Rudolf L. Z. Ganzoni, Miroslav Kosar, Yongqi Han, Rosa Maria Vitale, Pietro Amodeo, Xiaoting Li, Zhonghua Zha, Kacper J. Patej, Bilal Kicin, Taddäus E. N. Strunden, Lisa Reichert, Uxía Gómez-Bouzó, Themiya P. Perera, Kenneth Atz, Wolfgang Guba, Christian Bartelmus, Raphael Bigler, Paolo Tosatti, Stephan Bachmann, Tian Hua, David A. Sykes, Dmitry B. Veprintsev, Uwe Grether, Erick M. Carreira
Cannabinoid receptor type 2 (CB2R) is a prominent class A G protein-coupled receptor (GPCR) and is a therapeutic target of interest for inflammatory diseases, pain management, and neurodegenerative disorders. We report the development of ligands based on HU-308 that share a single central scaffold but bear diverse sidechains, enabling controlled modulation of GPCR activation. Structural modifications at a single position of the parent ligand allow modulation of the single-residue toggle switch of CB2R, Trp2586.48, and thereby control over receptor activity. A continuum of functional outcomes is achieved through interaction of the ligands with the CB2R toggle switch, leading to full agonism, partial agonism, neutral antagonism, or partial inverse agonism. Several low-efficacy ligands display protean behavior across assays, underscoring context-dependent modulation of CB2R and its importance in profiling such ligands. A notable compound within this series is CF3-substituted (S)-1, which displays distinct CB2R affinity, potency, and a biased CB2R signaling profile. We provide a rationale based on molecular dynamics simulations for the unique pharmacological profile observed and suggest that stabilization of an active receptor conformation occurs by close-contact interaction of (S)-1 with the CB2R toggle switch. Our findings demonstrate that strategic structural modifications of class A GPCR ligands may, by targeting a receptor's toggle switch, shift ligands to different positions along the efficacy spectrum, independent of their parent scaffold's original functional profile.
{"title":"Single-position ligand modifications tune CB2R activity by targeting the toggle switch","authors":"Rudolf L. Z. Ganzoni, Miroslav Kosar, Yongqi Han, Rosa Maria Vitale, Pietro Amodeo, Xiaoting Li, Zhonghua Zha, Kacper J. Patej, Bilal Kicin, Taddäus E. N. Strunden, Lisa Reichert, Uxía Gómez-Bouzó, Themiya P. Perera, Kenneth Atz, Wolfgang Guba, Christian Bartelmus, Raphael Bigler, Paolo Tosatti, Stephan Bachmann, Tian Hua, David A. Sykes, Dmitry B. Veprintsev, Uwe Grether, Erick M. Carreira","doi":"10.1039/d6sc00062b","DOIUrl":"https://doi.org/10.1039/d6sc00062b","url":null,"abstract":"Cannabinoid receptor type 2 (CB<small><sub>2</sub></small>R) is a prominent class A G protein-coupled receptor (GPCR) and is a therapeutic target of interest for inflammatory diseases, pain management, and neurodegenerative disorders. We report the development of ligands based on HU-308 that share a single central scaffold but bear diverse sidechains, enabling controlled modulation of GPCR activation. Structural modifications at a single position of the parent ligand allow modulation of the single-residue toggle switch of CB<small><sub>2</sub></small>R, Trp258<small><sup>6.48</sup></small>, and thereby control over receptor activity. A continuum of functional outcomes is achieved through interaction of the ligands with the CB<small><sub>2</sub></small>R toggle switch, leading to full agonism, partial agonism, neutral antagonism, or partial inverse agonism. Several low-efficacy ligands display protean behavior across assays, underscoring context-dependent modulation of CB<small><sub>2</sub></small>R and its importance in profiling such ligands. A notable compound within this series is CF<small><sub>3</sub></small>-substituted (<em>S</em>)-<strong>1</strong>, which displays distinct CB<small><sub>2</sub></small>R affinity, potency, and a biased CB<small><sub>2</sub></small>R signaling profile. We provide a rationale based on molecular dynamics simulations for the unique pharmacological profile observed and suggest that stabilization of an active receptor conformation occurs by close-contact interaction of (<em>S</em>)-<strong>1</strong> with the CB<small><sub>2</sub></small>R toggle switch. Our findings demonstrate that strategic structural modifications of class A GPCR ligands may, by targeting a receptor's toggle switch, shift ligands to different positions along the efficacy spectrum, independent of their parent scaffold's original functional profile.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"28 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soumi Das, Caini Zheng, Timothy P. Lodge, Joern Ilja Siepmann, Michelle Anna Calabrese, Theresa M. Reineke
