Para Position Research Articles

Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors

The inhibitory action of fifteen benzyloxy ortho/para-substituted chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 μM level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 μM, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50 = 0.12 μM). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). Ki values of B10 and B15 were 0.030 ± 0.001 and 0.033 ± 0.001 μM, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0 × 10–6 cm/s. Both compounds were stabilized in protein–ligand complexes by the π-π stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of − 74.57 and − 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R2 = 0.9125, Q2loo = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors.

Structural Factors That Determine the Activity of the Xenobiotic Reductase B Enzyme from Pseudomonas putida on Nitroaromatic Compounds

Xenobiotic reductase B (XenB) catalyzes the reduction of the aromatic ring or nitro groups of nitroaromatic compounds with methyl, amino or hydroxyl radicals. This reaction is of biotechnological interest for bioremediation, the reuse of industrial waste or the activation of prodrugs. However, the structural factors that explain the binding of XenB to different substrates are unknown. Molecular dynamics simulations and quantum mechanical calculations were performed to identify the residues involved in the formation and stabilization of the enzyme/substrate complex and to explain the use of different substrates by this enzyme. Our results show that Tyr65 and Tyr335 residues stabilize the ligands through hydrophobic interactions mediated by the aromatic rings of these aminoacids. The higher XenB activity determined with the substrates 1,3,5-trinitrobenzene and 2,4,6-trinitrotoluene is consistent with the lower energy of the highest occupied molecular orbital (LUMO) orbitals and a lower energy of the homo orbital (LUMO), which favors electrophile and nucleophilic activity, respectively. The electrostatic potential maps of these compounds suggest that the bonding requires a large hydrophobic region in the aromatic ring, which is promoted by substituents in ortho and para positions. These results are consistent with experimental data and could be used to propose point mutations that allow this enzyme to process new molecules of biotechnological interest.

Iridium‐Catalysed C−H Borylation of Fluoroarenes: Insights into the Balance between Steric and Electronic Control of Regioselectivity

AbstractThe iridium catalysed C−H borylation of polyfluorinated arenes and heteroarenes occurs rapidly and efficiently. As with other borylation reactions, whilst steric parameters dominate, an underlying electronic influence on reaction selectivity can be observed. Notably borylation regioselectivity in fluorinated (hetero)arenes is determined by purely electronic effects except for ortho‐borylation between two fluorine atoms where steric effects of fluorine substituents become apparent. Borylation at the para position with respect to fluorine is disfavoured whereas a strong electronic preference for borylation para to the azinyl nitrogen of pyridine is observed. When these features co‐operate high selectivity can be expected. For these reactions, computations based on transition state, rather than intermediate, energies in iridium geometries showed excellent agreement between predicted and observed selectivities.

Structure-activity relationship studies of benzothiazole-phenyl analogs as multi-target ligands to alleviate pain without affecting normal behavior

Soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are potential targets for several diseases. Previous studies have reported that concomitant selective inhibition of sEH and FAAH produced antinociception effects in an animal model of pain. However, the co-administration of a selective sEH inhibitor and a selective FAAH inhibitor might produce serious side effects due to drug-drug interactions that could complicate drug development in the long term. Thus, discovering dual sEH/FAAH inhibitors, single small molecules that can simultaneously inhibit both sEH and FAAH, would be a significant accomplishment in the medicinal chemistry field. Herein, we report the synthesis and biological evaluation of benzothiazole-phenyl-based analogs as potential dual sEH/FAAH inhibitors. This work represents a follow-up structure-activity relationship (SAR) and metabolic-stability studies of our best dual sEH/FAAH inhibitor identified previously, as well as in vivo evaluation of its effects on voluntary locomotor behavior in rats. Our SAR study indicates that trifluoromethyl groups on the aromatic rings are well tolerated by the targeted enzymes when placed at the ortho and para positions; however, they, surprisingly, did not improve metabolic stability in liver microsomes. Our behavioral studies indicate that doses of dual sEH/FAAH inhibitors that alleviate pain do not depress voluntary behavior in naïve rats, which is a common side effect of currently available analgesic drugs (e.g., opioids). Thus, dual sEH/FAAH inhibitors may be a safe and effective approach to treat pain.

