The prebiotic synthesis of ribose is thought to have played a key role in origin-of-life scenarios based on the RNA world hypothesis. As ribose is readily prone to decomposition, ribose-borate complexes, which are resistant to degradation under alkaline conditions, are often suggested to have protected ribose on early Earth. Prebiotic laboratory experiments exploring ribose-borate complexes, however, generally use high borate concentrations sourced from synthetic reagents that do not reflect the lower solubility of calcium-bearing borate minerals and the limited aqueous borate found in modern geological settings. Here, we describe how the presence of aqueous ribose can significantly increase the solubility of a range of borate-bearing minerals, even the characteristically less soluble calcium-containing borates. Furthermore, it is demonstrated that ribose-borate complexes prevent borate from calcium-induced precipitation, inhibiting its removal from solution and ensuring it remains chemically available for further downstream aqueous reactions. These findings will aid future prebiotic experiments in reflecting more geologically realistic conditions in the context of the RNA world hypothesis and also provide insight into the impact that prebiotic organo-mineralization may have played on geochemical systems on the early Earth.

Ribose–borate complexes play an important role in prebiotic chemistry, yet detailed, systematic structural characterization by NMR spectroscopy particularly of the 2:1 complexes has remained limited. The most widely cited study dates to 1988 by Chapelle and Verchere relying on 80 and 90 MHz magnets. Herein, we present updated structural characterization of ribose–borate complexes using one- and two-dimensional 1H and 13C NMR spectroscopy (performed with a 600 MHz instrument), including assignment of proton and carbon resonances via 1H–1H COSY and 1H–13C HSQC experiments. These assignments were corroborated and supported by density functional theory predictions of NMR chemical shifts. It is demonstrated that the homogeneous 2:1 complexes exist as diastereomeric pairs arising from R and S configurations at the spiro-boron center. In addition, 13C NMR spectroscopy suggests the presence of other heterogeneous 2:1 complexes that have not previously been reported or discussed. These results provide a more comprehensive reference for ribose–borate speciation, supporting future studies particularly in prebiotic chemistry.

Proton gradients across membranes are central to modern bioenergetics and are thought to have played a pivotal role in life’s emergence. We report that the autocatalytic formaldehyde-sulfite (FS) pH-clock reaction can generate such gradients when encapsulated in unilamellar phospholipid vesicles. POPC/POPG vesicles (~100 nm) containing sodium (bi)sulfite and the fluorescent pH probe HPTS were prepared by the thin-film hydration method, extruded and purified via size exclusion chromatography. Upon aqueous formaldehyde addition, a rapid rise in lumen pH was observed, resulting in a transmembrane pH gradient whose magnitude and kinetics were sensitive to initial lumen pH. Vesicles with lumen pH near 7.5 exhibited an increase to ~8.8 followed by a gradual decrease toward neutrality. 13C NMR spectroscopy confirmed encapsulation of the final FS product, hydroxymethanesulfonate. Vesicles doped with small percentages of oleic acid afforded faster proton transport, demonstrating the spike in pH can be controlled through membrane composition. These findings establish a simple, nonenzymatic route to transmembrane pH gradients and provide a rare experimental example of an autocatalytic reaction network confined within protocell-like vesicles.

Hydrogen peroxide (H2O2) is increasingly recognized as an important molecule in prebiotic chemistry that potentially had a large impact on life’s early evolution. We highlight recent examples of H2O2 in prebiotic syntheses that model potential protometabolic reactions. Recent discoveries have revealed multiple abiotic production mechanisms for H2O2, suggesting its prevalence in prebiotic and extraterrestrial environments, an idea that is supported by the detection of H2O2 in the Martian atmosphere and on the surfaces of icy moons. Given that Earth’s active geological processes have erased records of the earliest prebiotic chemical processes, we hypothesize that extraterrestrial environments that produce H2O2 such as Mars and icy moons may still have similar types of chemistry occurring, and the discovery of such reactions by advanced space missions would offer invaluable insights into prebiotic chemistry. To test our hypothesis, experimental and theoretical studies aimed at modeling prebiotic chemistry in these H2O2-producing environments are required. We propose the general principle of “Where There is Water, There is H2O2” as an astrobiology guideline that supplements and refines the traditional “Follow the Water” approach used to plan space missions.

The emergence of protocells, membranous compartments with encapsulated genetic material, was a crucial step in life’s origin and evolution. The hot spring hypothesis for the origin of life suggests that protocells with the capacity to encapsulate organic matter could have formed in hot spring pools during wet–dry (WD) cycling of hydrothermal fluids. Previous investigations have focused on mimicking WD cycles within a single pool, which precludes simulation of many hydrothermal field conditions, such as different mineralogies and variable temperature, pH, and water flow within and between multiple hot spring pools. Here, we present a modular 3D-printed hydrothermal field simulator that mimics many more aspects of the complex nature of hot spring fields by controlling the temperature, pH, and mineralogical variability of a series of linked pools. Furthermore, the pools can be programmed to experience fluid mixing between proximal pools and periodic WD cycling events. Results with the prototype hot spring field design demonstrate the ability to spontaneously form lipid vesicles that encapsulate organic matter within membranous compartments comprised of decanoic acid:decanol (4:1) or the phospholipids POPC:POPG (1:1). We observed that the vesicles formed during multiple WD cycles in the simulator pools displayed variation in their size distribution and differences in the number of membrane layers. Cargo encapsulation was favored in giant unilamellar vesicles and oligolamellar vesicles. Overall, the hot spring simulator offers a novel and customizable approach for studying multiple processes within hydrothermal field dynamics that include prebiotic chemical reactions, mineral surface catalysis, and the complexities of fluid mixing between proximal hot spring pools.