Periodic network morphologies such as the double gyroid (DG) are promising for a wide range of applications, from optical materials and organic semiconductors to separation membranes and drug delivery vehicles. While natural glycolipids are a constituent of cell membranes, synthetic glycolipids have emerged as candidates for producing thermotropic DG phases with sub-5 nm domains. Despite this potential, difficulties in producing stereochemically-pure glycolipids and a lack of known design rules governing DG self-assembly limit their broad use. Our recent work identified two key factors stabilizing DG in ten anomerically pure Guerbet cellobiosides: a bent molecular topology and moderate hydrogen bonding between sugar headgroups. However, the influence of glycolipid shape vs. hydrogen bonding could not be decoupled, as these factors depend on both headgroup and anomeric stereochemistry. To disentangle these effects, we synthesized 20 anomerically-pure Guerbet glycolipids with different disaccharide headgroups (lactose, maltose) and Guerbet tails (C8-C24) and compared them with ten similar cellobiosides. Analysis of the thermotropic phase behavior using differential scanning calorimetry, polarized optical microscopy, small-angle X-ray scattering, and complementary molecular simulations identified numerous cases of DG phase formations, with phase stability dependent on headgroup type and anomeric stereochemistry. With respect to molecular shape, high stability DG phases were promoted by molecules with kinks in topology at similar positions; the most stable DG phases also shared similar inter-molecular hydrogen bonding motifs between specific headgroup hydroxyls. Beyond revealing design guidelines for producing DG phases, this comprehensive understanding of glycolipid self-assembly may accelerate development of biomimetic materials, as the liquid crystalline behavior of natural glycolipids plays a pivotal role in biological functions.
{"title":"Influence of Molecular Shape and Hydrogen Bonding on Glycolipid Self-assembly into Thermotropic Gyroid Phases","authors":"Soumi Das, Caini Zheng, Timothy P. Lodge, Joern Ilja Siepmann, Michelle Anna Calabrese, Theresa M. Reineke","doi":"10.1039/d6sc00024j","DOIUrl":"https://doi.org/10.1039/d6sc00024j","url":null,"abstract":"Periodic network morphologies such as the double gyroid (DG) are promising for a wide range of applications, from optical materials and organic semiconductors to separation membranes and drug delivery vehicles. While natural glycolipids are a constituent of cell membranes, synthetic glycolipids have emerged as candidates for producing thermotropic DG phases with sub-5 nm domains. Despite this potential, difficulties in producing stereochemically-pure glycolipids and a lack of known design rules governing DG self-assembly limit their broad use. Our recent work identified two key factors stabilizing DG in ten anomerically pure Guerbet cellobiosides: a bent molecular topology and moderate hydrogen bonding between sugar headgroups. However, the influence of glycolipid shape vs. hydrogen bonding could not be decoupled, as these factors depend on both headgroup and anomeric stereochemistry. To disentangle these effects, we synthesized 20 anomerically-pure Guerbet glycolipids with different disaccharide headgroups (lactose, maltose) and Guerbet tails (C<small><sub>8</sub></small>-C<small><sub>24</sub></small>) and compared them with ten similar cellobiosides. Analysis of the thermotropic phase behavior using differential scanning calorimetry, polarized optical microscopy, small-angle X-ray scattering, and complementary molecular simulations identified numerous cases of DG phase formations, with phase stability dependent on headgroup type and anomeric stereochemistry. With respect to molecular shape, high stability DG phases were promoted by molecules with kinks in topology at similar positions; the most stable DG phases also shared similar inter-molecular hydrogen bonding motifs between specific headgroup hydroxyls. Beyond revealing design guidelines for producing DG phases, this comprehensive understanding of glycolipid self-assembly may accelerate development of biomimetic materials, as the liquid crystalline behavior of natural glycolipids plays a pivotal role in biological functions.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"113 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pritam Mahawar, Ganping Wang, Robert J Ward, Steven P Kelley, Laurent Maron, Justin R Walensky
To enhance our understanding of the electronic structure of early actinides, a synthetic methodology of using an Al(i) precursor, [(C5Me5)Al]4, was applied to both thorium and uranium dipnictido complexes. The cleavage of the E-E bond in dipnictido actinide complexes, [(C5Me5)2An(η2-E2R2)], An = Th, U; E = N, P, As; R = Ph or 2,4,6-Me3C6H2 (Mes), with 0.25 equivalents of [Al(C5Me5)]4, yields the heterobimetallic complexes, [(C5Me5)2An(µ2-ER)2Al(C5Me5)]. In the case of An = U, E = N, the U(vi) bis(imido) complex, [(C5Me5)2U(=NPh)2], is reduced by [(C5Me5)Al]. Based on the solid-state structures and DFT calculations, including Nucleus Independent Chemical Shift (NICS), all six complexes show aromaticity within the An-E-Al-E moiety. For Th, only σ-aromaticity is observed, but both σ + π aromaticity is observed in the U complexes.
