Origin of iodine preferential attack at sulfur in phosphorothioate and subsequent P-O or P-S bond dissociation.

Iodine-induced cleavage at phosphorothioate DNA (PT-DNA) is characterized by extremely high sensitivity (∼1 phosphorothioate link per 106 nucleotides), which has been used for detecting and sequencing PT-DNA in bacteria. Despite its foreseeable potential for wide applications, the cleavage mechanism at the PT-modified site has not been well established, and it remains unknown as to whether or not cleavage of the bridging P-O occurs at every PT-modified site. In this work, we conducted accurate ωB97X-D calculations and high-performance liquid chromatography-mass spectrometry to investigate the process of PT-DNA cleavage at the atomic and molecular levels. We have found that iodine chemoselectively binds to the sulfur atom of the phosphorothioate link via a strong halogen-chalcogen interaction (a type of halogen bond, with binding affinity as high as 14.9 kcal/mol) and thus triggers P-O bond cleavage via phosphotriester-like hydrolysis. Additionally, aside from cleavage of the bridging P-O bond, the downstream hydrolyses lead to unwanted P-S/P-O conversions and a loss of the phosphorothioate handle. The mechanism we outline helps to explain specific selectivity at the PT-modified site but also predicts the dynamic stoichiometry of P-S and P-O bond breaking. For instance, Tris is involved in the cascade derivation of S-iodo-phosphorothioate to S-amino-phosphorothioate, suppressing the S-iodo-phosphorothioate hydrolysis to a phosphate diester. However, hydrolysis of one-third of the Tris-O-grafting phosphotriester results in unwanted P-S/P-O conversions. Our study suggests that bacterial DNA phosphorothioation may more frequently occur than previous bioinformatic estimations have predicted from iodine-induced deep sequencing data.

Structure-based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL-5R/IL-5 interaction by gluing halogen bonds at their complex interface.

Human interleukin-5 (IL-5) cytokine mediates the development of eosinophils and is involved in a variety of immune inflammatory responses that play a major role in the pathogenesis of childhood asthma, leukemia, and other pediatric allergic diseases. The immunomodulatory cytokine functions by binding to its cognate cell surface receptor IL-5R in a sheet-by-sheet manner, which can be conformationally mimicked and competitively disrupted by a double-stranded cyclic AF18748 peptide. In this study, we systematically examined the co-crystallized complex structure of human IL-5R with AF18748 peptide and rationally designed a halogen bond to glue at the protein-peptide complex interface by substituting the indole moiety of AF18748 Trp13 residue with a halogen atom (X = F, Cl, Br, or I). High-level theoretical calculations imparted presence of the halogen bond between the oxygen atom (O) of IL-5R Glu58 backbone and the halogen atom (X) of AF18748 Trp13 side chain. Experimental assays confirmed that the halogen bond can promote peptide binding moderately or considerably. More importantly, the halogen bond not only enhances peptide affinity to IL-5R, but also improves peptide selectivity for its cognate IL-5R over other noncognate IL-R proteins. As might be expected, the affinity and selectivity conferred by halogen bond increase consistently in the order: H < F < Cl < Br < I. Structural modeling revealed that the halogen bond plus its vicinal π-cation-π stacking co-define a ringed noncovalent system at the complex interface, which involves a synergistic effect to effectively improve the peptide binding potency and recognition specificity.

The Impact of ortho-substituents on Bonding in Silver(I) and Halogen(I) Complexes of 2-Mono- and 2,6-Disubstituted Pyridines: An In-Depth Experimental and Theoretical Study.

The coordination nature of 2-mono- and 2,6-disubstituted pyridines with electron-withdrawing halogen and electron-donating methyl groups for [N-X-N]+ (X=I, Br) complexations have been studied using 15 N NMR, X-ray crystallography, and Density Functional Theory (DFT) calculations. The 15 N NMR chemical shifts reveal iodine(I) and bromine(I) prefer to form complexes with 2-substituted pyridines and only 2,6-dimethylpyridine. The crystalline halogen(I) complexes of 2-substituted pyridines were characterized by using X-ray diffraction analysis, but 2,6-dihalopyridines were unable to form stable crystalline halogen(I) complexes due to the lower nucleophilicity of the pyridinic nitrogen. In contrast, the halogen(I) complexes of 2,6-dimethylpyridine, which has a more basic nitrogen, are characterized by X-crystallography, which complements the 15 N NMR studies. DFT calculations reveal that the bond energies for iodine(I) complexes vary between -291 and -351 kJ mol-1 and for bromine between -370 and -427 kJ mol-1 . The bond energies of halogen(I) complexes of 2-halopyridines with more nucleophilic nitrogen are 66-76 kJ mol-1 larger than those of analogous 2,6-dihalopyridines with less nucleophilic nitrogen. The experimental and DFT results show that the electronic influence of ortho-halogen substituents on pyridinic nitrogen leads to a completely different preference for the coordination bonding of halogen(I) ions, providing new insights into bonding in halogen(I) chemistry.

