Proposed Mechanism Research Articles

The Effect of Chalcogen-Chalcogen Bond Formation in the New Delhi Metallo-β-Lactamase 1 Enzyme to Counteract Antibiotic Resistance.

New Delhi metallo-β-lactamase 1 (NDM-1) is an enzyme involved in the drug resistance of many bacteria against most of the widely adopted antibiotics, such as penicillins, cephalosporins, and carbapenems. Consequently, inhibiting NDM-1 swiftly has gained significant interest as a strategy to counteract this bacterial defense mechanism, thereby restoring the effectiveness of antibiotics. Among the inhibitors tested against the enzyme, ebselen (EbSe) showed particularly promising results. This molecule, renowned for its numerous benefits to the human body, targets the enzyme's active site at Cys208 with its selenium atom, facilitating the expulsion of the catalytic zinc ion from the active pocket. Since the inhibitory mechanism of EbSe remains poorly understood, gaining detailed information about it is highly desirable. In the present work, density functional theory calculations and μs-long molecular dynamics simulations are carried out to investigate the reaction mechanism of EbSe with NDM-1, unveiling the structural implications of the inhibition. A large model of the NDM-1 active site is built to investigate the different mechanistic proposals for the SeEbSe-SCys208 bond formation. Deeper insights into Lys211 are also provided to consolidate its role during the inhibition process. Furthermore, the chemical reaction with the ebsulfur (EbS) molecule is also investigated to compare its behavior with that of the periodic relative selenium. Molecular dynamics simulations, besides evidencing the role of the L3 and L10 loops in the occurrence of the inhibition, corroborate the Zn ion release from the active site as a result of the complete disruption of its coordination sphere caused by the creation of the SeEbSe-SCys208 covalent bond.

Direct Photochemical Synthesis of Substituted Benzo[b]fluorenes.

We report a new and straightforward route toward substituted benzo[b]fluorenes via the direct photochemical conversion of alkynylated chalcones. This transformation exploits a high-power light-emitting diode emitting ultraviolet A light to enable the rapid formation of the target products (tres = 5 min). A continuous flow approach thereby facilitates reproducibility and scalability, granting streamlined access to these important scaffolds and their derivatives. A mechanistic proposal based on a biradical species is presented and supported by deuteration studies.

Catalytic Construction of C(sp3)−Ge Bonds: Recent Advances and Future Perspectives

AbstractGermanium (Ge), a congener of carbon, possesses unique properties that hold extensive potential for applications across multiple domains. Recent years have seen significant progress in the development of carbon‐germanium bond formation strategies, particularly those for more challenging C(sp3)−Ge bonds. This review systematically summarizes the recent advances in C(sp3)−Ge bond forming methodologies, with particular emphasis on (1) the versatility of transition‐metals, including iron, nickel, copper, rhodium and palladium, as catalysts in broadening reaction scope and controlling selectivity; (2) the powerfulness of organic photocatalysis in achieving mild and selective bond formation, and (3) the sustainability of catalytic electrosynthesis in facilitating chemical oxidant‐/reductant‐ free conversions. Additionally, examples of (4) non‐catalytic strategies are also discussed. The representative scopes, as well as mechanistic proposals, of these protocols are highlighted. Through an overview on the current state of research, this review aims to offer insights into the catalytic construction of C(sp3)−Ge bonds, and provide perspectives on future research directions to address the current challenges.

Ring-Enlargement of in Situ Generated Cyclopropanones by the Reaction with Sulfonium Ylides: One-Pot Synthesis of Cyclobutanones.

In this report, we describe a simple method for the synthesis of 2-aryl-2-vinyl-cyclobutanones through the reaction of in situ generated cyclopropanones and cinnamylsulfonium ylides, representing an example of a formal carbene insertion into these three-membered rings. The cyclobutanones thus obtained are ideal substrates for palladium-catalyzed coupling reactions upon enol triflate formation, thereby providing access to densely functionalized cyclobutenes. A mechanistic proposal for the ring-enlargement is presented based on experimental evidence.

Computational Study on Flavin-Catalyzed Aerobic Dioxygenation of Alkenyl Thioesters: Decomposition of Anionic Peroxides.

