Halobenzene Derivatives Research Articles

Halogen Bonding: An Underestimated Player in Membrane-Ligand Interactions.

Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein-ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems, thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from a model phospholipid bilayer, thus supporting the existence of XB-mediated phospholipid-halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in the water-to-membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggest that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models.

Quantum-Chemistry Based Design of Halobenzene Derivatives With Augmented Affinities for the HIV-1 Viral G4/C16 Base-Pair.

The HIV-1 integrase (IN) is a major target for the design of novel anti-HIV inhibitors. Among these, three inhibitors which embody a halobenzene ring derivative (HR) in their structures are presently used in clinics. High-resolution X-ray crystallography of the complexes of the IN-viral DNA transient complex bound to each of the three inhibitors showed in all cases the HR ring to interact within a confined zone of the viral DNA, limited to the highly conserved 5′CpA 3′/5′TpG 3′ step. The extension of its extracyclic CX bond is electron-depleted, owing to the existence of the “sigma-hole.” It interacts favorably with the electron-rich rings of base G4. We have sought to increase the affinity of HR derivatives for the G4/C16 base pair. We thus designed thirteen novel derivatives and computed their Quantum Chemistry (QC) intermolecular interaction energies (ΔE) with this base-pair. Most compounds had ΔE values significantly more favorable than those of the HR of the most potent halobenzene drug presently used in clinics, Dolutegravir. This should enable the improvement in a modular piece-wise fashion, the affinities of halogenated inhibitors for viral DNA (vDNA). In view of large scale polarizable molecular dynamics simulations on the entirety of the IN-vDNA-inhibitor complexes, validations of the SIBFA polarizable method are also reported, in which the evolution of each ΔE(SIBFA) contribution is compared to its QC counterpart along this series of derivatives.

High-Pressure Crystallizations of meta-Dichlorobenzene and Dibromobenzene and Their Solid Solutions

Similar halobenzene derivatives 1,3-dichlorobenzene (m-C6H4Br2) and 1,3-dibromobenzene (m-C6H4Cl2) form crystals remarkably similar in the unit-cell dimensions, in two symmetry-independent molecules (Z′ = 2) and in their atomic positions along plane yz. However, the atomic x-coordinates are different and the space-group symmetry of m-C6H4Cl2 is P21/c and that of m-C6H4Br2 is P212121. These symmetries are not changed by isochoric recrystallizations at least to 2.7 and 1.6 GPa, respectively. The one-dimensional structural differences originate from one additional Br···Br halogen bond in otherwise very similar halogen···halogen bonds patterns. Of the m-C6H4Br2/m-C6H4Cl2 1:1 mixture a solid solution (symmetry of space-group P21/c) is formed at 0.5 GPa. However, an addition of methanol to the mixture counteracts the formation of the solid solution, and at 0.45 GPa the pristine m-C6H4Cl2 crystals precipitate. For the 1:1:6 mixture with methanol, a pressure of 1.0 GPa is required for the formation of solid solut...

Substituent-Modulated Affinities of Halobenzene Derivatives to the HIV-1 Integrase Recognition Site. Analyses of the Interaction Energies by Parallel Quantum Chemical and Polarizable Molecular Mechanics

The C-X bond of halobenzenes (X = Cl, Br) has a dual character, its electron density being depleted in its prolongation and built-up on its sides. We have recently considered three protein or nucleic acid recognition sites of halobenzenes and quantified the energy gains that either electron-attracting substituents or electron-donating ones contribute due to such a character (El Hage et al., paper in revision). Nonadditivity was found to impact the total interaction energies. We focus here on one recognition site, that of the HIV-1 integrase, in which the halobenzene ring of the drug elvitegravir is sandwiched between a guanine and a cytosine base. We perform energy-decomposition analyses of the ab initio quantum-chemistry (QC) binding energies of the parent halobenzene ring and its derivatives with this G-C base pair. In these complexes, the nonadditivity of ΔE could be traced back mostly to the polarization contribution Epol. In view of large-scale applications to the entirety of the complex formed between the integrase, the viral DNA, and the whole drug, the analyses were performed in parallel with a polarizable molecular mechanics method, SIBFA. This method could faithfully reproduce most features of the QC energies. This is due to its use of QC-derived distributed multipoles and polarizabilities, which enable us to account for both nonisotropy and nonadditivity.

Substrate-mediated interactions and intermolecular forces between molecules adsorbed on surfaces.

Adsorbate interactions and reactions on metal surfaces have been investigated using scanning tunneling microscopy. The manners in which adsorbates perturb the surface electronic structure in their vicinity are discussed. The effects these perturbations have on other molecules are shown to be important in overlayer growth. Interactions of molecules with surface steps are addressed, and each molecule's electron affinity is shown to dictate its adsorption sites at step edges. Standing waves emanating from steps are demonstrated to effect transient molecular adsorption up to 40 A away from the step edge. Halobenzene derivatives are used to demonstrate how the surface is important in aligning reactive intermediates.

