Nucleophilic Groups Research Articles

Visible-Light-Induced PhI(OAc)2-Mediated Alkylation of Heteroarenes with Simple Alkanes and Ethers.

The direct alkylation of heteroarenes with alkanes has been successfully achieved through visible-light-induced hypervalent iodine-mediated C-H functionalization of both coupling partners at ambient temperatures. This reaction proceeds via the in situ generation of nucleophilic alkyl radicals from alkanes through hydrogen atom transfer (HAT), followed by a Minisci-type reaction with heteroarenes. These mild reaction conditions have demonstrated their suitability for the alkylation of a wide range of heterocycles, including azoles, pyridines, quinolines, isoquinolines, and quinoxalinones.

Engineering porosity of MIL-101(Cr) using solvation effect

Toluene, a kind of volatile organic compounds (VOCs), serves as a vital constituent of PM2.5 and acts as a notable precursor to ozone. To improve the adsorption performance of adsorbents for toluene, MIL-101(Cr)-XmM with high porosity were synthesized using an in-situ growth restriction strategy. This research reveals that the solvation effect influences the rate of crystal nucleation and growth, leading to variations in the ratio of micropores to mesopores and overall porosity in MIL-101(Cr)-XmM. The high porosity of MIL-101(Cr)-1.6 mM facilitates a higher diffusion rate of particles and exposes a greater number of alkaline sites. Consequently, the adsorption performance of MIL-101(Cr)-1.6 mM for toluene demonstrates a remarkable 240% improvement compared to that of MIL-101(Cr)-1.2 mM. Molecular simulations unveils the impact of adsorption temperature, demonstrating the crucial role of van der Waals interactions in the adsorption of toluene, with a noteworthy inhibition of van der Waals interactions observed upon heating. Density functional theory(DFT) simulations show that toluene molecules tend to preferentially adsorb near the benzene ring of the ligand, primarily due to π-π stacking interactions. Simultaneously, the electrophilic channel with greater porosity can gather more nucleophilic groups, thereby enhancing the adsorption performance of toluene.

Synthesis, spectroscopic analysis (FT-IR, FT-Raman, UV, NMR), non-covalent interactions (RDG, IGM) and dynamic simulation on Bis(8‑hydroxy quinoline) salicylate salicylic acid

Using spectrum techniques and density functional theory (DFT) reckonings, structural, vibrational and electrical characteristics of Bis(8‑hydroxy quinoline) salicylate salicylic acid (8HQSA) were determined. Characterizing the chemical under inquiry involved employing FT-IR, FT-Raman, UV–vis spectral studies and single crystal X-ray diffraction (SCXRD). For the characterization, the B3LYP approach inside the structure of DFT was employed, with a 6–311++G(d,p) basis set. The structural study shows that the stability of 8HQSA crystalline structure arising from N–H⋯O, C–O⋯H and O–H⋯O hydrogen bonding interactions. The 1H and 13C NMR chemical shifts were calculated using Gauge Independent Atomic Orbital (GIAO) technical. Vibrational frequencies and molecular geometry were computed and likened with experimental data. Here, non-covalent interactions were deeply analyzed in terms of topological parameters (AIM), electron localization function (ELF), localized orbital locator (LOL), Hirshfeld surface and reduced density gradient (RDG) method. Weak interactions such as H-bonds, van der Waals and steric effect in 8HQSA were visualized and quantified by the independent gradient density (IGM) based on the trimolecular density. The hyper-conjugative and the delocalization of charge in 8HQSA have been elucidated by natural bonding orbital (NBO) while its chemical reactivity was studied and discussed by using molecular electrostatic potential surface (MEP), frontier molecular orbital (FMOs), density of state (DOS) and partial density of state (PDOS). The positions of the molecule's nucleophilic and electrophilic groups were ascertained using Fukui analysis. To describe the size, structure, and reactive sites of the molecules, the molecular electrostatic potential and total electron density are calculated. With a band gap (2.58 eV), FMO study indicates that the material is both bioactive and stable. The ADMET factor and drug similarity are used to predict 8HQSA's pharmokinetic characteristics. Based on the findings, it can be concluded that the 8HQSA particle is optimally crystallised and recommended as a preventative measure against bacterial and fungal infections. The stability of the title compound has been investigated via molecular dynamics simulations. In-vitro antimicrobial activity results clearly reveal that in all the four strains, activity increases with increase in compound concentration and the inhibition of the strains also increases. From both molecular docking and In-vitro Antimicrobial Activity the title compound can be certified that it inhibits antimicrobial activity.

