JACS Au最新文献

Biphotonic mechanisms with visible light excitation can generate highly reactive species for thermodynamically challenging reactions. Particularly prominent is the consecutive photoinduced electron transfer mechanism, in which excited radical ions are the presumed key catalytically active species. They benefit from extremely high redox powers but suffer from excited state lifetimes in the low picosecond range and are susceptible to photodegradation. This makes mechanistic elucidation difficult and sometimes leads to debate around the identity of the true catalytically active species. In this study, we address these challenges by presenting a fully resolved mechanism, in which a spectroscopically observable and quantifiable ground state p-terphenyl radical anion is generated through sensitized blue-to-ultraviolet triplet-triplet annihilation upconversion, followed by reductive quenching of the highly excited singlet species. Due to its ground-state reactivity, the p-terphenyl radical anion profits from a persistence time approaching the millisecond time scale. This allows it to avoid the problematic photodegradation pathways often encountered with excited-state organic radicals while still exhibiting a competitively high reduction potential. Our results establish blue-to-ultraviolet upconversion as a robust strategy for generating long-lived super-reductants via a consistent, controllable mechanism that enables the activation of small inert substrate molecules, including CO₂. This work is relevant in the broader context of advancing photochemistry through mechanistic research that complements synthetic approaches.

Constructing 2D/3D bilayer structured all-inorganic perovskites through cation exchange is critically challenging. So far, only a few reports have claimed 2D/3D heterostructure formation via in situ surface reconstruction or cation interdiffusion. Yet, the underlying mechanism remains elusive and a fundamental understanding is still lacking from both thermodynamic and mechanistic perspectives: why and how organic cations displace Cs⁺ ions. This work presents a detailed mechanistic study encompassing molecular design, experimental validation, and theoretical verification to elucidate the cation exchange mechanism behind this surface reconstruction process. We have specifically developed a novel ammonium iodide salt, namely, DMA-BzAI, by incorporating a strong electron-donating dimethylamino moiety on the para position of the benzene ring in the most commonly used benzylammonium iodide (BzAI). This design aims to decrease the polarization force of the spacer cation toward octahedral inorganic slabs, providing stronger driving forces for ionic substitution. In situ X-ray scattering analysis confirms the dynamic evolution of n = 1 2D perovskites on CsPbI₂Br perovskites by treating with DMA-BzAI, contrasting sharply to the case of BzAI. A comprehensive theoretical investigation, including Bader charge analysis, formation energy, and nudged elastic band calculations, further demonstrates that both thermodynamic favorability and low activation barriers allow DMA-BzA⁺ cations to go through cation exchange reactions to substitute the strongly bound Cs⁺ ions in the inorganic perovskite lattice, leading to in situ formation of 2D/3D bilayer structure, in alignment with experimental observations. These mechanistic results provide fundamental insights into the cation exchange mechanism behind 2D/3D heterojunction formation in inorganic perovskites, offering rational ligand design principles for future research.

We report a dual electrochemical-photochemical platform that enables selective hydroalkylation of N-aryl maleimides for the construction of C4-functionalized N-aryl succinimides in the presence of alcohol (as a solvent) and aryl diazo esters. Alternate electrode electrolysis (AEE) selectively promotes electrochemical reduction of N-aryl maleimides which undergoes cyclopropanation with a carbene (generated by blue LED irradiation of diazo esters), subsequent ketyl radical-mediated ring opening, and electro-oxidative nucleophilic attack by alcohol afford the densely substituted hydroalkylated succinimide derivative. No cross-reactivity or degradation of intermediates was observed. The protocol showcases high functional group tolerance, affording over 26 structurally diverse N-aryl succinimide derivatives, including the late-stage functionalization of aromatic amine-containing pharmaceutical scaffolds. A gram-scale synthesis underscores the scalability and operational simplicity of the process. Control experiments highlight the orthogonal yet complementary nature of the activation modes and provide mechanistic evidence supporting a stepwise paired electrolysis process aided with photochemical carbene generation pathway.