Substitution Effect on Self-Assembly and the Resulting Fluorescence Efficiency of Triangular Azo Chromophores

To investigate the effect of substituents and substitution positions on absorption and fluorescence spectroscopic properties, and self-assembled structures, we designed triangular azo chromophores (1-3) in which three azo groups are connected to a central ring. 1 and 2 where electron-donating methoxy (MeO) groups are attached to para and meta positions, respectively, had different melting temperatures and colors. A dilute para-MeO (1) solution was redder than 3 with electron-withdrawing bromo (Br) groups and liquefied at lower temperatures. The elongated structure formed as a result of the one-dimensional (1D) assembly of 1 showed little fluorescence, whereas the chopstick-shaped structure and the entangled fiber assembled from 2 and 3, respectively, were brightly red fluorescent. Our investigation suggest that the molecular geometry and steric effects play important roles in self-assembly and the resulting fluorescence characteristics.

Hydrogen Bonding in Platinum Indolylphosphine Polyfluorido and Fluorido Complexes.

The reaction of the Pt complexes cis-[Pt(CH3 )(Ar){Ph2 P(Ind)}2 ] (Ind=2-(3-methyl)indolyl, Ar=4-tBuC6 H4 (1 a), 4-CH3 C6 H4 (1 b), Ph (1 c), 4-FC6 H4 (1 d), 4-ClC6 H4 (1 e), 4-CF3 C6 H4 (1 f)) with HF afforded the polyfluorido complexes trans-[Pt(F(HF)2 )(Ar){Ph2 P(Ind)}2 ] 2 a-f, which can be converted into the fluoride derivatives trans-[Pt(F)(Ar){Ph2 P(Ind)}2 ] (3 a-f) by treatment with CsF. The compounds 2 a-f and 3 a-f were characterised thoroughly by multinuclear NMR spectroscopy. The data reveal hydrogen bonding of the fluorido ligand with HF molecules and the indolylphosphine ligand. Polyfluorido complexes 2 a-f show larger |1 J(F,Pt)|, but lower 1 J(H,F) coupling constants when compared to the fluorido complexes 3 a-f. Decreasing 1 J(P,Pt) coupling constants in 2 a-f and 3 a-f suggest a cis influence of the aryl ligands in the following order: 4-tBuC6 H4 (a) ≈4-CH3 C6 H4 (b)<Ph (c)≪4-FC6 H4 (d)<4-ClC6 H4 (e)<4-CF3 C6 H4 (f). In addition, the larger cis influence of aryl ligands bearing electron-withdrawing groups in the para position correlates with decreasing magnitudes of |1 J(F,Pt)| coupling constants. The interpretation of the experimental data was supported by quantum-chemical DFT calculations.

Photophysical and optical properties of 4-(4'-(diphenylamino)benzylidene)-2-phenyloxazol-5(4H)-ones induced by the peripheral substituent

Photophysical and optical properties of 4-(4'-(diphenylamino)benzylidene)-2-phenyloxazol-5(4H)-ones differing in the peripheral substituent have been investigated in chloroform, solvent mixture, polymer matrix and solid state. These properties are influenced by the nature of the substituent on the phenyl ring and the environment. The dye bearing phenyl group or without substituent in para position of the phenyl group in 2-phenyloxazol-5(4H)-one moiety has the brightest emission in a solid state, whereas the dye with cyano functional group possesses the strongest emission in chloroform. The spectral behavior of the tested dyes is dependent on the solvent mixture. The fluorescence of the oxazolone dye in CHCl3/MeOH was reduced due to hydrogen bond formation, whereas addition of water to the THF or DMSO indicate the enhancement in emission caused by aggregation induced emission (AIE). The absorption and fluorescence spectra of the oxazolone polymer thin film are shifted to blue compared to the dyes dissolved in chloroform.The surface topography of the oxazolone thin films was examined using atomic force microscopy (AFM). The optical properties of the dye layers and dyes immobilized in PMMA matrix were determined by spectroscopic ellipsometry (SE). The absorption coefficient, refractive index, extinction coefficient and the energy bandgap can be effectively manipulated by changing substituent in the dye structure.

