Nucleophilic Reaction Research Articles

Facile constructed meroterpenoids with novel hexadecahydroacephenanthrylene carbon skeleton using the biotransformation and chemical synthesis method

Bioaspermeroterpenoid A (1), the first meroterpenoid with an unprecedented hexadecahydroacephenanthrylene carbon skeleton, together with two analogues bioaspermeroterpenoids B and C (2 and 3) were co-isolated from the biotransformation extract of aspermeroterpene C by the fungus Penicillium herquei GZU-31-6. On the other hand, bioaspermeroterpenoid Aa (1a) featuring the same hexadecahydroacephenanthrylene carbon skeleton was synthesized from the precursor aspermeroterpene C by the nucleophilic addition reaction in the presence of CH3ONa. Furthermore, bioaspermeroterpenoids A and C showed good inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells with IC50 values of 26.08 and 7.50 µM, respectively, compared to the positive control (Indomethacin, IC50 24.1 µM). Especially, bioaspermeroterpenoids A and C also significantly suppressed the protein expression of iNOS and COX-2 at the concentration of 12.5 μM.

Spontaneous Generation of -CH2CN from Acetonitrile at the Air-Water Interface.

Acetonitrile (CH3CN) is considered a very stable molecule in aqueous solutions, and its deprotonation to produce strongly basic -CH2CN requires harsh conditions. CH3CN is also present in the atmosphere, but its chemical transformation pathway at the air-water interface is unknown. In this study, we discovered and verified the unprecedented spontaneous generation of -CH2CN from the CH3CN-H2O solution at the air-water interface of microdroplets, and revealed the indirect deprotonation mechanism of CH3CN by synergistic redox of •OH and electrons in the microdroplets through the capture of key intermediates and computational chemistry. In addition, the dynamic process of indirect deprotonation-protonation was also observed. The high reactivity of -CH2CN in the droplets was revealed via nucleophilic addition to acetone, benzaldehyde, and the parent CH3CN molecule. Furthermore, the -CH2CN generated in the microdroplets underwent a barrier-free nucleophilic addition reaction with CO2 to produce 2-cyanoacetic acid for CO2 fixation. The synergistic redox reaction process revealed in this study provides new insights into microdroplet chemistry, and the distinctive CH3CN reactions identified may provide new clues to unravel the mystery of the CH3CN transformation in the atmospheric environment.

Synthesis and redox catalysis of Carbodiphosphorane ligated stannylene.

Heavier group 14 carbene analogues, exhibiting transition-metal-like behavior, display remarkable capability for small molecule activation and coordination chemistry. However, their application in redox catalysis remains elusive. In this paper, we report the synthesis and isolation of a stannylene with carbodiphosphorane ligand. The nucleophilic reactivity at the divalent tin center is elucidated by computational and reactivity studies. Moreover, this stannylene exhibits catalytic activity in the hydrodefluorination reaction of fluoroarenes. Mechanistic investigations into the elementary steps confirm a SnII/SnIV redox cycle involving C-F oxidative addition, F/H ligand metathesis, and C-H reductive elimination. This low-valent SnII catalytic system resembles the classical transition metal catalysis. Notably, this represents metallomimetic redox catalysis utilizing carbene analogue with heavier group 14 element as a catalyst.

Fluorescent Sensing for the Detection and Quantification of Sulfur-Containing Gases.

Sulfur-containing gases, such as H2S and SO2, play significant roles in a multitude of biological processes affecting human life and health. Precise and efficient detection of these gases is therefore crucial for advancing one's understanding of their biological roles and developing effective diagnostic strategies. Fluorescent sensing offers a highly sensitive and versatile approach for detecting these gases. This Review examines the recent advances in the fluorescent detection of H2S and SO2, highlighting the key mechanisms involved in fluorescence signal transduction, including changes in intensity and wavelength shifts. The diverse array of probe molecules employed for this purpose, including those utilizing mechanisms such as nucleophilic reactions, Förster resonance energy transfer (FRET), and sulfur affinity interactions are explored. In additional to organic sensors, the focus of the Review is particularly directed toward quantum dot (QD) systems, emphasizing their tunable optical properties that hold immense potential for fluorescence sensing. Beyond the traditional III-V QDs, we delve into the emerging fluorescence sensors based on halide perovskite QDs, upconversion nanocrystals, and other novel materials. These advanced QD systems hold promise for the development of highly sensitive and cost-effective gas detectors, paving the way for significant advances in biomedical and environmental monitoring. This Review provides a comprehensive overview of the current state-of-the-art in QD-based fluorescence sensing of sulfur-containing gases and provides a multifaceted discussion comparing organic fluorescent sensors with QD sensors, highlighting the key challenges and opportunities for the integration of fluorescence sensing as it evolves. The Review aims to facilitate further research and development of innovative sensing platforms to enable more accurate and sensitive detection of these important gases.

