Halogen Atoms Research Articles

C(sp3)−F Bond Activation by Lewis Base‐Boryl Radicals via Concerted Electron‐Fluoride Transfer

AbstractSelective C−F bond activation through a radical pathway in the presence of multiple C−H bonds remains a formidable challenge, owing to the extraordinarily strong bond strength of the C−F bond. By the aid of density functional theory calculations, we disclose an innovative concerted electron‐fluoride transfer mechanism, harnessing the unique reactivity of Lewis base‐boryl radicals to selectively activate the resilient C−F bonds in fluoroalkanes. This enables the direct abstraction of a fluorine atom and subsequent generation of an alkyl radical, thus expanding the boundaries of halogen atom transfer reactions.

Chemoselective Dehydrogenation and Hetero-Arylation of Amides via Radical Translocation Enabled by Photoexcited Triplet Ketone Catalysis.

We herein report the chemoselective dehydrogenation and heteroarylation of amides through photoexcited triplet ketone catalysis. Under mild reaction conditions, the generated aryl radical through the halogen atom transfer (XAT) process further undergoes an intramolecular 1,5-HAT event to generate an α-amido alkyl radical, which then intercepted with either cobalt or a reduced cyano arene radical leads to dehydrogenated and heteroarylated products, respectively, in good yields.

Photo(Multicomponent) Reaction of Quinoxalin‐2(1H)‐ones with CBrCl3 and Styrenes by Mes‐Acr‐MeClO4

AbstractIn this study, we explored the use of Mes‐Acr‐MeClO4 as a visible light photocatalyst for multicomponent reactions involving quinoxalin‐2(1H)‐ones with CBrCl3 and styrene. The method showcases regioselective functionalization of quinoxalin‐2(1H)‐ones in a three‐component system, forming two C─C bonds in one pot. Mechanistic investigations suggest a radical‐mediated pathway, initiated by the photoexcitation of Mes‐Acr‐MeClO4, followed by halogen atom abstraction from CBrCl3. This approach provides a versatile and sustainable route for quinoxalin‐2(1H)‐one functionalization, with Mes‐Acr‐MeClO4 effectively facilitating the photocatalyzed multicomponent reaction under mild conditions and visible light irradiation, yielding high selectivity and efficiency.

Halogen-based quinazolin-4(3H)-one derivatives as MCF-7 breast cancer inhibitors: Current developments and structure-activity relationship.

Currently, cancer is a serious health challenge with predominance beyond restrictions. Breast cancer remains one of the major contributors to cancer-related morbidity and mortality in women. Chemotherapy continues to be crucial in the treatment of all variants of cancer. Several antitumor drugs are presently in different phases of clinical trials, whereas many more have been approved for clinical use. However, these drugs have the potential to cause adverse effects, and certain individuals may become resistant to them, which would eventually reduce the drug's efficacy. Therefore, it is essential to discover, develop, and improve newer anticancer drug molecules that could potentially inhibit proliferative pathways. In recent years, quinazolinone derivatives, more specifically halogen-substituted 4(3H)-quinazolinone, have drawn attention as a promising new class of chemotherapeutic agents. In addition, these molecules showed significant inhibition in micromolar ranges when tested in vitro against the MCF-7 cell line. Therefore, this study aims to emphasize the intriguing versatility of halogen atoms, providing an in-depth summary and highlighting recent developments in the anticancer properties of halogenated 4(3H)-quinazolinones. It also features a detailed discussion of the structure-activity relationship (SAR) of various functional groups and their interaction with amino acid residues utilizing molecular docking studies. The intent is to foster novel discoveries that can inspire innovative investigations in this domain. Hence, this study simplifies the drug design and development strategies by prolonging the array of pharmacologically active candidates.

