Stepwise Mechanism Research Articles

Cycloaddition of Butadiene with Perfluoroethylene: Prediction of a Periselectivity Switch under Pressure.

Defying the common Diels-Alder reactivity, the thermal cycloaddition between butadiene and tetrafluoroethylene (TFE) yields exclusively a [2 + 2] cycloadduct via a stepwise diradical mechanism. Here, we study the possibility of reverting to the normal [4 + 2] reactivity in this reaction under high pressure. DFT calculations using the eXtreme Pressure Polarizable Continuum Model (XP-PCM) suggest a more negative activation volume for the concerted [4 + 2] mechanism than the stepwise [2 + 2] mechanism and predict a switch in periselectivity at 1.4 gigapascal (GPa).

Prey detection by a stepwise visual template matching mechanism

Predators can improve prey capture using a search image, and recent prey provide a visual template with which subsequent prey are compared. Considering trout feeding responses to mayfly prey of different sizes and phenological availability across years, we tested if changing relative abundances (ratios) of prey of the same species, but different body sizes, shifted trout feeding behaviour. For example, we hypothesized that a feeding switch from larger to smaller prey required continuous exposure to the novel smaller prey. The hypothesis that continuous exposure to novel small prey results in their acceptance was not supported. Rather, we discovered that trout identify novel prey using a dynamic stepwise visual neural template prey matching process, which involves the formation of focal prey template based on size or type, rejection of novel prey that do not match the size or type templates and modification of the existing or development of multiple prey templates that eventually enabled recognition of novel, small prey. We also discovered trout store multiple visual prey templates in memory. These results have implications for predator and prey dynamics, optimal foraging, the persistence of rare prey, prey species coexistence and predator selection on prey phenology.

Wane-and-wax mechanism of nitrogenous disinfection byproducts with constant Cl/N peak under UV/chlorine treatment: Implication for new drinking water disinfection strategy

Nitrogenous disinfection byproducts (N-DBPs) are notorious for their serious health risks, yet nitrate (NO3-) mediates N-DBPs generation during UV/chlorine treatment remains unexplored. This study investigated the interaction of chlorine and NO3- on N-DBPs formation and developed a specific fragment-based screening method using UPLC-QTOF-MS to explore the underlying mechanism. Results showed that the chlorine-to-nitrogen (Cl/NO3--N) molar ratio significantly affects dichloroacetonitrile (DCAN) and dichloroacetamide (DCAM) generation, with peak concentrations at a Cl/NO3--N molar ratio of around 15. NO3- promotes the production of HO•, which positively correlates with DCAN and DCAM concentrations, also peaking at this ratio. Utilizing our developed method, three key hydroxyl-substituted intermediates that circumvent the previously reported “limiting-steps” in DCAN formation were identified. This reaction proceeds via a stepwise mechanism involving hydroxylation and chlorine substitution to produce hydroxyl-phenylacetonitrile and hydroxyl-chlorine-phenylacetonitrile. The conversion rate of hydroxyl-chlorine-phenylacetonitrile to DCAN was 8.6 times higher at Cl/NO3--N molar ratio of 15 compared to conditions without NO3-, attributed to the weakened bond strength of the side chain, as supported by density functional theory calculations. This study provides novel insights into the mechanistic pathways of DCAN and DCAM formation, critical for developing more effective drinking water disinfection technologies to control N-DBPs.

A Quantum Mechanical Approach to The Mechanism of Asymmetric Synthesis of Chiral Amine by Imine Reductase from Stackebrandtia Nassauensis.

