Benzene Substituents Research Articles

Quantum chemical explanation and APT atomic charge index of substituent orienting effect proposed by DFT calculation and MO Theory

AbstractIn organic chemistry textbooks, the electron resonance states are used to explain the orienting effect of benzene substituent. However, these resonance states do not exist in the C6H5‐S + E+ electrophilic addition, so the resonance state discussions actually are meaningless. The density functional theory (DFT) calculation shows that the C6H5‐S + E+ addition follows the transition state theory and needs to overcome a barrier. Benzene molecule C6H6 has two degenerate highest occupied molecular orbitals (HOMOs), but after becoming substituted benzenes, the two HOMOs split to HOMO and HOMO‐1 with different orbital energies and electron distributions. It makes the addition barrier on two or three benzene ring carbons is low, and the addition rate is fast, but the barrier of other carbons is high, and the rate is slow. Therefore, substituent splits the two degenerate HOMOs of benzene molecule, which is the origin of substituent orienting effect. For the substituted benzenes with halogen group ‐X and electron‐releasing group, their HOMO images alone can determine that the two types of substituents are the ortho‐ and para‐orienting groups, but for the substituted benzenes with electron‐withdrawing group, their HOMO alone cannot determine whether the substituent is a meta‐orienting group. The study found that atomic polar tensor (APT) charges are a good judgment index of substituent orienting effect because based on its physic‐chemical model, the charges represent the number of active electrons on the benzene ring carbons. The DFT calculation gives the APT charges of 19 mono‐substituted and 12 di‐substituted benzenes and some aromatic molecules. The APT charges can all correctly determine their orienting effects, showing that APT atomic charge from quantum theoretical calculation is a good substituent orienting index.

Effect of Substituents on Molecular Reactivity during Lignin Oxidation by Chlorine Dioxide: A Density Functional Theory Study.

Lignin is a polymer with a complex structure. It is widely present in lignocellulosic biomass, and it has a variety of functional group substituents and linkage forms. Especially during the oxidation reaction, the positioning effect of the different substituents of the benzene ring leads to differences in lignin reactivity. The position of the benzene ring branched chain with respect to methoxy is important. The study of the effect of benzene substituents on the oxidation reaction's activity is still an unfinished task. In this study, density functional theory (DFT) and the m062x/6-311+g (d) basis set were used. Differences in the processes of phenolic oxygen intermediates formed by phenolic lignin structures (with different substituents) with chlorine dioxide during the chlorine dioxide reaction were investigated. Six phenolic lignin model species with different structures were selected. Bond energies, electrostatic potentials, atomic charges, Fukui functions and double descriptors of lignin model substances and reaction energy barriers are compared. The effects of benzene ring branched chains and methoxy on the mechanism of chlorine dioxide oxidation of lignin were revealed systematically. The results showed that the substituents with shorter branched chains and strong electron-absorbing ability were more stable. Lignin is not easily susceptible to the effects of chlorine dioxide. The substituents with longer branched chains have a significant effect on the flow of electron clouds. The results demonstrate that chlorine dioxide can affect the electron arrangement around the molecule, which directly affects the electrophilic activity of the molecule. The electron-absorbing effect of methoxy leads to a low dissociation energy of the phenolic hydroxyl group. Electrophilic reagents are more likely to attack this reaction site. In addition, the stabilizing effect of methoxy on the molecular structure of lignin was also found.

Mechanism-Driven Development of N-(Quinolin-8-yl)-benzamide Coupling Reactions via C–H or N–H Activation