Ribose-borate complexes play an important role in prebiotic chemistry, yet detailed, systematic structural characterization by NMR spectroscopy particularly of the 2:1 complexes has remained limited. The most widely cited study dates to 1988 by Chapelle and Verchere relying on 80 and 90 MHz magnets. Herein, we present updated structural characterization of ribose-borate complexes using one-and two-dimensional 1H and 13C NMR spectroscopy (performed with a 600 MHz instrument), including assignment of proton and carbon resonances via 1H-1H COSY and 1H-13C HSQC experiments. These assignments were corroborated and supported by density functional theory predictions of NMR chemical shifts. It is demonstrated that the homogeneous 2:1 complexes exist as diastereomeric pairs arising from R and S configurations at the spiro-boron center. In addition, 13C NMR spectroscopy indicates the presence of other heterogeneous 2:1 complexes that have not previously been reported or discussed. These results provide a more comprehensive reference for ribose-borate speciation, supporting future studies particularly in prebiotic chemistry.

Dynamic covalent chemistry (DCC) provides a powerful framework for assembling complex molecular architectures under thermodynamic control. Here, we extend RNA DCC by harnessing the ability of RNase T1—traditionally used as a degradative enzyme—to catalyze reversible phosphodiester exchange. Although enzyme-mediated RNA ligation has been reported previously, such reactions typically required high substrate concentrations and yielded heterogeneous mixtures without structural control. By coupling catalysis to RNA folding, selective formation of well-defined hairpin products governed by thermodynamic stability was achieved. PAGE, LC-MS, and NMR analyses confirm high-fidelity ligation at low temperatures with yields up to 61%, directed by loop stability and stem complementarity. Four distinct RNA oligomers assemble into two hairpins in one pot without cross-ligation, demonstrating RNA DCC as a programmable strategy for equilibrium RNA assembly. This work outlines an RNase-catalyzed framework for structure-guided RNA recombination, showcasing an underexplored pathway for the ligation of folded RNA polymers.

A personal account of what its like to do astrobiology research in Australia.

Cyanogen chloride (NCCl) produced from the reaction of –CN with HOCl has previously been shown to afford activation of ribonucleotides. We now report that NCCl reacts with primary aliphatic amino acids to rapidly produce N-carbamoyl dipeptides in excellent yields (89–98%). Studies with l-alanine suggest that racemization of the amino acids does not occur significantly during the reaction. Quantum chemical (DFT) calculations predict that the mechanism proceeds via activated 2-amino-5­(4H)-oxazolone intermediates, which undergo amino acid nucleophilic attack. NCCl can also be generated in situ from glycine and HOCl, enabling the “sacrificial activation” of glycine to form N-carbamoyl diglycine. At 70 °C, selective peptide bond hydrolysis yields N-carbamoyl glycine, which is a known peptide precursor. The findings herein build upon prior work involving NCCl in prebiotic ribonucleotide synthesis and activation, highlighting its potential as a general chemical activator for the prebiotic condensation of life’s molecular building blocks.

Understanding abiotic carbon fixation provides insights into early Earth’s carbon cycles and life’s emergence in terrestrial hot springs, where iron sulfide (FeS), similar to cofactors in metabolic enzymes, may catalyze prebiotic synthesis. However, the role of FeS-mediated carbon fixation in such conditions remains underexplored. Here, we investigate the catalytic behaviors of FeS (pure and doped with Ti, Ni, Mn, and Co), which are capable of H2-driven CO2 reduction to methanol under simulated hot spring vapor-zone conditions, using an anaerobic flow chamber connected to a gas chromatograph. Specifically, Mn-doped FeS increases methanol production five-fold at 120 °C, with UV−visible light (300–720 nm) and UV-enhanced light (200–600 nm) further increasing this activity. Operando and theoretical investigations indicate the mechanism involves a reverse water-gas shift with CO as an intermediate. These findings highlight the potential of FeS-catalyzed carbon fixation in early Earth’s terrestrial hot springs, effective with or without UV light.

Radicals, with their unpaired electrons, exhibit unique chemical and physical properties that have long intrigued chemists. Despite early skepticism about their stability, the discovery of persistent radicals has opened new possibilities for molecular interactions. This review examines the mechanisms and applications of radically driven self-assembly, focusing on key motifs such as naphthalene diimides, tetrathiafulvalenes, and viologens, which serve as models for radical assembly. The potential of radical interactions in the development of artificial molecular machines (AMMs) are also discussed. These AMMs, powered by radical-radical interactions, represent significant advancements in non-equilibrium chemistry, mimicking the functionalities of biological systems. From molecular switches to ratchets and pumps, the versatility and unique properties of radically powered AMMs are highlighted. Additionally, the applications of radical assembly in materials science are explored, particularly in creating smart materials with redox-responsive properties. The review concludes by comparing AMMs to biological molecular machines, offering insights into future directions. This overview underscores the impact of radical chemistry on molecular assembly and its promising applications in both synthetic and biological systems.

