Nature Chemistry
Nature Chemistry is a monthly journal dedicated to publishing high-quality papers that describe the most significant and cutting-edge research in all areas of chemistry. As well as reflecting the traditional core subjects of analytical, inorganic, organic and physical chemistry, the journal features a broad range of chemical research including, but not limited to, bioinorganic and bioorganic chemistry, catalysis, computational and theoretical chemistry, environmental chemistry, green chemistry, medicinal chemistry, organometallic chemistry, polymer chemistry, supramolecular chemistry and surface chemistry. Other multidisciplinary topics such as nanotechnology, chemical biology and materials chemistry are also featured.
The mechanistic understanding of light-driven charge separation and charge-carrier transport within the frameworks of π-conjugated molecules is imperative to mimic natural photosynthesis and derive synthetic materials for solar energy conversion. In this regard, since the late 1980s, the distance and solvent dependence of stepwise (incoherent) charge-carrier hopping versus single-step (coherent) superexchange transport (tunnelling) have been studied in detail. Here we introduce structurally highly defined cofacially stacked donor–acceptor perylene bisimide arrays, which offer a high resemblance to natural systems. Similarity is achieved through controlling energy and electron transfer processes via intermolecular interactions between the π-stacked perylene bisimide subunits. Selective excitation of the donor induces electron transfer to the acceptor unit in polar solvents, facilitated by a ‘through-stack’ wire-like charge hopping mechanism with a low attenuation factor β = 0.21 Å−1, which suggests through-stack as being equally supportive for long-distance sequential electron transfer compared to the investigated ‘through-bond’ transfer along π-conjugated bridges. Understanding the distance dependence and mechanistic behaviour of light-driven charge separation is crucial to advance artificial photosynthesis and solar energy conversion. It has now been shown that donor–bridge–acceptor null-coupled perylene bisimide arrays are good candidates for generating long-lived excitons and display ‘through-stack’ photoinduced electron transfer through pronounced π-orbital overlap.
Degradation of carbon-backbone polymers, which make up most plastics, remains a formidable challenge owing to strong and inert main-chain C–C bonds. While incorporation of comonomers that generate backbone radicals under certain conditions can induce degradation of the polymer chain, such strategies yield complex oligomer mixtures. Here we report aromatization-driven C–C bond cleavage as a viable and powerful strategy to endow the degradability into carbon backbones using acrylic polymers as a model example. The key to this new strategy is the efficient, living, alternating addition copolymerization of acrylates with simple, commercially available and biorenewable coumarin using a frustrated Lewis pair cooperative catalyst. The resulting acrylic copolymers are strong, transparent thermoplastics with key thermal, optical, mechanical properties comparable or superior to poly(methyl methacrylate). Under strong base, alternating copolymers can completely degrade at room temperature through efficient cleavage of main-chain C–C bonds utilizing aromatization as a thermodynamic driving force, to generate pure, pharmaceutically valuable molecules, thus affording durable, robust yet fully degradable carbon-backbone acrylic polymers. Degradation of carbon-backbone polymers, which make up most plastics, remains a formidable challenge owing to their strong and inert main-chain C–C bonds. Now it has been shown that aromatization-driven C–C bond cleavage is a viable strategy to endow full degradability into carbon backbones under mild conditions.
Nature Chemistry - Publisher Correction: Amphoteric chalcogen-bonding and halogen-bonding rotaxanes for anion or cation recognition
A passive consequence of macromolecular condensation is the establishment of an ion concentration gradient between the dilute and dense phases, which in turn governs distinct electrochemical properties of condensates. However, the mechanisms that regulate the electrochemical equilibrium of condensates and their impacts on emergent physicochemical functions remain unknown. Here we demonstrate that the electrochemical environments and the physical and chemical activities of biomolecular condensates, dependent on the electrochemical potential of condensates, are regulated by aging-associated intermolecular interactions and interfacial effects. Our findings reveal that enhanced dense-phase interactions during condensate maturation continuously modulate the ion distribution between the two phases. Moreover, modulating the interfacial regions of condensates can affect the apparent pH within the condensates. To directly probe the interphase and interfacial electric potentials of condensates, we have designed and implemented electrochemical potentiometry and second harmonic generation-based approaches. Our results suggest that the non-equilibrium nature of biomolecular condensates might play a crucial role in modulating the electrochemical activities of living systems. The mechanisms that regulate the electrochemical equilibrium of condensates are not well understood. Now it has been shown that the aging process of biomolecular condensates can dynamically modulate the electrochemical equilibrium between phases, thereby affecting the physicochemical functions of condensates. This process potentially provides an active mechanism modulating intracellular ion flux.
Native folded proteins rely on sculpting the local chemical environment of their active or binding sites, as well as their shapes, to achieve functionality. In particular, proteins use hydration frustration—control over the dehydration of hydrophilic residues and the hydration of hydrophobic residues—to amplify their chemical or binding activity. Here we uncover that single-polymer-chain nanoparticles formed by random heteropolymers comprising four or more components can display similar levels of hydration frustration. We categorize these nanoparticles into three types based on whether either hydrophobic or hydrophilic residues, or both types, display frustrated states. We propose a series of physicochemical rules that determine the state of these nanoparticles. We demonstrate the generality of these rules in atomistic and simplified Monte Carlo models of single-polymer-chain nanoparticles with different backbones and residues. Our work provides insights into the design of single-chain nanoparticles, an emerging polymer modality that achieves the ease and cost of fabrication of polymeric material with the functionality of biological proteins. Native proteins use hydration frustration—regulating the dehydration of hydrophilic residues and the hydration of hydrophobic residues—to enhance their activity. Now it has been shown that single-polymer-chain nanoparticles made from random heteropolymers can exhibit similar hydration frustration, following design rules orthogonal to those of proteins.
