Key Intermediates Research Articles

(Invited) Reshaping Light with Hybrid Quantum Dot: Molecule Systems

Photon upconversion is an energy conversion process wherein a material absorbs two or more low-energy photons and uses their energy to generate high-energy photons. Upconversion systems that convert near-infrared light into the visible range can address current challenges in solar energy capture and near-infrared sensor design while materials that operate at higher energy, producing UV photons from visible light, can enable applications in photocatalysis and light-based 3D printing. Due to their high extinction coefficients and size-tunable optical properties, quantum dots have emerged as ideal photosensitizers for photon upconversion systems. In these systems, light absorbed by a quantum dot is passed to a molecule at its surface, placing the molecule into a spin-triplet state. Upconversion is achieved when two molecules in their triplet state encounter one another and undergo triplet fusion, a process that deexcites one molecule and promotes the other to a high-energy, emissive spin-singlet state. In this presentation, I will present spectroscopic measurements and electronic structure calculations that identify energy transfer rates and key intermediates involved in two quantum dot systems that respectively demonstrate red-to-blue and blue-to-UV photon upconversion. In the first system, which consists of silicon quantum dots functionalized with anthracene ligands, we find that by controlling the chemical structure of molecular tethers that covalently link anthracene to silicon, we can produce strongly coupled states wherein excited charge carriers are shared between silicon and anthracene. By controlling the energy of these states, we can optimize the system’s performance, achieving an upconversion quantum yield of 17.2%. In the second system, we use CsPbBr3 perovskite quantum dots to drive triplet energy transfer to naphthalene ligands. This energy transfer process is found to be highly sensitive to the structure of the chemical linker that binds naphthalene to CsPbBr3, which we attribute to modulation of the degree of wavefunction overlap between the states of the quantum dot energy donor and naphthalene energy acceptor.

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes.

Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron-glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by 1H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism.

An Engineered Imine Reductase for Highly Diastereo- and Enantioselective Synthesis of β-Branched Amines with Contiguous Stereocenters.

β-Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo- and enantioselective biocatalytic approach for preparing a broad range of β-branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution-asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild-type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9% ee, >99:1 dr, and >99% conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74% yield, >99.9% ee, and 98:2 dr at a challenging substrate loading of 110 g L-1. Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution-asymmetric reductive amination reaction system.

Reactivity of the phosphaethynolate anion with stabilized carbocations: mechanistic studies and synthetic applications.

The reactivity of sodium phosphaethynolate Na(OCP) towards various Mayr's reference electrophiles was investigated using conventional UV-visible and laser-flash photolysis techniques. The kinetic data, along with density functional theory (DFT) calculations, enabled the first experimental quantification of the phosphorus nucleophilicity of [OCP]-. Product studies of these reactions demonstrate the formation of secondary as well as tertiary phosphines. The mechanism of this unprecedented phosphorus-atom transfer reaction is thoroughly discussed, with key intermediates successfully isolated and characterized. Importantly, some bulky secondary phosphine oxides synthesized using this approach, have demonstrated high efficiency as ligands in the Suzuki coupling reaction.

Enhanced CO2 Adsorption and Conversion in Diethanolamine‐Cu Interfaces Achieving Stable Neutral Ethylene Electrosynthesis

AbstractMolecular modifications have shown tremendous potential in boosting the electrochemical CO2 reduction (CO2RR) to ethylene. However, the key mechanisms of modulation at the molecular level remain unclear, especially for the adsorption and activation of key intermediates (e.g., *CO2 and *CO). Here, report that a diethanolamine (DEA)‐modified Cu catalyst can reduce CO2 to ethylene with a faradaic efficiency of ≈50.5% with a partial current density of ≈155.7 mA cm−2 in the neutral conditions, which surpasses the Cu catalyst without molecular modification (≈28.5% and ≈95.6 mA cm−2). Density functional theory calculations demonstrate that DEA on the Cu surface boosts the adsorption and activation of CO2 and the following C–C coupling processes during the CO2RR‐to‐ethylene process. Molecular dynamics simulations suggest that the molecules distant from the Cu site have a CO2 enrichment effect. Operational stability achieved via the introduction of DEA molecules onto ketjen black, which then successively immobilized on the Cu nanoparticles and polytetrafluoroethylene electrodes to obtain a stable tripe‐phase boundary, realizing constant ethylene selectivity for 100 operating hours in a flow cell.