为了提高我们对早期锕系元素电子结构的理解，我们将Al(i)前体[(C5Me5)Al]4应用于钍和铀双镍配合物的合成方法。[(C5Me5)2An(η 2-E2R2)], An = Th， U中E-E键的断裂E = N， P, As；R = Ph = 2,4,6- me3c6h2 (Mes)，加入0.25等量的[Al(C5Me5)]4，得到杂双金属配合物[(C5Me5)2An（µ2- er）2Al(C5Me5)]。在An = U, E =N的情况下，U（vi）双（亚胺）络合物[(C5Me5)2U(=NPh)2]被[(C5Me5)Al]还原。基于固体结构和DFT计算，包括核不依赖化学位移（NICS），所有六个配合物都在An-E-Al-E部分显示芳香性。Th的配合物只有σ-芳香性，而U的配合物都有σ + π芳香性。
{"title":"Unusual bonding situations in Th(iv) and U(iv)-Al(iii) pnictogen complexes.","authors":"Pritam Mahawar, Ganping Wang, Robert J Ward, Steven P Kelley, Laurent Maron, Justin R Walensky","doi":"10.1039/d5sc09143h","DOIUrl":"https://doi.org/10.1039/d5sc09143h","url":null,"abstract":"<p><p>To enhance our understanding of the electronic structure of early actinides, a synthetic methodology of using an Al(i) precursor, [(C<sub>5</sub>Me<sub>5</sub>)Al]<sub>4</sub>, was applied to both thorium and uranium dipnictido complexes. The cleavage of the E-E bond in dipnictido actinide complexes, [(C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>An(<i>η</i> <sup>2</sup>-E<sub>2</sub>R<sub>2</sub>)], An = Th, U; E = N, P, As; R = Ph or 2,4,6-Me<sub>3</sub>C<sub>6</sub>H<sub>2</sub> (Mes), with 0.25 equivalents of [Al(C<sub>5</sub>Me<sub>5</sub>)]<sub>4,</sub> yields the heterobimetallic complexes, [(C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>An(<i>µ</i> <sub>2</sub>-ER)<sub>2</sub>Al(C<sub>5</sub>Me<sub>5</sub>)]. In the case of An = U, E = N, the U(vi) bis(imido) complex, [(C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>U(=NPh)<sub>2</sub>], is reduced by [(C<sub>5</sub>Me<sub>5</sub>)Al]. Based on the solid-state structures and DFT calculations, including Nucleus Independent Chemical Shift (NICS), all six complexes show aromaticity within the An-E-Al-E moiety. For Th, only σ-aromaticity is observed, but both σ + π aromaticity is observed in the U complexes.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12997793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The development of catalytic and eco-friendly P-umpolung strategy for the synthesis of chiral phosphorus-containing compounds presents substantial challenges. Herein, we report a method for accessing C-stereogenic phosphinates enabled by a synergistic diselenide/chiral guanidine catalytic system. This method avoids stoichiometric halogenating reagents, generating water as the sole byproduct. Mechanistic studies reveal that the electron-deficient diselenide catalyst catalyzes phosphorus polarity inversion, while the chiral guanidine activates the alcohol via Brønsted base catalysis. This strategy effectively achieves the kinetic resolution of secondary alcohols with similar steric substituents, offering a sustainable strategy to access phosphinates with stereogenic benzhydryl groups.
