Substituent Effect on N-Benzylideneanilines by DFT Energy Partition

To investigate the substituent effect on x-electron delocalization of the N-benzylideneaniline （NBA）, the vertical resonance energies △E^V（θ） of eleven substituted NBAs were separated into n and a parts at the B3LYP/6-311G（d） level of the Density Functional Theory （DFT）. When substituted with an electron-releasing group --OH, the calculated △E^V（θ） of NBA was increased, indicative of more resonance destabilization than the mother molecule. However, when substituted with an electron-withdrawing group -NO2, the calculated △E^V（θ） values indicated less resonance destabilization. The most destabilizing effect was observed especially when the -OH group located at the ortho-position of the aromatic ring in the fragment -N=CH-Ar. For most of the substituted NBA molecules, it was the destabilized a framework that determined the destabilizing feature of the vertical resonance energy, instead of the stabilized n system. When the -NO2 substituent at the para-position of the aromatic ring of the -N=CH-Ar group, the π system had the highest stabilizing effect while the σ framework exhibited the highest destabilizing effect. While the -NO2 substituent was at the para-position of the left aromatic ring （At-）, the NBA had the least vertical resonance energy value.     

Synthesis of 2‐amino‐4‐oxo‐5‐substitutedbenzylthiopyrrolo[2,3‐d]‐pyrimidines as potential inhibitors of thymidylate synthase

A series of ten novel 2‐amino‐4‐oxo‐5‐[(substitutedbenzyl)thio]pyrrolo[2,3‐d]pyrimidines 2‐11 were synthesized as potential inhibitors of thymidylate synthase and as antitumor agents. The analogues contain various electron withdrawing and electron donating substituents on the benzylsulfanyl ring of the side chains and were synthesized from the key intermediate 2‐amino‐4‐oxo‐6‐methylpyrrolo[2,3‐d]pyrimidine, 14 . Appropriately substituted benzyl mercaptans were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against human, Escherichia coli and Toxoplasma gondii thymidylate synthase and against human, Escherichia coli and Toxoplasma gondii dihydrofolate reductase. The most potent inhibitor, ( 6 ) which has a 4′‐methoxy substituent on the side chain, has an IC₅₀=25 μM against human thymidylate synthase. Contrary to analogues of general structure 1 , electron donating or electron withdrawing substituents on the side chain of 2‐11 had little or no influence on the human thymidylate synthase inhibitory activity.     

Asymmetric anionic polymerizations of 7‐(o‐substituted phenyl)‐2,6‐dimethyl‐1,4‐benzoquinone methides: Electrostatic interaction and steric,inductive, and resonance effects of the ortho‐substituent on the optical activity

7‐(o‐Substituted phenyl)‐2,6‐dimethyl‐1,4‐benzoquinone methides which have an electron‐donating methoxy‐(o‐OMe, 2a ) and methyl‐ (o‐Me, 2b ) substituents or an electron‐withdrawing cyano‐ (o‐CN, 2c ) and trifluoromethyl‐ (o‐CF₃, 2d ) substituents at the ortho‐position of the aromatic ring and 7‐(m‐substituted phenyl)‐2,6‐dimethyl‐1,4‐benzoquinone methide with an electron‐withdrawing trifluoromethyl‐ (m‐CF₃, 2e ) substituent at the meta‐position of the aromatic ring were synthesized, and their asymmetric anionic polymerizations using the complex of lithium 4‐isopropylphenoxide with (?)‐sparteine were carried out in toluene at 0 °C. The polymers with negative optical activity were obtained for all of five monomers, and their specific rotation values largely changed depending upon the substituents of the monomers. On the basis of the comparison of various substituents effects, it was found that the specific rotation of obtained polymers is significantly affected by the electronic effects such as inductive and resonance effects rather than the steric and electrostatic effects of the substituent. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 1048–1058     

