Nucleophilic Addition Research Articles

One‐Pot Synthesis of Ortho‐Halogen‐Substituted Aryl(Alkynyl)Phosphinates Via Aryne‐Phosphite‐Haloalkyne Coupling

AbstractThe one‐pot formation of two C−P bonds and one C−halogen bond was achieved through a mild three‐component coupling reaction utilizing arynes, phosphites, and haloalkynes. In this reaction, the aryl anion, generated from the nucleophilic addition of phosphite to aryne, directly attacked the halogen of the haloalkyne. The reaction proceeded smoothly with a wide substrate scope and good functional group tolerance. This operationally simple method enables direct access to ortho‐halogen‐substituted aryl(alkynyl)phosphinates. The synthetic utility of ortho‐halogen‐substituted aryl(alkynyl)phosphinates with prospective applications in natural product synthesis, medicinal chemistry, and materials chemistry has also been demonstrated.

A Photochemical Strategy towards Michael Addition Reactions of Cyclopropenes

The development of Michael addition reactions to conjugated cyclopropenes is a challenge in organic synthesis due to the fleeting and reactive nature of such strained Michael acceptor systems. Herein, the development of a photochemical approach towards such conjugated cyclopropenes is reported that serves as a strategic entry point to densely functionalized cyclopropanes in a diastereoselective fashion. The process involves the light‐mediated generation of transient cyclopropenyl α,β‐unsaturated esters from vinyl diazo esters, followed by an organic base catalyzed nucleophilic addition of N‐heterocycles to directly access β‐N‐heterocyclic cyclopropanoic esters. With this synergistic approach, various trisubstituted cyclopropanes bearing N‐heteroaryl and N‐heterocyclic rings such as indole, pyrrole, benzimidazole, isatin, pyridinone and quinolinone were accessed efficiently in good yield and decent to good diastereoselectivities. Further, β‐indolyl cyclopropanoic acids have been synthesized and were successfully evaluated as FABP‐4 inhibitors. Theoretical calculations have been performed to elucidate the mechanism which was further supported by experimental findings.

Bro̷nsted Acid-Catalyzed Regioselective [5 + 1] Annulation for the Synthesis of Indole-Fused Dihydrochromanes.

A Bro̷nsted acid-catalyzed [5 + 1] annulation of 2-(1H-indol-2-yl)phenols, a class of indole-based 1,5-CO-synthons, with aldehydes has been established. By this approach, various indole-fused dihydrochromanes were synthesized in moderate to good yields (up to 99%) with excellent regioselectivities. Control experiments not only showed the H-bonding interaction between the NH group of the substrates─and the acid catalyst is vital to realize this transformation─but also indicated that an indolylmethanol-type intermediate was possibly formed via the first step of nucleophilic addition of indole C3-position to aldehydes during the reaction process. This reaction represents the first Bro̷nsted acid-catalyzed regioselective [5 + 1] annulation of 2-(1H-indol-2-yl)phenols and provides a novel strategy for constructing biologically intriguing indole-fused dihydrochromane skeletons in a highly regioselective manner.

Exploring the covalent inhibition mechanisms of inhibitors with two different warheads acting on SARS-CoV-2 Mpro by QM/MM simulations

SARS-CoV-2 Mpro had been reported to react with covalent inhibitors 14c and C7, containing a vinyl sulfanilamide and chloromethylamide as the warheads, respectively. However, the detailed reaction mechanisms and warhead effects are still unclear. In this study, the initial state of the catalytic dyad Cys145/His41 is determined as neutral during the non-covalent binding, through MM-PBSA free energy calculations. The Potential of Mean Forces (PMFs) have been computed by QM/MM MD method, obtaining the free energy changes from reactants to products. Both reactions follow asynchronous mechanism. Except the similar proton transfer (PT1), subsequently, nucleophilic addition and an additional proton transfer (PT2) for 14c, while an SN2 nucleophilic substitution for C7 are underwent, respectively. The reaction activation barrier and free energy trends both are in consistent with the experimental IC50 results. Our research enhances understanding of the inhibitory mechanism, and provides insights for designing novel and more effective inhibitors targeting SARS-CoV-2 Mpro.