{"title":"Synergistic Diselenide/Guanidine Catalyzed Dehydrophosphorylation of 2-Nitrobenzhydrols to Access C-Stereogenic Phosphinates","authors":"Shang-Dong Yang, Jin-Yu Gong, Panpan Zhou, Yu-Hao Qiao, Zhichao Qi, Qian-Min Zuo, Qing-Xia Fang","doi":"10.1039/d5sc07228j","DOIUrl":"https://doi.org/10.1039/d5sc07228j","url":null,"abstract":"The development of catalytic and eco-friendly P-umpolung strategy for the synthesis of chiral phosphorus-containing compounds presents substantial challenges. Herein, we report a method for accessing C-stereogenic phosphinates enabled by a synergistic diselenide/chiral guanidine catalytic system. This method avoids stoichiometric halogenating reagents, generating water as the sole byproduct. Mechanistic studies reveal that the electron-deficient diselenide catalyst catalyzes phosphorus polarity inversion, while the chiral guanidine activates the alcohol via Brønsted base catalysis. This strategy effectively achieves the kinetic resolution of secondary alcohols with similar steric substituents, offering a sustainable strategy to access phosphinates with stereogenic benzhydryl groups.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"17 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shirley Hernandez, Vasilisa Krivovicheva, Adenilson Sousa-Silva, Xavier Solans-Monfort, Konstantin V. Bukhryakov
Alkyne metathesis, a widely used method for the synthesis of chemicals containing carbon–carbon triple bonds, relies exclusively on catalysts based on second and third-row transition metals. The development of a first-row metal-mediated alkyne metathesis would be a remarkable achievement from both fundamental and sustainability perspectives. In this study, we lay the groundwork for V-mediated alkyne metathesis. Thus, we demonstrated that V alkylidynes can react with various alkynes to produce cycloaddition products (metallacyclobutadienes), which are critical intermediates in the alkyne metathesis. Additionally, we conducted comprehensive computational studies to confirm the feasibility of the cycloreversion step needed to complete the alkyne metathesis transformation. Finally, we synthesized and characterized a series of new V alkylidynes, which can serve as essential starting materials for future development.
{"title":"Toward vanadium-mediated alkyne metathesis","authors":"Shirley Hernandez, Vasilisa Krivovicheva, Adenilson Sousa-Silva, Xavier Solans-Monfort, Konstantin V. Bukhryakov","doi":"10.1039/d6sc01683a","DOIUrl":"https://doi.org/10.1039/d6sc01683a","url":null,"abstract":"Alkyne metathesis, a widely used method for the synthesis of chemicals containing carbon–carbon triple bonds, relies exclusively on catalysts based on second and third-row transition metals. The development of a first-row metal-mediated alkyne metathesis would be a remarkable achievement from both fundamental and sustainability perspectives. In this study, we lay the groundwork for V-mediated alkyne metathesis. Thus, we demonstrated that V alkylidynes can react with various alkynes to produce cycloaddition products (metallacyclobutadienes), which are critical intermediates in the alkyne metathesis. Additionally, we conducted comprehensive computational studies to confirm the feasibility of the cycloreversion step needed to complete the alkyne metathesis transformation. Finally, we synthesized and characterized a series of new V alkylidynes, which can serve as essential starting materials for future development.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"11 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intermolecular haloesterification of alkenes is a practical platform for modular ester synthesis. However, current methods are restricted to aryl activated and directing-group contained alkenes, leaving low-reactivity, electron-deficient alkenes with alkyl substituents largely underexplored. Notably, electrophilic reaction involving chloroesterification of electron-deficient alkenes is also challenging duo to the difficulty of controlling selectivity. In this work, we present an electrochemically cooperative halogen cation delivery strategy that achieves modular electrophilic haloesterification of both activated and unactivated alkenes with good chemo-, regio-, and diastereoselectivity. It exhibits enhanced reactivity (with yields up to 90%) and selectivity (regioselectivities and diastereoselectivities exceeding 20:1), facilitated by the amide-mediated transfer of halogen cations to activate Cl+ donor and promote the generation of stable halogen-contained cation intermediates (β-halo carbocation or halonium), for the electrochemically oxidative ‘electrophile–nucleophile’ (‘E–Nu’) approach. Di-, tri-, and tetrasubstituted alkenes with various electronic properties, as well as terminal alkenes, have been successfully haloesterified, showcasing good tolerance to functional groups. Moreover, the strategy is applicable to gram-scale synthesis, and late-stage elaboration of bioactive compounds. It also enables the construction of quaternary carbons, even multiple contiguous ones in reactions.
