The structural anisotropy necessary to distinguish clockwise from counterclockwise motions in motor-molecules continuously rotating about a covalent single bond has previously been supplied by chiral fuelling systems or by enzymes. Here we report a class of rotary motors in which, like motor proteins, structural asymmetry in the motor itself causes directional rotary catalysis. A single stereogenic centre in azaindole–phenylethanoic acid motors is sufficient to produce diastereomeric intermediates of atropisomeric conformations in the catalytic cycle, generating 8:1 clockwise:counterclockwise directional bias in the motor’s rotary catalysis of diisopropylcarbodiimide hydration (motor substituent PhCH2–). One enantiomer of a chiral hydrolysis promoter increases the directionality to 30:1 for clockwise rotation (motor substituent CH3–), while the other enantiomer reverses the direction to 1:2 clockwise:counterclockwise. The experimental demonstration that a chiral molecular motor can be powered by a chemical fuel to rotate either with, or counter to, the motor’s dominant power stroke informs the understanding of how chemical energy is transduced through catalysis, the fundamental process that powers biology. The structural anisotropy necessary for the powered directional rotation of chemically fuelled molecular motors had previously been provided by chiral fuels or enzymes. Now it has been shown that asymmetry in the organocatalyst itself is sufficient for directional fuelled rotation. This informs how chemical energy is transduced through catalysis, the fundamental process that powers biology.

Rotaxane synthesis generally requires the macrocycle to contain recognition sites for the threaded axle or its building blocks. Here we show that flexible oligo(ethylene glycol) axles can instead promote the formation of macrocycles around themselves, enabling an inverted, metal-free active-template route to rotaxanes from simple building blocks. The axle accelerates amide-bond-forming macrocyclization through hydrogen bonding, giving [2]rotaxanes in up to 70% yield. Longer axles enable the iterative assembly of higher-order [n]rotaxanes, with up to four macrocycles threaded onto an octa(ethylene glycol) chain. The X-ray crystal structure of such a [5]rotaxane reveals a crowded helical stack of rings stabilized by aromatic stacking and hydrogen bonding, explaining the enhanced efficacy of the later macrocyclizations. Subsequent deletion of the newly formed amides gives structurally minimalist rotaxanes comprising an oligo(ethylene glycol) axle threaded through a cyclohydrocarbon. Removing the requirement for particular functional groups and structural motifs in rotaxane macrocycles increases the accessible structures of mechanically interlocked molecules.

Mechanical interlocking can profoundly alter coordination environments, yet its influence on metal-ligand self-assembly remains underexplored. Here we report on the coordination chemistry of a Star of David [2]catenane comprising two triply interlocked macrocycles, each containing 9 bipyridine units, and show that preorganization within this topologically constrained ligand fundamentally reshapes metalation pathways. Direct metalation with Fe(II), Co(II), Ni(II), or Cu(II) leads to kinetically trapped, ill-defined products, whereas Zn(II) rapidly and reversibly reforms a well-ordered hexanuclear catenate. Exploiting the lability of Zn(II)-bipyridine coordination, we demonstrate a stepwise transmetalation strategy that enables clean, quantitative access to the Fe(II), and otherwise inaccessible Co(II), Ni(II), and Cu(II), Star of David [2]catenates. Time-resolved mass spectrometry reveals discrete heterometallic intermediates, supporting a mechanism that minimizes large-scale mis-coordination and ligand reorganization during stepwise metal exchange. Single-crystal X-ray structures of the Co(II) and Cu(II) analogues confirm retention of the Star of David topology and reveal persistent incarceration of a counterion within the central cavity, even following other anion exchange and/or transmetalation. Partial crystallographic data for the Ni(II) system and spectroscopic consistency of the Fe(II) and Zn(II) analogues support structural conservation across the series. Oxidation of the Co(II)6-Star of David catenate smoothly affords the Co(III)6-analogue. Isothermal titration calorimetry shows that the Star of David catenates bind iodide within the central cavity with metal-dependent affinities reflecting both the coordination geometry and the residual anion occupancy. Together, these results establish stepwise transmetalation as a strategy for overcoming kinetic barriers in topologically complex coordination assemblies and highlight mechanical bonding as a design element for controlling metal ion reactivity and guest recognition.

