Nucleophilic Addition Mechanism Research Articles

A water-soluble colorimetric and turn-on fluorescence sensor for fast and sensitive detection of sulfite/bisulfite ions in real samples and live cells

Consuming an excessive amount of sulfites can have detrimental effects on human health. Therefore, it is essential to develop an effective technique to detect the presence of HSO3− in food samples and live cells. Herein, we have developed a colorimetric and turn-on fluorescent probe PI capable of efficiently detecting sulfite/ bisulfite (SO32− /HSO3−) in aqueous PBS buffer (pH 7.4). This probe PI is non-fluorescent due to intramolecular charge transfer (ICT), but becomes fluorescent in the presence of HSO3−. The reaction between SO32− /HSO3− and the probe disrupts π - conjugation by a nucleophilic addition mechanism, resulting in the inhibition of intramolecular charge transfer (ICT). This leads to changes in both the fluorescence and absorption spectra. The color of the probe PI changed from blue to colorless, making it easier to detect HSO3−with the naked eye. Our probe also demonstrates excellent sensitivity, selectivity, fast (reaction completed in 300 s), and a low limit of detection (LOD = 8.4 nM). Furthermore, it is effective in detecting levels of SO32− /HSO3− in water, sugar, and MDA-MB-231 live cancer cells.

Scandium-catalyzed chemoselective carbene insertion into N-H over S-H: access to o-alkylamine-diaryl disulfides.

Herein, we report a scandium-catalyzed chemoselective carbene insertion into a N-H bond over a S-H bond with disulfide formation. This reaction represents the first example of the synthesis of o-alkylamine-diaryl disulfides through the N-alkylation of o-aminobenzenethiol, while also undergoing oxidative coupling to form a S-S bond. Control experiments explain the chemo-selectivity of this rare-earth-metal Lewis acid-induced catalysis by a carbene outer-sphere nucleophilic addition mechanism. This method holds tremendous potential as a valuable tool for functionalizing advanced-synthetic-intermediates, offering numerous applications in medicinal and materials chemistry.

Particle-phase accretion forms dimer esters in pinene secondary organic aerosol.

Secondary organic aerosol (SOA) is ubiquitous in the atmosphere and plays a pivotal role in climate, air quality, and health. The production of low-volatility dimeric compounds through accretion reactions is a key aspect of SOA formation. However, despite extensive study, the structures and thus the formation mechanisms of dimers in SOA remain largely uncharacterized. In this work, we elucidate the structures of several major dimer esters in SOA from ozonolysis of α-pinene and β-pinene-substantial global SOA sources-through independent synthesis of authentic standards. We show that these dimer esters are formed in the particle phase and propose a mechanism of nucleophilic addition of alcohols to a cyclic acylperoxyhemiacetal. This chemistry likely represents a general pathway to dimeric compounds in ambient SOA.

High yield production of cyanidin-derived pyranoanthocyanins using 4-vinylphenol and 4-vinylguaiacol as cofactors.

Pyranoanthocyanins are anthocyanin-derived pigments with vivid colors and enhanced stability, making them promising food colorants. We evaluated two 4-vinylphenols, decarboxylated p-coumaric (pCA) and ferulic acid (FA), as cofactors for pyranoanthocyanin formation. Cyanidin-3-glycosides from saponified black carrot were incubated with 4-vinylphenol or 4-vinylguaiacol in different anthocyanin-to-cofactor molar ratios (1:1-1:30) to form pyranoanthocyanins. Formation efficiency (45°C, ≤96h) was compared to their respective precursors at a 1:30 ratio. Composition changes were monitored using uHPLC-PDA-ESI-MS/MS. Pyranoanthocyanin yields with 4-vinylphenol (13.8-33.4%) were ∼12× higher than with pCA and yields with 4-vinylguaiacol (8.1-31.0%) were ∼6.5× higher than with FA. Molar ratios of 1:5 and 1:10 yielded significantly more pyranoanthocyanins. Pyranoanthocyanin formation with 4-vinylphenols followed first-order kinetics, whereas formation with hydroxycinnamic acids followed zero-order kinetics. Detection of intermediate compounds was consistent with a nucleophilic addition and aromatization formation mechanism. Overall, pyranoanthocyanin formation with 4-vinylphenols was more efficient than with hydroxycinnamic acids.

