Imine Hydrolysis Research Articles

Discovery of peroxynitrite elevation in zinc ion-induced acute lung injury with an activatable near-infrared fluorogenic probe

Particulate matter derived from environmental pollution might contain zinc ions (Zn2+), and inhaling these particles exacerbates lung tissue's inflammatory response, impairing lung function and increasing the risk of acute lung injury (ALI). Zn2+ is known to contribute to oxidative stress, leading to elevated levels of reactive oxygen species such as peroxynitrite (ONOO-), which play a key role in the pathogenesis of ALI. Herein, a novel near-infrared fluorogenic probe, DCI-BT, was prepared for the specific detection of ONOO- based on the strategy of oxidative hydrolysis of imine to break into aldehyde. The response of DCI-BT to ONOO- was found to be extremely fast, and the addition of ONOO- would enhance its fluorescence intensity. Cell experiments showed that DCI-BT could efficiently indicate the changes in cellular ONOO- levels. Furthermore, employing DCI-BT, the Zn2+-induced endogenous ONOO- production in cells was successfully visualized, confirming that prolonged exposure to Zn2+ triggered cellular oxidative stress. Finally, the application of DCI-BT in the mice model of ALI was evaluated, and the results revealed that it had good biosafety and could effectively track the changes in ONOO- levels in the Zn2+-induced ALI model. Therefore, DCI-BT held promise as a valuable chemical tool for diagnosing and treating environmentally induced oxidative stress-related diseases.

Two-Step Noncatalyzed Hydrolysis Mechanism of Imines at the Air-Water Interface.

The hydrolysis of imines has long been assumed to be their main atmospheric fate, based on early studies in the field of organic chemistry. However, the hydrolysis mechanism and kinetics of atmospheric imines remain unclear. Here, an advanced Born-Oppenheimer molecular dynamics method was employed to investigate the noncatalyzed hydrolysis mechanism and kinetics at the air-water interface by selecting CH2NH as a model molecule. The results indicate that CH2NH exhibits a pronounced surface preference. The noncatalyzed hydrolysis of CH2NH follows a unique two-step reaction mechanism involving first proton transfer and then OH- transfer through the water bridge at the air-water interface, in contrast to the traditional one-step mechanism. The calculated reaction rate for the rate-determining step is 3.32 × 105 s-1, which is 2 orders of magnitude greater than that of the bulk phase. In addition, the involvement of the interfacial electric field further enhances the reaction rate by approximately 3 orders of magnitude. The noncatalyzed hydrolysis rate at both the air-water interface and the bulk phase is higher than that of the possible acid-catalyzed one, clarifying noncatalyzed hydrolysis as the dominant mechanism for CH2NH. This study elucidates that the noncatalyzed hydrolysis of atmospheric imines is feasible at the air-water interface and that the revealed unique two-step hydrolysis mechanism has significant implications in atmospheric and water environmental chemistry.

Enantioselective Carbon Isotope Exchange.

The synthesis of isotopically labeled organic molecules is vital for drug and agrochemical discovery and development. Carbon isotope exchange is emerging as a leading method to generate carbon-labeled targets, which are sought over hydrogen-based labels due to their enhanced stability in biological systems. While many bioactive small molecules bear carbon-containing stereocenters, direct enantioselective carbon isotope exchange reactions have not been established. We describe the first example of an enantioselective carbon isotope exchange reaction, where (radio)labeled α-amino acids can be generated from their unlabeled precursors using a stoichiometric chiral aldehyde receptor with isotopically labeled CO2 followed by imine hydrolysis. Many proteinogenic and non-natural derivatives undergo enantioselective labeling, including the late-stage radiolabeling of complex drug targets.

1O2 Mediated Conversion of β-Enaminonitriles to α-Keto Amides Photosensitized by Recyclable H2TPP in Visible Light.

We report a one-step approach for the conversion of β-enaminonitriles to synthetically versatile α-keto amides in moderate to high yields under visible light irradiation photosensitized by porphyrins. The method is mild, cost-effective, and sustainable and requires air as the sole reagent/oxidant. The reaction is believed to proceed via an ene-type pathway initiated by 1O2, followed by dehydration, imine hydrolysis, and subsequent nucleophilic substitution of the cyanide group by amine. The method offers a broad substrate scope and has also been extended for synthesis of α-keto esters with aliphatic alcohols as nucleophiles. The porphyrin recovered after the reaction can be reused multiple times.

