Nucleophilic Addition Research Articles

Functionalized Hydrocarbon Belts: Synthesis, Structure and Properties

AbstractHydrocarbon belts have drawn great attention because of their unique structures and tantalizing properties. Although a few belts and heteroatom‐doped analogs have been synthesized, belt molecules containing non‐hexagonal rings remain rare. Herein we report the construction and application of unprecedented zigzag‐type hydrocarbon belts which contain functionalized eight‐membered rings. The synthesis features fourfold intramolecular acylation reactions of resorcin[4]arene‐derived intermediates, which affords C4‐symmetric tetrabenzobelt[4]arene[4]cyclooctatrienones. Stereoselective ketone reduction with LiAlH4 and nucleophilic addition with alkynyllithiums provide the corresponding tetrahydroxylated belts. The tetraol and its methyl ether are powerful and selective hosts to form 2 : 1 and 1 : 1 complexes with cesium ion, respectively, with binding constants up to (1.71±0.33)×1011 M−2 and (1.50±0.16)×106 M−1. In addition, enantiopure C4‐symmetric belts can emit CPL with |glum| being around 0.01.

Functionalized Hydrocarbon Belts: Synthesis, Structure and Properties.

Hydrocarbon belts have drawn great attention because of their unique structures and tantalizing properties. Although a few belts and heteroatom-doped analogs have been synthesized, belt molecules containing non-hexagonal rings remain rare. Herein we report the construction and application of unprecedented zigzag-type hydrocarbon belts which contain functionalized eight-membered rings. The synthesis features fourfold intramolecular acylation reactions of resorcin[4]arene-derived intermediates, which affords C4-symmetric tetrabenzobelt[4]arene[4]cyclooctatrienones. Stereoselective ketone reduction with LiAlH4 and nucleophilic addition with alkynyllithiums provide the corresponding tetrahydroxylated belts. The tetraol and its methyl ether are powerful and selective hosts to form 2:1 and 1:1 complexes with cesium ion, respectively, with binding constants up to (1.71±0.33)×1011 M-2 and (1.50±0.16)×106 M-1. In addition, enantiopure C4-symmetric belts can emit CPL with |glum| being around 0.01.

Deoxygenative Radical Boration of Inert Amides via a Combination of Relay and Cooperative Catalysis.

One of the most challenging tasks in organic synthesis is to develop novel methodologies for rapid construction of complex molecules starting from easily available yet inert raw materials. In this context, multi-catalysis strategies have attracted great attention in the discovery of new reactivity profiles that may allow access to many difficult or unattainable transformations. So far the deoxygenative functionalization of ubiquitous amides is usually achieved by nucleophilic attack on the imine or iminium ion intermediate formed via activation of the C=O bond, and these functionalization reagents were often confined to C-based nucleophiles, which largely limited the diversity of the resultant amines. Herein, we disclose a combined strategy of relay and cooperative catalysis with a triple iridium-photoredox-organocatalysis system to achieve an unprecedented reductive boration of amides, affording valuable α-amino boron products which are viable building blocks. In this transformation, the Ir-catalyzed semi-reduction of amides is successfully incorporated with photo-organic catalyzed nucleophilic boryl radical addition, thus delivering the corresponding α-boryl amines in high efficiency.

Multi-Responsive Eight-State Bis(acridinium-Zn(II) porphyrin) Receptor.

A multi-responsive receptor consisting of two (acridinium-Zn(II) porphyrin) conjugates has been designed. The binding constant between this receptor and a ditopic guest has been modulated (i) upon addition of nucleophiles converting acridinium moieties into the non-aromatic acridane derivatives and (ii) upon oxidation of the porphyrin units. A total of eight states has been probed for this receptor resulting from the cascade of the recognition and responsive events. Moreover, the acridinium/acridane conversion leads to a significant change of the photophysical properties, switching from electron to energy transfer processes. Interestingly, for the bis(acridinium-Zn(II) porphyrin) receptor, charge-transfer luminescence in the near-infrared has been observed.