Flavin-dependent catalysts are widely applied to aerobic monooxygenation/oxidation reactions. In contrast, flavin-catalyzed aerobic dioxygenation reactions exhibit higher atomic economy but are less reported, not to mention the relevant mechanistic studies. Herein, a density functional theory study on flavin-catalyzed aerobic epoxidation-oxygenolysis of alkenyl thioesters was performed for the first time. Different from the previous mechanistic proposal, a pathway featuring two catalytic stages, monoanionic flavin-C(4a)-peroxide/oxide intermediates, and a reverse reaction sequence (epoxidation goes prior to oxygenolysis) was revealed. In comparison, the pathways involving dianionic flavin catalysts, monoanionic flavin-N(5)-(hydro)peroxide/C(10a)-peroxide, or neutral flavin-C(4a)-hydroperoxide/hydroxide/N(5)-oxide, and the pathways where oxygenolysis goes prior to epoxidation are less favored. Epoxidation goes through intramolecular substitution of the O-O bond of anionic flavin-C(4a)-peroxide by β-carbon, while the resulting flavin-C(4a)-oxide accomplishes the oxygenolysis. Furthermore, two other reaction modes, i.e., concerted O-O cleavage/1,2-shift of α-substituents and dyotropic rearrangement were discovered for the decomposition of other anionic peroxides, and preliminary rules were summarized for understanding the chemoselectivity for this process. This study sheds light on the different reaction features of numerous flavin-dioxygen derivatives, providing deeper insights into flavin-catalyzed dioxygenation reactions, and is expected to inspire experimental design based on unconventional anionic peroxides.

Water Participated Dual C(sp3)−C(sp3) Bond Cleavage of Cyclobutanones Catalyzed by Lewis Acid

AbstractLewis acid‐catalyzed ring‐opening reactions of cyclobutanones were mostly achieved through cleavage of a single C2−C3 bond to deliver cyclic products. Herein, an unprecedented Lewis acid catalyzed synergistic cleavage of both C2−C3 bonds in 3‐arylcyclobutanones was realized under participation of water, providing a series of aryl alkyl ketones in mild conditions. A broad scope of substrates decorated with various substituents were well accommodated. Mechanistic proposal including the function of water was unambiguously validated by experimental verification.

Pyrolytic conversion of glucose into hydroxymethylfurfural and furfural: Benchmark quantum-chemical calculations.

Quantum chemical methods have been intensively applied to study the pyrolytic conversion of glucose into hydroxymethylfurfural (HMF) and furfural (FF). Herein, we collect the most relevant mechanistic proposals from the recent literature and organize them into a single reaction network. All the transition structures (TSs) and intermediates are characterized using highly accurate ab initio methods and the possible reaction pathways are assessed in terms of the Gibbs energies of the TSs and intermediates with respect to β-glucopyranose, selecting a 2D ideal-gas standard state at 773 K to represent the pyrolysis conditions. Several pathways can lead to the formation of both HMF and FF passing through rate-determining TSs that have ΔG‡ values of ~49-50 kcal/mol. Both water-assisted mechanisms and nonspecific environmental effects have a minor impact on the Gibbs energy profiles. We find that the HMF → FF + CH2O fragmentation has a small ΔrxnG value and an accessible ΔG‡ barrier. Our computational results, which are in consonance with the kinetic parameters derived from lumped models, the results of isotopic labeling experiments and the reported HMF/FF molecular ratios, could be useful for modeling studies including on nonequilibrium kinetic effects that may render more information about product yields and the relevance of the various pathways.

Mechanistic Analysis of 5-Hydroxy γ-Pyrones as Michael Acceptor Prodrugs.

Substituted 5-hydroxy γ-pyrones have shown promise as covalent inhibitor leads against cysteine proteases and transcription factors, but their hydrolytic instability has hindered optimization efforts. Previous mechanistic proposals have suggested that these molecules function as Michael acceptor prodrugs, releasing a leaving group to generate an o-quinone methide-like structure. Addition to this electrophile of either water or an active site cysteine was purported to lead to inhibitor hydrolysis or enzyme inhibition, respectively. Through the use of kinetic nuclear magnetic resonance experiments, Hammett analysis, kinetic isotope effect studies, and density functional theory calculations, our findings suggest that enzyme inhibition and hydrolysis proceed by distinct pathways and are differentially influenced by substituent electronics. This mechanistic revision helps enable a more rational optimization for this class of promising compounds.