Based on triphenylamine-imidazole skeleton electrofluorochromic small organic molecules: Synthesis and electrofluorochromic properties

Five donor–acceptor (D-A) small organic molecule compounds were designed and synthesized by using triphenylamine (TPA) as the donor and imidazole as the acceptor. Through introducing different substituent groups at the para position of TPA, the excited state characteristics were adjusted, and a reversible and stable color change was obtained. These compounds exhibited good thermal properties. All five compounds were evaluated as small organic molecule materials for electrofluorochromism (EFC) and achieved luminescence conversion from blue to yellow at low voltages, and the compound 4e realized electroluminescence conversion at only 0.6 V due to the introduction of –OCH3. The stability of the EFC devices was demonstrated by the CV curves for 400 cycles. The color-changing voltages of EFC can be effectively reduced by adjusting the characteristics of ICT. This rational structural design of small organic molecules provides a new design strategy for the preparation of EFC materials.

Synthesis, characterization and antibacterial evaluation of N‐(2‐Morpholinoethyl)‐3‐phenylquinoxalin‐2‐amine derivatives

AbstractA series of substituted N‐(2‐Morpholinoethyl)‐3‐phenylquinoxalin‐2‐amines (5a–j) (5ab, 5ac) were synthesized in good yield and characterized for their structural confirmation. The pure quinoxaline products were screened for their in‐vitro antibacterial activity against Salmonella paratyphi, a well‐known food borne pathogen. The preliminary results revealed that among the series, compounds 5a, 5c, 5d, 5e, 5f, 5h, 5ab and 5ac bearing bromo, fluoro, methoxy, methyl groups at para position on phenyl ring which inturn substituted at third position of quinoxaline and methyl, benzoyl groups at sixth position on the quinoxaline were emerged as potential candidates by displaying antisalmonella activity. Among the potential candidates, compounds 5c, 5e, 5f and 5ac were effective against Salmonella whereas compounds 5a, 5f and 5ac effectively inhibited the biofilm formation of Salmonella.

Fluorinated triphenylphosphonium analogs improve cell selectivity and invivo detection of mito-metformin.

Triphenylphosphonium (TPP+) conjugated compounds selectively target cancercells by exploiting their hyperpolarized mitochondrial membrane potential. Todate, studies have focused on modifying either the linker or the cargo of TPP+-conjugated compounds. Here, we investigated the biological effects ofdirect modification to TPP+ to improve the efficacy and detection of mito-metformin (MMe), a TPP+-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining thesame signaling mechanism. Importantly, pCF3-MMe allowed quantitative monitoring of cellular accumulation via 19F-NMR invitro and invivo. Furthermore, adding trifluoromethyl groups to TPP+ reduced toxicity invivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP+-conjugated compounds.

Allyl-modified epoxy networks that break and reorganize at high temperatures to avoid Tg reduction

Epoxy resins often age during high-temperature use, causing a drop in Tg and a number of safety problems. Currently, no specific reports addressing this Tg drop are available. Here, we proposed that the Tg drop could be prevented by allyl modification, and designed a series of epoxy monomers containing allyl to demonstrate this view. First, the influence of allyl groups on epoxy monomers was evaluated. It was found that allyl groups could reduce the viscosity of the monomers and the curing rate. These monomers were cured by DDM into resin (virgin resin) and treated at 285 °C for 6 h (treated resin) until the double bond was consumed. By comparison, it was found that although the introduction of allyl groups reduces the Tg of the virgin resin, it does not adversely affect the thermal degradation temperature (Td5%). The Td5% and Tg of the allyl-containing treated resin did not drop significantly like those of the treated resin without allyl. Specially, the Td5% and Tg of an allyl-rich resin increased by + 49 and + 289 °C, respectively. According to further study of the network generated by allyl groups, the allyl group in the para position (relative to the glycidyl ether group) would produce greater cross-linking, whereas the intramolecular ring formation in the ortho position results in an imperfect network of the new resin. Finally, through qualitative analysis of the entire resin network, we believe that this is a result of the high-temperature destruction of the epoxy network and the formation of an allylic network.