QSAR of genotoxic active benzazoles§

Previously synthesized 2,5-disubstituted benzoxazole and benzimidazole derivatives, were tested for their genotoxic activity in the Bacillus subtilis rec? assay. The results revealed that 5-methyl-2-(p-aminobenzyl)benzoxazole exhibited the highest genotoxic response, which was comparable to 4-nitroquinoline 1-oxide (4-NQO), the reference agent of classical positive mutagen. Among the other tested compounds, four showed a genotoxic activity. A QSAR study revealed that structural parameters IY_C2H4 and IY_CH2O, indicating the bridge elements between the phenyl moiety and the fused ring system at position 2 and the quantum chemical parameter (ΔE?), showing the difference between HOMO and LUMO energies, were found significant for enhancing the genotoxic activity in these compounds. In addition, the substituent effects on positions R and R₁ were found important for the activity as well as holding a substituent possessing a maximum length with a minimum width property on position R₁ like alkyl groups. On the other hand, substituting position R with an electron donating group instead of electron withdrawing group increased the genotoxic activity.     

1,2,4‐Triazol‐3‐ylidenes with an N‐2,4‐Dinitrophenyl Substituent as Strongly π‐Accepting N‐Heterocyclic Carbenes

The synthesis and characterisation of a series of new Rh and Au complexes bearing 1,2,4‐triazol‐3‐ylidenes with a N‐2,4‐dinitrophenyl (N‐DNP) substituent are described. IR, NMR, single‐crystal X‐ray diffraction and computational analyses of the Rh complexes revealed that the N‐heterocyclic carbenes (NHCs) behaved as strong π acceptors and weak σ donors. In particular, a natural bond orbital (NBO) analysis revealed that the contributions of the Rh→C_carbene π backbonding interaction energies (ΔE_bb) to the bond dissociation energies (BDE) of the Rh? C_carbene bond for [RhCl(NHC)(cod)] (cod=1,5‐cyclooctadiene) reached up to 63 %. The Au complex exhibited superior catalytic activity in the intermolecular hydroalkoxylation of cyclohexene with 2‐methoxyethanol. The NBO analysis suggested that the high catalytic activity of the Au^I complex resulted from the enhanced π acidity of the Au atom.     

Synthesis and asymmetric anionic polymerization of substituted 7‐aryl‐2,6‐dimethyl‐1,4‐benzoquinone methides

Substituted 7‐aryl‐2,6‐dimethyl‐1,4‐benzoquinone methides which have an electron‐donating methoxy substituent at the para‐position (p‐OMe, 2a ) or an electron‐withdrawing chloro one at the para‐ (p‐Cl, 2b ), meta‐ (m‐Cl, 2c ) , and ortho‐positions (o‐Cl, 2d ) of the benzene ring were synthesized, and their asymmetric anionic polymerizations using the complex of lithium 4‐isopropylphenoxide with (?)‐sparteine were carried out in toluene at 0 °C. The polymers with negative specific rotation were obtained for all of four monomers, and the polymer obtained from 2a showed smaller specific rotation value than that of polymer having no substituent (p‐H, 1 ) on the phenyl group and the polymers obtained from 2b–d showed larger ones. It was found that the kind of a substituent and its substitution position on the phenyl group affect significantly the optical activity of polymers. The largest specific rotation value of [α]₄₃₅= ?153.2° was obtained in the polymerization of 2d with an ortho‐chloro substituent. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 437–444     

Synthesis and Properties of 2‐Phenylbenzoxazole‐Based Luminophores for in situ Photopolymerized Liquid‐Crystal Films

We report the synthesis of a series of blue‐emitting 2‐phenylbenzoxazoles (PBOs) substituted at either the 5‐ or 6‐position of the benzoxazole ring and the para‐position of the phenyl substituent. The thermal and optical properties of the materials can be rationalized in terms of the position of the substituent at the benzoxazole moiety and the electron‐withdrawing or electron‐donating character of the substituents. From the results, we conclude that the combination of an electron‐donating substituent at the benzoxazole fragment and an electron‐withdrawing one at the phenyl fragment has a more marked effect on the electronic properties of the aromatic PBO core than other possibilities. This particular combination gives luminophores that are suitable for optical applications on the basis of their high emission efficiency and photostability. In view of that, oriented films were prepared by in situ polymerization of a mixture of a liquid crystalline direactive matrix containing 5% (w/w) of the luminophore. The films exhibit linearly polarized emission.     

