Aromatic Substitution Reaction Research Articles

Efficient blue light-emitting polydibenzofluorenes through the integration of an anthracene unit

Series of light emitting polymers based on dibenzofluorene-acene have been synthesized through aromatic nucleophilic substitution reaction. The polymer displayed strong solubility in specific organic solvents with a polydispersity index of 1.5–2.0 and weight average molecular weight within the range from 25000 to 34000. At 420 nm the highest photoluminescence of the polymer solution was observed. The temperature of the thermal decomposition was determined by TGA and ranged from 300 to 446 °C while the value of Tg was between 120 and 140 °C. Cyclic voltammetry tests of polydibezofluorenes show that the compounds with HOMO and LUMO in the range 2.23–5.26 eV is stable under redox condition. The optical properties of these polydibenzofluorenes showed significant blue emissions in the polymers obtained.

Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras.

The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SN Ar) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.

Magnetic Nanoplatforms for in Situ Modification of Macromolecules: Synthesis, Characterization, and Photoinactivating Power of Cationic Nanoiman–Porphyrin Conjugates

A nanoplatform concept was developed to synthesize accessible photoactive magnetic nanoparticles (MNPs) of Fe3O4 coated with silica. This approach was based on the covalent binding of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPPF20) to aminopropyl-grafted MNPs by nucleophilic aromatic substitution reaction (SNAr) to obtain conjugate MNP-P1. After in situ modification, the remaining pentafluorophenyl groups of TPPF20 attached to MNPs were substituted by dimethylaminoethoxy groups to form MNP-P2. The basic amine group of these conjugates can be protonated in aqueous media. In addition, MNP-P1 and MNP-P2 were intrinsically charged to produce cationic conjugates MNP+-P1 and MNP+-P2+ by methylation. All of them were easily purified by magnetic decantation in high yields. The average size of the MNPs was ∼15 nm, and the main difference between these conjugates was the greater coating with positive charges of MNP+-P2+, as shown by the zeta potential values. Absorption spectra exhibited the Soret and Q bands characteristic of TPPF20 linked to MNPs. Furthermore, these conjugates showed red fluorescence emission of porphyrin with quantum yields of 0.011-0.036. The photodynamic effect sensitized by the conjugates indicated the efficient formation of singlet molecular oxygen in different media, reaching quantum yield values of 0.17-0.34 in N,N-dimethylformamide. The photodynamic activity of the conjugates was evaluated to inactivate the Gram-positive bacteria Staphylococcus aureus, the Gram-negative bacteria Escherichia coli, and the yeast Candida albicans. The modified cationic MNP+-P2+ was the most effective conjugate for photodynamic inactivation (PDI) of microorganisms. Binding of this conjugate to bacteria and photoinactivation capability was checked by means of fluorescence microscopy. Also, sustainable use by recycling was determined after three PDI treatments. Therefore, this methodology is a suitable scaffold for the in situ modification of conjugates, and in particular, MNP+-P2+ represents a useful photodynamic active material to eradicate microorganisms.

Green Approach of Solvent- and Catalyst Free Synthesis of Bis(indolyl)methanes under Visible Light Irradiation

An efficient procedure has been developed for the synthesis of bis(indolyl)methanes (3a-m) from condensation of indole (1) and various substituted aromatic aldehydes (2a-m) is described. The aromatic electrophilic substitution reactions of indole (1) with and various substituted aromatic aldehydes (2a-m) are achieved in solvent- and catalyst free condition using irradiation with 150W tungsten lamp (visible light irradiation). This methodology offers several advantages such as good yields, simple procedure, mild and environmentally benign conditions.

Kinetic Isotope Effects in Electrophilic Aromatic Halogenation of Dimethenamid in Chlor(am)inated Water Demonstrate Unique Aspects of Iodination

Electrophilic aromatic substitution reactions can initiate halogenated disinfection byproduct (DBP) formation. The rate-controlling step (RCS) of electrophilic aromatic halogenation is commonly ass...