We report an efficient lanthanide-template synthesis of a conformationally switchable molecular trefoil knot assembled from three 2,6-bis(1,2,3-triazol-4-yl)pyridine (btp) ligand strands. Coordination of Lu3+ organizes three btp building blocks into a trimeric circular helicate that, upon subsequent ring-closing olefin metathesis, gives a trefoil knotted coordination complex in 73% yield over two steps. Subsequent demetalation with tetraethylammonium fluoride quantitatively affords the corresponding metal-free 87-atom-loop trefoil knot. The metal-coordinated and metal-free knots were characterized by NMR spectroscopy, high-resolution mass spectrometry, and single-crystal X-ray diffraction. The metalated and metal-free knots adopt substantially different conformations to each other, in both solution and the solid state. In the Lu3+-bound knot the btp units are directed inward to coordinate the metal center, with the strand conformation further stabilized by pyridine-naphthalene π-stacking. In the metal-free knot the btp motifs are rotated outward, with the conformation stabilized by triazole C-H···O hydrogen bonding and naphthalene-naphthalene π-stacking. Reversible metalation and demetalation cleanly interconverts the two knot conformations, establishing btp building blocks as a simple and versatile platform for responsive entangled or woven molecular topologies.

Adaptive sensing underpins many biological processes. We present a strategy for artificial sensors that exploits the heightened responsiveness possible with out-of-equilibrium systems. We incorporate a Zn(II) allosteric binding site into a chemically fueled rotaxane information ratchet that catalyzes diisopropylcarbodiimide (DIC) hydration. Zn(II) coordination shifts the macrocycle distribution on the rotaxane axle, and this redistribution changes the catalytic rate of fuel-to-waste conversion. This couples Zn(II) binding to the nonequilibrium steady-state (NESS) macrocycle distribution produced by catalysis. As a result, the rate of catalysis can be used to measure the concentration of Zn(II) over a range that is inaccessible to titration experiments carried out at equilibrium. The strategy may prove useful for developing broad-range sensors that function through chemically fueled adaptive sensing.

David Leigh earned a PhD in crown ether chemistry from the University of Sheffield in 1987 and has held professorial positions at the Universities of Warwick, Edinburgh, Manchester, and East China Normal University. Landmark examples from his laboratory include the introduction of synthetic molecular ratchets and the first catalysis-driven small-molecule motors. The latter were recently used to demonstrate the transduction of chemical energy through motor catalysis, the fundamental process underpinning biology.

We report the in situ quantification of directional rotation of a new type of catalysis-driven rotary motor featuring a phenyl carboxylic acid rotor attached to a 7-azaindole-N-oxide stator through a biaryl C-N bond. Continuous directional rotation of the rotor about the stator is driven by the achiral motor's rotary catalysis of carbodiimide hydration in the presence of a chiral pyrrolidinylpyridine-N-oxide. The catalytic cycle features an intermediate O-acyl-azaindole-N-oxide ester tether formed between the carboxylic acid of the rotor and the N-oxide of the stator. Face-selective cleavage of the tether by the chiral pyrrolidinylpyridine-N-oxide additive generates relatively long-lived diastereomeric pyridine-N-oxide esters of the phenyl carboxylic acid. These are hydrolyzed during the catalytic cycle to reform the carboxylic acid resting state of the motor, completing net directional 360° rotation. In contrast to previous catalysis-driven motor-molecules, the motor's directionality could be determined directly from the transient concentrations of the diastereomeric intermediates formed during rotary catalysis. This avoids reliance on restricted rotation models to assess motor directionality and provides direct access to other key performance indicators such as motor speed and catalytic, coupling and fuel efficiency. The in situ-determined directionality of the motor was found to be in excellent agreement with the directionality determined from a restricted rotation model, supporting both the efficacy of the new approach and the validity of using appropriately designed restricted rotation models. The results establish a straightforward method for the in situ quantification of various aspects of motor behavior, aiding the design and optimization of artificial molecular motors.

We report a strategy for catenane synthesis that does not require persistent strong binding interactions on the components nor the addition of templates. The kinetically controlled process features the condensation of a diamine and a p ‐nitrophenol diester accelerated through the cavity of a crown ether. Amidation first generates a linear monoamide bearing an amine at one terminus of the chain and a p ‐nitrophenol ester at the other. This intermediate undergoes macrocyclization via a second amidation reaction through the crown ether cavity, resulting in interlocked macrocycles. Carrying out a similar macrocyclization reaction via ring‐closing alkene metathesis (which is not accelerated through the crown ether cavity) affords macrocycle but no catenane, demonstrating that the metal‐free active template synthesis enables the synthesis of catenanes despite the absence of strong intercomponent binding. A series of catenanes were synthesized in yields of up to 77%. X‐Ray crystallography shows networks of weak intercomponent amide–ether hydrogen bonds in the catenanes, a rarely observed interaction adopted as a result of mechanical interlocking trapping the functional groups in close proximity.