Construction and application of fluorescent probe and sensing aerogel with ability to detect hydrogen sulfide

The dyeing, wastewater acidification and anaerobic treatment processes in the textile always produce a large amount of hydrogen sulfide (H2S), which will be harmful to the human beings. The fluorescent detection of H2S with highly specific and sensitive probe is of significance. Here, using the 2, 7-dichlorofluorescein (DCF) derivative DCF-MPYM as the fluorophore, a fluorescent probe M1 for specifically recognizing H2S was designed and synthesized by introducing 2-chloro-5-nitrobenzoic acid into the oxanthracene moiety of DCF-MPYM. The introduction of 2-chloro-5-nitrobenzoic acid results in DCF-MPYM being in a closed-loop state, thus, the fluorescence quantum yield (Φ) of the probe M1 was low. The characteristic of weak fluorescence plays an important role in the use of a fluorescent probe. The fluorescence titration and selectivity results demonstrated that the probe M1 could selectively detect H2S, and its detection limit for H2S was calculated to be 45.31 μM. The reaction mechanism of the probe was verified by the high-resolution mass spectrometry (HRMS) and liquid chromatography as the nucleophilic addition of H2S to the probe M1, which induced the cleavage of ester bond and subsequently restored the spectral properties of DCF-MPYM. To bring the probe M1 into practical application, the fluorescent aerogel CMC-M1 was constructed by mixing the probe M1 and carboxymethyl cellulose sodium (CMC-Na) aerogel, and the fluorescent aerogel can be applied in absorbing and removing H2S in water. The adsorption capacity and removal efficiency of CMC-M1 for H2S were 0.626 mg·g−1 and 99.36 %. The investigation of adsorption kinetic showed that the adsorption effect of CMC-M1 towards Na2S was mainly chemical adsorption. In addition, the fluorescent aerogel CMC-M1 can be applied for qualitative, quantitative detection and effective removal of H2S in dyeing and finishing wastewater.

Lysine-regulated turing structure membrane via interfacial polymerization for enhanced Li+/Mg2+ separation

The development of advanced membranes with precise ion selectivity is essential for efficient Li+/Mg2+ separation. In this study, we synthesized a novel Lys-TMC membrane via a nucleophilic addition reaction between Lysine and trimesoyl chloride (TMC), yielding in a negatively charged surface interconnected by amide bonds. We systematically investigated the effects of varying Lys:TMC ratios on the membrane’s chemical structure, surface morphology, and ion separation performance. Our results revealed that the degree of cross-linking increases initially with the Lysine content, reaching an optimum at a Lys:TMC ratio of 10:1, where the membrane exhibited prominent Turing patterns on its surface. These patterns were critical for achieving effective ion separation. In contrast, excessive Lysine led to spontaneous polymerization, resulting in irregular ‘stone-like’ structures and the loss of Turing patterns. The optimally cross-linked Lys-TMC membrane displayed superior Li+/Mg2+ separation performance, highlighting the crucial role of controlled cross-linking and Turing structure formation in enhancing ion selectivity. This work provides a mechanistic understanding of the relationship between Turing structure formation and ion sieving performance, offering a promising strategy for designing advanced separation membranes.

Facile Synthesis of Phthalazinone/Isoindolinone Substituted Fluorescence Active Indolo[1,2‐a]quinoxaline Derivatives via ANRORC and Fluorescence Turn Off Sensing of Fe2+

AbstractSynthesis of a series of indolo[1,2‐a]quinoxaline derivatives substituted with phthalazinones/isoindolinones/carbonyl benzoylesters at C‐4 position have been accomplished under open air rt/heating conditions following ANRORC (Addition of Nucleophile, Ring Opening and Ring Closure) mechanism. Initially condensation of 2‐(1‐indolyl)‐aniline and ninhydrin generates a spirocyclic intermediate 5′H‐spiro[indene‐2,6′‐indolo[1,2‐a]quinoxaline]‐1,3‐dione, which upon reaction with various nucleophiles like hydrazine/phenylhydrazine, amines and alcohols affords C‐4 substituted indolo[1,2‐a]quinoxalines in high yield (up to ~88 %) via ANRORC. The photophysical investigation shows that the quinoxaline derivatives possess significant fluorescence property with high quantum yield (QY~11.0–17.0). The N‐phenylphthalazinone substituted indolo[1,2‐a]quinoxaline, a molecule structurally similar to 2,2′‐bipyridine system, can efficiently and selectively detect Fe2+ through fluorescence turn off sensing.