Visible-Light-Induced Photocatalytic Deoxygenative Benzylation of Quinoxalin-2-(1H)-ones with Carboxylic Acid Anhydrides.

A visible-light-induced photocatalytic deoxygenative benzylation of quinoxalin-2-(1H)-ones is herein described. This novel approach provides a mild, simple, and practical route to 3-benzylquinoxalin-2(1H)-ones from ubiquitous and safe carboxylic acid anhydrides. A wide range of substrates with different substituents were well-tolerated and efficiently transformed to various functionalized 3-benzylquinoxalin-2(1H)-ones with great potential for valuable applications in drug discovery. Mechanistic investigations suggest H2O as a proton source, while hydroxyl-containing quinoxalin-2(1H)-ones may be key intermediates of the photocatalytic deoxygenative process.

Micro-Structure Engineering in Pd-InOx Catalysts and Mechanism Studies for CO2 Hydrogenation to Methanol.

Significant interest has emerged for the application of Pd-In2O3 catalysts as high-performance catalysts for CO2 hydrogenation to CH3OH. However, precise active site control in these catalysts and understanding their reaction mechanisms remain major challenges. In this investigation, a series of Pd-InOx catalysts were synthesized, revealing three distinct types of active sites: In-O, Pd-O(H)-In, and Pd2In3. Lower Pd loadings exhibited Pd-O(H)-In sites, while higher loadings resulted in Pd2In3 intermetallic compounds. These variations impacted catalytic performance, with Pd-O(H)-In catalysts showing heightened activity at lower temperatures due to the enhanced CO2 adsorption and H2 activation, and Pd2In3 catalysts performing better at elevated temperatures due to the further enhanced H2 activation. In situ DRIFTS studies revealed an alteration in key intermediates from *HCOO over In-O bonds to *COOH over Pd-O(H)-In and Pd2In3 sites, leading to a shift in the main reaction pathway transition and product distribution. Our findings underscore the importance of active site engineering for optimizing catalytic performance and offer valuable insights for the rational design of efficient CO2 conversion catalysts.

SYNTHESIS AND REACTIVITY OF CARBOHYDRATES CONTAINING 3‐MEMBERED HETEROCYCLES, KEY PRECURSORS OF MODIFIED SUGARS AND MIMETICS

Molecules containing three‐membered heterocycles, including oxiranes (epoxides), thiiranes (episulfides) and aziridines, are considered privileged structures as they serve as key precursors or intermediates for the synthesis of a varied range of organic compounds, such as natural products, mimetics and pharmaceuticals. The principal advantage of this type of heterocycles is their reactivity towards the nucleophilic ring‐opening, which usually occurs in a regioselective manner, resulting in the formation of 1,2‐disubstituted products. When attached to a chiral scaffold, such as a carbohydrate molecule, the ring‐opening process is usually highly diastereoselective. Therefore, these compounds have been extensively employed in the field of carbohydrates for the synthesis of enantiomerically pure modified sugars that are useful as glycobiology tools. This review presents an overview of the recent methodologies developed for the construction of epoxide, thiirane, and aziridine rings from common or modified sugars. Due to their structural similarity to carbohydrates, three‐membered heterocyclic derivatives of cyclitols and carbasugars have been included. All these compounds, and their ring‐opening derivatives have shown to be crucial in the synthesis of glycomimetics, which display diverse biological activities. These include enzyme inhibition, binding to lectin receptors, and more recently, the use as probes for the diagnosis and monitoring of diseases.