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.

Studies About the Effect of Halogenated Solvents on the Fluorescence Properties of 9-Aryl-Substituted Isoquinolinium Derivatives - A Case Study.

It was demonstrated that 9-aryl-substituted isoquinolinium derivatives have significantly increased fluorescence quantum yields in halogenated solvents, mostly pronounced in chloroalkanes, which appears to be specific for this type of solvents. Further analysis with selected halogenated solvents revealed that the type and number of halogen substituents and the dielectric constant of the solvent have a distinct impact on the emission quantum yield. The solvent effect is explained by a solvation of the charge shift (CS) state by attractive halogen-π interactions (halogen bond), which impedes the torsional relaxation of the excited state.

Halogen Bond via an Electrophilic π-Hole on Halogen in Molecules: Does It Exist?

This study reveals a new non-covalent interaction called a π-hole halogen bond, which is directional and potentially non-linear compared to its sister analog (σ-hole halogen bond). A π-hole is shown here to be observed on the surface of halogen in halogenated molecules, which can be tempered to display the aptness to form a π-hole halogen bond with a series of electron density-rich sites (Lewis bases) hosted individually by 32 other partner molecules. The [MP2/aug-cc-pVTZ] level characteristics of the π-hole halogen bonds in 33 binary complexes obtained from the charge density approaches (quantum theory of intramolecular atoms, molecular electrostatic surface potential, independent gradient model (IGM-δginter)), intermolecular geometries and energies, and second-order hyperconjugative charge transfer analyses are discussed, which are similar to other non-covalent interactions. That a π-hole can be observed on halogen in halogenated molecules is substantiated by experimentally reported crystals documented in the Cambridge Crystal Structure Database. The importance of the π-hole halogen bond in the design and growth of chemical systems in synthetic chemistry, crystallography, and crystal engineering is yet to be fully explicated.

Using Hybrid PDI-Fe3O4 Nanoparticles for Capturing Aliphatic Alcohols: Halogen Bonding vs. Lone Pair-π Interactions.

In this study, Fe3O4 nanoparticles (FeNPs) decorated with halogenated perylene diimides (PDIs) have been used for capturing VOCs (volatile organic compounds) through noncovalent binding. Concretely, we have used tetrachlorinated/brominated PDIs as well as a nonhalogenated PDI as a reference system. On the other hand, methanol, ethanol, propanol, and butanol were used as VOCs. Experimental studies along with theoretical calculations (the BP86-D3/def2-TZVPP level of theory) pointed to two possible and likely competitive binding modes (lone pair-π through the π-acidic surface of the PDI and a halogen bond via the σ-holes at the Cl/Br atoms). More in detail, thermal desorption (TD) experiments showed an increase in the VOC retention capacity upon increasing the length of the alkyl chain, suggesting a preference for the interaction with the PDI aromatic surface. In addition, the tetrachlorinated derivative showed larger VOC retention times compared to the tetrabrominated analog. These results were complemented by several state-of-the-art computational tools, such as the electrostatic surface potential analysis, the Quantum Theory of Atoms in Molecules (QTAIM), as well as the noncovalent interaction plot (NCIplot) visual index, which were helpful to rationalize the role of each interaction in the VOC···PDI recognition phenomena.

Halogen Bond Unlocks Ultra-High Birefringence.

Anisotropy is crucial for birefringence (Δn) in optical materials, but optimizing it remains a formidable challenge (Δn > 0.3). Supramolecular frameworks incorporating π-conjugated components are promising for achieving enhanced birefringence since their structural diversity and inherent anisotropy. Herein, we first synthesized (C6H6NO2)+Cl- (NAC). And then constructed a halogen bonded supramolecular framework I+(C6H4NO2)- (INA) by halogen aliovalent substitution of Cl- with I+. The organic moieties are protonated and deprotonated nicotinic acid (NA), respectively. The antiparallel arrangement of birefringent-active units in NAC and INA leads to significant differences in bonding characteristics between interlayer and intralayer domains. Moreover, [O···I+···N] halogen bond in 1D [I+(C6H4NO2)-] chain exhibits stronger interactions and stricter directionality, resulting in a more pronounced in-plane anisotropy between the intrachain and interchain directions. Consequently, INA exhibits exceptional birefringent performance, with a value of 0.778 at 550 nm, twice that of NAC (0.363 at 550 nm). This value significantly exceeds those of commercial birefringent crystals, such as CaCO3 (0.172 at 546 nm), and is the highest reported value among ultraviolet birefringent crystals. This work presents a novel design strategy that employs halogen bonds as connection sites and modes for birefringent-active units, opening new avenues for developing high-performance birefringent crystals.

