Nucleophilic Groups Research Articles

Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs).

Atropisomers, arising from conformational restriction, are inherently chiral due to the intersecting dissymmetric planes. Since there are numerous applications of enantiopure atropisomers in catalyst design, drug discovery, and material science, the asymmetric preparation of these highly prized molecules has become a flourishing field in synthetic chemistry. A number of catalysts, synthetic procedures, and novel concepts have been developed for the manufacture of the atropisomeric molecules. However, due to the intrinsic properties of different types of atropisomers featuring biaryl, hetero-biaryl, or non-biaryl architectures, only very few methods pass the rigorous inspection and are considered generally applicable. The development of a broadly applicable synthetic strategy for various atropisomers is a challenge. In this Account, we summarize our recent studies on the enantioselective synthesis of atropisomers using the vinylidene ortho-quinone methides (VQMs) as pluripotent intermediates.The most appealing features of VQMs are the disturbed aromaticity and axial chirality of the allene fragment. At the outset, the applications of VQMs in organic synthesis have been neglected due to their principal liabilities: ephemeral nature, extraordinary reactivity, and multireaction sites. The domestication of this transient intermediate was demonstrated by in situ catalytic asymmetric generation of VQMs, and the reactivity and selectivity were fully explored by judiciously modifying precursors and tuning catalytic systems. A variety of axially chiral heterocycles were achieved through five-, six-, seven- and nine-membered ring formation of VQM intermediates with different kinds of branched nucleophilic functional groups. The axially chiral C-N axis could be constructed from VQM intermediates via N-annulation or desymmetrization of preformed C-N scaffolds. We take advantage of the high electrophilicity of VQMs toward a series of sulfur and carbon based nucleophiles leading to atropisomeric vinyl arenes. Furthermore, chiral helical compounds were realized by cycloaddition or consecutive annulation of VQM intermediates. These achievements demonstrated that the VQMs could work as a nuclear parent for the collective synthesis of distinct and complex optically active atropisomers. Recently, we have realized the isolation and structural characterization of the elusive VQMs, which were questioned as putative intermediates for decades. The successful isolation of VQMs provided direct evidence for their existence and an unprecedented opportunity to directly investigate their reactivity. The good thermal stability and reserved reactivity of the isolated VQMs demonstrated their great potential as synthetic reagents and expanded the border of VQM chemistry.

Visible-light-driven removal of tetracycline hydrochloride and microplastics (HDPE) by nano flower hybrid heterojunction NH2-MIL-88B(Fe)/MoS2 via enhanced electron-transfer

NH2-MIL-88B (Fe) heterostructure-based photocatalysts exhibit high activity in photocatalytic environmental remediation and energy conversion, but many challenges remain. Novel high-performance heterostructure curd composite (NH2-MIL-88B(Fe)/MoS2) by in situ deposition of MoS2 on NH2-MIL-88B(Fe) using NH2-MIL-88B(Fe) as a precursor) preparation method was successfully developed. The photodegradation efficiency of tetracycline hydrochloride (TC) was 96.44%, and the salinity was 72.36%. NH2-MIL-88B(Fe)/MoS2-2 photocatalyst has degraded microplastic fragments and high-density polyethylene film (HDPE) in water. Multiple analyses confirmed that after binding NH2-MIL-88B(Fe) to MoS2, The light absorption, recombination resistance, carrier lifetime, and specific surface area of the hybrid system were all enhanced. LC-MS detected and identified the emerging intermediates, revealing possible degradation pathways. The toxicity evaluation of the intermediate showed that NH2-MIL-88B(Fe)/MoS2 could also reduce the toxicity of TC through photocatalytic reaction. The charge transfer mechanism analysis and density functional theory calculations show that more photoinduced active species (h+, O2– and OH) are excited on the NH2-MIL-88B (Fe)/MoS2 heterojunction. The excited reactive species attack tetracycline hydrochloride's nucleophilic and free radical reaction sites. The results of this study provide necessary inspiration and guidance for the development and application prospects of NH2-MIL-88B (Fe)/MoS2 in environmental remediation.

Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction.

The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands.

Direct C-H Allylation of Unactivated Alkanes by Cooperative W/Cu Photocatalysis.

Here we report a photocatalytic methodology that enables the direct allylation of strong aliphatic C–H bonds with simple allylic chlorides. The method relies on a cooperative interaction of two metal catalysts in which the decatungstate anion acts as a hydrogen-atom abstractor generating a nucleophilic carbon-centered radical that engages in an SH2′ reaction with an activated allylic π-olefin–copper complex. Because of this dual catalysis, the protocol allows for the functionalization of a range of chemical feedstocks and natural products under mild conditions in short reaction times.

Achieving simultaneous hydrogen evolution and organic pollutants degradation through the modification of Ag3PO4 using Cs2AgBiBr6 quantum dots and graphene hydrogel

The Ag3PO4/Cs2AgBiBr6 quantum dots/graphene hydrogel (ACGH) photocatalytic system was designed. The Cs2AgBiBr6 quantum dots (CABBQDs) and graphene hydrogel (rGH) solved the insufficient redox ability and easy photocorrosion of Ag3PO4, at the same time, the novel system achieved full-spectrum-driven photoreforming to use for efficient photocatalytic hydrogen evolution and simultaneous organic compounds photodegradation. The feasibility study of alternative sacrificial agents evaluated higher simultaneous photocatalytic activity in tetracycline hydrochloride (TC) compared to general sacrificial agents (methanol, Na2S/Na2SO3, acid orange and glucose). The yield of hydrogen production and simultaneous photodegradation efficiency of TC were 5965.8 μmol/g and 98.32 % respectively in 6 h. And the hydrogen production rate in TC solution was more than twice that of general sacrificial agents within 24 h. Meanwhile, the mechanism exploration elucidated the photogenerated charge transfer path to generate the water splitting and photoinduced oxidizing species (h+, OH, ·O2-). The Hirshfeld atomic charges on TC and methanol molecules were calculated by density functional theory to predict the initial attack sites. Results indicated that the CCO and CNC fragments on TC molecules were inferred as nucleophilic attack and radical attack sites. And more electrons on TC could give to ACGH constantly for hydrogen production than methanol. The yield of hydrogen production and simultaneous degradation efficiency of TC remained at 3683.24 μmol/g and 93.22 % respectively in six photocatalytic cycle experiments, showing the reusability of ACGH. The simultaneous hydrogen production and degradation of organic pollutants of ACGH could proceed in actual municipal wastewater.

Effect of curvature on the activation energy of monomethylation of carbon belts: a DFT study

Alkylation of the cylindrical part of single-walled carbon nanotubes can improve solubility and oriented aggregation. In this study, the activation energy of the monomethylation of carbon belt surfaces was investigated using density functional theory to clarify the effect of curvature on nucleophilic radical addition. The activation energy decreases with increasing curvature, and at κ = 0.290 Å−1, it is approximately half (7.1 kcal·mol−1) of that of the monomethylation of flat graphene flakes. The curvature significantly affects the repulsive energy between the CH3 and carbon belt portions, as well as local deformation around the bonding site.

Design of a New Hydrazine Moiety-Based Near-Infrared Fluorescence Probe for Detection and Imaging of Endogenous Formaldehyde In Vivo.