Rebek Imide Platforms as Model Systems for the Investigation of Weak Intermolecular Interactions

A Rebek imide receptor with an acetylene‐linked phenyl ring complexes 2,6‐di(isobutyramido)pyridine in (CDCl₂)₂ via triple H‐bonding and π–π‐stacking interactions, and the influence of para‐substituents on both rings was investigated by ¹H NMR binding titrations. When the phenyl ring was extended to biphenyl and the C(4)‐pyridine substituent varied, interaction energies increased in the order CH₃CH₂???phenyl<CH₃S???phenyl<phenyl???phenyl?N‐methylcarboxamide???phenyl, highlighting the energetic gain from π stacking on amide fragments. The predicted preference of amide–π stacking for an antiparallel alignment of the local dipoles could not be confirmed with the studied system. Different substituents were introduced in the para position of the phenyl ring and their interaction with bound 2,6‐di(isobutyramido)pyridine was investigated. Theoretical predictions that the mere introduction of a substituent has a stabilizing effect on π–π stacking, regardless of its electronic nature, were experimentally confirmed.     

Ethyl methyl 1,4‐dihydro‐4‐(3‐nitrophenyl)‐2,6‐bis(1‐piperidylmethyl)­pyridine‐3,5‐dicarboxylate

In the title compound, C₂₈H₃₈N₄O₆, the 4‐aryl substituent occupies a pseudo‐axial position approximately orthogonal to the plane of the di­hydro­pyridine ring [88.1 (3)°]. The di­hydro­pyridine ring adopts a flattened boat conformation. The H atom on the pyridine N atom is involved in a bifurcated intramolecular hydrogen bond, the acceptors being the N atoms of the two piperidyl­methyl groups [N?N 2.629 (4) and 2.695 (4) Å].     

Substituent effect in para substituted Cr(CO)5-pyridine complexes

Systematic studies on the substituent effect in para substituted Cr(CO)₅-pyridine complexes have been carried out on the basis of DFT quantum-chemical calculations. Ten simple and mostly common substituents were chosen in order to analyze possibly the largest spectrum of substituent effects. The following substituents were taken into consideration: NO, NO₂, CN, CHO, F, H, CH₃, OCH₃, OH and NH₂. Additionally, the Cr-N and Cr-C bonds were characterized on the basis of Atoms in Molecules topological analysis of electron density. It has been found that the substituents in position 4 of the pyridine ring influence the Cr-N bond of Cr(CO)₅-pyridine complex in a systematic manner, as a result of with, the pyridine moiety has a diversified ability of participating in the interaction with the Cr atom of Cr(CO)₅ moiety. It has also been found, that the electron withdrawing substituents additionally stabilize the Cr-N bond, whereas the electron donating ones weaken it. The substituent effect mainly affects the π-component of the Cr-N bond. This effect proceeds in the whole Cr-pyridine-R moiety, and it is additionally reflected in the corresponding changes in metal-carbonyl bonds, particularly the trans Cr-CO bond.     

Synthesis of 8‐substituted tetrahydro‐γ‐carbolines

The Fischer reaction is applied to the synthesis of 8‐substituted tetrahydro‐γ‐carbolines with electron‐donating or electron‐withdrawing groups, using catalytic or thermal methods. The reaction conditions must be varied according to the nature of the N 1 substituent of the piperidone. The best results are observed when a releasing group is present on the arylhydrazine and a benzyl substituent on the nitrogen of piperidone. Formation of carbolines with a withdrawing substituent is observed in soft acidic conditions; in others, reaction ended at the hydrazone level or did not evolve.     

