Bromine Substituents Research Articles

Synthesis, molecular structure, spectral analysis, and biological activity of new malonamide derivatives as α-glucosidase inhibitors

Two new malonamide derivatives were synthesized via the Michael addition of N1,N3-di(pyridin-2-yl)malonamide to α,β-unsaturated ketones using a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalyst at room temperature. All reactions efficiently furnished the desired malonamide derivatives, which differed only in their substitution on one phenyl group, with one derivative bearing a bromine substituent and the other bearing a methyl group. The structures of newly synthesized compounds were then elucidated by single-crystal X-ray diffraction, infrared spectroscopy, NMR spectroscopy, mass spectrometry, and elemental analysis. In addition, the synthesized compounds were evaluated for their in vitro cytotoxicity against cancer cell lines and for α-glucosidase inhibition. The target compounds exhibited enhanced α-glucosidase inhibition activity (i.e., IC50 = 12.8 ± 0.1 and 28.4 ± 0.2 μM) compared to the common drug acarbose (IC50 = 840 ± 1.73 μM). Both compounds were found to be non-cytotoxic against H460 (lung carcinoma) and T3T (normal fibroblast) cell lines. In addition, the bromo-substituted derivative exhibited weak cytotoxic against cervical cancer HeLa (IC50 = 13.8 ± 0.4 μM) and breast cancer MCF-7 (IC50 = 21.11 ± 0.88 μM) cell lines, while the methyl-substituted derivative showed weak cytotoxicity against the MCF-7 cell line (IC50 = 47.9 ± 0.7 μM). Density functional theory (DFT) B3LYP/6-311G(d,p) calculations were employed to examine the molecular structures and electronic properties of the prepared compounds. As expected, the bromo-derivative (2.2377 D) exhibited a higher polarity than the methyl-derivative (1.9160 D). Furthermore, the HOMO and LUMO diagrams were constructed and the electronic spectra of both compounds were assigned using time-dependent (TD)-DFT calculations. Finally, the calculated NMR chemical shifts correlated well with the experimental data.

ANTIPROLIFERATIVE ACTIVITY OF NEW 6-BROMINE DERIVATIVES OF 7-ANILINO-1-ARYLISOQUINOLINEQUINONES

A variety of 6-bromine-containing 7-anilino-1-arylisoquinolinequinones 2a-g were synthesized to evaluate their half-wave potentials and in vitro antiproliferative activity on gastric and leukemia cancer cell lines. The new compounds displayed significant IC50 values in the range: 1.31 to 11.04 μM. The structure activity relationship analysis of the new series suggest that the antiproliferative activity is dependent, in part, on the push-pull electronic effects of the nitrogen and bromine substituents inserted into the redox fragment of the 1-arylisoquinolinequinone scaffold. Linear regression analysis provided satisfactory relationships between the log IC50 and ClogP values for the AGS gastric cancer cell line.

Influence of the halogen and organometallic function in a KCTP (Co)polymerization

ABSTRACTThe effect of changing the halogen and the organometallic function in a Kumada Catalyst Transfer Polycondensation (KCTP) of poly(3‐alkylthiophene)s (P3AT) is investigated. On the one hand, the bromine substituent is replaced with chlorine in the commonly used 2‐bromo‐5‐chloromagnesio‐3‐hexylthiophene. The effect on the homopolymerization is clear, since the stickiness decreases remarkably, but copolymerizations are hardly affected when a chlorinated monomer is used. Second, the option of changing the organometallic function is considered. Because also organozinc compounds provide a controlled P3AT polymerization with Ni(dppp)Cl2, but are less reactive than organomagnesium compounds, the effect of using zinc in one monomer during a copolymerization is investigated. However, it is found that the organometallic functions exchange during mixing of the monomers. Consequently, no effect is observed during copolymerizations. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 3701–3706

Effect of bromine substituent on optical properties of aryl compounds

AbstractSubstituents significantly affect optical properties of organic compounds. In this study, a series of organic compounds were synthesized. Ultraviolet‐visible and cyclic voltammetry spectra were determined. The relationships between the number of π electron in an aryl ring and the redshift (and molecular orbital energy levels) were studied. To investigate mechanisms of the bromine substituent effects, theoretical calculations were carried out. Ultraviolet‐visible spectra of bromine‐containing compounds exhibit obvious redshifts (0.04‐0.17 eV) of the maximal absorption wavelengths and enhanced absorbance (11%‐57%) compared with corresponding reference compounds. The lowest unoccupied and highest occupied molecular orbital energy levels of compounds containing bromine substituents are 0.05 to 0.60 and 0.02 to 0.40 eV lower than that of corresponding reference compounds. On the whole, the redshifts and the reduced molecular orbital energy levels caused by bromine substituent decrease with the increase in the number of π electron in an aryl ring. The effects would be attributed to strong p‐π conjugation between p electron in the bromine substituent and π electrons in aryl rings. Therefore, this paper suggests a useful way for tuning optical absorption and molecular orbital energy levels of aryl compounds.