Liposomal Formulations of Novel BODIPY Dimers as Promising Photosensitizers for Antibacterial and Anticancer Treatment

Synthesis, photochemical properties, liposomal encapsulation, and in vitro photodynamic activity studies of novel BODIPY dimer connected at meso-meso positions and its brominated and iodinated analogs were described. UV-Vis measurements indicated that the dimeric structure of obtained BODIPYs did not significantly influence the positions of the absorption maxima. Emission properties and singlet oxygen generation studies revealed a strong heavy atom effect of brominated and iodinated BODIPY dimers, manifested by fluorescence intensity reduction and increased singlet oxygen generation ability compared to analog without halogen atoms. For the in vitro photodynamic activity studies, dimers were incorporated into two different types of liposomes: positively charged DOTAP:POPC and negatively charged POPG:POPC. The photoinactivation studies revealed high activity of brominated and iodinated dimers incorporated into DOTAP:POPC liposomes on both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. Anticancer studies on human breast adenocarcinoma MDA-MB-231 and human ovarian carcinoma A2780 cells revealed that DOTAP:POPC liposomes containing brominated and iodinated dimers were active even at low nanomolar concentrations. In addition, they were more active against MDA-MB-231 cells than A2780 cells, which is particularly important since the MDA-MB-231 cell line represents triple-negative breast cancer, which has limited therapeutic options.

Homogenous Palladium-Catalyzed Dehalogenative Deuteration and Tritiation of Aryl Halides with D2/T2 Gas.

Hydrogen isotopically labeled compounds have extensive utility across diverse domains, especially in drug discovery and development. However, synthesis of the labeled compounds with exclusive site selectivity and/or high isotope incorporation is challenging. One widely employed method is heterogeneous palladium(0)-catalyzed (such as Pd/C) dehalogenative deuteration and tritiation with D2/T2 gas. While commonly used, the method faces two long-standing challenges related to insufficient isotope incorporation and functional group tolerance, particularly with aryl bromides and chlorides. These long-standing issues pose a substantial obstacle in the synthesis of deuterated drug molecules and high-specific-activity tritium tracers. Herein, we present a novel palladium catalytic system using Zn(OAc)2 as an additive, enabling novel homogenous dehalogenative deuteration/tritiation using D2/T2 gas. Under mild reaction conditions, a wide range of drug-like aryl halides and pseudohalides undergo selective deuteration with complete isotope incorporation. The reaction displays excellent compatibility with diverse functional groups, including multiple bonds and O/N-benzyl, and cyano groups, which are frequently problematic in the Pd/C reactions. Furthermore, this method was successfully applied to the tritiation of four halogenated pharmaceutically relevant molecules, resulting in predictable high specific activity per halogen atom (26.5-27.7 Ci/mmol). Notably, the developed system allows gram-scale preparation of a deuterium-containing intermediate, a crucial step in synthesizing a deuterium-labeled drug molecule. A key intermediate, Pd(Ar)OAc, is proposed to activate hydrogen gas during dehalogenative deuteration and tritiation, and Zn(OAc)2 plays an essential role in inhibiting Pd poisoning by halides.

Catalytic Aldehyde-Alkyne Couplings Triggered by Ketyl Radicals.

A general and flexible platform for catalytic aldehyde-alkyne couplings triggered by ketyl radicals is described. This open-shell strategy necessitates only a catalytic quantity of a photoredox catalyst, along with Hünig's base (DIPEA) as a halogen atom transfer reagent. The reaction proceeds through sequential steps involving activation, halogen atom transfer, and radical addition. This carbonyl-alkyne coupling exhibits a wide substrate scope and functional group compatibility and has been successfully applied to the late-stage modification of complex architectures.

Halogen Impact on the Supramolecular Organization of Chiral Phthalimide Emitters Displaying Room Temperature Phosphorescence.