Metallacyclobutadienes: Intramolecular Rearrangement from Kinetic to Thermodynamic Isomers.

Metallacyclobutadienes (MCBDs) are key intermediates of alkyne metathesis reactions. There are in principle two isomerization pathway from kinetic to thermodynamic MCBDs, intermolecular and intramolecular. However, systems that simultaneously isolate two kinds of MCBD isomers have not been achieved, thus restricting the mechanistic studies of the isomerization. Here the reactivity of a metallapentalyne that contains an M≡C bond within the aromatic ring, with alkynes to afford a series of MCBD-fused metallapentalenes is studied. In some cases, both kinetic and thermodynamic products are isolated in the same system, which has never been observed in previous MCBD reactions. Furthermore, the isomerization of MCBD-fused metallapentalenes is investigated both experimentally and theoretically, indicating that it is an intramolecular process involving a metallatetrahedrane (MTd) intermediate. This research provides experimental evidence demonstrating that one MCBD can undergo intramolecular rearrangement to transform into another.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and β-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Selective aerobic oxidation of cumene to acetophenone via N-hydroxymaleimide fabricated by a sequential copolymerization and imidization

Selective oxidation of cumene to value-added acetophenone is of great importance and environmental friendliness. N-hydroxymaleimide (NHMI) was immobilized on a polymer substrate via co-polymerization followed by an imidization in this work, and the catalyst was characterized and tested for oxidation of cumene to acetophenone. The catalyst was found active and selective for the transformation from cumene to acetophenone. The optimized catalyst exhibited a cumene conversion of 93.3 % and a selectivity to acetophenone of 79.2 %. The cumene oxidation catalyzed by the immobilized NHMI copolymers may proceed in the presence of the cocatalyst Co2+ by a radical way based on the key intermediates or free radicals for the chain propagation of the auto-oxidation reaction observed. Accordingly, a reaction network and mechanism were proposed. The synthesized NHMI catalysts and the fabrication method may shed some light on the development of immobilized catalysts for the activation and selective oxidation of benzylic C−H bonds.

Cobalt-Doped Bismuth Nanosheet Catalyst for Enhanced Electrochemical CO2 Reduction to Electrolyte-Free Formic Acid.

Electrochemical carbon dioxide (CO2) reduction reaction (CO2RR) to valuable liquid fuels, such as formic acid/formate (HCOOH/HCOO-) is a promising strategy for carbon neutrality. Enhancing CO2RR activity while retaining high selectivity is critical for commercialization. To address this, we developed metal-doped bismuth (Bi) nanosheets via a facile hydrolysis method. These doped nanosheets efficiently generated high-purity HCOOH using a porous solid electrolyte (PSE) layer. Among the evaluated metal-doped Bi catalysts, Co-doped Bi demonstrated improved CO2RR performance compared to pristine Bi, achieving ~90 % HCOO- selectivity and boosted activity with a low overpotential of ~1.0 V at a current density of 200 mA cm-2. In a solid electrolyte reactor, Co-doped Bi maintained HCOOH Faradaic efficiency of ~72 % after a 100-hour operation under a current density of 100 mA cm-2, generating 0.1 M HCOOH at 3.2 V. Density functional theory (DFT) results revealed that Co-doped Bi required a lower applied potential for HCOOH generation from CO2, due to stronger binding energy to the key intermediates OCHO* compared to pure Bi. This study shows that metal doping in Bi nanosheets modifies the chemical composition, element distribution, and morphology, improving CO2RR catalytic activity performance by tuning surface adsorption affinity and reactivity.

Evidence on C-C Coupling to Acetate as Key Reaction Intermediate in Photocatalytic Reduction of CO2 over Pt/TiO2.