Theoretical Studies on Structures, Properties and Dominant Debromination Pathways for Selected Polybrominated Diphenyl Ethers.

The B3LYP/6-311+G(d)-SDD method, which considers the relativistic effect of bromine, was adopted for the calculations of the selected polybrominated diphenyl ethers (PBDEs) in the present study, in which the B3LYP/6-311+G(d) method was also applied. The calculated values and experimental data for structural parameters of the selected PBDEs were compared to find the suitable theoretical methods for their structural optimization. The results show that the B3LYP/6-311+G(d) method can give the better results (with the root mean square errors (RMSEs) of 0.0268 for the C–Br bond and 0.0161 for the C–O bond) than the B3LYP/6-311+G(d)-SDD method. Then, the B3LYP/6-311+G(d) method was applied to predict the structures for the other selected PBDEs (both neutral and anionic species). The lowest unoccupied molecular orbital (LUMO) and the electron affinity are of a close relationship. The electron affinities (vertical electron affinity and adiabatic electron affinity) were discussed to study their electron capture abilities. To better estimate the conversion of configuration for PBDEs, the configuration transition states for BDE-5, BDE-22 and BDE-47 were calculated at the B3LYP/ 6-311+G(d) level in both gas phase and solution. The possible debromination pathway for BDE-22 were also studied, which have bromine substituents on two phenyl rings and the bromine on meta-position prefers to depart from the phenyl ring. The reaction profile of the electron-induced reductive debromination for BDE-22 were also shown in order to study its degradation mechanism.

ChemInform Abstract: Synthesis and Some Properties of Alkynyl Derivatives of 1,3‐Dialkylperimidones. An Example of the 1,2‐Palladium Migration in the Sonogashira Reaction.

AbstractSubstrates bearing 1,2,3 or 4 bromine substituents are investigated in Sonogashira reactions with alkynes (II) and (VI).

An Expeditious Synthesis of 8-Methoxy-1-tetralone

8-Methoxy-1-tetralone was synthesized in a concise and efficient manner involving a sequential palladium-mediated cross-coupling reaction (Heck), catalytic hydrogenation, and intramolecular acylation mediated by Eaton’s reagent or Lewis acids. The pivotal step in the synthesis was the use of a bromine substituent at the benzenoid C4 position of the intermediate methyl 4-arylbutyric ester to ensure cyclization ortho to the methoxy moiety and obviate cyclization at the para position to the thermodynamically preferred 6-methoxy-1-tetralone, the sole product obtained in the absence of this blocking group.

Synthesis and Multibromination of Nanosized Helical Aromatic Amide Foldamers via Segment-Doubling Condensation.

The synthesis of very long helical aromatic amide foldamers was thought to be limited by steric hindrance associated with stable folded conformations. This difficulty may be overcome by using pure reagents, relatively high concentrations, and long reaction times. Bromine substituents and careful identification and elimination of anhydride byproducts both greatly improve chromatographic purification, giving access to pure products amenable to a segment-doubling synthesis of sequences composed of up to 96 monomers. An efficient one-pot multibromination of helical oligomers is also reported.

Computational analysis for antimicrobial active pyrano[2,3-d]pyrimidine derivatives on the basis of theoretical and experimental ground

Annulated pyrano[2,3-d]pyrimidine derivatives were synthesized with methoxy, hydroxyl, nitrile and bromine substituents in its skeleton and correlated by electronic effect of substituents on the magnitude of antimicrobial activity. The different electron donating and electron withdrawing substituents of the pyrano[2,3-d]pyrimidine derivatives exerted positive influence on its antimicrobial activity against some Gram positive and Gram negative bacteria such as, Bacillus cereus, Staphylococcus aureus, Klebsiella pneumonia, Pseudomonas aureus and Escherichia coli, respectively. Antibacterial screening revealed that the presence of heteroaryl, cyano and amino groups on pyrano[2,3-d]pyrimidine skeleton increases its penetrating power on bacterial cell wall and becomes more biologically active. All the pyrano[2,3-d]pyrimidine derivatives were characterized by IR, 1H NMR, 13C NMR and mass spectra.