SYNTHESIS AND MASS SPECTROMETRIC CHARACTERISTICS OF 1-(AMINOARYL)BENZIMIDAZOLES

As a result of two-stage synthesis, a number of 1-(aminoaryl)benzimidazoles, potential biologically active substances, were obtained. During the first stage, an aromatic nucleophilic substitution reaction, 2-R-benzimidazoles reacted with halogen-nitroarenes. The process proceeded under mild conditions, this indicates a good nucleophilic properties of benzimidazole. It has been shown that during reduction, depending on the structure of 1-(nitroaryl)benzimidazoles in an acidic medium, in addition to the main process, acid-catalyzed isomerization can occur. Rearrangement was observed during the reduction of 1-(2-nitroaryl)benzimidazoles. The presence of a methyl group at the 2 position of the benzimidazole ring of these compounds hindered the rearrangement. When carrying out the reaction under conditions of heterogeneous catalysis in the reactor for flow hydrogenation, isomerization was also not observed. The use of 1-(4-nitroaryl)benzimidazoles as a substrate resulted in the formation of only one product. The mass spectral characteristics of 1-(aminoaryl)benzimidazoles were studied. The peak attribution of the molecular ion [M]+ was carried out by recording mass spectra with electrospray ionization. Ways of fragmentation of the molecular ion of these compounds under the influence of electron impact are proposed. Characteristic ions are identified. It was established that the fragmentation of the molecular ion of 1-(aminoaryl)benzimidazoles began either by elimination of the substituents, followed by cleavage of the two C—N bonds in imidazole, or by elimination of the HCN fragment of the imidazole ring and further elimination of the substituents. As a result, the formation of the cation radical of N-phenylbenzenediamine with m/z 181 was occurred. The fragmentation of this ion was carried out similarly to aromatic amines via elimination of a neutral HCN molecule. Further decay of alkylarylamine ions led to a group of characteristic fragmentation ions. Thus, mass spectrometry can be effectively used to identify N-aryl substituted benzimidazoles, as well as their decomposition products.

Dual Reactivity of 3a,6a-Diaza-1,4-diphosphapentalene: π-Donor versus n-Donor.

Herein, we present the synthesis, single-crystal X-ray structures, and spectroscopic properties for the 1:1 donor-acceptor complexes of 1,2,4,5-tetracyanobenzene (TCNB) with annelated 3a,6a-diaza-1,4-diphosphapentalenes (DDPs) based on cyclohexanone azine (2) and tetralone azine (4). These are the first complexes of an organic π-acceptor with donor phosphorus heterocycles. According to the X-ray study, the DDPs and TCNB molecules are alternately stacked with interplanar distances of 3.335 and 3.404 Å for 2 and 4, respectively, which are suitable for intermolecular π···π interactions. The bond lengths and angles in the component molecules agree with values for neutral species, and the infrared spectra indicate a very slight degree of ionicity. The estimated HOMO-LUMO gap from the onset of optical absorption (1.40 eV) is in agreement with the band gap estimated from the density functional theory calculations for 2 (1.47 eV). By contrast, in a reaction with the related electron acceptor, tetrachloroterephthalonitrile, the DDPs proved to be donors of lone electron pairs in a nucleophilic aromatic substitution reaction of chlorine atoms demonstrating the duality of their electronic nature.

Synthesis and Antibacterial, Antioxidant, and Molecular Docking Analysis of Some Novel Quinoline Derivatives

2-Chloroquinoline-3-carbaldehyde and 2-chloro-8-methylquinoline-3-carbaldehyde derivatives were synthesized through Vilsmeier formulation of acetanilide and N-(o-tolyl)acetamide. Aromatic nucleophilic substitution reaction was used to introduce various nucleophiles in place of chlorine under different reaction conditions. The carbaldehyde group was oxidized by permanganate method and reduced with metallic sodium in methanol and ethanol. The synthesized compounds were characterized by UV-Vis, IR, and NMR. The antibacterial activity of the synthesized compounds was screened against two Gram-positive bacteria (Bacillus subtilis ATCC6633 and Staphylococcus aureus ATCC25923) and two Gram-negative bacteria (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853). Most of the compounds displayed potent activity against two or more bacterial strains. Among them, compounds 6 and 15 showed maximum activity against Pseudomonas aeruginosa with mean inhibition zones of 9.67 ± 1.11 and 10.00 ± 0.44 mm, respectively, while ciprofloxacin showed mean inhibition zone of 8.33 ± 0.44 mm at similar concentration. On the other hand, compound 8 exhibited maximum activity against Escherichia coli with inhibition zones of about 9.00 ± 0.55 mm at 300 μg/mL and 11.33 ± 1.11 mm at 500 μg/mL. The radical scavenging activity of these compounds was evaluated using 1,1-diphenyl-2-picryl hydrazyl (DPPH), and all of them displayed moderate antioxidant activity, with compound 7 exhibiting the strongest activity. The molecular docking study of the synthesized compounds was conducted to investigate their binding pattern with DNA gyrase, all of them were found to have minimum binding energy ranging from –6.0 to –7.33 kcal/mol, and the best result was achieved with compound 11. The findings of the in vitro antibacterial and molecular docking analysis demonstrated that the synthesized compounds have potential of antibacterial activity and can be further optimized to serve as lead compounds.

