architectures exhibiting interesting structural properties in crystal engineering have garnered significant attention. In this context, the current work highlights the use of 1-(4-(4-bromophenyl)piperazin-1-yl)-2-chloroethan-1-one (3) as a valuable synthon for evaluating the conspicuous role of several types of noncovalent interactions governing the formation of supramolecular assemblies. Compound 3 was successfully synthesized in good yield using a facile two-step approach and characterized through spectroscopic and X-ray crystallographic methods. Noncovalent interactions including C—H…O, C—H…Cl, C—H…π as well as C—Br…Cl halogen bonds were found as the key contacts in the crystal packing of compound 3. DFT calculations were employed to identify and assess the impact of the C—Br…Cl halogen bond, utilizing MEP, QTAIM, and NBO analyses. These studies confirmed that the Br atom acts as the halogen bond donor and the Cl atom as the halogen bond acceptor. Assessment of urease inhibitory efficacy revealed that the tested compound exhibits a 16-folds superior inhibition than thiourea. Computational modeling analysis augmented the in vitro results by exhibiting numerous favorable binding interactions between compound 3 and active site residues such as TYR32, LYS709, PHE712, ASP730, VAL744 and MET746. The pharmacokinetic evaluation classified the investigated piperazine derivative into a druggable compound.

Perhalogenated Anilines as Bifunctional Donors of Hydrogen and Halogen Bonds in Cocrystals with Ditopic Nitrogen-Containing Acceptors.

In this study, we examine the experimental and theoretical capabilities of two perhalogenated anilines, 2,3,5,6-tetrafluoro-4-bromoaniline (btfa) and 2,3,5,6-tetrafluoro-4-iodoaniline (itfa) as hydrogen and halogen bond donors. A series of 11 cocrystals derived from the two anilines and selected ditopic nitrogen-containing acceptors (4,4'-bipyridine, 1,2-bis(4-pyridyl)ethane, and 1,4-diazabicyclo[2.2.2]octane) in 1:1 and 2:1 stoichiometries were prepared by liquid-assisted grinding and crystallization from solution. Crystallographic analysis revealed bifunctional donor properties in both anilines. The dominant supramolecular interaction in four cocrystals of btfa is the N-H···Nacceptor hydrogen bond between btfa and acceptor molecules, while in the one remaining cocrystal, donor and acceptor molecules are connected via the N-H···Nacceptor hydrogen bond and the Br···Nacceptor halogen bond. In two cocrystals of itfa, the dominant supramolecular interaction is the I···Nacceptor halogen bond between itfa and acceptor molecules, while in the remaining four cocrystals, donor and acceptor molecules are additionally connected by the N-H···Nacceptor hydrogen bond. Periodic density-functional theory (DFT) calculations have been conducted to assess the formation energies of these cocrystals and the strengths of the established halogen and hydrogen bonds. Molecular DFT calculations on btfa and itfa indicate that the differences in electrostatic potential between the competing sites on the molecules are 261.6 and 157.0 kJ mol-1 e-1, respectively. The findings suggest that itfa, with a smaller electrostatic potential difference between donor sites, is more predisposed to act as a bifunctional donor.

Fluoro and Trifluoromethyl Benzoyl Hypoiodite Complexes with Substituted Pyridines.

Based on the prior observation of the trifluoroacetate hypoiodite, CF3C(O)OI, demonstrating the largest σ-hole of a neutral halogen bond donor, a series of mono- and bis-carbonyl hypoiodites utilising trifluoromethyl or fluorine substituents at various positions of a parent benzoyl skeleton have been synthesised. The carbonyl hypoiodite complexes were prepared via cation exchange of the silver(I) cations with iodine(I) from the respective silver(I) carboxylates and dicarboxylates as the synthetic precursors. A range of pyridinic Lewis bases of varying nucleophilicities were used to stabilise the carbonyl hypoiodites to further probe their properties. The silver(I) intermediates with these Lewis bases were also isolated for silver(I) pentafluorobenzoate, providing additional insight into the cation exchange reaction. All complexes were characterised both in solution (1H, 1H-15N HMBC, 19F) and in the solid state (SCXRD), permitting insights into the formation of the elusive pyridine-iodine(I) cation.

Hypervalent Iodine(III) Mediated Halogen Bonded Supramolecular Chiral System with Cholesteryl Naphthalimides.