Triflyl [18F]Fluoride as a Solution for Base-sensitive Late-stage Nucleophilic Aromatic 18F-Fluorination Reactions.

Fluorine-18 is the predominant radionuclide used to label Positron Emission Tomography (PET) tracers. One outstanding challenge in nucleophilic aromatic radiofluorination reactions is the sensitivity of precursors and catalysts for basic reaction conditions, which are necessary for the work-up of [18F]fluoride, resulting in limited reproducibility. Triflyl [18F]fluoride is a new [18F]fluoride source that allows freedom in choice of type and amounts of base and cryptand. The aim of the current work is to explore the scope and limitations of triflyl [18F]fluoride in the late-stage nucleophilic aromatic 18F-fluorination of various functionalized precursors, exploring reduced amounts of base and cryptand. The assessment allowed for the application of this new nucleophilic [18F]fluoride reagent to the successful radiosynthesis of boron, stannane, hypervalent iodonium ylide and phenol substrates bearing electron-deficient, -neutral and -rich functional groups as well as the clinically relevant PET tracers [18F]FPEB, [18F]mFBG and [18F]SynVesT-1.

Defining the Synthetic Scope of ortho-Quinone Methides by Quantifying Their Electrophilicity.

A series of aryl-substituted ortho-quinone methides (oQMs) was synthesised and structurally characterised. Kinetic studies of the nucleophilic additions of carbanions (reference nucleophiles) to oQMs were used to determine second-order rate constants k2 for the carbon-carbon bond forming reactions (20°C, DMSO) at the oQMs' exocyclic π-bond. Analysing the kinetic data by the linear free energy relationship lg k2 = sN(N+E) revealed the Mayr electrophilicities E of the oQMs. The electrophilicities E of oQMs correlate linearly with Hammett substituent constants and experimentally determined reduction potentials Epred as well as with quantum-chemically calculated methyl anion affinities (MAAs), which provides valuable tools for prediciting the reactivity of further types of oQMs. Embedding the oQMs in Mayr's reactivity scales enables to predict novel nucleophilic reaction partners for oQMs and can productively be used to prepare simple Michael adducts as well as 4+2 or 4+1 cyclisation products as demonstrated in this work by several novel reactions with neutral or negatively charged C-, N-, and S-nucleophiles.

Catalytic Concerted SNAr Reactions of Fluoroarenes by an Organic Superbase.

We herein propose that the catalytic concerted SNAr reaction is a powerful method to prepare functionalized aromatic scaffolds. Classic stepwise SNAr reactions involving addition/elimination processes require the use of electron-deficient aromatic halides to stabilize Meisenheimer intermediates, despite their widespread use in medicinal chemistry research. Recent efforts have been made to develop concerted SNAr reactions involving a single transition state, allowing the use of electron-rich substrates based on the use of stoichiometric amounts of strong bases or reactive nucleophiles. This study demonstrates that, without the use of such reagents, the organic superbase t-Bu-P4 efficiently catalyzes the concerted SNAr reactions of aryl fluorides regardless of their electronic nature. The key to establishing this system is the dual activation of aryl fluoride and anionic nucleophiles by the t-Bu-P4 catalyst. Furthermore, this catalysis allows excellent functional group tolerance, utilization of diverse nucleophiles, and late-stage functionalization of bioactive compound derivatives. These findings make possible diverse applications in chemical synthesis and pharmaceutical development.

Physical and Chemical Dual Confinement Promotes Controllable Synthesis of Loose-Structured Azine-Linked Nanofilms for Fast Molecular Separation.