Internal B ← O Bond Facilitated Photo/Thermal Isomerization of Tetra-Coordinated Boranes

A new series of O∧C-chelate tetra-coordinated boranes with naphtha-aldehyde as the chelate backbone have been synthesized. Their photophysical and photochemical properties have been examined, which show that all of the compounds can undergo both photo and thermal transformations, generating aryl-migrated [1,2]oxaborinine derivatives as the major products. 1,3-Sigmatropic shifts and an intramolecular nucleophilic addition mechanism are proposed for the photochemical and thermal conversion pathways, respectively.

A NIR‐II Fluorescent Probe for Hydrogen Sulfide Detection Based on Blocking Intramolecular Charge Transfer

AbstractA NIR‐II fluorescent probe (Et‐1080) for H2S detection was fabricated based on the intramolecular charge transfer blocking mechanism. The enhanced electron density of the indole donor further drove the Et‐1080′s absorption and emission to the NIR‐II region with a high molar absorption coefficient and acceptable fluorescence quantum yield. The C=N double bond of electron‐deficient indole can react with H2S rapidly via a nucleophilic addition mechanism, resulting in the destruction of conjugated structure and fluorescence quenching of the Et‐1080 molecule. The probe showed high selectivity and sensitivity to H2S, which could realize the rapid detection of H2S in NIR‐II band and showed great potential in the further disease diagnosis associated with H2S.

4-Этоксиметилен-2-фенил-5(4Н)-оксазолон в реакциях с различными гетероциклическими аминами

The analysis of the literature data has showed that there is no information on the behavior in 5(4H)-oxazolones with amines under the conditions of a sealed vessel reactor, which makes it possible to obtain heterocyclic systems with different amines. We have developed and presented an easy, fast, reliable and innovative method for the preparation of a new series of compounds with synthetic and biological potential, based on the interaction of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone and heterocyclic amines with different ring sizes and sets heteroatoms using a sealed vessel reactor. Based on the results obtained, it has been found that the transformation proceeds by the mechanism of nucleophilic addition of Michael. The scheme of the conducted interaction has been discussed. Initially, the amino group of the amine used is attacked at the exocyclic C=C bond of the initial substrate, ethoxymethylenexazolone, proceeding with the elimination of a well-leaving ethoxy group in the form of an ethanol molecule, which leads to the final 4-hetarylaminomethylidene derivatives of oxazol-5(4H)-one. In the course of the work, it has been found that the use of a sealed vessel reactor makes it possible to reduce the time of transformations, to achieve an increase in selectivity and yields of target products compared to the usual type of activation of the reaction mixture, such as boiling in ethanol. It has been shown that not only the type of activation, but also the nature of the solvent used affects the rate of the reaction. It has been found that under these conditions the transfor mation proceeds with the preservation of the oxazol-5(4Н)-one ring. Control over the course of reactions, determination of individuality and identification of the obtained compounds have been carried out by TLC, elemental analysis, IR-, NMR spectroscopy.

“On Water” Effect for Green Click Reaction: Spontaneous Polymerization of Activated Alkyne with “Inert” Aromatic Amine in Aqueous Media

“On Water” Effect for Green Click Reaction: Spontaneous Polymerization of Activated Alkyne with “Inert” Aromatic Amine in Aqueous Media

EPR spectroscopic evidence of iron-catalysed free radical formation in chronic mountain sickness: Dietary causes and vascular consequences

Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = <0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = <0.001 vs. CMS-) subsequent to liberation of free ‘catalytic’ iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = <0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = <0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = <0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r = −0.692 to 0.595, P = <0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+. Trial registryClinicalTrials.gov; No: NCT01182792; URL: www.clinicaltrials.gov.

