Site-specific integration of reversibly taggable furylalanine into nonribosomal peptides Selective bioconjugation reactions enable important drug delivery strategies, relying on taggable moieties incorporated into bioactive compounds. To address a pressing need for biosynthetic access to reactive, bioactive natural products, a customizable approach to the de novo biosynthesis of Diels-Alder-taggable natural product analogs was established, and its applicability was demonstrated in bioconjugation reactions. The developed biosynthetic platform enables the broader implementation of site-selective modifications in peptide therapeutics.

Online now: Site-specific integration of reversibly taggable furylalanine into nonribosomal peptides

Nanophase structuring in simple ternary solvents mediates reaction kinetics Ternary solvents of water, a water-miscible polar organic solvent, and oil can form nanophases that modulate click reaction kinetics. Rate enhancement occurs for a select range of ternary compositions only when hydrophobic reactants are used. Reagent co-localization inside oil-in-water nanophases is proposed as the mechanism for rate enhancement.

Online now: Nanophase structuring in simple ternary solvents mediates reaction kinetics

Array of bimetallic metallophthalocyanine-based metal-organic frameworks for chemiresistive detection and differentiation of toxic gases This work describes the synthesis, characterization, and fundamental investigation of nine octahydroxyl-linked, two-dimensional conductive metal-organic frameworks (cMOFs) based on metallophthalocyanine (MPc). These cMOFs were fabricated into sensor devices, which demonstrated parts per million (ppm)-level sensitivity toward H2S, NO, and CO and machine-learning-assisted differentiation of gaseous analytes.

Online now: Array of bimetallic metallophthalocyanine-based metal-organic frameworks for chemiresistive detection and differentiation of toxic gases

Chasing nature’s anion binders Synthetic molecular cages achieve high-affinity anion recognition in water that matches the performance of anion-binding proteins from nature. The anion binding is driven solely by hydrogen bonds.

Online now: Chasing nature’s anion binders

Swarm intelligence for chemical reaction optimization The authors introduce ⍺-PSO, combining swarm intelligence with machine learning for interpretable and automated chemical reaction optimization. By discovering optimal conditions faster than established methods while providing chemists with transparent decision-making, ⍺-PSO enables more efficient chemical process development, accelerating drug manufacturing and sustainable synthesis.

Online now: Swarm intelligence for chemical reaction optimization

Water-triggered photocatalytic oxidative coupling of methane toward C2H6 over Au/GaN nanoarchitecture Upgrading abundant methane to valuable ethane typically requires immense industrial energy. This work presents a sustainable alternative using only sunlight and water. By employing an engineered nanomaterial, light generates active radicals from water that gently break methane’s tough chemical bonds. This unique water-triggered pathway prevents unwanted over-oxidation, delivering ethane with exceptional selectivity and stability. This conceptual breakthrough paves a remarkably green and economically viable route for next-generation chemical manufacturing beyond fossil fuels.

Online now: Water-triggered photocatalytic oxidative coupling of methane toward C2H6 over Au/GaN nanoarchitecture

Out-of-equilibrium confinement catalysis mediated by compressive force Mechanical forces play essential roles in living systems, from hearing and touch to cellular mechanosensing. Inspired by this idea, we show that mechanical force can power supramolecular systems. Applying force distorts a molecular cage and lifts it to a higher-energy state, allowing the guest to escape. Coupled with spontaneous reassembly, this process forms a continuous non-equilibrium cycle. This work introduces mechanical force as a programmable energy input for dissipative supramolecular systems.

Online now: Out-of-equilibrium confinement catalysis mediated by compressive force

Expanding the territory to post-assembly modification of metallacages The functionalization of metallacages represents a pivotal prerequisite for unlocking their potential in biomedical applications. Now, Moreno-Alcántar, Casini, and co-workers report in Cell Reports Physical Science a comprehensive strategy enabling the efficient post-assembly modification (PAM) of Pt(II) cages via amide coupling and click chemistry for in vivo use. This strategy expands the scope of metallacage-based drug delivery, imaging, and supramolecular radiotheranostics.

Online now: Expanding the territory to post-assembly modification of metallacages

Single-molecule FRET enables the detection of site-specific α-synuclein serine phosphorylation Single-molecule fluorescence resonance energy transfer (smFRET) combined with phosphorylation-selective labeling enables site-specific detection of protein phosphorylation. Using α-synuclein as a model system, this approach resolves phosphorylation patterns within individual proteoforms with picomolar sensitivity, providing a platform for analyzing heterogeneous posttranslational modifications.

Online now: Single-molecule FRET enables the detection of site-specific α-synuclein serine phosphorylation

The third wave of enzyme engineering: Navigating the AI-powered IDEA paradigm Enzyme engineering has evolved from random directed evolution to knowledge-guided rational design and is now entering an artificial intelligence (AI)-driven third wave. To capture AI’s transformative impact, we propose the investigate-design-execute-analyze (IDEA) framework, which illustrates how AI integrates across the entire enzyme engineering pipeline—from enzyme discovery and biocatalyst design to experimental validation and mechanistic analysis. This framework serves as a roadmap for leveraging advanced AI to reprogram enzyme engineering workflows, establishing a new paradigm for intelligent biocatalyst design.