Role of donor-acceptor functional groups in N3P3 cyclic-triphosphazene backbone. Unraveling bonding characteristics from natural orbitals within an extended transition state-natural orbital for the chemical valence scheme

The formation of cyclophosphazenes containing several ligands or substituent groups gives rise to an attractive derivative set, for development of novel applications, with variable properties. Here, it is possible to unravel the role of different functional groups attached to the N₃P₃ backbone, to reach a better understanding of the bonding character in the cyclic [─P─N─] skeleton. We employed the extended transition state-natural orbital for the chemical valence scheme to unravel the σ and π orbital kernels that are involved in the assembling of such structures, by varying the acceptor-donor characteristics of the ─CF₃, ─NO₂, ─COOH, ─CN, ─NH₂, ─OH, and ─OCH₃ groups, where ─NO₂ behaves as a stronger electron-withdrawing substituent rather than ─CF₃, ─COOH, and ─CN, denoting that the nature of the ligand-phosphazene interaction contributes to some degree to the bond strength of the cyclic [─P─N─] backbone. Our results reveal that the electron-withdrawing ─NO₂ group leads to higher σ and π [─P─N─] orbital-energy contributions, which is reflected in a shortening of the [─P─N─] distance, contrasting with the case of electron-donating groups such as ─NH₂, ─OH, and ─OCH₃ within the phosphazene set. These insights allow further variation and modulation of the bonding in the [─P─N─] ring.     

Electronic Effects of para‐Substitution on the Melting Points of TAAILs

Owing to numerous new applications, the interest in “task‐specific” ionic liquids increased significantly over the last decade. But, unfortunately, the imidazolium‐based ionic liquids (by far the most frequently used cations) have serious limitations when it comes to modifications of their properties. The new generation of ionic liquids, called tunable aryl–alkyl ionic liquids (TAAILs), replaces one of the two alkyl chains on the imidazolium ring with an aryl ring which allows a large degree of functionalization. Inductive, mesomeric, and steric effects as well as potentially also π π and π π⁺ interactions provide a wide range of possibilities to tune this new class of ILs. We investigated the influence of electron‐withdrawing and ‐donating substituents at the para‐position of the aryl ring (NO₂, Cl, Br, EtO(CO), H, Me, OEt, OMe) by studying the changes in the melting points of the corresponding bromide and bis(trifluoromethanesulfonyl)imide, (N(Tf)₂⁻), salts. In addition, we calculated (B3LYP/6‐311++G(d,p)) the different charge distributions of substituted 1‐aryl‐3‐propyl‐imidazolium cations to understand the experimentally observed effects. The results indicated that the presence of electron‐donating and ‐withdrawing groups leads to strong polarization effects in the cations.     

N‐Bridged Annulated BODIPYs: Synthesis of Highly Fluorescent Blueshifted Dyes

A series of novel BODIPY dyes has been prepared through the introduction of an N‐bridged annulated meso ‐phenyl ring at one of the β‐positions of the BODIPY core. An unusual blueshift of the main spectral bands is observed, since the fusion of a meso ‐substituent results in a marked relative destabilization of the LUMO. The greater rigidity of the ring‐fused structure leads to very high fluorescence quantum yields. The position of the main spectral bands can be fine‐tuned by introducing electron withdrawing and donating groups onto the meso ‐phenyl ring.     