Biotransformation of OH-PBDEs by pig liver microsomes: Investigating kinetics, identifying metabolites, and examining the role of different CYP isoforms

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are of great concern due to their potential risk to animal and human health. The biotransformation potential of OH-PBDEs in organisms is important for the understanding of their health risk. In the present study, the biotransformation of 3′-OH-2,4-di-BDE (3′-OH-BDE-7), 4′-OH-2,2′,4-tri-BDE (4′-OH-BDE-17) and 3-OH-2,2′,4,4′-tetra-BDE (3-OH-BDE-47) by pig liver microsomes was studied. Compared with their precursor PBDEs, the three OH-PBDEs were more readily biotransformed by pig liver microsomes, and the biotransformation rate followed the order: 3′-OH-BDE-7 > 4′-OH-BDE-17 > 3-OH-BDE-47. These results revealed that the biotransformation rate of OH-PBDEs was decreased with an increase in the number of bromine substituents. Cleavage of the diphenyl ether bond was the dominant pathway for biotransformation of the three OH-PBDEs by pig liver microsomes, while debromination and hydroxylation were found to be of less importance. CYP3A4 was suggested to be the specific enzyme responsible for the biotransformation of OH-PBDEs via associated inhibition assay. These findings may enrich our understanding of health risk associated with OH-PBDEs in mammals and human beings.

Effects of the position and number of bromine substituents on the concentration-mediated 2D self-assembly of phenanthrene derivatives.

The effects of the position and number of bromine substituents on the self-assembled patterns of phenanthrene derivatives by changing multiple weak intermolecular interactions were investigated at the 1-octanoic acid/graphite interface at different concentrations by scanning tunneling microscopy. Two Br substituted DBHP molecules (2,7-DBHP, 3,6-DBHP) and BHP without a Br group formed a linear lamellar pattern by the van der Waals interactions between the alkoxyl chains in each lamella at high concentrations, which forces the phenanthrene derivatives to self-organize in a π-π stacked edge-on conformation. On decreasing the solution concentration, owing to the molecule-molecule van der Waals force and BrBr halogen bonds or the molecule-solvent cooperative BrO (C[double bond, length as m-dash]O) hydrogen and BrHO-hydrogen bonds, 2,7-DBHP molecules were found to form two kinds of network structures, whereas 3,6-DBHP molecules formed only a zigzag pattern due to the intermolecular BrBr van der Waals type interactions. One bromine substituted phenanthrene derivative (3-DBHP) formed a dislocated linear pattern by two C-HBr hydrogen bonds in each dimer. These observations revealed that an important modification of the position and number of halogen substituents might dramatically change the self-assembly behaviors by different intermolecular interactions including BrBr and BrO halogen bonding, BrBr van der Waals type interactions, and HBr hydrogen bonding. DFT calculations were explored to unravel how slightly tuning the molecular structure defines the geometry of a 2D self-assembled nanoarchitecture through the different elementary structural units having BrBr and BrH interactions.

Synthesis, characterization, and X-ray crystal structures of copper(II) and nickel(II) complexes with two bis(thiosemicarbazone) ligands and investigation of their electrochemical behavior

Two new bis(thiosemicarbazone) ligands having a halogen substituent on the non-coordinating phenyl rings, namely 2-[1-(2-{3-[2-({2-[(4-bromoanilino)carbothioyl]hydrazono} methyl)phenoxy]propoxy}phenyl)methylidene]-N1-(4-bromophenyl)-1-hydrazinecarbothiamide (H2L3) and 2-[1-(2-{3-[2-({2-[(4-bromoanilino)carbothioyl]hydrazono}methyl)phenoxy]-2-hydroxypropoxy}phenyl) methylidene]-N1-(4-bromophenyl)-1-hydrazinecarbothiamide (H3L4), were used in the synthesis of a series of CuII and NiII complexes [Cu(L3)]·MeOH, [Cu(HL4)], [Ni(L3)], and [Ni(HL4)]·MeOH. The complexes were characterized by physicochemical and spectroscopic methods. Single-crystal X-ray structures of [Cu(L3)]·MeOH, [Cu(HL4)], and [Ni(L3)] showed that the metal centers are coordinated by two imine nitrogen atoms and two sulfur atoms in a distorted square-planar coordination geometry. Electrochemical investigations showed that all of these CuII and NiII complexes were reversibly reducible. Although the bromine substituent on the phenyl ring and the hydroxyl group are far from the metal centers, they have an effect on the redox potentials of the NiII/I and CuII/I couples.