Room temperature phosphorescence from organic materials has attracted an increasing attention in the recent years due to their potential application in various advancing technologies, notably in bioimaging and displays. In this context, heavy atoms such as halogen ones revealed useful tools to enhance the spin-orbit coupling (SOC) of molecular organic phosphors. However, the effect of halogen at the supramolecular level remains less understood, especially in the field of molecular crystals where additional factors can impact the phosphorescence emission. Here, we investigate external effect of halogens on the phosphorescence of chiral phthalimides molecular crystals. The results show that changing the nature of the halogen atom onto the phthalimide core leads to an evolution of the photophysical properties of the materials which does not necessarily follow the classical trend imposed by the expected internal heavy atom effect. Beyond this aspect, we showed that the halogen atom has a profound impact on the packing between the chromophores at the supramolecular level which is of paramount importance towards the optical properties (PLQY and lifetimes) of the different phosphors examined.

Can Deep Learning Search for Exceptional Chiroptical Properties? The Halogenated [6]Helicene Case

AbstractThe relationship between chemical structure and chiroptical properties is not always clearly understood. Nowadays, efforts to develop new systems with enhanced optical properties follow the trial‐error method. A large number of data would allow us to obtain more robust conclusions and guide research toward molecules with practical applications. In this sense, in this work we predict the chiroptical properties of millions of halogenated [6]helicenes in terms of the rotatory strength (R). We have used DFT calculations to randomly create derivatives including from 1 to 16 halogen atoms, that were then used as a data set to train different deep neural network models. These models allow us to i) predict the Rmax for any halogenated [6]helicene with a very low computational cost, and ii) to understand the physical reasons that favour some substitutions over others. Finally, we synthesized derivatives with higher predicted Rmax obtaining excellent correlation among the values obtained experimentally and the predicted ones.

Enzyme (α-Glucosidase, α-Amylase, PTP1B & VEGFR-2) Inhibition and Cytotoxicity of Fluorinated Benzenesulfonic Ester Derivatives of the 5-Substituted 2-Hydroxy-3-nitroacetophenones

The prevalence of small multi-target drugs containing a fluorinated aromatic moiety among approved drugs in the market is due to the unique properties of this halogen atom. With the aim to develop potent antidiabetic agents, a series of phenylsulfonic esters based on the conjugation of the 5-substituted 2-hydroxy-3-nitroacetophenones 1a–d with phenylsulfonyl chloride derivatives substituted with a fluorine atom or fluorine-containing (-CF3 or -OCF3) group were prepared. Their structures were characterized using a combination of spectroscopic techniques complemented with a single-crystal X-ray diffraction (XRD) analysis on a representative example. The compounds were, in turn, assayed for inhibitory effect against α-glucosidase, α-amylase, protein tyrosine phosphatase 1 B (PTP1B) and the vascular endothelial growth factor receptor-2 (VEGFR-2) all of which are associated with the pathogenesis and progression of type 2 diabetes mellitus (T2DM). The antigrowth effect of selected compounds was evaluated on the human breast (MCF-7) and lung (A549) cancer cell lines. The compounds were also evaluated for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The results of an in vitro enzymatic study were augmented by molecular docking (in silico) analysis. Their ADME (absorption, distribution, metabolism and excretion) properties have been evaluated on the most active compounds against α-glucosidase and/or α-amylase to predict their drug likeness.

DFT based analysis of pressure driven mechanical, opto-electronic, and thermoelectric properties in lead-free InGeX3 (X = Cl, Br) perovskites for solar energy applications