β-Hairpin peptides with RNA-binding sequences mimicking the central two β-strands of the RNA recognition motif (RRM) protein domain have been observed to bind in a 2:1 fashion to a series of RNA homooligonucleotides in aqueous solution (PBS buffer, pH 7.40) with binding energies (−27 to −35 kJ mol–1) similar to those of full-size protein RRMs. The peptides display mild selectivities with respect to the binding of the different homooligomers. Binding studies in 500 mM magnesium chloride suggest that the complex formation is not predominantly driven by Coulombic attraction. These peptides represent a starting point for further studies of non-Coulombic binding of RNA by peptides and proteins, which is important in the context of contemporary biology, potential therapeutic applications, and prebiotic peptide–RNA interactions.

Cyclic nucleoside phosphates have been shown previously to be adequately activated to oligomerise under dry conditions. Herein, it is demonstrated that 3′,5′-cyclic adenosine monophosphate (3′,5′-cAMP) and glycine when subjected to dehydration under alkaline conditions form phosphoramidate-linked conjugates. Solid-state reaction mechanisms investigated by DFT suggest why the reaction does not occur efficiently in the aqueous phase.

- The only prebiotic chemistry book with a chemical focus
- A student-friendly and engaging introduction
- Uses a range of examples to convey basic concepts in prebiotic chemistry
- Examines chemical phenomena that have been classified by chemists in different ways over the last 150 years

Autocatalysis has been proposed to play critical roles during abiogenesis. These proposals are at odds with a limited number of known examples of abiotic (and, in particular, inorganic) autocatalytic systems that might reasonably function in a prebiotic environment. In this study, we broadly assess the occurrence of stoichiometries that can support autocatalytic chemical systems through comproportionation. If the product of a comproportionation reaction can be coupled with an auxiliary oxidation or reduction pathway that furnishes a reactant, then a Comproportionation-based Autocatalytic Cycle (CompAC) can exist. Using this strategy, we surveyed the literature published in the past two centuries for reactions that can be organized into CompACs that consume some chemical species as food to synthesize more autocatalysts. 226 CompACs and 44 Broad-sense CompACs were documented, and we found that each of the 18 groups, lanthanoid series, and actinoid series in the periodic table has at least two CompACs. Our findings demonstrate that stoichiometric relationships underpinning abiotic autocatalysis could broadly exist across a range of geochemical and cosmochemical conditions, some of which are substantially different from the modern Earth. Meanwhile, the observation of some autocatalytic systems requires effective spatial or temporal separation between the food chemicals while allowing comproportionation and auxiliary reactions to proceed, which may explain why naturally occurring autocatalytic systems are not frequently observed. The collated CompACs and the conditions in which they might plausibly support complex, “life-like” chemical dynamics can directly aid an expansive assessment of life’s origins and provide a compendium of alternative hypotheses concerning false-positive biosignatures.

Carbohydrate biosynthesis is fundamental to modern terrestrial biochemistry, but how this collection of metabolic pathways originated remains an open question. Prebiotic sugar synthesis has focused primarily on the formose reaction and Kiliani–Fischer homologation; however, how they can transition to extant biochemical pathways has not been studied. Herein, a nonenzymatic pathway for pentose production with similar chemical transformations as those of the pentose phosphate pathway is demonstrated. Starting from a C6 aldonate, namely, gluconate, nonselective chemical oxidation yields a mixture of 2-oxo-, 4-oxo-, 5-oxo-, and 6-oxo-uronate regioisomers. Regardless at which carbinol the oxidation takes place, carbonyl migration enables β-decarboxylation to yield pentoses. In comparison, the pentose phosphate pathway selectively oxidizes 6-phosphogluconate to afford the 3-oxo-uronate derivative, which undergoes facile subsequent β-decarboxylation and carbonyl migration to afford ribose 5-phosphate. The similarities between these two pathways and the potential implications for prebiotic chemistry and protometabolism are discussed.

Autocatalytic chemical reaction systems have been proposed to play critical roles during the transition from an abiotic world to one that contains living systems. These proposals are at odds with a limited number of known examples of abiotic (and in particular, inorganic) autocatalytic systems that might reasonably function in a prebiotic environment. In this study, we broadly assess the occurrence of stoichiometries that can support autocatalytic chemical systems through comproportionation reactions. If the product of a comproportionation process can be coupled with an auxiliary oxidation or reduction pathway that furnishes a reactant, then a candidate comproportionation-based autocatalytic cycle (CompAC) structure can exist. Using this strategy, we surveyed the literature and chemical databases for reactions that can be organized into CompACs that consume some chemical species as food to synthesize more autocatalysts. 226 CompACs and 44 Broad-sense CompACs were documented, and it was found that each of the 18 groups, lanthanoid series, and actinoid series in the periodic table has at least two CompACs. Our findings demonstrate that stoichiometric relationships underpinning abiotic autocatalysis could broadly exist across a range of geochemical and cosmochemical conditions, some of which are substantially different from the modern Earth. At the same time, the observation of some autocatalytic systems requires effective spatial or temporal separation between the food chemicals while allowing comproportionation and auxiliary reactions to proceed, which may explain why naturally occurring autocatalytic systems are not frequently observed. The collated CompACs and the conditions in which they might plausibly support complex, “life-like” chemical dynamics, can directly aid an expansive assessment of life’s origins and provide a compendium of alternative hypotheses concerning false-positive biosignatures.