The mechanistic details of the oxidative coupling of compounds with a number of different redox centers are investigated using N-(quinolin-8-yl)-benzamide (L) as a model substrate. The control of the chemical or electrooxidation parameters in the absence or presence of a cobalt catalyst makes it possible to obtain regioselectively different oxidative coupling products (ortho- vs para-C–H/C–H vs C–H/N–H vs N–H/N–H). The results indicate that the operative mechanism depends on the type of oxidized reaction center and the oxidant nature. Oxidation affects the para-C–H bond in quinoline or the N–H fragment or the ortho-C–H bond in the benzene substituent in the molecule. The intermediate Co(II)[L–H]2 complex and C–H-activated CoIII metallacycle with benzamide ligands, which are shown to oxidize at close potentials, have been isolated and characterized by various techniques, including X-ray diffraction and voltammetry. The strength of the oxidizing agent affects the formation of a particular product, though not acting as the determining factor. Two-electron oxidation of Co(II)[L–H]2 yields to C–N coupling, but one-electron oxidation of Co(III) leads to ortho-C–C coupling. All electrochemical reactions are performed under mild conditions at room temperature without adding special reagents (oxidants, halides, phosphines, etc.).

Visible‐light‐switchable azobenzenes: Molecular design, supramolecular systems, and applications

AbstractPhotocontrol of functional molecules and supramolecular systems provides promising directions for the development of innovative materials and technologies. Reversible photoswitches that can isomerize among different states play a vital role in such photoresponsive systems. However, the commonly used UV light for triggering the isomerization of photoswitches such as azobenzene (AB) has limited their applications in functional material systems because UV light penetrates poorly and causes damage to materials or biological tissues. Accordingly, tremendous endeavors have been devoted to the development of visible‐light‐switchable molecules and expand their new applications in various fields. Herein, we highlight the strategies of molecule design for visible‐light‐switchable ABs by discussing the effects of benzene substituents on the absorption spectrum. Based on this, visible‐light‐responsive supramolecular systems with metal–organic frames, cyclodextrins, nanoparticles, and biomolecules (DNAs, peptides, and proteins) are elaborated. Then, the light‐responsive mechanical properties and their emerging applications in actuators, biological systems, information storage, energy storage, nonlinear optical devices, and photoswitchable adhesives are discussed. Finally, a summary of the challenges and perspective on visible‐light‐switchable ABs are outlined.Key points Structural design strategies for visible‐light‐responsive azobenzenes Visible‐light‐responsive supramolecular azobenzene systems in different research areas ranging from chemistry to biology Their light‐responsive mechanical properties and emerging applications

Synthesis, antimicrobial activity and 3D-QSAR study of novel 5-substituted-1,3,4-thiadiazole Schiff base derivatives

In this study, 21 new thiadiazole Schiff base derivatives were synthesized based on the reactive group splicing principle, and the structures of the target compounds were confirmed and characterized by 1H NMR, FT-IR and HRMS. The inhibition activity of the compounds was tested in vitro against Escherichia coli, Staphylococcus aureus, Aspergillus niger, Rhizopus, Penicillium, Botrytis cinerea and Alternaria using mycelial growth rate method. The results showed that most of the compounds exhibited good biological activity at a dose of 50 µg/mL. Among them, compounds 2b, 2r, and 2a exhibited inhibition rates against the tested microbe comparable to that of the control drug Chlorothalonil. A preliminary three-dimensional quantitative conformational relationship (3D-QSAR) study of the inhibitory activity of the target compounds against Aspergillus niger was carried out using CoMFA and CoMSIA, and the model results showed that increasing the volume of the 2- and 6-positions of benzene ring A and the 3-position substituent of benzene ring B, decreasing the volume of the 5-position substituent benzene ring A; increasing hydrophobic groups at the 6-position of benzene ring A and the 2′-position of benzene ring B; increasing the 3′-position hydrogen bond donor group and decreasing the 3′-position hydrogen bond acceptor group of benzene ring B can improve the biological activity of the compounds. The inhibitory activity of the compounds can be improved.

High Efficiency of over 25% and Long Device Lifetime of over 500 h at 1000 nit in Blue Fluorescent Organic Light-Emitting Diodes.