Lead halide perovskites have distinct physiochemical properties and demonstrate remarkable power conversion efficiency. We used density functional theory to investigate the electrical, optical, structural, and elastic features of non-toxic InGeCl3 and InGeBr3 halide perovskite compounds at different hydrostatic pressures, from 0 to 8 GPa. InGeCl3 and InGeBr3 halide perovskite exhibit noteworthy changes in their electronic and optical properties under different pressure conditions. When the pressure is 0 GPa, the direct bandgap for InGeCl3 is 0.886 eV, and for InGeBr3 it is 0.536 eV. This gap decreases as the pressure rises. Specifically, InGeBr3 exhibits conducting properties at 3 GPa due to its larger bromine atoms, whereas InGeCl3 requires a higher pressure of 6 GPa to achieve similar conductivity. This type of nature suggests that larger halogen atoms reduce the bandgap more effectively under pressure. As the pressure increases, the behavior of the lattice constant and unit cell volume decreases constantly, from 5.257 and 145.267 Å3 for InGeCl3 to 5.509 and 167.168 Å3 for InGeBr3 at 0 GPa for both compounds. When subjected to pressure, the bonds between In-X and Ge-X atoms experience compression, leading to a decrease in surface area and an enhancement in mechanical strength. Overall, the compounds exhibit characteristics of semiconductors, as evidenced by evaluations of their electrical properties. As pressure increases, the bandgap decreases linearly, narrowing until it aligns with the Fermi level, leading to a transition toward a metallic state. In addition, the pressure induces a rise in the electrical density of states around the Fermi level by displacing valence band electrons in an upward direction. As pressure increases, the electron density peak shifts to lower photon energy values. Notably, InGeCl3 exhibits a more pronounced shift in this peak compared to InGeBr3, indicating greater sensitivity to pressure. In terms of optical properties, both compounds demonstrate significant absorption coefficients in the visible region, suggesting their potential suitability for photovoltaic applications. The dielectric constant, absorption, and reflectivity values all increase gradually as pressure increases. The absorption spectra shift toward longer wavelengths. Furthermore, the mechanical properties analysis reveals that all InGeX3 compounds are mechanically stable up to 8 GPa pressure.

Photo-Induced Three-Component Reaction for the Construction Of α-Tertiary Amino Acid Derivatives.

The synthesis of α-tertiary amino acids (ATAAs), which are pivotal components in natural metabolism and pharmaceutical innovation, continues to attract significant research interest. Despite substantial advancements, the pursuit of a facile, versatile, and resource-efficient methodology remains an area of active development. In this work, we introduce a visible light-triggered three-component reaction involving readily available nitrosoarenes, N-acyl pyrazoles, and allyl or (bromomethyl)benzenes under mild conditions. This approach enables the straightforward assembly of a wide array of ATAA derivatives (42 examples) in commendably high yields (up to 89 %). Mechanistic investigations elucidate that the reaction proceeds through a dehydration condensation between nitrosoarenes and N-acyl pyrazoles to generate ketimine intermediates. This is followed by a light-driven halogen atom transfer (XAT) process and a radical addition, culminating in the formation of the desired products. The approach showcases excellent functional group compatibility and late-stage derivatization potential, offering new insights and avenues for the synthesis of ATAA analogs.

3,4-Dihalo-5-hydroxy-2(5H)-furanones: Highly Reactive Small Molecules.

3,4-Dichloro-5-hydroxy-2(5H)-furanone and its dibromo analog are highly reactive molecules. Both are members of the 2(5H)-furanone family, which are important as pharmacophores present in drugs and natural products. Compounds possessing the 2(5H)-furanone skeleton isolated from plants and marine organisms exhibit bioactivity against various microorganisms and viruses and can also be used in other medical treatments. The structures of these 3,4-dihalo-2(5H)-furanones cause their high reactivity due to the presence of a carbonyl group on the C2 carbon conjugated with a double bond and a hydroxyl group on the C5 carbon. Two labile halogen atoms on carbons 3 and 4 offer additional possibilities for the introduction of other substituents. These structural features make 3,4-dihalo-5-hydroxy-2(5H)-furanones versatile reactants in chemical synthesis. In this review, we present methods of 3,4-dihalo-5-hydroxy-2(5H)-furanone synthesis, their applications as substrates in various chemical transformations, and examples of their biologically active derivatives.

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.

Advances in Light Promoted Transformation of N-Heterocyclic Carbene-Ligated Boryl Radical

Organoboron compounds are integral to modern life, with extensive applications in synthesis, materials science, medicine, and various other domains closely linked to human endeavors. NHC-BH3, noted for its stability, ease of synthesis, and high reactivity as a boryl radical precursor, has emerged as a key focus in boryl radical chemistry. Recently, the visible-light-induced single electron transfer (SET) and hydrogen atom transfer (HAT) processes have garnered considerable interest, presenting innovative strategies for generating boryl radicals from NHC-BH3. In the context of this review, our focus is on the synthesis of C-B and X-B bonds under visible light irradiation, facilitated by NHC-BH3. Furthermore, we explored the role of NHC-BH3 as a hydrogen donor or halogen atom transfer reagent in the construction of C-C bond.

