Halogen Bond Formation Research Articles

Ni‐Catalyzed Chelation‐Assisted Direct Functionalization of Inert C—H Bonds

During the last two decades, impressive advancements have been achieved in transition metal‐catalyzed chelation‐assisted C—H functionalization reaction. While reactions in this field are still dominated by precious 4d or 5d metals (e.g., Pd, Rh, Ir), the 3d base metals (e.g., Ni, Co, Cu, Fe) have made significant headway partially due to their relatively large abundance, low cost, low toxicity as well as their occasionally occurred novel reactivity when compared to their noble cousins. This review will give a comprehensive summary on Ni‐catalyzed functionalization of inert C—H bonds assisted by chelation groups. For clarity, the content is classified by the newly formed chemical bonds, namely C—C, C—N, C—chalcogen and C—halogen bond formation.

Nucleation mechanisms of iodic acid in clean and polluted coastal regions

In coastal regions, intense bursts of particles are frequently observed with high concentrations of iodine species, especially iodic acid (IA). However, the nucleation mechanisms of IA, especially in polluted environments with high concentrations of sulfuric acid (SA) and ammonia (A), remain to be fully established. By quantum chemical calculations and atmospheric cluster dynamics code (ACDC) simulations, the self-nucleation of IA in clean coastal regions and that influenced by SA and A in polluted coastal regions are investigated. The results indicate that IA can form stable clusters stabilized by halogen bonds and hydrogen bonds through sequential addition of IA, and the self-nucleation of IA can instantly produce large amounts of stable clusters when the concentration of IA is high during low tide, which is consistent with the observation that intense particle bursts were linked to high concentrations of IA in clean coastal regions. Besides, SA and A can stabilize IA clusters by the formation of more halogen bonds and hydrogen bonds as well as proton transfers, and the binary nucleation of IA-SA/A rather than the self-nucleation of IA appears to be the dominant pathways in polluted coastal regions, especially in winter. These new insights are helpful to understand the mechanisms of new particle formation induced by IA in clean and polluted coastal regions.

Synthesis and biotesting of new carrier prodrugs of 2-methoxyestradiol

To overcome the metabolic instability of anticancer agent 2-methoxyestradiol, two its dichloroacetylated prodrugs and three new control compounds have been synthesized and evaluated in different in vitro assays with cancer cells A549 and MCF-7. Both prodrugs demonstrated an intrinsic cytotoxicity to A549 cells with no effect on the cellular microtubule network. Molecular modeling has revealed putative weak halogen bond formation of 17-O-dichloroacetylated 2-methoxyestradiol with GTP in the a-tubulin subunit.

Rapid Identification of Halogen Bonds in Co-Crystalline Powders via 127 I Nuclear Quadrupole Resonance Spectroscopy.

127 I nuclear quadrupole resonance (NQR) spectroscopy is established as a rapid and robust method to indicate the formation of iodine-nitrogen halogen bonds in co-crystalline powders. Once the relevant spectral frequency range has been established, diagnostic 127 I NQR spectra can be acquired in seconds. The method is demonstrated for a series of co-crystals of 1,4-diiodobenzene. Changes in the 127 I quadrupolar coupling constant (CQ ) by up to 74.4 MHz correlate with the length of the C-I donor covalent bond and inversely with the I⋅⋅⋅N halogen-bond length. The predictive power of this technique is validated on two previously unknown co-crystalline powders prepared mechanochemically. Single-crystal growth via co-sublimation and structure determination by single-crystal X-ray diffraction cross-validates the findings. Natural localized molecular-orbital analyses provide insight into the origins of the quadrupolar coupling constants.

Aggregation of molecular halide perovskite Cs4PbX6: A first-principles investigation

The molecular form of cesium-based halide perovskite materials, Cs4PbX6, has received attention in recent years since it offers interesting optoelectronic properties that are not observed in other dimensions of the halide perovskite materials. In this manuscript, we employ first principles calculations to investigate the aggregates of the Cs4PbX6 to explore the nature of the molecular halide perovskite structures, since the aggregates are common during the synthesis of the halide perovskite materials and dictate their optoelectronic properties. We identify two types of dimeric aggregate structures of Cs4PbX6, which originates from the formation of halogen bonds between two single units and the sharing of cation atoms, respectively. We find that the aggregates could be responsible for the variations in the UV–vis absorption spectra, and their electronic properties are strongly dependent on the halogen substitution. This study helps the fundamental understanding of the aggregation of molecular halide perovskite materials toward optoelectronic applications.

Ultrafast Charge Transfer and Structural Dynamics Following Outer-Valence Ionization of a Halogen-Bonded Dimer.

