Nucleophilic Aromatic Substitution Reaction Research Articles

Micellar catalyzed hydroxylation of 1,2,3-trichloro-4,6-dinitrobenzene: Role of cationic head group–π interaction

The micellar catalysis of the hydroxylation of 1,2,3-trichloro-4,6-dinitrobenzene (DNTCB) with aqueous NaOH, to synthesize 2-chloro-4,6-dinitroresorcinol (CDNR), was studied using cationic, anionic and non-ionic surfactants at different concentrations to promote the reaction kinetics. The micellar catalysis using cationic surfactants at optimum concentrations was effective giving highest conversion of DNTCB (92–100%), which was ascribed to high solubilization capacity of the micellar solutions for DNTCB, surface positive charges of micelles increasing OH– ions concentration near micellar surface, and the cation-π interaction of surfactant molecules (through cationic head group) with DNTCB molecules. The cation-π interaction plays important role in solubilization process, substrate activation and catalysis of the reaction. The higher surfactant concentrations retard the reaction owing to strong solubilization of DNTCB in micelles and reduced OH– ions concentration around the micelles. The cationic micellar solutions at optimum surfactant concentrations can be effective catalytic system for the aromatic nucleophilic substitution reactions.

Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines.

The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification, hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-bromopyridines proceeds via pyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines to a single 4-substituted product.

Bis(pentafluorophenyl)-o-carborane and its arylthio derivatives: synthesis, electrochemistry and optical properties.

Synthesis of 1,2-bis(pentafluorophenyl)-o-carborane and its arylthio-derivatives is reported. The regioselective arylthiolation was successfully achieved via nucleophilic aromatic substitution (SNAr) reaction. A series of bis(perfluoroaryl)-o-carboranes with various para-substituents showed strong multicolor emission in the solid-state (Φf up to 47%), suggesting an aggregation-induced emission (AIE) character in this motif.

Dynamics of a gas-phase SNAr reaction: non-concerted mechanism despite the Meisenheimer complex being a transition state.

The commonly accepted mechanism of the nucleophilic aromatic substitution (SNAr) reaction has been found to be governed by the nature of the Meisenheimer structure on the potential energy surface. A stable Meisenheimer intermediate favors a stepwise mechanism, while a Meisenheimer transition state favors a concerted mechanism. Here, we show by using a detailed potential energy map (using the DFT and DLPNO-CCSD(T)/CBS methods) and ab initio classical trajectory simulations that the F- + C6H5NO2 SNAr reaction involves a Meisenheimer transition state and follows a stepwise mechanism in contrast to the expected concerted pathway. The stepwise mechanism observed in the trajectory simulations takes place by the formation of various ion-dipole and σ-complexes. While the majority of the trajectories follow the multi-step mechanism and avoid the minimum energy path, a considerable fraction exhibit a roaming atom mechanism where the F atom hovers around the phenyl ring before the formation of the products.

Reaction-Based Amine and Alcohol Gases Detection with Triazine Ionic Liquid Materials.

We demonstrated in this work the use of affinity ionic liquids, AIL 1 and AIL 2, for chemoselective detection of amine and alcohol gases on a quartz crystal microbalance (QCM). These detections of gaseous amines and alcohols were achieved by nucleophilic aromatic substitution reactions with the electrophilic 1,3,5-triazine-based AIL 1 thin-coated on quartz chips. Starting with inexpensive reagents, bicyclic imidazolium ionic liquids AIL 1 and AIL 2 were readily synthesized in six and four synthetic steps with high isolated yields: 51% and 63%, respectively. The QCM platform developed in this work is readily applicable and highly sensitive to low molecular weight amine gases: for isobutylamine gas (a bacterial volatile) at 10 Hz decrease in resonance frequency (i.e., ΔF = −10 Hz), the detectability using AIL 1 was 6.3 ppb. Our preliminary investigation on detection of the much less nucleophilic alcohol gas by AIL 1 was also promising. To our knowledge, no example to date of reports based on nucleophilic aromatic substitution reactions demonstrating sensitive gas detection in these triazine ionic liquids on a QCM has been reported.