N-monofluoromethyl amides (N-CH2F) have been challenging to prepare. Now, a general method for the synthesis of N-CH2F amides is developed. The strategy can be applied for the N-CH2F modification of peptides and drug derivatives. Moreover, the N-CH2F amides are relatively stable in various media, which could be beneficial for drug development.
Transfer hydrogenation is widely practised across all segments of chemical industry, yet its application to aryl halide reductive cross-coupling is undeveloped because of competing hydrogenolysis. Here, exploiting the distinct reactivity of PdI species, an efficient catalytic system for the reductive cross-coupling of activated aryl bromides with aryl iodides via formate-mediated hydrogen transfer is described. These processes display orthogonality with respect to Suzuki and Buchwald–Hartwig couplings, as pinacol boronates and anilines are tolerated and, owing to the intervention of chelated intermediates, are effective for challenging 2-pyridyl systems. Experimental and computational studies corroborate a unique catalytic cycle for reductive cross-coupling where the PdI precatalyst, [Pd(I)(PtBu3)]2, is converted to the dianionic species, [Pd2I4][NBu4]2, from which aryl halide oxidative addition is more facile. Rapid, reversible Pd-to-Pd transmetallation delivers mixtures of iodide-bridged homo- and hetero-diarylpalladium dimers. The hetero-diarylpalladium dimers are more stable and have lower barriers to reductive elimination, promoting high levels of cross-selectivity. Transfer hydrogenation is challenging to apply to aryl halide reductive cross-couplings because of competing hydrogenolysis. Now aryl halide cross-couplings mediated by sodium formate have been developed. These processes display orthogonality to Suzuki and Buchwald–Hartwig couplings as pinacol boronates and anilines are tolerated and, owing to chelated intermediates, effective for challenging 2-pyridyl systems.
Methyltransferases are a broad class of enzymes that catalyse the transfer of methyl groups onto a wide variety of substrates and functionalities. In their most striking variant, bifunctional methyltransferase–cyclases both transfer a methyl group onto alkenes and induce cyclization (methylcyclization). Although recent years have seen substantial advances in the methylation of alkenes, especially hydromethylation, the reactivity demonstrated by bifunctional methyltransferase–cyclases in nature has yet to be developed into a synthetically viable method. Here we report a silver(I)-mediated electrophilic methylcyclization that rivals selectivities found in enzymes while not being limited by their inherent substrate specificity. Our method benefits from the use of commercial reagents, is applicable to a wide range of substrates, including heterocycles, and affords unique structures that are difficult to access via conventional synthetic methods. Furthermore, computational studies have been utilized to unravel the underlying mechanism and ultimately support a stepwise cationic reaction pathway with a rate-limiting methyltransfer. Bifunctional methyltransferase–cyclases both transfer a methyl group to alkenes and induce cyclization—a process called methylcyclization. Now a non-enzymatic silver(I)-mediated electrophilic methylcyclization has been reported. The reaction uses commercial reagents, is applicable to a wide range of substrates and affords structures that are difficult to access by conventional synthetic methods.
The emergence of bacterial antimicrobial resistance threatens to undermine the utility of antibiotic therapy in medicine. This threat can be addressed, in part, by reinventing existing antibiotic classes using chemical synthesis. Here we present the discovery of BT-33, a fluorinated macrobicyclic oxepanoprolinamide antibiotic with broad-spectrum activity against multidrug-resistant bacterial pathogens. Structure–activity relationships within the macrobicyclic substructure reveal structural features that are essential to the enhanced potency of BT-33 as well as its increased metabolic stability relative to its predecessors clindamycin, iboxamycin and cresomycin. Using X-ray crystallography, we determine the structure of BT-33 in complex with the bacterial ribosome revealing that its fluorine atom makes an additional van der Waals contact with nucleobase G2505. Through variable-temperature 1H NMR experiments, density functional theory calculations and vibrational circular dichroism spectroscopy, we compare macrobicyclic homologues of BT-33 and a C7 desmethyl analogue and find that the C7 methyl group of BT-33 rigidifies the macrocyclic ring in a conformation that is highly preorganized for ribosomal binding. Antibiotic resistance can be addressed by reinventing classes of antibiotics through chemical synthesis. Here BT-33—a fully synthetic antibiotic—affords broad-spectrum activity against the bacterial ribosome. X-ray crystallography, theoretical calculations and structure–activity relationship studies reveal the structural features that contribute to the enhanced antibacterial activity and metabolic stability of BT-33.