In this study, a multiple resonance (MR) type blue emitter is synthesized, characterized, and evaluated for highly efficient and stable blue fluorescent organic light-emitting diodes (OLEDs). The MR blue fluorescent emitter has a di-tert-butyl benzene substituent in the MR core structure to minimize quenching mechanisms by intermolecular interaction. The emitter shows a high photoluminescence quantum yield and small full width at half maximum of 22 nm, which realize high external quantum efficiency (EQE) of 11.4% in the single unit OLED and device lifetime up to 95% of the initial luminance (LT95 ) of 208 h at 1000 cd m-2 and over 10000 h at 100 cd m-2 . The optimized tandem device of the new blue emitter achieves high EQE over 25% and extremely long LT95 of over 500h at 1000 cd m-2 and 30000 h at 100 cd m-2 . The lifetime of this work is one of the best data of blue OLED lifetime reported in the literature.

Ligand Exchange Reaction of Ferrocene with Substituted Benzenes

Ligand exchange reaction is one of the typical reactions of ferrocene. In this paper, ligand exchange reactions were carried out between ferrocene and various substituted benzenes using aluminum chloride catalysis. The product yields of the reactions with alkanoyl- and alkoxybenzenes were low because of the coordination of aluminum chloride to the oxygens of the benzene substituents. Comparing the reactions using o- and p-dimethoxybenzene, the former was revealed to be less reactive; this is likely due to the deviation of the π-electrons of its benzene ring being larger.

Machine Learning for Predicting Risk of Drug-Induced Autoimmune Diseases by Structural Alerts and Daily Dose

An effective approach for assessing a drug’s potential to induce autoimmune diseases (ADs) is needed in drug development. Here, we aim to develop a workflow to examine the association between structural alerts and drugs-induced ADs to improve toxicological prescreening tools. Considering reactive metabolite (RM) formation as a well-documented mechanism for drug-induced ADs, we investigated whether the presence of certain RM-related structural alerts was predictive for the risk of drug-induced AD. We constructed a database containing 171 RM-related structural alerts, generated a dataset of 407 AD- and non-AD-associated drugs, and performed statistical analysis. The nitrogen-containing benzene substituent alerts were found to be significantly associated with the risk of drug-induced ADs (odds ratio = 2.95, p = 0.0036). Furthermore, we developed a machine-learning-based predictive model by using daily dose and nitrogen-containing benzene substituent alerts as the top inputs and achieved the predictive performance of area under curve (AUC) of 70%. Additionally, we confirmed the reactivity of the nitrogen-containing benzene substituent aniline and related metabolites using quantum chemistry analysis and explored the underlying mechanisms. These identified structural alerts could be helpful in identifying drug candidates that carry a potential risk of drug-induced ADs to improve their safety profiles.

Study on the Spontaneous Combustion Tendency of Coal Based on Grey Relational and Multiple Regression Analysis.

The correlation between the spontaneous combustion tendency of coal and its properties are of great importance for safety issues, environmental concerns, and economic problems. In this study, the relationship between multiple parameters, different from the previous single parameter, and the spontaneous combustion tendency was analyzed. The comprehensive judgment index (CJI), which indicates the tendency of coal spontaneous combustion, was obtained for samples collected from different mines. The CJI was measured by the cross-point temperature and had a negative correlation with the spontaneous combustion tendency. Physical pore structures and chemical functional groups were characterized based on cryogenic nitrogen adsorption and Fourier transform infrared spectroscopy measurements, respectively. For analyzing the effect of coal properties on the spontaneous combustion tendency, the grey relational grade was determined by the grey relational analysis between the CJI and the pore structures and functional groups of coal. The grey relational grade of the benzene substituent with CJI had a maximum of 0.8642, and the macropores had the minimum, 0.4169. The higher the gray relational grade was, the more relevant the spontaneous combustion tendency was, indicating that the benzene substituent was the most relevant. To better predict the spontaneous combustion tendency, the average pore diameter, hydroxyl, methyl, methylene, and benzene substituent with a high grey relational grade were selected. Finally, the multiple regression prediction model of CJI was established. The R squared coefficient, significance level, F-distribution, t-distribution, collinearity diagnosis, and residual distribution of the model met the requirements. In addition, two coal samples were selected to verify the spontaneous combustion tendency model. The relative errors between the predicted CJI value and the experimental CJI value were 1.42 and 4.25%, respectively. These small relative errors verified the reasonableness and validity of the prediction model.