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes.

The construction of C(sp3)-C(sp3) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, we report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp3)-C(sp3) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (SH2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp3-hybridized carbon scaffolds.

Sustained zero-order release of dexamethasone after incorporation into crosslinked PEG-dendrons using click reactions

Hydrogel-based localised drug delivery minimises systemic side effects and a linear release profile ensuring a sustained drug release over time, crucial for long-term therapy. The current paper describes the use of the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAc) to append azidified Dexamethasone (Dex) onto dendrons of first- and second-generation PEGs. Crosslinking with thiolated PEGs using either thiol-acrylate or nucleophilic addition reactions yielded gels containing β-thio-ether ester groups that imparted enhanced hydrolytic susceptibility. In vitro gel degradation was followed gravimetrically and expressed as swelling ratios. Thiol-acrylate crosslinked hydrogels exhibited zero-order Dex release kinetics over 11, 27, and 16 days (G1, G1-star, and G2). Crosslinking the G1-gels by nucleophilic addition also resulted in linear release and the end point was reached in 5 days. Hydrolysis was accounted as the main release mechanism for covalently bound Dex, while physically incorporated Dex showed undefined rapid burst or first-order release, with most of the drug released in the initial 1–3 days. Eluates from covalently bound Dex maintained high activity, whereas Trap-Dex gels lost activity over time, as detected by the upregulation of luciferase expression from a transformed cell line. This novel chemistry combination offers precise drug release control applicable beyond Dex to drugs with suitable nucleophilic groups.

Metals/bisulfite system involved generation of 24-sulfonic-25-ene ginsenoside Rg1, a potential quality control marker for sulfur-fumigated ginseng

Ginseng is a most popular health-promoting food with ginsenosides as its main bioactive ingredients. Illegal sulfur-fumigation causes ginsenosides convert to toxic sulfur-containing derivatives, and reduced the efficacy/safety of ginseng. 24-sulfo-25-ene ginsenoside Rg1 (25-ene SRg1), one of the sulfur-containing derivatives, is a potential quality control marker of fumigated ginseng, but with low accessibility owing to its unknown generation mechanism. In this study, metals/bisulfite system involved generation mechanism was investigated and verified. The generation of 25-ene SRg1 in sulfur-fumigated ginseng is that SO2, formed during sulfur-fumigation, reacted with water and ionized into HSO3−. On the one hand, under the metals/bisulfite system, HSO3− generates HSO5− and free radicals which converted ginsenoside Rg1 to 24,25-epoxide Rg1; on the other hand, as a nucleophilic group, HSO3− reacted with 24,25-epoxide Rg1 and further dehydrated to 25-ene SRg1. This study provided a technical support for the promotion of 25-ene SRg1 as the characteristic quality control marker of sulfur-fumigated ginseng.

Electrochemical Site‐Selective Alkylation of Tropones via Formal C(sp3)−C(sp2) Coupling Reaction

AbstractThe first site‐selective electrochemical alkylation of tropones is realized by reacting 2‐acetoxytropones and redox‐active‐esters (RAEs). The electroreductive protocol enables the preparation of mono‐ and disubstituted tropones in high yields (up to 71%) under very mild conditions. Dedicated voltammetric measurements served for the identification of 2‐acetoxytropones as a class of valuable trapping agents of nucleophilic radical species and shed light on the whole mechanistic profile. Wide tolerance towards functional groups (27 examples) and application to late‐stage functionalization of a bioactive compound (i. e. Colchicine analogue), emphasize the synthetic impact of the present methodology.