Synthetic organic chemists continually draw inspiration from biocatalytic processes to innovate synthetic methodologies beyond existing catalytic platforms. Within this context, although 1,2-amino migration represents a viable biochemical process, it remains underutilized within the synthetic organic chemistry community. Here we present a biomimetic 1,2-amino migration accomplished through the synergistic combination of biocatalytic mechanism and photoredox catalysis. This platform enables the modular synthesis of γ-substituted β-amino acids by utilizing abundant α-amino-acid derivatives and readily available organic molecules as coupling partners. This mild method features excellent substrate and functionality compatibility, affording a diverse range of γ-substituted β-amino acids (more than 80 examples) without the need for laborious multistep synthesis. Mechanistic studies, supported by both experimental observations and theoretical analysis, indicate that the 1,2-amino migration mechanism involves radical addition to α-vinyl-aldimine ester, 3-exo-trig cyclization and a subsequent rearrangement process. We anticipate that this transformation will serve as a versatile platform for the highly efficient construction of unnatural γ-substituted β-amino acids. Enzyme-catalysed 1,2-amino migration represents a viable biochemical process that is currently underutilized within the synthetic organic chemistry community. Building upon this biocatalytic mechanism, a biomimetic photoredox-catalysed 1,2-amino migration method has been developed. By integrating photoredox-catalysed conditions, this approach enables the modular synthesis of a diverse library of γ-substituted β-amino acids.
Elena De Vita and Rebecca Page reflect on the unique properties of phosphate, an essential building block with versatile functions in living systems. Modulating protein phosphorylation is an effective therapeutic strategy, with emerging approaches highlighting the continuous development in this area of drug discovery.
There are many steps to preparing a research article for publication, from generating the figures and writing the draft, to responding to reviewers. Shira Joudan explains how their group approaches this task, specifically during the preparation of the research group’s first paper.
The crystalline sponge method enables single-crystal X-ray diffraction analysis of guests absorbed within single-crystalline porous materials. However, its application with large or highly polar guests remains challenging. In this study, we addressed some of these limitations using palladium-based octahedron-shaped M6L4 (Td) coordination cages as crystalline sponges. The key to facilitate the crystallization of the cage is the addition of large aromatic polysulfonates (‘sticker’ anions); the symmetry mismatch between the cage and the sticker (D2h) results in a low-symmetry space group (P $$\bar{1}$$ ), preventing guest disorder and leading to the formation of guest-accessible channels in the crystal. Guests can be encapsulated either before or after cage crystallization. The size and host–guest properties of the cavity enable analysis of a broad range of compounds, including water-soluble molecules, large amphiphilic molecules (molecular weight of ~1,200) and molecular aggregates. We have demonstrated the versatility of the cage–sticker strategy through its application to a triaugmented triangular-prism-shaped M9L6 cage, extending the guest scope to medium-sized pharmaceutical molecules. The crystalline sponge method enables the structural characterization of non-crystalline compounds through encapsulation in a porous material. Now it is shown that palladium-based coordination cages in combination with polysulfonate anions form low-symmetry crystals that can be used as crystalline sponges to determine the structure of a wide variety of compounds, including large amphiphilic molecules.
N-monofluoromethyl (N-CH2F) amides, combining amide and monofluoromethyl motifs, represent a practical modification of the amide bond that can mimic N-CH3 amides. Despite the potential value in transforming peptides and peptidomimetics with N-CH2F, the very existence of this structure has been controversial. Here we report the preparation of N-CH2F amides and carbamates via simple and robust chemical methods. The syntheses of N-CH2F amides were achieved via successive acylation and fluorination of imines and directly used in the modification of drugs, peptides and heteroaryl amides without racemization or epimerization. The use of triethylamine is the key to the separation of N-CH2F amides. The stability of nine structurally diverse N-CH2F amides was tested in eight different media, showing that most compounds remained 60–100% intact for 24 h. The monofluoromethyl (CH2F) motif is valuable as it can mimic CH3 and CH2OH motifs frequently found in bioactive molecules, but the synthesis of N-CH2F amides is challenging. Now the synthesis of numerous N-CH2F amides has been achieved via successive acylation and fluorination of imines, enriching pathways for N-methylation of biomolecules.
Enantioselective C(sp3)–H alkylation of easily accessible saturated heterocycles is challenging. Now, a nickel-catalysed enantioselective C(sp3)–H alkylation of saturated nitrogen and oxygen heterocycles with olefins has been developed, offering an efficient strategy for the stereoselective formation of C(sp3)–C(sp3) bonds.
Despite cross-coupling strategies that enable the functionalization of aromatic heterocycles, the enantioselective C(sp3)–H alkylation of readily available saturated hydrocarbons to construct C(sp3)–C(sp3) bonds remains a formidable challenge. Here we describe a nickel-catalysed enantioselective C(sp3)–H alkylation of saturated heterocycles using olefins, providing an efficient strategy for the stereoselective construction of C(sp3)–C(sp3) bonds. Using readily available and stable olefins and simple saturated nitrogen and oxygen heterocycles as prochiral nucleophiles, the coupling reactions proceed under mild conditions and exhibit broad scope and high functional group tolerance. Furthermore, the enantio- and diastereoselective C(sp3)–H alkylation of saturated hydrocarbons with alkenyl boronates has been achieved, enabling the synthesis of versatile alkyl boronates containing 1,2-adjacent C(sp3) stereocentres. Application of this approach to the late-stage modification of natural products and drugs, as well as to the enantioselective synthesis of a range of chiral building blocks and natural products, is demonstrated. The enantioselective C(sp3)–H alkylation of saturated hydrocarbons to construct C(sp3)–C(sp3) bonds is challenging. Now a nickel-catalysed enantioselective C(sp3)–H alkylation of saturated heterocycles using olefins has been developed. The enantio- and diastereoselective C(sp3)–H alkylation of saturated hydrocarbons with alkenyl boronates has also been achieved to give alkyl boronates containing 1,2-adjacent C(sp3) stereocentres.
