JACS Au最新文献

A fundamental understanding of the solution properties of conjugated ladder polymers (CLPs) is essential for advancing their design, synthesis, and solution processing toward high-performance optoelectronic applications. Nevertheless, elucidating the solution conformation of CLPs remains a significant challenge in the field of polymer physics, owing to the difficulty of synthesizing defect-free samples, their intrinsically low solubility that results in weak signals and limited analytical accuracy, the pronounced tendency of CLPs to aggregate even when dissolved, and the absence of reliable theoretical models. Here, these fundamental challenges are addressed by the synthesis, neutron scattering measurements, and computational simulations of two model CLPs, LP1 and LP2. Owing to their bulky three-dimensional side chains, LP1 and LP2 exhibit a non-aggregated character and high dispersibility as single polymer chains. Small-angle neutron scattering revealed unexpectedly low persistence lengths (L _p) of 3-5 nm. The L _p being similar to those of non-ladder conjugated polymers such as P3HT indicates the long-range conformational semiflexibility of CLPs despite them possessing a ladder-type constitution. Machine learning-based molecular dynamics simulations further showed that the semiflexibility of these CLP chains mainly results from the pronounced out-of-plane deformations, which is synergistically influenced by the steric congestion of the side chains. Overall, a comprehensive experimental and computational approach demonstrates that CLPs, despite their fused-ring polyaromatic backbones, are best described as ribbon-like semiflexible chains, in contrast to the common belief that they are rigid-rod polymers.

Understanding and controlling polaron dynamics are pivotal for improving charge transport in sodium-air batteries. Here, we employ real-time time-dependent density functional theory to investigate the ultrafast photoinduced dynamics of hole polarons (HPs) and electron polarons (EPs) in Na₂O₂ under femtosecond laser excitation. In the ground state, both polarons are highly localized and exhibit high dissociation barriers, 0.52 eV for HPs and 1.36 eV for EPs, limiting their thermally activated mobility. Upon photoexcitation, HP exhibits an increased occupation of π* antibonding orbitals, which weakens the O-O bond and drives coherent stretching oscillations. This process culminates in spontaneous, barrierless polaron dissociation with the release of mobile holes into the valence band, enabling enhanced charge delocalization and facilitating polaron hopping. In contrast, EP undergoes an additional population of σ* antibonding orbitals, further stabilizing the elongated O-O bond and increasing the dissociation barrier, thereby suppressing carrier mobility. This asymmetric photoresponse arises from an orbital-selective excitation pathway coupled to distinct bonding character at the polaron sites. These findings unveil a fundamental design principle for tuning polaronic conductivity via light and highlight the potential of optical modulation strategies for improving performance in metal-air batteries.

Synthetic polymers are important components of modern functional materials. Developing efficient polymerization processes with "clickable" features will enhance the diversity of available structures and facilitate exploration of new properties. In this work, we developed a strategy to synthesize isoindolin-1-one-based alternating copolymers through a new mode of step-growth polycondensation of functionalized bis-ortho-phthalaldehyde and diamine monomers. The reaction was performed in DMF and catalyzed by pyridine/AcOH at room temperature, affording linear copolymers with high molecular weights. This reaction enabled the production of alternating copolymers in a modular manner, where different functional units could be simply incorporated by varying the linker units in monomer structures. This approach was further expanded to synthesize branched and cross-linked polymer networks by introducing a triamine brancher and a dithiol cross-linker into the polymerization system. Some of the isoindolin-1-one-based copolymers behaved as thermoplastic elastomers, demonstrating the potential of this polymerization in materials sciences.

Herein, the total synthesis of the antimalarial natural products, koshidacins A and B, is disclosed. We developed an inverse peptide elongation sequence to elaborate the linear tetrapeptide by leveraging a soluble hydrophobic tag (TCbz group) for liquid-phase peptide synthesis. The key advances involve head-to-tail macrocyclization to provide the carrier-supported cyclic tetrapeptide and photoinduced deaminative alkylation to edit the native peptide residue that enabled us to construct the requisite alkyl chain in this unique natural product family.