The asymmetric synthesis of tetrahydroisoquinolines (THIQs) has gained importance in recent years due to their significant potential in drug development studies. In this study, the conversion of 1-methyl-3,4-dihydroisoquinoline substrate to a chiral amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline, under the catalysis of the stereoselective imine reductase enzyme from Stackebrandtia nassauensis (SnIR) was investigated in detail to elucidate the mechanism and explain the experimental enantioselectivity. The results were found to be in agreement with the experimental data. To elucidate the reaction mechanism, quantum mechanical calculations were performed by considering a large cluster of the active site of the enzyme. In this regard, possible reaction pathways leading to both R- and S-products with the corresponding intermediates and the transition states for the hydride transfer from the cofactor to the substrate were considered by density functional theory (DFT) calculations, and the factors contributing to the observed stereoselectivity were sought. The calculations supported a stepwise mechanism rather than the concerted protonation and the hydride transfer steps. The stereoselectivity in the hydride transfer was found to be due not only to the stability of the enzyme-subtrate complex but also to the corresponding reaction barriers. The calculations were performed at the wB97XD/6-311+G(2df,2p)//B3LYP/6-31G(d,p) level of theory using the PCM approach.

Stepwise or Concerted Mechanisms? Rethinking of the Classical Carbocation Rearrangement Reaction

Stepwise or Concerted Mechanisms? Rethinking of the Classical Carbocation Rearrangement Reaction

Direct Synthesis for Benzofuro[3,2-d]pyrimidin-2-Amines via One-Pot Cascade [4+2] Annulation/Aromatization between Benzofuran-Derived Azadienes and Carbodiimide Anions.

The chemoselective [4+2] annulation/aromatization reactions between benzofuran-derived azadienes and N-Ts cyanamides are developed, affording a convenient method for synthesizing benzofuro[3,2-d]pyrimidin-2-amines under mild conditions. Herein, N-Ts cyanamides participated in reactions selectively via carbodiimide anion intermediates and the corresponding cyanamide anion intermediates derived products were not observed. The proposed chemoselective stepwise reaction mechanism was well supported by DFT calculations.

Syn-Propanethial S-Oxide as an Available Natural Building Block for the Preparation of Nitro-Functionalized, Sulfur-Containing Five-Membered Heterocycles: An MEDT Study.

The regio- and stereoselectivity and the molecular mechanisms of the [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and selected conjugated nitroalkenes were explored theoretically in the framework of the Molecular Electron Density Theory. It was found that cycloadditions with the participation of nitroethene as well as its methyl- and chloro-substituted analogs can be realized via a single-step mechanism. On the other hand, [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and 1,1-dinitroethene can proceed according to a stepwise mechanism with a zwitterionic intermediate. Finally, we evaluated the affinity of model reaction products for several target proteins: cytochrome P450 14α-sterol demethylase CYP51 (RSCB Database PDB ID: 1EA1), metalloproteinase gelatinase B (MMP-9; PDB ID: 4XCT), and the inhibitors of cyclooxygenase COX-1 (PDB:3KK6) and COX-2 (PDB:5KIR).

Model catalytic studies on the thermal dehydrogenation of the benzaldehyde/cyclohexylmethanol LOHC system on Pt(111).

We investigated the dehydrogenation reaction and the thermal robustness of the liquid organic hydrogen carrier (LOHC) couple benzaldehyde/cyclohexylmethanol on a Pt(111) model catalyst in situ in synchrotron radiation photoelectron spectroscopy- and complementary temperature-programmed desorption experiments. The system stores hydrogen in a cyclohexyl group and a primary alcohol functionality and achieves an attractive hydrogen storage capacity of 7.0 mass%. We observed a stepwise dehydrogenation mechanism, characterized by a low temperature dehydrogenation of the alcohol group at 235 K. However, stability limitations challenge the system's applicability as reversible hydrogen storage solution, as the resultant aldehyde was found to decompose during the dehydrogenation of its cyclohexyl group (between 250 and 350 K). A comparison of cyclohexylmethanol with the structurally related secondary alcohol (1-cyclo-hexylethanol; 6.3 mass% hydrogen) revealed a parallel stepwise dehydrogenation pattern for both compounds, but a technically relevant superior thermal robustness of the latter. This demonstrates the influence of the alcohol group's substitution degree on the dehydrogenation characteristics of alcohol-functionalized LOHC compounds. Density functional theory calculations are in good agreement with the experimentally observed stability trend.