We report the co-polymerization of glycol nucleic acid (GNA) monomers with unsubstituted and substituted dicarboxylic acid linkers under plausible early Earth aqueous dry-down conditions. Both linear and branched co-polymers are produced. Mechanistic aspects of the reaction and potential roles of these polymers in prebiotic chemistry are discussed.

The formose reaction is often cited as a prebiotic source of sugars and remains one of the most plausible
forms of autocatalysis on the early Earth. Herein, we investigated how cyanamide and 2-aminooxazole,
molecules proposed to be present on early Earth and precursors for nonenzymatic ribonucleotide
synthesis, mediate the formose reaction using HPLC, LC-MS and 1
H NMR spectroscopy. Cyanamide was
shown to delay the exponential phase of the formose reaction by reacting with formose sugars to form
2-aminooxazole and 2-aminooxazolines thereby diverting some of these sugars from the autocatalytic
cycle, which nonetheless remains intact. Masses for tetrose and pentose aminooxazolines, precursors for
nucleotide synthesis including TNA and RNA, were also observed. The results of this work in the context
of the chemoton model are further discussed. Additionally, we highlight other prebiotically plausible
molecules that could have mediated the formose reaction and alternative prebiotic autocatalytic systems.

Abstract
The origin of life on Earth required myriads of chemical and physical processes. These include the formation of the planet and its geological structures, the formation of the first primitive chemicals, reaction, and assembly of these primitive chemicals to form more complex or functional products and assemblies, and finally the formation of the first cells (or protocells) on early Earth, which eventually evolved into modern cells. Each of these processes presumably occurred within specific prebiotic reaction environments, which could have been diverse in physical and chemical properties. While there are resources that describe prebiotically plausible environments or nutrient availability, here, we attempt to aggregate the literature for the various physicochemical properties of different prebiotic reaction microenvironments on early Earth. We introduce a handful of properties that can be quantified through physical or chemical techniques. The values for these physicochemical properties, if they are known, are then presented for each reaction environment, giving the reader a sense of the environmental variability of such properties. Such a resource may be useful for prebiotic chemists to understand the range of conditions in each reaction environment, or to select the medium most applicable for their targeted reaction of interest for exploratory studies.

Abstract not available.

A prevailing strategy in origins of life studies is to explore how chemistry constrained by hypothetical prebiotic conditions could have led to molecules and system level processes proposed to be important for life’s beginnings. This strategy has yielded model prebiotic reaction networks that elucidate pathways by which relevant compounds can be generated, in some cases, autocatalytically. These prebiotic reaction networks provide a rich platform for further understanding and development of emergent “life-like” behaviours. In this review, recent advances in experimental and analytical procedures associated with classical prebiotic reaction networks, like formose and Miller-Urey, as well as more recent ones are highlighted. Instead of polymeric networks, i.e., those based on nucleic acids or peptides, the focus is on small molecules. The future of prebiotic chemistry lies in better understanding the genuine complexity that can result from reaction networks and the construction of a centralised database of reactions useful for predicting potential network evolution is emphasised.

A previously proposed synthesis of pyrimidine ribonucleotides makes use of ultraviolet (UV) light to convert β-d-ribocytidine-2′,3′-cyclic phosphate to β-d-ribouridine-2′,3′-cyclic phosphate, while simultaneously selectively degrading synthetic byproducts. Past studies of the photochemical reactions of pyrimidines have employed mercury arc lamps, characterized by narrowband emission centered at 254 nm, which is not representative of the UV environment of the early Earth. To further assess this process under more realistic circumstances, we investigated the wavelength dependence of the UV-driven conversion of β-d-ribocytidine-2′,3′-cyclic phosphate to β-d-ribouridine-2′,3′-cyclic phosphate. We used constraints provided by planetary environments to assess the implications for pyrimidine nucleotides on the early Earth. We found that the wavelengths of light (255–285 nm) that most efficiently drive the deamination of β-d-ribocytidine-2′,3′-cyclic phosphate to β-d-ribouridine-2′,3′-cyclic phosphate are accessible on planetary surfaces such as those of the Hadean-Archaean Earth for CO2-N2-dominated atmospheres. However, continued irradiation could eventually lead to low levels of ribocytidine in a low-temperature, highly irradiated environment, if production rates are slow.

Chemical evolution, from simple molecules to complex systems, is fundamental to modern origins of life research, and complex reaction networks are often supposed to have operated on the early Earth. Herein, a variety of compounds useful particularly for RNA synthesis − namely, cyanogen chloride, cyanamide, and nitrile precursors to simple sugars − are produced in short order by a chemical reaction network starting from hydrogen cyanide and driven by gamma radiolysis. The radiolytic yield of cyanamide was found to be proportional to the concentration of chloride, an often overlooked spectator anion. Aqueous irradiation of hydrogen cyanide in the presence of sodium chloride also affords cyanogen chloride, a possible intermediate in the radiolytic synthesis of cyanamide. Meanwhile, the synthesis of simple sugar precursors is proposed to proceed through a Kiliani-Fischer homologation mechanism made possible by the reducing power of the solvated electron and hydrogen atom. Such a reaction network has the potential to serve as a model for better understanding and engineering chemical evolution of complex mixtures in the laboratory that could have happened on the early Earth.