Online now: The third wave of enzyme engineering: Navigating the AI-powered IDEA paradigm

Bimetallic synergistic catalysis in MOFs toward transforming CO2 into carbonates with a record turnover number Constructed from unique [Cu12In18] nanocages, the porous heterometallic framework CuIn-CPT enables synergistic catalysis between its [Cu4] and [In3] clusters for efficient conversion of CO2 to value-added carbonates under mild conditions. A record turnover number of 4,844 is achieved, which is ten times greater than that of previously reported catalysts.

Online now: Bimetallic synergistic catalysis in MOFs toward transforming CO2 into carbonates with a record turnover number

Programming extracellular protein fate with peptide chimeras Although targeted protein degradation has revolutionized intracellular drug discovery, strategies against extracellular disease-causing proteins remain limited. In Cell, Teng et al. introduce synthetic peptide programmed lysosome targeting chimeras (SPYTACs) to couple extracellular target recognition with receptor-mediated uptake and degradation, reframing extracellular protein degradation as a problem of molecular design.

Online now: Programming extracellular protein fate with peptide chimeras

Single-shot solid-phase synthesis of insulins and their A/B-chain heterodimeric analogs Current synthetic approaches for insulin remain labor-intensive and time-consuming. Reported herein is the first single-shot SPPS strategy, which enables enhanced automation and the rapid total synthesis of various insulins and other A/B-chain heterodimeric bioactive peptides in just three steps over 2–3 days.

Online now: Single-shot solid-phase synthesis of insulins and their A/B-chain heterodimeric analogs

Predict the ceiling Ceiling temperature represents a critical parameter for designing recyclable polymers that support a circular economy and mitigate plastic pollution. In the April issue of Cell Reports Sustainability, Broadbelt and co-workers report a machine-learning framework for predicting ceiling temperatures, providing chemists with a powerful virtual screening tool for the design of recyclable polymers.

Online now: Predict the ceiling

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Chem's April Issue is online now! This month's cover comes from the Zhang and Tang groups, from their piece where they demonstrate that through space interactions, a photoswitch can enable record setting circularly polarized luminescence. You can read this and more here www.cell.com/issue/S2451-...

Wetting transparency of graphene across length scales: Macroscopic transparency but nanoscopic mirror-like behavior Graphene/water interfaces underpin desalination, sensing, energy, and neuromorphic technologies, yet how substrate-supported graphene modulates interfacial water remains unclear. Using surface-specific vibrational spectroscopy and molecular dynamics, we show that graphene is macroscopically transparent but nanoscopically polarizes to counter substrate electrostatics, reorganizing nearby water. This provides new design rules for controlling interfacial water.

Online now: Wetting transparency of graphene across length scales: Macroscopic transparency but nanoscopic mirror-like behavior

Iridium-mediated methane dehydrogenation and methylidene (=CH2) transfer An iridium complex catalyzes the dehydrogenative coupling of methane and benzene via a methylidene Ir=CH2 species generated through a double methane C–H activation process. A parallel Ir-catalyzed cycle produces formic acid from hydrogen and the carbon dioxide employed as the solvent under supercritical conditions.

Online now: Iridium-mediated methane dehydrogenation and methylidene (=CH2) transfer

Transitioning aliphatic C–H functionalization from bench to plant: Is decatungstate photocatalysis ready for the leap yet? Direct C–H functionalization transforms the most abundant bond in organic molecules into a powerful synthetic handle, enabling step- and atom-economic access to molecular complexity. Decatungstate photocatalysis has become a powerful tool for aliphatic C–H bond elaboration under mild conditions, yet its impact remains largely confined to academic laboratories. This perspective re-examines decatungstate photocatalysis from a process-oriented viewpoint, outlining the mechanistic insights, technological challenges, and design principles required to translate this methodology into scalable and sustainable chemical manufacturing.

Online now: Transitioning aliphatic C–H functionalization from bench to plant: Is decatungstate photocatalysis ready for the leap yet?

B−H oxidation enables modular synthesis of vicinally trifunctionalized boron-rich clusters Icosahedral carboranes are unique 3D pharmacophores in drug discovery, but achieving selective multifunctionalization—particularly vicinal trifunctionalization on the boron vertices—remains a major challenge due to the spatial and electronic constraints. This article presents a regioselective B−H hydroxylation and uses the hydroxyl group to facilitate Pd-catalyzed trifunctionalization of icosahedral carborane, incorporating highly functionalized NH heterocycles and anilines. The remaining hydroxyl group serves as a synthetic handle for introducing bioactive motifs, thereby significantly advancing carboranes for broader biological applications.

Online now: B−H oxidation enables modular synthesis of vicinally trifunctionalized boron-rich clusters

Group transfer radical polymerization: Translating organic synthesis to functional polymers Radical-mediated functional group migration—a well-established concept in organic synthesis—has recently been translated into polymer science, giving rise to group transfer radical polymerization (GTRP). This strategy effectively overcomes the long-standing challenges associated with the radical polymerization of α-olefins and enables the synthesis of sequence-defined, polar-functionalized polyolefins, offering a versatile platform for precision polymer synthesis. In this perspective, we survey the four key mechanistic platforms developed within the GTRP framework and identify future opportunities in this rapidly evolving field.