Surgical Management for Boutonniere Disease

Boutonniere disease is a hand injury causing extension lag or restriction in the proximal interphalangeal joint and hyperextension in the distal interphalangeal joint. This condition often arises from direct laceration or closure damage to the central tendon, rheumatoid arthritis, osteoarthritis, Dupuytren contracture, pulley injury, burns, and other conditions. Surgical management for Boutonniere deformity relies on the expertise of the attending physician and involves both non-surgical and surgical options. In acute cases, conservative therapy should be pursued, while in chronic cases, conservative management may be advised. Surgical intervention is used to transform excessive extension force of the distal interphalangeal joint into extension force of the proximal interphalangeal joint. This is necessary to heal an open rupture of the central tendon. Surgical techniques for chronic deformity are complex due to variables and hand surgeons' expertise. There is no definitive surgical therapy for persistent buttonhole deformity, but several approaches have been documented in case studies. These include terminal tenotomy, collateral band surgery, central tendon surgery, tendon transfer and grafting, stepwise extension mechanism readjustment surgery, and arthrodesis. Central tendon surgery addresses the central tendon, where injured tissue transforms into scar tissue, resulting in delayed extension of the proximal interphalangeal joint. Tendon transfer or grafting have been documented for rotator cuff mechanism rehabilitation, but no definitive guidance exists for these techniques. Curtis treatment introduced a sequential therapy approach for traumatic buttonhole deformity, which involves splinting, excising the transverse reticular ligament, resecting and lengthening the collateral ligament, and repositioning the core tendon. Arthrodesis may be applicable in cases of advanced arthritis, coronal plane deformity, functional impairment, or elderly patients. There are no definitive indications for surgical interventions for persistent buttonhole deformity, and outcomes may be variable or inferior. Understanding the deformity, its progression, and patient's functional constraints is crucial for effective treatment

A Stepwise Electrochemical Baeyer-Villiger Oxidation with Water as the Oxygen Source.

Baeyer-Villiger oxidation is a method with a 125-year history that produces lactones through a synergistic mechanism by reaction with stoichiometric peracids. Therefore, substituted lactones can be obtained from only substituted cyclic ketones. In this context, an electrochemical Baeyer-Villiger oxidation was developed using a CeO2@PbO2@Ti electrode, which produces substituted lactones through a stepwise mechanism. PbO2, in combination with a benzoic acid molecular catalyst, can generate and utilize reactive oxygen species from electrochemical water splitting to serve as the oxidant. CeO2 is designed to promote the stepwise mechanism while suppressing the synergistic mechanism. Therefore, substituted lactone can be produced from unsubstituted cyclic ketone with high selectivity (77%) and yield (20 mM) through a carbocation rearrangement process. The developed stepwise electrochemical Baeyer-Villiger oxidation, using water as the oxygen source, offers a new green approach to organic synthesis.

Catalytic asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrones with aryl enol ethers

Chiral aryl cyclohex-3-en ether scaffold is widely present in bioactive natural products and drugs. The exploitation of efficient and enantioselective methods for the construction of aryl cyclohex-3-en ether scaffold is significant. Herein we disclose a chiral N,N’-dioxide/Lewis acid complex-catalyzed asymmetric inverse-electron-demand Diels–Alder (IEDDA) reaction using electron-deficient 3-carboalkoxyl-2-pyrones and less electron-enriched aryl enol ethers as reactants. A wide range of non- and 1,2-disubstituted acyclic aryl enol ethers are applicable to deliver diverse chiral bridged bicyclic lactones in high yields and stereoselectivities (up to 95% yield, >20:1 dr, 97:3 er). The bridged bicyclic lactone core can be easily converted into chiral aryl cyclohex-3-en ether scaffold. Notably, DFT calculations revealed a stepwise and endo mechanism to explain the high enantioselectivity controlled by the cooperative effect of the steric factors and the dispersion interactions between ligands and enol ethers.