Water creates special problems for prebiotic chemistry, as it is thermodynamically favorable for amide and phosphodiester bonds to hydrolyze. The availability of alternative solvents with more favorable properties for the formation of prebiotic molecules on the early Earth may have helped bypass this so-called “water paradox”. Formamide (FA) is one such solvent, and can serve as a nucleobase precursor, but it is difficult to envision how FA could have been generated in large quantities or accumulated in terrestrial surface environments. We report here the conversion of aqueous acetonitrile (ACN) via hydrogen cyanide (HCN) as an intermediate into FA by γ-irradiation under conditions mimicking exposure to radioactive minerals. We estimate that a radioactive placer deposit could produce 0.1‒0.8 mol FA km−2 year−1. A uraninite fission zone comparable to the Oklo reactors in Gabon can produce 0.1‒1 mol m−2 year−1, orders of magnitude greater than other scenarios of FA production or delivery for which reaching sizeable concentrations of FA are problematic. Radioactive mineral deposits may be favorable settings for prebiotic compound formation through emergent geologic processes and FA-mediated organic chemistry.

The tractable history of life records a successive emergence of organisms composed of hierarchically organized cells and greater degrees of individuation. The lowermost object level of this hierarchy is the cell, but it is unclear whether the organizational attributes of living systems extended backward through prebiotic stages of chemical evolution. If the systems biology attributes of the cell were indeed templated upon prebiotic synthetic relationships between subcellular objects, it is not obvious how to categorize object levels below the cell in ways that capture any hierarchies which may have preceded living systems. In this paper, we map out stratified relationships between physical components that drive the production of key prebiotic molecules starting from radiolysis of a small number of abundant molecular species. Connectivity across multiple levels imparts the potential to create and maintain far-from-equilibrium chemical conditions and to manifest nonlinear system behaviors best approximated using automata formalisms. The architectural attribute of “information hiding” of energy exchange processes at each object level is shared with stable, multitiered automata such as digital computers. These attributes may indicate a profound connection between the system complexity afforded by energy dissipation by subatomic level objects and the emergence of complex automata that could have preceded biological systems.

The promiscuous encapsulation of π-electron-rich guests by the π-electron-deficient host, cyclobis(paraquat-p-phenylene) (CBPQT4+), involves the formation of 1:1 inclusion complexes. One of the most intensely investigated charge-transfer (CT) bands, assumed to result from inclusion of a guest molecule inside the cavity of CBPQT4+, is an emerald-green band associated with the complexation of tetrathiafulvalene (TTF) and its derivatives. This interpretation was called into question recently in this journal based on theoretical gas-phase calculations that reinterpreted this CT band in terms of an intermolecular side-on interaction of TTF with one of the bipyridinium (BIPY2+) units of CBPQT4+, rather than the encapsulation of TTF inside the cavity of CBPQT4+. We carried out DFT calculations, including solvation, that reveal conclusively that the CT band emerging upon mixing TTF with CBPQT4+ arises from the formation of a 1:1 inclusion complex. In support of this conclusion, we have performed additional experiments on a [2]rotaxane in which a TTF unit, located in the middle of its short dumbbell, is prevented sterically from interacting with either one of the two BIPY2+ units of a CBPQT4+ ring residing on a separate [2]rotaxane in a side-on fashion. This [2]rotaxane has similar UV/Vis and 1H NMR spectroscopic properties with those of 1:1 inclusion complexes of TTF and its derivatives with CBPQT4+. The [2]rotaxane exists as an equimolar mixture of cis- and trans-isomers associated with the disubstituted TTF unit in its dumbbell component. Solid-state structures were obtained for both isomers, validating the conclusion that the TTF unit, which gives rise to the CT band, resides inside CBPQT4+.

Nucleobase modifications dramatically alter nucleic acid structure and thermodynamics. 2-thiouridine (s2U) is a modified nucleobase found in tRNAs and known to stabilize U:A base pairs and destabilize U:G wobble pairs. The recently reported crystal structures of s2U-containing RNA duplexes do not entirely explain the mechanisms responsible for the stabilizing effect of s2U or whether this effect is entropic or enthalpic in origin. We present here thermodynamic evaluations of duplex formation using ITC and UV thermal denaturation with RNA duplexes containing internal s2U:A and s2U:U pairs and their native counterparts. These results indicate that s2U stabilizes both duplexes. The stabilizing effect is entropic in origin and likely results from the s2U-induced preorganization of the single-stranded RNA prior to hybridization. The same preorganizing effect is likely responsible for structurally resolving the s2U:U pair-containing duplex into a single conformation with a well-defined H-bond geometry. We also evaluate the effect of s2U on single strand conformation using UV- and CD-monitored thermal denaturation and on nucleoside conformation using 1H NMR spectroscopy, MD and umbrella sampling. These results provide insights into the effects that nucleobase modification has on RNA structure and thermodynamics and inform efforts toward improving both ribozyme-catalyzed and nonenzymatic RNA copying.

