Electrophilic Aromatic Substitution Research Articles

Facile Access to Phosphorus Ylide-fused Heteroarenes Possessing Tunable Optoelectronic Properties and High Nonlinear Optical Performances.

We report here a novel family of ylidic P-heteroarenes (P1-P6), structurally featuring unique phosphonium cyclopentadienylide (P-Cp)-fused π-skeletons and synthetically prepared via an unexpected one-pot [2+3]/[3+3] phospha-annulation reaction. While the facile and modular synthesis allows the fine-tuning of their optical absorptions and redox properties, single-crystallographic and theoretical analysis of these P-heteroarenes further reveal that the fusion of P-Cp moiety leads to substantial intramolecular charge-separated features with high ylidic character values of up to 84 %. Benefitted from such dipolar structures, these P-heteroarenes not only allows stepwise electrophilic substitution reaction for further structural π-expansions, but also exhibit excellent nonlinear optical (NLO) responses and optical limiting (OL) performances comparable to or exceed those of C60. As a model compound, the persistent radical-anion salt of P5a was also prepared through chemical reduction, thus offering valuable insights into the electronic structures of reduced P-ylidic species. Our work not only established a highly efficient synthetic method toward new P-heteroarenes, but also provide fundamental understanding of those fused-ring ylidic P-heterocycles with promising NLO/OL applications.

Tuning Tetramethoxy-acridiniums for Fluorophores and Organic Photoredox Catalysis.

Tetramethoxy substituted alkyl-acridiniums are readily available by facile nucleophilic aromatic substitution on tris(dimethoxyphenyl)carbenium, but are non-fluorescent, presumably due to intramolecular photoinduced electron transfer quenching. In this work we introduce electron withdrawing groups by electrophilic aromatic substitution reactions, leading to fluorescence turn-on. The acridiniums are moderately fluorescent (ϕf = 20%) with long fluorescene lifetimes (τf = 9 ns). The positive excited state reduction potentials (E*red = +1.6 V) make the TMAcr+ excellent electron acceptors in the excited state, and efficient reductive photoredox catalysts able to oxidize a broad range of substrates.

Poly(arylene ether)s via Cu(II)-Catalysis.

Poly(arylene ether)s (PAEs) are a versatile class of thermoplastic materials with commercial importance. Currently their synthesis relies predominantly on either nucleophilic or electrophilic aromatic substitution reactions, severely limiting the scope of available PAEs. Herein, we report the copper(II)-catalyzed polycondensation of electronically unactivated aryl bromides with bisphenols to afford a wide range of new PAEs. These PAEs are characterized by their thermal and mechanical properties. Functional PAEs were produced that have reversible acid- and redox-triggered chromophores incorporated into the backbone, which illustrates the utility of these methods.

Quantitative Kinetics of the Rapid Bromination of Isoxazole in Bromide-Free Aqueous Medium using Hydrodynamic Voltammetry

The kinetics of rapid bromination of isoxazole by molecular bromine at pH 4.7 have been studied quantitatively. Bromination of isoxazole is an electrophilic substitution reaction where the inductive effect and resonance effect govern reactivity and orientation respectively. Isoxazoles have a broad range of applications in pharmaceuticals and therapeutics. Hence the quantitative kinetic study will help in these applications. The bromination reactions are rapid electrophilic substitution reactions with a half-life of a few seconds, therefore the kinetic data regarding the bromination was lacking thus far. A distinct technique known as hydrodynamic voltammetry was used to perform the kinetics of the reaction. Only molecular bromine gets reduced on the working electrode during the reactions. As the solution lacked bromide ions, a decrease in the concentration of molecular Br2 was measured with reference to diffusion current using a rotating platinum electrode (RPE). During the work, a saturated calomel electrode (SCE) was used as a reference electrode. Bromination of isoxazole followed second-order kinetics with an equal initial concentration of reactants. Thermodynamic parameters were obtained based on rate constants at five different temperatures. The obtained rate constants and activation energy were used to comment on the mechanism of the electrophilic substitution reaction. Thus, the present work quantitatively verifies the reactivity of the isoxazole in the bromination reaction.

Electrophilic aromatic substitution of electron-rich arenes with N-fluorobenzenesulfonimide (NFSI) as an electrophile.

An efficient amidation of electron-rich arenes using NFSI as a nitrogen source has been successfully disclosed. This amidation process can be easily conducted at elevated temperatures, without the need for catalysts or additives. A wide range of arenes substituted with hydroxy, alkoxy, or carbonyl groups were found to be compatible, yielding the desired amination products. Computational study shows that the amidation proceeds via an electrophilic aromatic substitution pathway, comprising a three-step process that includes substitution, addition, and elimination, which differs slightly from the classical mechanism.