Improving Zonisamide Manufacturing: Insights into Stereochemistry and Mechanisms for Continuous Optimization

AbstractZonisamide is a heterocyclic sulfonamide widely employed as anticonvulsant. In this work, we report an efficient process for the preparation of zonisamide, obtained in a six‐step synthesis from phenyl salicylate with an overall 31 % yield. The key step is represented by a base‐promoted intramolecular rearrangement of a β‐ketosultone oxime, leading to the concomitant formation of the benzisoxazole ring and of the exocyclic sulfonic group. This intriguing transformation is investigated with a combination of analytical techniques (NMR, HRMS, PXRD), leading to a preliminary mechanistic proposal.

Repurposing Mander's reagent for the first direct carbonyl deoxycyanation: Synthesis of oxoalkenenitriles from 1,3-diketones

The deoxycyanation of ketones is an uncommon reaction. Recently, we demonstrated that alkyl cyanoformates, such as methyl cyanoformate (Mander's reagent) or ethyl cyanoformate, can perform deoxycyanation on 1,3-diketones to deliver oxoalkenenitriles directly. This represents a significant departure from the typical reactivity of these reagents, which are predominantly used for the synthesis of β-ketoesters (α-acylation). By transitioning from lithium bases to amine-based bases, the selectivity of the acylation shifts from carbon to oxygen, yielding an enol carbonate intermediate. Density Functional Theory (DFT) investigations and in vitro experiments corroborate the synthetic outcome, namely, the synthesis of oxonitriles via deoxycyanation. The reaction mechanism was studied, revealing a series of sequential additions and eliminations consistent with the mechanistic proposal for the generation of a major byproduct, which poses one of the main drawbacks of this method. Although this approach was proven to be non-general, it represents the first direct synthesis of oxoalkenenitriles through a deoxycyanation process, thereby deviating from the conventional C-selective applications of alkyl cyanoformates.

Interfacial Engineering of Mn Porphyrin/Au Electrodes for Identifying MnOx as the Active Species under Oxygen Evolution Reactions.

Understanding the influence of surface structural features at a molecular level is beneficial in guiding an electrode's mechanistic proposals for electrocatalytic reactions. The relationship between structural stability and catalytic activity significantly impacts reaction performance, even though atomistic knowledge of active sites remains a topic of discussion. In this context, this work presents scanning tunneling microscopy (STM) results for the highly ordered arrangement of manganese porphyrin molecules on a Au(111) surface; STM allows us to monitor active sites at a molecular level to focus on long-standing issues with the electrocatalytic process, especially the exact nature of the real active sites at the interfaces. After water oxidation, manganese porphyrin rapidly decomposes into active catalytic species as bright protrusions. These newly formed active species drastically lost catalytic activity, up to 82%, through only acid treatment, one of the oxide removal methods, not by deionized water and acetone treatments. STM results of the obviated active species on the Au surface by an acidic solution support the forfeited catalytic activity. In addition, it shows a 67% decrement in catalytic activity by adsorption of phosphonic acid, one of the oxide's preferred adsorption materials, compared to the pristine one. Based on these observations, we confirm that the newly formed active species, as water oxidation catalysts, mostly consist of manganese oxides. Notable findings of our work provide molecular evidence for the active sites of Au and modified Au electrodes that spur the future development of water oxidation catalysts.