Developing chemical toolkits for mRNA modification has remained an immense challenge, driven by the inherent difficulties in targeting mRNA molecules. Antisense oligonucleotides (ASOs) offer a promising framework for targeting specific mRNA sequences, yet they do not possess the capacity to alter the structure of mRNA except through enzyme-mediated hydrolysis. We developed a platinum-(IV)-ASO strategy that combines the sequence specificity of ASOs with the reactivity of platinum to functionalize nucleic acids, including short RNA and mRNA, in a selective enzyme-free manner. Access to Pt-(IV)-ASO constructs was made possible by an equatorial Pt-(IV) ammine derivatization strategy, allowing for the conjugation of carboxylic acids directly to the Pt core. Reactivity with 21-mer RNA and full-length mRNA by Pt-ASO constructs was demonstrated, and the conjugated products were characterized using a suite of orthogonal techniques, such as electrophoretic mobility shift assay, MALDI-TOF MS, temperature-dependent dissociation assay, and RT-qPCR. Constructs were optimized for their reactivity and selectivity, allowing for Pt-(IV)-PMO constructs with subnanomolar IC₅₀ values in an RNA competition assay. This Pt-(IV)-ASO platform facilitates new avenues for RNA modification by providing a strategy for functionalizing nucleic acids with potential applications in molecular biology research.

Fluorescent double-helical monometallofoldamers [Ag-(1)₂]-[PF₆] were constructed by the mononuclear complexation of two bipyridine strands 1 featuring two L-shaped dibenzopyrrolo-[1,2-a]-[1,8]-naphthyridine units at both ends with a Ag-(I) cation. These monometallofoldamers exhibited double-helical/open conformational switching. [(R)-Ag-(1c)₂]-[PF₆] with chiral side chains induced a single-handed helix sense and enabled precise control of M/P helicity switching in response to a solvent. This complex also exhibited strong fluorescence and circularly polarized luminescence (CPL) inversion switching upon M/P helicity inversion. For instance, [(R)-Ag-(1c)₂]-[PF₆] exhibited positive CPL in CH₂Cl₂ (φ_F = 0.69, g _lum = 1.9 × 10^-3) and negative CPL in toluene (φ_F = 0.79, g _lum = -2.0 × 10^-3). This double helix also aggregated in polar solvents, which led to CPL inversion switching induced by temperature- and concentration-dependent aggregation.

Imine reductases (IREDs) are powerful biocatalysts to afford valuable enantioenriched amines via the stereoselective reduction of imines. While significant progress has been made in expanding their catalytic capabilities, direct reduction of electron-rich alkenes by IREDs remains a formidable challenge and is unprecedented in biology. Here, we report the reprogramming of an IRED from Sinorhizobium (SinIRED) to catalyze the enantioselective reduction of enamides. Through directed evolution, the final optimized SinIRED-V5 variant is able to reduce a variety of enamides and deliver diverse protected chiral amines in up to 97% yield and >99:1 enantiomeric ratio (e.r.). Mechanistic studies suggest a novel synergistic pathway involving enamine-imine tautomerization followed by NADPH-mediated hydride transfer process. This work expands the catalytic versatility of IREDs and provides the first known example of IRED-catalyzed reduction of electron-rich enamides.

Continuous-flow technology has emerged as a powerful platform for resource-economical molecular synthesis, thereby addressing key limitations of conventional batch processes through unparalleled control of temperature and residence time as well as improved heat and mass transfer. Especially, the application of flow chemistry to CH functionalization bears unique potential. By leveraging otherwise inert CH bonds as latent functional groups, the step- and atom-economical access to value-added molecular architectures from abundant and readily available starting materials is facilitated. Thereby, flow reactor technology enables superior heat and mass transfer, accelerated kinetics, and direct scalability, promoting operationally simple, safe, and sustainable transformations. Continuous-flow has proven enabling in photo- and electrocatalysis as well as their synergistic merger in photoelectrochemical catalysis. In addition, these strategies unlock the use of earth-abundant catalysts and renewable solvents, while streamlining molecular synthesis.