An Efficient Synthesis of 3‐Substituted Isoquinoline and Pyridine Derivatives by Gold Catalyzed Intramolecular Cyclization from o‐Alkynyloximes

A one‐pot reaction was developed efficiently by AuCl₃ catalyzed intramolecular cyclization of aromatic o‐alkynyloximes and 2‐alkynylcycloalkene‐1‐carbaldoximes leading to the formation of isoquinoline and pyridine derivatives with high yields. This methodology has been applied for aromatic as well as aliphatic systems. Aromatic o‐alkynyloximes are benzene and naphthalene, whereas electron‐donating groups are 4‐methoxybenzene, 4‐methylbenzene, and 4‐methoxy‐5‐methylbenzene. There are electron‐withdrawing groups such as chloro and nitrobenzene o‐alkynyl oximes, and the same methodology has been successfully applied to pyridine and piperonal, which is also extended to aliphatic rings such as five‐member, six‐member, seven‐member, and eight‐member 2‐alkynylcycloalkene‐1‐carbaldoximes.     

Generation of “Sumanenylidene”: A Ground‐State Triplet Carbene on a Curved π‐Conjugated Periphery

We have observed the generation of sumanenylidene ( 2 ), a divalent, neutral‐carbon species at the benzylic position of sumanene ( 1 ). We also clarified both experimentally and theoretically that the ground state of compound 2 was a triplet state and that its singlet–triplet energy gap (ΔE_ST) was similar to that in fluorenylidene. The curved structure of compound 2 led to slightly better spin delocalization over the two adjacent aromatic rings than in planar systems, because of the unpaired spins on the σ and π orbitals. Synthetic application of the carbene precursor, diazosumanene ( 5 ), with a variety of thiocarbonyl compounds revealed its utility for the preparation of tetrasubstituted alkene compounds (e.g., that contain a strongly electron‐donating unit) that are directly conjugated to the sumanene ( 1 ) moiety.     

Photophysical Properties of Fluorescent 2‐(Phenylamino)‐1,10‐phenanthroline Derivatives†

The present study details the experimental and theoretical characterization of the photophysical properties of 14 examples of 2‐(phenylamino)‐1,10‐phenanthrolines ( 1 ). The absorption spectra of 1 are substituent‐dependent but in a general manner present absorption bands at wavelengths of ~230; ~300; ~335 and a shoulder at ~380 nm. Electron‐donating groups (EDG) and electron‐withdrawing groups (EWG), respectively, result in bathochromic and hypsochromic shifts. Compounds 1 are highly luminescent, in contrast to phenanthroline, and emit in the region between 350 and 500 nm with substituent‐dependent λ_max emission. The emission spectra show a redshift for EDG (4‐OMe 62 nm; 4‐Me 19 nm) and a blueshift for EWG (4‐CN 41 nm; 4‐CF₃ 38 nm) relative to the emission of the unsubstituted parent compound 1a . Plotting the ${\mathbf{\lambda }}_{\mathbf{max}}^{\mathbf{\text{EM}}}$ against Hammett σ+ constants gave an excellent linear correlation demonstrating the electron‐deficient nature of the excited state and how the substituents (de)stabilize S₁. Theoretical calculations revealed a HOMO‐LUMO π‐π* electronic transition to S₁ which in combination with difference (S₁–S₀) in electron density maps revealed charge‐transfer character. Strongly electron‐withdrawing substituents switch off the charge transfer to give rise to a local excitation.     

Design,synthesis and biological evaluation of 2,4‐diamino‐6‐methyl‐5‐substitutedpyrrolo[2,3‐d]pyrimidines as dihydrofolate reductase inhibitors

Nine novel nonclassical 2,4‐diamino‐6‐methyl‐5‐mioarylsubstituted‐ 7H ‐pyrrolo[2,3‐d]pyrimidines 2‐10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6‐diamino‐6‐methyl‐7H‐pyrrolo[2,3‐d]‐pyrimidine, 14 . Compound 14 , was in turn obtained by chlorination of 4‐position of 2‐amino‐6‐methylpyrrolo[2,3‐d]pyrimidin‐4(3H)‐one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat‐derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1‐naphthyl side chain. In this series of compounds electron‐withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.     