Catalytic coupling of 1-(2-(allyloxy)phenyl)-2-yn-1-ols and isonitriles for the synthesis of 2-(benzofuran-2-yl)acetamides: A combined experimental and theoretical study

A new catalytic approach to the synthesis of an important sub-class of benzofuran derivatives (namely, 2-(benzofuran-2-yl)acetamides, known to possess significant biological activities) has been developed. The new method is based on the use of Pd(PPh3)4 as simple and commercially available catalyst, readily prepared 1-(2-(allyloxy)phenyl)-2-yn-1-ols, and commercially available isonitriles. Formation of benzofuran-2-yl)acetamides derives from a mechanistic pathway involving an ordered sequence of steps, that are, oxidative addition of the phenoxyallyl moiety to Pd(0), isonitrile insertion, water attack to the ensuing (allyl)(imidoyl)palladium complex, β-H elimination from the H-O-C-Pd(allyl) moiety with formation of an allylpalladium hydride species and a 2-(3-hydroxybenzofuran-2(3H)-ylidene)acetamide intermediate, followed by reduction of the latter by (allyl)PdH and MeOH. This mechanistic proposal has been corroborated by DFT studies, while the structures of representative products have been confirmed by X-ray diffraction analysis.

IA-LSTM: Interaction-Aware LSTM for Pedestrian Trajectory Prediction.

Predicting the trajectory of pedestrians in crowd scenarios is indispensable in self-driving or autonomous mobile robot field because estimating the future locations of pedestrians around is beneficial for policy decision to avoid collision. It is a challenging issue because humans have different walking motions, and the interactions between humans and objects in the current environment, especially between humans themselves, are complex. Previous researchers focused on how to model human-human interactions but neglected the relative importance of interactions. To address this issue, a novel mechanism based on correntropy is introduced. The proposed mechanism not only can measure the relative importance of human-human interactions but also can build personal space for each pedestrian. An interaction module, including this data-driven mechanism, is further proposed. In the proposed module, the data-driven mechanism can effectively extract the feature representations of dynamic human-human interactions in the scene and calculate the corresponding weights to represent the importance of different interactions. To share such social messages among pedestrians, an interaction-aware architecture based on long short-term memory network for trajectory prediction is designed. Experiments are conducted on two public datasets. Experimental results demonstrate that our model can achieve better performance than several latest methods with good performance.

Catalysed Aryl Amine Syntheses via Azides: From Azidation of Aryl Halides to Azide Reduction and Direct Amination

AbstractThis review summarises and discusses aryl amine and azide syntheses from aryl halides employing azides. The majority of the reported reactions proceed with copper catalysis or mediation. Often, an aryl azide is formed in the first step, which is then reduced in situ to an aryl amine in a second step. The occurrence of the second step, the reduction, depends on the chosen reaction conditions and the substrates. The formation of only aryl azides through Cu‐mediated C−N bond formations is discussed, followed by mediated and catalytic aryl azide reduction employing different catalytic systems, and azidation with in situ azide reduction to amines, viz. azidation‐amination strategies. The azidation‐amination allows for the synthesis of complex heterocycles in multi‐step one‐pot procedures, of which several are summarised here. Examples of the application of azidation‐amination for synthesising important aryl amines employed in or as biologically active compounds, catalysis and materials science are also summarised. Finally, conducted control reactions have been collected and discussed in combination with mechanistic proposals. This literature survey allows us to pinpoint design criteria for the azide reduction to valuable amines, which includes the choice of reaction conditions such as solvent system and additives, involved metal and promising substrates.

The Role of Lysozyme in the Formation of Bioinspired Silicon Dioxide.

Several organisms are able to polycondensate tetraoxosilicic(IV) acid to form silicon(IV) dioxide using polycationic molecules. According to an earlier mechanistic proposal, these molecules undergo a phase separation and recent experimental evidence appears to confirm this model. At the same time, polycationic proteins like lysozyme can also promote polycondensation of silicon(IV) dioxide, and they do so under conditions that are not compatible with liquid-liquid phase separation. In this manuscript we investigate this conundrum by molecular simulations.

Differentially Private Average Consensus for Networks With Positive Agents.

This research paper addresses the problem of achieving differentially private average consensus for multiagent systems (MASs) consisting of positive agents. A novel randomized mechanism is introduced that employs nondecaying positive multiplicative truncated Gaussian noises to maintain the positivity and randomness of the state information over time. A time-varying controller is developed to achieve mean-square positive average consensus, and convergence accuracy is evaluated. The proposed mechanism is shown to preserve (ϵ,δ) -differential privacy of MASs, and the privacy budget is derived. Numerical examples are provided to illustrate the effectiveness of the proposed controller and privacy mechanism.

