Nucleophilic Aromatic Substitution Reaction Research Articles

Ad Hoc Adjustment of Photoredox Properties by the Late-Stage Diversification of Acridinium Photocatalysts.

The steadily growing interest in substituting precious-metal photoredox catalysts with organic surrogates is vibrantly sustained by emerging methodologies to vary their photochemical behavior. Herein, we report an ad hoc approach for the preparation of acridinium salts with a particularly broad range of photoredox properties. The method involves an aryne-imine-aryne coupling to a linchpin tetrafluoro acridinium salt for a late-stage diversification by nucleophilic aromatic substitution reactions to form diaminoacridinium and undescribed aza-rhodol photocatalysts. The different functionalities and redox properties of the organic acridinium photocatalysts render them suitable for bifunctional photoredox catalysis and organocatalytic photochemical C-N cross-couplings.

Sulfur Bridged New Metal-Free and Metallo Phthalocyanines Carrying 1,2,4-Triazole Rings and Their Photophysicochemical Properties

The novel metal-free (4 ) zinc(II) (5), lead(II) (6), cobalt(II) (7) and copper(II) (8) phthalocyanines containing 1,2,4-triazole groups connected to the phthalocyanine ring by S-bridge were synthesized and characterized. For this purpose, the original 2-(4-chlorobenzoyl)-N-(4-fluorophenyl)hydrazinecarbothioamide (1) was synthesized as a result of the reaction of 4-chlorobenzyl hydrazide and 4-fluorophenyl isothiocyanate. It was obtained 5-(4-chlorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (2), which is a new compound by the ring closure reaction of 1. The other original compound 4-[5-(4-chlorophenyl)-4-(4-fluorophenyl)-4H-[1,2,4]triazol-3-yl sulfanyl]-phthalonitrile (3) was synthesized by the nucleophilic aromatic substitution reaction of 4-nitrophthalonitrile and compound 2. Starting from the new phthalonitrile (3), the metal-free (4), zinc(II) (5), lead(II) (6), cobalt(II) (7) and copper(II) (8) phthalocyanines were prepared. Totally eight new compounds were synthesized, and their structures were characterized by 1H NMR, 13C NMR, FT-IR, MALDI-TOF MS and UV-vis spectral data in this work. The photophysical and photochemical properties of the synthesized phthalocyanines were investigated for determination of their usability as photosensitizers for photodynamic therapy applications. Thus, remarkable results were obtained.

A two-photon “turn-on” fluorescent probe for both exogenous and endogenous selenocysteine detection and imaging in living cells and zebrafish

Selenocysteine (Sec) is recognized as the 21st amino acid employing as an essential building block for selenoproteins (SePs), which plays a significant role in various physiological processes. Therefore, there is an urgent need to reasonably develop some reliable and rapid methods for Sec detection in biological systems. In this work, we reported a new two-photon (TP) fluorescent probe BNT-Sec for Sec detection and imaging in living cells and zebrafish with two part: (1) a D-π-A-structured naphthalene derivative as a TP fluorophore; (2) a well-know Sec responsive site with strong intromolecular charge transfer effect (ICT) to selectively detect endogenous and exogenous. In the presence of Sec, probe BNT-Sec can initiate a Se-dependent specific aromatic nucleophilic substitution reaction, which exhibited BNT-Sec had a large fluorescence intensity enhancement with ~18.9-fold at 510 nm, a high sensitivity low LOD value’ 10.6 nM, good light stability, strong specificity, pH stability and low cytotoxicity. In addition, BNT-Sec can be conveniently used to detect Sec in living cells and zebrafish for TP imaging due to the great TP measurement properties of fluorophore, exhibiting it has the potential to reveal the role of selenocysteine in physiological and pathological processes in further biological applications.

Fluorinated quinone derived organosulfur copolymer cathodes for long-cycling, thermostable and flexible lithium–sulfur batteries

Organosulfur copolymers are promising cathode materials in lithium–sulfur batteries because of adjustable molecular structure, tunable electrochemical properties and excellent processability. However, conventional organosulfur copolymers suffer from poor electronic/ionic conductivity and low sulfur content, which limit rate capability and energy density. Herein, fluorinated quinone-derived organics are copolymerized with sulfur via convenient nucleophilic aromatic substitution (SNAr) reaction. The homogeneous distribution of sulfur over poly(tetrafluorohydroquinone)-sulfur (PTFHQS) at molecular level endows excellent Li+ ion diffusivity and fast redox kinetics. The abundant semi-ionic C–F bonds with polar characteristic have strong interactions with polysulfides, thus diminishing the shuttle effect. In result, flexible PTFHQS cathode with ~ 71 wt% sulfur content exhibits high discharge capacity of 643 mAh gtotal–1 (906 mAh gsulfur–1) at 0.5C, stable Coulombic efficiency (>99%), good rate performance of 307 mAh gtotal–1 (432 mAh gsulfur–1) 2.0C, excellent cycling stability (capacity retention of 87% for 600cycles), and functions normally at elevated working temperature (80 °C). Compared to another copolymer of sulfurized tetrafluoro-p-benzoquinone monomer (TFBQS), molecular structure characterization and electrochemical analysis verifies that pre-polymerized skeleton of PTFHQS is conducive to the homogeneous distribution and efficient utilization of sulfur species. We expect this work will bring inspiration to exploit organosulfur compounds with rational molecular structures and convenient synthesis routes for lithium–sulfur batteries.