Effect of para (p) position methoxy group on thesynthesis of Benzohydrazide derivatives from Methylbenzoate starting material

The synthesis of N'-benzylidenebenzohydrazide and N'-(4-methoxybenzylidene)benzo hydrazide had performed through condensation reaction. The reaction was performed in two stageswith methylbenzoate as the initial material. The firstphase was obtained benzohydrazide by reacting methylbenzoate and hydrazine hydrate, the second phase was obtainedthe compound of N'-benzylidenebenzohydrazide and N '-(4-methoxyibenzylidene)benzohydrazide by reacting benzohydrazide and benzaldehyde/4-methoxybenzaldehyde. The results were obtained respectively 87% and 92%. Puritytest was done by thin layer chromatography (TLC) and melting point. The melting point of benzohydrazide was 108-111oC. N'-benzylidene benzohydrazide m.p. 104-108oC and N'-(4-methoxybenzylidene)benzohydrazide m.p. 159-161oC.Identifications synthesized were confirmed by UV-VIS, FT-IR and 1H-NMR spectroscopy.

Study of the Electrochemical Behavior of N-Substituted-4-Piperidones Curcumin Analogs: A Combined Experimental and Theoretical Approach

The electrochemical behavior of N-methyl- and N-benzyl-4-piperidone curcumin analogs were studied experimentally and theoretically. The studied compounds present different substituents at the para position in the phenyl rings (-H, -Br, -Cl, -CF3, and -OCH3). We assessed their electrochemical behavior by differential pulse and cyclic voltammetry, while we employed density functional theory (DFT) M06 and M06-2x functionals along with 6-311+G(d,p) basis set calculations to study them theoretically. The results showed that compounds suffer a two-electron irreversible oxidation in the range of 0.72 to 0.86 V, with surface concentrations ranging from 1.72 × 10-7 to 5.01 × 10-7 mol/cm2. The results also suggested that the process is diffusion-controlled for all compounds. M06 DFT calculations showed a better performance than M06-2x to obtain oxidation potentials. We found a good correlation between the experimental and theoretical oxidation potential for N-benzyl-4-piperidones (R2 = 0.9846), while the correlation was poor for N-methyl-4-piperidones (R2 = 0.3786), suggesting that the latter suffer a more complex oxidation process. Calculations of the BDEs for labile C-H bonds in the compounds suggested that neither of the two series of compounds has a different tendency for a proton-coupled electron transfer (PCET) oxidation process. It is proposed that irreversible behavior is due to possible dimerization of the compounds by Shono-type oxidation.

Iminophosphine platinum(II) complexes containing long chain aniline derivatives: synthesis, characterization, and anticancer properties

A series of iminophosphine ligands (1a-g) have been prepared from the condensation reaction of 2-(diphenylphosphino)benzaldehyde with aniline and aniline derivatives containing linear hydrocarbon chains of varying lengths in the para position. The corresponding platinum(II) complexes (2a-g) were synthesized by reaction of [PtCl2(η2-coe)]2 (coe = cis-cyclooctene) and two equivalents of 1a-g. Full characterization of all new ligands and platinum complexes was performed including multi-nuclear NMR spectroscopy as well as an X-ray diffraction study for compound 2d (derived from 4-hexylaniline). The cytotoxic properties of the platinum complexes against two glioma cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric method were examined.

Photochromism of tetrahydroindolizines. Part XXVI: Mechanochemical synthesis, tunable photophysical properties and combined experimental and theoretical studies of novel photochromic tetrahydroindolizines