Formaldehyde (FA), the smallest molecular aldehyde with strong reducing properties, could regulate body homeostasis endogenously during physiological and pathological processes. The effective near-infrared (NIR) fluorescent probe is needed as a visualizer of FA in biologic organisms. In this work, a novel NIR fluorescent Probe-NHNH2 was designed on the basis of Probe-NH2 via introducing a strong nucleophilic hydrazine group, which can be used as a quenching and recognizing moiety for the detection of FA. With the treatment of FA, the hydrazine group of Probe-NHNH2 undergoes condensation and achieves a turn-on NIR fluorescence signal at a wavelength of 706 nm. The spectroscopic performance of Probe-NHNH2 for FA was evaluated, and it exhibited high sensitivity and selectivity for the detection of FA in solution. Moreover, compared to the amine moiety-based Probe-NH2, which our group reported, we found that hydrazine moiety-based Probe-NHNH2, exhibited a better reaction time of within 10 min and a lower detection limit of 0.68 μM, reflecting that the reaction of FA with hydrazine moiety is faster and more sensitive than that of FA with the amino group. More importantly, Probe-NHNH2 was successfully applied to real-time imaging of endogenous FA by reacting with effective stimulant tetrahydrofolate and scavenger sodium bisulfite in zebrafish and mice. It is expected that we can provide a new rapid, sensitive NIR fluorescence theoretical basis for FA detection and in vivo imaging applications.

Rational design of Lewis acid-base bifunctional nanopolymers with high performance on CO2/epoxide cycloaddition without a cocatalyst

Based on the Schiff base reaction and post-modification strategy, novel nanocomposites of pyridine-zinc-based ionic porous organic polymers (Py-Zn@IPOPX, X = Br, I, Ac) were constructed and structurally characterized. Various Py-Zn@IPOPX were applied to the transformation of CO2 and epoxides into cyclic carbonates, and their catalytic activities were studied and discussed in detail. The results showed that Py-Zn@IPOPI possesses Lewis acid-base bifunctional features, and also modified with superior nucleophilic active groups, which exerted an important synergistic effect on activation of CO2 and epoxide, and ring-opening of epoxide. Under co-catalyst/solvent-free conditions, Py-Zn@IPOPI could afford 96 % PC yield and 99 % selectivity at 120 °C and 2.0 MPa CO2 pressure for 6 h, and turnover frequency (TOF) was high to 230 h−1. Moreover, the reusability and versatility of the catalyst were examined, and the catalytic mechanism was speculated according to the obtained results. Compared with previously reported porous polymer catalysts, Py-Zn@IPOPI requires much greener and milder reaction conditions while avoids the use of a co-catalyst, displaying bright prospects for the design and synthesis of ionic porous organic polymers for CO2 activation and utilization.

Design, synthesis, and antitumor study of a series of novel 1-Oxa-4-azaspironenone derivatives

A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, β unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity. The majority of the compounds had moderate to potent activity against A549 human lung cancer cells, MDA-MB-231 breast cancer cells, and Hela human cervical cancer cells. Among them, the compound 6d showed the strongest effect on A549 cell line with IC50 of 0.26 μM; the compound 8d showed the strongest cytotoxicity on MDA-MB-231 cell line with IC50 of 0.10 μM; and the compound 6b showed the strongest activity on Hela cell line with IC50 of 0.18 μM.

Glycidamide and cis-2-butene-1,4-dial (BDA) as potential carcinogens and promoters of liver cancer - An in vitro study.

Acrylamide and furan are environmental and food contaminants that are metabolized by cytochrome P450 2E1 (CYP2E1), giving rise to glycidamide and cis-2-butene-1,4-dial (BDA) metabolites, respectively. Both glycidamide and BDA are electrophilic species that react with nucleophilic groups, being able to introduce mutations in DNA and perform epigenetic remodeling. However, whereas these carcinogens are primarily metabolized in the liver, the carcinogenic potential of acrylamide and furan in this organ is still controversial, based on findings from experimental animal studies. With the ultimate goal of providing further insights into this issue, we explored in vitro, using a hepatocyte cell line and a hepatocellular carcinoma cell line, the putative effect of these metabolites as carcinogens and cancer promoters. Molecular alterations were investigated in cells that survive glycidamide and BDA toxicity. We observed that those cells express CD133 stemness marker, present a high proliferative capacity and display an adjusted expression profile of genes encoding enzymes involved in oxidative stress control, such as GCL-C, GSTP1, GSTA3 and CAT. These molecular changes seem to be underlined, at least in part, by epigenetic remodeling involving histone deacetylases (HDACs). Although more studies are needed, here we present more insights towards the carcinogenic capacity of glycidamide and BDA and also point out their effect in favoring hepatocellular carcinoma progression.

