Electrophilic Reactions Research Articles

C-H Insertion from Isolable Copper Benzylidenes.

Despite the utility of copper catalysts for the insertion of carbene moieties into C-H bonds, the copper carbene intermediate often invoked in these transformations has not been isolated. Herein, we describe the synthesis and structural characterization of a series of copper benzylidenes utilizing the sterically encumbered dipyrrin ligand (EmL)H. These isolated copper carbenes demonstrate intramolecular insertion into the primary C(sp3)-H bond of the ligand (EmL)H and intermolecular insertion into ethereal and allylic C-H bonds. The copper carbenes isolated are best described as Cu(I) carbene adducts akin to canonical Fischer carbenes, given their diamagnetic ground state and electrophilic carbene reactivity. Furthermore, the insertion chemistry can be rendered catalytic utilizing a more sterically exposed dipyrrin ligand (ArFL)H. The ability to isolate and observe stoichiometric C-H insertion and olefin cyclopropanation from well-characterized copper benzylidenes illuminates their viability as catalytic intermediates and their participation in potential catalyst deactivation pathways.

Cd(II)-based fish-bone-like 1D coordination polymer: structural elucidation and computational study

{[Cd(L)2(PBT)2]}n (1) [H2L = 5-nitro-isophthalic acid; PBT = 2-pyridin-4-ylbenzothiazole], 1D Coordination Polymer (1D-CP), is characterized by single crystal X-ray diffraction. The structure of 1 contains carboxylate bridges of L2- to Cd(II), where one carboxylate chelates to Cd(II) and the other -COO bridges to two neighboring Cd(II) centers that then form eight-membered dinuclear metallacycles (Cd2C2O4). The 1D chains self-assemble via H-bonding and π⋅⋅⋅π interactions to form a supramolecular aggregate that resembles a fish-bone pattern. These interactions are further explored by Hirshfeld Surface Analysis. Density Functional Theory (DFT) computations using the crystallographic parameters of 1 predicted an energy gap, ΔE (EHOMO – ELUMO) of 3.67 eV, which is comparable to the experimental band gap obtained from a Tauc’s plot, 3.73 eV. The band gap value demonstrates the semiconducting character and may be used for device fabrication. Furthermore, molecular electrostatic potential (MEP) shows strong electrophilic reaction potential and predicts reactive sites. The PBT ligand is emissive (370 nm) while H2L is non-emissive. DMF suspensions of 1 emit at 525 nm with a long lifetime, 0.715 ns compared to the lifetime of PBT (0.05 ns). This supports that extended conjugation occurs upon formation of the 1D-CP, altering the photophysics.

Photoinduced Vitamin-B12-Catalyzed meta-C-H Bromination/Chlorination of Phenol Derivatives Assisted by a U-Shaped Nitrile Template.

A photoinduced vitamin-B12-catalyzed meta-C-H bromination/chlorination of phenol derivatives was established using a nitrile directing template and N-bromosuccinimide (NBS)/N-chlorosuccinimide (NCS) as halogenated reagents, and a series of meta-bromination/chlorination products were obtained in yields of 51 to 80%. This strategy overcame the selectivity problem of phenols, which have difficulty obtaining meta-products through conventional electrophilic reactions. Furthermore, natural product resveratrol and an intermediate of the γ-secretase inhibitor were successfully synthesized, which demonstrates the practicability of this method.

Adsorption sites and interactions of pigments in molasses-based distillery effluent on starch-based composites: Ternary competitive adsorption and theoretical calculations