{"title":"Electrochemically Cooperative Halogen Cation Delivery Enables Modular Electrophilic Haloesterification of Both Activated and Unactivated Alkenes","authors":"Hehuan Xu, Duo-Duo Qian, Yi Fan, Jia-Jia Zhang, Chang-Le Guo, Hai-Chao Xu","doi":"10.1039/d6sc00279j","DOIUrl":"https://doi.org/10.1039/d6sc00279j","url":null,"abstract":"Intermolecular haloesterification of alkenes is a practical platform for modular ester synthesis. However, current methods are restricted to aryl activated and directing-group contained alkenes, leaving low-reactivity, electron-deficient alkenes with alkyl substituents largely underexplored. Notably, electrophilic reaction involving chloroesterification of electron-deficient alkenes is also challenging duo to the difficulty of controlling selectivity. In this work, we present an electrochemically cooperative halogen cation delivery strategy that achieves modular electrophilic haloesterification of both activated and unactivated alkenes with good chemo-, regio-, and diastereoselectivity. It exhibits enhanced reactivity (with yields up to 90%) and selectivity (regioselectivities and diastereoselectivities exceeding 20:1), facilitated by the amide-mediated transfer of halogen cations to activate Cl<small><sup>+</sup></small> donor and promote the generation of stable halogen-contained cation intermediates (β-halo carbocation or halonium), for the electrochemically oxidative ‘electrophile–nucleophile’ (‘E–Nu’) approach. Di-, tri-, and tetrasubstituted alkenes with various electronic properties, as well as terminal alkenes, have been successfully haloesterified, showcasing good tolerance to functional groups. Moreover, the strategy is applicable to gram-scale synthesis, and late-stage elaboration of bioactive compounds. It also enables the construction of quaternary carbons, even multiple contiguous ones in reactions.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"11 17 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Understanding the sodium-storage mechanism in hard carbon (HC) anodes is crucial for advancing sodium-ion battery (SIB) technology. However, the intrinsic complexity of HC microstructures and their interactions with sodium remain not fully elucidated. We present a multiscale methodology that integrates grand-canonical Monte Carlo (GCMC) simulations with a machine-learning interatomic potential based on the Gaussian approximation potential (GAP) framework to investigate sodium insertion mechanisms in hard carbons with different levels of porosity, achieved by simulating structural models with densities ranging from 0.7 to 1.9 g cm$^{-3}$. Structural and thermodynamic analyses reveal the interplay between pore size and accessibility and the relative contributions of adsorption, intercalation, and pore filling to the overall storage capacity. Low-density carbons favor pore-filling, achieving extremely high capacities at near-zero voltages, whereas high-density carbons primarily store sodium through adsorption and intercalation, leading to lower but more stable capacities. Intermediate-density carbons ($1.3-1.6$ g cm$^{-3}$) provide the most balanced performance, combining moderate capacity (480 and 310 mAh g$^{-1}$), safe operating voltages, and minimal volume expansion ($<10$%). These findings establish a direct correlation between carbon density and electrochemical behavior, providing atomic-scale insight into how hard carbon morphology governs sodium-storage. The proposed framework offers a rational design principle for optimizing HC-based SIB anodes toward high energy density and long-term cycling stability.