Nitrogen-to-functionalized carbon atom transmutation of pyridine.

The targeted and selective replacement of a single atom in an aromatic system represents a powerful strategy for the rapid interconversion of molecular scaffolds. Herein, we report a pyridine-to-benzene transformation via nitrogen-to-carbon skeletal editing. This approach proceeds via a sequence of pyridine ring-opening, imine hydrolysis, olefination, electrocyclization, and aromatization to achieve the desired transmutation. The most notable features of this transformation are the ability to directly install a wide variety of versatile functional groups in the benzene scaffolding, including ester, ketone, amide, nitrile, and phosphate ester fragments, as well as the inclusion of meta-substituted pyridines which have thus far been elusive for related strategies.

Thienoisoindigo-based recyclable conjugated polymers for organic electronics

Imine-based semiconducting polymers with thienoisoindigo-based monomers are 90% recoverable upon imine hydrolysis, enabling closed-loop recycling.

Dual role of arsenite in hydrolysis and post-hydrolysis fluorescence sensing of selective pH-dependent probes.

In comparison to the sensing activity, the reactivity of arsenite (AsO2-) is less explored. Herein, we focused on AsO2- reactivity studies based on its pKa and compared the study with other common anions. All three pKa values of arsenite are >9.0, affording a flexible working pH range to design a probe for reactivity studies. We designed and synthesized six pH dependent benzothiazole-based Schiff bases, namely, 1-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)naphthalen-2-ol (1), 5-(diethylamino)-2-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)phenol (2), 9-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-ol (3), 5-methoxy-2-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)phenol (4), 4-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)benzene-1,3-diol (5), and 2-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)phenol (6), as probes for hydrolysis studies containing 5% water in acetonitrile. In spite of the presence of water in the solution, no hydrolysis was observed for all the probes in the absence of a salt. In the presence of selected sodium salts of various anions in solution, intramolecular charge transfer (ICT) was observed after the deprotonation of an aromatic hydroxy group at the ortho position with respect to the imine groups within the probes. Among the studied anions, selective AsO2- induced imine hydrolysis was observed for probes 1 and 4. In the case of 5 with both o- and p-hydroxy groups, no hydrolysis was observed in the presence of AsO2-. Probe 6 with only the o-hydroxy group showed very fast hydrolysis with poor selectivity. The p-hydroxy group in 4-(((6-nitrobenzo[d]thiazol-2-yl)imino)methyl)phenol (7) resulted in poor AsO2- induced hydrolysis. The aldehyde, which was generated after hydrolysis of probe 1, showed selective emission at 450 nm in the presence of AsO2-. The time dependent hydrolysis reaction of probe 1 controls the emission intensity enhancement.

Access to Cyclopentenone via Pd(0)-Catalyzed Reductive Cyclization of (Z)-5-Iodo-4-pentenenitrile.

A ligand-free Pd(0)-catalyzed cyclization of (Z)-5-iodo-4-pentenenitrile has been realized with the help of HCO2H reductant, which is followed by imine hydrolysis to afford cyclopentenone derivatives in moderate to good yields. Control experiments clearly points out that the proton originally came from HCO2H plays a crucial role on protonation of the resultant imido-Pd2+ intermediate. This protocol features mild condition, operational simplicity, as well as wide functional group tolerance.

Oscillatory dynamics in a reaction network based on imine hydrolysis.

We have built an autocatalytic reaction network, based on the hydrolysis of certain imines, which exhibits bistability in an open system. The positive feedback originates from the interplay of fast acid-base equilibria, leading to hydroxide ion production, and pH-dependent hydrolysis rates. The addition of a first-order removal of the autocatalyst can result in sustained pH oscillations close to physiological conditions. The unit-amplitude pH oscillations are accompanied by the stoichiometric conversion of imine into amine back and forth. A systematic parameter search is carried out to characterize the rich observable dynamics and identify the evolving bifurcations.

Formal γ-C(sp3)-H Activation of Ketones via Microwave-Promoted and Iminyl-Radical-Mediated 1,5-Hydrogen Atom Transfer.

Microwave irradiation of O-phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and in situ imine hydrolysis. The Lewis acid InCl3·H2O facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCH2CO2H instead of InCl3·H2O as an additive. C-O and C-C bond formation could both be accomplished by this method.

