Halogen Substituents Research Articles

Organic room-temperature phosphorescence from halogen-bonded organic frameworks: hidden electronic effects in rigidified chromophores.

Development of purely organic materials displaying room-temperature phosphorescence (RTP) will expand the toolbox of inorganic phosphors for imaging, sensing or display applications. While molecular solids were found to suppress non-radiative energy dissipation and make the RTP process kinetically favourable, such an effect should be enhanced by the presence of multivalent directional non-covalent interactions. Here we report phosphorescence of a series of fast triplet-forming tetraethyl naphthalene-1,4,5,8-tetracarboxylates. Various numbers of bromo substituents were introduced to modulate intermolecular halogen-bonding interactions. Bright RTP with quantum yields up to 20% was observed when the molecule is surrounded by a Br⋯O halogen-bonded network. Spectroscopic and computational analyses revealed that judicious heavy-atom positioning suppresses non-radiative relaxation and enhances intersystem crossing at the same time. The latter effect was found to be facilitated by the orbital angular momentum change, in addition to the conventional heavy-atom effect. Our results suggest the potential of multivalent non-covalent interactions for excited-state conformation and electronic control.

Design, Synthesis and Anticancer Evaluation of New 7-O-Alkylation Genistein Derivatives

Genistein is a phytoestrogen compound which possesses multiple biological activities such as anti-cancer, while its application is limited by poor pharmacokinetic properties. Structural modification is an effective approach to get genistein derivatives with better activities and approved pharmacokinetic properties. Based on previous research work, we synthesized two series of genistein derivatives bearing halogen substituents, and evaluated their inhibitory effects on the cancer cell lines MCF-7, MDA-MB-231, and MDA-MB-435. Among these derivatives, compound XI displayed the best inhibitory activity against MCF-7, MDA-MB-231 and MDA-MB-435 cell lines in vitro, which is worth further studies.

Halogen Bonds Fabricate 2D Molecular Self-Assembled Nanostructures by Scanning Tunneling Microscopy

Halogen bonds are currently new noncovalent interactions due to their moderate strength and high directionality, which are widely investigated in crystal engineering. The study about supramolecular two-dimensional architectures on solid surfaces fabricated by halogen bonding has been performed recently. Scanning tunneling microscopy (STM) has the advantages of realizing in situ, real-time, and atomic-level characterization. Our group has carried out molecular self-assembly induced by halogen bonds at the liquid–solid interface for about ten years. In this review, we mainly describe the concept and history of halogen bonding and the progress in the self-assembly of halogen-based organic molecules at the liquid/graphite interface in our laboratory. Our focus is mainly on (1) the effect of position, number, and type of halogen substituent on the formation of nanostructures; (2) the competition and cooperation of the halogen bond and the hydrogen bond; (3) solution concentration and solvent effects on the molecular assembly; and (4) a deep understanding of the self-assembled mechanism by density functional theory (DFT) calculations.

X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak non-covalent interactions, chemotherapeutic activities and QM/MM binding energy

A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with a known closely related structure has been performed to delineate the effect of halogen substituents and the role of weak intermolecular interactions in their supramolecular architectures. The adamantane-isothiourea hybrid derivatives used in the present study are (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-phenylisothiourea (1), C24H27BrN2S and (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-(3-chlorophenyl)isothiourea (2), C24H26BrClN2S, characterized by X-ray crystallography. The X-ray structures revealed that the molecular conformation of 1 and 2 are different and stabilized by intramolecular C–H···N interactions. In addition, a short intramolecular H···H contact is formed in 2. The Hirshfeld surface analysis was used to delineate the nature of different intermolecular interactions and their contributions toward crystal packing. The quantitative analysis of strengths of molecular dimers existed in 1 and 2 has been performed using the PIXEL method. The electrostatic potential map clearly revealed nature and strength of σ-holes at Br and Cl atoms. The topological analysis was used to characterize the nature and the strength of various intermolecular interactions including the type I Br···Br contact. Interestingly, all the H–H bonding observed in 1 and 2 show closed-shell in nature. Further, an in-vitro antimicrobial activity studies suggest that the title compounds exhibited potent antibacterial activity against all the tested Gram-positive bacterial strains and Gram-negative Escherichia coli. Compound 2 showed marked anti-proliferative activity against MCF-7 and HeLa cell lines. Communicated by Ramaswamy H. Sarma

Structural Aspects of the Ortho Chloro- and Fluoro- Substituted Benzoic Acids: Implications on Chemical Properties.