Complementary Site-Selective Halogenation of Nitrogen-Containing (Hetero)Aromatics with Superacids.

Site-selective functionalization of arenes that is complementary to classical aromatic substitution reactions remains a long-standing quest in organic synthesis. Exploiting the generation of halenium ion through oxidative process and the protonation of the nitrogen containing function in HF/SbF5 , the chlorination and iodination of classically inert Csp2 -H bonds of aromatic amines occurs. Furthermore, the superacid-promoted (poly)protonation of the molecules acts as a protection, favoring the late-stage selective halogenation of natural alkaloids and active pharmaceutical ingredients.

The Effect of the Leaving Group in N-Heterocyclic Carbene-Catalyzed Nucleophilic Aromatic Substitution Reactions

Abstract We report here that the reactivity order of the leaving group is F > Cl ≥ Br > I in N-heterocyclic carbene-catalyzed CSNAr reactions of aryl halides bearing an α,β-unsaturated amide. Based on a qualitative Marcus analysis, the nature of the transition state in this catalytic CSNAr is primarily determined by the potential energy of the Meisenheimer complex, even though it is not involved as a discrete intermediate in the reaction pathway.

Synthesis of a conjugated polymer with ring-fused pyridinium units via a postpolymerization intramolecular cyclization reaction

The synthesis of a novel conjugated polymer containing fused pyridinium units in its main chain is reported. A precursor polymer possessing pyridine and tetrafluorophenylene moieties was reacted in the presence of Lewis acid additives to promote the intramolecular nucleophilic aromatic substitution (SNAr) reaction. The polymer reaction with BE3-OEt2 gave a product polymer soluble in polar organic solvents, and the successful formation of fused pyridinium ring structures was spectroscopically confirmed. The electrochemical and optical properties of the synthesized polymers were also investigated, suggesting that the polymer product has a narrower band gap than the precursor polymer. The synthesis of a novel conjugated polymer containing fused pyridinium units in its main chain is reported. A precursor polymer possessing pyridine and tetrafluorophenylene moieties was reacted in the presence of Lewis acid additives to promote the intramolecular nucleophilic aromatic substitution (SNAr) reaction. The polymer reaction with BE3-OEt2 gave a product polymer soluble in polar organic solvents, and the successful formation of fused pyridinium ring structures was spectroscopically confirmed. The electrochemical and optical properties of the synthesized polymers were also investigated.

The use of an aromatic substitution reaction in the spectrophotometric determination of selected amino or thiol containing drugs

A simple spectrophotometric method is described for the determination of acetylcysteine (I) and captopril (II) as representative examples of thiols, as well as amlodipine besylate (III) and heptaminol hydrochloride (IV) as amine examples. The method is based on the reaction of these drugs with the activated halide 2,4-dinitrofluorobenzene (DNFB) in aqueous borate buffer to yield yellow colored products. Beer's law was obeyed over the concentration ranges of 4-12, 2.4-16.8, 8-28 and 5-25 μg mL-1 for (I), (II), (III), and (IV), respectively. The different experimental parameters were studied and optimized. The proposed method was validated according to the USP 27 criteria and was found suitable for the quantitation of the cited compounds in their pharmaceutical preparations without interference from common excipients.