Iridium‐Catalyzed Enantioselective Allylic Substitutions of Racemic, Branched Trichloroacetimidates with Heteroatom Nucleophiles: Formation of Allylic C−O, C−N, and C−S Bonds

AbstractA broadly applicable methodology for the regio‐ and enantioselective construction of branched allylic carbon‐heteroatom bonds from racemic, secondary allylic trichloroacetimidates has been developed. The branched allylic substrates undergo dynamic kinetic asymmetric substitution reactions with a number of unactivated anilines and carboxylic acids as well as unactivated aromatic thiols in the presence of a chiral bicyclo[3.3.0]octadiene‐ligated iridium catalyst. The allylic C−O, C−N, and C−S bond containing products are obtained in synthetically useful yield and selectivity. Mechanistic studies suggest that the iridium‐catalyzed enantioselective substitution reactions of heteroatom nucleophiles with allylic trichloroacetimidate substrates through an outer‐sphere nucleophilic addition mechanism. In addition, the chiral diene‐ligated iridium catalyst is effective at promoting asymmetric aminations of acyclic secondary anilines. Importantly, this catalytic iridium methodology enables the use of alkyl substituted allylic electrophiles.magnified image

Recent Advances in Theoretical Studies on Transition-Metal-Catalyzed Carbene Transformations.

Metal carbene plays a vital role in modern organic synthesis. The neutral divalent carbon of metal carbene renders it an active intermediate throughout a range of reactions. In experiments, diverse metal carbene-related transformation reactions have been established, including transition-metal-catalyzed cross-coupling reactions using N-heterocyclic carbenes as ligands, metal carbene insertion into σ bonds, cyclopropanations, ylide formation, and so forth. The remarkable progress achieved in synthetic chemistry, in turn, has increased the demand for mechanistic studies of carbene chemistry. A thorough understanding of reaction mechanisms can extend the application scope of metal carbene compounds and inspire the rational design of new carbene transformation reactions.Density functional theory (DFT) calculations have been performed in our group to gain more mechanistic insights into metal carbene-related reactions. This account focuses on computational studies of transition-metal-catalyzed carbene transformation reactions with nucleophiles. The generation of metal carbene or metal-ligated free carbene and subsequent carbene transformation pathways is discussed. According to our mechanistic studies of carbene transformation with nucleophiles, three generalized reaction models are summarized, including the intramolecular migratory insertion of metal carbene, intermolecular nucleophilic addition toward metal carbene, and outer-sphere nucleophilic addition to the metal-ligated free carbene.In general, the intermolecular nucleophilic addition mechanism is commonly proposed since metal carbene has an electrophilic carbene carbon. From a mechanistic point of view, the intramolecular migratory insertion mechanism is also widely used because metal carbene insertion into σ bonds formally occurs through this mechanism. An outer-sphere nucleophilic addition mechanism is proposed for reactions that form a metal-ligated free carbene complex instead of the commonly proposed metal carbene. The metal-ligated free carbene complex contains a naked carbene carbon that is not coordinated with the metal center. In this case, a transition-metal catalyst is used only as a Lewis acid, and nucleophilic addition occurs directly at the free carbene carbon. Our computational results suggested that outer-sphere nucleophilic addition is a facile step because metal ligation could stabilize the transition state as well as the generated intermediate. The intramolecular migratory insertion mechanism also has a low energy barrier due to the lack of an entropy penalty. Carbene formation from carbene precursors is usually the rate-determining step, except in intermolecular nucleophilic addition, and the reactivity of nucleophiles has a significant influence on the overall reaction rate. We can also envision that the weak nucleophilicity of nucleophiles would suppress outer-sphere nucleophilic addition. These computational studies showcase the characteristics of three carbene transformation models, and we hope that it will spur the development of mechanistic studies of carbene chemistry.

Effect of the anionic center hydration on the activation barrier of intramolecular nucleophilic addition in αβ-unsaturated oximes

The mechanism of intramolecular nucleophilic addition in αβ-unsaturated oximes, as well as the effect of the anionic center hydration with one and two water molecules on the activation barriers of intramolecular cyclization, was studied using the B2PLYP-D2/6-311+G**//B3LYP(D)/6-31+G* method with the solvation effects included within the SMD model. The activation barrier for nucleophilic addition of the anionic center of the oxime group to the carbon skeleton of 3-ethyl-N-hydroxy-5-phenylpenten-3-imine-2 is about 21 kcal/mol. During the hydration of the anionic center with one water molecule, a strong complex is formed, which increases the activation barrier by ∼ 6 kcal / mol. The addition of a second water molecule leads to an even higher activation barrier (ΔG‡ = 28 kcal/mol), but promotes the binding of the leaving hydroxide ion.