Selective hydroxylation of sesquiterpenes remains a major challenge in synthetic chemistry due to their chemical homogeneity and steric complexity. Here, we report the Rieske oxygenase (RO)-catalyzed hydroxylation of sesquiterpenes using cumene dioxygenase (CDO) from Pseudomonas fluorescens IP01. Wild-type CDO catalyzed the monohydroxylation of the sesquiterpene β-bisabolene, producing ring-hydroxylated β-bisabolene-5-ol and tail-hydroxylated (S)-β-bisabolene-13-ol in a 64:21 ratio, with a total product formation of 0.43 ± 0.07 mM. A single-loop deletion variant, L284del, enhanced both total product formation and selectivity toward the ring-hydroxylated product, producing 1.40 ± 0.08 mM and enabling preparative-scale isolation (17 mg, 0.08 mmol, 39% yield). Another single-loop variant, I288del, similarly increased total product formation while shifting regioselectivity from ring- to tail-hydroxylation in a 5:81 ratio, generating 1.07 ± 0.04 mM tail-hydroxylated product and enabling its preparative-scale isolation (24 mg, 0.11 mmol, 55% yield). To understand this clear switch in regioselectivity, we conducted molecular dynamics (MD) and adaptive steered MD simulations. This revealed that I288del increased the substrate tunnel openness and frequency of access, promoting a tail-first orientation of the substrate. This preorientation enhanced the probability of reactive conformations in proximity to the catalytic iron. Binding energy calculations further supported a loss of orientation bias in I288del, giving further insight into the regioselectivity shift. Additional engineering yielded the variant N279T_I288del_A321T, which enhanced the formation of the tail-hydroxylated compound to 1.58 ± 0.26 mM. Further, variant I288del enabled the conversion of α-santalene, a reaction not catalyzed by the wild-type enzyme. Our study provides mechanistic insight into how tunnel dynamics and substrate preorientation govern selectivity in RO-catalyzed C-H functionalization.

The robust structure and tunable properties of 12-vertex carborane clusters make them highly attractive constituents of 2D and 3D self-assembled materials as well as for various potential applications. These molecules offer new possibilities related to their characteristic features such as low conformational freedom, high thermal and chemical stability, and relatively high inherent dipole moment. We synthesized and fully characterized bis-meta-carborane-thiol ( mm -SH), a rod-like molecule with two meta-carborane units connected by a single bond, acting as a molecular rotor. In its supramolecular crystal structure, this molecule exhibits an intriguing packing arrangement driven by the interplay between the SH group of a particular conformation, which affects intermolecular hydrogen interaction, and intramolecular dipole-dipole interactions. This interesting interplay manifests itself clearly in the single-crystal supramolecular arrangement, which we have analyzed experimentally as well as computationally. The respective self-assembled monolayer (SAM) of this dipole-responsive carborane constituent was prepared on flat silver and gold substrates and investigated using surface sensitive techniques such as X-ray photoelectron spectroscopy, scanning tunneling microscopy (STM), low-energy electron diffraction (LEED), and ellipsometry. The mm-SH molecules form a highly ordered structure on the Ag(111) surface, which was measured via LEED and STM with submolecular resolution. It is the first cluster constituent of SAMs that can, by rotation, change the orientation and magnitude of its inherent dipole moment ranging from 0.64 to 3.78 D. Furthermore, the formation of nanomembranes by low-energy electron irradiation of the SAMs (with an effective thickness of 5 ± 1 Å) is presented.

LRP6 is a Wnt coreceptor and plays a key role in Wnt signal transduction. However, the molecular mechanism of LRP6 action in the Wnt signaling cascade has not been fully elucidated. In this study, a small molecule compound SLD1121 is synthesized and identified as a novel agonist of the Wnt/β-catenin signaling pathway. Our results showed that SLD1121 could enhance Wnt signaling through targeting LRP6. SLD1121 interacted with the intracellular domain of LRP6, stabilized LRP6, and accelerated its nuclear translocation. Moreover, SLD1121 promoted the association of LRP6 with β-catenin, or TCF4 or LEF1 in the nucleus, resulting in the expression of Wnt regulatory genes and stemness-associated genes. In a hair regeneration model of C57BL/6J mice, SLD1121 induced the transition of hair follicles from the telogen to anagen phase in the mouse hair growth cycle through the activation of Wnt/β-catenin signaling, resulting in enhanced hair growth of mice. Collectively, our results provide a novel insight into the molecular mechanism for the LRP6-mediated Wnt signaling cascade. By targeting LRP6, SLD1121 has the potential to be used as a therapeutic agent for alopecia.