Combining Skin Adhesive Tape with Incisional Negative Pressure Wound Therapy for Gaping Spinal Wound Dehiscence: A Case Report

The authors present a case report of spinal wound dehiscence successfully treated with a combination of incisional negative pressure wound therapy and skin adhesive tapes. This article discusses the technique, benefits and limitations, and finally provides a proposed mechanism of action.

Mechanism of Ni-Catalyzed Photochemical Halogen Atom-Mediated C(sp3)-H Arylation.

Within the context of Ni photoredox catalysis, halogen atom photoelimination from Ni has emerged as a fruitful strategy for enabling hydrogen atom transfer (HAT)-mediated C(sp3)-H functionalization. Despite the numerous synthetic transformations invoking this paradigm, a unified mechanistic hypothesis that is consistent with experimental findings on the catalytic systems and accounts for halogen radical formation and facile C(sp2)-C(sp3) bond formation remains elusive. We employ kinetic analysis, organometallic synthesis, and computational investigations to decipher the mechanism of a prototypical Ni-catalyzed photochemical C(sp3)-H arylation reaction. Our findings revise the previous mechanistic proposals, first by examining the relevance of SET and EnT processes from Ni intermediates relevant to the HAT-based arylation reaction. Our investigation highlights the ability for blue light to promote efficient Ni-C(sp2) bond homolysis from cationic NiIII and C(sp2)-C(sp3) reductive elimination from bipyridine NiII complexes. However interesting, the rates and selectivities of these processes do not account for the productive catalytic pathway. Instead, our studies support a mechanism that involves halogen atom evolution from in situ generated NiII dihalide intermediates, radical capture by a NiII(aryl)(halide) resting state, and key C-C bond formation from NiIII. Oxidative addition to NiI, as opposed to Ni0, and rapid NiIII/NiI comproportionation play key roles in this process. The findings presented herein offer fundamental insight into the reactivity of Ni in the broader context of catalysis.

Selective activation of methane on hydroxyapatite surfaces: Insights from machine learning and density functional theory

The electrocatalytic conversion of methane has attracted considerable attention owing to its ability to operate under mild conditions, thereby avoiding peroxidation. Recently, hydroxyapatite (HAP), an environmental-friendly and cost-effective electrocatalyst, was found to have high catalytic selectivity for the methane activation to produce alcohols. However, the overall activation mechanism still remains elusive and thus limits further improvement of the catalytic performance. In this study, we employed machine learning-assisted molecular dynamics simulations to analyze the structural modifications in the HAP with defects during sintering. Density functional theory calculations were performed to explore the catalytic mechanism of methane on various sintered surfaces of HAP. During the sintering of HAP, the presence of H2O or O vacancies causes the migration of H2O and OH species from the bulk phase toward the surface. On the basis of our simulations, the H2O or OH migration reduces the overpotential of oxygen evolution reactions and alters the stability of intermediates. It largely impacts the selectivity of methane activation and different products can be obtained depending on the defect modes. Our mechanistic proposal then fundamentally challenges the prevailing opinion that active sites are exclusively confined to the surface of HAP. Our work may pave the way for designing and synthesizing novel electrocatalysts with enhanced performance and efficiency.

Microkinetic Model as a Crucial Tool for Understanding Homogeneous Catalysis

AbstractMicrokinetic modeling is a computational tool that allows simulating the evolution of the concentration of catalytically relevant species with time, providing a description of the catalytic system closer to the experimental. Microkinetic models have been mainly applied in organometallic catalysis as a means for validating mechanistic proposals by comparing experimental and computed rates and concentrations at a given time. However, this tool becomes very useful when studying complicated reaction mechanisms, aiding in identifying the catalyst resting state, optimizing reaction conditions, or improving the catalyst design. In this Concept, we focus on these applications of microkinetic modeling through the discussion of some selected examples. In addition, we also point out some of the challenges and limitations we may face when building microkinetic models, which may explain why they are still underused.