Covalent modification of poly(vinyl chloride) via organometallic Barbier reaction

The development of efficient synthetic methodologies for chemical functionalization and modification of existing polymers to improve or diversify the physicochemical and mechanical properties is an ongoing quest in macromolecular science. This is especially true for the generation of polymeric materials out of commercial/commodity polymers via structural tailoring since these polymers are produced in vast quantities and are structurally diverse. In this study, we report on benign chemical modification of an important commercial polymer, poly(vinyl chloride) (PVC) via Barbier reaction. The methodology is based on the employment of magnesium metal to generate nucleophilic alkyl-magnesium chloride groups on polymer backbone and addition of these nucleophilic centers to electrophilic carbonyl groups. The synthetic procedure can be implemented in a one-pot fashion by utilizing commonly available aldehyde or epoxide bearing compounds along with elemental magnesium. The Barbier addition of PVC backbone generated alkyl-magnesium chloride groups on the model aldehyde substrates with different structures were achieved with > 84 % functionalization degrees. It was shown that the functionalization degrees can easily be regulated by the simple alteration of employed magnesium ratio to backbone present alkyl chloride groups. Functionalization studies were investigated via 1H NMR, FT-IR and SEC analyses as well as contact angle measurements. Considering the wide industrial/ research utilization of poly(vinyl chloride) together with commercial availability, abundant reactive alkyl chloride bonds in backbone chains of this polymer offer easy to implement structural tailoring via proposed organometallic Barbier reaction.

Structural and mechanistic study of antimonite complexation with organic ligands at the goethite-water interface

Antimony is a re-emerging contaminant, and its complexation with natural organic matter is rising to ever-increasing levels due to global climate change, which has far-reaching impacts on its environmental fate and mobility. A molecular-level understanding of the interactions between Sb(III) and organic ligands at the solid-liquid interface is of paramount importance in deciphering the effect of these organic ligands. Herein, we identified and characterized Sb(III)-organic ligand complexes in solution and at the goethite-water interface using complementary techniques. The FT-ICR MS, XANES, and DFT calculations show that organic ligands bind Sb(III) through nucleophilic functional groups, such as -COO-, -OH and -HS. The formation of surface ternary Sb(III)-bridging complexes retarded the Sb(III) surface precipitation starting from 3.8mg-Sb/L to a much higher level at 8.3-13.5mg-Sb/L. The strong bond between Sb(III) and organic ligands is the key factor to inhibit Sb(III) adsorption, surface precipitation and oxidation under sunlight irradiation. Our results showed the chemical basis for the multifaceted functions of organic ligands in stabilizing trace metalloids such as Sb(III) in the environment.

Chemical Conjugation to Less Targeted Proteinogenic Amino Acids.

Protein bioconjugates are in high demand for applications in biomedicine, diagnostics, chemical biology and bionanotechnology. Proteins are large and sensitive molecules containing multiple different functional groups and in particular nucleophilic groups. In bioconjugation reactions it can therefore be challenging to obtain a homogeneous product in high yield. Numerous strategies for protein conjugation have been developed, of which a vast majority target lysine, cysteine and to a lesser extend tyrosine. Likewise, several methods that involve recombinantly engineered protein tags have been reported. In recent years a number of methods have emerged for chemical bioconjugation to other amino acids and in this review, we present the progress in this area.

Interaction of Pyrogallol-Containing Polyphenols with Mucin Reinforces Intestinal Mucus Barrier Properties.