Study on the degradation and pyrolysis of 2-fluoromethcathinone

Gas chromatography-mass spectrometry (GC-MS) is the first choice for law enforcement agencies in various countries to analyze new psychoactive substances (NPS) because of its advantages and complete databases. For synthetic cathinone-type NPS (SCat), alkalization and extraction processes before GC-MS analysis are essential. However, the base form of SCat is unstable, causing it to quickly degrade in solution and cause pyrolysis at the GC-MS injection inlet. In this study, we investigated the degradation of ethyl acetate and pyrolysis at the GC-MS injection inlet of 2-fluoromethcathinone (2-FMC), the most unstable SCat. Using gas chromatography-quadruple/time-of-flight mass spectrometry (GC-Q/TOF-MS) combined with the predicted data from theoretical calculations and the analysis of mass spectrometry (MS) fragmentation, the structures of 15 2-FMC degradation and pyrolysis products were identified. Among them, 11 products were produced during degradation, and six products were obtained from pyrolysis (two of which were the same as the degradation products). At the same time, the degradation and pyrolysis pathways of 2-FMC were provided. The balance between keto-enol and enamine-imine tautomerism triggered the primary degradation pathway of 2-FMC. The subsequent degradation started from the tautomer with a hydroxyimine structure, including imine hydrolysis, oxidation, imine-enamine tautomerism, intramolecular ammonolysis of halobenzene, and hydration to generate a series of degradation products. The secondary degradation reaction was the ammonolysis of ethyl acetate to yield N-[1-(2’-fluorophenyl)-1-oxopropan-2-yl]-N-methylacetamide and the byproduct, N-[1-(2’-fluorophenyl)-1-oxopropan-2-yl]-N-methylformamide. In the pyrolysis of 2-FMC, the major reactions were dehydrogenation, intramolecular ammonolysis of halobenzene, and defluoromethane. The achievements of this manuscript not only study 2-FMC degradation and pyrolysis but also lay the foundation for the study of SCat stability and their accurate analysis by GC-MS.

Reprocessable and Chemically Recyclable Hard Vitrimers Based on Liquid-Crystalline Epoxides.

The rapid increase in demand for recyclable and reusable thermosets has necessitated the development of materials with chemical structures that exhibit these features. Thus, functional mesogenic epoxide monomers bearing both ester and imine groups that can be vitrimerized and recycled are reported herein. The compounds show mesophase characteristics at 100-200°C and can be converted into hard epoxides by a common curing reaction. The obtained hard epoxides have high isotropic thermal conductivity (≈0.64 W m-1 K-1 ), which is derived from their highly ordered microstructures. The cured products can be easily reprocessed through imine metathesis and transesterification, and decomposed products can be obtained through imine hydrolysis under acidic or basic conditions and subsequently be re-cured. Surprisingly, recycled materials can be repeatedly reprocessed or chemically decomposed. The reprocessed materials retain the properties of their pristine counterparts, and the recycled products preserve the advantages of the hard thermosets without alteration to any of their unique properties. A dehydration reaction occurs between the residual hydroxyl groups during the re-hardening, which dramatically increases the glass transition temperature by ≈60°C. These reprocessable and recyclable vitrimers demonstrate the effectiveness and environmental friendliness of the molecular design strategy reported herein.

Vanillin-Derived Thermally Reprocessable and Chemically Recyclable Schiff-Base Epoxy Thermosets.

The paradigm shift from traditional petroleum-based non-recyclable thermosets to biobased repeatedly recyclable materials is required to move toward circular bioeconomy. Here, two mechanically and chemically recyclable extended vanillin-derived epoxy thermosets are successfully fabricated by introduction of Schiff-base/imine covalent dynamic bonds. Thermoset 1 (T1) is based on linear monomer 1 (M1) with two alcohol end groups and one imine bond, while thermoset 2 (T2) is based on branched monomer 2 (M2) with three alcohol end-groups and three imine-groups. Thermosets are obtained by reaction of monomer 1 (M1) and monomer 2 (M2) with trimethylolpropane triglycidyl ether. The structure of the monomers and thermosets is confirmed by nuclear magnetic resonance and Fourier transform infrared spectroscopic techniques. Both thermosets exhibit good thermal and mechanical properties and they are stable in common organic solvents. Furthermore, they can be thermally reprocessed through compression molding with good recovery of the mechanical properties. Last but not least, the fabricated thermosets can be rapidly and completely chemically recycled to water-soluble aldehydes and amines by imine hydrolysis at room temperature in 0.1m HCl solution. This is promising for development of future materials with multiple circularity by different routes.