Fabrication of ionic liquid-functionalized covalent organic frameworks for friction and wear reduction

Herein, the ionic liquid functionalized covalent organic frameworks (COFs) nanosheets were successfully prepared via solvothermal reaction and then surface modification. Firstly, the COF with –OH groups (COF-OH) can bond with isocyanate (TDI) via the reactions between –OH group of COF-OH and para-NCO group of TDI, then the NH2-ionic liquid ([NH2C2MIm][Br]) can graft onto COF-OH surface (Br-IL@COF-OH) via nucleophilic addition reactions between –NH2 and ortho-NCO group. The as-prepared Br-IL@COF-OH exhibited outstanding lubrication performance as oil-based lubrication additives, with a trace amount addition of 2.0 wt%, the friction coefficient decreases from 0.144 to 0.102, and the wear volume decreases from 1.38 × 104 μm3 to 2.58 × 103 μm3, nearly 81.4%. The remarkable tribological properties are derived from the formation of stable protective film, which is composed of a physical adsorption layer via grafting ionic liquid and the friction film via tribochemical reaction.

Intermolecular Dearomative 1,2-Amination/Carbonylation via Nucleophilic Addition of Simple Amines to Arene π-Bonds.

The incorporation of the privileged amino functionality is of paramount importance in organic synthesis. In contrast to the well-developed amination methods for alkenes, the dearomative amination of arenes is largely underexplored due to the inherently inert reactivity of arene π-bonds and selectivity challenges. Herein, we report an intermolecular dearomative aminofunctionalization via direct nucleophilic addition of simple amines to chromium-bound arenes. This multicomponent 1,2-amination/carbonylation reaction enables rapid access to complicated alicyclic compounds containing amino and amide functionalities from benzene derivatives under CO-gas-free conditions, which also represents the first application of nitrogen-based nucleophiles in η6-coordination-induced arene dearomatizations.

A theoretical study of the mechanisms, regio- and enantioselectivities associated with rhodium-catalyzed allylic alkylation reactions using hard benzylzinc nucleophiles

A systematic theoretical study of rhodium-catalyzed allylic alkylation reactions using hard benzylzinc nucleophiles was performed. The mechanisms were investigated in detail together with the regioselectivity associated with the branched and linear pathways and the intriguing anti- (as opposed to syn-) diastereoselectivity of this process. The preferred mechanism was found to be initiated by the oxidative addition of the rhodium(I) complex followed by migration of the benzyl nucleophile to the Rh center. The subsequent nucleophilic addition of a benzyl group to the η3-allyl moiety takes place via the formation of a new C–C bond to afford the final allylic benzylation product. This proposed mechanism readily explains the experimental observation that the products obtained from such reactions are branched (as opposed to linear) with an anti-configuration (as opposed to a syn-configuration). This work also provides reasons for the lower regioselectivity observed for a OCO2tBu leaving group or cyanophenyl/secondary amide substituents at the 4-position of the substrate. The present study is expected to assist in the rational design of potential substrates for analogous reactions.

N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry

Oxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.5 Å apart unlike canonical FAD-dependent oxidoreductases. One site could accommodate glycine and the other glycinothricin or glycylthricin. Moreover, an intermediate-enzyme adduct with a NOS-covalent linkage was observed in the later site, where it acts as a two-scissile-bond linkage facilitating nucleophilic addition and cofactor-free decarboxylation. The chain length of nucleophilic acceptors vies with bond cleavage sites at either N–O or O–S accounting for N-formimidoylation or N-iminoacetylation. The resultant product is no longer sensitive to aminoglycoside-modifying enzymes, a strategy that antibiotic-producing species employ to counter drug resistance in competing species.

Structural Features of Diacyldodecaheterocycles with Pseudo-C2-Symmetry: Promising Stereoinductors for Divergent Synthesis of Chiral Alcohols.

Pseudo-C2-symmetric dodecaheterocyclic structures, which possess two acyl/aroyl groups disposed on either a cis- or trans-relative configuration, were prepared from the naturally occurring (-)-(1R)-myrtenal. Addition of Grignard reagents (RMgX) to the diastereoisomeric mixture of these compounds unexpectedly showed that nucleophilic additions to the two prochiral carbonyl centers gave the same stereochemical result in both cis/trans diastereoisomers, making unnecessary the separation of this mixture. Noticeably, both carbonyl groups showed different reactivity because one of them is attached to an acetalic carbon and the other to a thioacetalic carbon. Furthermore, addition of RMgX to the carbonyl attached to the former carbon takes place through the re face, while addition to the second one proceeds through the si face, thus affording the corresponding carbinols in a highly diastereoselective process. This structural feature allowed the sequential hydrolysis of both carbinols, yielding separately (R)- and (S)-1,2-diols after reduction with NaBH4. The mechanism of the asymmetric Grignard addition was explained by density functional theory calculations. This approach contributes to the development of the divergent synthesis of structurally and/or configurationally different chiral molecules.

