Nucleophilic Reaction Research Articles

Synthesis and diverse crystal packing in o-, m- and p-bis(carbonylthioureido)benzenes containing bisferrocenes.

Three bisferrocene-based bis(acylthiourea) positional isomers, namely, 1,2-bis(ferrocenylcarbonylthioureido)benzene (1), 1,3-bis(ferrocenylcarbonylthioureido)benzene (2) and 1,4-bis(ferrocenylcarbonylthioureido)benzene (3), all [Fe2(C5H5)2(C20H16N4O2S2)], have been synthesized via facile nucleophilic addition reactions of 2.3 equivalents of ferrocenoyl isothiocyanate with o-, m- and p-phenylenediamine, respectively. The structures of the three new synthesized isomers were fully characterized by 1H NMR, 13C NMR, IR and UV-Vis spectroscopy, elemental analyses and cyclic voltammetry. In addition, the structures of acetone monosolvated compound 1 (1·CH3COCH3), as well as compounds 2 and 3, have been determined by single-crystal X-ray diffraction. A combination of intermolecular N-H...S and C-H...S hydrogen bonds connects the components of compound 1·CH3COCH3 into infinite helix chains. Two pairs of different N-H...S and C-H...S intermolecular hydrogen bonds, as well as N-H...O and C-H...π co-operating interactions, link the molecules of compound 2 into a two-dimensional network. In contrast, compound 3 displays a one-dimensional double-chain array via two intermolecular C-H...S hydrogen bonds. Therefore, the three reported positional isomers present unique individual crystal assemblies.

Pyridinamide Ion Pairs: Design Principles for Super-Nucleophiles in Apolar Organic Solvents.

A comprehensive analytical protocol combining conductivity, diffusion-ordered NMR (DOSY), and photometric kinetic measurements is employed to analyze the nucleophilic reactivity of pyridinamide ion pairs in low-polarity organic solvents. The association patterns of these systems are found to strongly depend on cation size, with larger cations favoring the formation of cationic triple ion sandwich complexes together with free and highly nucleophilic anions. Kinetic studies using the ionic strength-controlled benzhydrylium method demonstrate that pyridinamide ions exhibit significantly higher nucleophilicities as compared to established organocatalysts, particularly in low-polarity solvents. Nucleophilicities are furthermore found to correlate well with Brønsted basicities measured in water and with Lewis basicities calculated in dichloromethane. Taken together, these findings provide quantitative guidelines for the future design of highly active Lewis base catalysts.

Phthalonitrile resins based on biomass vanillin with high storage modulus and good processing window

Bio-based phthalonitrile resins were synthesized using a two-step process. Initially, vanillin underwent a nucleophilic reaction with nitro and potassium carbonate to form intermediates, which were then dissolved in N, N-dimethylformamide. The intermediate was divided into two portions, with 4,4’-oxydianiline and 4,4’-methylenedianiline added to each portion, respectively, to produce two different vanillin-based phthalonitrile monomers: OVA monomer and DVA monomer. The successful synthesis of these two bio-based phthalonitrile monomers was confirmed using Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Differential scanning calorimetry was employed to study the processability of the monomers, revealing that OVA monomer and DVA monomer had a wide processing window of 110°C and 69°C, respectively, which were advantageous for resin processing. Dynamic mechanical analysis showed that the storage modulus of the OVA and DVA resins reached 4818 MPa and 3526 MPa, respectively, with a 24-h water absorption rate of only 1.03% and 0.90%. This study presents a viable method for synthesizing bio-based phthalonitrile resins, which can be widely utilized as functional and structural materials in daily life due to their renewability, degradability, and minimal environmental impact.

Highly Nucleophilic Pyridinamide Anions in Apolar Organic Solvents due to Asymmetric Ion Pair Association.

Free ions in organic solvents of low polarity would be valuable tools for the activation of low-reactivity substrates. However, the formation of unreactive ion pairs at concentrations relevant for synthesis has prevented the success of this concept so far. On the example of highly nucleophilic pyridinamide phosphonium salts in dichloromethane, we show that asymmetric aggregation offers a solution to this general problem. A combination of conductivity, diffusion-ordered NMR (DOSY), and kinetic measurements utilizing a refined ionic strength-controlled benzhydrylium ion methodology enables unique insight into the aggregation/association state of the ions and the nucleophilicity of the involved anions. This approach reveals that pyridinamide tetraphenylphosphonium salts aggregate in dichloromethane solution asymmetrically to form sandwich-type cations and anions together with their free counterions. The nucleophilicity of free pyridinamide ions exceeds that of the neutral reference nucleophile 9-azajulolidine (TCAP) by up to 2 orders of magnitude. Based on these results, we suggest that asymmetric aggregation in organic solvents of low polarity might be a general pathway to boost the reactivity of anionic nucleophiles.