Patchy particles have directional interactions that enable self-assembly into materials with precisely tailored microstructures. The patches are usually rigid, but a study now shows that flexible patches can fluctuate between an on- and off-state, which dramatically affects the assembly process.
The removal of SO2 from flue gas remains a challenge. Adsorption-based separation of SO2 using porous materials has been proposed as a more energy-efficient and cost-effective alternative to more traditional methods such as cryogenic distillations. Here we report a flexible hydrogen-bonded organic framework (HOF-NKU-1) that enables the sieving of SO2 through the guest-adaptive response and shape-memory effect of the material. HOF-NKU-1 exhibits a high selectivity of 7,331 for the separation of SO2/CO2 and a high SO2 storage density of 3.27 g cm−3 within the pore space at ambient conditions. The hydrophobic nature of HOF-NKU-1 enables high dynamic SO2 uptake and SO2 recovery, even in conditions of 95% humidity. The SO2/CO2 separation mechanism is studied through combinatorial gas sorption isotherms, breakthrough experiments and single-crystal diffraction studies, paving the way for the development of multifunctional shape-memory porous materials in the future. The efficient removal of SO2 from flue gas remains a considerable challenge. Now a flexible hydrogen-bonded organic framework has been developed that exhibits high selectivity for SO2 capture from flue gas mixtures, enabled by the material’s guest-adaptive behaviour and shape-memory properties.
In nature, the ability to catalyse reactions is primarily associated with proteins and ribozymes. Inspired by these systems, peptide-based catalysts have been designed to accelerate chemical reactions and/or ensure regio- and stereoselective transformations. We wondered whether other biomolecules (such as glycans) could be designed to perform catalytic functions, expanding the portfolio of synthetic functional oligomers. Here we report a glycan foldamer inspired by the natural Sialyl Lewis X antigen that acts as catalyst in a chemical reaction. This glycan-based catalyst benefits from structural rigidity and modular adaptability, incorporating a substrate-recognition motif alongside a catalytic active site. Leveraging the inherent ability of carbohydrates to engage in CH–π interactions with aromatic substrates, we demonstrate the recruitment and functionalization of a tryptophan via a Pictet–Spengler transformation. Our modular glycan catalyst accelerates the reaction kinetics, enabling the modification of tryptophan-containing peptides in aqueous environments. Our findings pave the way for the development of glycan-based catalysts and suggest the possibility of catalytic capabilities of glycans in biological contexts. In nature, catalysis is generally performed by proteins and ribozymes. Now it has been shown that glycans can be designed to perform catalysis. Exploiting carbohydrate–aromatic interactions, a glycan foldamer enables a Pictet–Spengler transformation of tryptophan and tryptophan-containing peptides in water.
1,5-Disubstituted bicyclo[2.1.1]hexanes are bridged scaffolds with well-defined exit vectors that are becoming increasingly popular building blocks in medicinal chemistry because they are saturated bioisosteres of ortho-substituted phenyl rings. Here we have developed a Lewis-acid-catalysed [2 + 2] photocycloaddition to obtain these motifs as enantioenriched scaffolds, providing an efficient approach for their incorporation in a variety of drug analogues. Retention of the biological activity of the bicyclo[2.1.1]hexane-containing analogues in the specific proteins targeted by the original drugs has confirmed the suitability of this moiety to serve as a bioisostere of ortho-substituted phenyl rings. Moreover, we have studied the potential of the different enantiomers of the drug analogues to selectively induce cytotoxicity in a panel of tumour cell lines, observing markedly differential effects for the two enantiomers and a substantial improvement over the corresponding sp2-based drugs. This showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its biological properties. The incorporation of saturated bioisosteres of phenyl rings has emerged as an appealing strategy in drug-discovery programmes. However, stereocontrolled access to these sp3-hybridized skeletons remains elusive. Now, the enantioselective synthesis of bicyclo[2.1.1]hexanes has been achieved through a Lewis-acid-catalysed [2 + 2] photocycloaddition, making it possible to obtain different drug analogues with improved properties.
The cytoskeleton provides internal organization, resistance and other essential functionalities to cells; but complex regulation makes natural components challenging to engineer for synthetic systems. Now, designer polymers are shown to assemble as a multifunctional, biomimetic cytoskeleton in artificial cells.
The C–H functionalization of inert alkanes has long been one of the most challenging reactions in organic synthesis. Now, the use of hypervalent iodine reagents has enabled the diverse functionalization of various aliphatic C–H bonds under blue light irradiation, achieving a high level of reactivity and selectivity.
The electrocatalytic reduction of CO2 involves electron/proton transfers, with hydrogenation of intermediates occurring via surface-bound hydrogen or hydrogen originating from water. Now, isotope-labelling studies have elucidated the relative contributions of both pathways on copper electrocatalysts, offering new perspectives on achieving selectivity control.