The structural basis of pyridoxal-5′-phosphate-dependent β-NAD-alkylating enzymes

SbzP is a unique pyridoxal-5′-phosphate-dependent enzyme, which catalyses a [3+2] annulation between the pyridinium ring of β-nicotinamide adenine dinucleotide (β-NAD) and an electron rich β,γ-unsaturated quinonoid derived from S-adenosylmethionine in natural product azaindane antibiotics biosynthesis. The SbzP-mediated annulation has been proposed to be a rare tandem C–C bond formation, but its structural basis and catalytic mechanism remain largely unknown. Here we report the β-NAD-complexed structure of PseP (SbzP homologue), identified by cryo-electron microscopy. Structure-based mutagenesis, stopped-flow analysis, thermal shift and surface plasmon resonance analysis identified the important residues for the substrate binding. Molecular dynamics simulations provided insights regarding how the enzyme orients the Cγ of the unsaturated quinonoid to β-NAD. In addition, density functional theory calculations confirmed that the proposed stepwise mechanism is more likely than a pericyclization mechanism. This study provides the structural basis of a pyridoxal-5′-phosphate-dependent enzyme that catalyses nucleophilic Cγ addition and β-NAD processing in natural product biosynthesis.

Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5

Two-thirds of signaling hormones and one-third of approved drugs exert their effects by binding and modulating the G protein-coupled receptors (GPCRs) activation. While the activation mechanism for monomeric GPCRs has been well-established, little is known about GPCRs in dimeric form. Here, by combining transition pathway generation, extensive atomistic simulation-based Markov state models, and experimental signaling assays, we reveal an asymmetric, stepwise millisecond allosteric activation mechanism for the metabotropic glutamate receptor subtype 5 receptor (mGlu5), an obligate dimeric class C GPCR. The dynamic picture is presented that agonist binding induces dimeric ectodomains compaction, amplified by the precise association of the cysteine-rich domains, ultimately loosely bringing the intracellular 7-transmembrane (7TM) domains into proximity and establishing an asymmetric TM6-TM6 interface. The active inter-domain interface enhances their intra-domain flexibility, triggering the activation of micro-switches crucial for downstream signal transduction. Furthermore, we show that the positive allosteric modulator stabilizes both the active inter-domain 7TM interface and an open, extended intra-domain ICL2 conformation. This stabilization leads to the formation of a pseudo-cavity composed of the ICL2, ICL3, TM3, and C-terminus, which facilitates G protein coordination. Our strategy may be generalizable for characterizing millisecond events in other allosteric systems.

Low‐carbon optimal scheduling strategy for multi‐agent integrated energy system of the park based on Stackelberg–Nash game

AbstractUnder the background of achieving the dual‐carbon goal, the park is a natural experimental field for practicing the dual‐carbon goal. A low‐carbon optimal scheduling strategy for a multi‐agent park‐integrated energy system (P‐IES) based on the Stackelberg–Nash game is proposed. Firstly, a low‐carbon P‐IES scheduling model is established, considering the two‐stage operation of power‐to‐gas (P2G) technology and reward–punishment stepwise carbon trading mechanism. Then, a two‐layer game optimisation model is proposed with a park‐integrated energy system operator (P‐IESO) as the leader and multiple low‐carbon P‐IESs as followers. Among them, the parks are connected with each other through the power trading channels. Then, the Nash equilibrium solution is obtained by the iterative search method, and the uniqueness of the equilibrium solution of the game is proven, so as to determine the optimal pricing strategy of the operator. Finally, a typical industrial park is taken as an example for simulation verification. The example analysis verifies that the model can effectively reduce the system's carbon emissions and improve the park's economic benefits and low‐carbon levels, thereby achieving the coordinated development of low‐carbon and economic performance in the park.