A rapid and scalable method for visible light induced bromination of uracil derivatives in a falling film looping photoreactor.

Visible light induced green synthesis of 5-bromouracil derivatives using N-bromosuccinimide (NBS) in acetonitrile under batch operation with a constant photon flux of 46 μmol s-1 is reported. This methodology has shown excellent tolerance with various 6-substituted and N-substituted uracils and is also applicable for various pyrimidine and arene derivatives. The reaction proceeded through the formation of a bromine molecule via a radical pathway followed by an electrophilic substitution reaction, and this hybrid nature of the reaction pathway in the presence of light made the process faster. We successfully synthesized twenty-one derivatives and characterized them using various spectroscopic methods. Finally, the three different modules of the looping falling film reactor were used to show the successive scalability of the process with comparable photonic characteristics and reaction conditions. We achieved milligram to multigram scale reaction with almost equal efficiency and maximum productivity up to 1.2 kg per day.

Comparative Study of Catalysis Strategies: Friedel-Crafts Alkylation Vs. Michael's Addition of Indoles to Nitroalkenes

Indoles are critical in natural amalgamation for their flexible jobs in drugs, regular items, and material science, exhibiting huge pharmacological and compound reactivity. Due to their versatility and high reactivity, nitroalkenes are essential electrophilic partners in organic synthesis. While indoles and nitroalkenes are used in both Michael addition and Friedel-Crafts alkylation for producing carbon-carbon bonds, the catalyst types and reactions involved are different. Michael addition employs conjugate addition, whereas Friedel-Crafts alkylation employs electrophilic aromatic substitution. Each technique has a different level of selectivity and distinct synthetic applications. This review examines the advancements and persistent challenges in catalysis, focusing on the comparative methodologies of Friedel-Crafts alkylation and Michael addition involving indoles and nitroalkenes. Emphasizing green chemistry principles, it discusses the potential for sustainable and efficient synthetic processes through the use of innovative catalysts, including photocatalysis and biocatalysis. The integration of computational studies and interdisciplinary collaboration is essential for developing economically viable and environmentally responsible chemical synthesis, ultimately contributing to the creation of advanced materials and pharmaceuticals.

Palladium-Catalyzed Ortho Alkoxylation of Oxazoline Derivatives: An Avenue to Reach Meta-Substituted Electron-Rich Arenes Exploiting Oxazoline as a Removeable Directing Group.

An efficient and highly regioselective palladium-catalyzed oxazoline-directed alkoxylation is reported. The reaction proceeds under air and mild temperatures (60 °C). A series of alcohols can be used as alkoxylating agents and concomitantly act as reaction solvents, whereas primary and secondary alcohols are tolerated. Furthermore, fluorinated alcohols can be applied as well, introducing pharmaceutically relevant fluorine-containing groups. 1,3-Dialkoxylated products can be further subjected to hydrolysis transforming the oxazoline-directing group to a carboxylic acid, which can be removed by decarboxylation if desired. This approach demonstrates the capability to reverse the conventional site selectivity of electrophilic aromatic substitution reactions, since it allows the synthesis of arenes with two electron-donating groups in a 1,3-relationship.

Comparative Study on Catalysis Strategies: Friedel-Crafts Alkylation vs. Michael Addition of Indoles to Nitroalkenes

Indoles are critical in natural amalgamation for their flexible jobs in drugs, regular items, and material science, exhibiting huge pharmacological and compound reactivity. Due to their versatility and high reactivity, nitroalkenes are essential electrophilic partners in organic synthesis. While indoles and nitroalkenes are used in both Michael addition and Friedel-Crafts alkylation for producing carbon-carbon bonds, the catalyst types and reactions involved are different. Michael addition employs conjugate addition, whereas Friedel-Crafts alkylation employs electrophilic aromatic substitution. Each technique has a different level of selectivity and distinct synthetic applications. This review aims to examine the advancements and persistent challenges in catalysis, focusing on the comparative methodologies of Friedel-Crafts alkylation and Michael addition involving indoles and nitroalkenes. Emphasizing green chemistry principles, it discusses the potential for sustainable and efficient synthetic processes through the use of innovative catalysts, including photocatalysis and biocatalysis. The integration of computational studies and interdisciplinary collaboration is essential for developing economically viable and environmentally responsible chemical synthesis, ultimately contributing to the creation of advanced materials and pharmaceuticals.