Rapid Synthesis of Primary Amides Using Ammonia Borane.

We report the rapid synthesis of primary amides by directly using commercially available ammonia borane (NH3·BH3), sodium hexamethyldisilazide (NaHMDS), and esters. The success of this protocol relies on NH3·BH3 as the nitrogen source being considerably more convenient and NaHMDS being an excellent proton abstractor but not participating in the nucleophilic addition reaction. The reaction had a wide substrate scope containing bioactive molecules, and most of the substrates were efficiently amidated over 90% yields.

Catalytic Serine Labeling in Nonaqueous, Acidic Media.

Chemoselective modification of alkylalcohols (e.g., serine residues) on proteins has been a daunting challenge especially in aqueous media. Herein, we report chemical modifications of alkylalcohols in protein and cell lysate samples using carboxylic acid-based bioconjugation media. The acidic medium is not only useful to suppress reactivity of other nucleophiles in proteins, but the medium also serves as a potentially biomolecule-compatible solvent. The acid-catalyzed acylation strategy has a unique selectivity paradigm compared to the common active-serine-targeted method and would act as a new strategy for studying biological roles of serine residues.

Nucleophilic cleavage of C–F bonds by Brønsted base for rapid synthesis of fluorophosphate materials

Abstract Fluorochemicals are a rapidly expanding class of materials used in a variety of fields including pharmaceuticals, metallurgy, agrochemicals, refrigerants, and in particular, alkali metal ion batteries. However, achieving one-step synthesis of pure fluorophosphate compounds in a well-controlled manner remains a formidable challenge due to the volatilization of fluorine during the heat treatment process. One feasible method is to cleave the C–F bond in polytetrafluoroethylene (PTFE) during synthesis to create a fluorine-rich atmosphere and strongly reducing environment. However, the inert nature of the C–F bond in PTFE presents a significant obstacle, as it is the strongest single bond in organic compounds. To address this predicament, we propose a fluorine-compensating strategy that involves cleavage of the C–F bonds by nucleophilic SN2-type reactions of Brønsted base (ammonia) enabling fluorine compensation. The decomposed products (NH2· and C·) also resulting in the formation of micropores (via NH3 escape) and in-situ carbon coating (via C· polymerization). The resultant cathode delivers a superior potassium storage capability including high rate performance and capacity retention. This contribution not only overcomes the obstacles associated with the inert C–F bond in fluororesin, but also represents a significant step forward in the development of fluorine-containing compounds.

A prediction model for electrical strength of gaseous medium based on molecular reactivity descriptors and machine learning method.

Ionization and adsorption in gas discharge are similar to electrophilic and nucleophilic reactions. The molecular descriptors characterizing reactions such as electrostatic potential descriptors are useful in predicting the electrical strength of environmentally friendly gases. In this study, descriptors of 73 molecules are employed for correlation analysis with electrical strength. These molecular descriptors are categorized into two types: area-related descriptors and reactivity-related descriptors. Furthermore, the predictive performance between statistical models and machine learning models is compared. The statistical models include multiple linear regression, and polynomial regression, while machine learning models consist of K-nearest neighbors, random forest, and gradient boosting decision trees. The results indicate that machine learning models are generally better than statistical models in terms of predictive accuracy and stability, with gradient boosting decision trees demonstrating the best performance. Specifically, the coefficient of determination and mean squared error on the testing set after 1000 training iterations are 0.864 and 0.105, respectively. Therefore, the application of molecular reactivity descriptors and machine learning methods can effectively predict the electrical strength of gaseous medium. The Gaussian 16 software is employed to optimize the molecular structure with the M06-2X functional and def2 series basis sets in this study. Then, the Multiwfn is utilized for wavefunction analysis to obtain molecular surface descriptors.