Effect of Side Chain Substituent Volume on Thermoelectric Properties of IDT-Based Conjugated Polymers.

A p-type thermoelectric conjugated polymer based on indacenodithiophene and benzothiadiazole is designed and synthesized by replacing normal aliphatic side chains (P1) with conjugated aromatic benzene substituents (P2). The introduced bulky substituent on P2 is detrimental to form the intensified packing of polymers, therefore, it hinders the efficient transporting of the charge carriers, eventually resulting in a lower conductivity compared to that of the polymers bearing aliphatic side chains (P1). These results reveal that the modification of side chains on conjugated polymers is crucial to rationally designed thermoelectric polymers with high performance.

A supramolecular 3D structure constructed from a new metal chelate self-assembled from Sn(NCS)2 and phenyl(pyridin-2-yl)methylenepicolinohydrazide

Synthesis and detailed structural characterization of a new coordination compound [Sn(HL)2(NCS)2]·0.5MeOH (1·0.5MeOH), synthesised from a mixture of SnSO4 and KNCS with a bulky organic ligand phenyl(pyridin-2-yl)methylenepicolinohydrazide (HL) in MeOH, is reported. The metal is N6O2 octacoordinated by two tridentate ligands HL through the pyridyl-imine units and the carbonyl oxygen atoms, and its coordination sphere is completed by two N-bound isothiocyanate anions to form the mononuclear heteroleptic complex. The crystal packing of 1·0.5MeOH is strongly dictated by aromatic pyridine and benzene substituents in the structure of coordinated ligands HL. The pyridine rings are involved in intermolecular π(Py)···π(Py) stacking interactions, yielding a 2D supramolecular layer. These 2D layers are further interlinked in the orthogonal direction through intermolecular π(Ph)···π(Ph) stacking interactions, yielding a 3D supramolecular structure. The structure of 1·0.5MeOH is further stabilized by weak non-covalent interactions of the type C–H···S and C–H···π(Py). Latter interactions have been studied using density functional theory (DFT) and molecular electrostatic potential (MEP) surface calculations and characterized using the quantum theory of atoms-in-molecules (QTAIM).

Design, synthesis and biological activity of N5-substituted tetrahydropteroate analogs as non-classical antifolates against cobalamin-dependent methionine synthase and potential anticancer agents

Cobalamin-dependent methionine synthase (MetH) is involved in the process of tumor cell growth and survival. In this study, a novel series of N5-electrophilic substituted tetrahydropteroate analogs without glutamate residue were designed as non-classical antifolates and evaluated for their inhibitory activities against MetH. In addition, the cytotoxicity of target compounds was evaluated in human tumor cell lines. With N5-chloracetyl as the optimum group, further structure research on the benzene substituent and on the 2,4-diamino group was also performed. Compound 6c, with IC50 value of 12.1 μM against MetH and 0.16–6.12 μM against five cancer cells, acted as competitive inhibitor of MetH. Flow cytometry studies indicated that compound 6c arrested HL-60 cells in the G1-phase and then inducted late apoptosis. The molecular docking further explained the structure-activity relationship.

Electrochromism and electrochromic devices of new extended viologen derivatives with various substituent benzene

New electrochromic devices based on six extended viologen derivatives with various aromatic substituents were manufactured and systematically investigated. With the introduction of various substituents, six extended viologen derivatives exhibit an unprecedented electrochromic property among previous researches on viologens. Electrochromic devices containing these derivatives as the working electrode present vivid color changes, high optical contrast, fast response and excellent durability. Additionally, the extended skeletal pyridine π-system endows these viologens derivatives with unanticipated electrofluorochromic behavior, which provides the devices of these extended viologens multifunction. To sum up, preeminent optical and electrical performances indicate that these extended viologen derivatives are promising for new-generation electrochromic applications.

Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1,3-benzoxazine derivatives

Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis. The resultant ferrocenyl 1,3-benzoxazine compounds displayed high potency and selectivity against the investigated diseases, with IC50 values in the low and sub-micromolar range against both chloroquine-sensitive (3D7) and resistant (Dd2) strains of the Plasmodium falciparum parasite. On the other hand, antitrypanosomal (Trypanosoma brucei brucei) potencies were observed between 0.15 and 38.6 μM. The majority of the compounds were not active against breast cancer cells (HCC70), however, for the toxic compounds, IC50 values ranged from 11.0 to 30.5 μM. Preliminary structure-activity relationships revealed the basic oxazine sub-ring and lipophilic benzene substituents to be conducive for biological efficacy of the ferrocenyl 1,3-benzoxazines reported in the study. DNA interaction studies performed on the most promising compound 4c suggested that DNA damage may be one possible mode of action of this class of compounds.

Evaluation of a series of phenyl-type stationary phases in supercritical fluid chromatography with the linear solvation energy relationship model and its application to the separation of phenolic compounds

In recent years, supercritical fluid chromatography (SFC) has become a powerful tool in modern analytical chemistry, and the diversity of stationary phases in SFC promotes phenyl-type phases to confront with a significant resurgence of interest. In this paper, a series of phenyl-type stationary phases with different substituted benzenes involving N-propylbenzamide (PB), 4-fluoro-N-propylbenzamide (PB-F), and 4-ethyl-N-propylbenzamide (PB-ET) were synthesized. Retention mechanism of these phases in SFC was investigated using a linear solvation energy relationship (LSER) model. The phenyl-type stationary phases with all positive parameters can provide all types of interaction, typically involving hydrogen bonding, dipole-dipole and dispersive interactions. The different benzene's substituents of the stationary phases mainly affected their hydrogen bonding and dipole-dipole interactions, which could be reflected by the angle between the solvation vectors to some extent. The k-k plot showed that the selectivity difference of phenyl-type stationary phases was closely related to the type of solute. Thus, based on twenty-five natural phenolic compounds, two systems with high orthogonality (63.49%) were constructed using three columns, namely phenyl column (PHE) × PB-F and PB × PB-F. Finally, after investigating the influence of chromatographic conditions, ten flavonoids could be separated by using PB, PB-F and PHE columns in SFC.

Selective Excited-State Dynamics in a Unique Set of Rationally Designed Ni Porphyrins

In this work, we report the design and photophysical properties of a unique class of Ni porphyrins, in which the tert-butyl benzene substituents at the meso positions of the macrocycle were tethered by ethers with alkyl linkers. This not only results in the permanently locked ruf distortion of the macrocycle but also enables the engineering of the degree of distortion through varying the length of alkyl linkers, which addressed the complication of uncertainty in the specific structural distortions that has long plagued the porphyrin photophysical community. Using advanced time-resolved optical and X-ray absorption spectroscopy, we observed tunability in the excited-state relaxation pathway depending on the degree of distortion and characterized the associated transient intermediate structure. These findings provide a new avenue to afford accessibility to a wide range of excited-state properties in nonplanar porphyrins.

Determination of the best functional and basis sets for optimization of the structure of hypervalent iodines and calculation of their first and second bond dissociation enthalpies

AbstractHypervalent iodines are widely used in organic chemistry, and their most important feature is the three‐center four‐electron bond. However, there have been few reports on the measurement of their bond dissociation enthalpy (BDE). Therefore, in many cases, BDE is estimated by computational calculations. However, the value of a calculated BDE usually varies depending on the choice of functional and basis set, and the best method for making an accurate evaluation of the three‐center four‐electron bond has not been determined. We succeeded in determining the best functional and basis set to calculate the three‐center four‐electron bond to within 0.79% error and 0.53 standard deviation. Using the optimal functional and basis set, the first and second BDEs of several hypervalent iodines are calculated, and as the effect of benzene substituents was investigated, negative correlation was observed in the Hammett plot. In addition, the effect of ortho‐substituent in cyclic hypervalent iodine was found to be significant. Furthermore, the decomposition route of hypervalent iodine is calculated. The value of a calculated BDE usually varies depending on the choice of functional and basis set. We succeeded in determining the best functional and basis sets to calculate the three‐center four‐electron bond of hypervalent iodine to within 0.79% error and 0.53 standard deviation. Using the optimal functional and basis sets, the first and second BDEs of several hypervalent iodines are calculated, and additionally, the decomposition route of hypervalent iodine is calculated.