Photocatalytic conversion of CO2 with H2O is an attractive application that has the potential to mitigate environmental and energy challenges through the conversion of CO2 to hydrocarbon products such as methane. However, the underlying reaction mechanisms remain poorly understood, limiting real progress in this field. In this work, a mechanistic investigation of the CO2 photocatalytic reduction on Pt/TiO2 is carried out using an operando FTIR approach, combined with chemometric data processing and isotope exchange of (12CO2 + H2O) toward (13CO2 + H2O). Multivariate curve resolution analysis applied to operando spectra across numerous cycles of photoactivation and the CO2 reaction facilitates the identification of principal chemical species involved in the reaction pathways. Moreover, specific probe-molecule-assisted reactions, including CO and CH3COOH, elucidate the capacity of selected molecules to undergo methane production under irradiation conditions. Finally, isotopic exchange reveals conclusive evidence regarding the nature of the identified species during CO2 conversion and points to the significant role of acetates resulting from the C-C coupling reaction as key intermediates in methane production from the CO2 photocatalytic reduction reaction.

Applications of 4-alkynylated pyrazol-3-ones: Synthesis of pyrazol-4-yl furan- and/or thiophene-2-carboxylates

Chemical reactivity and applications of 4-alkynylated pyrazol-3-ones are described. A facile access to the synthesis of novel pyrazol-4-yl furan- and/or thiophene-2-carboxylates through the ring transformation and subsequent acylation of 4-alkynylated pyrazol-3-ones as the key intermediates, which were prepared from pyrazole-4,5-dione and terminal alkynes, in moderate to good yields is achieved. All the synthesized compounds were characterized by spectroscopic analysis.

Green Late-Stage Functionalization of Tryptamines.

An efficient and rapid protocol for the oxidative halogenation of tryptamines with 10 % aqueous NaClO has been developed. This reaction is featured by its operational simplicity, metal-free conditions, no purification, and high yield. Notably, the resulting key intermediates are suitable for further functionalization with various nucleophiles, including amines, N-aromatic heterocycles, indoles and phenols. The overall transformation exhibits broad functional-group tolerance and is applicable to the late-stage functionalization of complex biorelevant molecules.

Gold(I)-Catalyzed Functionalization of Pyrrole Derivatives: Stereoselective Synthesis of 7,8-Disubstituted 7,8-Dihydroindolizin-6(5H)-ones.

A gold-catalyzed cycloisomerization/nucleophilic addition/C-O rearrangement was developed starting from readily available pyrrole precursors. This efficient synthesis of 7,8-dihydroindolizin-6(5H)-ones (with the creation of new C-C and C-O bonds) allows access to key intermediates for the synthesis of natural and biologically active molecules. The functionalization process was independently optimized for both carbon and oxygen nucleophiles, and the versatility of this methodology was established by the synthesis of 36 different pyrrole derivatives (yields up to 90%).

The Simpler the Better: One‐Pot Production of γ‐Valerolactone from Biomass Conversion through All‐In‐One Sc(OTf)3 Catalyzed Cascade Reaction

Abstractγ‐Valerolactone (GVL) derived from non‐edible biomass resources has attracted much intense attention from both academia and industry, due to its excellent properties as green solvent and ideal renewable feedstock for production of bioenergy and biorefinery. However, the practical application of current synthetic technologies is restricted by complicated catalyst system and high production cost so far. Here we report a simple but highly efficient method to realize one‐pot synthesis of bio‐derived GVL by a series of Lewis acidic triflates (M(OTf)3 (M=Sc3+, Ln3+)) under mild condition, achieving up to 78 % GVL yield from furfural (FUR) without any additives or pretreatments. Systematic mechanistic studies, including reaction monitoring, identification of key intermediates and deuterium control experiments disclose the nature of such one‐pot conversion by all‐in‐one Sc(OTf)3. This system exhibits several excellent features such as commercially available and inexpensive catalyst, 100 % carbon atom‐economy, environmentally friend, simple preparation and separation procedures. This method could also be applied to the upstream raw materials, including xylose, hemicellulose and even corncob, achieving GVL in 36 %, 35 % and 21 % yields in one‐pot manner, respectively.