The nonenzymatic synthesis of nucleic acids, in particular, RNA, and the template-directed synthesis of artificial organic molecules, such as macrocycles, catenanes and rotaxanes, have both undergone significant development since the last half of the 20th century. The intersection of these two fields affords insights into how template effects can lead to information copying and storage at the molecular level. Mechanistic examples of model template-directed RNA replication experiments as well as those for totally artificial organic template-directed syntheses will be discussed. The fact that templates typically bind to their reacted products more tightly than their unreacted substrates may be a mechanistic feature necessary to store information in the form of nucleic acids. Understanding the mechanisms of nonenzymatic RNA synthesis is not only essential for testing the RNA world hypothesis in the context of the origin of life on Earth and other planetary bodies, but may one day afford chemists the insights to construct their own artificial molecular replicators.

Suppression of the dimerization of the viologen radical cation by cucurbit[7]uril (CB7) in water is a well-known phenomenon. Herein, two counter-examples are presented. Two viologen-containing thread molecules were designed, synthesized, and thoroughly characterized by 1H DOSY NMR spectrometry, UV/Vis absorption spectrophotometry, square-wave voltammetry, and chronocoulometry: BV4+, which contains two viologen subunits, and HV12+, which contains six. In both threads, the viologen subunits are covalently bonded to a hexavalent phosphazene core. The corresponding [3]- and [7]pseudorotaxanes that form on complexation with CB7, that is, BV4+⊂(CB7)2 and HV12+⊂(CB7)6, were also analyzed. The properties of two monomeric control threads, namely, methyl viologen (MV2+) and benzyl methyl viologen (BMV2+), as well as their [2]pseudorotaxane complexes with CB7 (MV2+⊂CB7 and BMV2+⊂CB7) were also investigated. As expected, the control pseudorotaxanes remained intact after one-electron reduction of their viologen-recognition stations. In contrast, analogous reduction of BV4+⊂(CB7)2 and HV12+⊂(CB7)6 led to host–guest decomplexation and release of the free threads BV2(.+) and HV6(.+), respectively. 1H DOSY NMR spectrometric and chronocoulometric measurements showed that BV2(.+) and HV6(.+) have larger diffusion coefficients than the corresponding [3]- and [7]pseudorotaxanes, and UV/Vis absorption studies provided evidence for intramolecular radical-cation dimerization. These results demonstrate that radical-cation dimerization, a relatively weak interaction, can be used as a driving force in novel molecular switches.

Artificial muscles are an essential component for the development of next-generation prosthetic devices, minimally invasive surgical tools, and robotics. This communication describes the design, synthesis, and characterisation of a mechanically interlocked molecule (MIM), capable of switchable and reversible linear molecular motion in aqueous solution that mimics muscular contraction and extension. Compatibility with aqueous solution was achieved in the doubly bistable palindromic [3]rotaxane design by using radical-based molecular recognition as the driving force to induce switching.

Motor molecules present in nature convert energy inputs, such as a chemical fuel or incident photons of light, into directed motion and force biochemical systems away from thermal equilibrium. The ability not only to control relative movements of components in molecules but also to drive their components preferentially in one direction relative to each other using versatile stimuli is one of the keys to future technological applications. Herein, we describe a wholly synthetic small-molecule system that, under the influence of chemical reagents, electrical potential, or visible light, undergoes unidirectional relative translational motion. Altering the redox state of a cyclobis­(paraquat-p-phenylene) ring simultaneously (i) inverts the relative heights of kinetic barriers presented by the two terminione a neutral 2-isopropylphenyl group and the other a positively charged 3,5-dimethylpyridinium unitof a constitutionally asymmetric dumbbell, which can impair the threading/dethreading of a [2]­pseudorotaxane, and (ii) controls the ring’s affinity for a 1,5-dioxynaphthalene binding site located in the dumbbell’s central core. The formation and subsequent dissociation of the [2]­pseudorotaxane by passage of the ring over the neutral and positively charged termini of the dumbbell component in one, and only one, direction relatively defined has been demonstrated by (i) spectroscopic (1H NMR and UV/vis) means and cyclic voltammetry as well as with (ii) DFT calculations and by (iii) comparison with control compounds in the shape of constitutionally symmetrical [2]­pseudorotaxanes, one with two positively charged ends and the other with two neutral ends. The operation of the system relies solely on reversible, yet stable, noncovalent bonding interactions. Moreover, in the presence of a photosensitizer, visible-light energy is the only fuel source that is needed to drive the unidirectional molecular translation, making it feasible to repeat the operation numerous times without the buildup of byproducts.