Different modes of attachment of graphitic carbon nitrides on glassy carbon electrode and their electrocatalytic activity

The present investigation reveals the attachment of graphitic carbon nitride nanosheets (GCNS) on glassy carbon (GC) electrode by adsorption, drop casting and potentiodynamic methods and their electrocatalytic activity. The bulk GCN was derived from urea and then converted into GCNS via water exfoliation aided by sonication. The GCNS was then directly attached to the GC electrode (GCNS-a) by immersing it in GCNS for 12 h. The initial adsorption of GCNS on the GC electrode is similar to Michael's like nucleophilic addition, and subsequent attachment may occur via π-π stacking. In the next mode of attachment, GCNS was fabricated by drop casting (GCNS-b) a known quantity of GCNS and dried at room temperature. In the third mode of attachment (GCNS-c), GCNS was fabricated on GC electrode by fifteen potential cycles in 0.1 M H2SO4 containing 1 mg mL−1 GCNS. The GCNS modified by these three different protocols were characterized by scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). The SEM studies reveal that the morphology of GCNS varies with respect to the mode of attachment. The GCNS modified by potential cycling shows termitarium like structure whereas sheet like structure and an aggregated transparent thin sheet were noticed for direct adsorption and drop casting methods, respectively. Among the three different modes of attachments, improved electroactive surface area (EAS) and less charge transfer resistance (RCT) value were obtained for GC/GCNS-c electrode. Further, the GCNS attached by potentiodynamic method exhibited enhanced electrocatalytic performance towards ascorbic acid (ASA), dopamine (DPA) and hydrogen peroxide (HDP) in contrast to GCNS modified by adsorption and drop casting methods. The elevated electrochemical activity was due to larger EAS and lower impedance of GCNS-c electrode. The oxidation current increased linearly increases when increasing the concentration of HDP from 100 nM to 1 mM and the limit of detection was 5.2 nM (S/N = 3). Further, GCNS-c electrode also selectively determines HDP in the presence of 500-fold higher concentration of major interferents.

Synthesis of 1,2‐Dihydrofuro[3,4‐d]pyrimidine Derivatives as Potential VEGFR‐2 Inhibitors, and Proposed Mechanism for the 5,6‐Dihydro‐4H‐furo[3,4‐c]pyrrol‐4‐one

AbstractThe fourteen novel 1,2‐dihydrofuro[3,4‐d]pyrimidine compounds were synthesized from 4‐(2‐azido‐2‐oxoethyl)furan‐3‐carbonyl azide, by the two selected Curtius rearrangement, nucleophilic addition, and intramolecular cyclization reactions. Molecular docking studies of these compounds were performed with vascular endothelial growth factors receptor‐2 (VEGFR‐2) tyrosine kinase (PDB ID:3WZE). Cytotoxicity studies against human prostate cancer cells (DU145), revealed that compound 8 e has cytotoxic potential. Additionally, in‐silico ADME studies appeared that most of the synthesized compounds obeyed Lipinski's rule. Also, the mechanism for 5,6‐dihydro‐4H‐furo[3,4‐c]pyrrol‐4‐one, which occurs in the reaction of isocyanate 2 with thiols, was proposed. The azide group acts as the leaving group in this reaction.

Fluoroalkylations and Fluoroalkenylations with Iodonium Salts.

Synthesis and applications of fluoroalkyl and fluoroalkenyliodonium salts are summarized in this account article, focusing preferably to the reagents designed in our laboratory in the last decade. Among these reagents trifluoroethyl(aryl)iodonium salts have been used most frequently to build carbon-carbon and carbon-heteroatom bonds in simple nucleophilic substitutions and through transition metal catalyzed coupling reactions. Iodonium salts equipped with unsaturated fluorinated function showed diverse reactivity due to their electron deficient character, and these molecular motifs enable cycloadditions and nucleophilic additions to prepare fluorinated carbo- and heterocyclic molecules. Beyond the overview of existing transformations, with the presented collection, we aim to inspire future developments of iodonium reagents and their application in organic synthesis.

Nanoarchitecture of a Ti3C2@TiO2 Hybrid for Photocatalytic Antibiotic Degradation and Hydrogen Evolution: Stability, Kinetics, and Mechanistic Insights.