Anion-Substituted Hybrid Zinc Halides with Remarkable Dielectric Switches.

Thermo-responsive dielectric switching hybrid halides, displaying reversible dielectric bistability, have recently made them highly versatile and attractive for their structural tunability and rich functional properties. However, the substantial improvement of the dielectric switching operating range is limited near room temperature, and obtaining ultra-wide dielectric switching temperature region is a major challenge. Herein, a remarkable dielectric switching effect is reported with ultra-wide dielectric switching temperature region in a hybrid halide system, caused by dipolar orientational polarization ascribing order-disorder phase transitions. The new A2BX4 hybrid halide [C6H5(CH2)4NH3]2ZnBr4 (4PBA-ZnBr4) with an ultra-wide dielectric hysteresis loop of about 55K near room temperature is designed successfully through halogen substitution. Meanwhile, structurally similar hybrid materials 4PBA-ZnI4 were designed as controls. More interestingly, the crystal structure, phase transition temperature (Tc), dielectric and semiconductor properties exhibit significant discrepancies as the halogen atoms vary from Br to I. This discovery provides an efficiently regulated anionic framework to construct hybrid halides with ultra-wide high dielectric switching and reliable cycling stability by assembling with various cations, making them potentially excellent candidates for highly responsive room temperature smart switches or transducer devices.

Study of halogen interactions in dichlorovinyldiazenes: Structural analysis, DFT simulation and molecular modeling

In recent years, our research group has synthesized about two hundred different dihalogenated vinyldiazenes. The analysis revealed that the type (conformation) of the compounds is the same-"bike stop", but the properties and nature of intermolecular interactions are different. The concepts of the nature of halogen-halogen relationships recommended by IUPAC (2013) do not explain the nature of the observed intermolecular interactions in the synthesized systems. In this paper, for the first time, using the examples of the compounds presented below, an algorithm is built for the relationship between the structure of synthesized compounds and their properties, and the nature of non-covalent interactions involving the chlorine atom.The molecules presented in this paper were studied by the DFT method using the hybrid potential of B3LYP with the Gaussian 09 software package. The extended basis 6-311++G(d,p) with polarization and diffusion functions was used for calculations. Conducted NBO analysis of atomic charge populations. Calculations of the structural parameters of the synthesized systems were carried out in order to study the reactivity, molecular properties and identify the nature of non-covalent interactions involving the halogen atom. It has been established that the Cl–C–Cl triad has a flat geometry and is capable of forming atypical non-covalent interactions both with each other and with various coplanar systems.

Soft-hard zwitterionic additives for aqueous halide flow batteries.

Aqueous redox flow batteries with halide-based catholytes (where the halogen atom (X) is Br or I) are promising for sustainable grid energy storage. However, the formation of polyhalides during electrochemical charging and the associated phase separation into X2 limits the operable state of charge (SoC), results in vaporization and self-discharge inefficiencies, and spurs complete device failure1-3. Here we introduce soft-hard zwitterionic trappers (SH-ZITs) as complexing agents composed of a polyhalide-complexing 'soft' cationic motif and a water-soluble 'hard' anionic motif to enable homogeneous halide cycling. More than 300 structures were designed and 13 were characterized, showcasing the ability to complex polyhalides in homogeneous aqueous solution, to deter cation-exchange membrane crossover and to alter the electrochemical electrode mechanism. In flow battery cycling at a standard catholyte SoC of 66.6 per cent (stoichiometrically X3-), an average coulombic efficiency of more than 99.9 per cent at 40 milliamperes per square centimetre with no apparent decay was observed after more than 1,000 cycles over 2 months, with stability at elevated temperatures also demonstrated. Interestingly, SH-ZITs enable homogeneous cycling of the halide catholyte up to 90 per cent SoC at 2 moles per litre (47.7 ampere-hours per litre) for bromide, revealing previously unknown polyhalide regimes to be studied. Ultimately, SH-ZIT enables ultrahigh catholyte capacity utilization up to over 120 ampere-hours per litre at 80 per cent SoC with homogeneous cycling as well as the ability to pair with a zinc anode in a hybrid flow battery.