Metal-polyphenol nanodots loaded hollow MnO2 nanoparticles with a “dynamic protection” property for enhanced cancer chemodynamic therapy

Chemodynamic therapy (CDT) is a novel cancer therapeutic strategy. However, barriers such as high glutathione (GSH) concentration and low concentration of metal ions intracellular reduce its treatment effect. In this work, a nanosystem named GA-Fe@HMDN-PEI-PEG with a “dynamic protection” property was reported for enhanced cancer CDT. Mesoporous hollow manganese dioxide (MnO2) nanoparticle (HMDN) was prepared to load gallic acid-ferrous (GA-Fe) nanodots fabricated from gallic acid (GA) and ferrous ion (Fe2+). Then the pores of HMDN were blocked by polyethyleneimine (PEI), which was then grafted with methoxy poly(ethylene glycol) (mPEG) through a pH-sensitive benzoic imine bond. mPEG could protect the nanoparticles (NPs) against the nonspecific uptake by normal cells and enhance their accumulation in the tumor. However, in the slightly acidic tumor microenvironment, hydrolysis of benzoic imine led to DePEGylation to reveal PEI for enhanced uptake by cancer cells. The reaction between HMDN and GSH could consume GSH and obtain manganese ion (Mn2+) for the Fenton-like reaction for CDT. GA-Fe nanodots could also offer Fe for the Fenton reaction, and reductive GA could reduce the high-valence ions to low-valence for reusing in Fenton and Fenton-like reactions. These properties allowed GA-Fe@HMDN-PEI-PEG for precise medicine with a high utilization rate and common side effects.

Asymmetric Cyclopropanation with 4-Aryloxy-1-sulfonyl-1,2,3-triazoles: Expanding the Range of Rhodium-Stabilized Donor/Acceptor Carbenes to Systems with an Oxygen Donor Group.

Rhodium-catalyzed enantioselective synthesis of 1-phenoxycyclopropane-1-carbaldehydes by intermolecular cyclopropanation of terminal alkenes followed by imine hydrolysis is described. This methodology utilizes 4-aryloxy-1-sulfonyl-1,2,3-triazoles as the carbene precursors and the chiral dirhodium(II) tetracarboxylates Rh2(S-NTTL)4 or Rh2(S-DPCP)4 as the catalysts. These reactions are considered to proceed via rhodium-stabilized donor/acceptor carbene intermediates, and these studies demonstrate that a heteroatom donor group is compatible with an enantioselective transformation.

Multicomponent Pseudorotaxane Quadrilateral as Dual-Way Logic AND Gate with Two Catalytic Outputs.

A multicomponent pseudorotaxane quadrilateral was reversibly toggled between three distinct switching states. Switching in the forward conversion was achieved by addition of H+ and K+ ions, and switching in the reverse direction was performed by addition of 18-crown-6 and 1-aza-18-crown-6. In both the forward and backward ways, the inputs operated an AND gate with distinct catalytic outputs. While in the forward direction the logic AND operation starting from a heteroleptic five-component assembly turned "ON" an imine hydrolysis as output (AND-1), in the inverse direction a Michael addition was ignited as the output starting from a seven-component aggregate following the AND gate logic (AND-2).

C≡N triple bond cleavage via transmembrane hydrogenation

Renewable-energy-powered electrosynthesis is an emerging green alternative to thermochemical routes. Against this backdrop, acetonitrile valorization is an important target because it is industrially produced in excess. Here we developed a catalytic system that converts acetonitrile into acetaldehyde and NH3 using an H-permeable Pd membrane reactor. In this system, H is abstracted from water in an aqueous electrolyte and transferred across the Pd membrane and is used to hydrogenate acetonitrile with up to 60% faradic efficiency (FE) for NH3 generation. We also constructed a unique infrared (IR) spectroelectrochemical cell that enabled us to probe the reaction as it occurred. This helped us deduce that the reaction proceeded through an imine hydrolysis pathway. Finally, we extended the scope of this system to four additional nitrile reactants. This work establishes a new electrochemical route to nitrile hydrogenation and opens up promising avenues in electrosynthetic technologies.

In Situ-Activated Phospholipid-Mimic Artemisinin Prodrug via Injectable Hydrogel Nano/Microsphere for Rheumatoid Arthritis Therapy.