Halogen-Bonded Organic Frameworks (XOFs) Based on N⋠⋠⋠Br+⋠⋠⋠N Bonds: Robust Organic Networks Constructed by Fragile Bonds.

Organic frameworks face a trade-off between the framework stability and the bond dynamics, which necessitates the development of innovative linkages that can generate stable frameworks without hindering efficient synthesis. Although iodine(I)-based halogen-bonded organic frameworks (XOFs) have been developed, constructing XOFs based on bromine(I) is desirable yet challenging due to the high sensitivity of bromine(I) species. In this work, we present the inaugural construction of stable bromine(I)-bridged two-dimensional (2D) halogen-bonded organic frameworks, XOF(Br)-TPy-BF4/OTf, based on sensitive [N⋅⋅⋅Br⋅⋅⋅N]+ halogen bonds. The formation of XOF(Br)-TPy-BF4/OTf was monitored by 1H NMR, XPS, IR, SEM, TEM, HR-TEM, SEAD. Their framework structures were established by the results from PXRD, theoretical simulations and SAXS. More importantly, XOF(Br) displayed excellent chemical and thermal stabilities. They exhibited stable two-dimensional framework structures in various organic solvents and aqueous media, even over a wide pH range (pH 3-12), while the corresponding model compounds BrPy2BF4/OTf decomposed quickly even in the presence of minimal water. Furthermore, the influence of the counterions were investigated by replacing BF4 with OTf, which improved the stability of XOF(Br). This characteristic enabled XOF(Br) to serve as an efficient oxidizing reagent in aqueous environments, in contrast with the sensitivity of BrPy2BF4/OTf, which performed well only in organic media. This study not only deepens our fundamental understanding of organic frameworks but also opens new avenues for the development and application of multifunctional XOFs.

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.

Computationally rational design of metal-involving halogen bonds with π-covalency: Structures and bonding analysis.

Traditional π-covalent interactions have been proved in the non-metal halogen bond adducts formed by chloride and halogenated triphenylamine-based radical cations. In this study, we have rationally designed two metal-involving halogen bond adducts with π-covalency property, such as [L1-Pd···I-PTZ]+ (i.e., 1) and [L2-Pd···I-PTZ]+ (i.e., 2), in which the square-planar palladium complexes serve as halogen bond acceptor and 3,7-diiodo-10H-phenothiazine radical cation (i.e., [I-PTZ]•+ ) acts as halogen bond donor. Noncovalent interaction analysis and quantum theory of atoms in molecules analysis revealed that there are notable halogen bond interactions along the Pd···I direction without genuine chemical bond formed in both designed adducts. Energy decomposition analysis together with natural orbital for chemical valence calculations were performed to gain insight into their bonding nature, which demonstrated the presence of remarkable π-covalent interactions and σ-covalent interactions in both 1 and 2. We therefore proposed a new strategy for building the metal-involving halogen bonds with π-covalency property, which will help the further development of new types of halogen bonds.

Modeling Type-1 Iodothyronine Deiodinase with Peptide-Based Aliphatic Diselenides: Potential Role of Highly Conserved His and Cys Residues as a General Acid Catalyst.

Type-1 iodothyronine deiodinase (ID-1) catalyzes the reductive elimination of 5'-I and 5-I on the phenolic and tyrosyl rings of thyroxine (T4), respectively. Chemically verifying whether I atoms with different chemical properties undergo deiodination through a common mechanism is challenging. Herein, we report the modeling of ID-1 using aliphatic diselenide (Se-Se) and selenenylsulfide (Se-S) compounds. Mechanistic investigations of deiodination using the ID-1-like reagents suggested that the 5'-I and 5-I deiodinations proceed via the same mechanism through an unstable intermediate containing a Se⋅⋅⋅I halogen bond between a selenolate anion, reductively produced from Se-Se (or Se-S) in the compound, and an I atom in T4. Moreover, imidazolium and thiol groups, which may act as general acid catalysts, promoted the heterolytic cleavage of the C-I bond in the Se⋅⋅⋅I intermediate, which is the rate-determining step, by donating a proton to the C atom.

Comparison of the Ability of N-Bases to Engage in Noncovalent Bonds.