High consumption of polyphenol-rich green tea, coffee, fruits, and vegetables is associated with a low risk of human chronic diseases. Recent studies highlight the relevance of polyphenol-mediated gut microbiota modulation and its impact on mucus barrier. Herein, we study the direct interaction of epicatechin (EC), epigallocatechin gallate (EGCG), and tannic acid (TA) with intestinal mucin by isothermal titration calorimetry and multiple particle tracking and the impact on mucus barrier using ex vivo mucus and Caco-2/HT29-MTX cocultures. Results show that pyrogallol-containing polyphenols EGCG and TA exhibit strong binding to intestinal mucin and reinforce mucus barrier, whereas EC does not. ECGG and TA also mitigate gliadin-mediated cytotoxicity and inflammation. The chemical binding of EGCG and TA to the nucleophilic thiol groups of mucins shows their roles as cross-linkers of mucin networks. These results bring a novel understanding of the health benefits of polyphenols and provide support for the consumption of pyrogallol-containing beverages like green tea as a potential dietary therapy for gluten-related disorders.

Transformation of L-DOPA and Dopamine on the Surface of Gold Nanoparticles: An NMR and Computational Study.

Gold nanoparticles (AuNPs) have found applications in biomedicine as diagnostic tools, but extensive research efforts have been also directed toward their development as more efficient drug delivery agents. The high specific surface area of AuNPs may provide dense loading of molecules like catechols (L-DOPA and dopamine) on nanosurfaces, enabling functionalization strategies for advancing conventional therapy and diagnostic approaches of neurodegenerative diseases. Despite numerous well-described procedures in the literature for preparation of different AuNPs, possible transformation and structural changes of surface functionalization agents have not been considered thoroughly. As a case in point, the catechols L-DOPA and dopamine were selected because of their susceptibility to oxidation, cyclization, and polymerization. To assess the fate of coating and functionalization agents during the preparation of AuNPs or interaction at the nano-bio interface, a combination of spectroscopy, light scattering, and microscopy techniques was used while structural information and reaction mechanism were obtained by NMR in combination with computational tools. The results revealed that the final form of catechol on the AuNP nanosurface depends on the molar ratio of Au used for AuNP preparation. A large molar excess of L-DOPA or dopamine is needed to prepare AuNPs funtionalized with fully reduced catechols. In the case of molar excess of Au, the oxidation of catechols to dopamine quinone and dopaquinone was promoted, and dopaquinone underwent intramolecular cyclization in which additional oxidation products, leukodopachrome, dopachrome, or its tautomer, were formed because of the larger intrinsic acidity of the more nucleophilic amino group in dopaquinone. MD simulations showed that, of the oxidation products, dopachrome had the highest affinity for binding to the AuNPs surface. The results highlight how a more versatile methodological approach, combining experimental and in silico techniques, allows more reliable characterization of binding events at the surface of AuNPs for possible applications in biomedicine.

A Nucleophilic Chemical Probe Targeting Electrophilic Functional Groups in an Untargeted Way to Explore Cysteine Modulators in Natural Products.

The vital roles of biologically relevant cysteines have been discovered from proteins that are promising targets for new drugs or chemical tools. Therefore, new electrophilic small molecules that can covalently modulate these cysteines have attracted immense interest. Because of their extremely wide chemical diversity, electrophilic natural products (NPs) have been studied as promising sources of cysteine modulators. Previous studies have developed chemical probes to facilitate the detection and isolation of electrophilic NPs. To address the problems with the current methods, including their low sensitivity, high false-positive rate, and dependence on performing manual processing with a plethora of spectra, we report a chemical probe that can first covalently capture electrophilic NPs from natural resources and then produce sensitive reporter ion signals that are specific for the detected NPs. We applied this untargeted method to explore electrophilic NPs from natural resources and found that the complexity of electrophilic NPs was beyond our expectations. We used this chemical probe to identify a new electrophilic furanosesterterpene (BG-1) from an extract of Ginkgo biloba that targets the Cys207 of acyl-CoA thioesterase 7 (ACOT7).