Online now: Group transfer radical polymerization: Translating organic synthesis to functional polymers

Exploration of protein degradability enables fully endogenous MrTAC degraders Targeted protein degradation selectively eliminates disease-causing proteins by using small-molecule degraders. Here, we integrate fundamental biology with small molecules to study a methylation-driven signal for lysosomes. Insight into methylarginine degrons enables the development of methylarginine-targeting chimeras (MrTACs), which degrade pathogenic proteins by recruiting protein arginine methyltransferases (PRMTs). We assess the utility of existing PRMT inhibitors for MrTAC design and demonstrate that group-transfer chemistry can transform inhibitory ligands into silent recruiters, thereby generating the first series of fully endogenous MrTACs.

Online now: Exploration of protein degradability enables fully endogenous MrTAC degraders

Regulating the topology and pore size of covalent metal-organic framework for boosting catalytic CO2 conversion Tuning the topology and pore size of covalent metal-organic frameworks (CMOFs) can significantly boost their performance in converting CO2. Heteropore structures and reduced pore sizes dramatically enhance CO2 uptake and activity, even under humid flue gas conditions, providing a clear design strategy for efficient carbon capture and conversion.

Online now: Regulating the topology and pore size of covalent metal-organic framework for boosting catalytic CO2 conversion

(R)evolutionary energy-storage density: Dewar pyrimidones inspired by nature In Science, Han and co-workers establish pyrimidone derivatives and their Dewar photoisomers as a new class of photoswitches for molecular solar thermal energy storage (MOST). The photoswitches exhibit record-high energy densities up to 1.65 MJ/kg and release sufficient heat to boil water within 1 s, moving MOST toward concrete applications.

Online now: (R)evolutionary energy-storage density: Dewar pyrimidones inspired by nature

Screening, designing, and elucidating anti-dissolving dual atomic sites for highly durable proton exchange membrane fuel cells Iron-based single-atom catalysts hold great potential to replace the platinum group catalysts in proton exchange membrane fuel cells, but their instability in acid environments is the main challenge for practical applications. By introducing a novel structural descriptor φ, we design and prepare a Cr/Fe-NC catalyst that is composed of Cr-Fe bimetallic sites embedded in nitrogen-doped carbon matrix, which demonstrated substantially improved activity and stability. This descriptor-driven strategy establishes a general principle for rationally designing anti-dissolving sites, paving the way for a new generation of durable and non-precious catalysts in fuel cells.

Online now: Screening, designing, and elucidating anti-dissolving dual atomic sites for highly durable proton exchange membrane fuel cells

From absolute barriers to responsiveness: How London dispersion modulates kinetic-thermodynamic relationships We show that London dispersion does more than lower reaction barriers: it reshapes how barriers respond to thermodynamic driving forces. By separating intrinsic reactivity from thermodynamic effects, we demonstrate that dispersion modulates barrier sensitivity and influences selectivity and its robustness across substrates. This framework reframes dispersion as a tunable design parameter for controlling kinetic-thermodynamic relationships in chemical reactions.

Online now: From absolute barriers to responsiveness: How London dispersion modulates kinetic-thermodynamic relationships

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Electrochemical reductive carboxylation with carbon dioxide using water as the reductant Carboxylation with CO2 provides an efficient method for the synthesis of carboxylic acids. We report here a novel approach that employs water as the reductant for the nickel-catalyzed reductive carboxylation with CO2, which efficiently circumvents the traditionally used stoichiometric amounts of metallic or organic reductants. A divided electrochemical cell equipped with proton exchange membranes was implemented to convert CO2 into complex carboxylic acids in moderate to good yields, coupled with evolution of O2, thus mimicking the process of photosynthesis to a certain degree.

Online now: Electrochemical reductive carboxylation with carbon dioxide using water as the reductant

Oxygen-atom replacement in non-strained cyclic ethers A phosphine-mediated oxygen-atom replacement of non-strained cyclic ethers is reported, enabling rapid assembly of N-, S-, and Se-heterocyclic and carbocyclic molecules. Remarkable functional group compatibility and applications in pharmaceutical synthesis highlight the utility of this strategy in drug discovery.

Online now: Oxygen-atom replacement in non-strained cyclic ethers

Alcoholysis of nylon 6 waste to ε-caprolactam promoted by phosphoric acid Materials made from nylon 6 are widely used but difficult to recycle back into their original monomer, ε-caprolactam. This work introduces a simple acid-catalyzed alcoholysis method that enables efficient and selective depolymerization of nylon 6 into ε-caprolactam. Additionally, this process shows excellent compatibility with a range of real-world nylon 6 materials, including post-consumer fishing net waste, thread, 3D-printing filament, fabric, and carpet, offering a practical pathway toward closed-loop recycling with both environmental and economic benefits.

Online now: Alcoholysis of nylon 6 waste to ε-caprolactam promoted by phosphoric acid