Double-activated nucleophilic aromatic substitution polymerization by bis-ortho-trifluoromethyl groups to soluble para-poly(biphenylene oxide)

Poly(biphenylene oxide)s (PBPOs) containing two pendent trifluoromethyl groups were synthesized from AB-type monomers, 4ʹ-hydroxy-4-fluoro-3,5-bis(trifluoromethyl)biphenyl and its 3ʹ-hydroxyl isomer. The displacement reaction of fluorine leaving group activated by the two trifluoromethyl groups at the ortho-positions produced high-molecular-weight polymers with Mn up to 101,000 g/mol, indicating the nucleophilic aromatic substitution reaction proceeded effectively. PBPOs with para-, meta-, and mixed ether linkages were obtained and well characterized by FTIR and 1H/19F NMR spectroscopies. All PBPOs were amorphous and soluble in a wide range of organic solvents, and exhibited even more enhanced thermal stability than the previously reported two meta-trifluoromethyl substituted analogues. Increasing the para-linkage fraction in the polymer generally improved solubility and increased Tg in contrast to the meta-trifluoromethyl case, where para-linked polymer was poorly soluble and semicrystalline. This suggests that the ortho-trifluoromethyl substituents are more effective for the synthesis of para-linked PBPOs. They also showed low refractive indices and birefringence values.

Design, synthesis, characterization and fluorescence property evaluation of dehydroacetic acid-based chalcones

In this study, we decided to synthesize some new chalcone-type dyes derived from dehydroacetic acid (DHA) by the condensation of 4-amino-substituted benzaldehyde with DHA under the base-catalyzed condition and investigate their ability for rearrangement in acidic condition. For this purpose, initially we prepared the 4-aminobenzaldehyde derivatives via nucleophilic aromatic substitution reaction of 4-fluorobenzaldehyde with variety of amines in the presence of K2CO3 as base in DMF. The Knoevenagel condensation of DHA with 4-aminobenzaldehyde derivatives results in the desired compounds. In continuation, Fries rearrangement applied on DHA-chalcone compounds results in characterization of new pyranilidene-type derivatives. The optical responses of new dyes containing UV–Vis absorption and fluorescence spectroscopy were measured in dichloromethane (ET = 40 kcal/mol). Pyranilidene derivatives show low λmax values in comparison with chalcones, and molecule with strong dipole, in polar solvents, shows the bathochromic shift due to more stabilization of excited state in compared with ground state of molecule. Large stocks shifts were obtained for synthesized compounds.

A water-soluble fluorescent probe for the detection of thiophenols in water samples and in cells imaging

Water pollution is the main cause of death of aquatic organisms such as fish et al. Content of thiophenols in water samples is an important indicator for assessing the degree of water pollution. The development of fluorescent probes with high selectivity and high sensitivity to detect thiophenols in water samples is extremely important in both environmental and life sciences. Although several fluorescent probes for thiophenols detection have been reported in recent years, most of them required the assistance of organic solvents to remedy the restriction caused by the poor water solubility of the probe, which did not fully reflect the actual situation of thiophenols in actual water samples. To fully overcome this shortage, we modified the 1,8-naphthylimide moiety with carboxyl to obtain a water-soluble fluorescent probe which could react with thiophenols specifically through nucleophilic aromatic substitution reaction (SNAr) reaction with turn-on fluorescent responses. The corresponding detection limit was 71nM. Supported by the spectroscopic changes, test strips based on the probe could detect thiophenols quantificationally and conveniently. At the same time, the probe could detect thiophenols in water sample with quantitative recovery. Besides, cell imaging experiments demonstrated the possibility of the probe to detect thiophenols in living cells.

Synthesis of Highly Substituted Pyridines via [4 + 2] Cycloadditions of Vinylallenes and Sulfonyl Cyanides.

A convergent strategy for the synthesis of multisubstituted pyridines is described. Vinylallenes combine with commercially available arylsulfonyl cyanides in Diels-Alder cycloadditions to generate isopyridine cycloadducts that are converted to pyridines upon further heating or addition of a base. The 2-sulfonylpyridine products undergo nucleophilic aromatic substitution reactions with oxygen and carbon nucleophiles to provide access to a variety of highly substituted pyridines.

A convenient green synthetic approach to the synthesis of novel bioactive selenolo[2,3‐c]pyrazoles as antibacterial and antifungal agents

AbstractA series of new pyrimidine, triazine, and isoindole heterocycles fused to the selenolopyrazole ring system was synthesized by various condensation reactions of the amino selenolopyrazole carboxamide 1, which was performed by a new green methodology. The pyrimidinone compound 6 was used as a versatile precursor for several aromatic nucleophilic substitution reactions to produce the sulfanyl pyrimidines 10a‐c and the corresponding amines 11a‐c and 12a, b. Assignment of the chemical structures for the newly synthesized compounds was confirmed by elemental and spectral analyses including Fourier transform infrared (FTIR), 1H‐NMR, and 13C‐NMR and mass spectroscopy for some of them. Furthermore, some of these compounds were screened against various pathogenic bacterial and fungal strains. Their results demonstrated that some of them revealed remarkable antimicrobial activities.

Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities

The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 = 5.4 μM) and amastigote (IC50 = 12.0 μM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 = 8.8 and 8.7 μM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11 were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size and π-π interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzi-nitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our design strategy was capable of generating novel and active Bnz analogs.

Synthesis of Emissive Heteroacene Derivatives via Nucleophilic Aromatic Substitution.

A synthetic approach for preparing a variety of heterocyclic tetrahydropentacene derivatives via nucleophilic aromatic substitution reactions of bidentate nucleophiles and tetrafluoroterephthalonitrile was developed. X-ray crystallography of several products revealed that the compounds containing oxygen and nitrogen heteroatoms are highly planar and engage in π-stacking, while the compounds containing sulfur are bent and do not stack as effectively. The compounds were also highly emissive, and the heteroatom had a significant impact on the emission and electrochemical properties.

Development of a water-soluble near-infrared fluorescent probe for endogenous cysteine imaging.

We designed and synthesized a water-soluble near-infrared (NIR) fluorescent probe with the recognition unit of the cyanine-like structure and acrylate group. Through an aromatic ring nucleophilic substitution reaction based on sulfhydryl moiety, an off-on fluorescence response toward cysteine (Cys) was realized. The probe exhibited excellent spectral performance with an emission wavelength of 720nm and a detection limit of 0.20μM. The spectral properties, selectivity and anti-interference performance of the probe were systematically investigated. Density functional theory (DFT) calculations were conducted to clarify the luminescence mechanism of the probe. Furthermore, the probe was successfully applied to the detection of free Cys in human serum and the NIR imaging of endogenous Cys in living cells. Thus, the probe has a promising application prospect in clinical diagnosis and fluorescence imaging.

Post-side chain engineering of difluorinated benzothiadiazole-based conjugated microporous polymer for enhanced photocatalytic H2 evolution

Recently, donor-acceptor (D–A) conjugated polymers are regarded as promising photocatalysts for water splitting, however, direct polymerization of conjugated polymers bearing various functional groups is still limited. Herein, we have developed a post-functionalization strategy for difluorinated-benzothiadiazole based conjugated polymers (BBT-FF), and one of the two electron-withdrawing fluorine (F) could be replaced by electron-donating alkoxyl group (RO-) via nucleophilic aromatic substitution (SNAr) reaction. For the as-prepared BBT-FCO in which the methoxyl group (CH3O-) was incorporated, it exhibited comparable photocatalytic H2 evolution rate (HER) to the same polymer which was synthesized by direct polymerization. While the aliphatic chain of alkoxyl groups was extended, increased surface hydrophobicity impair the photocatalytic performance. In order to promote hydrophilicity of the polymers, BBT-FF was further functionalized by different kinds of oligo(ethylene glycol) (OEG), and optimized BBT-FC8O5 exhibited the highest HER, reaching 311 μmol h−1 which is 2.46 times higher than BBT-FF. Density functional density calculations suggested that OEG side chain is beneficial to the nitrogen active sites of BT units via proton-coupled electron transfer (PCET) mechanism. Our research provides a facile method to investigate structure-property interrelationship of D-A conjugated polymers for photocatalytic hydrogen evolution.

First Example of Cationic Cyclopentadienyliron Based Chromene Complexes and Polymers: Synthesis, Characterization, and Biological Applications

The present work encompasses development of a new class of active antimicrobial agents of the ɳ6-arene-ɳ5-cyclopentadienyliron (II) complexes and polymers to expand the existing family of antimicrobials. The design of the first example of these cationic organoiron complexes, incorporating chromene moieties, was successfully accomplished in good yield via the Steglich esterification, followed by the nucleophilic aromatic substitution reactions to isolate their polymeric analogues. Meanwhile, the structural identities of the new materials were confirmed using 1H and 13C NMR, IR, and elemental analysis. The molecular weight of the new polymeric materials was estimated using viscosity measurements, and was found to be in the range of 10,000 and 31,000. The chromene-containing organoiron complexes displayed reversible reduction behaviors as their functionalized polymers. Meanwhile, the TGA thermogram revealed initial weight losses due to the cleavage of the cationic iron moieties, while the second weight losses were dependent upon the etheric linkages in the polymer backbones. This study, therefore, focuses on the exploration of the antimicrobial and antitumor performance of the new materials along with their structure activity relationship.