Selective monodeuteration enabled by bisphosphonium catalyzed ring opening processes

The selective incorporation of a deuterium atom into small molecules with high selectivity is highly valuable for medical and chemical research. Unfortunately, this remains challenging due to the complete deuteration caused by commonly used hydrogen isotope exchange strategies. We report the development of a photocatalytic selective monodeuteration protocol utilizing C–C bond as the unconventional functional handle. The synergistic combination of radical-mediated C–C bond scission and deuterium atom transfer processes enables the effective constructions of benzylic CDH moieties with high selectivity for monodeuteration. The combinational use of a bisphosphonium photocatalyst, thiol catalyst, and CH3OD deuteration agent provides operationally simple conditions for photocatalytic monodeuteration. Moreover, the photoinduced electron transfer process of the bisphosphonium photocatalyst is elucidated through a series of spectroscopy experiments, identifying a peculiar back electron transfer process that can be regulated by subsequent nucleophilic additions.

Enantioselective Au(I)-Catalyzed Cycloisomerization/Addition of Oxygen Nucleophiles to 2-Alkynylenones by the Tethered Counterion-Directed Catalysis Strategy.

The tethered counterion-directed catalysis (TCDC) strategy enables the Au(I)-catalyzed highly enantioselective synthesis of bicyclic furan derivatives via a reaction sequence combining the cycloisomerization of 2-alkynyl enones and the addition of nucleophiles. A large range of oxygenated nucleophiles, such as water, alcohols, carboxylic acids, and peroxides, have successfully been used as nucleophiles, delivering the chiral furane derivatives in high enantioselectivities (mostly above 90% enantiomeric excess). The CPAphosAuCl complexes were used with catalytic loadings as low as 0.2 mol % in most cases, in combination with silver carbonate as the chloride abstractor.

Construction of a Lanthanide Cage with a Hollow-Walled Cavity and Large Windows to Promote Nucleophilic Additions

Construction of a Lanthanide Cage with a Hollow-Walled Cavity and Large Windows to Promote Nucleophilic Additions

HBr/TMSO/HFIP Mediated Chemoselective Modifications of Pyrrolo[2,1‐a]Isoquinolines

AbstractThe combination of HBr, TMSO (tetramethylene sulfoxide) and HFIP (hexafluoroisopropanol) has been utilized in the modification of pyrrolo[2,1‐a]isoquinoline derivatives through bromination, dimerization and sulfenylation respectively. In these processes, HBr serves as the source of bromine and TMSO acts as an oxidant. HFIP also plays an essential role for the oxidative dimerization. Chemoselectivity can be easily controlled by adjusting the parameters such as reaction time, ratio of reagents and the addition of nucleophile.

Highly Strained, Fully π‐Conjugated Porphyrin Cyclophanes: Template‐free Synthesis and Global Aromaticity

Porphyrin‐based nanohoops, nanorings, and cages with fully π‐conjugated structures are highly sought after, but their synthesis remains challenging. Herein, we report the template‐free synthesis of a highly strained, bithiophene‐bridged porphyrin cyclophane (1) from a porphyrin quinone via a stereoselective nucleophilic addition followed by intermolecular Yamamoto coupling strategy. X‐ray crystallographic analyses of 1 and its dication 12+ reveal significantly distorted cyclophane‐like geometries, with calculated strain energies of 51.2 and 80.7 kcal/mol, respectively. While the neutral compound 1 exhibits localized aromaticity, the dication 12+ is globally aromatic, with the porphyrin unit displaying weak antiaromaticity. Additionally, the dication 12+ undergoes nucleophilic addition with chloride, relieving strain. This work presents a novel synthetic strategy for highly strained, fully π‐conjugated systems with intriguing electronic properties and chemical reactivity.

Highly Strained, Fully π-Conjugated Porphyrin Cyclophanes: Template-free Synthesis and Global Aromaticity.

Porphyrin-based nanohoops, nanorings, and cages with fully π-conjugated structures are highly sought after, but their synthesis remains challenging. Herein, we report the template-free synthesis of a highly strained, bithiophene-bridged porphyrin cyclophane (1) from a porphyrin quinone via a stereoselective nucleophilic addition followed by intermolecular Yamamoto coupling strategy. X-ray crystallographic analyses of 1 and its dication 12+ reveal significantly distorted cyclophane-like geometries, with calculated strain energies of 51.2 and 80.7 kcal/mol, respectively. While the neutral compound 1 exhibits localized aromaticity, the dication 12+ is globally aromatic, with the porphyrin unit displaying weak antiaromaticity. Additionally, the dication 12+ undergoes nucleophilic addition with chloride, relieving strain. This work presents a novel synthetic strategy for highly strained, fully π-conjugated systems with intriguing electronic properties and chemical reactivity.