A fluorescent probe for detection homocysteine in green and NIR, and cysteine/glutathione in NIR regions

A fluorescent probe (NBD-XA) containing benzoxadiazole and xanthen moieties was designed and synthesized to detect homocysteine (Hcy) in green and near infrared (NIR), and cysteine/glutathione (Cys/GSH) in NIR regions, whose detection mechanism was based on the nucleophilic aromatic substitution reaction between the fluorescent probe and sulfhydryl of biothiols, and the following different rearrangement reactions for these biothiols. Meanwhile, NBD-XA exhibited low cytotoxicity, and was successfully applied for bioimaging in living cells.

Synthesis of novel pyridine and pyrimidine derivatives as potential inhibitors of HIV-1 reverse transcriptase using palladium-catalysed C-N cross-coupling and nucleophilic aromatic substitution reactions

Synthesis of novel pyridine and pyrimidine derivatives as potential inhibitors of HIV-1 reverse transcriptase using palladium-catalysed C-N cross-coupling and nucleophilic aromatic substitution reactions

Iterative Exponential Growth of Oxygen-Linked Aromatic Polymers Driven by Nucleophilic Aromatic Substitution Reactions.

This work presents the first transition metal-free synthesis of oxygen-linked aromatic polymers by integrating iterative exponential polymer growth (IEG) with nucleophilic aromatic substitution (SNAr) reactions. Our approach applies methyl sulfones as the leaving groups, which eliminate the need for a transition metal catalyst, while also providing flexibility in functionality and configuration of the building blocks used. As indicated by 1) 1H-1H NOESY NMR spectroscopy, 2) single-crystal X-ray crystallography, and 3) density functional theory (DFT) calculations, the unimolecular polymers obtained are folded by nonclassical hydrogen bonds formed between the oxygens of the electron-rich aromatic rings and the positively polarized C–H bonds of the electron-poor pyrimidine functions. Our results not only introduce a transition metal-free synthetic methodology to access precision polymers but also demonstrate how interactions between relatively small, neutral aromatic units in the polymers can be utilized as new supramolecular interaction pairs to control the folding of precision macromolecules.

Highly stable dioxin-linked metallophthalocyanine covalent organic frameworks

We report a series of highly stable metallophthalocyanine-based covalent organic frameworks (MPc-dx-COFs) linked by robust 1,4-dioxin bonds constructed through nucleophilic aromatic substitution (SNAr) reaction. The chemical structures and crystallinity of the COFs largely remain unchanged even after treating with boiling water (90 °C), concentrated acids (12 mol/L HCl) or bases (12 mol/L NaOH), oxidizing (30% H2O2) or reducing agents (1 mol/L NaBH4) for three days due to their stable M-Pc building blocks and resilient dioxin linkers. With metallated phthalocyanine active sites regularly arranged in the stable framework structures, MPc-dx-COFs can be directly used as efficient electrocatalysts for the oxygen reduction reaction (ORR) without pyrolysis treatment that has commonly been used in previous studies.

Interconnectivity between Surface Reactivity and Self-Assembly of Kemp Elimination Catalyzing Nanorods.

Understanding the fundamental facts behind dynamicity of catalytic processes has been a longstanding quest across disciplines. Herein, we report self-assembly of catalytically active gold nanorods that can be regulated by tuning its reactivity towards a proton transfer reaction at different pH. Unlike substrate-induced templating and co-operativity, the enhanced aggregation rate is due to alteration of catalytic surface charge only during reactivity as negatively charged transition state of reactant (5-nitrobenzisoxazole) is formed on positively charged nanorod while undergoing a concerted E2-pathway. Herein, enhanced diffusivity during catalytic processes might also act as an additional contributing factor. Furthermore, we have also shown that nanosized hydrophobic cavities of clustered nanorods can also efficiently accelerate the rate of an aromatic nucleophilic substitution reaction, which also demonstrates a catalytic phenomenon that can lead to cascading of other reactions where substrates and products of the starting reactions are not directly involved.