Thin-film composite (TFC) membranes, featuring nanoscale film thickness and customizable pore structures, hold promise for solute-solute separations. However, achieving on-demand molecular sieving requires fine control over the membrane microstructure. Here, the concept of physical and chemical dual confinement (PCDC) is introduced to fabricate loose-structured TFC membranes via confined interfacial polymerization (IP). This concept leverages the synergistic effects of physically restricted monomer diffusion and a chemically inhibited reaction to achieve controlled nanofilm growth. Dorsal addition of the aqueous phase to the hydrogel reduces the diamine diffusion via electrostatic and H-bonding interactions within its nanopores. The prepassivation of hydrazine using acid protonation effectively weakens its ability for nucleophilic reactivity. This confined IP between twisted TFPA and short-chain hydrazine yielded loosely structured azine-linked nanofilms, which displayed a high permeability of 53.4 LMH bar-1 and effective differentiation of binary mixtures. This PCDC concept offers a useful guideline to finely tailor polymeric nanofilms for precise separations.

DFT molecular modeling investigation and optical properties characterization of CR-39 films

Abstract In this study, the structural and optical characteristics of CR-39 films were investigated both theoretically and experimentally. A number of parameters for the CR-39 structure were theoretically computed by the density functional theory (DFT) method at B3LYP/6–311 G (p, d) level of theory. FTIR and UV/Vis spectroscopy were used to determine the structure compositions and the optical parameters of the CR39 film, respectively. The computed and experimental findings show good concordance. It was found that the CR-39 compound’s total energy, dipole moment, and energy difference between the LUMO and HOMO were, respectively, −994.575 a.u., 2.772 Debye, and 7.045 eV. The MEP showed a progressive change in color, with blue signifying a low electron density and red denoting a high electron density linked to nucleophilic reactivity and electrophilic reactivity. Further, the positive charges on all hydrogen atoms, which range from 0.16506 to 0.22032 a.u., imply that they are acceptors. The positive H34 is strongly produced when electrons from the negatively charged C17 are taken up. Because they are donor atoms, part of the carbon atoms in the structure is negative, while the other atoms are positive. The highest electronegative atoms H23 and H24 were substituted, resulting in the extremely negative carbon atom C7 (−0.32436). According to the experimentally determined absorption coefficient and energy gap values, CR-39 films may find application in optoelectronic devices.

Novel s-triazine derivatives as potential anticancer agents: Synthesis, DFT, DNA binding, molecular docking, MD simulation and in silico ADMET profiling

The ongoing challenge of cancer in modern medicine highlights the urgent need for targeted therapeutic strategies, particularly against the EGFR/PI3K/AKT/mTOR signalling pathways, which are pivotal in tumorigenesis. This study presents the design, synthesis, characterization, DNA binding studies and computational evaluation of a novel series of trisubstituted s-triazine derivatives 3a–n as potential anticancer agents. The synthetic methodology utilized the reaction of various oxygen-containing nucleophiles with cyanuric chloride via nucleophilic aromatic substitution, yielding the corresponding target products with high yield and purity. Density Functional Theory (DFT) calculations utilizing the B3LYP level provided insights into the electronic properties of the compounds, with derivatives 3f, 3n, and 3l displaying the lowest energy gaps and highest electrophilicity indices, indicative of their enhanced reactivity. DNA binding results from UV–Vis absorption spectroscopy confirmed the groove mode of binding for the most potent compound 3f with the binding constant (Kb) value of 6.75 × 104 M−1. Molecular docking studies against DNA (PDB ID: 3EY0) and EGFR (PDB ID: 6V6O) revealed strong binding affinities, with compound 3f (R1= ethoxy, R2= 3-CF3) exhibiting a notable binding energy of -8.9 kcal/mol and −9.1 kcal/mol respectively. Additionally, these compounds showed significant binding interactions with PI3K (PDB ID: 5HJB) and mTOR (PDB ID: 4JSV), suggesting their potential as dual inhibitors of the PI3K/AKT/mTOR pathway. The drug-likeness and ADMET profiles further support the therapeutic promise of compound 3f bearing a 3-trifluoromethyl substituent.