Site-Selective Polyfluoroaryl Modification and Unsymmetric Stapling of Unprotected Peptides.

Peptide stapling is recognized as an effective strategy for improving the proteolytic stability and cell permeability of peptides. In this study, we present a novel approach for the site-selective unsymmetric perfluoroaryl stapling of Ser and Cys residues in unprotected peptides. The stapling reaction proceeds smoothly under very mild conditions, exhibiting a remarkably rapid reaction rate. It can furnish stapled products in both liquid and solid phases, and the presence of nucleophilic groups other than Cys thiol within the peptide does not impede the reaction, resulting in uniformly high yields. Importantly, the chemoselective activation of Ser β-C(sp3)-H enables the unreacted -OH to serve as a reactive handle for subsequent divergent modification of the staple moiety with various therapeutic functionalities, including a clickable azido group, a polar moiety, a lipid tag, and a fluorescent dye. In our study, we have also developed a visible-light-induced chemoselective C(sp3)-H polyfluoroarylation of the Ser β-position. This reaction avoids interference with the competitive reaction of Ser -OH, enabling the precise late-stage polyfluoroarylative modification of Ser residues in various unprotected peptides containing other highly reactive amino acid residues. The biological assay suggested that our peptide stapling strategy would potentially enhance the proteolytic stability and cellular permeability of peptides.

Alkene dialkylation by triple radical sorting.

The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism1-8. Biomimetic9,10 SH2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp3)-C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)-C(sp3) bonds, greatly accelerating access to complex molecules and drug-like chemical space11. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways12,13. Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a distinct mechanistic approach for alkene dialkylation.

Site‐Selective Pyridination of Benzylic and Allylic C−H bonds via Radical‐Radical Cross‐Coupling

AbstractHerein, we report a modular photocatalytic platform for the site‐selective pyridination of saturated hydrocarbon compounds employing organic photoredox catalysis to forge new carbon‐carbon bonds. The site‐selective C−H pyridination could couple benzylic/allylic C−H bonds with pyridylphosphonium salts, which installed directly and regioselectively from C−H heteroarenes through a radical‐radical cross coupling mechanism. This synthetic methodology could tolerate a variety of functional groups, complex heteroarenes, even late‐stage functionalization of pharmaceuticals selectively.

Trivalent Nickel-Catalyzing Electroconversion of Alcohols to Carboxylic Acids.

The comprehension of activity and selectivity origins of the electrooxidation of organics is a crucial knot for the development of a highly efficient energy conversion system that can produce value-added chemicals on both the anode and cathode. Here, we find that the potential-retaining trivalent nickel in NiOOH (Fermi level, -7.4 eV) is capable of selectively oxidizing various primary alcohols to carboxylic acids through a nucleophilic attack and nonredox electron transfer process. This nonredox trivalent nickel is highly efficient in oxidizing primary alcohols (methanol, ethanol, propanol, butanol, and benzyl alcohol) that are equipped with the appropriate highest occupied molecular orbital (HOMO) levels (-7.1 to -6.5 eV vs vacuum level) and the negative dual local softness values (Δsk, -0.50 to -0.19) of nucleophilic atoms in nucleophilic hydroxyl functional groups. However, the carboxylic acid products exhibit a deeper HOMO level (<-7.4 eV) or a positive Δsk, suggesting that they are highly stable and weakly nucleophilic on NiOOH. The combination (HOMO, Δsk) is useful in explaining the activity and selectivity origins of electrochemically oxidizing alcohols to carboxylic acid. Our findings are valuable in creating efficient energy conversions to generate value-added chemicals on dual electrodes.