Catalytic Oxygen Activation over the Defective CuO Nanoparticles for Ultrafast Dehalogenation.

The nucleophilic superoxide radical (O2•-)-based dehalogenation reaction shows great potential to degrade the toxic halogenated organic compounds (HOCs). But such an O2•--mediated reductive reaction often suffers from the competition of the secondary oxidative species (e.g., •OH), leading to inferior electron efficiency and possible disinfection byproduct formation. Here, an O2•--dominant ultrafast dehalogenation system is developed via molecular O2 activation by the oxygen vacancy (OV)-rich CuO nanoparticles (nCuO). The nCuO delivers a remarkable dechlorination rate constant of 3.92 × 10-2 L min-1 m-2 for 2,4-dichlorophenol, much higher than that of the conventional zerovalent (bi)metals. The absorbed O2 on the nCuO surface is exclusively responsible for O2•- generation, and its reactivity increases with the elevated OV content because of the enhanced orbital hybridization between the O p- and Cu d-orbitals. More importantly, the ubiquitous carbonate species firmly bound to the surface OVs block the formation of the secondary oxidative species via H2O2 activation, assuring the dominant role of the in situ generated O2•- for the selective HOC dehalogenation. The carbonate-deactivated OVs of the nCuO can be feasibly recovered via air annealing for sustainable dehalogenation. This work provides a new opportunity for selective O2•- generation via interfacial defect engineering for dehalogenation and other environmental applications.

Synthetic fluorescent organic molecule for the detection of diethylcyanophosphonate via ON-OFF sensing mechanism: paper strips system for real-time application

ABSTRACT Imidazo[1,2-a] pyridine-based two probes with different substituents containing oxime and hydroxyl functional groups were synthesised and evaluated for detection of tabun nerve agent simulant diethylcyanophosphonate (DCNP). The nucleophile hydroxyl group present on both the probes can be rapidly phosphorylated by DCNP through a nucleophilic substitution reaction. The probes were fluorescent and on reacting with DCNP underwent fluorescence OFF, which can be visualised under a UV lamp at 365 nm wavelength. The limit of detection for probes 1 and 2 was calculated as 0.66 μM and 0.54 μM, respectively. The mechanism of detection was studied using spectroscopic techniques revealed that the hydroxyl group is involved in the reaction with DCNP. The probes were found selective for the detection of DCNP in presence of other electrophilic interfering agents. Results were obtained in aqueous media and probes can be used directly for the rapid and sensitive detection of DCNP in water without any pretreatment.

Accessing Illusive E Isomers of α-Ester Hydrazones via Visible-Light-Induced Pd-Catalyzed Heck-Type Alkylation.

A visible-light-induced Pd-catalyzed stereoselective synthesis of alkylated ester hydrazones has been developed. This method operates via generation of a nucleophilic carbon-centered radical from alkyl bromide, iodide, or redox-active ester, followed by its addition to hydrazone, and a subsequent desaturation by palladium. The majority of products have E configuration, which are inaccessible by conventional condensation methods. In addition, a sequential C,N-alkylation protocol has been developed: a reaction between 1,3-dihalides and glyoxylate-derived hydrazone, delivering tetrahydropyridazines.

Visible‐Light‐Promoted Radical Cyclization and N−N Bond Cleavage Relay of N‐Aminopyridinium Ylides for Access to 2,3‐Difunctionalized Indoles

AbstractReported herein is a photocatalytic platform for the vicinal aminopyridylation of indoles. The accurate difunctionalization reaction undergoes a tandem process involving a radical‐mediated 1,3‐dipolar cycloaddtion which generated from the single‐electron oxidation of N‐aminopyridinium ylides, a cleavage of the N−N bond as well as an oxidation of indoline ring. The electrophilic pyridyl and nucleophilic amino groups can be installed simultaneously into a wide range of indoles under mild and metal‐free conditions. Moreover, the protocol shows high levels of step and atom economy.magnified image