Lysine-regulated turing structure membrane via interfacial polymerization for enhanced Li+/Mg2+ separation

The development of advanced membranes with precise ion selectivity is essential for efficient Li+/Mg2+ separation. In this study, we synthesized a novel Lys-TMC membrane via a nucleophilic addition reaction between Lysine and trimesoyl chloride (TMC), yielding in a negatively charged surface interconnected by amide bonds. We systematically investigated the effects of varying Lys:TMC ratios on the membrane’s chemical structure, surface morphology, and ion separation performance. Our results revealed that the degree of cross-linking increases initially with the Lysine content, reaching an optimum at a Lys:TMC ratio of 10:1, where the membrane exhibited prominent Turing patterns on its surface. These patterns were critical for achieving effective ion separation. In contrast, excessive Lysine led to spontaneous polymerization, resulting in irregular ‘stone-like’ structures and the loss of Turing patterns. The optimally cross-linked Lys-TMC membrane displayed superior Li+/Mg2+ separation performance, highlighting the crucial role of controlled cross-linking and Turing structure formation in enhancing ion selectivity. This work provides a mechanistic understanding of the relationship between Turing structure formation and ion sieving performance, offering a promising strategy for designing advanced separation membranes.

Unveiling the influence of open metal sites in quasi ZIF-67 for eco-friendly catalysis of solvent-free aldehyde cyanosilylation

Quasi metal–organic frameworks (Q-MOFs) containing a high density of open metal centers are considered as an effective method of expanding the effectiveness of defective MOF-based catalysts. To achieve this, quasi ZIF-67 (Q-ZIF-67), having large scale structural defects in the framework, is produced through partial deligandation of ZIF-67 under controlled thermal treatment at 310 °C in air. This generates many unsaturated cobalt centers as Lewis acid sites, and results in the coexistence of micro and meso-pores within the Q-ZIF-67 network. Subsequently Q-ZIF-67 was employed in the catalytic cyanosilylation of benzaldehyde with trimethylsilyl cyanide, resulting in the corresponding cyanohydrin within 30 min under solvent free-conditions in air at 40 °C and room temperature with TOF values of 1.62, 1.53 min−1, respectively. The related cyanohydrin product was identified via 1H NMR. Importantly, Q-ZIF-67 displayed a highly efficient heterogeneous Lewis acid catalyst for the cyanosilylation of benzaldehyde compared to the pristine ZIF-67 and related cobalt oxide. Furthermore, investigating the impact of the electron-donating and electron-withdrawing para-substitutions on benzaldehyde revealed that electron-withdrawing groups are suitable for nucleophilic reactions. It was also observed that there was no significant decrease in catalytic activity after five catalytic runs. Thus, the Q-ZIF-67 has considerable potential as environmentally friendly catalyst for wide range of practical application in aldehyde cyanosilylation reactions.

Comparison of the Reactivity for the Solvent Extraction of Gold(iii) from Concentrated HCl Solutions Among D2EHPA, PC 88A, and Cyanex 272

ABSTRACT In this study, the chemical reactivity of three organophosphorus acidic extractants (D2EHPA, PC 88A, and Cyanex 272) was compared for the extraction of the anionic gold(III) complex, AuCl4 −, from the concentrated hydrochloric acid solutions. The extraction behavior was examined by varying the hydrochloric acid concentration from 1 to 9 M. Among the three extractants, only Cyanex 272 showed significant efficiency in extracting Au(III) with the extraction percentage was proportional to hydrochloric acid concentration. In contrast, the extraction of Au(III) by D2EHPA and PC 88A was not significant. FT-IR spectra analysis indicated that the P=O bond in Cyanex 272 weakened after extraction, suggesting its involvement in the process. Based on the structural differences between the extractants and the observed dependence of gold(III) extraction on the hydrochloric acid concentration, a nucleophilic addition reaction was proposed as the extraction mechanism. Specifically, the phosphoryl oxygen of protonated Cyanex 272 likely forms a coordinate bond with the gold ion in AuCl4 −, facilitating its extraction. This mechanism was supported by both extraction and spectroscopic data, making Cyanex 272 a promising candidate for the selective extraction of Au(III) from highly acidic solutions. The findings offer insights into the extraction of metal ions using organophosphorus extractants in highly acidic environments.