Designing of a visible-light-driven semiconductor-based heterojunction with suitable band alignment and well-defined interfacial contact is considered to be an effective strategy for the transformation of solar-to-chemical energy and environmental remediation. In this context, MXenes have received tremendous attention in the research community due to their merits of abundant derivatives, elemental composition, excellent metallic conductivity, and surface termination groups. Meanwhile, a facile synthetic strategy for MXene-derived TiO2 nanocomposites with stable framework and higher photocatalytic activity under visible-light irradiation still remains a challenge for researchers. Herein, we report a novel synthetic strategy of preparing a two-dimensional Ti3C2@TiO2 nanohybrid by a facile reflux method under acidic conditions. In this oxidation reaction, protonation of the hydroxyl terminal group of MXene creates Ti more electrophilic and susceptible to an oxidative nucleophilic addition reaction with the presence of both water and oxygen. The physicochemical properties of the nanohybrid Ti3C2@TiO2 were verified by varieties of characterization techniques. High-resolution transmission electron microscopy and X-ray photoelectron spectroscopy analysis specifically elucidated the intimate interfacial interaction between Ti3C2 and TiO2. The optimized Ti3C2@TiO2-48 h photocatalyst exhibited the highest tetracycline hydrochloride (TCH, 90% in 90 min) degradation efficiency in comparison to pristine TiO2 with a rate constant (k) of 0.02463 min-1. The major contribution of •O2- and •OH radicals throughout photocatalytic TCH degradation was confirmed by the trapping experiment. Moreover, the photocatalyst showed the highest hydrogen generation rate of 140.8 μmol h-1 along with an apparent conversion efficiency of 2.2%. The excellent photocatalytic activity of Ti3C2@TiO2 originated from the superior electrical conductivity of cocatalyst Ti3C2, which facilitated spatial photogenerated e-/h+ separation and transfer at the Ti3C2 MXene@TiO2 interface. Overall, this research work will describe a promising protocol of designing MXene-derived photocatalysts toward efficient environmental remediation and wastewater treatment applications.

Arynes in Natural Product Synthesis

Abstract: Arynes are a unique class of intermediates used in synthetic organic chemistry, and research interest has been intensely focused on their peculiar reactivities. Arynes have been researched for almost a century. However, difficulties in monitoring these reactive species, as well as difficulties in creating synthetically viable techniques for their synthesis and trapping, have restricted their application. A key tactic for achieving the racemic and enantiopure total synthesis of a broad variety of natural compounds or their structural derivatives. The chemistry of arynes has advanced significantly over the past thirty years, particularly in the field of transition metal carbon- carbon and carbon-heteroatom bond-forming mechanisms. The field’s fast growth is largely attributable to the development of mild aryne production processes. To create a natural product with complex organic molecules, the role of aryne intermediates was non-replaceable. These organic substances are often used in medicine, therapies, or as raw material for the synthesis of other substances. Moreover, they may perform important biological tasks. There are numerous methods for synthesizing natural compounds including total synthesis, semi-synthesis, and biosynthesis. Total synthesis is the process of creating natural products entirely chemically from basic precursors as well as it can be produced in large quantities and can reveal information about its biological activity. One of the developments in Arynes’ chemistry is the chemical rearrangements brought about by this electrophilic intermediate. It is not feasible to use conventional methods in a single step. This review article discusses how arynes are used to create natural products. Arynes has a wide range of functionality in the field of scientific research. The evolution of this method has made a tremendous change in the total synthesis of natural products. Benzynes enabled creative synthesis in mild conditions. The transformation has expanded to investigate various reaction classes such as nucleophilic addition, (4+2), and (2+2) cycloaddition strategies and metal-catalyzed reactions are shown and explained in this article. This review will provide an idea about how the arynes act as an intermediate in those reaction mechanisms and enlighten the scope of these aryne intermediate.