The functionalization of aliphatic C–H bonds is a crucial step in the synthesis and transformation of complex molecules relevant to medicinal, agricultural and materials chemistry. As such, there is substantial interest in the development of general synthetic platforms that enable the efficient diversification of aliphatic C–H bonds. Here we report a hypervalent iodine reagent that releases a potent hydrogen atom abstractor for C–H activation under mild photochemical conditions. Using this reagent, we demonstrate selective (N-phenyltetrazole)thiolation of aliphatic C–H bonds for a broad scope of substrates. The synthetic utility of the thiolated products is showcased through various derivatizations. Simply by altering the radical trapping agent, our method can directly transform C–H bonds into diverse functionalities, including C–S, C–Cl, C–Br, C–I, C–O, C–N, C–C and C=C bonds. Aliphatic C–H functionalization is a valuable tool in organic synthesis. Now a hypervalent iodine reagent has been shown to release a potent hydrogen atom abstractor for C–H activation under mild photochemical conditions. This enables the transformation of C–H bonds into diverse functional groups with tunable control over the site selectivity.
Petroleum-derived polyolefins exhibit diverse properties and are the most important and largest volume class of plastics. However, polyolefins are difficult to efficiently recycle or break down and are now a persistent global contaminant. Broadly replacing polyolefins with bio-derived and degradable polyethylene-like materials is an important yet challenging endeavour towards sustainable plastics. Here we report a solution for circular bio-based polyethylene-like materials synthesized by acceptorless dehydrogenative polymerization from linear and branched diols and their catalytic closed-loop recycling. The polymerization and depolymerization processes utilize earth-abundant manganese complexes as catalysts. These materials exhibit a wide range of mechanical properties, encompassing thermoplastics to plastomers to elastomers. The branched diols, produced through a thiol–ene click reaction, can be polymerized to plastics with significantly enhanced tensile properties, toughness and adhesive properties. These materials could be depolymerized back to monomers through hydrogenation and were separatable with a monomer recovery of up to 99%, unaffected by the presence of dyes and additives. Overall, this system establishes a route to more sustainable plastics. Bio-based polyethylene-like materials with tunable thermal and mechanical properties have been synthesized from plant-derived diols using an acceptorless dehydrogenative polymerization strategy. Now it has been shown that this atom-economical and mass-economical approach employing non-precious metal catalysts enables closed-loop recycling and advances sustainable solutions for the circular plastic economy.
The amphoteric character of chalcogen bonding (ChB) and halogen bonding (XB) donor atoms for anion or cation recognition is demonstrated using interlocked host molecules. A family of neutral tri- and tetradentate ChB and/or XB [2]rotaxanes exhibit Lewis acidic halide anion and Lewis basic metal cation binding at the same chalcogen or halogen donor site.
Skeletal editing of heterocyclic building blocks offers an appealing way to expand the accessible chemical space by diversifying molecular scaffolds for drug discovery. Despite the recent boom in this area, catalytic strategies that directly introduce fluorine into the backbone of small-ring heterocycles remain rare owing to the challenges of strain-induced ring cleavage and defluorination. Here we describe a copper-catalysed approach for skeletal expansion of oxygen heterocycles by reaction with a difluorocarbene species generated in situ to induce carbon atom insertion. The α,α-difluoro-oxetane products are potential surrogates of oxetane, β-lactone and carbonyl pharmacophores on the basis of their computed molecular properties and electrostatic potential maps. The utility of this approach is highlighted by synthesis of various drug-like molecules and fluorinated isosteres of biologically active compounds. Experimental and computational investigations provide insight into the mechanism and the unique role of the copper catalyst in promoting both ring-opening and cyclization steps of the reaction. Catalytic methods to introduce fluorine into the backbone of small-ring heterocycles are challenging due to the problems of strain-induced ring cleavage and defluorination. Now, a copper catalyst mediates insertion of an in situ-generated difluorocarbene into oxygen heterocycles, affording ring-expanded fluorinated pharmacophores. Experimental and computational studies provide insights into the mechanism.
Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, we found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), we show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. Our results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, we provide evidence that other proton pump inhibitors can be activated in the same way. We conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments. Proton pump inhibitors (PPIs) are prodrugs that are activated by protonation in the highly acidic environment of the stomach lining. Now, coordination of PPIs to protein-bound zinc ions is revealed as another pathway to PPI activation. Acting as a Lewis acid, the zinc ion facilitates conjugation of the drug to zinc-coordinating cysteine residues.
The on-surface synthesis of two-dimensional (2D) polymers from monomers represents a useful strategy for designing lattice, orbital and spin symmetries. Like other 2D materials, the ordered stacking of 2D polymers into bilayers may allow developing unique optoelectronic, charge transport and magnetic properties not found in the individual layers. However, controlling layer stacking of 2D polymers remains challenging. Here we describe a method for synthesizing 2D polymer bilayers or bilayer 2D covalent organic frameworks at the liquid–substrate interface through the direct condensation of monomers. More importantly, we also show how factors such as monomer structure and solvent mixture influence the bilayer stacking modes and how, under certain conditions, large-area moiré superlattices emerge from the twisted bilayer stacking. This finding offers new opportunities for the design of bilayer stacked framework materials with tunable electronic and structural properties. On-surface synthesis of two-dimensional polymers is a useful strategy for designing the lattice, orbital and spin symmetries of materials, but controlling their layer stacking remains challenging. Now, a method to synthesize bilayer two-dimensional covalent organic frameworks at a liquid–substrate interface through monomer condensation has been developed; large-area moiré superlattices emerge from the twisted bilayer stacking.