Reversible Nucleophilic Ring-Opening of Tetraoxapentacene Derivatives: Accessing New Materials for Thermally Activated Delayed Fluorescence.

We report the unexpected nucleophilic ring-opening reaction of electron deficient dioxins in the presence of carbazole under basic conditions. This nucleophilic ring-opening reaction is reversible under basic conditions in the absence of nucleophiles. Further, we demonstrate that this unexpected reactivity can be used to prepare novel donor-acceptor compounds that are emissive in solution and as thin films and exhibit thermally activated delayed fluorescence (TADF).

Nucleophilic Displacement Reactions of Silver-Based Metal-Organic Chalcogenolates.

We report nucleophilic displacement reactions that can increase the dimensionality or coordination number of silver-based metal-organic chalcogenolates (MOChas). MOChas are crystalline ensembles containing one-dimensional (1D) or two-dimensional (2D) inorganic topologies with structures and properties defined by the choice of metal, chalcogen, and ligand. MOChas can be readily prepared from a variety of small-molecule ligands and metals or metal ions. Although MOChas offer ligand diversity, most reported examples use relatively small ligands, typically involving short alkyl chains, aryl rings, or molecular cages. This is because larger, more complex molecules often yield poor product morphologies with indeterminate structures. In this study, we overcame this limitation by employing a ligand exchange strategy whereby a 1D MOCha, silver(I) methyl 2-mercaptobenzoate (2MMB), is used as a silver source for preparing 2D examples. The reaction proceeds generally toward products composed of the stronger nucleophile. We show that the reaction prefers displacing 1D topologies to yield 2D ones and replacing thiolates with selenolates. We performed a study to characterize the mechanism by which organic chalcogenols and dichalcogenides exchange with MOChas. The collected data and product analysis support a proposed mechanism of nucleophilic substitution, explaining how both organic chalcogenols and dichalcogenides can displace ligands in MOChas. This work provides a new synthetic route that will enable the preparation of more elaborate MOChas and heterostructures thereof. This approach enabled the preparation of previously inaccessible oligophenyl MOChas, which were successfully solved via small-molecule serial femtosecond crystallography (smSFX) at the SPring-8 Ångström Compact Free Electron LAser (SACLA) facility.

Mechanistic Perspective on Oxygen Activation Chemistry by Flavoenzymes.

Flavin-dependent enzymes catalyze a panoply of chemical transformations essential for living organisms. Through oxygen activation, flavoenzymes could generate diverse flavin-oxygen species that mediate numerous redox and non-redox transformations. In this review, we highlight the extensive oxygen activation chemistry at two sites of the flavin cofactor: C4a and N5 sites. Oxygen activation at the C4a site generates flavin-C4aOO(H) species for various monooxygenation reactions, while activation at the N5 site produces negatively charged flavin-N5OOH species, which act as highly reactive nucleophiles or bases. The selective oxygen activation at either the C4a or N5 site depends on the nature of substrates and is controlled by the active site architecture. These insights have expanded our understanding of oxygen activation chemistry in flavoenzymes and will serve as a foundation for future efforts in enzyme engineering and redesign.

Domino Reaction for the Synthesis of Substituted Pyrano[3',4':3,4]cyclopenta[1,2-c]chromenes Involving Double Ring Formation.

Herein, we present a green cascade approach for synthesizing a range of chemoselective polysubstituted pyrano[3',4':3,4]cyclopenta[1,2-c]chromenes containing a chiral stereocenter. The strategy involves a metal-free nucleophilic reaction between dialkyl (2E)-2-{2-oxo-3-[(2E)-3-aryl-2-propenoyl]-2H-chromen-4-yl}-2-butenedioates and α,α-dicyanoolefins under reflux conditions in ethanol solvent. Mechanistic studies have shown that the reaction proceeds via a cascade of steps, including Michael addition, intramolecular C- and O-cyclization, intramolecular trans-esterification, [1,2]-H and [1,5]-methoxy- and ethoxy carbonyl shift, and finally aromatization to yield the desired product. In this method, three bonds (2C-C and C-O) form in one pot, simultaneously forming two new cyclopentane and pyrano rings by double cyclization reactions. Other advantages of this method are that it has a simple operation, readily available starting materials, a chemoselective cascade process, transition metal-free, synthetically useful yields, and green conditions by using ethanol as a solvent.