Theoretical studies on charge transport and optical properties of diarylmaleic anhydride derivatives as organic light-emitting materials

Abstract The charge transport and optical properties of aromatic ring substituents symmetrically-substituted diarylmaleic anhydrides is studied based on the Marcus–Hush theory and quantum chemistry calculations. The molecule with benzene substituents (1) exhibits the balanced hole and electron charge transport properties. Among three molecules, molecule with thiophene substituents (2) shows the maximum carrier mobility. The frontier molecular orbitals analysis turned out that molecule with indole substituents (3) is characterized as intramolecular charge transfer. The absorption and emission spectra indicate that the aromatic substituents can affect optical properties of molecules. 2 might be promising luminescent material for organic light-emitting diodes.

Thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives: Design, synthesis, insecticidal activities, structure-activity relationship and molecular-modeling studies

Owing to thioether diverse physicochemical properties by non-covalent interactions with bio-macromolecules, thioether derivatives containing heterocyclic moiety are known for their interesting insecticidal bioactivities and attracting considerable attention as neuroactive insecticides. Here we synthesis a series of novel thioether bridged N-phenylpyrazole derivatives incorporating various (hetero)aromatic substituents into 4-position of the pyrazole ring. Structure-activity relationship (SAR) studies resulted in compounds 6d and 7d with the most potent insecticidal activity among the series containing various substituted benzene substituents (LC50 = 13.70–25.47 μg/g). Further optimization to increase the lipophilicity and charge density of aromatic substituents of compounds 6d and 7d resulted in compounds 12d, 14d and 16d with sulfur-containing heterocycle substituents possessing good insecticidal activity against Musca domestica L. among the series (LC50 = 0.67–1.30 μg/g). The thioether bridge N-phenylpyrazole derivatives, which exhibit different length of the spacer arm introduced between N-phenylpyrazole moiety and the (hetero)aromatic substituents, were also prepared and evaluated. By contrast, the insecticidal activities of compounds containing the short thioether bridge, 1,2-bis((hetero)aromatic thio) ethane, are higher than that containing the long thioether bridge, 1,3-bis((hetero)aromatic thio) propane. The results of molecular docking and pharmacophore analyses indicated A299, T303, and L306 of a subunit were essential to form non-covalent interactions contacts with the ligands. Specially, the sulfur-containing heterocycle substituent derivatives 12d and 14d as the sterically favored areas could form the important hydrophobic interactions with the deeper residue P295.

Cyclic tetranuclear iron-carbonyl complex containing thiobisbenzenethiolate ligands: Synthesis and structural characterization

Abstract A new macromolecular double-butterfly Fe/S carbonyl cluster, [Fe2(CO)6]2(μ-4,4′-thiobisbenzenethiolato)2 (1), a model for the active site of [Fe-Fe] hydrogenases, has been prepared and characterized by spectroscopic methods and X-ray crystallography. The molecular structure of 1 contains two units of S2Fe2(CO)6 covalently linked to two thiobisbenzene groups to form a 26-membered metallocycle with the benzene substituents on sulfur adopting an ae stereochemistry. The Fe-Fe bond in 1 is 2.5046(5) A which is close to that of the enzyme and related complexes. Crystals of 1 obtained from dichlormethane solution of [Fe2(CO)6]2(μ-4,4′-thiobisbenzenethiolato)2 contain two dichloromethane molecules trapped in the cavity of 1. Infrared spectrum of 1 has peaks at 2071, 2030, and 1972 cm−1 charateristic of the presence of the Fe2(CO)6 core. Spectroscopic evidence suggest significant electronic interaction between the thiobisbenzene moieties and the S2Fe2(CO)6 units in 1.