Gold recovery using environmentally benign chemistry is imperative from an environmental perspective. Here we report the spontaneous assembly of a one-dimensional supramolecular complex with an extended {[K(OH2)6][AuBr4](α-cyclodextrin)2}n chain superstructure formed during the rapid co-precipitation of α-cyclodextrin and KAuBr4 in water. This phase change is selective for this gold salt, even in the presence of other square-planar palladium and platinum complexes. From single-crystal X-ray analyses of six inclusion complexes between α-, β- and γ-cyclodextrins with KAuBr4 and KAuCl4, we hypothesize that a perfect match in molecular recognition between α-cyclodextrin and [AuBr4]− leads to a near-axial orientation of the ion with respect to the α-cyclodextrin channel, which facilitates a highly specific second-sphere coordination involving [AuBr4]− and [K(OH2)6]+ and drives the co-precipitation of the 1:2 adduct. This discovery heralds a green host–guest procedure for gold recovery from gold-bearing raw materials making use of α-cyclodextrin—an inexpensive and environmentally benign carbohydrate.

The redox chemistry of a newly synthesized small dendrimer containing six peripheral viologen units and a phosphazene core is described. The one-electron reduction of each viologen (total six electrons) leads to intermolecular dimerization of the reduced viologens borne by the same phosphorous atom, resulting in a color change from colourless to purple providing it with potential electrochromic applications.

Fashioned through billions of years of evolution, biological molecular machines, such as ATP synthase, myosin, and kinesin, use the intricate relative motions of their components to drive some of life’s most essential processes. Having control over the motions in molecules is imperative for life to function, and many chemists have designed, synthesized, and investigated artificial molecular systems that also express controllable motions within molecules. Using bistable mechanically interlocked molecules (MIMs), based on donor–acceptor recognition motifs, we have sought to imitate the sophisticated nanoscale machines present in living systems. In this Account, we analyze the thermodynamic characteristics of a series of redox-switchable [2]rotaxanes and [2]catenanes. Control and understanding of the relative intramolecular movements of components in MIMs have been vital in the development of a variety of applications of these compounds ranging from molecular electronic devices to drug delivery systems.

The ability of the diradical dicationic cyclobis­(paraquat-p-phenylene) (CBPQT2(•+)) ring to form inclusion complexes with 1,1′-dialkyl-4,4′-bipyridinium radical cationic (BIPY•+) guests has been investigated mechanistically and quantitatively. Two BIPY•+ radical cations, methyl viologen (MV•+) and a dibutynyl derivative (V•+), were investigated as guests for the CBPQT2(•+) ring. Both guests form trisradical complexes, namely, CBPQT2(•+)⊂MV•+ and CBPQT2(•+)⊂V•+, respectively. The structural details of the CBPQT2(•+)⊂MV•+ complex, which were ascertained by single-crystal X-ray crystallography, reveal that MV•+ is located inside the cavity of the ring in a centrosymmetric fashion: the 1:1 complexes pack in continuous radical cation stacks. A similar solid-state packing was observed in the case of CBPQT2(•+) by itself. Quantum mechanical calculations agree well with the superstructure revealed by X-ray crystallography for CBPQT2(•+)⊂MV•+ and further suggest an electronic asymmetry in the SOMO caused by radical-pairing interactions. The electronic asymmetry is maintained in solution. The thermodynamic stability of the CBPQT2(•+)⊂MV•+ complex was probed by both isothermal titration calorimetry (ITC) and UV/vis spectroscopy, leading to binding constants of (5.0 ± 0.6) × 104 M–1 and (7.9 ± 5.5) × 104 M–1, respectively. The kinetics of association and dissociation were determined by stopped-flow spectroscopy, yielding a kf and kb of (2.1 ± 0.3) × 106 M–1 s–1 and 250 ± 50 s–1, respectively. The electrochemical mechanistic details were studied by variable scan rate cyclic voltammetry (CV), and the experimental data were compared digitally with simulated data, modeled on the proposed mechanism using the thermodynamic and kinetic parameters obtained from ITC, UV/vis, and stopped-flow spectroscopy. In particular, the electrochemical mechanism of association/dissociation involves a bisradical tetracationic intermediate CBPQT(2+)(•+)⊂V•+ inclusion complex; in the case of the V•+ guest, the rate of disassociation (kb = 10 ± 2 s–1) was slow enough that it could be detected and quantified by variable scan rate CV. All the experimental observations lead to the speculation that the CBPQT(2+)(•+) ring of the bisradical tetracation complex might possess the unique property of being able to recognize both BIPY•+ radical cation and π-electron-rich guests simultaneously. The findings reported herein lay the foundation for future studies where this radical–radical recognition motif is harnessed particularly in the context of mechanically interlocked molecules and increases our fundamental understanding of BIPY•+ radical–radical interactions in solution as well as in the solid-state.