Activation mechanism of persulfate by Fe3C-based materials for efficient benzo-a-pyrene abatement in wastewater: The reversed direct electron transfer from persulfate to contaminants

Herein, an unusual reserved direct electron transfer (r-DET) process from persulfate (PS) to contaminants was observed on the surface of Fe3C with N-doped C shell supported on carbon nanotubes (Fe3C@CN-CNTs). The Fe3C-based materials were synthesized via a facile sol–gel method employing melamine, glucose, FeCl3, and commercial multi-walled CNTs. The activation mechanisms were fully explored with a comparison of Fe3C@CN-CNTs and other Fe3C-based materials for the effective abatement of benzo-a-pyrene (BaP), a typical persistent organic pollutant in industrial wastewater. Electrochemical measurements, zeta potential monitoring, and Mössbauer spectroscopy indicated that the lack of CN shell result the relatively large particle size of Fe3C on Fe3C-CNTs, leading to more negatively charged surface and abundant OH during PS activation. Nevertheless, the superparamagnetic fraction with a fine particle size on the surface of Fe3C@CN and Fe3C@CN-CNTs potentially leads to a more positively charged surface, enhancing the zeta potential of surface adsorbed BaP and benefiting the r-DET. Through r-DET, oxidized PS and reduced BaP formed as intermediates, accelerating the overall degradation of BaP in Fe3C@CN-CNTs/PS. The degradation pathways, cytotoxicity, and operation conditions of BaP degradation by Fe3C@CN-CNTs/PS were thoroughly investigated. Additionally, Fe3C@CN-CNTs were found to promote the nucleophilic reaction between Cl− and PS, producing free chlorine and enhancing BaP degradation efficiency in chloride-containing wastewater. Overall, this study presents a new insight for the PS-based r-DET process and offers a promising approach for treating organically-contaminated wastewater.

Amine Exchange of Aminoalkylated Phenols as Dynamic Reaction in Benzoxazine/Amine-Based Vitrimers.

Bisfunctional benzoxazine and polyether diamine-based polymers show Arrhenius-like stress-relaxation varying with stoichiometry and polymerization temperatures proving vitrimeric behavior. Molecular structural investigations reveal the presence of different aminoalkylated phenols occurring at varying ratios depending on polymer composition and polymerization conditions. The vitrimeric mechanism is found to involve an amine exchange reaction of aminoalkylated phenols in an equilibrium reaction like a nucleophilic substitution reaction. As determined by molecular studies and dissolution experiments in reactive solvents, aliphatic and aromatic primary as well as aliphatic secondary amines in the polybenzoxazine structure can act as nucleophiles in reaction with electrophilic methylene bridges. Thus, aminoalkylated phenols proved to be a relevant structural motif resulting in a vitrimeric polybenzoxazine due to amine exchange reaction.

Ni(II)-catalyzed asymmetric alkenylation and arylation of aryl ketones with organoborons via 1,5-metalate shift

Chiral tertiary alcohols are an important structural motif, however, the general and efficient methodologies for their synthesis are less reported. Herein, we report a Ni(ІІ)-catalyzed asymmetric alkenylation and arylation of aryl ketones with organoborons under air via a 1,5-metalate shift strategy to obtain chiral tertiary allylic alcohols and diaryl alcohols. The reaction demonstrates good functional group tolerance and delivers chiral tertiary alcohols with good to excellent results. Furthermore, this method can be applied to the late-stage modification of drugs and the efficient synthesis of natural products. Notably, the reaction proceeds through an outer-sphere mechanism. The Ni(II) complex functions both as a Lewis acid to activate the ketone and create a chiral environment, and as coordination bridge linking the ketone and the organoboron-derived “ate” complex, facilitating the 1,5-metalate shift without forming a C-Ni bond. This approach contrasts with traditional transition metal-catalyzed nucleophilic addition reactions that involve carbon-metal bond formation.