Halogen bonding acknowledged as a noteworthy weak interaction, has gained growing recognition in the field of supramolecular chemistry. In this study, we selected structurally rigid diaryliodonium ions (I(III)) with two biaxial σ-holes as halogen-bond donors, to bind with three chiral acceptor molecules bearing cholesteryl and naphthalimides with distinct geometries. The abundant carbonyl oxygen atoms in side-arm substituents function as multiple acceptors for halogen bonding. The self-aggregation of chiral acceptor molecules demonstrates adaptiveness to solvent media, evidenced by the inversion of the Cotton effect and the morphological evolution from spherical to rod-like nanoarchitectures in different solvent systems. The distinct geometries of the acceptor molecules conferred various binding modes with I(III). The introduction of I(III) as a halogen-bond donor regulates the aggregation of the donors, achieving amplification of chiroptical signals and inheriting solvent responsiveness from the self-aggregated assembly. This study successfully utilized rational structural design and multimodal control strategies to achieve regulation of supramolecular chirality.

Diphenylene Iodonium as a Prominent Halogen Bond Donor: The Case of Human Monoamine Oxidase B.

Herein we have investigated the formation and interplay of several noncovalent interactions (NCIs) involved in the inhibition of human monoamine oxidase B (MAO B). Concretely, an inspection of the Protein Data Bank (PDB) revealed the formation of a halogen bond (HlgB) between a diphenylene iodonium (DPI) inhibitor and a water molecule present in the active site, in addition to a noncovalent network of interactions (e. g. lone pair-π, hydrogen bonding, OH-π, CH-π and π-stacking interactions) with surrounding protein residues. Several theoretical models were built to understand the strength and directionality features of the HlgB in addition to the interplay with other NCIs present in the active site of the enzyme. Besides, a computational study was carried out using DPI as HlgB donor and several electron rich molecules (CO, H2O, CH2O, HCN, pyridine, OCN-, SCN-, Cl- and Br-) as HlgB acceptors. The results were analyzed using several state-of-the-art computational tools. We expect that our results will be useful for those scientists working in the fields of rational drug design, chemical biology as well as supramolecular chemistry.

An Iridium Complex as Bidentate Halogen Bond-Based Anion Receptor Featuring an IncreasedOptical Response.

We present a luminescent Ir(III) complex featuring a bidentate halogen bond donor site capable of strong anion binding. The tailor-made Ir(III)(L)2 moiety offers a significantly higher emission quantum yield (8.4 %) compared to previous Ir(III)-based chemo-sensors (2.5 %). The successful binding of chloride, bromide and acetate is demonstrated using emission titrations. These experiments reveal association constants of up to 1.6×105 M-1. Furthermore, a new approach to evaluate the association constant by utilizing the shift of the emission was used for the first time. The experimentally observed characteristics are supported by quantum chemical simulations.

Halogen Bond-Assisted Supramolecular Dimerization of Pyridinium-Fused 1,2,4-Selenadiazoles via Four-Center Se2N2 Chalcogen Bonding.

The synthesis and structural characterization of α-haloalkyl-substituted pyridinium-fused 1,2,4-selenadiazoles with various counterions is reported herein, demonstrating a strategy for directed supramolecular dimerization in the solid state. The compounds were obtained through a recently discovered 1,3-dipolar cycloaddition reaction between nitriles and bifunctional 2-pyridylselenyl reagents, and their structures were confirmed by the X-ray crystallography. α-Haloalkyl-substituted pyridinium-fused 1,2,4-selenadiazoles exclusively formed supramolecular dimers via four-center Se···N chalcogen bonding, supported by additional halogen bonding involving α-haloalkyl substituents. The introduction of halogens at the α-position of the substituent R in the selenadiazole core proved effective in promoting supramolecular dimerization, which was unaffected by variation of counterions. Additionally, the impact of cocrystallization with a classical halogen bond donor C6F3I3 on the supramolecular assembly was investigated. Non-covalent interactions were studied using density functional theory calculations and topological analysis of the electron density distribution, which indicated that all ChB, XB and HB interactions are purely non-covalent and attractive in nature. This study underscores the potential of halogen and chalcogen bonding in directing the self-assembly of functional supramolecular materials employing 1,2,4-selenadiazoles derived from recently discovered cycloaddition between nitriles and bifunctional 2-pyridylselenyl reagents.

Evaluation of Concomitant Halogen and Pnictogen Bonds in Cocrystals of Imines Derived from 2-Nitrobenzaldehyde and 4-Haloaniline.