Lewis base phase transfer catalyst promoted solvent‐free nucleophilic reactions in ionic liquids: Quantum chemical analysis for cooperative enhancement in SN2 reaction rates

Lewis base phase transfer catalyst promoted solvent‐free nucleophilic reactions in ionic liquids: Quantum chemical analysis for cooperative enhancement in <scp>S_N2</scp> reaction rates

Nucleophilic and Electrophilic Molybdenum Terminal Oxo Complexes by Coordination-Induced Bond Weakening of Hydroxo O-H Bonds.

The extent of coordination-induced bond weakening in aquo and hydroxo ligands bonded to a molybdenum(III) center complexed by a dianionic, pentadentate ligand system was probed by reacting the known complex (B2Pz4Py)Mo(III)-NTf2, I, with degassed water or dry lithium hydroxide. The aquo adduct was not observed, but two LiNTf2-stabilized hydroxo complexes were fully characterized. Computational and experimental work showed that the O-H bond in these complexes was significantly weakened (to ≈57 kcal mol-1), such that these compounds could be used to form the diamagnetic, d2 neutral terminal molybdenum oxo complex (B2Pz4Py)Mo(IV)O, 2, by hydrogen atom abstraction using the aryl oxyl reagent ArO• (Ar = 2,4,6-tri-tert-butylphenyl). Oxidation of the neutral hydroxo derivative further facilitated the production of 2 by significantly enhancing the acidity of the hydroxyl proton. Speciation in these processes was probed by electrochemical and chemical experiments. The terminal oxo complex 2 was smoothly oxidized by one electron to the cationic [(B2Pz4Py)Mo(V)O]+[A]- derivatives [2]+[A]- (A = NTf2 or Al[OC(CF3)3]4 depending on the oxidizing agent used). Both Mo(IV) and Mo(V)+ oxo complexes were fully characterized with their nucleophilic and electrophilic reaction behavior probed by conducting reactions with the Lewis acid B(C6F5)3 and the Lewis base PPh3. Neutral oxo complex 2 reacts only with the Lewis acid, while the cationic [2]+[A]- reacts only with PPh3, the former by adduct formation and the latter via phosphine oxidation.

Recent Advances in Diversity-Oriented Synthesis of N-containing Organic Molecules Through Carbodiimide-based Reactions.

Carbodiimides (R-N=C=N-R) are well-known intermediates for the preparation of a variety of N-containing compounds, including heterocycles and amide linkages. Be-cause of their high reactivity and easy availability, carbodiimides have been broadly used as building blocks in the synthesis of structurally complex and diverse heterocyclic com-pounds in multi-component reactions (MCRs). Recent advances in diversity-oriented syn-thesis with carbodiimide-based MCRs are discussed in this minireview and are classified into different sections based on the key transformation involved in the reactions, such as heteroannulation and nucleophilic addition reactions which containing metal-catalyzed re-actions, multi-component reactions, and catalyst-free reactions subsections.

Strained Dehydro‐[2,2]‐paracyclophane Enabled Planar Chirality Construction and [2.2]Paracyclophane Functionalization

Planar chirality found tremendous use in many fields, such as chemistry, optics, and materials science. In particular, planar chiral [2.2]paracyclophanes (PCPs) are a type of structurally interesting and practically useful chiral compounds bearing unique electronic and photophysical properties and thus have been widely used in π‐stacking polymers, organic luminescent materials, and as a valuable toolbox for developing chiral ligands or organocatalysts. However, the synthesis of chiral PCP derivatives remains a longstanding challenge. Current synthetic methods primarily rely on chiral preparative liquid chromatography separation or chemical and kinetic resolution reactions. Here, we report an enantioconvergent alkynylation of an in situ‐formed dehydro‐[2,2]‐paracyclophane intermediate by asymmetric copper(I) catalysis. This approach enables the efficient synthesis of valuable planar chiral PCP building blocks and heterocycles with good yields and excellent enantioselectivity. The success of this reaction lies in the development of a practical route to access strained dehydro‐[2,2]‐paracyclophane intermediates, which can also be utilized in various strain‐release nucleophilic or cycloaddition reactions to synthesize diverse functionalized PCPs. DFT calculations of this reaction suggest that the enantioselectivity is determined by the aryne complexation with chiral copper(I) acetylide and the subsequent insertion reaction.

Strained Dehydro-[2,2]-paracyclophane Enabled Planar Chirality Construction and [2.2]Paracyclophane Functionalization.