Cytochrome P450-catalyzed oxidation of halobenzene derivatives.

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTCytochrome P450-Catalyzed Oxidation of Halobenzene DerivativesIvonne M. C. M. Rietjens, Cathaline den Besten, Robert P. Hanzlik, and Peter J. van BladerenView Author Information Department of Biochemistry, Agricultural University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands, Department of Drug Safety, Solvay Duphar B.V., P.O. Box 900, 1381 CP Weesp, The Netherlands, Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, and Department of Toxicology, Agricultural University, Tuinlaan 5, 6703 HE Wageningen, and TNO Nutrition and Food Research Institution, Zeist, The Netherlands Cite this: Chem. Res. Toxicol. 1997, 10, 6, 629–635Publication Date (Web):June 16, 1997Publication History Received26 June 1996Published online16 June 1997Published inissue 1 June 1997https://doi.org/10.1021/tx9601061Copyright © 1997 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views783Altmetric-Citations52LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (231 KB) Get e-AlertsSUBJECTS:Aromatic compounds,Ethers,Hydrocarbons,Metabolism,Peptides and proteins Get e-Alerts

A quantitative structure-activity relationship for the direct photohydrolysis of meta-substituted halobenzene derivatives in water

A quantitative structure-activity relationship (QSAR) is developed for the photolysis of meta-substituted halobenzene derivatives in water. With the exception of meta-chlorinated and -fluorinated benzonitriles and -fluorinated benzoic acids, upon irradiation of these compounds the carbon-halogen bond with the lowest bond strength is broken, whereupon the corresponding hydroxyl-derivative is being formed. In low concentrations the benzene-derivatives were irradiated at wavelengths ranging from 250 – 350 nm, to determine the pseudo-first order reaction rate constants. With the measured rate constants, the relative energy distribution of the light source used and the UV-spectra of the starting compounds, the quantum yields for photohydrolysis, Φ, were calculated relative to 3-chlorophenol. Only for the compounds undergoing photohydrolysis, the calculated quantum yields were 10log-transformed and correlated to generally available structural parameters for the ground state. The best correlation was obtained with the bond strength of the carbon-halogen bond to be broken and the summed inductive and steric constants of the substituents as parameters.

The development of quantitative structure activity relationships for the direct photolysis of substituted haloaromatics in aqueous environments

Rates of aqueous photodegradation of a number of meta-substituted halobenzene derivatives were measured in the laboratory at wavelengths ranging from 250 to 350 run. Photohydrolysis of all compounds studied is the main transformation process, generally accounting for over 95% of the amount of starting material converted. Quantum yields of this process were calculated using 3-chlorophenol as a reference, taking into account both the absorption characteristics of the compounds studied and the spectral energy distribution of the light source used. With the aim of developing a structure-reactivity relationship, measured quantum yields of photohydrolysis were correlated to a number of readily available molecular descriptors. The best correlation was obtained using a combination of the following descriptors: (1) the carbon-halogen bond strength, and (2) the summation of the steric factors of all substituents. The QSARs derived are well suited to predict rates of photohydrolysis of given halogenated compounds under realistic environmental conditions.

Mechanism of photodegradation of aqueous organic pollutants. 2. Measurement of the primary rate constants for reaction of hydroxyl radicals with benzene and some halobenzenes using an EPR spin-trapping method following the photolysis of hydrogen peroxide

rn The technique of spin trapping, with EPR detection of spin adducts, has been applied to the study of the photodegradation of benzene, chlorobenzene, bromobenzene, iodobenzene, o-dichlorobenzene, m-dichlorobenzene, and p-dichlorobenzene sensitized by the photolysis of HzOz in aqueous solution. By employing a competition kinetic scheme and relative initial slopes or signal amplitudes, plus published rate constants for the reaction of *OH radicals with the spin trap (DMPO), it has been possible to obtain rate constants for the reaction of *OH radicals with benzene and its halo derivatives. Rate constants obtained by this method at neutral and acidic solutions are similar to published methods using pulse radiolysis, where available. Significant differences were found for measurements carried out in basic solutions. The rate constants do not vary much among the halobenzene derivatives studied, and an average rate constant of -5.0 X lo9 M-l could be used for any of these compounds.

ChemInform Abstract: The Synthesis of 3‐Hydroxymethyldibenzo(b,f)thiepin 5,5‐Dioxide, a Prostaglandin Antagonist.

AbstractThe aniline (Ia) undergoes Sandmeyer reaction, yielding the halobenzene derivatives (Ib) and (Ic), which are treated with thiophenol (II) to yield the diaryl sulfide (Id).