Synthesis,crystal structure and cytotoxic activity of novel 5‐methyl‐4‐thiopyrimidine derivatives

This article presents the synthesis of three new 4‐thiopyrimidine derivatives obtained from ethyl 4‐methyl‐2‐phenyl‐6‐sulfanylpyrimidine‐5‐carboxylate as the starting material, namely, ethyl 4‐[(4‐chlorobenzyl)sulfanyl]‐6‐methyl‐2‐phenylpyrimidine‐5‐carboxylate, C₂₁H₁₉ClN₂O₂S, ( 2 ), {4‐[(4‐chlorobenzyl)sulfanyl]‐6‐methyl‐2‐phenylpyrimidin‐5‐yl}methanol, C₁₉H₁₇ClN₂OS, ( 3 ), and 4‐[(4‐chlorobenzyl)sulfanyl]‐5,6‐dimethyl‐2‐phenylpyrimidine, C₁₉H₁₇ClN₂S, ( 4 ), which vary in the substituent at the 5‐position of the pyrimidine ring. The compounds were characterized by ¹H NMR, ¹³C NMR, IR and mass spectroscopies, and also elemental analysis. The molecular structures were further studied by single‐crystal X‐ray diffraction. Compound ( 2 ) crystallizes in the space group P with one molecule in the asymmetric unit, whereas compounds ( 3 ) and ( 4 ) crystallize in the space group P2₁/c with two and one molecule, respectively, in their asymmetric units. The conformation of each molecule is best defined by the dihedral angles formed between the pyrimidine ring and the planes of the two aryl substituents attached at the 2‐ and 4‐positions. The only structural difference between the three compounds is the substituent at the 5‐position of the pyrimidine ring, but they present significantly different features in the hydrogen‐bond interactions. Compound ( 2 ) displays a one‐dimensional chain formed by hydrogen bonds and the chains are further extended into a two‐dimensional network. Molecules of ( 3 ) and ( 4 ) generate one‐dimensional chains formed through intermolecular interactions. The study examines the cytotoxicity of compounds ( 3 ) and ( 4 ) against Human umbilical vein endothelial cells (HUVEC) and HeLa, K562 and CFPAC cancer cell lines. The presence of the hydroxymethyl and methyl groups in ( 3 ) and ( 4 ), respectively, offers an interesting new insight into the structures and behaviour of these derivatives. Compound ( 4 ) was found to be nontoxic against CFPAC and HUVEC; however, it shows weak activity against the HeLa and K563 cell lines. The presence of a hydroxy group in ( 3 ) significantly increases its cytotoxicity towards both, i.e. the cancer (HeLa, K562 and CFPAC) and normal (HUVEC) cell lines.     

Substituent effects in trans‐p,p′‐disubstituted azobenzenes: X‐ray structures at 100 K and DFT‐calculated structures

The crystal and molecular structures of two para‐substituted azobenzenes with π‐electron‐donating –NEt₂ and π‐electron‐withdrawing –COOEt groups are reported, along with the effects of the substituents on the aromaticity of the benzene ring. The deformation of the aromatic ring around the –NEt₂ group in N,N,N′,N′‐tetraethyl‐4,4′‐(diazenediyl)dianiline, C₂₀H₂₈N₄, (I), may be caused by steric hindrance and the π‐electron‐donating effects of the amine group. In this structure, one of the amine N atoms demonstrates clear sp²‐hybridization and the other is slightly shifted from the plane of the surrounding atoms. The molecule of the second azobenzene, diethyl 4,4′‐(diazenediyl)dibenzoate, C₁₈H₁₈N₂O₄, (II), lies on a crystallographic inversion centre. Its geometry is normal and comparable with homologous compounds. Density functional theory (DFT) calculations were performed to analyse the changes in the geometry of the studied compounds in the crystalline state and for the isolated molecules. The most significant changes are observed in the values of the N=N—C—C torsion angles, which for the isolated molecules are close to 0.0°. The HOMA (harmonic oscillator model of aromaticity) index, calculated for the benzene ring, demonstrates a slight decrease of the aromaticity in (I) and no substantial changes in (II).