Chemically stable anion exchange membranes based on C2-Protected imidazolium cations for vanadium flow battery

Imidazolium-based anion exchange membranes (AEMs) are attractive as the separator for vanadium redox flow battery (VFB) application. However, the lack of fundamental understanding of the correlations between imidazolium chemical structure and their physical properties as well as cell performance constraints the design of advanced AEMs in VFBs. In this work, by designing the “clickable” imidazolium compounds from C2-methyl or C2-phenyl substituted imidazolium to C2-phenyl substituted benzimidazolium, a series of PSf-based AEMs having pendant C2-protected imidazolium derivatives were prepared by efficient CuAAC reaction to explore how the nature of C2 substitution affected the electrochemical property of AEMs and the resulting VFB performance. Interestingly, PSf-MIm with C2-methyl protected imidazolium group showed lowest area resistance (0.3 Ω cm2, IEC = 1.66 meq./g) in 3 M H2SO4 aqueous solution but unfavorable vanadium permeability due to its highest swelling ratio. The introduction of bulky C2-phenyl substituted benzimidazolium led to the distinct microphase separation in PSf-PhBIm membrane, and thus reduced water uptake, high vanadium selectivity, and comparable conductivity were observed. As a result, the single VFB with PSf-MIm-1.2 membrane exhibited better electrochemical performance with a coulombic efficiency (CE) of 97.0%, and an energy efficiency (EE) of 82.4% at a current density of 120 mA/cm2, higher than those of Nafion N115 membrane (EE = 75.5%) and unsubstituted imidazolium-based AEMs (EE = 80.6%). More importantly, both ex situ stability testing in 1.5 M (VO2)2SO4/3 M H2SO4 solution for 90 days and in situ cycling performance at a current density of 120 mA/cm2 demonstrated that the chemical structure of C2-substituted imidazolium based AEMs remained intact after stability tests as confirmed by NMR analysis, while significant degradation was found for unsubstituted PSf-Im membrane via possible nucleophilic addition mechanism. Therefore, the VFB with PSf-MIm membrane showed the best long-term durability with only 34.1% loss in EE for 3638 h of operating (4800 cycles). This work not only fills the knowledge gap on the structure-property relationship of imidazolium-based AEMs for VFB application, but also gives us new directions to design stable AEMs for durable VFBs.

Stereoselective synthesis of 2-(2,4-dinitrophenyl)hydrazono- and (2-tosylhydrazono)-4-oxo-thiazolidine derivatives and screening of their anticancer activity

Stereoselective synthesis of (Z)-methyl 2-[(Z)-3-substituted 2-[2-(2,4-dinitrophenyl)hydrazono]-4-oxothiazolidine-5-ylidene]acetates and (Z)-methyl 2-[(Z)-3-substituted 2-[2-(tosylhydrazono)-4-oxothiazolidine-5-ylidene]acetates via the cyclization of N-substituted 2-arylhydrazino-carbothioamides with dialkyl acetylenedicarboxylates in absolute ethanol is reported. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The mechanism of nucleophilic addition and the role of electronic factors were discussed. The anticancer activity of the newly synthesized compounds was evaluated against a panel of 60 cell lines derived from 9 different types of cancers including, leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers and the results revealed that the cyclohexyl derivative has a significant broad anticancer activity, especially against different leukemia and colon cancer cell lines.

A spiropyran-acylhydrazone dyad: Uncovering another way of cleaving the Cspiro-O bond of the classical photochromic molecule

Spiropyran, as famous molecular sensor, can transform from its closed forms into the corresponding opened merocyanine through Cspiro-O bond cleavage when an analyte attacks the spirocarbon or oxygen atom in the spiropyran. Herein, a spiropyran-acylhydrazone dyad 4 is synthesized followed by spiropyran-like 5 and non-spiropyran diacylhydrazone 6 obtained simultaneously, and its reactivity to nucleophiles is investigated. Thus a third attacking position, located at the carbon atom opposite to the oxygen connected to Cspiro, is found, which involves Cspiro-O bond cleavage and recombination. Consequently, a nucleophilic addition mechanism in spiropyran is proposed. 4 and 5 both can discriminate Mg2+ from Ca2+ with different response time and sensitivity, while non-spiropyran 6 does not respond to the two metal ions. This work not only discovers an outstanding sensor for discriminating Mg2+ from Ca2+, but also provides new insight for transforming and modifying spiropyrans.