We study the temporal evolution of the CH2O···ClF halogen-bonded dimer following vertical ionization out of outer-valence molecular orbitals on a femtosecond time scale, employing mixed quantum-classical molecular dynamics simulations. The charge density pattern in the ground state that is suitable for the formation of the ground-state halogen bond can be changed upon ionization. Depending on the molecular orbital that gets ionized, the change in the charge density transiently strengthens or weakens the halogen bond through altering the electrostatic interaction. A transient increase in the halogen bond strength is observed if the ionization enhances the positive charge on the halogen atom provided that the electron donor site possesses some negative charge. The evolution of the system following ionization is driven by energetic stabilization through transferring the electronic charge from the halogen bond acceptor/electron donor (CH2O) to the halogen bond donor/electron acceptor (ClF). The charge transfer oscillations are at the same time governed by the covalent bond vibrations.

The Hydrogen Bond and Beyond: Perspectives for Rotational Investigations of Non-Covalent Interactions.

In the last decade, experiment and theory have expanded our vision of non-covalent interactions (NCIs), shifting the focus from the conventional hydrogen bond to new bridging interactions involving a variety of weak donor/acceptor partners. Whereas most experimental data originate from condensed phases, the introduction of broadband (chirped-pulse) microwave fast-passage techniques has revolutionized the field of rotational spectroscopy, offering unexplored avenues for high-resolution studies in the gas phase. We present an outlook of hot topics for rotational investigations on isolated intermolecular clusters generated in supersonic jet expansions. Rotational spectra offer very detailed structural data, easily discriminating the isomeric or isotopic composition and effectively cancelling any solvent, crystal, or matrix bias. The direct comparison with quantum mechanical predictions provides insight into the origin of the inter- and intramolecular interactions with much greater precision than any other spectroscopic technique, simultaneously serving as test-bed for fine-tuning of theoretical methods. We present recent examples of rotational investigations around three topics: oligomer formation, chiral recognition, and identification of halogen, chalcogen, pnicogen, or tetrel bonds. The selected examples illustrate the benefits of rotational spectroscopy for the structural and energetic assessment of inter-/intramolecular interactions, which may help to move from fundamental research to applications in supramolecular chemistry and crystal engineering.

Halogen Bonding and Cooperative Effects in Chlorine Clathrate: Ab Initio Periodic Study

The possibility of forming halogen bonds inside the clathrate cages is an intriguing question. On the basis of X-ray measurements, a proposition of “multidirectional halogen bonding” was made, and ...

Single-Crystal NMR Characterization of Halogen Bonds.

Oxygen-17-enriched triphenylphosphine oxide and three of its halogen-bonded cocrystals featuring 1,4-diiodotetrafluorobenzene and 1,3,5-trifluoro-2,4,6-triiodobenzene as halogen bond donors have been characterized by 31P and 17O single-crystal NMR spectroscopy. Single-crystal NMR allows for the measurement of not only the magnitudes of various NMR interaction tensors, but also their orientations relative to the crystal lattice and therefore relative to the halogen bonds themselves. 31P chemical shift tensors, 17O chemical shift tensors, 17O quadrupolar coupling tensors, and 31P-17O indirect nuclear spin-spin (J) coupling tensors are reported here for P═O···I halogen bonds. The angular deviations in the directions of the pseudo-unique components of the 31P chemical shift tensors, the 17O chemical shift tensors, and the 17O quadrupolar coupling tensors from the direction of the oxygen-iodine halogen bond correlate with the deviations in linearity of the P═O···I halogen bond. There is also a clear decrease in anisotropy and an increase in asymmetry of the J(31P,17O) coupling tensors attributable to the formation of iodine-oxygen halogen bonds. The small but quantifiable changes in the tensors are consistent with the weak nature of these halogen bonds relative to the P═O motif. Overall, this work establishes single-crystal NMR as a novel probe of halogen bonds in solids. Analysis of the results has provided insights into the correlations between the magnitude and orientation of various NMR interaction tensors and the local geometry of the halogen bond. Gauge-including projector-augmented wave computations corroborate the experimental findings.

Molecular Beam Scattering Experiments as a Sensitive Probe of the Interaction in Bromine-Noble Gas Complexes.

This paper reports for the first time molecular beam experiments for the scattering of He, Ne, and Ar by the Br2 molecule, with the aim of probing in detail the intermolecular interaction. Measurements have been performed under the experimental condition to resolve the glory pattern, a quantum interference effect observable in the collision velocity dependence of the integral cross section. We analyzed the experimental data with a reliable potential model defined as a combination of an anisotropic van der Waals component with the additional contribution due to charge transfer and polar flattening effects related to the formation of an intermolecular halogen bond. The model involves few parameters, whose values are related to fundamental physical properties of the interacting partners, and it allows an internally consistent comparison of the stability of the gas-phase adducts formed by Br2 moiety with different noble gases as well as homologous complexes with the Cl2 molecule. The same model appears to be also easily generalized to describe the interaction of diatomic halogen molecules in the excited B(3Π) electronic state where the halogen bond contribution tends to vanish and more anisotropic van der Waals components dominate the structure of the complexes with noble gases.