The pigment present in molasses-based distillery effluent constitutes a primary factor influencing its degradation. Adsorption is an effective approach to eliminate pigment from wastewater. In this study, a cationic cassava starch (CCS) magnetic composite (CCS@Fe3O4) was prepared and used as adsorbents for the removal of undesirable pigments. The adsorption behaviors of caffeic acid (CA), gallic acid (GA), and melanoidin (ME) on CCS@Fe3O4 in the wastewater were investigated using single and ternary competitive adsorption systems. The equilibrium adsorption capacities of CA, GA, and ME on CCS@Fe3O4 were 197.04, 195.55, and 623.97 mg/g at the optimized conditions (0.3 mg/mL CCS@Fe3O4 dosage, temperature of 38 °C, and pH of 7). The adsorption kinetic model showed that chemisorption accounted for most of the adsorption of CA, GA, and ME on CCS@Fe3O4. The adsorption mechanisms of pigments on CCS@Fe3O4 were explored at the molecular level through quantum chemical calculations. The electrostatic potentials (ESP), average local ionisation energy (ALIE), and Fukui indices calculation indicated that the quaternary ammonium group in CCS@Fe3O4 was more susceptible to electrophilic reactions. The CC and benzene rings in CA and GA, and the COO- in ME, represent sites of attack for quaternary ammonium during adsorption. Furthermore, the competitive adsorption results, adsorption energy, and electron transfer data demonstrated that the adsorption capacity of CCS@Fe3O4 for pigments followed the order ME>GA>CA. Overall, the competitive adsorption mechanisms of CA, GA, and ME on CCS@Fe3O4 were unveiled, with quantum chemical calculations offering crucial insights into the adsorption process.

In Vitro Characterization of Kitasetaline Biosynthesis Reveals a Bifunctional P450 Decarboxylase and a Vinyl β-Carboline Intermediate Susceptible to Nonenzymatic Thiol Addition.

Kitasetaline is one of the very few β-carbolines isolated from bacteria. It features a unique N-acetylcysteine moiety linked to the β-carboline core through a thioether bond. While earlier in vivo experiments identified the gene cluster and reported several putative biosynthetic intermediates, how the C-S bond linkage is constructed has remained elusive. Herein, in vitro reconstitution of kitasetaline biosynthesis reveals the involvement of a Pictet-Spenglerase (KslB) and a promiscuous dehydrogenase (KslA) that generate the characteristic β-carboline ring system. In addition, the P450 enzyme KslC was found to catalyze oxidative decarboxylation of 1-(2-carboxyethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid to yield the biosynthetic intermediate 1-vinyl-9H-pyrido[3,4-b]indole-3-carboxylic acid. KslC is also capable of catalyzing further oxidation of its product to yield an N-hydroxylated side product. Importantly, the vinyl intermediate was found to undergo nonenzymatic nucleophilic addition by N-acetyl-l-cysteine to generate the C-S bond leading directly to kitasetaline without the involvement of a mycothiolated intermediate proposed in a previous biosynthetic model. Thus, this work not only demonstrates that biosynthesis of β-carboline compounds is rich in unexpected chemistry but also adds to the growing realization that biological thiolation reactions are often nonenzymatic in nature, relying instead on enzymatic formation of reactive electrophiles.

Unlocking the C-centered ring-opening of phosphiranium ions for a straightforward entry to functionalized phosphines

Phosphorus chemistry occupies a pivotal position in contemporary organic chemistry but significant synthetic challenges still endure. In this report, a class of electrophilic phosphiranium salts, bearing fluorinated benzyl quaternizing groups, is introduced for the direct synthesis of diversely β-functionalized phosphines. We show that, in comparison with regular quaternary phosphiranium salts, these species display the sought balance of excellent stability and high electrophilic reactivity that allow the unlocking of the C-centered ring-opening reactions with different classes of weak nitrogen-, sulfur- and oxygen protic nucleophiles.

Oxidative halogenation enabled by 2-haloethanol and aqueous H2O2 under metal-free conditions

Electrophilic halogenation reactions have been recognized as robust approaches to accessing synthetically useful organohalides. Herein, we disclose an exclusive oxidative halogenation pathway, which highlights the use of 2-haloethanol (X ​= ​Cl, Br, I) as the halogenating reagent and aqueous H2O2 as the green oxidant. This method is applicable to various halogenative transformations including halogenation of olefins, alkynes and arenes, which were rarely realized by the previous oxidative halogenation systems. The obtained halogenated products can serve as versatile linchpins for further synthetic applications as demonstrated by the total synthesis of Bulgarein.

β-Selective 2-Deoxy- and 2,6-Dideoxyglucosylations Catalyzed by Bis-Thioureas.

We present methods for β-selective 2-deoxy- and 2,6-dideoxyglucosylations of natural products, carbohydrates, and amino acids using bis-thiourea hydrogen-bond-donor catalysts. Disarming ester protecting groups were necessary to counter the high reactivity of 2-deoxyglycosyl electrophiles toward non-stereospecific SN1 pathways. Alcohol and phenol nucleophiles with both base- and acid-sensitive functionalities were compatible with the catalytic protocol, enabling access to a wide array of 2-deoxy-β-O-glucosides.