Halochromic properties of sulfonphthaleine dyes in a textile environment: The influence of substituents

The application of pH-sensitive dye molecules onto textile materials is a promising method for the development of sensor materials. Ten commonly used pH-indicators, namely sulfonphthaleine dyes, are applied onto polyamide 6 using two distinct methods: conventional dyeing of fabrics and dye-doping of nanofibres. The influence of the substituents of each dye on their interaction with polyamide, as well as the difference between both application methods is investigated. For the conventionally dyed fabrics, halogen substituents are needed to result in a pH-sensitive fabric. This can be traced back to halogen bonding and is supported by theoretical simulations. Dye-doped nanofibrous non-wovens show significant dye leaching, which can be understood based on the very acidic electrospinning solution. The use of a complexing agent improves the leaching properties, especially for dyes containing four bromine substituents. These findings indicate the importance of halogen substituents on sulfonphthaleines for further research in the development of pH-sensitive sensors.

Some new indole–coumarin hybrids; Synthesis, anticancer and Bcl-2 docking studies

Hybrid molecules have attracted attention for their improved biological activity, selectivity and lesser side effects profile, distinct from their individual components. In the quest for novel anticancer drug entities, three series of indole–coumarin hybrids – 3-(1-benzyl-1H-indol-2-yl)-2H-chromen-2-ones, 2-(2-oxo-2H-chromen-3-yl)-1H-indole-3-carbaldehydes and 2-(2-oxo-2H-chromen-3-yl)-1H-indole-3-carboxylic acids were synthesized. All the synthesized compounds were characterized by spectral techniques like IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. In silico docking studies of synthesized molecules with apoptosis related gene Bcl-2 that is recognized to play an important role in tumerogenesis were carried out. Dose-dependent cytotoxic effect of the compounds in human breast adenocarcinoma (MCF-7) and normal cell lines were assessed using MTT assay and compared with that of the standard marketed drug, Vincristine. Compound 4c had a highly lipophilic bromine substituent capable of forming halogen bond and was identified as a potent molecule both in docking as well as cytotoxicity studies. Flow cytometric cell cycle analysis of 4c exhibited apoptotic mode of cell death due to cell cycle arrest in G2/M phase. Structure activity relationship of these hybrid molecules was also studied to determine the effect of steric and electronic properties of the substituents on cell viability.

Crystal structure of 3-bromo-2-hy-droxy-benzo-nitrile.

The crystal structure of the title compound, C7H4BrNO, has been determined, revealing a partial mol­ecular packing disorder such that a 180° rotation of the mol­ecule about the phenol C—O bond results in disorder of the bromine and nitrile groups. The disorder has been parameterized as a disorder of only the bromine and nitrile substituents on a unique phenol ring. An intra­molecular O—H⋯Br contact occurs. In the crystal, O—H⋯Br/O—H⋯Nnitrile hydrogen bonding is present between the disordered bromine and nitrile substituents and the phenol group, forming a spiral chain about a twofold screw axis extending parallel to the b-axis direction. Within this spiral chain, the mol­ecules also inter­act, forming offset face-to-face π-stacking inter­actions with plane-to-centroid distance of 3.487 (1) Å.

Quantum ferroelectricity in charge-transfer complex crystals.

Quantum phase transition achieved by fine tuning the continuous phase transition down to zero kelvin is a challenge for solid state science. Critical phenomena distinct from the effects of thermal fluctuations can materialize when the electronic, structural or magnetic long-range order is perturbed by quantum fluctuations between degenerate ground states. Here we have developed chemically pure tetrahalo-p-benzoquinones of n iodine and 4–n bromine substituents (QBr4–nIn, n=0–4) to search for ferroelectric charge-transfer complexes with tetrathiafulvalene (TTF). Among them, TTF–QBr2I2 exhibits a ferroelectric neutral–ionic phase transition, which is continuously controlled over a wide temperature range from near-zero kelvin to room temperature under hydrostatic pressure. Quantum critical behaviour is accompanied by a much larger permittivity than those of other neutral–ionic transition compounds, such as well-known ferroelectric complex of TTF–QCl4 and quantum antiferroelectric of dimethyl–TTF–QBr4. By contrast, TTF–QBr3I complex, another member of this compound family, shows complete suppression of the ferroelectric spin-Peierls-type phase transition.