On the electroreduction mechanism of halobenzenes: Part I. A quantum chemical approach

The half-wave potentials of various halobenzene derivatives in aprotic solvents correlate with the charge on the halogen atom being reduced and with the energy of the first unoccuppied σ molecular orbital, calculated using the MNDO method. These correlations explain the ortho effect observed in the dihalogen derivatives. Open-shell calculations of the radical anions demonstrate their existence as metastable intermediates. Chlorobenzene has been chosen as a model in order to study the breaking of the CX bond by the reaction coordinate method. According to these results, two possible reduction mechanisms are discussed.

13C, 77Se and 125Te NMR in ortho‐halogenated seleno‐ and telluro‐phenetoles

Abstract77Se and 125Te chemical shifts have been measured for o‐halogenated seleno‐ and telluro‐phenetoles. Correlations exist between these parameters and the halogen electronegativities or the 13C chemical shifts, except for the fluorine derivatives. The chalcogen shifts are related to the shifts of various nuclei in halobenzene derivatives, namely 1H in benzenes, 13C in toluenes, 15N in anilines and 19F in fluorobenzenes. 77Se and 125Te chemical shifts are correlated in the o‐halogenated seleno‐ and telluro‐phenetoles and in chalcogen analogues of o‐methoxy‐selenoanisole and ‐tellurophenetole: Δδ(Te) = 1.60Δδ(Se). The observed gradient is close to values previously reported for other selenides and tellurides, but differs from the value observed in heterocycles. This observation is discussed.

Site of protonation in the reaction of gaseous Brønsted acids with halobenzene derivatives

AbstractThe site of protonation in the reaction of gaseous Brønsted acids with chlorobenzene and fluorobenzene derivatives has been examined using deuterium labelling of chlorobenzene and deuterated reagent gases (D2 and N2/D2). In the protonation of chlorobenzene by [H3]+ ∼30% of the [MHHCl]+ fragment ions arise from a chlorine‐protonated species while ∼70% arise from a ring‐protonated species in which complete hydrogen scrambling has occurred. In the reaction of [N2H]+ with chlorobenzene ∼75% of the fragment ions arise from the chlorine‐protonated form with ∼25% arising from the ring‐protonated form of [MH]+. By contrast fluorobenzene fragments almost entirely from the fluorine‐protonated form. Similar results are obtained for dihalobenzenes. The mechanistic implications are discussed.

Effect of protonation exothermicity on the reaction of gaseous Brønsted acids with halobenzene derivatives

AbstractThe protonation of haloaromatics by [N2H]+ and [CO2H]+ has been studied by chemical ionization mass spectrometry. In general, the fragmentation reactions following protonation by [CO2H]+ are similar to those observed following protonation by [CH5]+, while the fragmentation reactions induced by protonation by [N2H]+ are intermediate between those observed on reaction with [CH5]+ and with [H3]+. These results are consistent with the conclusion that the fragmentation mode is determined by the protonation exothermicity since the proton affinity of CO2 is the same as that of CH4 while the proton affinity of N2 is intermediate between that of CH4 and H2.

Specific substituent effects in the dehalogenation of halobenzene derivatives by the gaseous Broensted acid CH5+

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSpecific substituent effects in the dehalogenation of halobenzene derivatives by the gaseous Broensted acid CH5+Hei-Wun Leung and Alex G. HarrisonCite this: J. Am. Chem. Soc. 1980, 102, 5, 1623–1628Publication Date (Print):February 1, 1980Publication History Published online1 May 2002Published inissue 1 February 1980https://doi.org/10.1021/ja00525a027RIGHTS & PERMISSIONSArticle Views76Altmetric-Citations19LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (705 KB) Get e-Alerts Get e-Alerts

Effect of reaction energetics on the hydrogen chemical ionization mass spectra of halobenzene derivatives. Estimates of the heats of formation of substituted phenyl cations

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEffect of reaction energetics on the hydrogen chemical ionization mass spectra of halobenzene derivatives. Estimates of the heats of formation of substituted phenyl cationsHei-Wun Leung and A. G. HarrisonCite this: J. Am. Chem. Soc. 1979, 101, 12, 3168–3173Publication Date (Print):June 1, 1979Publication History Published online1 May 2002Published inissue 1 June 1979https://doi.org/10.1021/ja00506a005RIGHTS & PERMISSIONSArticle Views70Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (681 KB) Get e-Alerts Get e-Alerts

Concerning the mechanism of dehalogenation of halobenzene derivatives by gaseous Broensted acids

Concerning the mechanism of dehalogenation of halobenzene derivatives by gaseous Broensted acids

Synthesis of Aromatic Phosphonic Acids and their Derivatives. II. Some Halobenzene Derivatives

Synthesis of Aromatic Phosphonic Acids and their Derivatives. II. Some Halobenzene Derivatives