Facile Access to Phosphorus Ylide‐fused Heteroarenes Possessing Tunable Optoelectronic Properties and High Nonlinear Optical Performances

We report here a novel family of ylidic P‐heteroarenes (P1‐P6), structurally featuring unique phosphonium cyclopentadienylide (P‐Cp)‐fused π‐skeletons and synthetically prepared via an unexpected one‐pot [2+3]/[3+3] phospha‐annulation reaction. While the facile and modular synthesis allows the fine‐tuning of their optical absorptions and redox properties, single‐crystallographic and theoretical analysis of these P‐heteroarenes further reveal that the fusion of P‐Cp moiety leads to substantial intramolecular charge‐separated features with high ylidic character values of up to 84%. Benefitted from such dipolar structures, these P‐heteroarenes not only allows stepwise electrophilic substitution reaction for further structural π‐expansions, but also exhibit excellent nonlinear optical (NLO) responses and optical limiting (OL) performances comparable to or exceed those of C60. As a model compound, the persistent radical‐anion salt of P5a was also prepared through chemical reduction, thus offering valuable insights into the electronic structures of reduced P‐ylidic species. Our work not only established a highly efficient synthetic method toward new P‐heteroarenes, but also provide fundamental understanding of those fused‐ring ylidic P‐heterocycles with promising NLO/OL applications.

Robust Catalytic SEAr H/D Exchange of Arenes with D2O: Metal‐Free Deuteration of Natural Complexes and Drugs

AbstractA catalytic metal‐free approach for the H/D exchange in aromatic compounds using D2O as the terminal deuterating reagent has been developed. This metal‐free protocol employs a triaryl carbenium as the mediator and showcases a wide applicability in the late‐stage deuteration of various natural products and small‐molecule drugs. Gram‐scale deuteration was successfully demonstrated with β‐Estradiol, highlighting the method‘s practicability. Detailed mechanistic insights, supported by DFT calculations, unveiled the essential role of in situ generated acidic species in this electrophilic aromatic substitution process. This newly developed method offers a sustainable and versatile alternative to traditional metal‐catalyzed H/D exchange techniques, addressing challenges such as the use of expensive metals, impurity formation, and the necessity for residual metal removal from the final products.

One-step synthesis of [15]paracyclophane and [16]paracyclophane via Pd-catalyzed C(sp2)–C(sp3) coupling and the cyclohexane-encapsulating crystal structure of [16]paracyclophane

Abstract Macrocycles consisting of methylene-bridged aromatic rings had been synthesized by aromatic electrophilic substitution reactions, thus limiting the substrates to electron-rich aromatic compounds. In this work, we developed a novel method for 1-step synthesis of [15]paracyclophane (PCP) and [16]PCP by the self-condensation of 4-bromobenzyl bromide via a Pd-catalyzed desulfinative coupling reaction between C(sp2) and C(sp3) carbon atoms. In the crystal structure, [16]PCP encapsulated cyclohexane and formed a 1D columnar structure

Dinuclear Cobalt(II) Bis-Dipyrromethane Complexes: Synthesis via Divergent Transmetalation Reactions.

A bis-dipyrromethane ligand, 4,4'-bis(1,1-bis(3,5-dimethyl-1H-pyrrol-2-yl)ethyl)-1,1'-biphenyl, [H4-MeBDPM-BPh] (1), is synthesized via acid-catalyzed electrophilic aromatic substitution of 2,4-dimethylpyrrole with 4,4'-diacetylbiphenyl. Subsequent deprotonation of 1 with n-BuLi yields the corresponding Li-salt [Li4-MeBDPM-BPh] (2). Transmetalation involving 2 and either CoCl2 or [Co(HMDS)2] (HMDS = -N(Si(CH3)3)2) results in dinuclear Co(II) complexes. In the case of CoCl2, the formation of the ate-complex 2[Li(THF)4][(MeBDPM-BPh){Co(μ-Cl)2Li(THF)2}2] (3) is observed where each metal center occupies a tetrahedral geometry with noninteracting metal centers. However, when utilizing [Co(HMDS)2], the dinuclear complex 2[Li(THF)4][(MeBDPM-BPh){Co(HMDS)}2] (4) is obtained with the formation of LiHMDS as the product of elimination. The Co metal centers of complex 4 are both three-coordinate and trigonal planar. Displacement of LiHMDS from 4 readily occurs upon treatment with the ylide base, H2CPPh3, yielding the neutral complex [(MeBDPM-BPh){Co(H2CPPh3)2}2] (5). At room temperature, complexes 3-5 have magnetically noninteracting metal centers with S = 3/2 spin states.