Herein, eighteen novel photochromic tetrahydroindolizines (THIs) have been successfully prepared using a well-established mechanochemical synthetic approach. These products were obtained in good to excellent yields and the purification process was relatively straightforward devoid of any isolation challenges. The new THIs incorporate various substituents in region C (base part) which include both electron donating and withdrawing groups in the ortho, meta and para positions of the phenyl ring. The absorption maxima (λmax) of both closed form (THI) and the colored form (betaine, after UV-irradiation) were spectrophotometrically determined in dichloromethane solution. The colored betaines displayed two absorption maxima, one between 472 and 485 nm, and the second one appearing in the white region between 658 and 724 nm with tailing extending to the near infra-red (NIR) region. The impact of the nature and position of substituent in the 10′b-phenyl ring on the absorption of the betaines indicated that substitution in the ortho-position with absorption maxima between 658 and 690 nm leads to a hypsochromic shift largely caused by the steric effect of the substituents in the o-position of the THI molecule 10′b-phenyl ring compared to the meta- and para-substituted species with absorption maxima between 700 and 724 nm. The calculated ring closure thermodynamic activation parameters of colored betaines were found to be in good agreement with previous reported results. The 1,5-electrocyclization reaction kinetics of the investigated photochromic THIs were monitored and calculated. Intriguingly, substitution with electron donating and withdrawing groups in the o-, m-, and p-positions of the phenyl ring enabled distinctive tunability of the kinetic behavior. Furthermore, possible mechanism of the thermal 1,5-electrocyclization back reaction of betaines was explored based on density functional theory calculations (DFT), delivering more understanding into ring opening and ring closure processes in addition to the distinct THI-substituents effect (region C). The geometries and the relative energies of the THI, betaine isomers, and transition states along reaction coordinates were optimized and assessed by DFT. Based on the obtained synthetic methodology results, unprecedent tunability of the photochromic properties and the combined experimental and theoretical studies, the current work launches a new dimension and contributes further developments to the field of high-performance photochromic materials.

Exploring the fluorination effect mechanism on charge transport in organic solar cells

The fluorination in organic solar cells (OSCs) impacts the photoelectric properties of conjugated polymers. Here, two benzo [1,2-c:4,5-c’] dithiophene-4,8-dione (T1) based donor polymers with different numbers of fluorine substitutions (F1 and F2) have been investigated. Through density functional theory (DFT), optimized structures, frontier molecular orbitals (FMOs), energy gaps, electron affinity energies (EAs) and ionization potentials (IPs) of the fluorinated polymers were studied. Simultaneously, one used time-dependent density functional theory (TD-DFT) to simulate the absorption spectra of F1 and F2 polymer molecules. The impact mechanism of F atoms for the above parameters was explained in depth. Then, through constructing the molecular dimer model, the hole mobility based on Marcus’ theory was calculated for two systems, suggesting that the hole mobility of F1 (with two fluorine atoms introduced in the specific para position of the benzene unit) was greater than that of F2. Finally, the ideal photovoltaic parameters of donor–acceptor compounds were theoretically investigated, and the reasons for performance differences were analyzed from the micro level. The research helps understand the influence of specific fluorine atom substitution on the structure, spectrum, electrochemical parameters, charge transfer and photovoltaic properties, and provides a theoretical guideline for the molecular fluorination modification strategy of excellent OSCs.

Grafted dinuclear zinc complexes for selective recognition of phosphatidylserine: Application to the capture of extracellular membrane microvesicles

Microvesicles (MVs) are key markers in human body fluids that reflect cellular activation related to diseases as thrombosis. These MVs display phosphatidylserine at the outer leaflet of their plasma membrane as specific recognition moieties. The work reported in this manuscript focuses on the development of an original method where MVs are captured by bimetallic zinc complexes. A set of ligands have been synthetized based on a phenol spacer bearing in para position an amine group appended to a short or a longer alkyl chain (for grafting on surface) and bis(dipicolylamine) arms in ortho position (for zinc coordination). The corresponding dibridged zinc phenoxido and hydroxido complexes have been prepared in acetronitrile in presence of triethylamine and characterized by several spectroscopic techniques. The pH-driven interconversion studies for both complexes in H2O:DMSO (70:30) evidence that at physiologic pH the main species are mono-bridged by the phenoxido spacer. An X-Ray structure obtained from complex 2 (based on the ligand with the amine group on the short chain) in aqueous medium confirms the presence of a mono-bridged complex. Then, the complexes have been used for interaction studies with short-chain phospholipids. Both have established the selective recognition of the anionic phosphatidylserine model versus zwitterionic phospholipids (in solution by 31P NMR and after immobilization on solid support by surface plasmon resonance (SPR)). Moreover, both complexes have also demonstrated their ability to capture MVs isolated from human plasma. These complexes are thus promising candidates for MVs probing by a new approach based on coordination chemistry.