Planar chirality found tremendous use in many fields, such as chemistry, optics, and materials science. In particular, planar chiral [2.2]paracyclophanes (PCPs) are a type of structurally interesting and practically useful chiral compounds bearing unique electronic and photophysical properties and thus have been widely used in π-stacking polymers, organic luminescent materials, and as a valuable toolbox for developing chiral ligands or organocatalysts. However, the synthesis of chiral PCP derivatives remains a longstanding challenge. Current synthetic methods primarily rely on chiral preparative liquid chromatography separation or chemical and kinetic resolution reactions. Here, we report an enantioconvergent alkynylation of an in situ-formed dehydro-[2,2]-paracyclophane intermediate by asymmetric copper(I) catalysis. This approach enables the efficient synthesis of valuable planar chiral PCP building blocks and heterocycles with good yields and excellent enantioselectivity. The success of this reaction lies in the development of a practical route to access strained dehydro-[2,2]-paracyclophane intermediates, which can also be utilized in various strain-release nucleophilic or cycloaddition reactions to synthesize diverse functionalized PCPs. DFT calculations of this reaction suggest that the enantioselectivity is determined by the aryne complexation with chiral copper(I) acetylide and the subsequent insertion reaction.

V‐/O‐Doping to Endow Ag2S‐based Bimetal Oxysulfide with Sulfur Vacancies and Heterovalent States for Rapid Reduction of Organic and Cr(VI) Pollutants in the Dark

AbstractA novel AgVOS oxysulfide catalyst for rapid catalytic reduction of toxic organic substances and Cr(VI) under dark is synthesized by a facile method. With the V/O co‐doping, the doped Ag2S catalyst has the effectively regulated electron transfer performance, the hydrazine‐driven V5+‐to‐V4+ reduction to disturb charge equilibrium, and the formed sulfur vacancy balanced by oxygen doping to maintain charge equilibrium. The formed sulfur vacancy acts as the active site for electrophilic nucleophilic reaction, while the orbital hybridization of O2p and S3p stabilizes the valence state of S2−. A suitable ratio of n(V4+/V5+) is regulated during the hydrazine‐driven synthesis to facilitate the electron transfer and enhance the V5+‐to‐V4+ reduction reaction. V/O co‐doped AgVOS‐3 prepared by a suitable hydrazine content exhibits super catalytic reduction performance of organic 4‐NP (4‐nitrophenol), MB (methyl blue), MO (methyl orange), and RhB (Rhodamine B, 20 ppm, 100 mL) dyes, which are completely reduced within 8, 8, 10, and 8 min, respectively. In comparison, Cr6+ (50 ppm, 100 mL) is also completely reduced within 6 min by AgVOS‐3, indicating its good catalytic reduction activity for organic and inorganic mixture pollutants. Furthermore, AgVOS‐3 has good stability after cyclic tests to maintain a reduction efficiency of 96.5%. Therefore, the AgVOS catalyst shows a promising application for industrial wastewater treatment.

Nucleophilic Reactions of Phosphorothioate Oligonucleotides.

The nucleophilic reaction between phosphorothioate oligonucleotides and electrophilic reagents has become a cost-effective and efficient approach for oligonucleotide functionalization. This method allows for the precise incorporation of desired chemical structures at specific sites on the phosphorothioate backbone through conjugation with electrophilic groups. The reaction is characterized by its high reactivity and yield, as well as its ability to enhance the hydrophilicity of otherwise hydrophobic compounds. Importantly, this modification preserves the structural and functional integrity of the oligonucleotides, making it a topic of significant interest in nucleic acid research. This article reviews recent advancements in the covalent conjugation of phosphorothioate oligonucleotides with various electrophilic compounds. The article starts with an overview of the mechanisms and general reaction conditions involved in nucleophilic reactions. It then proceeds to examine the distinctive properties and benefits of various electrophilic reagents, offering insights that can inform the rational design of phosphorothioate oligonucleotide functionalization. Finally, the article addresses both the challenges and opportunities in this field, providing perspectives on future theoretical and practical developments to enhance the application of phosphorothioate oligonucleotides in areas like structural analysis, drug develop, drug delivery, fluorescent labeling, and nucleic acid nanotechnology.