Three imines have been prepared by condensation of 2-nitrobenzaldehyde and 4-haloanilines (halo = Cl, Br, and I) with functionalities that enabled them to act as both halogen and pnictogen bond donors; however, both interactions were found to be absent in the solid state. The prepared imines were further cocrystallized with 1,3-diiodotetrafluorobenzene and 1,3,5-triiodotetrafluorobenzene as halogen bond donors. Six novel cocrystals were prepared by means of liquid-assisted mechanochemical synthesis and by crystallization from solution. All six cocrystals were of 1:1 stoichiometry and comprised a N···I halogen bond between an iodine atom of the perhalogenated halogen bond donor and the imino nitrogen atom of the imine acting as an acceptor. Additionally, in all six cocrystals, the imine molecules were interconnected by NO2···NO2 pnictogen bonding interactions. Computational analysis has shown that the NO2···NO2 exhibits bond critical point electron densities in the region (4.897-8.306) × 10-3 e Å-3 and interaction energies of 23.6-27.7 kJ mol-1, whereas the N···I halogen bonds generally have higher critical point electron densities ((1.795-1.937) × 10-2 e Å-3), but the corresponding total interaction energies are lower (19.4-20.4 kJ mol-1). Statistical analysis of the appearance of NO2···NO2 contacts concomitantly with halogen or hydrogen bonds seems to indicate that there is a positive correlation between the presence of NO2···NO2 pnictogen bonding interactions and other directional interactions in crystal structures.

Comparison of N···I and N···O Halogen Bonds in Organoiodine Cocrystals of Heterocyclic Aromatic Diazine Mono-N-oxides.

A series of cocrystals of halogen bond donors 1,4-diiodotetrafluorobenzene (p-F4DIB) and tetraiodoethylene (TIE) with five aromatic heterocyclic diazine mono-N-oxides based on pyrazine, tetramethylpyrazine, quinoxaline, phenazine, and pyrimidine as halogen bonding acceptors were studied. Structural analysis of the mono-N-oxides allows comparison of the competitive occurrence of N···I vs O···I interactions and the relative strength and directionality of these two types of interactions. Of the aromatic heterocyclic diazine mono-N-oxide organoiodine cocrystals examined, six exhibited 1:1 stoichiometry, forming chains that utilized both N···I and O···I interactions. Two cocrystals presented 1:1 stoichiometry with exclusive O···I interactions. Two cocrystals displayed a 2:1 stoichiometry-one characterized solely by O···I interactions and the other solely by N···I interactions. We have also compared these interactions to those present in the corresponding diazines, some of which we report here and some which have been previously reported. In addition, a computational analysis using density functional theory (M062X/def2-SVPD) was performed on these two systems and has been compared to the experimental results. The calculated complex formation energies were, on average, 4.7 kJ/mol lower for the I···O halogen bonding interaction as compared to the corresponding N···I interaction. The average I···O interaction distances were calculated to be 0.15 Å shorter than the corresponding I···N interactions.

Elucidating the Role of Electron-Donating Groups in Halogen Bonding.

Computational quantum chemical techniques were utilized to systematically examine how electron-donating groups affect the electronic and spectroscopic properties of halogen bond donors and their corresponding complexes. Unlike the majority of studies on halogen bonding, where electron-withdrawing groups are utilized, this work investigates the influence of electron-donating substituents within the halogen bond donors. Statistical analyses were performed on the descriptors of halogen bond donors in a prescribed set of archetype, halo-alkyne, halo-benzene, and halo-ethynyl benzene halogen bond systems. The σ-hole magnitude, binding and interaction energies, and the vibrational X···N local force constant (where X = Cl, Br, I, and At) were found to correlate very well in a monotonic and linear manner with all other properties studied. In addition, enhanced halogen bonds were found when the systems contained electron-donating groups that could form intramolecular hydrogen bonds with the electronegative belt of the halogen atom and adjacent linker features.

Halogen Bonding versus Nucleophilic Substitution in the Co-Crystallization of Halomethanes and Amines

Haloalkanes and amines are common halogen-bond (XB) donors and acceptors as well as typical reagents in nucleophilic substitution reactions. Thus, crystal engineering using these molecules requires an understanding of the interchange between these processes. Indeed, we previously reported that the interaction of quinuclidine (QN) with CHI3 in acetonitrile yielded co-crystals showing a XB network of these two constituents. In the current work, the interactions of QN with C2H5I or 1,4-diazabicyclo[2.2.2]octane (DABCO) with CH2I2 led to nucleophilic substitution producing I− anions and quaternary ammonium (QN-CH2CH3 or DABCO-CH2I+) cations. Moreover, the reaction of QN with CHI3 in dichloromethane afforded co-crystals containing XB networks of CHI3 with either Cl− or I− anions and QN-CH2Cl+ counter-ions. A similar reaction in acetone produced XB networks comprising CHI3, I− and QN-CH2COCH3+. These distinctions were rationalized through a computational analysis of XB complexes and the transition-state energies for the nucleophilic substitution. It indicated that the outcome of the reactions was determined mostly by the relative energies of the products. The co-crystals obtained in this work showed bonding between the cationic (DABCO-CH2I+, QN-CH2Cl+) or neutral (CHI3) XB donors and the anionic (I−, Cl−) or neutral (CHI3) acceptors. Their analysis showed comparable electron and energy densities at the XB bond critical points and similar XB energies regardless of the charges of the interacting species.