Comparison of the Reactivity for the Solvent Extraction of Gold(iii) from Concentrated HCl Solutions Among D2EHPA, PC 88A, and Cyanex 272

ABSTRACT In this study, the chemical reactivity of three organophosphorus acidic extractants (D2EHPA, PC 88A, and Cyanex 272) was compared for the extraction of the anionic gold(III) complex, AuCl4 −, from the concentrated hydrochloric acid solutions. The extraction behavior was examined by varying the hydrochloric acid concentration from 1 to 9 M. Among the three extractants, only Cyanex 272 showed significant efficiency in extracting Au(III) with the extraction percentage was proportional to hydrochloric acid concentration. In contrast, the extraction of Au(III) by D2EHPA and PC 88A was not significant. FT-IR spectra analysis indicated that the P=O bond in Cyanex 272 weakened after extraction, suggesting its involvement in the process. Based on the structural differences between the extractants and the observed dependence of gold(III) extraction on the hydrochloric acid concentration, a nucleophilic addition reaction was proposed as the extraction mechanism. Specifically, the phosphoryl oxygen of protonated Cyanex 272 likely forms a coordinate bond with the gold ion in AuCl4 −, facilitating its extraction. This mechanism was supported by both extraction and spectroscopic data, making Cyanex 272 a promising candidate for the selective extraction of Au(III) from highly acidic solutions. The findings offer insights into the extraction of metal ions using organophosphorus extractants in highly acidic environments.

Photocatalytic generation of alkyl carbanions from aryl alkenes

AbstractOrganometallic reagents are routinely used as fundamental building blocks in organic chemistry to rapidly diversify molecular fragments via carbanion intermediates. However, the catalytic generation of carbanion equivalents, particularly from sp3-hybridized alkyl scaffolds, remains an underdeveloped goal in chemical synthesis. Here we disclose an approach for the generation of alkyl carbanions via single-electron reduction of aryl alkenes, enabled by multi-photon photoredox catalysis. We demonstrate that photocatalytically induced alkyl carbanions engage in intermolecular C–C bond-forming reactions with carbonyl electrophiles. Central to this method is the controlled formation of an alkene distonic radical anion intermediate that undergoes nucleophilic addition, followed by a kinetically favoured reductive polar crossover to produce a second carbanion available for further diversification. The versatility of this protocol was illustrated by the development of four distinct intermolecular C–C bond-forming reactions with aromatic alkenes (hydroalkoxylation, hydroamidation, aminoalkylation and carboxyaminoalkylation) to generate a range of valuable and complex scaffolds.

Dual-channel fluorescent probe for detecting SO2 and Hg2+, and dynamic imaging SO2 under Cd2+ in alfalfa (Medicago sativa)

BackgroundAs an antioxidant, SO2 plays a critical role in maintaining the plant's redox balance. At the same time, Hg2+ as heavy metals, will accumulate in plants through soil, often disrupting physiological processes in plants. However, few studies have been reported to examine changes in Hg2+ and SO2 in plants. Here, we developed a dual-channel fluorescent probe NYD, which can differentiate between the detection of Hg2+ and SO2. ResultsThe probe exhibits high sensitivity (LOD, 44 nM for Hg2+ and 26 nM for SO2). When Hg2+ and HSO3− deprotect and attack the double bond by nucleophilic addition, significant emission of fluorescence at 475 nm and 574 nm with blue and red fluorescence respectively. In addition, NYD has the capability to detect the levels of Hg2+ and SO2 in cells and alfalfa seedlings. Meanwhile, the findings indicated that alfalfa seedlings were exposed to Cd2+, which led to redox imbalance and increased endogenous SO2 production. SignificanceWe anticipate that this research will contribute to a better understanding of the functions of SO2 under oxidative stress induced by Cd2+.