The lone pair of the N atom is a common electron donor in noncovalent bonds. Quantum calculations examine how various aspects of the base on which the N is located affect the strength and other properties of complexes formed with Lewis acids FH, FBr, F2 Se, and F3 As that respectively encompass hydrogen, halogen, chalcogen, and pnicogen bonds. In most cases the halogen bond is the strongest, followed in order by chalcogen, hydrogen, and pnicogen. The noncovalent bond strength increases in the sp

Characterization of Ambroxol and Its Hydrochloride Salt Crystals by Bromine K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and X-Ray Crystal Structure Analysis.

Polymorphic crystals of ambroxol, forms I and II, and form A ambroxol hydrochloride crystals were characterized with bromine K-edge X-ray absorption near-edge structure (XANES) spectroscopy and single-crystal X-ray structure analysis. The XANES spectra had unique shapes depending on the crystal forms. Refined single-crystal structures revealed different interatomic interactions around bromine atoms, such as C-H…Br and N-H…Br hydrogen bonds, Br…O halogen bonds, and N-H…π interactions. Differences in these weak interactions could affect the electronic states of the bromines, resulting in differences in the XANES spectra. The results demonstrated that weak non-conventional interatomic interactions could alter the shape of XANES spectra. Hence, the spectra could be used for evaluating polymorphs of active pharmaceutical ingredients.

Halogen Bonding Involving Isomeric Isocyanide/Nitrile Groups.

2,3,5,6-Tetramethyl-1,4-diisocyanobenzene (1), 1,4-diisocyanobenzene (2), and 1,4-dicyanobenzene (3) were co-crystallized with 1,3,5-triiodotrifluorobenzene (1,3,5-FIB) to give three cocrystals, 1·1,3,5-FIB, 2·2(1,3,5-FIB), and 3·2(1,3,5-FIB), which were studied by X-ray diffraction. A common feature of the three structures is the presence of I···Cisocyanide or I···Nnitrile halogen bonds (HaBs), which occurs between an iodine σ-hole and the isocyanide C-(or the nitrile N-) atom. The diisocyanide and dinitrile cocrystals 2·2(1,3,5-FIB) and 3·2(1,3,5-FIB) are isostructural, thus providing a basis for accurate comparison of the two types of noncovalent linkages of C≡N/N≡C groups in the composition of structurally similar entities and in one crystal environment. The bonding situation was studied by a set of theoretical methods. Diisocyanides are more nucleophilic than the dinitrile and they exhibit stronger binding to 1,3,5-FIB. In all structures, the HaBs are mostly determined by the electrostatic interactions, but the dispersion and induction components also provide a noticeable contribution and make the HaBs attractive. Charge transfer has a small contribution (<5%) to the HaB and it is higher for the diisocyanide than for the dinitrile systems. At the same time, diisocyanide and dinitrile structures exhibit typical electron-donor and π-acceptor properties in relation to the HaB donor.

Halogen Bond-Involving Self-Assembly of Iodonium Carboxylates: Adding a Dimension to Supramolecular Architecture.

We designed 0D, 1D, and 2D supramolecular assemblies made of diaryliodonium salts (functioning as double σ-hole donors) and carboxylates (as σ-hole acceptors). The association was based on two charge-supported halogen bonds (XB), which occurred between IIII sites of the iodonium cations and the carboxylate anions. The sequential introduction of the carboxylic groups in the aryl ring of the benzoic acid added a dimension to the 0D supramolecular organization of the benzoate, which furnished 1D-chained and 2D-layered structures when terephthalate and trimesate anions, correspondingly, were applied as XB acceptors. The structure-directing XB were studied using DFT calculations under periodic boundary conditions and were followed by the one-electron-potential analysis and the Bader atoms-in-molecules topological analysis of electron density. These theoretical methods confirmed the existence of the XB and verified the philicities of the interaction partners in the designed solid-state structures.

Supramolecular Dimer as High-Performance pH Probe: Study on the Fluorescence Properties of Halogenated Ligands in Rigid Schiff Base Complex.

The development of high-performance fluorescence probes has been an active area of research. In the present work, two new pH sensors Zn-3,5-Cl-saldmpn and Zn-3,5-Br-saldmpn based on a halogenated Schiff ligand (3,5-Cl-saldmpn = N, N'-(3,3'-dipropyhnethylamine) bis (3,5-chlorosalicylidene)) with linearity and a high signal-to-noise ratio were developed. Analyses revealed an exponential intensification in their fluorescence emission and a discernible chromatic shift upon pH increase from 5.0 to 7.0. The sensors could retain over 95% of their initial signal amplitude after 20 operational cycles, demonstrating excellent stability and reversibility. To elucidate their unique fluorescence response, a non-halogenated analog was introduced for comparison. The structural and optical characterization suggested that the introduction of halogen atoms can create additional interaction pathways between adjacent molecules and enhance the strength of the interaction, which not only improves the signal-to-noise ratio but also forms a long-range interaction process in the formation of the aggregation state, thus enhancing the response range. Meanwhile, the above proposed mechanism was also verified by theoretical calculations.