Nanoporous poly(ether sulfone) from polylactide-b-poly(ether sulfone)-b-polylactide precursor

We report a route to synthesize polylactide-b-poly(ether sulfone)-b-polylactide (PLA-b-PES-b-PLA) containing PES and PLA, which provide a mechanically robust framework and a sacrificial template for pore formation, respectively. High-molar mass PES terminated with fluorine groups was synthesized by the step-growth nucleophilic aromatic substitution (SNAr) reaction, and the chain ends were transformed into benzylic hydroxyl groups by chain end modification. Growth of the PLA using the hydroxyl groups as initiating sites via chain-growth ring opening transesterification polymerization (ROTEP) produced the target triblock copolymer. Although the step-growth polymerization produced a PES middle block with high dispersity, small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) analyses indicated the formation of an ordered lamellar morphology. We further demonstrated that a nanoporous PES with slit-like pores could be obtained by selective removal of the PLA.

C-S coupling with nitro group as leaving group via simple inorganic salt catalysis

An efficient and practical synthetic protocol to synthesize nonsymmetrical aryl thioethers by nucleophilic aromatic substitution (SNAr) reaction of nitroarenes by thiols with potassium phosphate as the catalyst is described. Various moderate to strong electron-withdrawing functional groups are tolerated by the system to provide thioethers in a good to excellent yields. We also showed that the present method allows access to 3 drug examples in a short reaction time. Finally, mechanistic studies suggest that the reaction may form the classic Meisenheimer complex through a two-step addition-elimination mechanism.

Aromatic Nucleophilic Substitution of FOX-7: Synthesis and Properties of 1-Amino-1-Picrylamino-2,2-Dinitroethylene (APDE) and Its Potassium Salt [K(APDE)

Two energetic compounds, 1-amino-1-picrylamino-2,2-dinitroethylene (APDE) and its potassium salt [K(APDE)] were synthesized through an aromatic nucleophilic substitution reaction between FOX-7 and picryl chloride. APDE and K(APDE) were characterized by elemental analysis, IR, NMR spectroscopy, and X-ray diffraction. APDE has a 3D wavy layered stacking structure similar to FOX-7. K(APDE) (peak temperature (Tip )=185.6 °C and impact sensitivity (IS)=19.6 J) presents better stability than APDE (tap =133.3 °C and IS=15.7 J). The reasons why the stability of APDE is lower than that of FOX-7 and picryl chloride are analyzed. The detonation velocity (D) and detonation pressure (P) of APDE (8.36 km s-1 and 31.3 Gpa) are close to those of FOX-7 and RDX. The thermal decomposition of K(APDE) is very violent, and its detonation performance (D=9.14 km s-1 and P=38.6 Gpa) is comparable to that of HMX, indicating that K(APDE) has good potential to be a high explosive.

Multiple Covalent Triazine Frameworks with Strong Polysulfide Chemisorption for Enhanced Lithium‐Sulfur Batteries

AbstractEndowed with high theoretical energy density, low cost, and environmental friendliness, lithium‐sulfur batteries have a promising future in energy storage. The volume expansion of the sulfur cathode, shuttle effects, and the insulating nature of polysulfide result in poor cycling stability and limit practical applications of lithium‐sulfur batteries. In this work, these matters are relieved by physically and chemically restricting sulfur species in highly fluorinated sulfur‐rich multiple covalent triazine frameworks synthesized through nucleophilic aromatic substitution reaction chemistry. It exhibits a specific capacity of 681 mAh g−1 and capacity retention of 62.6 % after 400 cycles, indicating a 0.09 % degradation per cycle. The superiority in cycle performance is attributed to the homogeneous distribution of sulfur, covalent bonding of sulfur, and affinity for polysulfide of triazine rings.

Hückel and Möbius Aromaticity in Charged Sigma Complexes.

In sigma complexes, intermediates in nucleophilic and electrophilic aromatic substitution and other reactions, delocalization in the aromatic ring is formally disrupted. Unexpectedly, computational evidence is presented that favorable processes contain aromatic sigma complexes. Tetracoordinated carbon therein surprisingly employs orbitals that are more similar to sp2 than to sp3 hybrids in sigma bonds with adjacent ring atoms. Both leaving groups and nucleo- or electrophiles may donate electrons to the π-system depending on the availability of p-type orbitals to fulfill Hückel (4N+2) or Möbius (4N) rules of aromaticity in analogy to conjugated transition-metal metallacycles.