了解硬碳（HC）阳极中钠离子的储存机理对钠离子电池（SIB）技术的发展至关重要。然而，HC微观结构的内在复杂性及其与钠的相互作用尚未完全阐明。我们提出了一种多尺度方法，该方法将大规范蒙特卡罗（GCMC）模拟与基于高斯近似势（GAP）框架的机器学习原子间势相结合，通过模拟密度为0.7至1.9 g cm$^{-3}$的结构模型来研究具有不同孔隙度的硬碳中的钠插入机制。结构和热力学分析揭示了孔隙大小与可达性之间的相互作用，以及吸附、插层和孔隙填充对总存储容量的相对贡献。低密度碳有利于孔隙填充，在接近零电压时获得极高的容量，而高密度碳主要通过吸附和插层储存钠，导致容量较低但更稳定。中密度碳（$1.3-1.6$ g cm$^{-3}$）提供了最平衡的性能，结合了中等容量（480和310 mAh g$^{-1}$），安全的工作电压和最小的体积膨胀（$<10$%）。这些发现建立了碳密度和电化学行为之间的直接关联，提供了原子尺度上硬碳形态如何控制钠储存的见解。该框架为优化hc基SIB阳极以实现高能量密度和长期循环稳定性提供了合理的设计原则。
{"title":"Density-dependent sodium-storage mechanisms in hard carbon materials","authors":"Alexis Front, Tapio Ala-Nissila, Miguel A. Caro","doi":"10.1039/d6sc00030d","DOIUrl":"https://doi.org/10.1039/d6sc00030d","url":null,"abstract":"Understanding the sodium-storage mechanism in hard carbon (HC) anodes is crucial for advancing sodium-ion battery (SIB) technology. However, the intrinsic complexity of HC microstructures and their interactions with sodium remain not fully elucidated. We present a multiscale methodology that integrates grand-canonical Monte Carlo (GCMC) simulations with a machine-learning interatomic potential based on the Gaussian approximation potential (GAP) framework to investigate sodium insertion mechanisms in hard carbons with different levels of porosity, achieved by simulating structural models with densities ranging from 0.7 to 1.9 g cm$^{-3}$. Structural and thermodynamic analyses reveal the interplay between pore size and accessibility and the relative contributions of adsorption, intercalation, and pore filling to the overall storage capacity. Low-density carbons favor pore-filling, achieving extremely high capacities at near-zero voltages, whereas high-density carbons primarily store sodium through adsorption and intercalation, leading to lower but more stable capacities. Intermediate-density carbons ($1.3-1.6$ g cm$^{-3}$) provide the most balanced performance, combining moderate capacity (480 and 310 mAh g$^{-1}$), safe operating voltages, and minimal volume expansion ($<10$%). These findings establish a direct correlation between carbon density and electrochemical behavior, providing atomic-scale insight into how hard carbon morphology governs sodium-storage. The proposed framework offers a rational design principle for optimizing HC-based SIB anodes toward high energy density and long-term cycling stability.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"1 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ariel Wang, Bayu Ahmad, Carolyn Ma, Phillip John Milner, Richard Y. Liu
Compared to conventional methods, directly light-driven separations are promising strategies to achieve high selectivity while lowering energy cost. This perspective examines recent progress in photoswitch-enabled separations with a focus on concentration of CO2 and selective anion recovery from water. We highlight key design strategies for photo-pH-swing capture and identify current practical limitations toward translating solar-driven separations into technologies with meaningful impact.
{"title":"Organic Photochemistry for Directly Light-Driven Separations","authors":"Ariel Wang, Bayu Ahmad, Carolyn Ma, Phillip John Milner, Richard Y. Liu","doi":"10.1039/d6sc01308b","DOIUrl":"https://doi.org/10.1039/d6sc01308b","url":null,"abstract":"Compared to conventional methods, directly light-driven separations are promising strategies to achieve high selectivity while lowering energy cost. This perspective examines recent progress in photoswitch-enabled separations with a focus on concentration of CO<small><sub>2</sub></small> and selective anion recovery from water. We highlight key design strategies for photo-pH-swing capture and identify current practical limitations toward translating solar-driven separations into technologies with meaningful impact.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"213 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We disclose a method for the net coupling of nucleophiles with a single C-F bond of unactivated (trifluoromethyl)alkanes.The process occurs via an initial base-promoted dehydrofluorination/defluorinative nucleophilic addition cascade to generate vinylfluoride intermediates that undergo a rapid hydrofluorination second step to yield gem-difluorinated products. Thus, the aliphatic-CF3 group of commercial building blocks and complex medicinal compounds can now be transformed into numerous classes of valuable α,α-difluoro(thio)ether substructures in an efficient and modular manner.