Quinone reactivity: Investigation of their contribution to nonenzymatic browning

AbstractBrowning is a severe problem in the juice industry, which is tremendously affected by quinone (Q) reactivity. Here, the formation rate, electrophilicity, and oxidizing ability of different quinones were investigated. LC/MS was applied to monitor the loss of polyphenols and quinones in model systems during storage. Mathematical modeling of collected LC/MS data was conducted to derive the rate constants of various reactions. Polyphenols containing catechol or pyrogallol groups are more susceptible to oxidation. Periodic acid and quinone mediated oxidation were faster than the autoxidation of polyphenols. Chlorogenic acid (CQA) and 4‐methylcatechol (4MC) only containing B ring can hardly contribute to browning. They must combine with A ring to form yellow polymers. Furthermore, the electrophilicity and oxidizing ability order of quinone is: CQA‐Q ≈ 4MC‐Q > catechin quinone (CAT‐Q) ≈ epicatechin quinone (EC‐Q) > gallic acid quinone (GA‐Q). It was possible that CAT‐Q and EC‐Q would undergo nucleophilic addition with their A rings and GA‐Q's extra hydroxyl group might contribute to the electrons, resulting in lower reactivity. This work innovatively evaluated the reactivity of diverse polyphenols and quinones, attempting to illustrate their contributions to nonenzymatic browning. These findings provide a new perspective to restrain the browning in the juice processing industry.

Phosphine-Catalyzed Tandem Annulation of Allenylic Alcohols with 1,1-Dicyanoalkenes

The phosphine-catalyzed tandem annulation of allenylic alcohols with 1,1-dicyanoalkenes has been developed, giving various bicyclic tetrahydrocyclopentafuran derivatives in 40-89% yields with moderate to excellent diastereoselectivities. The fused ring was furnished through a sequential (3 + 2) annulation/nucleophilic addition reaction. The unusual nucleophilic addition of an alkoxide ion to a cyano group led to a formation of tetrahydrofuran ring having an imino substituent.

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.

Synthesis of 2-Sulfonylthiazoles via Heteroaryl C–H Sulfonylation of Thiazole N-Oxides

AbstractDescribed here is an efficient method for the modular synthesis of 2-sulfonylthiazole derivatives via heteroaryl C–H sulfonylation. The protocol is composed of two stages involving O-activation of thiazole N-oxides and nucleophilic addition of a sulfinate, which induces N(3)-deoxygenation and C(2)-sulfonylation. The vicarious substitution is performed most effectively by using 4-methoxybenzoyl chloride for O-acylation while employing sodium [tert-butyl(dimethyl)silyloxy]methanesulfinate (TBSOMS-Na) as the nucleophile. The sulfones thus obtained can be converted to an array of thiazolyl sulfones, sulfonamides, and sulfonyl fluorides by displacing the silyloxymethyl moiety with alkyl, aryl, amino, and fluoro groups. The C–H sulfonylation approach, in combination with a sulfoxylate (SO2 2–) strategy, provides direct access to sulfonylated thiazole scaffolds without recourse to the use of 2-halothiazoles.

Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives.

Since 18251, compounds with the molecular formula C6H6-most notably benzene-have been the subject of rigorous scientific investigation2-7. Of these compounds, 1,2,3-cyclohexatriene has been largely overlooked. This strained isomer is substantially (approximately 100 kcal mol-1) higher in energy compared with benzene and, similar to its relatives benzyne and 1,2-cyclohexadiene, should undergo strain-promoted reactions. However, few experimental studies of 1,2,3-cyclohexatriene are known8-12. Here we demonstrate that 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes, including diverse cycloadditions, nucleophilic additions and σ-bond insertions. Experimental and computational studies of an unsymmetrical derivative of 1,2,3-cyclohexatriene demonstrate the potential for highly selective reactions of strained trienes despite their high reactivity and short lifetimes. Finally, the integration of 1,2,3-cyclohexatrienes into multistep syntheses demonstrates their use in rapidly assembling topologically and stereochemically complex molecules. Collectively, these efforts should enable further investigation of the strained C6H6 isomer 1,2,3-cyclohexatriene and its derivatives, as well as their application in the synthesis of important compounds.

Difluorocarbene-Triggered [1+5] Annulation: Access to Functionalized 1,1-Difluoro-1,9a-dihydropyrido[2,1-c][1,4]thiazine Derivatives

Difluorocarbene-triggered [1+5] annulation is developed to access 1,1-difluoro-1,9a-dihydropyrido[2,1-c][1,4]thiazine-3,4-dicarboxylate derivatives in satisfactory to good yields via the direct reaction of potassium bromodifluoroacetate and pyridinium 1,4-zwitterionic thiolates under heating. Pyridinium 1,4-zwitterionic thiolates first nucleophilically attack difluorocarbene generated from potassium bromodifluoroacetate followed by an intramolecular nucleophilic addition to pyridiniums. This method provides an expeditious route to introduce the difluoromethyl group into the 1,9a-dihydropyrido[2,1-c][1,4]thiazine ring, even to modify drug molecules.