Improving stereoselectivity of phosphotriesterase (PTE) for kinetic resolution of chiral phosphates.

Specific stereoisomer is paramount as it is vital for optimizing drug efficacy and safety. The quest for the isolation of desired stereoisomer of active pharmaceutical ingredients or key intermediates drives innovation in drug synthetic and biocatalytic methods. Chiral phosphoramidate is an important building block for the synthesis of antiviral drugs such as remdesivir and sofosbuvir. Given the clinical potency of the (Sp)-diastereomer of the drugs, an enzyme capable of completely hydrolyzing the (Rp)-diastereomer is needed to achieve the purified diastereomers via biocatalytic reaction. In this study, protein engineering of phosphotriesterase (PTE) was aimed to improve the specificity. Employing rational design and site-directed mutagenesis, we generated a small library comprising 24 variants for activity screening. Notably, W131M and I106A/W131M variants demonstrated successful preparation of pure (Sp)-diastereomer of remdesivir and sofosbuvir precursors within a remarkably short hydrolysis time (<20min). Our work unveils a promising methodology for producing pure stereoisomeric compounds, utilizing novel biocatalysts to enable the chemoenzymatic synthesis of phosphoramidate nucleoside prodrugs.

Charge Redistribution in High-Entropy Perovskite Oxide Porous Nanotubes Boosts Nitrate Electroreduction to Ammonia.

High-entropy perovskite oxides are promising materials in the field of electrocatalysis due to their advantages such as large spatial composition regulation, entropy effects, and tunable material properties. However, the preparation of high-entropy perovskite oxides with stable and controllable structures still remains challenging. Herein, we fabricated a series of high-entropy perovskite oxide porous nanotubes (PNTs) by electrospinning as efficient electrocatalysts for the nitrate reduction reaction (NO3RR). We further revealed that the different diffusion and decomposition behaviors of metal ions and polymers during the calcination process are the key to the formation of high-entropy perovskite oxide PNTs. Especially, LaSrNiCoMnFeCuO3 PNTs show excellent performance of the NO3RR, achieving the maximum NH3 Faradaic efficiency of almost 100%, yield rate of 1657.5 μg h-1 mgcat.-1, and durable stability after successive cycling, being one of the best electrocatalysts for the NO3RR. The mechanism studies show that the charge redistribution induced by the multisite synergistic effect and abundant unsaturated sites in the high-entropy perovskite oxide PNTs favors the adsorption of NO3- and key intermediates and reduces the catalytic energy barrier, thus further achieving high NO3- conversion efficiency.

Refining metallic nano-copper by electron-rich black carbon for superior Fenton-like catalysis in water purification: The capacitive regulation of corrosive electron transfer

Transition metals are promising catalysts for environmental remediation. However, their low reactivity, poor stability and weak reusability largely limit practical applications. Herein, we report that the electron-rich dissolved black carbon (DBC) incorporated into the nanoscale zero-valent copper (nZVCu) can boost intrinsic reactivity, structural stability and cyclic reusability for superior peroxymonosulfate (PMS) activation and pollutant degradation. A series of refractory pollutants can be effectively removed on the DBC/nZVCu, in comparison with the nZVCu reference. Hydroxyl radical (‧OH) is identified as the dominant reactive oxygen species by electron spin resonance (ESR) and chemical quenching tests, mediated by the metastable Cu(III) as the key reactive intermediate. The electron-rich DBC protects nanoscale Cu from oxidative corrosion to slow down the surface formation of inert CuO layer, rendered by the thermodynamically and dynamically capacitive regulation of corrosive electron transfer from metallic core. By this refining way, the conducive DBC improves the neighboring utilization of reactive electron during metal corrosion, oxidant activation, radical generation and pollutant degradation in Fenton-like catalysis. Our findings suggest that the ubiquitous DBC can be an efficient chelating agent to refine transition metals by serving as the surface deactivator and electron mediator, and take new insights into their environmental and agricultural geochemistry.