A DFT investigation on aromatic nucleophilic substitution (SNAr) reaction between 4-fluoro-1-naphthaldehyde/4-fluoro-2-naphthaldehyde/1-fluoro-2-naphthaldehyde/1-fluoronaphthalene and methylthiolate ion in gas phase and in protic/aprotic solvents

We have investigated the mechanism of aromatic nucleophilic substitution (SNAr) reaction between 4-fluoro-1-naphthaldehyde/4-fluoro-2-naphthaldehyde/1-fluoro-2-naphthaldehyde/1-fluoronaphthalene with methylthiolate by DFT calculations at B3LYP/6–31+G (d,p) level of theory in gas phase and also in polar protic/aprotic solvents. The results show that aromatic nucleophilic substitution reaction proceeds by concerted mechanism via formation of single transition state as it has lower activation energy barrier as compared with stepwise mechanism. The introduction of solvent increases the activation energy barrier indicating significant effect of solvents on transition state. The activation energy barrier was found to be a minimum in gas phase then in DMSO which is followed by protic polar solvents methanol and water. Thus, the polar aprotic solvent DMSO works best for aromatic nucleophilic substitution of fluorine. The presence of a formyl group was found to be essential for reaction to take place, and in the gas phase as well as in solution phase, the order of reactivity was found to be 4-fluoro-1-naphthaldehyde > 1-fluoro-2-naphthaldehyde > 4-fluoro-2-naphthaldehyde > 1-fluoronaphthalene.

Tunable Control of the Hydrophilicity and Wettability of Conjugated Polymers by a Postpolymerization Modification Approach.

A facile method to prepare hydrophilic polymers by a postpolymerization nucleophillic aromatic substitution reaction of fluoride on an emissive conjugated polymer (CP) backbone is reported. Quantitative functionalization by a series of monofunctionalized ethylene glycol oligomers, from dimer to hexamer, as well as with high molecular weight polyethylene glycol is demonstrated. The length of the ethylene glycol sidechains is shown to have a direct impact on the surface wettability of the polymer, as well as its solubility in polar solvents. However, the energetics and band gap of the CPs remain essentially constant. This method therefore allows an easy way to modulate the wettability and solubility of CP materials for a diverse series of applications.

Synthesis, spectroscopic properties and photodynamic activity of Zn(II) phthalocyanine-polymer conjugates as antimicrobial agents

Conjugates of Zn(II) phthalocyanine to chitosan (CS) and polyethylenimine (PEI) were synthetized through the following stages: first a phthalonitrile substituted by a (carbomethoxy)phenoxy group (Pn 1) was obtained by nucleophilic aromatic substitution reaction, then a AB3 Zn(II) phthalocyanines (ZnPc 2) was synthesized by the ring expansion reaction of boron(III) subphthalocyanine (SubPc) chloride with Pn 1. After hydrolysis of ZnPc 2, a Zn(II) phthalocyanine bearing a carboxylic acid group (ZnPc 3) was obtained, which was conjugated to CS (CH-ZnPc 4) and PEI (PEI-ZnPc 5) by amide bond. UV–visible absorption and fluorescence spectra presented the characteristic bands of the Zn(II) phthalocyanine in N,N-dimethylformamide (DMF), with appropriate fluorescence quantum yield. Also, the conjugation of Zn(II) phthalocyanine to polymers was confirmed by IR spectra. These conjugates were able to photosensitize singlet molecular oxygen in DMF and aqueous medium. Moreover, they induced the formation of superoxide anion radical in the presence of NADH. The results showed that type II pathway is involved in the photodecomposition of Trp sensitized by these conjugates, although there is also a contribution from the type I mechanism. Photoinactivation of microorganisms was investigated in Candida albicans, Staphylococcus aureus and Escherichia coli and, varying the concentration of CH-ZnPc 4 and PEI-ZnPc 5 and the irradiation times. Both conjugates were efficient in the eradication of S. aureus by PDI, while that PEI-ZnPc 5 was the most effective for photokilling C. albicans. These conjugates were little active to photoinactivation of E. coli. However, the addition of CS allowed to improve the photocytotoxicity towards this Gram-negative bacterium. These results indicate that PEI-ZnPc 5 is an efficient photosensitizer to inactivate S. aureus and C. albicans. In addition, it is capable of killing E. coli cells in the presence of CS.

Synthesis of fluorine-containing prenylated benzophenones

In this study, an effective route to synthesize fluorine-containing prenylated benzophenones was developed. Friedel–Crafts acylation and electrophilic aromatic substitution reactions were the key reactions of this synthesis to achieve these fluorinated prenylated benzophenones. The use of DBU in the prenylation step achieved only the C-prenylated benzophenones, whereas K2CO3 produced the C- and O-prenylated benzophenones.