Research on Thermodynamic Properties of Polybrominated Diphenylamine by Neural Network

Based on the location of bromine substituents and conjugation matrix, a new substituent position index 0X not only was defined, but also molecular shape indexes Km and electronegativity distance vectors Mm of diphenylamine and 209 kinds of polybrominated diphenylamine (PBDPA) molecules were calculated. Then the quantitative structure-property relationships (QSPR) among the thermodynamic properties of 210 organic pollutants and 0X, K3, M29, M36 were founded by Leaps-and-Bounds regression. Using the four structural parameters as input neurons of the artificial neural network, three satisfactory QSPR models with network structures of 4:21:1, 4:24:1, and 4:24:1 respectively, were achieved by the back-propagation algorithm. The total correlation coefficients R were 0.9999, 0.9997, and 0.9995 respectively and the standard errors S were 1.036, 1.469, and 1.510 respectively. The relative mean deviation between the predicted value and the experimental value of S⊖, ΔfH⊖ and ΔfG⊖ were 0.11%, 0.34% and 0.24% respectively, which indicated that the QSPR models had good stability and superior predictive ability. The results showed that there were good nonlinear correlations between the thermodynamic properties of PBDPAs and the four structural parameters. Thus, it was concluded that the ANN models established by the new substituent position index were fully applicable to predict properties of PBDPAs.

Spectroscopic investigation on the sonodynamic damage to protein in the presence of eosine B

In this work, bovine serum albumin (BSA) and eosine B (EB) were selected as a model protein and sonosensitizer, respectively. The sonodynamic damage to protein in the presence of EB and its mechanism were studied by means of absorption and fluorescence spectra. The results indicated that the synergistic effects of ultrasound and EB can efficiently damage the BSA molecules, and the damage of protein could be mainly due to the generation of reactive oxygen species (ROS). The damage degree of protein increased with the increase of ultrasonic time and EB concentration because of the increased quantities of ROS. Hydroxyl free radical (OH) was the major mediators of the ultrasound-inducing proteins damage in the presence of EB. In addition, the quantities of ROS from the diphenylcarbazide (DPCI)–EB solutions and the DPCI–fluorescein (FS) solutions with or without ROS scavengers were contrasted, respectively. The results show that FS mainly produce OH, but the quantities of ROS in the presence of FS were lower than those of EB, which indicates that the nitro and bromine substituent groups on the benzene ring of FS increase the quantity of ROS, but do not change the kinds of ROS.

Different electronic and charge-transport properties of four organic semiconductors Tetraazaperopyrenes derivatives

Tetraazaperopyrenes (TAPPs) derivatives are high-performance n-type organic semiconductor material families with the remarkable long-term stabilities. The charge carrier mobilities in TAPPs derivatives crystals were calculated by the density functional theory (DFT) method combined with the Marcus–Hush electron-transfer theory. The existence of considerable C–H…F–C bonding defines the conformation of the molecular structure and contributes to its stability. We illustrated how it is possible to control the electronic and charge-transport parameters of TAPPs derivatives as a function of the positions, a type of the substituents. It is found that the core substitution of TAPPs has a drastic influence on the charge-transport mobilities. The maximum electron mobility value of the core-brominated 2,9-bis (perfluoroalkyl)-substituted TAPPs is 0.521cm2V−1s−1, which appear in the orientation angle 95° and 275°. The results demonstrate that the TAPPs with bromine substituents in ortho positions exhibit the best charge-transfer efficiency among the four different TAPP derivatives.

Gas Permeability of Hexaphenylbenzene Based Polymers of Intrinsic Microporosity

The synthesis and characterization of a series of novel hexaphenylbenzene (HPB) based polymers of intrinsic microporosity (PIM-HPBs) containing methyl, bromine, and nitrile substituents are reported. The successful formation of thin films from these polymers allowed the evaluation of the influence of the substituents on intrinsic microporosity and gas permeability. Analysis by the time-lag method also yielded information about gas diffusion coefficients and, indirectly, the gas solubility. The gas permeability varies as a function of the polarity of the substituents and shows a significant increase after treatment of the samples with methanol, especially for films cast from THF as the solvent. This enhancement, which is mostly due to an increase in the diffusion coefficient, is only partially lost upon aging of the membranes for 5 months. Measurements at different feed pressures confirm the typical dual mode sorption behavior, with increasing diffusivity and decreasing permeability and solubility as a function of the feed pressure.