Stepwise Attention-Guided Multiscale Fusion Network for Lightweight and High-Accurate SAR Ship Detection

Many exceptional deep learning networks have demonstrated remarkable proficiency in general object detection tasks. However, the challenge of detecting ships in synthetic aperture radar (SAR) imagery increases due to the complex and various nature of these scenes. Moreover, sophisticated large-scale models necessitate substantial computational resources and hardware expenses. To address these issues, a new framework is proposed called a stepwise attention-guided multiscale feature fusion network (SAFN). Specifically, we introduce a stepwise attention mechanism designed to selectively emphasize relevant information and filter out irrelevant details of objects in a step-by-step manner. Firstly, a novel LGA-FasterNet is proposed, which incorporates a lightweight backbone FasterNet with lightweight global attention (LGA) to realize expressive feature extraction while reducing the model’s parameters. To effectively mitigate the impact of scale and complex background variations, a deformable attention bidirectional fusion network (DA-BFNet) is proposed, which introduces a novel deformable location attention (DLA) block and a novel deformable recognition attention (DRA) block, strategically integrating through bidirectional connections to achieve enhanced features fusion. Finally, we have substantiated the robustness of the new framework through extensive testing on the publicly accessible SAR datasets, HRSID and SSDD. The experimental outcomes demonstrate the competitive performance of our approach, showing a significant enhancement in ship detection accuracy compared to some state-of-the-art methods.

Theoretical uncovering of the chalcogen element regulated ESDPT behaviors for 2,5-bis(2-benzoxazolyl)-hydroquinone derivatives.

Inspired by the captivating allure of exquisitely regulated characteristics exhibited by 2-(2-hydroxyphenyl)-benzoxazole and its derivatives in the realms of photochemistry and photophysics, our current endeavor primarily revolves around delving into the intricacies of photo-induced excited state reactions for derivatives of 2,5-bis(2-benzoxazolyl)-hydroquinone (BBHQ). Given the significant impact of chalcogen element doping, herein we predominantly focus on exploring the excited state behaviors of BBHQ-OO, BBHQ-SS, and BBHQ-SeSe fluorophores. Our simulations, resulting from variations in geometry and vertical excitation charge reorganization, reveal atomic-electronegativity-dependent hydrogen bonding interactions and charge recombination induced by photoexcitation that can significantly enhance the excited state intramolecular double proton transfer (ESDPT) reaction for BBHQ-OO, BBHQ-SS, and BBHQ-SeSe fluorophores. By constructing potential energy surfaces (PESs) and identifying transition states (TS), we unveil the ultrafast stepwise ESDPT mechanism due to the low potential barriers. Additionally, by employing heterosubstituted BBHQ-OS and BBHQ-OSe compounds, we rigorously validate the stepwise ESDPT mechanism regulated by chalcogen atomic electronegativity. We sincerely anticipate that the modulation of solvent polarity on excited state behaviors will pave the way for groundbreaking advancements in luminescent materials.

Theoretical investigation of the excited-state intramolecular double proton transfer process of 2,2'-(benzo[1,2-d:4,5-d']bis(thiazole)-2,6-diyl)diphenol.

In this work, the excited state intramolecular double proton transfer (ESIDPT) mechanism of 2,2'-(benzo[1,2-d:4,5-d']bis(thiazole)-2,6-diyl)diphenol (BTAP) is proposed using density functional theory (DFT) and time-dependent DFT (TDDFT). The changes in bond lengths, bond angles and IR vibrational spectra associated with two intramolecular hydrogen bonds of BTAP upon photoexcitation indicate that the hydrogen bonds are strengthened in the excited state, facilitating the ESIDPT process. Investigation of the constructed S1-state potential energy surface proposes that BTAP prefers a stepwise ESIDPT mechanism. Electronic spectra and frontier molecular orbitals (FMOs) are also presented to illustrate the luminescent properties of BTAP.