Ultralong Room-Temperature Phosphorescence in Ca(II) Metal-Organic Frameworks Based on Nicotinic Acid Ligands.

In recent years, metal-organic framework (MOF) materials with long persistent luminescence (LPL) have inspired extensive attention and presented various applications in security systems, information anticounterfeiting, and biological imaging fields. However, obtaining LPL materials with ultralong lifetime remains challenging. Halogen atoms, as nonmetallic elements existing in the frameworks, can not only induce the heavy-atom effect, effectively enhancing spin-orbit coupling and promoting intersystem crossing (ISC) processes, but also suppress non-radiative transition of the triplet states through the intra- and intermolecular interactions. Specifically, fluorine atoms with the strongest electronegativity may form intermolecular aggregate interlockings through halogen-bonding interactions that restrict molecular motions and vibrations, thereby improving phosphorescent lifetime. With the aforementioned considerations, two distinct types of MOFs with/without fluorine atoms (namely, Ca-MOF and 5FCa-MOF) were synthesized. Notably, by introducing fluorine atoms into MOFs, fluorine-induced intermolecular aggregate interlockings effectively enhanced the phosphorescent lifetime of 5FCa-MOF exceeding 264 ms compared to that of Ca-MOF (103.94 ms). Remarkably, both MOFs displayed bright LPL to the naked eye after removal of the irradiation source, especially 5FCa-MOF which can last for about 2 s. By introducing fluorine atoms, 5FCa-MOF exhibits greatly enhanced ISC with a rate constant up to 4.1 × 106 s-1 and suppressed non-radiative decay down to 3.73 s-1, thereby extending the LPL time. The thus obtained LPL provides potential in information encryption, security systems, optical anticounterfeiting, and so on.

Pharmacophore‐Based Modeling, Synthesis, and Biological Evaluation of Novel Quinazoline/Quinoline Derivatives: Discovery of EGFR Inhibitors with Low Nanomolar Activity

AbstractThe main aim of this study is to obtain novel molecules that are more selective on cancer cells compared to healthy cells. For this purpose, four hit molecules are identified using 11 new pharmacophore hypotheses followed by scanning the in‐house database. Then, based on those hit molecules, the synthesis and analysis of four different series (three quinazolines and one quinoline series) are carried out, and their anticancer activity is investigated. Finally, by using molecular docking and dynamics simulation methods, binding mode and structure–activity relationship are examined. Among the quinazolin‐4(3H)‐one derivatives, those containing halogen atom are found to be potentially effective, while the best epidermal growth factor receptor (EGFR) inhibition and apoptosis induction are displayed by compounds containing 4‐amino‐1,2,4‐triazole moiety. Notably, four compounds (4h, 8d, 8l, and 8m) show EGFR inhibition activity at 5.298 ± 0.164, 5.46 ± 0.221, 2.670 ± 0.124, and 2.191 ± 0.908 × 10−9 m, their inhibitory activity is similar to or stronger than gefitinib (IC50: 4.169 ± 0.156 × 10−9 m). In addition, EGFR inhibitor concentration of 4g, 8e, and 8o is determined as 27588 ± 6.945, 52.41 ± 2.312, and 33657 ± 8.512 × 10−9 m. These findings indicate that generated pharmacophore hypotheses successfully determine new EGFR inhibitors. In conclusion, four novel compounds, more active than gefitinib with fewer side effects, are reached, and the structure–activity relationships are clarified.