A chemical probe capable for fluorescent and colorimetric detection to Cu2+ and CN− based on coordination and nucleophilic addition mechanism

A salamo-like chemical probe HL with novel structure for continuous recognition of Cu2+ and CN− was synthesized by Schiff base reaction. Some meticulous researches on the properties of probe HL had been carried out by UV–Vis spectra and fluorescence spectra, high-resolution mass spectra and nuclear magnetic resonance spectra. The probe HL could identify Cu2+ by dual channels, and the formed copper(II) complex L-Cu2+ could be used as a probe to recognize CN− in the visible region, and could realize naked eye recognition with color changed from bright yellow to red. Combining the color changes and smartphones, a cost-effective real-time detection method which named the RGB analysis method had been developed for on-site detection of CN− content. In addition, the lowest detection limit for Cu2+ and CN− could reach 2 × 10−8 M and 2.52 × 10−8 M, respectively. And a good recovery was obtained when determining the CN− in the real water samples.

A simple fluorophore-imine ensemble for colorimetric and fluorescent detection of CN- and HS- in aqueous solution.

Colorimetric and fluorescent detection of cyanide and hydrogen sulfide ions has been effected using a simple organic probe in H2O:DMSO (20:80, v/v) medium. The probe exhibits a colour change from pale-yellow to red upon addition of these analytes under normal light and fluorescent change from green to red under UV lamp. Other competitive ions show no observable colour or fluorescence change. The binding constants of cyanide and hydrogen sulfide ions with the probe determined using fluorescence titration data are found to be 2.1×104 and 1.6×104 M-1, respectively. The probe fluorimetrically detects the analytes in a wide pH range (4-10). 1H and 13C NMR studies suggest that the probe senses cyanide ion through deprotonation and nucleophilic addition mechanism and hydrogen sulfide ion via deprotonation mechanism. Detection limits of cyanide and hydrogen sulfide are determined to be 0.15 and 1μM, respectively. The practical utility of the probe has been demonstrated by same dual mode detection of cyanide in food materials like bitter almond, cassava flour and sprouting potato.

A novel ratiometric fluorescent probe for "naked-eye" detection of sulfite ion: Applications in detection of biological SO32- ions in food and live cells.

A new "turn-on" luminescent probe PI has been designed and synthesized for the selective detection of sulfite ions based on the mechanism of nucleophilic addition. The designed probe PI owns naked eye detection, excellent selectivity, sensitivity, rapid response (150 s) and low limits of detection (LOD) of 0.57 μM, which is an agreeable limit by the world wide expert food additive committees. Furthermore, the probe PI was used to recognize the sulfite ions level in realistic samples and live cells.

A highly sensitive turn-on fluorescent probe for real-time detecting hypochlorite and its application in living cells

It is very necessary to develop real-time, highly sensitive and selective fluorescent probes for hypochlorite (ClO−) in living cells owing to hypochlorite's important role in pathological and physiological processes and its short life. Herein, a pyrene Schiff's base derivative was successfully developed for real-time (within seconds), highly sensitive detecting ClO− with a low detection limit (5.7 nM) and wide pH range (4.0–11.0) based on nucleophilic addition and subsequent hydrolysis mechanism. The probe has aggregation-induced emission properties and emits yellow fluorescence (544 nm) in PBS solution, while it exhibits blue fluorescence in other organic solvents (426 nm (THF) - 460 nm (MeOH)). The probe can be used to response ClO− in A549 cells with low cytotoxicity, a good cell membranes penetration and good biocompatibility. Cell uptake experiment indicates that probe getting into the cells is energy-dependent and is not attributed to endocytosis. Moreover, the probe is successfully used in real water sample to detect ClO− and it can be expected to be applied to ClO− participated biological and pathological functions in biological systems.

Recent Progress in Chemosensors Using Aldehyde-bearing Fluorophores for the Detection of Specific Analytes and their Bioimaging.

In recent years, aldehyde-appended fluorescence probes have attracted increasing attention. Fluorescent biological imaging includes many modern applications for cell and tissue imaging in biomedical research. Meanwhile, the nucleophilic mechanism is a very simple and convenient procedure for the preparation of aldehyde-sensing probes. This tutorial review focuses on aldehyde-bearing chemosensors based on nucleophilic addition mechanism with biological applications.