In situ-activated therapy is a decent option for localized diseases with improved efficacies and reduced side effects, which is heavily dependent on the local conversion or activation of bioinert components. In this work, we applied a phospholipid-mimic artemisinin prodrug (ARP) for preparing an injectable nano/microsphere to first realize an in situ-activated therapy of the typical systemically administrated artemisinin-based medicines for a localized rheumatoid arthritis (RA) lesion. ARP is simultaneously an alternative of phospholipids and an enzyme-independent activable prodrug, which can formulate "drug-in-drug" co-delivery liposomes with cargo of partner drugs (e.g., methotrexate). To further stabilize ARP/methotrexate "drug-in-drug" liposomes (MTX/ARPL) for a long-term intra-articular retention, a liposome-embedded hydrogel nano/microsphere (MTX/ARPL@MS) was prepared. After the local injection, the MTX/ARPL could be slowly released because of imine hydrolysis and targeted to RA synovial macrophages and fibroblasts simultaneously. ARP assembly is relatively stable before cellular internalization but disassembled ARP after lysosomal escape and converted into dihydroartemisinin rapidly to realize the effective in situ activation. Taken together, phospholipid-mimic ARP was applied for the firstly localized in situ-activated RA therapy of artemisinin-based drugs, which also provided a brand-new phospholipid-mimic strategy for other systemically administrated prodrugs to realize a remodeling therapeutic schedule for localized diseases.

Dynamic covalent chemistry of imines for the development of stimuli-responsive chitosan films as carriers of sustainable antifungal volatiles

The aim of this work was to develop pH-responsive antifungal chitosan (CS) films based on the reversible bonding of the naturally occurring volatile aldehydes: cinnamaldehyde (CN), citral (CT) and their saturated derivatives hydrocinnamaldehyde (HC) and citronellal (CO) that have antifungal properties. Acid-catalyzed bonds were created by condensation of the carbonyl functional group of aldehydes with amino groups in CS films to yield imines which was confirmed by Attenuated Total Reflectance – Fourier Transform Infrared Spectroscopy (ATR-FTIR) and 13C solid-state nuclear magnetic resonance (13C NMR). α,β-unsaturated CN and CT were more reactive than their derivatives, reaching around 60% degree of substitution of aldehydes to chitosan films compared to 25% for HC and CO. Imines created with α,β-unsaturated aldehydes and aromatic HC remained quite stable at neutral pH. With regard to the hydrolysis of imines at pH 4, around 35% of anchored α,β-unsaturated aldehydes were lost, this value being 80% for HC whereas 100% of CO was lost after the first week of film immersion in buffered solution. The differences in the extent of hydrolysis of imine bonds depended on both the pH of the aqueous medium and also the chemical structure of the aldehyde. Curiously, it was observed α,β-unsaturated aldehydes exerted crosslinking effects on CS films since they did not disintegrate in water at pH 3. The crosslinking mechanism is discussed in the text. The antifungal activities of the developed films were tested against Penicillium expansum and Botrytis cinerea by the micro-atmosphere method using a double Petri dish system. Mold growth was completely inhibited by imine-CN-CS films activated at pH 4.

A compact fluorescence/circular dichroism dual-modality probe for detection, differentiation, and detoxification of multiple heavy metal ions via bond-cleavage cascade reactions

Selective detection of multiple analytes in a compact design with dual-modality and theranostic features presents great challenges. Herein, we wish to report a coumarin-thiazolidine masked d-penicillamine based dual-modality fluorescent probe COU-DPA-1 for selective detection, differentiation, and detoxification of multiple heavy metal ions (Ag+, Hg2+, Cu2+). The probe shows divergent fluorescence (FL) /circular dichroism (CD) responses via divergent bond-cleavage cascade reactions (metal ion promoted C-S cleavage and hydrolysis at two distinctive cleavage sites): FL “turn-off” and CD “turn-on” for Ag+ (no hydrolysis), FL “turn-on” and CD “turn-off” for Hg2+ (imine hydrolysis), and FL “self-threshold ratiometric” and CD “turn-off” for excess Cu2+ (lactone and imine hydrolysis), providing the first example of a fluorescence/CD dual-modality probe for multiple species with complimentary responses. Moreover, the bond-cleavage cascade reactions also lead to the formation of d-penicillamine heavy metal ion complexes for potential detoxification treatments.