Mechanistic studies on phosphine-catalyzed [4 + 3] annulation of β′-acetoxy allenoate with 1C,3N-dinucleophile

The mechanism and role of catalyst on the PPh3-catalyzed [4 + 3] annulation reaction have been systematically investigated using density functional theory (DFT) method. Based on the calculations, the possible mechanism contains six steps: nucleophilic addition of PPh3 to allenoate to give Z-configured intermediate, cleavage of CO bond for forming phosphonium diene, nucleophilic addition of phosphonium diene with anionic 1C,3N-dinucleophile, intramolecular [1,5]-proton shift, ring-closure, and dissociation of catalyst. Non-covalent interaction (NCI) analysis shows that the O⋯P interaction would be the key for leading to the Z-configured pathway more favorable and electron localization function (ELF) analysis indicates that the implication of PPh3 can significantly lower the energy barrier involved in CO cleavage process, which mainly because the addition of PPh3 reduces the electron density of CO bond and thus facilities the cleavage of CO bond. This theoretical study would provide some clues for understanding the role of catalyst in a catalytic reaction.

Stereoselective Construction of Less-Accessible Acyclic Quaternary Carbon Stereocenters via Rhodium-Catalyzed Allylic Alkylation of β,β-Disubstituted Enesulfinamides.

In the presence of Wilkinson's catalyst, the N-sulfinyl metalloenamines derived from NH-deprotonation of β,β-disubstituted enesulfinamides undergo nucleophilic allylic substitution with allyl carbonate, affording α-allylated ketimines with high stereoselectivity. These allylation products possess challenging acyclic quaternary stereocenters containing one allyl group and two alkyl groups that are both sterically and electronically similar (e.g., Me and Et). By utilizing appropriate stereoisomers of enesulfinamides, it becomes feasible to selectively access each of the four potential stereoisomers of the allylation products, thereby facilitating the selective synthesis of stereoisomers of α-tertiary chiral amines featuring a β-quaternary stereocenter through imino nucleophilic addition.

Stereoselective Synthesis of trans-1,2,4-Trihydrobenzo[d][1,2]azaphosphinine 3-Oxides from In Situ Formed Phosphenes and Formaldimines.

Various trans-1,2,4-trihydrobenzo[d][1,2]azaphosphinine 3-oxides are synthesized highly stereoselectively from in situ generated phosphenes and formaldimines under microwave irradiation. Aryl(diazo)methyl(diaryl)phosphine oxides first undergo the Wolff rearrangement to generate phosphenes. Imines, in situ generated from 1,3,5-triazinanes or paraformaldehyde and primary amines, nucleophilically attack the phosphenes followed by a tandem stereoelectronic effect-controlled intramolecular nucleophilic addition and aromatization to give final trans-1,2,4-trihydrobenzo[d][1,2]azaphosphinine 3-oxides, exhibiting completely different annuloselectivity from linear nonformaldimines.

Revealing the Role of Organic Ligands in Deep-Blue-Emitting Colloidal Europium Bromide Perovskite Nanocrystals.

Europium halide perovskites are promising candidates for environmentally benign blue-light emitters with their narrow emission line width. However, the development of high-photoluminescence quantum yield (PLQY) colloidal europium halide perovskite nanocrystals (PNCs) is hindered by limited synthetic methods and elusive reaction mechanisms. Here, we provide an effective synthetic route for achieving high-PLQY deep-blue-emitting colloidal CsEuBr3 PNCs. Using two Br-organic ligand precursors, oleylammonium bromide (OLAMHBr) and trioctylphosphine dibromide (TOPBr2), we identified distinct phase evolution routes involving Eu2+:CsBr, Cs4EuBr6, and CsEuBr3. The OLAMHBr precursor initially promotes the formation of the Eu2+:CsBr phase, which reorganizes into the CsEuBr3 perovskite phase via proton transfer. In contrast, the TOPBr2 precursor induces the formation of core/shell Cs4EuBr6/CsBr PNCs, which subsequently transform into CsEuBr3 through nucleophilic addition. The TOPBr2 route exhibited enhanced CsEuBr3 phase homogeneity, resulting in a significantly higher PLQY (40.5%; full width at half-maximum (fwhm) = 24 at 430 nm), compared to the OLAMHBr route (16.5% at 418 nm). Notably, the phase-pure CsEuBr3 PNCs demonstrated a world-record PLQY among the reported blue-emitting lead-free PNCs that exhibit a narrow emission line width (fwhm <25 nm). This work highlights the significant role of organic ligands in the colloidal synthesis of CsEuBr3 PNCs and their potential as nontoxic, solution-processable blue-light emitters.