Red‐Emitting Pyrazole Azo Hydrazone and Its Metal Complexes for Photophysical Probing, Latent Fingerprints, Anti‐counterfeiting, and Biological Studies

ABSTRACTThe present paper discusses the synthesis of unprecedented red‐emitting mono‐azo compound pyrazole azo fluorescent tag (PAFT) by a diazotization method, followed by an electrophilic substitution reaction. Further, the metal complex of PAFT is also prepared by refluxing the ethanolic solution of the ligand with the corresponding metal (RuCl3 and C4H6CuO4.H2O) salts under suitable experimental conditions. The synthesized fluorophore PAFT displays intense fluorescence in the aggregate state and has excellent qualities, including high purity, low cost, eco‐friendliness, and good photostability. These unique characteristics of PAFT led to the development of new fluorescence‐based technology for the in situ viewing of latent fingerprints. Various spectroscopic and analytical techniques are used to confirm the structural characteristics of the synthesized compounds, including UV–Vis, FT‐IR, (1H) NMR, HRMS, TGA, VSM, ESR, and powder XRD methods. The potency of the antibacterial activity of the compounds was evaluated. The results revealed that compound PAFT and [Ru(PAFT)Cl3] H2O showed excellent sensitivity at 0.8 μL/mL against the Gram‐positive bacteria Staphylococcus aureus.

Fabrication of charged and zwitterionic nanofiltration membranes and anti-adhesion analysis using quartz crystal microbalance with dissipation and atomic force microscopy

Three nanofiltration (NF) membranes (positive charge, negative charge and near charge neutrality) were fabricated to investigate the anti-adhesion mechanism. Among them, the NF membrane with positive charge was synthesized through an electrophilic substitution reaction between the amino group of polyethyleneimine (PEI) and the chloromethyl groups of chloromethyl polysulfone (CMPSf) on a supporting polysulfone (PSf)/CMPSf blend membrane. The NF membrane with negative charge was fabricated through polycondensation using 1, 3, 5-benzenetricarbonyl trichloride (TMC) as a reactive monomer on the positive charge NF membrane. Subsequently, the near charge neutral zwitterion NF membrane (ZNF) was prepared by grafting 3-((2-aminoethyl) dimethylammonio) propane-1-sulfonate (sulfobetaine) (ADSS) onto the negative charge NF membrane. The anti-adhesion behaviors of the NF membranes during the dye selective separation were analyzed by Atomic force microscopy (AFM) and quartz crystal microbalance with dissipation (QCM-D). The results demonstrated that the near charge neutral ZNF membrane displayed a higher dyes rejection (>94.4 %) and higher flux recovery rates (>88.1 %) than charged NF membranes. Meanwhile, the near charge neutral ZNF membrane demonstrated the lowest amounts of dye deposition compared with charged NF membranes, such as reactive blue 4 (R4) for 509.9 ng/cm2, basic blue 24 (BB 24) for 269.0 ng/cm2, rhodamine B (RB) for 197.4 ng/cm2). Additionally, the near charge neutral ZNF membrane with the thicker hydration layer (121.7 nm) displayed weaker interaction forces (−4.8 nN to −7.4 nN) with the dyes than the charged membranes (−10.4 nN to −28.6 nN). Finally, an anti-adhesion mechanism involved charged shielding effect and hydration layer formation was proposed. These observations provide comprehensive insights into the anti-adhesion mechanism of ZNF membrane.

Rapid aqueous-phase dark reaction of phenols with nitrosonium ions: Novel mechanism for atmospheric nitrosation and nitration at low pH.

Dark aqueous-phase reactions involving the nitrosation and nitration of aromatic organic compounds play a significant role in the production of light-absorbing organic carbon in the atmosphere. This process constitutes a crucial aspect of tropospheric chemistry and has attracted growing research interest, particularly in understanding the mechanisms governing nighttime reactions between phenols and nitrogen oxides. In this study, we present new findings concerning the rapid dark reactions between phenols containing electron-donating groups and inorganic nitrite in acidic aqueous solutions with pH levels <3.5. This reaction generates a substantial amount of nitroso- and nitro-substituted phenolic compounds, known for their light-absorbing properties and toxicity. In experiments utilizing various substituted phenols, we demonstrate that their reaction rates with nitrite depend on the electron cloud density of the benzene ring, indicative of an electrophilic substitution reaction mechanism. Control experiments and theoretical calculations indicate that the nitrosonium ion (NO+) is the reactive nitrogen species responsible for undergoing electrophilic reactions with phenolate anions, leading to the formation of nitroso-substituted phenolic compounds. These compounds then undergo partial oxidation to form nitro-substituted phenols through reactions with nitrous acid (HONO) or other oxidants like oxygen. Our findings unveil a novel mechanism for swift atmospheric nitrosation and nitration reactions that occur within acidic cloud droplets or aerosol water, providing valuable insights into the rapid nocturnal formation of nitrogen-containing organic compounds with significant implications for climate dynamics and human health.