An Efficient Multi‐Component Double Friedel‐Crafts Alkylation of Isatin: Access to Unsymmetrical and Symmetrical 3, 3‐Diaryl oxindoles

AbstractAcetic acid‐mediated three‐component double Friedel–Crafts alkylation reaction for the synthesis of α, α‐diaryl oxindole derivatives is demonstrated. The reaction is successful with various isatin, indole, and N, N‐disubstituted aniline derivatives. The efficiency of the reaction is further enhanced by a four‐component reaction of isatin, electrophiles and acetic anhydride for the synthesis of N‐acylated 3,3‐diaryl oxindole derivatives facilitated by dual activation of C3 and N1 acetylation in a single‐step. Various unsymmetrical and symmetrical 3,3‐diaryl oxindoles were prepared in single‐step MCR reaction under easy to operate reaction conditions.

Quantum Chemical Calculation on ScCl3-NaCl-KCl Molten Salt System

Background: The study of the ionic structure of the ScCl3-NaCl-KCl molten salt system is of guiding significance for the production of metal Sc and Sc alloy by molten salt electrolysis using ScCl3-NaCl-KCl molten salt system as electrolyte. However, limited research has been conducted on the structural analysis of molten salt within this system using Raman spectroscopy. Methods: The Gaussian and GaussView programs are used to simulate Sc-Cl ionic groups that may exist in the ScCl3-NaCl-KCl molten salt system based on density functional theory (DFT) and calculate their theoretical Raman spectra. Then, the wave function analysis of these Sc-Cl ionic groups is carried out using the Multiwfn program. Results: When the ScCl3-NaCl-KCl system is used as the electrolyte, it is considered that the 8 Sc atom in ScCl74− ionic groups is most easily reduced by electrochemistry at the cathode when the concentrations of eight Sc-Cl ionic groups are the same. In Sc2Cl7− Sc2Cl82− and Sc2Cl93− ionic groups, the sites that are most likely to attract electrophiles to attack and react are 1Cl and 7Cl, respectively, and the two Sc atoms located in the "chlorine bridge" structure contribute the most to LUMO orbitals, and nucleophiles will preferentially attack the Sc atoms located in the "chlorine bridge" structure. For Sc2Cl7−、Sc2Cl82− and Sc2Cl93− ionic groups, which have two Sc atoms, the bonds formed between Sc and Cl in the "chlorine bridge" structure have the smallest bond order, so the bonds formed by Sc and Cl in the "chlorine bridge" structure break first during the reaction, and then the bond formed by Sc and Cl located at both ends of the whole structure breaks Conclusion: The key information, such as bond length, point group structure, and theoretical Raman spectral characteristic peak after optimization, are obtained by the Gaussian and GaussView programs. The net atomic charge in each ionic group, the direction of electron migration during the formation of the ionic groups, the sites where electrophilic and nucleophilic reactions are most likely to occur in each ionic group, and the order of bond breaking during chemical reactions are obtained by the Multiwfn program.

In-depth quantitative and theoretical study of ambident electrophilies of 2-bromo-3-X-5-nitrothiophenes

As part of our continuing studies into the electron deficient nature of five-membered ring heterocycles, specifically 2‑methoxy-3-X-5-nitrothiophenes and 3-X-5-nitrothiophene, we report here a kinetic study of σ-complexation reactions involving 2‑bromo-3,5-dinitrothiophene 1 and various nitroalkyl anions in aqueous solution at 20 °C. Theoretical calculations at the density functional theory (DFT) level were performed to confirm the proposed mechanism. From the previously reported nucleophilicity parameters N and sN for the nucleophiles 2 and the derived second-order rate constants, the electrophilicity parameter (E) at the C-4 position of thiophene 1 was quantified according to the linear free enthalpy relationship log k (20 °C) = sN (E + N). Mayr's approach accurately predicted the rate constants for the reactions of this thiophene 1 with a series of para-substituted phenoxide anions in water at 20 °C. A reasonable correlation between calculated global electrophilicity index ω values and experimental electrophilic reactivities was observed and discussed.