The ever-increasing demand in the development of host molecules for the recognition of charged species is stimulated by their fundamental roles in numerous biological and environmental processes. Here, capitalizing on the inherent amphoteric nature of anisotropically polarized tellurium or iodine atoms, we demonstrate a proof of concept in charged guest recognition, where the same neutral host structure binds both cations or anions solely through its chalcogen or halogen donor atoms. Through extensive 1H nuclear magnetic resonance titration experiments and computational density functional theory studies, a library of chalcogen-bonding (ChB) and halogen-bonding (XB) mechanically interlocked [2]rotaxane molecules, including seminal examples of all-ChB and mixed ChB/XB [2]rotaxanes, are shown to function as either Lewis-acidic or Lewis-basic multidentate hosts for selective halide anion and metal cation binding. Notably, the exploitation of the inherent amphoteric character of an atom for the strategic purpose of either cation or anion recognition constitutes the inception of a previously unexplored area of supramolecular host–guest chemistry. The importance of charged species in numerous biological and environmental processes has stimulated the development of host molecules for their selective recognition. Now anisotropically polarized halogen- and chalcogen-bonding [2]rotaxanes are demonstrated to exhibit dual Lewis-acidic and Lewis-basic amphoteric properties for anion or cation recognition via the same donor atoms.
Cyclic crown ethers bind metal cations to form host–guest complexes. Lesser-known inverse crowns are rings of metal cations that encapsulate anionic entities, enabling multiple deprotonation reactions, often with unusual selectivity. Self-assembly of a cycle of metal cations around the multiply charged carbanion during the deprotonation reaction is the driving force for this reactivity. Here we report the synthesis of a pre-assembled inverse crown featuring Na+ cations and a redox-active Mg0 centre. Reduction of N2O followed by N2 release and subsequent encapsulation of O2− demonstrates its reduce-and-capture functionality. Calculations reveal that this essentially barrier-free process involves a rare N2O2− dianion, embedded in the metalla-cycle. The inverse crown can adapt itself for binding larger anions like N2O22− through a self-reorganization process involving ring expansion. The redox-active inverse crown combines the advantages of a strong reducing agent with anion stabilizing properties provided by the ring of metal cations, leading to high reactivity and selectivity. Following the building principles of crown ethers for cation encapsulation, inverse crowns are rings of metals that bind anions. Now a redox-active inverse crown ether featuring Na+ cations and Mg0 has been shown to reduce epoxides, N2O, S8 or O2 by combining anion complexation by the ring of metal cations with the reducing power of Mg0.
Atomically dispersed heterogeneous catalysts offer the opportunity to design active sites with molecular precision. A recent proliferation of synthetic strategies and advanced characterization tools has propelled broad interest in leveraging these catalysts in diverse areas of chemistry beyond thermal heterogeneous catalysis, including but not limited to organic synthesis, electrochemistry, photochemistry and environmental chemistry. This Perspective aims to arm researchers in this area with the methodological framework and fundamental principles to accurately assess the degree of uniformity of heterogeneous catalyst active sites, and to link the synthesis, structure and function of atomically dispersed catalysts to one another. A paedagogical discussion of catalyst structural dynamics and active-site-specific characterization is supplemented with recent case studies that illustrate these fundamentals. This analysis shows how progress can be guided by requiring that the characterization of active sites is connected to their kinetic behaviour in the form of turnover rates and by leveraging the thermokinetic factors that control active site structures and their dynamics. Atomically dispersed heterogeneous catalysts impact diverse areas of chemistry through the design of active sites with molecular precision, but this vision is not fully realized. This Perspective presents the fundamental principles and methodological framework to guide progress in the field.
Anion vacancies on metal oxide surfaces have been studied as either active sites or promoting sites in various chemical reactions involving oxidation/reduction processes. However, oxide materials rarely work effectively as catalysts in the absence of transition metal sites. Here we report a Ba–Si orthosilicate oxynitride–hydride as a transition-metal-free catalyst for efficient ammonia synthesis via an anion-vacancy-mediated mechanism. The facile desorption of H− and N3− anions plus the flexibility of the crystal structure can accommodate a high density of electrons at vacancy sites, where N2 can be captured and directly activated to ammonia through hydrogenation processes. The ammonia synthesis rates reach 40.1 mmol g−1 h−1 at 300 °C by loading ruthenium nanoparticles. Although not found to dissociate N2, Ru instead facilitates the formation of anion vacancies at the Ru–support interface. This demonstrates a new route for anion-vacancy-mediated heterogeneous catalysis. N2 reduction to ammonia typically requires transition metal catalysts, proceeding via a strong metal–nitrogen interaction. Now a Ba–Si orthosilicate oxynitride–hydride has been shown to function as a transition-metal-free catalyst for ammonia synthesis through an anion-vacancy-mediated mechanism, where electrons at the vacancy sites facilitate N2 activation.