This article presents a detailed comprehensive investigation of the ortho fluoro- and chloro- substituted benzoic acids both, as isolated molecules and in the crystalline phase. Quantum chemical calculations performed within the density functional theory (DFT) formalism are used to investigate the potential energy landscapes of the molecules, taking into special consideration the effects of the interactions between the carboxylic group and the ortho halogen substituents, as well as the nature of these later on the structure and properties of the investigated systems. The structures of the relevant conformers of the molecules are discussed in comparative terms, and used to rationalize experimental data obtained for the compounds in the gas phase and isolated in low-temperature inert matrices. The UV-induced photofragmentation reactions of two of the compounds isolated in cryogenic inert matrices were studied as illustrative cases. The structures of the crystals reported previously in the literature are revisited and discussed also in a comparative basis. Particular emphasis is given to the analysis of the intermolecular interactions in the different crystals, using Hirshfeld surface analysis, the CE-B3LYP energy decomposition model and the HOMA index, and to their correlation with thermodynamic data.

Phase Transition and Band Gap Regulation by Halogen Substituents on the Organic Cation in Organic–Inorganic Hybrid Perovskite Semiconductors

In the last decade, hybrid materials have received widespread attention. In particular, hybrid lead halide perovskite-type semiconductors are very attractive owing to their great flexibility in band gap engineering. Here, by using precise molecular modifications, three one-dimensional perovskite-type semiconductor materials are designed and obtained: [Me3 PCH2 X][PbBr3 ] (X=H, F, and Cl for compounds 1, 2, and 3, respectively). The introduction of a heavier halogen atom (F or Cl) to [Me4 P]+ increases the potential energy barrier required for the tumbling motion of the cation, hence achieving the transformation of the phase transition temperature from low temperature (192 K) to room temperature (285 K) and high temperature (402.3 K). Moreover, the optical band gaps reveal a broadening trend with 3.176 eV, 3.215 eV, and 3.376 eV along the H→F→Cl series, which is attributed to the formation of the structural distortion.

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor.

Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds 4j (IC50 = 1.51 ± 0.09 µM) and 4k (IC50 = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound 4e showed considerable cytotoxicity against both tested cell lines, MCF7 (IC50 = 5.46 ± 0.71 µM) and A2780 (IC50 = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds 4j (IC50 = 0.245 µM) and 4k (IC50 = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC50 = 0.131 µM). A molecular docking study of 4j and 4k confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.

Surface-Confined Metal–Organic Precursors Comprising Naphthalene-Like Derivatives with Differently Distributed Halogen Substituents: A Monte Carlo Model

The on-surface synthesis of organic polymers has been recently recognized as a useful method to create low-dimensional covalently bonded structures with tailorable topology and functions. In this work, the Monte Carlo simulation method was used to study the metal–organic precursors of covalent polymers formed in the Ullmann-type coupling reaction of halogenated naphthalene derivatives. To this purpose, a coarse-grained model was proposed in which the monomers, represented by a pair of interconnected segments, and two-coordinate metal atoms (one segment) were adsorbed on a triangular lattice-mimicking (111) catalytically active crystalline surface. Different distributions of halogen atoms in the naphthalene molecules were modeled using the directional interactions assigned to these units, sustaining the resulting metal–tecton reversible links. Depending on the halogen content and distribution, the simulations predicted the creation of diverse supramolecular connections such as linear and cyclic aggregates and other more complex forms. Moreover, in the case of prochiral monomers, the calculations demonstrated basic structural differences between the enantiopure and racemic assemblies in which chiral separation or mixing was observed. The obtained results can be helpful in directing the surface-assisted polymerization reactions toward organic structures with predefined size, shape, symmetry, and connectivity.

Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

AbstractFidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of Clostridium difficile infections. Based on the analysis of a cryo‐EM structure of fidaxomicin binding to its target enzyme (RNA‐polymerase), a cation‐π interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in the search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents through a Pd‐catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo‐fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.

Effects of monohalogenated terminal units of non-fullerene acceptors on molecular aggregation and photovoltaic performance

Three small molecule acceptors (SMAs), named ZF, ZC and ZB, have been designed and synthesized for organic solar cells (OSCs) by introducing single F, Cl and Br atom on each terminal unit, respectively. The effects of different halogen substituent on molecular aggregation, photophysical and photovoltaic performance have been systematically studied. Owing to its strong electronegativity of halogens, all the acceptors with monohalogenated terminal units possess red-shifted absorption spectra and deeper frontier energy levels compared to the corresponding acceptor without halogen substituents reported in the literature. Among the SMAs, ZB with brominated terminal units was found to show the higher molar absorption coefficient (2.31 × 105 M−1 cm−1), more orderly face-on π-π stacking, higher electron mobility and more favorable morphology when blended with PM6. As a result, the PM6:ZB OSCs yielded a high power conversion efficiency (PCE) of up to 15.23% with a high short-circuit current density (Jsc) of 26.38 mA cm−2, while the corresponding ZF- and ZC-based devices showed the relatively inferior PCEs of 13.36% and 14.71%, respectively. These results demonstrated that the modulation of electron-withdrawing halogen substituents on terminal group provides a promising strategy to design and synthesize efficient SMAs for fabricating high-performance OSCs.

INTERACTION OF 1,3λ 4 δ 2 ,2,4-BENZODITHIADIAZINES WITH NEUTRAL AND CHARGED S-ELECTROPHILES: SCl 2 , C 6 F 5 SCl, AND NS2 +

Reactions of 1,3λ 4 δ 2 ,2,4-benzothiadiazines with SCl 2 , C 6 F 5 SCl, and [NS 2 ][SbF 6 ] leading to 1,2,3-benzodithiazolium salts (Herz salts) were investigated. The relative rate of reaction with SCl 2 significantly depends on the nature of the substituent and its position in the carbocycle. Halogen substituents Cl, Br, and I slow down the reaction, especially if located closely to the heterocycle (positions 5 and 8). In the case of C 6 F 5 SCl and R = H, chlorination of the carbocycle and opening of the heterocycle also takes place with the formation of 7chloro-1,3λ 4 δ 2 ,2,4-benzothiadiazine аnd C 6 F 5 –S–N=S=N–Ar (Ar = 2-Cl-6-F 5 C 6 SC 6 H 3 ), respectively. In the reaction with NS 2 + , along with contraction of the heterocycle, also its expansion occurs with the formation of 1,2,4λ 4 δ 2 ,3,5-benzotrithiadiazepine. Authors: Alexander Yu. Makarov*, Irina Yu. Bagryanskaya, Vladimir V. Zhivonitko

Enzymatic assays for the assessment of toxic effects of halogenated organic contaminants in water and food. A review

Halogenated organic compounds are a particular group of contaminants consisting of a large number of substances, and of great concern due to their persistence in the environment, potential for bioaccumulation and toxicity. Some of these compounds have been classified as persistent organic pollutants (POPs) under The Stockholm Convention and many toxicity assessments have been conducted on them previously. In this work we provide an overview of enzymatic assays used in these studies to establish toxic effects and dose-response relationships. Studies in vivo and in vitro have been considered with a particular emphasis on the impact of halogenated compounds on the activity of relevant enzymes to the humans and the environment. Most information available in the literature focuses on chlorinated compounds, but brominated and fluorinated molecules are also the target of increasing numbers of studies. The enzymes identified can be classified as enzymes: i) the activities of which are affected by the presence of halogenated organic compounds, and ii) those involved in their metabolisation/detoxification resulting in increased activities. In both cases the halogen substituent seems to have an important role in the effects observed. Finally, the use of these enzymes in biosensing tools for monitoring of halogenated compounds is described.

Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells.