Rationalization of the effects of hydrogen bond donor solvent and nucleofugicity of fluoride ion on nucleophilic aromatic substitution reactions in non-polar aprotic solvent: reaction of 2,4-dinitrofluorobenzene with cyclohexylamine in toluene and toluene

The kinetics of the reaction of 2,4-dinitrofluorobenzene with cyclohexylamine were studied at different concentrations in toluene and toluene-alkanol mixtures. The reaction was not base-catalysed in toluene. Addition of small amounts of hydrogen-bond donor solvent, alkanol (ranging from methanol to hexanol) to the toluene medium of the reactions produced a different effect in comparison to uncatalysed reactions — slight increase in rate of reaction. The results are rationalized in terms of the effect of amine-solvent interaction on the nucleophilicity of the amine in addition to some other factors operating through cyclic transition states leading to products. It is also attributed to the peculiar nature of fluoride ion as a leaving group.

Promotion Energy Analysis Predicts Reaction Modes: Nucleophilic and Electrophilic Aromatic Substitution Reactions.

To develop an approach to pre-emptively predict the existence of major reaction modes associated with a chemical system, based on exclusive consideration of reactant properties, we build herein on the valence bond perspective of chemical reactivity. In this perspective, elementary chemical reactions are conceptualized as crossovers between individual diabatic/semilocalized states. As demonstrated, the spacings between the main diabatic states in the reactant geometries-the so-called promotion energies-contain predictive information about which types of crossings are likely to occur on a potential energy surface, facilitating the identification of potential transition states and products. As an added bonus, promotion energy analysis provides direct insight into the impact of environmental effects, e.g., the presence of (polar) solvents and/or (local) electric fields, on a mechanistic landscape. We illustrate the usefulness of our approach by focusing on model nucleophilic and electrophilic aromatic substitution reactions. Overall, we envision our analysis to be useful not only as a tool for conceptualizing individual mechanistic landscapes but also as a facilitator of systematic reaction-network exploration efforts. Because the emerging VB descriptors are computationally inexpensive (and can alternatively be inferred through machine learning), they could be evaluated on-the-fly as part of an exploration algorithm. The so-predicted reaction modes could subsequently be examined in detail through computationally more-demanding methods.

A red-to-near-infrared fluorescent probe for the detection of thiophenol based on a novel hydroxylflavone-quinoline-amino molecular system with large Stokes shift

In this work, we synthesized a novel long-wavelength-emitting fluorophore FQ-OH based on a novel designed hydroxylflavone-quinoline-amino molecular system with both intramolecular charge transfer (ICT) and excited-state intramolecular proton transfer (ESIPT) process, enabling FQ-OH with strong fluorescence in a wide range of 550–800 nm, covering red-to-near-infrared emission region and large stokes shift as much as 162 nm. Due to the promising spectra property, FQ-OH was then fabricated into a red-to-near-infrared fluorescent probe FQ-DNP for the selective detection of thiophenol via aromatic nucleophilic substitution (SNAr) reaction mechanism. Spectra assays in the solution demonstrated that FQ-DNP displayed prominent turn-on fluorescence response to thiophenol in 550–800 nm with emission peak at 627 nm, excellent selectivity, and exceptional sensitivity (detection limit as low as 7.2 nM). In addition, thiophenol in vapor form could be detected by FQ-DNP coated test papers enabling naked eye detection. Moreover, FQ-DNP was utilized for detecting thiophenol in environmental samples and showed great recovery results. Furthermore, biological application of FQ-DNP in living cells through cell imaging study demonstrated apparent intracellular fluorescence enhancement before/after thiophenol addition.

Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives

Nucleophilic aromatic substitution (SNAr) reactions can provide metal-free access to synthesize monosubstituted aromatic compounds. We developed efficient SNAr conditions for p-selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10-phenylphenothiazine (PTH) derivatives. The resulting polyfluoroarene-bearing PTH derivatives were subjected to a second SNAr reaction to generate highly functionalized PTH derivatives with potential applicability as photocatalysts for the reduction of carbon–halogen bonds.

Rate and Yield Enhancements in Nucleophilic Aromatic Substitution Reactions via Mechanochemistry.

A variety of nucleophilic aromatic substitution reactions were carried out mechanochemically to great advantage. On average, reactions rates were nine-times faster. The corresponding kinetic studies presented provide the clearest head-to-head kinetic comparisons between mechanochemical and conventional systems at identical temperatures. Attempts are provided at classifying the kinetics of one example. Removal of polar, protic solvents from these reactions presents environmental benefits to a reaction class whose kinetics are heavily dependent on such solvents.