Unraveling Strong Supramolecular Assembly of a Novel Pyrene Based Hg(II)‐complex: Insights from Hirshfeld Surface, FMO and Molecular Electrostatic Potential (MEP) Analyses

AbstractA rare pyrene‐based coordination compound of Hg(II) [Hg(L)2] (1) (where, HL=2‐((Pyren‐1‐ylmethylene)amino)benzenethiol) was synthesized and characterized by single crystal X‐ray diffraction (SC‐XRD) analysis. Crystallographic analysis revealed that complex 1 has seesaw geometry with HL coordinated as a bidentate ligand to a metal ion. The role of weak forces like π⋅⋅⋅π and CH⋅⋅⋅π interactions in influencing the self‐assembly process appears to be of importance. The electronic structure of the complex was predicted using DFT calculations with mixed basis set. DFT calculated structural parameters are in good agreement with the experimentally obtained parameters from XRD. Molecular reactivity and stability of the complex has been assessed through frontier molecular orbital analysis. Evaluation of molecular electrostatic potential (MEP) displays the electrophilic and nucleophilic reactivity sites. The Hirshfeld surface analysis clearly indicates C−H⋅⋅⋅π interactions and π⋅⋅⋅π stacking interactions are responsible to extend the supramolecular network of the complex. Analyses of the Finger print plots suggest that H⋅⋅⋅H and H⋅⋅⋅C contacts are major interactions for stabilizing the molecular crystal.

Updating Reaction Mechanistic Domains for Skin Sensitization: 1. Nucleophilic Skin Sensitizers.

It has long been recognized that skin sensitizers either are electrophilic or can be activated to electrophilic species. Several nonanimal assays for skin sensitization are based on this premise. In the course of a project to update dermal sensitization thresholds (DST), we found a substantial number of sensitizers, with no electrophilic or pro-electrophilic alerts, that could be simply explained in terms of the sensitizer acting as a nucleophile. In some cases, the nucleophilic center is a sulfur or phosphorus atom, while in others, it is an aromatic carbon atom. For carbon-centered nucleophiles, a quantitative mechanistic model based on a combination of Hammett σ+ and logP values has been derived. This has been applied to rationalize several groups of known sensitizers with no electrophilic or pro-electrophilic alerts, including anacardic acids and cardols, which are known human sensitizers associated with, inter alia, cashew nut oil, mango, and Ginkgo biloba. The possibility of nucleophilic sensitization needs to be considered when evaluating new chemicals for skin sensitization potential and potency by nonanimal assays, particularly those based on the premise that skin sensitization is dependent upon reactions of electrophiles with skin protein-based nucleophiles.

Evaluating the Utility of the MSTI Assay in Predicting Compound Promiscuity and Cytotoxicity.

Nonspecific reactive chemicals often interfere with the interpretation of high-throughput assay results because of their promiscuity and/or cytotoxicity. Using a high-throughput assay to identify such compounds is necessary to efficiently rule out potential assay artifacts. The MSTI, (E)-2-(4-mercaptostyryl)-1,3,3-trimethyl-3H-indol-1-ium, assay uses a thiol-containing fluorescent probe to screen for electrophile reactivity and could potentially be used to determine nonspecific reactive compounds. The Tox21 10K compound library was previously screened against a panel of ∼80 cell-based and biochemical assays, including the biochemical MSTI assay. In this study, we compared the MSTI assay activity of the Tox21 10K compounds with their promiscuity and cytotoxicity as reflected by their activities across the Tox21 assay panel to determine: (1) if this assay is predictive of a compound's promiscuity and cytotoxicity and (2) what chemical features create inconsistent results between the MSTI assay activity and promiscuity/cytotoxicity (false negatives and false positives). We found that the MSTI assay can predict a chemical's promiscuity/cytotoxicity with a 0.55 sensitivity and 0.97 specificity. Out of 3,407 unique compounds evaluated, we identified 92 false positive and 227 false negative results. Several structural features such as carboxamides and alkyl halides were found to be apparent in 53% (p = 2.4 × 10-07) and 19% (p = 4.3 × 10-06) of the false positives and negatives, respectively. The results of this analysis will help identify the potential challenges of this high-throughput assay and allow researchers to identify if a compound will be cytotoxic or promiscuous in an efficient manner.

Copper-Catalyzed Asymmetric Hydrogenation of Unsymmetrical ortho-Br Substituted Benzophenones.