The synthesis and the dynamic behavior of a bistable [2]rotaxane, based on a reverse donor–acceptor motif containing naphthalene diimide (NpI) and 4,4′-bipyridinium (BIPY2+) as two electron-deficient stations and bis-1,5-dioxynaphthalene[38]crown-10 (BDNP38C10) as the electron-rich ring, is described. A functionalized tetraarylmethane moiety has been incorporated between the two stations in order to control the free energy barrier for the shuttling of the BDNP38C10 on the dumbbell component. The bistable [2]rotaxane was synthesized using the so-called “threading-followed-by-stoppering” approach and characterized by NMR spectroscopy and mass spectrometry. Initially, the BDNP38C10 ring resides on the NpI station on account of the synthetic approach employed in the synthesis of the bistable [2]rotaxane. 1H NMR spectroscopy was used to follow the equilibration process between the two translational isomers of the bistable [2]rotaxane—namely, NpI ⊂ BDNP38C10 and BIPY2+ ⊂ BDNP38C10. After 72 h, equilibrium was reached with a 3 : 2 ratio of the two translational isomers in favor of the NpI ⊂ BDNP38C10 co-conformation in CD3CN. The rate of relaxation of the crown ether from NpI ⊂ BDNP38C10 back to BIPY2+ ⊂ BDNP38C10 was associated with a rate constant of 2.2 ± 0.3 × 10−5 s−1 (t1/2 = 3.4 h), corresponding to a free energy of activation of 23.8 ± 0.1 kcal mol−1. Cyclic voltammetry (CV) reveals that the BDNP38C10 ring can be enticed to pass over the speed bump onto the neutral BIPY0 unit upon the generation of the NpI2− dianion, even although the neutral BIPY0 has presumably little or no affinity for the BDNP38C10 ring.

Two donor−acceptor [3]catenanescomposed of a tetracationic molecular square, cyclobis(paraquat-4,4′-biphenylene), as the π-electron deficient ring and either two tetrathiafulvalene (TTF) and 1,5-dioxynaphthalene (DNP) containing macrocycles or two TTF-butadiyne-containing macrocycles as the π-electron rich componentshave been investigated in order to study their ability to form TTF radical dimers. It has been proven that the mechanically interlocked nature of the [3]catenanes facilitates the formation of the TTF radical dimers under redox control, allowing an investigation to be performed on these intermolecular interactions in a so-called “molecular flask” under ambient conditions in considerable detail. In addition, it has also been shown that the stability of the TTF radical-cation dimers can be tuned by varying the secondary binding motifs in the [3]catenanes. By replacing the DNP station with a butadiyne group, the distribution of the TTF radical-cation dimer can be changed from 60% to 100%. These findings have been established by several techniques including cyclic voltammetry, spectroelectrochemistry and UV−vis−NIR and EPR spectroscopies, as well as with X-ray diffraction analysis which has provided a range of solid-state crystal structures. The experimental data are also supported by high-level DFT calculations. The results contribute significantly to our fundamental understanding of the interactions within the TTF radical dimers.

The tendency for viologen radical cations to dimerize has been harnessed to establish a recognition motif based on their ability to form extremely strong inclusion complexes with cyclobis(paraquat-p-phenylene) in its diradical dicationic redox state. This previously unreported complex involving three bipyridinium cation radicals increases the versatility of host–guest chemistry, extending its practice beyond the traditional reliance on neutral and charged guests and hosts. In particular, transporting the concept of radical dimerization into the field of mechanically interlocked molecules introduces a higher level of control within molecular switches and machines. Herein, we report that bistable and tristable [2]rotaxanes can be switched by altering electrochemical potentials. In a tristable [2]rotaxane composed of a cyclobis(paraquat-p-phenylene) ring and a dumbbell with tetrathiafulvalene, dioxynaphthalene and bipyridinium recognition sites, the position of the ring can be switched. On oxidation, it moves from the tetrathiafulvalene to the dioxynaphthalene, and on reduction, to the bipyridinium radical cation, provided the ring is also reduced simultaneously to the diradical dication.

The reduction of a redox-active ligand is shown to drive reversible switching of a Cu(I) [2]pseudorotaxane ([2]PR+) into the reduced [3]pseudorotaxane ([3]PR+) by a bimolecular mechanism. The unreduced pseudorotaxanes [2]PR+ and [3]PR2+ are initially self-assembled from the binucleating ligand, 3,6-bis(5-methyl-2-pyridine)-1,2,4,5-tetrazine (Me2BPTZ), and a preformed copper-macrocycle moiety (Cu-M+) based on 1,10-phenanthroline. X-ray crystallography revealed a syn geometry of the [3]PR2+. The UV−vis−NIR spectra show low-energy metal-to-ligand charge-transfer transitions that red shift from 808 nm for [2]PR+ to 1088 nm for [3]PR2+. Quantitative analysis of the UV−vis−NIR titration shows the stepwise formation constants to be K1 = 8.9 × 108 M−1 and K2 = 3.1 × 106 M−1, indicative of negative cooperativity. The cyclic voltammetry (CV) and coulometry of Me2BPTZ, [2]PR+, and [3]PR2+ shows the one-electron reductions at E1/2 = −0.96, −0.65, and −0.285 V, respectively, to be stabilized in a stepwise manner by each Cu+ ion. CVs of [2]PR+ show changes with scan rate consistent with an EC mechanism of supramolecular disproportionation after reduction: [2]PR0 + [2]PR+ = [3]PR+ + Me2BPTZ0 (KD*, kd). UV−vis−NIR spectroelectrochemistry was used to confirm the 1:1 product stoichiometry for [3]PR+:Me2BPTZ. The driving force (ΔGD* = −5.1 kcal mol−1) for the reaction is based on the enhanced stability of the reduced [3]PR+ over reduced [2]PR0 by 365 mV (8.4 kcal mol−1). Digital simulations of the CVs are consistent with a bimolecular pathway (kd = 12 000 s−1 M−1). Confirmation of the mechanism provides a basis to extend this new switching modality to molecular machines.