Synthesis and properties of quinazoline-based versatile exciplex-forming compounds.

Three compounds, bearing a quinazoline unit as the acceptor core and carbazole, dimethyldihydroacridine, or phenothiazine donor moieties, were designed and synthesized in two steps including a facile copper-catalyzed cyclization and a nucleophilic aromatic substitution reaction. The photophysical properties of the compounds, based on theoretical calculations and experimental measurements, as well as the electrochemical and thermal properties, are discussed. The synthesized compounds form glasses with glass-transition temperatures ranging from 116 °C to 123 °C. The ionization potentials estimated by cyclic voltammetry of the derivatives were in the range of 5.22–5.87 eV. The 3,6-di-tert-butylcarbazole-substituted quinazoline-based compound forms a sky-blue emitting exciplex in solid mixture with the acceptor 2,4,6-tris[3-(diphenylphosphinyl)phenyl]-1,3,5-triazine as well as an orange emitting exciplex with the donor 4,4′,4″-tris[3-methylphenyl(phenyl)amino]triphenylamine. A white OLED based on these versatile exciplex systems with a relatively high maximum brightness of 3030 cd/m2 and an external quantum efficiency of 0.5% was fabricated.

Highly Selective Fluorescent 4-(4-(Diethylamino)-2-Hydroxystyryl)-1-Methylpyridine Iodide and Nitrobenzofurazan Based Probe for Cysteine with Application in Living Cells

Biological thiols, such as homocysteine, cysteine, and glutathione play key roles in physiological processes. However, due to the similarity of their structures and chemical properties, it has been a challenge to distinguish these compounds. In this work, a new fluorescent probe (E)-4-(4-(diethylamino)-2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)oxy) styryl)-1-methylpyridine iodide (Y-OH-NBD) is reported for the determination of cysteine. Based on the nucleophilic aromatic substitution and rearrangement cascade reaction, Y-OH-NBD was demonstrated to be a selective turn-on fluorescence probe for cysteine without interferences and probe consumption caused by high concentration of glutathione in phosphate buffer pH 7.4 containing 5% dimethyl sulfoxide. The Y-OH-NBD system determined cysteine with a response time of less than 5 min and a low limit of detection equal to 1.88 µM. Moreover, the probe showed low cytotoxicity and was conveniently applied to image intracellular cysteine in HeLa cells, indicating its significant potential biological applications.

Chiral Ligand‐Mediated Nucleophilic Aromatic Substitution of Naphthoic Acids: A Fast and Efficient Access to Axially Chiral Biaryls

A transition metal‐free synthesis of enantioenriched biaryls from aryllithium species has been developed. This approach relies on atropoenantioselective nucleophilic aromatic substitution (SNAr) reaction of unprotected naphthoic acids. The ability of a diverse set of chiral ligands to mediate this transformation has been investigated. 1,2‐diether ligands outperform their diamine counterparts and the best enantiocontrol was obtained with readily accessible enantiopure trans‐1,2‐dimethoxycyclohexane. This SNAr reaction offers an efficient and rapid access to enantioenriched binaphthalenes, phenylnaphthalene, and phenanthrylnaphthalenes (up to 94:6 er).

Exploring the scope of indole interaction with 1,2-dicarbonyl compounds

The 1,2-dicarbonyl compounds have received extensive attention due to their high reactivity and toxicity in vitro and in vivo. Availability of scavenging compounds may facilitate development of efficient strategies for their control. The concept of in situ generation of carbonyl trapping agents is an intriguing proposition and has been demonstrated with amino acid tryptophan. Ability of indole to undergo electrophilic aromatic substitution reaction was studied in the past with methylglyoxal. To confirm the generality of this reaction, model systems containing indole and several 1,2-dicarbonyl compounds were prepared and reacted at room temperature (RT) and at 150 °C and analyzed by ESI-qTOF-MS/MS and isotopic labeling technique. Indole showed ability to capture all the tested 1,2-dicarbonyls. Longer chain 1,2-dicarbonyls showed higher temperature dependency than shorter chain in their reactivity towards indole. Furthermore, the ability of indole to scavenge Strecker aldehydes was also demonstrated in alanine/glucose and in a bread model systems using [13C-2]indole.