{"title":"A Brønsted Acid-Base Approach for the Net Monoselective C-F Substitution of (Trifluoromethyl)alkanes","authors":"Nicholas James Coradi, Jeffrey S. Bandar","doi":"10.1039/d6sc01042c","DOIUrl":"https://doi.org/10.1039/d6sc01042c","url":null,"abstract":"We disclose a method for the net coupling of nucleophiles with a single C-F bond of unactivated (trifluoromethyl)alkanes.The process occurs via an initial base-promoted dehydrofluorination/defluorinative nucleophilic addition cascade to generate vinylfluoride intermediates that undergo a rapid hydrofluorination second step to yield <em>gem</em>-difluorinated products. Thus, the aliphatic-CF<small><sub>3</sub></small> group of commercial building blocks and complex medicinal compounds can now be transformed into numerous classes of valuable α,α-difluoro(thio)ether substructures in an efficient and modular manner.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"234 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Florian Leiss-Maier, Joshua Behringer, Ghulam Mustafa, Anna Heider, Rahel Mühlhofer, Andreas Sebastian Sebastian Klein, Michael Groll, Cathleen Zeymer
De novo designed metalloenzymes and photoenzymes are a valuable addition to the biocatalytic toolbox. We previously introduced PhotoLanZymes (PLZ), a family of lanthanide-dependent photoredox enzymes that enable radical carbon-carbon bond cleavages of diol substrates upon Ce(III/IV) binding and visible-light irradiation. While rational optimization increased their catalytic activity and photostability, the first generation of PLZ variants was limited by slow lanthanide binding and a lack of enantioselectivity. Here, we demonstrate that coupling computational redesign with directed evolution provides an effective strategy to overcome these limitations. First, we reduced the cavity size to enhance substrate interactions with the protein's active site, which facilitated initial enantiocontrol. Simultaneously, the AI-guided redesign approach improved the lanthanide binding kinetics. We then performed directed evolution to selectively accelerate the photocatalytic turnover for one of the substrate enantiomers, yielding a PLZ variant with markedly improved enantioselectivity. These results underscore the value of integrating AI-guided protein design with laboratory evolution to obtain stereoselective de novo metalloenzymes and photoenzymes.
{"title":"Computational redesign and directed evolution of a lanthanide-dependent photoredox enzyme for enantioselective diol cleavage","authors":"Florian Leiss-Maier, Joshua Behringer, Ghulam Mustafa, Anna Heider, Rahel Mühlhofer, Andreas Sebastian Sebastian Klein, Michael Groll, Cathleen Zeymer","doi":"10.1039/d5sc08010j","DOIUrl":"https://doi.org/10.1039/d5sc08010j","url":null,"abstract":"De novo designed metalloenzymes and photoenzymes are a valuable addition to the biocatalytic toolbox. We previously introduced PhotoLanZymes (PLZ), a family of lanthanide-dependent photoredox enzymes that enable radical carbon-carbon bond cleavages of diol substrates upon Ce(III/IV) binding and visible-light irradiation. While rational optimization increased their catalytic activity and photostability, the first generation of PLZ variants was limited by slow lanthanide binding and a lack of enantioselectivity. Here, we demonstrate that coupling computational redesign with directed evolution provides an effective strategy to overcome these limitations. First, we reduced the cavity size to enhance substrate interactions with the protein's active site, which facilitated initial enantiocontrol. Simultaneously, the AI-guided redesign approach improved the lanthanide binding kinetics. We then performed directed evolution to selectively accelerate the photocatalytic turnover for one of the substrate enantiomers, yielding a PLZ variant with markedly improved enantioselectivity. These results underscore the value of integrating AI-guided protein design with laboratory evolution to obtain stereoselective de novo metalloenzymes and photoenzymes.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"31 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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