Nature Chemistry - Author Correction: Engineering a DNA polymerase for modifying large RNA at specific positions
Supramolecular networks are abundantly present in nature and, like crystalline materials, often develop from an initial nucleation site, followed by growth based on directional interactions between components. Traditionally, the binding strength and directionality of interactions is thought to dictate nucleation and crystal growth, whereas structural flexibility favours defects. Usually, macromonomers present multiple binding sites with relative intramolecular flexibility, but the effects of such flexibility on regulating network formation have been given little attention. Here we introduce the concept of ‘interface flexibility’ and demonstrate its critical importance in the nucleation and growth of supramolecular networks. As a model system, we use trisymmetric DNA-based macromonomers, which organize into hexagonal networks through weak π–π interactions at their tips. The directional nature and low spatial tolerance of π–π interactions mean that small shifts in orientation have a large effect on effective valency. We show that too much interface flexibility disrupts network formation, regardless of affinity. Tuning the interface flexibility greatly expands the available design space for synthetic supramolecular materials. Supramolecular ordered networks are formed through directional interactions of uniform macromonomer building blocks. Now it has been shown that, rather than intermolecular affinity, the flexibility of the binding interface (‘interface flexibility’) dominates the mechanism of self-assembly. This study provides an intuitive understanding of the role of interface flexibility in supramolecular self-assembly.
Lithium–sulfur batteries promise high energy density storage but show poor stabilities owing to uncontrolled polysulfide dissolution. Although limiting polysulfide solvation to establish quasi-solid-state sulfur reaction can decouple electrode reactions from the electrolyte volume, this approach suffers from slow reaction kinetics. Here we propose a surface-localized polysulfide-solvation strategy to mediate the reaction of ‘quasi-solid’ polysulfide by leveraging an organic phase mediator with a weakly solvating electrolyte. This electrolyte restricts polysulfide dissolution globally while the phase mediator complexes with the surface polysulfide, promoting polysulfide solvation at the surface and facilitating fast surface-localized solution-phase sulfur reactions. Lithium–sulfur batteries using surface-localized phase mediation show excellent rate performance with 494 mA h g−1-sulfur at 16 C and stabilized cycling for 300 cycles with 90.2% capacity retention. The strategy enables steady operation of a 2.4 Ah 331 Wh kg−1 pouch cell. Our work highlights the advantages of surface phase mediation in controlling electrode reaction pathways and kinetics via electrolyte rational design. Lithium–sulfur batteries are a promising electrochemical energy storage technology; however, they are limited by the dissolution of polysulfide intermediates. Now, it has been shown that sparingly solvating electrolytes containing a phase mediator can avoid polysulfide dissolution and accelerate surface-localized solution-phase sulfur reaction to improve battery performances.
Many open questions about the origins of life are centred on the generation of complex chemical species. Past work has characterized specific chemical reactions that might lead to biological molecules. Here we establish an experimental model of chemical evolution to investigate general processes by which chemical systems continuously change. We used water as a chemical reactant, product and medium. We leveraged oscillating water activity at near-ambient temperatures to cause ratcheting of near-equilibrium reactions in mixtures of organic molecules containing carboxylic acids, amines, thiols and hydroxyl groups. Our system (1) undergoes continuous change with transitions to new chemical spaces while not converging throughout the experiment; (2) demonstrates combinatorial compression with stringent chemical selection; and (3) displays synchronicity of molecular populations. Our results suggest that chemical evolution and selection can be observed in organic mixtures and might ultimately be adapted to produce a broad array of molecules with novel structures and functions. Origins-of-life research has focused on specific chemical reactions that might lead to biological molecules. Now an experimental model of chemical evolution based on oscillating water activity has been established. This system undergoes continuous chemical change, and demonstrates combinatorial compression, stringent chemical selection and synchronicity of molecular populations.
Biomolecular condensates composed of proteins and RNA are one approach by which cells regulate post-transcriptional gene expression. Their formation typically involves the phase separation of intrinsically disordered proteins with a target mRNA, sequestering the mRNA into a liquid condensate. This sequestration regulates gene expression by modulating translation or facilitating RNA processing. Here we engineer synthetic condensates using a fusion of an RNA-binding protein, the human Pumilio2 homology domain (Pum2), and a synthetic intrinsically disordered protein, an elastin-like polypeptide (ELP), that can bind and sequester a target mRNA transcript. In protocells, sequestration of a target mRNA largely limits its translation. Conversely, in Escherichia coli, sequestration of the same target mRNA increases its translation. We characterize the Pum2–ELP condensate system using microscopy, biophysical and biochemical assays, and RNA sequencing. This approach enables the modulation of cell function via the formation of synthetic biomolecular condensates that regulate the expression of a target protein. Formation of biomolecular condensates composed of proteins and RNA facilitates the regulation of gene expression by modulating translation or facilitating RNA processing. Now, synthetic ribonucleoprotein granules created with engineered intrinsically disordered proteins selectively sequester mRNA and enhance protein translation in cells. These highly liquid-like condensates exchange biomolecules across the cell and facilitate target mRNA and ribosome partitioning.