Multifunctional Aluminum Pre-treatments from End-Functionalized Phosphonic Acid Self-Assembled Monolayers.

Aluminum alloys are used in advanced engineering applications as they possess a combination of favorable properties, including high strength, lightweightness, good corrosion resistance, machineability, and recyclability. Such applications often require forming the sheets into the final components, which is typically aided by an oil-based lubricant, followed by joining them using adhesives, which is hampered by residual lubricant. In this work, aluminum surfaces were modified with different self-assembled monolayers (SAMs), with the goal of significantly reducing the amount of lubricant while simultaneously improving friction properties, forming, and bonding performance. Our results show that SAMs terminated with hydrophilic and nucleophilic end groups give rise to high-energy surfaces with wetting properties that are stable over time. These surfaces showed significantly improved surface wetting by the lubricant, which in turn resulted in an improved forming performance at reduced lubricant coat weights. Moreover, the nucleophilic SAM termination provided outstanding performance in adhesive bonding tests under corrosive conditions.

A Dual Cobalt and Photoredox Catalysis for Hydrohalogenation of Alkenes.

We demonstrate hydrohalogenation of aliphatic alkenes with collidine·HX salts through dual photoredox/cobalt catalysis. The dual catalysis enables conversion of a proton and a halide anion from collidine·HX salt to a nucleophilic hydrogen radical equivalent and an electrophilic halogen radical equivalent and delivery of them to an alkene moiety. This protocol allows for introduction of fluorine, chlorine, bromine, or iodine atom to alkene, producing highly functionalized alkyl halides.

Does the radical GPRI strongly depend on the population scheme? A comparative study to predict radical attack on unsaturated molecules with the radical general-purpose reactivity indicator.

The reactivity of 22 unsaturated molecules undergoing attack by a methyl radical (⋅CH3) have been elucidated using the condensed radical general-purpose reactivity indicator (condensed radical GPRI) appropriate for relatively nucleophilic or electrophilic molecules. Using the appropriate radical GPRI equation for electrophilic attack or nucleophilic radical attack, seven different population schemes were used to assign the most reactive atoms in each of the 22 molecules. The results show that the condensed radical GPRI is sensitive to the population scheme chosen, but less sensitive than the radical Fukui function. Therefore, the reliability of these methods depends on the population scheme. Our investigation indicates that the condensed radical GPRI is most accurate in predicting the dominant products of the methyl radical addition reactions on a variety of unsaturated molecules when the Hirshfeld, Merz-Singh-Kollman, or Voronoi deformation density population schemes are used. Furthermore, for all populations schemes in the majority of instances where the radical Fukui function failed the radical GPRI was able to identify the most reactive atom under certain reactivity conditions.

Nitrile Imines as Peptide and Oligonucleotide Photo-Cross-Linkers in Gas-Phase Ions.

Nitrile imines produced by photodissociation of 2,5-diaryltetrazoles undergo cross-linking reactions with amide groups in peptide-tetrazole (tet-peptide) conjugates and a tet-peptide-dinucleotide complex. Tetrazole photodissociation in gas-phase ions is efficient, achieving ca. 50% conversion with 2 laser pulses at 250 nm. The formation of cross-links was detected by CID-MS3 that showed structure-significant dissociations by loss of side-chain groups and internal peptide segments. The structure and composition of cross-linking products were established by a combination of UV-vis action spectroscopy and cyclic ion mobility mass spectrometry (c-IMS). The experimental absorption bands were found to match the bands calculated for vibronic absorption spectra of nitrile imines and cross-linked hydrazone isomers. The calculated collision cross sections (CCSth) for these ions were related to the matching experimental CCSexp from multipass c-IMS measurements. Loss of N2 from tet-peptide conjugates was calculated to be a mildly endothermic reaction with ΔH0 = 80 kJ mol-1 in the gas phase. The excess energy in the photolytically formed nitrile imine is thought to drive endothermic proton transfer, followed by exothermic cyclization to a sterically accessible peptide amide group. The exothermic nitrile imine reaction with peptide amides is promoted by proton transfer and may involve an initial [3 + 2] cycloaddition followed by cleavage of the oxadiazole intermediate. Nucleophilic groups, such as cysteine thiol, did not compete with the amide cyclization. Nitrile imine cross-linking to 2'-deoxycytidylguanosine was found to be >80% efficient and highly specific in targeting guanine. The further potential for exploring nitrile-imine cross-linking for biomolecular structure analysis is discussed.