Halogen Bond to Experimentally Significant N-Heterocyclic Carbenes (I, IMe2, IiPr2, ItBu2, IPh2, IMes2, IDipp2, IAd2; I = Imidazol-2-ylidene).

The subjects of the article are halogen bonds between either XCN or XCCH (X = Cl, Br, I) and the carbene carbon atom in imidazol-2-ylidene (I) or its derivatives (IR2) with experimentally significant and systematically increased R substituents at both nitrogen atoms: methyl = Me, iso-propyl = iPr, tert-butyl = tBu, phenyl = Ph, mesityl = Mes, 2,6-diisopropylphenyl = Dipp, 1-adamantyl = Ad. It is shown that the halogen bond strength increases in the order Cl < Br < I and the XCN molecule forms stronger complexes than XCCH. Of all the carbenes considered, IMes2 forms the strongest and also the shortest halogen bonds with an apogee for complex IMes2⋯ICN for which D0 = 18.71 kcal/mol and dC⋯I = 2.541 Å. In many cases, IDipp2 forms as strong halogen bonds as IMes2. Quite the opposite, although characterized by the greatest nucleophilicity, ItBu2 forms the weakest complexes (and the longest halogen bonds) if X ≠ Cl. While this finding can easily be attributed to the steric hindrance exerted by the highly branched tert-butyl groups, it appears that the presence of the four C-H⋯X hydrogen bonds may also be of importance here. Similar situation occurs in the case of complexes with IAd2.

Substituent-Guided Cluster Nuclearity for Tetranuclear Iron(III) Compounds with Flat {Fe4(µ3-O)2} Butterfly Core.

The tetranuclear iron(III) compounds [Fe4(µ3-O)2(µ-LZ)4] (1-3) were obtained by reaction of FeCl3 with the shortened salen-type N2O2 tetradentate Schiff bases N,N'-bis(salicylidene)-o-Z-phenylmethanediamine H2LZ (Z = NO2, Cl and OMe, respectively), where the one-carbon bridge between the two iminic nitrogen donor atoms guide preferentially to the formation of oligonuclear species, and the ortho position of the substituent Z on the central phenyl ring selectively drives towards Fe4 bis-oxido clusters. All compounds show a flat almost-symmetric butterfly-like conformation of the {Fe4(µ3-O)2} core, surrounded by the four Schiff base ligands, as depicted by both the X-ray molecular structures of 1 and 2 and the optimized geometries of all derivatives as obtained by UM06/6-311G(d) DFT calculations. The strength of the antiferromagnetic exchange coupling constants between the iron(III) ions varies among the three derivatives, despite their magnetic cores remain structurally almost unvaried, as well as the coordination of the metal ions, with a distorted octahedral environment for the two-body iron ions, Feb, and a pentacoordination with trigonal bipyramidal geometry for the two-wing iron ions, Few. The different magnetic behavior within the series of examined compounds may be ascribed to the influence of the electronic features of Z on the electron density distribution (EDD) of the central {Fe4(µ3-O)2} core, substantiated by a Quantum Theory of Atoms In Molecules (QTAIM) topological analysis of the EDD, as obtained by UM06 calculations 1-3.

Tuning of the Electrostatic Potentials on the Surface of the Sulfur Atom in Organic Molecules: Theoretical Design and Experimental Assessment.

Noncovalent sulfur interactions are ubiquitous and play important roles in medicinal chemistry and organic optoelectronic materials. Quantum chemical calculations predicted that the electrostatic potentials on the surface of the sulfur atom in organic molecules could be tuned through the through-space effects of suitable substituents. This makes it possible to design different types of noncovalent sulfur interactions. The theoretical design was further confirmed by X-ray crystallographic experiments. The sulfur atom acts as the halogen atom acceptor to form the halogen bond in the cocrystal between 2,5-bis(2-pyridyl)-1,3,4-thiadiazole and 1,4-diiodotetrafluorobenzene, whereas it acts as the chalcogen atom donor to form the chalcogen bond in the cocrystal between 2,5-bis(3-pyridyl)-1,3,4-thiadiazole and 1,3,5-trifluoro-2,4,6-triiodobenzene.