Imidazo[2,1-b][1,3,4]thiadiazoles: Microwave-assisted synthesis, gas phase thermolysis and integrative mechanistic approach

The present study, deals with the synthesis of 2-substituted-6-phenyl-imidazo[2,1-b][1,3,4]thiadiazoles from 2-amino-5-substituted-1,3,4-thiadiazoles and 2-bromo-1-phenylethanone, which was carried out applying a microwave-assisted aqueous procedure. Furthermore, the gas-phase thermal behaviour of these imidazothiadiazoles in flash vacuum pyrolysis reactions has been studied. It has been shown that thermolysis conditions induce thiadiazole fragmentation to give indole-carbonitriles and other nitriles. The quantum chemical calculations support a stepwise mechanism for the fragmentation of imidazothiadiazoles to afford products.

Development of an ammonia/diesel combustion mechanism for high ammonia energy ratio: Validation of the mechanisms in kinetic simulation and RCCI optical engine simulation

Ammonia blending in diesel is an efficient combustion strategy that overcomes the combustion resistance of ammonia while maintaining high engine adaptability. A smaller and accurate chemical kinetic mechanism is crucial for exploring the application of ammonia/diesel in engine. This study, based on the stepwise validation and optimization mechanisms, developed a novel ammonia/diesel mechanism comprising 130 species and 772 reactions. The mechanism was validated through kinetic verification for ammonia, n-dodecane, diesel and ammonia/diesel fuel. For profound understanding of the low-temperature autoignition chemistry of ammonia/diesel, applying this mechanism construct precise CFD models in RCCI optical engine. The results indicate that this mechanism can accurately capture ignition under high AER, wide working conditions, and low-temperature conditions. In the kinetic analysis, the C–N interaction reaction, particularly C2H4+NH2=C2H3+NH3, plays a crucial role in predicting the IDT of ammonia/diesel. In addition, NH2 undergoes deoxygenation reaction with HO2, converting inactive radicals HO2 into OH active radicals, enhances the reactivity of ammonia/diesel under low-temperature conditions. Applying the mechanism to CFD models, the model accurately predicts the pressure and heat release rate in RCCI optical engine, capturing the phenomenon of the high-temperature flame rapidly spreading towards the low-temperature regions in the cylinder. The research on this mechanism can construct accurate CFD model for optimizing efficient and clean combustion simulations of ammonia/diesel.

Abstract Mo121: Sarcomere activation biosensor reveals key functional differences in live cell active states between cardiac and skeletal muscle

The sarcomere is the functional unit of striated muscle contraction. Previous studies have provided valuable information about the sarcomeric proteins and modulators that are necessary for activation of contraction through inter-myofilament signaling. This work has revealed key differences in contraction kinetics and paradigms between cardiac, slow skeletal, and fast skeletal muscle. We seek here to expand these studies through the use of myofilament incorporated Förster Resonance Energy Transfer (FRET) fluorescent biosensor in live, intact muscle. This biosensor fuses fluorescent donor and acceptor proteins to the N- and C-terminals of fast skeletal and cardiac (slow) troponin C, respectively, and allows for the monitoring in real-time of the stepwise physiological mechanism of muscle sarcomere activation in an intact system which preserves significant features of the muscle, including excitation-contraction coupling and load. This biosensor has been designed and validated in both cardiac and skeletal muscle and using intact muscles from transgenic animals we have demonstrated FRET fluorescence in cardiac papillaries, extensor digitorum longus, and soleus muscles. This biosensor has shown unique sarcomere activation properties between cardiac and skeletal muscle, notably the emergence of a prolonged return to baseline of the FRET signal in loaded fast and slow skeletal muscle, which is evidence of a “primed state” of myofilament activation unique to skeletal muscles under load. Elucidation of the “primed state” of sarcomere activation is evidence of a transient memory of recent activity enabling the enhanced contraction properties of skeletal muscle. This finding advances previous understanding of skeletal muscle activation, including summation and tetanic contraction, which is not possible in cardiac muscle. The implementation of this biosensor provides a new approach to interrogate the essential physiological features of muscle sarcomere activation and contraction and adds a valuable new tool for small molecule and gene-based discoveries for muscle disease remediation.