The asymmetric hydrogenation of benzophenones, catalyzed by low-activity earth-abundant metal copper, has hitherto remained a challenge due to the substrates equipped with two indistinguishably similar aryl groups. In this study, we demonstrated that the prochiral carbon of the ortho-bromine substrate exhibits the highest electrophilicity and high reactivity among the ortho-halogen substituted benzophenones, as determined by the Fukui function (f+) analysis and hydrogenation reaction. Considering that the enantiodirecting functional bromine group can be easily derivatized and removed in the products, we successfully achieved a green copper-catalyzed asymmetric hydrogenation of ortho-bromine substituted benzophenones. This method yielded a series of chiral benzhydrols with excellent results. The utility of this protocol has been validated through a gram-scale reaction and subsequent product transformations. Hirshfeld partition (IGMH) and energy decomposition analysis (EDA) indicate that the CH···HC multiple attractive dispersion interactions (MADI) effect between the catalyst and substrate enhances the catalyst's activity.

Synthesis, DFT Calculations, and Biological Studies of New 2-Cyano-3-(Naphthalene-1-yl) Acryloyl Amide Analogues as Anticancer Agents.

A set of novel naphthalene derivatives was synthesized via investment of the electrophilic reaction center of the easily obtainable starting substance, 2-cyano-3-(naphthalen-1-yl)acryloyl chloride (1), with various nitrogen nucleophiles and assessed as potential antitumor agents. The chemical structures of these derivatives were completely specified using several spectral and elemental analyses. The antiproliferative efficacy of the discovered compounds against the human cancer cell lines HepG2 and MCF-7 was investigated. Compounds 12b and 9 have more potent anticancer activity versus MCF-7 breast cancer. DFT calculations for the synthesized compounds were studied to determine molecular geometry, frontier orbital analysis, and molecular electrostatic potential. Compound 2 has the lowest energy gap, the highest softness, and the lowest hardness molecule. Also, the electrophilicity values of the studied molecules provide evidence for their biological effectiveness, as compound 9 had significant antiproliferative activity and a high value of electrophilicity (ω) (0.190 eV).

Synthesis of Dihalonaphthalenes via Silver-Catalyzed Halogenation and Electrophilic Cyclization of Terminal Alkynols.

Herein, we report a silver-catalyzed halogenation and electrophilic cyclization reaction based on the trifunctionalization of terminal alkynols with NBS or iodine monochloride in a step-efficient synthetic way to produce homo/heterodihalogenated naphthalene derivatives bearing two different halogen atoms in moderate to good yields. This methodology readily accommodates various functional groups, including electron-withdrawing nitro, cyano, acid-sensitive dioxazolyl, and alkoxy groups.

Catalytic Asymmetric Mannich-Type Reaction of α-Haloacetonitriles.

An asymmetric Mannich-type addition of aldimines and haloacetonitriles is reported here, yielding halogenated aminonitriles with excellent stereoselectivity, facilitated by a pincer Ni(II) complex as a catalyst. Haloacetonitriles are recognized as reactive electrophiles, and the possibility of their use as a pronucleophile has been almost neglected for many years. The resulting adduct can be readily converted into various valuable derivatives, including chiral aziridines, starting from chlorinated compounds.

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.

One-Step Synthesis of [18F]Aromatic Electrophile Prosthetic Groups via Organic Photoredox Catalysis.

To avoid the harsh conditions that are oftentimes adopted in direct radiofluorination reactions, conjugation of bioactive ligands with 18F-labeled prosthetic groups has become an important strategy to construct novel PET agents under mild conditions when the ligands are structurally sensitive. Prosthetic groups with [18F]fluoroarene motifs are especially appealing because of their stability in physiological environments. However, their preparation can be intricate, often requiring multistep radiosynthesis with functional group conversions to prevent the decomposition of unprotected reactive prosthetic groups during the harsh radiofluorination. Here, we report a general and simple method to generate a variety of highly reactive 18F-labeled electrophiles via one-step organophotoredox-mediated radiofluorination. The method benefits from high step-economy, reaction efficiency, functional group tolerance, and easily accessible precursors. The obtained prosthetic groups have been successfully applied in PET agent construction and subsequent imaging studies, thereby demonstrating the feasibility of this synthetic method in promoting imaging and biomedical research.