Leveraging long-lived arenium ions in superacid for meta-selective methylation

Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C–H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, we report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. This study demonstrates that this reaction is driven by the generation of long-lived arenium intermediates generated by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients.

Robust Catalytic SEAr H/D Exchange of Arenes with D2O: Metal-Free Deuteration of Natural Complexes and Drugs.

A catalytic metal-free approach for the H/D exchange in aromatic compounds using D2O as the terminal deuterating reagent has been developed. This metal-free protocol employs a triaryl carbenium as the mediator and showcases a wide applicability in the late-stage deuteration of various natural products and small-molecule drugs. Gram-scale deuteration was successfully demonstrated with β-Estradiol, highlighting the method's practicability. Detailed mechanistic insights, supported by DFT calculations, unveiled the essential role of in situ generated acidic species in this electrophilic aromatic substitution process. This newly developed method offers a sustainable and versatile alternative to traditional metal-catalyzed H/D exchange techniques, addressing challenges such as the use of expensive metals, impurity formation, and the necessity for residual metal removal from the final products.

Effect of the Fe0/PMS advanced oxidation system on the removal of aromatic organic compounds

The aromatic organic compounds present in groundwater environments have low contents, high toxicity, long half-lives and stable chemical properties, which increase the difficulty of degradation under natural conditions. In this study, an zero-valent iron activated peroxymonosulfate system (Fe0/PMS) was constructed to remove common aromatic organic compounds in groundwater. The results showed that at an initial pH of 7.0, Fe0=0.3 g/L, PMS= 0.5 mM, and initial concentration of organic matter (C0) =0.1 mM, the removal efficiency of the seven aromatic organic compounds by the Fe0/PMS system reached more than 70 %, which shows good removal ability. Alcohol quenching tests and liquid chromatography time-of-flight mass spectrometry tests showed that the main active oxygen species in the system were SO4•─ and OH•, which could efficiently degrade aromatic organic compounds through electrophilic substitution, hydroxylation, carbonylation and decarboxylation reactions and reduce the biological toxicity of organic compounds in wastewater to a certain extent. In the long-term dynamic reaction process, the removal rate of aromatic organic compounds in actual groundwater by the Fe0/PMS system can be maintained above 75 %, and the complex structure can be effectively destroyed. This research can provide a theoretical basis for the efficient treatment of aromatic organic compounds in groundwater.

Study on the effect of conditioner on NOx precursor control behavior from sewage sludge pyrolysis: Focusing on conditioner assessments and in-situ fixation mechanism

The nitrogen transformation during sludge pyrolysis is affected by the dewater conditioner. However, the comparative analysis of the conditioner under identical pyrolysis conditions has been previously absent. In this study, Ca-, Fe- and Al-based conditioners were selected as the representatives. A comprehensive evaluation considering the cost of the conditioners and the product characteristics was conducted. Additionally, the in-situ fixation mechanism of the conditioner on nitrogen-containing gas was concurrently revealed. Among the six conditioners, CaO and AlCl3 were identified as the top performers, ranking first and second, respectively. Furthermore, Fe/Ca-based conditioners reduced NH3 and HCN release by 1.5 ∼ 5.53 % and 0 ∼ 1.55 %, respectively, by facilitating the conversion of amine-N to a more stable form in condensable fraction. Fe promoted volatile amine-N cyclization, while Ca encouraged its dehydrogenation. Both Fe/Ca-based conditioners increased 7.5 ∼ 14.8 % nitrogen retention in char, by inhibiting the decomposition of protein-N. Al-based conditioners had little effect on NH3 and HCN, but contributed to 2.3 ∼ 2.8 % production of stabilized nitrogen in char. The introduction of Cl in Fe/Ca/Al chloride conditioners would promote the decomposition of inorganic ammonium salts to produce NH3 at 30 ∼ 185 °C. And Cl also reacted with volatiles through electrophilic substitution reaction, leading to the formation of halogenated hydrocarbons in condensable fraction and the release of more NH3, HCN, and HNCO at 30 ∼ 465 °C. The findings of this study provide a detailed comparative analysis of various conditioners under uniform conditions and reveal the in-situ fixation mechanism of nitrogen-containing gas. This will provide guidance for the sludge conditioning-dewatering-drying integrated treatment and disposal.