Study of the Mechanism of 7‐exo‐trig Cyclizations of Aryl, Vinyl, and Alkyl Radicals on Oxime Ethers

AbstractIn this work, we conducted a study of 7‐exo‐trig cyclizations mechanism involving aryl, vinyl, and alkyl radicals on oxime ethers. Initially, the reaction of brominated oxime ether 9 a with (TMS)3SiH and AIBN gave rise to aryl radicals that underwent a 7‐exo‐trig cyclization on the oxime ether, yielding dibenzoxepine 10 a, and the ipso reaction and reduction products were obtained as well. Approximate rate constants at 80 °C for the 7‐exo‐trig (1.0×108 s−1) and the ipso cyclization (4.3×107 s−1) were determined by competition experiments. DFT calculations showed good agreement with the experimental results. The reduction rate constant of the N‐alkoxyaminyl radical with (TMS)3SiH was calculated to be 4.1×10−1 M−1 s−1; while the rate constants for the 7‐exo‐trig cyclizations of vinyl and alkyl radicals on the oxime ether were estimated in the ranges of 106 s−1–108 s−1 and 103 s−1–108 s−1, respectively. The 7‐exo‐trig cyclization reactions involving aryl, vinyl, and alkyl radicals with oxime ethers were found to be an exothermic and irreversible process, with the oximic carbon showing a preference for nucleophilic alkyl radicals. This kinetic study contributes to the deeper understanding of radical‐mediated cyclizations, enabling the efficient design of complex synthetic routes.

Palladium-catalyzed cascade cyclization of α,β-unsaturated N-tosylhydrazones with iodoarenes: access to 2H-chromenes and 2H-quinolines.

A palladium-catalyzed cascade reaction of α,β-unsaturated N-tosylhydrazones with iodoarene derivatives containing a nucleophilic group has been developed, which provides facile access to 2H-chromenes and 2H-quinolines, respectively. Additionally, the double Pd-carbene migratory insertion/nucleophilic substitution processes for the synthesis of a ternary heterocyclic skeleton were possible in the developed catalytic system.

Aminomethylations of electron-deficient compounds-bringing iron photoredox catalysis into play.

The α-functionalisation of N-containing compounds is an area of broad interest in synthetic chemistry due to their presence in biologically active substances among others. Visible light-induced generation of nucleophilic α-aminoalkyl radicals as reactive intermediates that can be trapped by electron-deficient alkenes presents an attractive and mild approach to achieve said functionalisation. In this work, [Fe(iii)(phtmeimb)2]PF6 (phtmeimb = phenyl(tris(3-methylimidazol-2-ylidene))borate), an N-heterocyclic carbene (NHC) complex based on Earth-abundant iron, was used as photoredox catalyst to efficiently drive the formation of α-aminoalkyl radicals from a range of different α-trimethylsilylamines and their subsequent addition to a number of electron-deficient alkenes under green light irradiation. Mechanistic investigations elucidated the different reaction steps of the complete photocatalytic cycle. In terms of yields and substrate scope, we show that [Fe(iii)(phtmeimb)2]PF6 can compete with noble metal photoredox catalysts, for instance outcompeting archetypal [Ru(bpy)3]Cl2 under comparable reaction conditions, illustrating that iron photocatalysts can efficiently facilitate photoredox reactions of synthetic value.