Anecdotal reports and preliminary clinical trials suggest that the psychoactive alkaloid ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder. Here we report a gram-scale, seven-step synthesis of ibogaine from pyridine. Key features of this strategy enabled the synthesis of three additional iboga alkaloids, as well as an enantioselective total synthesis of (+)-ibogaine and the construction of four analogues. Biological testing revealed that the unnatural enantiomer of ibogaine does not produce ibogaine-like effects on cortical neuron growth, while (−)-10-fluoroibogamine exhibits exceptional psychoplastogenic properties and is a potent modulator of the serotonin transporter. This work provides a platform for accessing iboga alkaloids and congeners for further biological study. Preliminary clinical trials suggest that ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, Now, a strategy for the scalable, asymmetric total synthesis of ibogaine has been developed that also provides access to iboga analogues. Biological testing identified a psychoplastogenic iboga analogue that is a potent modulator of the serotonin transporter.
Understanding the hydrogenation pathway in electrochemical CO2 reduction is important for controlling product selectivity. The Eley–Rideal mechanism involving proton-coupled electron transfer directly from solvent water is often considered to be the primary hydrogen transfer route. However, in principle, hydrogenation can also occur via the Langmuir–Hinshelwood mechanism using surface-adsorbed *H. Here, by performing CO2 reduction with Cu in H2O–D2O mixtures, we present evidence that the Langmuir–Hinshelwood mechanism is probably the dominant hydrogenation route. From this, we estimate the extent to which each mechanism contributes towards the formation of six important CO2 reduction products. Through computational simulations, we find that the formation of C–H bonds and O–H bonds is governed by the Langmuir–Hinshelwood and Eley–Rideal mechanism, respectively. We also show that promoting the Eley–Rideal pathway could be crucial towards selective multicarbon product formation and suppressing hydrogen evolution. These findings introduce important considerations for the theoretical modelling of CO2 reduction pathways and electrocatalyst design. CO2 electroreduction to higher-value carbons can occur through adsorbed hydrogen or through proton-coupled electron transfer from water. Understanding the impact of each route on product selectivity is challenging. Now H/D isotopic labelling reveals the contribution of each mechanism towards product formation and shows that adsorbed hydrogen dominates the reaction.
Perovskite solar cells represent a promising class of photovoltaics that have achieved exceptional levels of performance within a short time. Such high efficiencies often depend on the use of molecule-based selective contacts that form highly ordered molecular assemblies. Although this high degree of ordering usually benefits charge-carrier transport, it is disrupted by structure deformation and phase transformation when subjected to external stresses, which limits the long-term operational stability of perovskite solar cells. Here we demonstrate a molecular contact with an orthogonal π-skeleton that shows better resilience to external stimuli than commonly used conjugated cores. This molecular design yields a disordered, amorphous structure that is not only highly stable but also demonstrates exceptional charge selectivity and transport capability. The perovskite solar cells fabricated with this orthogonal π-skeleton molecule exhibited enhanced long-term durability in accelerated-ageing tests. This orthogonal π-skeleton functionality opens new opportunities in molecular design for applications in organic electronics. Perovskite solar cells often rely on ordered molecular contacts for favourable charge-carrier transport, and any organizational disruption reduces device efficiency. Now a contact featuring an orthogonal π-skeleton has been shown to afford a high resilience to external stimuli plus long-term durability in accelerated-ageing tests.
Niki Mavragani and Muralee Murugesu discuss the discovery, structure and properties of Mn12, a prototypical single-molecule magnet.
Artificial intelligence is being used in many aspects of chemical research. Bruce Gibb discusses top-down and bottom-up approaches to the development of AI, highlighting the issues with cultural divides and the challenges of data quality. He also introduces 'Eric', a potential AI research assistant for the future chemist.
Rechargeable lithium-ion batteries can exhibit a voltage decay over time, a complex process that diminishes storable energy and device lifetime. Now, hydrogen transfer from the electrolyte solvent to the metal oxide cathode has been demonstrated as an operative self-discharge mechanism.
The substitution of an aromatic ring with a C(sp3)-rich bicyclic hydrocarbon, known as bioisosteric replacement, plays a crucial role in modern drug discovery. Substituted bicyclo[1.1.1]pentanes (BCPs) are particularly noteworthy owing to their uniquely three-dimensional stereochemical complexity. 1,3-Difunctionalized BCPs have been widely used as bioisosteres for para-substituted phenyl rings, and they have been incorporated into numerous lead pharmaceutical candidates. 2-Substituted BCPs (substituted at the bridge position) can function as alternatives to ortho- or meta-substituted arene rings; however, the general and efficient construction of these scaffolds remains challenging, particularly if performed in an enantioselective manner. Here we present an approach for synthesizing enantioenriched 2-substituted BCPs by a nitrogen-atom insertion-and-deletion strategy, involving a chiral Brønsted acid-catalytic enantioselective cycloaddition of bicyclo[1.1.0]butanes with imines and nitrogen deletion of resulting aza-bicyclo[2.1.1]hexanes (aza-BCHs) with generally good enantiopurity retention. Mechanistic experiments verify the radical pathway. Chiral BCPs have been readily incorporated into medicinally relevant molecules, and a drug analogue has been successfully prepared enantioselectively. Substituted bicyclo[1.1.1]pentanes (BCPs) are widely used as bioisosteres for para-substituted phenyl rings, providing improved pharmacological profiles for drug candidates, but strategies for the preparation of chiral BCPs remain limited. Now a route to chiral bridge-substituted BCPs has been developed via a nitrogen-atom insertion-and-deletion strategy, enabling a practical avenue towards chiral BCP bioisosteres of lomitapide.
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