Calcium ions regulate a wide array of physiological functions including cell differentiation, proliferation, muscle contraction, neurotransmission, and fertilization. The endoplasmic reticulum (ER) is the major intracellular Ca2+ store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP3) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca2+ sensing stromal interaction molecules (STIM) located in the ER membrane and the channel forming Orai proteins in the plasma membrane (PM). The resulting active STIM/Orai complexes form highly selective Ca2+ channels that facilitate a measurable Ca2+ influx into the cytosol followed by successive refilling of the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). STIM and Orai have attracted significant therapeutic interest, as enhanced SOCE has been associated with several cancers, and mutations in STIM and Orai have been linked to immunodeficiency, autoimmune, and muscular diseases. 2-Aminoethyl diphenylborinate (2-APB) is a known modulator and depending on its concentration can inhibit or enhance SOCE. We have synthesized several novel derivatives of 2-APB, introducing halogen and other small substituents systematically on each position of one of the phenyl rings. Using a fluorometric imaging plate reader (FLIPR) Tetra-based calcium imaging assay we have studied how these structural changes of 2-APB affect the SOCE modulation activity at different compound concentrations in MDA-MB-231 breast cancer cells. We have discovered 2-APB derivatives that block SOCE at low concentrations, at which 2-APB usually enhances SOCE.

Conformers, electronic states, and diabolical conical intersections in the valence photoelectron spectroscopy of halocyclohexanes.

The threshold photoelectron spectrum (TPES) of halocyclohexanes C6H11X (X = Cl, Br, and I) was recorded at the Swiss Light Source and assigned with the help of density functional theory and equation-of-motion ionization potential coupled cluster calculations. Dyson orbitals show that the first two electronic states of the cation arise by symmetry breaking of the doubly degenerate eg orbitals in cyclohexane as perturbed by the halogen or by perturbation of the halogen lone pair by the cyclohexane ring scaffold in the case of light and heavy halogen substituents, respectively. When the resulting two states (A″ and A') are coupled via a conical intersection in CS symmetry, they are smoothly connected by molecular orbital rotation when the nuclear symmetry is relaxed. Even then, barriers at avoided crossings lead to distinct A' and pseudo-A″ minima, which contribute to the TPES separately. As axial and equatorial conformers are present in commensurate abundance at room temperature, four transitions are conceivable for each substituent in the low-energy range. Three of these could be identified, and their energy could be determined for each sample. Transitions to A' states are associated with a smaller geometry change and exhibit stronger origin transitions. Yet, most notably in X = Br, they do not correspond to the adiabatic ionization energy, which is indicated by a weak and broad band to the pseudo-A″ state with a lower onset energy. Franck-Condon vibrational analysis of the TPES coupled with quantum chemical calculations can provide insights into the behavior of conformers as well as strongly coupled electronic states.

Recent Advances in Synthetic Application and Engineering of Halogenases

AbstractHalogenating enzymes are able to introduce halogen substituents under ambient conditions using non‐hazardous reagents with intriguing selectivity, which is highly desired in green chemistry. Although C−H functionalization such as halogenation is a well‐known transformation in synthetic chemistry, the selective incorporation of halogens using conventional chemical approaches often remains challenging. Therefore, enzyme‐based strategies have been emerging as valuable alternatives in recent years. Inspired by manifold developments of enzymatic halogenation, this review focuses on advances of halogenating enzymes and their application with particular emphasis on FAD‐dependent halogenases (FDHs). Catalytic strategies, application scope and engineering of FDHs are outlined pointing to the increasing utility of halogenases as promising biocatalysts. Current limitations as well as potential future developments of their synthetic utility are being discussed.

Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy.

In the fight against cancer, photodynamic therapy is generating great interest thanks to its ability to selectively kill cancer cells without harming healthy tissues. In this field, ruthenium(II) polypyridyl complexes, and more specifically, complexes with dipyrido[3,2-a:2',3'-c]phenazine (dppz) as a ligand are of particular interest due to their DNA-binding and photocleaving properties. However, ruthenium(II) polypyridyl complexes can sometimes suffer from low lipophilicity, which hampers cellular internalisation through passive diffusion. In this study, four new [Ru(dppz-X2 )3 ]2+ complexes (X=H, F, Cl, Br, I) were synthesized and their lipophilicity (logP), cytotoxicity and phototoxicity on cancerous and noncancerous cell lines were assessed. This study shows that, counterintuitively, the phototoxicity of these complexes decreases as their lipophilicity increases; this could be due solely to the atomic radius of the halogen substituents.