ПОЛУЧЕНИЕ ИСКУССТВЕННЫХ ПОЛИМЕРОВ НА ОСНОВЕ ЦЕЛЛЮЛОЗЫ

The production of artificial polymers with a complex of useful physical and chemical properties is based on three main methods of their synthesis is polymerization, polycondensation and modification. At the same time, the modification of polymers has now found wide application, including for the production of cellulose ethers, among which cellulose nitrate ester is one of the large-scale products. Through reactions of functional groups, cellulose nitrate can be converted into new compounds in nucleophilic substitution reactions. The interaction of 4,4',5,5'-Tetranitro-2,2'-bi-1H-imidazole (TNBI) with cellulose nitrate C6H7O2(OH)0,87(ONO2)2,13 in the medium of dimethylformamide at a temperature of 70-72 oC and different reaction times 1, 2, 3 and 4 hours was studied. The main directions of the reaction were identified, namely, nucleophilic substitution nitrate groups of cellulose nitrate for a fragment of a THБИ; partial hydrolysis of nitrate groups; depolymerization and destruction of the polymer chain with the breaking of β-glycosidic bonds and joining at the ends of the polymer chain in the positions C1 and C4 of the fragment of a TNBI molecule. Based on the results of experimental data and physical and chemical studies, the chemical composition and structure of the reaction products obtained are determined and the scheme of interaction of cellulose nitrate with TNBI is presented. It was found that the product of interaction of cellulose nitrate with TNBI, obtained at the maximum reaction time 4 hours at a temperature of 70 oC has the lowest degree of substitution of nitrate groups. A further increase the reaction time does not lead to a significant increase in the content of the TNBI fragment in the products, since there is a strong degradation of the initial polymer, which makes it difficult to isolate high-molecular products was found. The possibility of a directed change in the composition of chemically modified cellulose nitrates at different stages of synthesis to obtain products with controlled composition and properties has been established.

From 'halogen' to 'tetrel' bonds: matrix isolation IR spectroscopic and quantum mechanical studies of the effect of central atom substitution in donor tetrahalogens on binary complex formation with formic acid.

Binary complex formation between silicon tetrachloride (SiCl4) and formic acid (FA) has been observed in an argon matrix environment. Such complex formation manifests as spectral shifts in signature vibrations of the latter, namely the νCO, νC-O and νO-H vibrations. Quantum chemical calculations reveal that the most stable conformers of the complex involve predominantly the tetrel bond, which has been defined in existing literature as a variant of the "σ-hole" interactions. Here, regions of positive electrostatic potential on the tetrahedral face of SiCl4 act as electrophilic centers (σ-hole) to which the nucleophilic carbonyl group of FA is able to bind. Atoms-in-molecules analysis predicts a bond critical point along the non-covalent contact between the tetrel atom Si and the carbonyl oxygen on FA, corroborating the presence of the tetrel bond. The hyperconjugative interaction parameters at the binding interface obtained from Natural Bond Orbital (NBO) analysis are also consistent with such observations. Although apparently similar to SiCl4, there are noticeable differences in the binding preferences of the lower homologue carbon tetrachloride (CCl4). The binary complexes of the latter with the same FA acceptor molecule have been previously shown to involve halogen bonded, rather than tetrel bonded interactions (Banerjee and Bhattacharya, Spectrochim. Acta Mol. and Biomol. Spectrosc., 2021, 250, 119355). Such variations in the nature of non-covalent interactions of these tetrahalogens are attributed to differences in the distribution of electronic charge density surrounding the central tetrel atom, as obtained from mappings of their electrostatic potential surfaces. Our combined experimental and theoretical findings therefore provide direct evidence of the growing propensity of tetrel atoms to engage in tetrel bonding as we move lower down Group 14, and re-assert the reluctance of the smaller and more electronegative carbon atom to serve as a tetrel bond participant.