Synthesis and anticancer activity of chalcone–quinoxalin conjugates

Two series of quinoxaline–chalcone conjugates have been prepared by aldolic condensation and aromatic nucleophilic substitution reaction, and their anticancer activity against three cancer cell lines including benign prostatic hyperplasia epithelial cell (BPH-1), neuron-like rat pheochromocytoma cell line (PC12) and human breast cancer cell line (MCF-7) were evaluated in vitro. All of the synthesized compounds exhibited moderate to good activity against the cancer cell lines selected. Particularly, Compound A5 showed the excellent potent activity against BPH-1 and MCF-7 with IC50 values of 10.4 and 9.1 μM, respectively, which is similar to doxorubicin (14.1 and 9.2 μM, respectively). As well as compound B6 exhibited most excellent activity toward PC12 with IC50 values of 16.4 μM. Compound A10 exhibited 55.4, 36.8 and 54.5 folds higher selectivity for BPH-1, PC12 and MCF-7 cells than for HEK-293 cell, respectively. In addition, theoretical biological activities of compounds A5 and A10 were evaluated by SwissADME.

Synthesis and Antimicrobial Activity of Some Novel 7-Chloro-4-aminoquinoline Derivatives

A number of novel 7-chloro-4-aminoquinoline derivatives have been efficiently synthesized by nucleophilic aromatic substitution reaction of 4,7-dichloroquinoline with α,ω-diaminoalkanes of variable carbon-chain length. Treatment of the intermediates with substituted aromatic/heteroaromatic aldehydes has led to the corresponding Schiff bases. Structures of the products have been elucidated from FTIR, 1H, and 13C NMR, and mass spectra. Antimicrobial tests of the compounds have indicated that the most active ones displayed MIC values in the range of 1.5 to 12.5 µg/mL, however they displayed no antifungal activity. According to the accumulated data, length of the carbon-chain linker and electronic properties of the compounds are decisive for their biological activity. Molecular docking studies have supported the above relationships.

Polyfunctionalized biaryls accessed by a one-pot nucleophilic aromatic substitution and sigmatropic rearrangement reaction cascade under mild conditions

Abstract A practical synthetic method has been developed for polyfunctionalized biaryls based on a facile one-pot nucleophilic aromatic substitution (SNAr) reaction and [5,5]- or [3,3]-sigmatropic rearrangement reaction cascade. Under mild basic conditions, N-arylhydroxylamines reacted with o-activated fluoro (het)arenes to form N,O-diarylhydroxylamine intermediates which underwent spontaneously selective [5,5]-sigmatropic rearrangement reaction to produce diverse functionalized 4-amino-4′-hydroxy-1,1′-biaryls. A sequential SNAr reaction and [3,3]-sigmatropic rearrangement took place between N-arylhydroxylamines and 2-fluoropyridine derivatives or 4-fluorobenzonitrile to afford functionalized 2-amino-2′-hydroxy-1,1′-biaryls. As invaluable and unique building blocks, the resulting biaryls were applied in the straightforward synthesis of N2,O2-coronarene, carbazole, aza- and diaza carbazole derivatives.

Phosphinylation of Non‐activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms

AbstractNon‐activated aryl fluorides reacted with potassium diorganophosphinites through a nucleophilic aromatic substitution (SNAr) reaction. Remarkably, both electron‐neutral and electron‐rich aryl fluorides participated in the reaction with substantially stabilized anionic P nucleophiles to form the corresponding tertiary phosphine oxides. Quantum chemical calculations suggested a nucleophile‐dependent mechanism that involves both concerted and stepwise SNAr reaction pathways.

Phosphinylation of Non-activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms.

Non-activated aryl fluorides reacted with potassium diorganophosphinites through a nucleophilic aromatic substitution (SN Ar) reaction. Remarkably, both electron-neutral and electron-rich aryl fluorides participated in the reaction with substantially stabilized anionic P nucleophiles to form the corresponding tertiary phosphine oxides. Quantum chemical calculations suggested a nucleophile-dependent mechanism that involves both concerted and stepwise SN Ar reaction pathways.

Palladium-Catalyzed Denitrative α-Arylation of Ketones with Nitroarenes.

The palladium-catalyzed α-arylation of ketones with readily available nitroarenes and nitroheteroarenes provides access to useful α-aryl and α-heteroaryl ketones. The use of the Pd/BrettPhos catalysts was critical to achieve high efficiency for these transformations, whereas other catalysts led to decreased yields or no conversions. The intramolecular type substrate was also applied in this methodology and gave a chromone derivative. Polyaromatic carbonyl compounds can be easily obtained by multicomponent tandem reactions, via nucleophilic aromatic substitution (SNAr) or cross-coupling reaction followed by this denitrative arylation. Kinetic experiments show that the electronic effect of nitrobenzenes has a greater effect on the reaction rate than the electronic effect of ketones.