The reaction between C-terminal α-thioester and N-terminal cysteinyl peptides is known as native chemical ligation (NCL). Alkyl α-thioesters are traditionally prepared in NCL due to their higher thermodynamic stability, which endows resistance to hydrolysis and easier peptide handling. However, the ligation kinetics of these species are slow, and the reaction times exceed the practical limits for chemical protein synthesis. Therefore, conversion to a more reactive phenyl α-thioesters through thiol-thioester exchange is usually employed to enhance the NCL reaction rate. In addition, phenyl thiols can reverse the formation of the less reactive branched thioesters, i.e., thioesters formed with internal Cys residues, and thiolactones. Interestingly, the fastest NCL rates are achieved with phenyl α-selenoesters, though phenylselenol is a poor catalyst for the selenol-(α-alkyl thioester) exchange, particularly with β-branched residues. Hence, it is usually necessary to preform the phenyl α-selenoester and protect internal cysteine residues to preserve the kinetic advantage. Moreover, an ∼2-5-fold excess of the N-terminal cysteine acceptor peptide is typically required to prevent the competition from the cysteine of the ligation product for the phenyl α-selenoester donor that leads to the branched thioester formation. Based on these precedents, we have designed sodium 2-selenoethanesulfonate (SeESNa) as a new selenol catalyst that can overcome these limitations. SeESNa reacts with alkyl α-thioester, N-acyl benzotriazole, and N-acylurea peptides, giving α-SeESNa species. We have determined the rate constants for the ligation with preformed α-SeESNa peptides and show that it is a superior catalyst compared to the known 4-mercaptophenylacetic and 4-mercaptobenzoic acids. The utility of SeESNA was proved through the synthesis of the cardiotoxin A5, a snake venom peptide that contains eight cysteines, without orthogonal cysteine protection. Importantly, it has enabled expressed protein ligation under folding conditions with extraordinary speed, as shown with the Sonic Hedgehog and SUMO2 proteins. Thus, SeESNa is envisaged to have broad applicability in synthetic and semisynthetic protein chemistry.

In/postsource fragments (ISFs) arise during electrospray ionization or ion transfer in mass spectrometry when molecular bonds break, generating ions that can complicate data interpretation. Although ISFs have been recognized for decades, their contribution to untargeted metabolomicsparticularly in the context of the so-called "dark matter" (unannotated MS or MS/MS spectra) and the "dark metabolome" (unannotated molecules)remains unsettled. This ongoing debate reflects a central tension: while some caution against overinterpreting unidentified signals lacking biological evidence, others argue that dismissing them too quickly risks overlooking genuine molecular discoveries. These discussions also raise a deeper question: what exactly should be considered part of the metabolome? As metabolomics advances toward large-scale data mining and high-throughput computational analysis, resolving these conceptual and methodological ambiguities has become essential. In this perspective, we propose a refined definition of the "dark metabolome" and present a systematic overview of ISFs and related ion forms, including adducts and multimers. We examine their impact on metabolite annotation, experimental design, statistical analysis, computational workflows, and repository-scale data mining. Finally, we provide practical recommendationsincluding a set of dos and do nots for researchers and reviewersand discuss the broader implications of ISFs for how the field explores unknown molecular space. By embracing a more nuanced understanding of ISFs, metabolomics can achieve greater rigor, reduce misinterpretation, and unlock new opportunities for discovery.

Tuberculosis caused by Mycobacterium tuberculosis (Mtb) is one of the most dangerous diseases globally. Mtb poses a heavy death toll, especially in low-resource settings, where inadequate diagnostic capabilities greatly hinder treatment and prevention. Here, we present a rapid and cost-effective bacilli-capturing method that uses magnetic nanoclusters conjugated with mycobacteriophages. The mycobacteriophages provide Mtb recognition functionality, and the binding of the nanoparticles with attenuated Mtb H37Rv and Mycobacterium bovis Bacillus Calmette-Guérin (BCG) was visualized by electron microscopy. The magnetic nanocrystal clusters have an excellent separation efficiency. A nearly 100% capturing efficiency and high specificity toward mycobacteria species were obtained. Magnetically separated mycobacteria were disrupted by ultrasound to facilitate the rapid release of cellular adenosine triphosphate (ATP) for bioluminescent detection. Using portable and inexpensive devices, we achieved rapid detection of Mtb at as low as 1000 bacilli per sample in artificial sputum, urine, and whole porcine blood within 35 min. This method demonstrates excellent potential for point-of-care tuberculosis diagnosis in resource-limited settings.