Halogen Bonds of Halotetrafluoropyridines in Crystals and Co-crystals with Benzene and Pyridine.

The structures of the three para-substituted halotetrafluoropyridines with chlorine, bromine, and iodine have been determined in the solid state (X-ray diffraction). The structures of these compounds and that of pentafluoropyridine were also determined in the gas phase (electron diffraction). Structures in the solid state of the bromine and iodine derivatives exhibit halogen bonding as a structure-determining motif. On the way to an investigation of halogen bond formation of halotetrafluoropyridines in the solid state with the stronger Lewis base pyridine, co-crystals of benzene adducts were investigated to gain an understanding of the influence of aryl-aryl interactions. These co-crystals showed halogen bonding only for the two heavier halotetrafluoropyridines. In the pyridine co-crystals halogen bonding was observed for all three para-halotetrafluoropyridines. The formation of homodimers and heterodimers with pyridine is also supported by quantum-chemical calculations of electron density topologies and natural bond orbitals.

Molecular dynamics investigation of halogenated amyloidogenic peptides.

Besides their biomolecular relevance, amyloids, generated by the self-assembly of peptides and proteins, are highly organized structures useful for nanotechnology applications. The introduction of halogen atoms in these peptides, and thus the possible formation of halogen bonds, allows further possibilities to finely tune the amyloid nanostructure. In this work, we performed molecular dynamics simulations on different halogenated derivatives of the β-amyloid peptide core-sequence KLVFF, by using a modified AMBER force field in which the σ-hole located on the halogen atom is modeled with a positively charged extra particle. The analysis of equilibrated structures shows good agreement with crystallographic data and experimental results, in particular concerning the formation of halogen bonds and the stability of the supramolecular structures. The modified force field described here allows describing the atomistic details contributing to peptides aggregation, with particular focus on the role of halogen bonds. This framework can potentially help the design of novel halogenated peptides with desired aggregation propensity. Graphical abstract Molecular dynamics investigation of halogenated amyloidogenic peptides.

Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.

Synthesis of a novel brominated vinylic fatty acid with antileishmanial activity that effectively inhibits the Leishmania topoisomerase IB enzyme mediated by halogen bond formation

Abstract Many marine derived fatty acids, mainly from sponges, possess vinylic halogenated moieties (bromine or iodine) but their assessment as antileishmanial candidates remains elusive. In this work, we undertook the first total synthesis of a novel series of 2-allyl-3-halo-2-nonadecenoic acids, which preferentially inhibit the Leishmania DNA topoisomerase IB enzyme (LTopIB) over the human topoisomerase IB enzyme (hTopIB). The synthesis of 2-allyl-3-bromo-2E-nonadecenoic acid (1a) and 2-allyl-3-chloro-2E-nonadecenoic acid (2a) was achieved through a palladium catalyzed haloallylation of 2-nonadecynoic acid (2-NDA) using either allyl bromide or allyl chloride in the presence of PdCl2(PhCN)2 in 57–83 % overall yields. Among the new halogenated synthetic compounds, 1a was the most inhibitory of LTopIB with an EC50 = 7 μM, while the shorter chain analogs 2-allyl-3-bromo-2E-dodecenoic acid (1b) and 2-allyl-3-chloro-2E-dodecenoic acid (2b), synthesized from 2-dodecynoic acid, were not inhibitory of LTopIB (EC50 > 100 μM) resulting in the overall order of inhibition 1a > 2-NDA > 2a > > 1b ≅ 2b. The acids 1a and 2a inhibit LTopIB by a Gimatecan-independent mechanism. The enhanced LTopIB inhibition of 1a was computationally rationalized in terms of a halogen bond between the bromine in 1a and a DNA phosphate (binding energy = − 4.85 kcal/mol). Acid 1a also displayed preferential cytotoxicity towards Leishmania infantum amastigotes (EC50 = 2.5 μM) over L. infantum promastigotes (EC50 > 25 μM).