Controlled Synthesis of α‐Mono‐ and α,α‐Di‐Halogenated Ketones Through Coupling of Halogenated Diboromethanes with Carboxylic Acid Esters

Halogenated gem‐diboron reagents, as structurally unique gem‐diborylalkanes, are crucial in organic synthesis chemistry. Herein, we report a strategy with controlled synthesis of α‐mono‐ and α,α‐di‐halogenated ketones through nucleophilic addition reaction of halogenated diboromethanes with carboxylic acid esters. The substrate scope is broad and the nucleophilic addition reaction proceeds from a diverse range of carboxylic acid esters with bromo‐ or chloro‐diborylmethanes. Moreover, an intriguing heterocyclic compound has been serendipitously synthesized as well.

Modular Room Temperature Synthesis of Sulfoximidoyl Amidines Enabled by Pd-Catalyzed Cascade Aza-Claisen Rearrangement Strategy.

Reported herein is a concise synthesis of sulfoximidoyl amidines enabled by a Pd-catalyzed cascade aza-Claisen rearrangement and nucleophilic reaction at room temperature. Free NH-sulfoximines and N-allylynamides were employed as the modular building blocks to produce the expected sulfoximine amidine derivatives in highly chemoselective models and in 100% atom efficiency. A broad range of functional groups were well tolerated under these gentle reaction conditions to give the desired products in generally good to excellent yields.

Nucleophilic addition of bulk chemicals with imines using N-functionalized hydroxylamine reagents as precursors

C–C and C–X bond forming reactions are essential tools in organic synthesis, constantly revolutionizing human life. Among the key methods for constructing new chemical bonds are nucleophilic addition reactions involving imines. However, the inherent challenges in synthesizing and storing imines have stimulated interest in designing stable precursors, which generates imines in situ during the reaction. This approach offers a promising alternative to traditional strategies and holds significant potential for future applications. Here we report a direct and general nucleophilic addition of imines with cost-effective feedstocks and easily accessible nucleophiles, specifically utilizing N‑functionalized hydroxylamine reagents as bench-stable precursors. This methodology streamlines the synthesis of various products, such as amino acid derivatives, through a wide range of reaction types, including C–C, C–N, C–O, and C–S bond constructions. Mechanistic studies and DFT calculations provide insights into a plausible reaction mechanism that supports the in-situ imine formation.

A deoxyfluoroalkylation-aromatization strategy to access fluoroalkyl arenes.

Fluoroalkyl arenes (Ar-RF) are valuable substructures present in several FDA-approved drugs, patents, agrochemicals, and materials, and complementary strategies that enable access to a broad spectrum of Ar-RF compounds benefit these applied fields. Herein, we report a deoxyfluoroalkylation-aromatization strategy to convert cyclohexanones into broad-spectrum Ar-RF containing compounds. Generally, the fluoroalkyl sources were activated to participate in a 1,2-addition reaction followed by aromatization in a sequence that contrasts more common preparations of these Ar-RF compounds, such as (i) transition-metal catalyzed cross-coupling reactions of aryl electrophiles and nucleophiles, and (ii) radical fluoroalkylation reactions of C-H bonds of arenes. Considering the range of cyclohexanone-derived substrates that could be prepared and used, this strategy can be creatively employed to deliver a broad spectrum of highly substituted fluoroalkyl arenes.

A mitochondria-targeted iridium(III) complex-based sensor for endogenous GSH detection in living cells.

Glutathione (GSH) plays an important role in maintaining redox homeostasis in biological systems. Development of reliable glutathione sensors is of great significance to better understand the role of biomolecules in living cells and organisms. Based on the advantages of the photophysical properties of iridium complexes, we proposed a "turn-on" phosphorescent sensor. Ir-DNFB has the characteristics of a large Stokes shift, high sensitivity for GSH detection, low cytotoxicity, and extremely short response time, and can specifically analyze glutathione in living cells and highly target endogenous glutathione in mitochondria. The N-H group on the imidazole ring of Ir-DNFB could form a new electrostatic interaction with the α-carboxyl group on the glutamate moiety of glutathione. The nucleophilic attack reaction was regulated by the sulfhydryl group on GSH, following which the ether bond linking the 2,4-dinitrobenzene to probe Ir-DNFB was broken, accompanied with a phosphorescence enhancement. Most importantly, the process of recognizing glutathione was not affected by other amino acids. Overall, this work provided a very useful tool for rapidly distinguishing between normal, inflammatory, and progressive tumor cells.