Aromatic carboxylic acid derivatives are ubiquitous structural motifs in organic chemistry, which find widespread use as synthetic intermediates or target compounds for various applications. An ideal way to access these compounds is by C-H functionalization of a simple arene with a C1-building block like CO. State of the art methods, however, require the use of prefunctionalized arenes or substrates bearing directing groups, which negatively impact the step economy and/or significantly limit the scope of such processes. Herein we describe Pd-catalysts for the nondirected C-H alkoxycarbonylation of simple arenes. The protocol offers a highly efficient approach toward the synthesis of aromatic esters and enables the functionalization of a broad range of substrates. The predominantly sterically controlled regioselectivity renders the process complementary to electrophilic aromatic substitution reactions. We demonstrate the synthetic versatility of the obtained products to access diverse classes of compounds and present mechanistic studies to derive a plausible reaction mechanism.

The direct use of aryl chlorides in Suzuki-Miyaura cross-coupling remains a long-standing challenge due to the inert nature of the C-Cl bond. Herein, we report the first nickel-catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides under solvent-minimized, heated mechanochemical conditions. Employing liquid-assisted grinding (LAG) and thermal input, a broad range of electron-deficient and electron-rich aryl chlorides were successfully coupled with aryl boronic acids in under 1 h. The methodology was translated to a twin-screw extrusion (TSE) process, enabling continuous production at scales up to 400 mmol and 65 g isolated product. This work demonstrates a sustainable, scalable strategy for C-C bond formation using readily available feedstocks, highlighting the synergy between nickel catalysis, mechanochemistry, and continuous flow processing.

Precise and rapid detection of bacterial infection in vivo remains a significant challenge in clinical practice. In response to this challenge, several pathogen-specific positron emission tomography (PET) tracers have been developed, including the fluorine-18-labeled sorbitol derivative [¹⁸F]-FDS, which shows great promise in detecting bacterial infections in patients. In this study, we tested the hypothesis that the diagnostic performance of [¹⁸F]-FDS could be modulated via regioselective glycosylation to improve radiotracer stability, broaden organism sensitivity, and tune pharmacodynamics. A synthetic sequence was developed, whereby the common radiotracer [¹⁸F]-FDG was converted chemoenzymatically to α- and β-linked disaccharides via reverse phosphorolysis and subsequently reduced to the corresponding glycosylated [¹⁸F]-FDS derivatives. This strategy allowed the syntheses of glucopyranosyl-d-sorbitol analogs [¹⁸F]-FNT (α-1,3 linked), [¹⁸F]-FMT (α-1,4 linked), [¹⁸F]-FLT (β-1,3 linked), and [¹⁸F]-FCT (β-1,4 linked). Among these tracers, the α-linked analogs [¹⁸F]-FNT and [¹⁸F]-FMT showed greater uptake in both Gram-positive and Gram-negative pathogens compared to the β-linked analogs [¹⁸F]-FLT and [¹⁸F]-FCT. In vivo time-course PET imaging of [¹⁸F]-FNT and [¹⁸F]-FMT in uninfected mice revealed favorable pharmacokinetics, including rapid urinary excretion, minimal hepatobiliary retention, and low off-target signals. PET imaging using [¹⁸F]-FNT and [¹⁸F]-FMT detected Klebsiella pneumoniae pulmonary infections in mice with high infected/uninfected tissue ratios (∼6-fold). [¹⁸F]-FNT also showed high infected/uninfected tissue ratios (∼28-fold) in Staphylococcus aureus myositis, whereas the parent [¹⁸F]-FDS tracer was not taken up by the Gram-positive organisms tested. Our findings highlight the potential for PET tracer glycosylation as a tool to modulate target specificity and improve imaging sensitivity. These results also establish [¹⁸F]-FNT as a highly promising PET tracer with a high translational potential for detecting bacterial infection in vivo.