Mechanisim investigation on the enhanced and selective photoelectrochemical oxidation of atrazine on molecular imprinted mesoporous TiO2

In this work, enhanced and selective photoelectrochemical (PEC) oxidation of atrazine was realized on molecular imprinted mesoporous TiO2 (MI-meso-TiO2). The investigation revealed that, for one hand, the surface MI sites could function as surface defects for accelerating the separation of photogenerated holes and electrons, leading to enhanced generation of hydroxyl radicals. For the other hand, the MI sites showed enhanced binding affinity toward atrazine, resulted from the formation of multiple hydrogen bonds and halogen bonds etc., which was testified by in situ ATR-FTIR spectra. It led to the enhanced adsorption and improved local concentration of atrazine on the electrode surface. Both the two factors contributed to the improved PEC oxidation activity for atrazine on MI-meso-TiO2 compared with that on meso-TiO2. Moreover, the high binding affinity between MI sites and atrazine resulted in the selective recognition ability toward atrazine in the presence of the coexisting pollutants, so that selective PEC oxidation of atrazine in complex polluted water samples was successfully achieved on MI-meso-TiO2 with the apparent rate constant of 0.25 h−1, whereas that on meso-TiO2 was only 0.08 h−1. This work provided something new for explaining the selective and enhanced PEC performance on molecular imprinting catalyst.

Halogen-bonded cocrystallization with phosphorus, arsenic and antimony acceptors

The formation of non-covalent directional interactions, such as hydrogen or halogen bonds, is a central concept of materials design, which hinges on using small compact atoms of the 2nd period, notably nitrogen and oxygen, as acceptors. Heavier atoms are much less prominent in that context, and mostly limited to sulfur. Here, we report the experimental observation and theoretical study of halogen bonds to phosphorus, arsenic and antimony in the solid state. Combining 1,3,5-trifluoro-2,4,6-triiodobenzene with triphenylphosphine, -arsine, and -stibine provides cocrystals based on I···P, I···As and I···Sb halogen bonds. The demonstration that increasingly metallic pnictogens form halogen bonds sufficiently strong to enable cocrystal formation is an advance in supramolecular chemistry which opens up opportunities in materials science, as shown by colossal thermal expansion of the cocrystal involving I···Sb halogen bonds.

An efficient synthesis of benzothiazole using tetrabromomethane as a halogen bond donor catalyst.

An efficient and mild protocol has been developed for the synthesis of 2-substituted benzothiazole under solvent- and metal-free conditions using CBr4 as the catalyst. This process involves the activation of a thioamide through halogen bond formation between the sulphur atom of the thioamide and bromine atom of the CBr4 molecule. The presence of halogen-bonding interaction between N-methylthioamides and tetrabromomethane has been demonstrated with several control experiments, spectroscopic analysis and density functional theory (DFT). This methodology has a wide substrate scope for the synthesis of both 2-alkyl and 2-aryl substituted benzothiazoles.

Correlation of the partial charge-transfer and covalent nature of halogen bonding with the THz and IR spectral changes.

The electronic structural origin of the THz and IR spectral changes occurring upon halogen-bond formation is examined by employing the technique of electron density analysis. Theoretical calculations and analyses are conducted for the complexes of pentafluoroiodobenzene (C6F5I) and nitryl chloride (O2NCl) formed with other (halogen-bond accepting) molecules taken as typical examples. It is shown that, in the case of the C-I stretching mode of C6F5I appearing in the THz spectral region, the intensity enhancement occurring upon halogen-bond formation arises from the intermolecular charge flux and (together with the vibrational frequency) is correlated to the partial charge-transfer and covalent nature of the halogen bond. For the N-Cl stretching vibration of O2NCl, it is shown that the high-frequency shift occurring upon complex formation with NH3 arises mainly from the electrostatic effect, while the reduction of its IR intensity arises from the polarization effect and, to a larger extent, from the intermolecular charge flux. These results indicate, therefore, that there are some observable spectroscopic properties in the THz and IR region that are mainly controlled by (and, hence, shed light on) the partial charge-transfer and covalent nature of halogen bonding.

Chirality-dependent halogen bonds in axially chiral quinazolin-4-one derivatives bearing ortho-halophenyl groups

In the crystals of racemic axially chiral quinazolinones, the formation of intermolecular halogen bonds was detected.

Photoresponsive halogen bonded polycatenar liquid crystals

Photosensitive liquid crystalline materials whose properties could be modified with UV–visible light irradiation are of special interest for photosensitive and photoswitching materials. Herein we represent the first examples of light-responsive halogen bonded supramolecular polycatenars. Photoswitchable liquid-crystalline aggregates were designed and prepared via halogen bond formation between a non-mesogenic taper shaped tetrafluoroiodobenzene based halogen bond-donor and non-mesogenic or mesogenic azopyridine derivatives as halogen bond-acceptors. The liquid crystalline behaviour of the prepared materials was characterized by differential scanning calorimetry (DSC), polarized optical microscope (POM) and X-ray diffraction (XRD). Upon irradiation with UV light, the complexes undergo fast and reversible photoinduced phase transition. Interestingly, some of these halogen-bonded polycatenars exhibit enantiotropic liquid crystalline phases over wide temperature ranges which are the widest among all previously reported photoresponsive perfluoroaryliodide based supramolecular halogen bonded liquid crystals.