Interaction of 1,3λ4δ2,2,4-benzodithiadiazines with neutral and charged S-electrophiles: SCl2, C6F5SCl, and NS2+

Reactions of 1,3λ4δ2,2,4-benzothiadiazines with SCl2, C6F5SCl, and [NS2][SbF6] leading to 1,2,3-benzodithiazolium salts (Herz salts) were investigated. The relative rate of reaction with SCl2 significantly depends on the nature of the substituent and its position in the carbocycle. Halogen substituents Cl, Br, and I slow down the reaction, especially if located closely to the heterocycle (positions 5 and 8). In the case of C6F5SCl and R = H, chlorination of the carbocycle and opening of the heterocycle also takes place with the formation of 7-chloro-1,3λ4δ2,2,4-benzothiadiazine and C6F5–S–N=S=N–Ar (Ar = 2-Cl-6-F5C6SC6H3), respectively. In the reaction with NS2+, along with contraction of the heterocycle, also its expansion occurs with the formation of 1,2,4λ4δ2,3,5-benzotrithiadiazepine.

Palladium/Copper‐catalyzed Oxidation of Aliphatic Terminal Alkenes to Aldehydes Assisted by p‐Benzoquinone

AbstractThe development of an anti‐Markovnikov Wacker‐type oxidation for simple aliphatic alkenes is a significant challenge. Herein, a variety of aldehydes can be selectively obtained from various unbiased aliphatic terminal alkenes using PdCl2(MeCN)2/CuCl in the presence of p‐benzoquinone (BQ) under mild reaction conditions. Isomerization of the terminal alkene to the internal alkene was suppressed via slow addition of the starting material to the reaction mixture. In addition to the Pd catalyst, CuCl and BQ were essential in order to obtain the anti‐Markovnikov product with high selectivity. Terminal alkenes bearing a halogen substituent afforded their corresponding aldehydes with high anti‐Markovnikov selectivity. The halogen acts as a directing group in the reaction. DFT calculations indicate that a μ‐chloro Pd(II)−Cu(I) bimetallic species with BQ coordinated to Cu is the catalytically active species in the case of a terminal alkene without a directing group.

Phosphorus(III)-Mediated, Tandem Deoxygenative Geminal Chlorofluorination of 1,2-Diketones.

Tetrasubstituted carbon containing two different halogen substituents was constructed in a single-step operation by utilizing the carbene-like reactivity of dioxaphospholene through the tandem reaction of electrophilic and nucleophilic halogenating reagents. It was crucial to devise non-dealkylatable phosphoramidite, which enabled the efficient formation of geminal chlorofluorides from various 1,2-diketones with (PhSO2)2NF and n-Bu4NCl. In addition, selective functionalization of the chlorine substituent was demonstrated, and the absence of halogen scrambling was confirmed.

Direct bromination and iodination of the trispyrazolyl borate ligand in TpRu(nbd)Cl and the effect of Tp4−X ligands on redox potentials and catalysis

Traditional syntheses of Tp (trispyrazolylborate, HB(pz)3) ligands often require extreme conditions that are incompatible with some pyrazole derivatives. In contrast, an alternative direct functionalization of the Tp ligand could offer more compatible conditions. To prove this principle, direct bromination or iodination of TpRu(nbd)Cl is reported herein, and Sonogashira cross-coupling of the iodinated ligand with an alkyne could be performed at ambient temperature. This direct halogenation strategy allows rapid access to several halogenated Tp4−XRu(nbd)Cl derivatives from TpRu(nbd)Cl in a single step and to diversified ruthenium complexes having functionalized Tp ligands in minimal additional steps. The influence of the halogen substituents on the physical and chemical properties of the complexes was also examined. Ligand exchange in the presence of modified ligands was facile. Halogenation caused the standard reduction or oxidation potential to shift 200 mV in the positive direction and reduced efficacy in ruthenium catalyzed epoxyalkyne rearrangement during examination of a literature hypothesis relating catalysis to reduction and oxidation potentials.