Structural and antimicrobial property changes of veterinary antibiotics in thermal treatment

Agricultural application contributes major consumption of antibiotics worldwide. As veterinary antibiotics are poorly metabolized by animals, most of them end up in agricultural waste, which is increasingly subject to thermal treatment, such as torrefaction, pyrolysis, etc. However, there is a lack of research on their thermal decomposition mechanisms and products elucidation. Therefore, this study investigated the thermal decomposition of four major veterinary antibiotics groups (β-lactams, tetracyclines, fluoroquinolones, sulfonamides) with emphasis on their thermal stability, structural transformation and antibacterial activity. Results show that thermal treatment can remove the parent antibiotics with their antibacterial activity except for gatifloxacin (GAT). Although the parent form of GAT was fully removed at 200 °C, its products showed significant antibacterial activity against E. coli. We present novel evidence that the PhO-CH3 chemical bond on GAT preferentially brake to generate methyl radical, which underwent a substitution reaction at the para position of phenol. This reaction also occurred during the thermal decomposition of antibiotic analogues, balofloxacin and moxifloxacin, whose thermolysis products also showed significant antibacterial activity. Furthermore, these thermolysis products may present potentially cardiotoxic and pose higher risks to human health than their parent forms, based on the comparison with a group of drugs withdrawn from the market.

Disentangling Excimer Emission from Chiral Induction in Nanoscale Helical Silica Scaffolds Bearing Achiral Chromophores.

The synthesis and characterization of diketopyrrolopyrroles and perylenemonoimidodiesters linked to a substituted benzoic acid in the ortho, meta, and para positions, are reported. Grafting of these dyes on the surface of chiral silica nanohelices is used to probe how the morphology of the platform at the mesoscopic level affects the induction of chiroptical properties onto achiral molecular chromophores. The grafted structures are weakly (diketopyrrolopyrroles) or strongly (perylenemonoimidodiesters) emissive, exhibiting both locally-excited state emission and a broad, structureless emission assigned to excimers. The dissymmetry factors obtained using circular dichroism highlight optimized supramolecular organization between the chromophores for enhancing the chiroptical properties of the system. In the ortho- derivatives, poor organization due to steric hindrance is reflected in a low density of chromophores on walls of the silica-nanostructures (<0.1 vs. >0.3 and up to 0.6 molecules/nm2 for the ortho and meta or para derivatives, respectively) and lower gabs values than in the other derivatives (gabs <2×10-5 vs 6×10-5 for the ortho and para derivatives, respectively). The para derivatives presented a better organization and increased values of gabs . All grafted chromophores evidence varying degrees of excimer emission which was not found to directly correlate to their grafting density.

The relative favorability of placing substituents ortho or para in the cationic intermediate for electrophilic aromatic substitution

AbstractRegioselectivity in electrophilic aromatic substitution (EAS) is partly governed by how well a preexisting substituent stabilizes or destabilizes the cationic intermediate formed by addition of an electrophile. Such intermediates were modeled computationally (G4) by adding a proton ortho, meta, or para to an existing substituent on a benzene ring. The effect of a meta substituent depends on the electronic character, as measured by the Hammett substituent constant σm or, better yet, σ+m. Similarly, the effect of a para or ortho substituent correlates with σ+p (= σ+). However, the influence of a substituent at the para position is 10% stronger than at the ortho position. Frontier molecular orbital arguments rationalize this observation. Consequently, the ortho:para product ratio in EAS is expected to depend, at least in part, on σ+p, with greater electron‐donating character associated with a greater preference for para over ortho. The ortho‐substituted cationic intermediate can even be favored over both meta and para if the electron‐withdrawing character is sufficient to favor ortho over para but insufficient to favor meta over either. This phenomenon is observed to occur in at least some cases when the quantity σ+p–σm falls between –0.5 and 0.