Cells display a range of mechanical activities enabled by the cytoskeleton, a viscoelastic hydrogel manipulated by motor proteins powered through catalysis. This raises the question of how the acceleration of a chemical reaction can enable the energy released from that reaction to be transduced, and thereby work to be done, by a molecular catalyst. Here we demonstrate the molecular-level transduction of chemical energy to mechanical force in the form of the powered contraction and powered re-expansion of a crosslinked polymer gel driven by the directional rotation of embedded artificial catalysis-driven molecular motors. Continuous 360° rotation of the rotor about the stator of motor-molecules incorporated within the polymeric framework of the gel, twists the polymer chains of the crosslinked network around one another (either clockwise or anti-clockwise, depending on the chirality of the fuelling system). This progressively increases writhe and tightens entanglements, causing macroscopic contraction of the gel to ~70% of its original volume. The limit of contraction corresponds to the stall force of the motor; the point at which, despite catalysis continuing, the untwisting force exerted by the entwined strands balances conformation selection in the motor’s catalytic cycle. Subsequent addition of the opposite enantiomeric fuelling system powers rotation of the motor-molecules of the contracted gel in the reverse direction, unwinding the entanglements and causing the gel to re-expand. Continued powered twisting of the strands in the new direction causes the gel to contract once again. The experimental demonstration of work against a load by a synthetic catalyst, and the mechanism of the transduction of energy by a catalyst through kinetic asymmetry in its acceleration of a fuel-to-waste reaction, informs both the debate surrounding the mechanism of force generation by biological motors and the design principles for artificial molecular nanotechnology.

A daisy chain architecture without a preferred low energy arrangement of the mechanically linked components is presented. The molecular design combines a rigid-rod type oligophenylene ethynylene subunit with an oligoethylene glycol macrocycle that features a bipyridine coordination site. The daisy chain dimer was synthesized via kinetic trapping of the interlocked structure using a Cadiot-Chodkiewicz active metal template reaction. Comparison of the isolated interlocked dimer with its monomeric analogue indicates the presence of a variety of different geometries for the molecular daisy chain. The dynamic sliding motion in the daisy chain is studied by variable temperature UV-vis and nuclear magnetic resonance (NMR) spectroscopy experiments, which point to a highly mobile system even at low temperatures.

Chemically fueled molecular motors are key to life’s most fundamental processes. In recent years, theoretical and experimental insights garnered from chemistry, biology, and physics have led to an understanding of the molecular basis of catalysis-driven motor mechanisms. Unlike their biological counterparts, for which evolutionary baggage and complexity often preclude a complete untangling of the reasons behind particular aspects of their mechanisms, artificial small-molecule motors operate with mechanisms that are entirely knowable. Here, we outline how key performance indicators, such as speed, stalling force, and fuel efficiency, are related to distinct structural and mechanistic features, contextualizing the analysis with both biological and small-molecule examples. These provide rational design principles for functional chemically fueled molecular machinery and benchmarking comparisons with biomolecular machinery. We have made available as a Jupyter notebook an interactive visualization tool that highlights how the key performance indicators change and depend upon the underlying kinetics of chemical fueling: https://github.com/JoaquinBaixerasBuye/Performance-Characteristics-of-Motors.

Continuous directionally biased 360 degrees rotation about a covalent single bond was recently realized in the form of a chemically fueled 1-phenylpyrrole 2,2 '-dicarboxylic acid rotary molecular motor. However, the original fueling system and reaction conditions resulted in a motor directionality of only similar to 3:1 (i.e., on average a backward rotation for every three forward rotations), along with a catalytic efficiency for the motor operation of 97% and a fuel efficiency of 14%. Here, we report on the efficacy of a series of chiral carbodiimide fuels and chiral hydrolysis promoters (pyridine and pyridine N-oxide derivatives) in driving improved directional rotation of this motor-molecule. We outline the complete reaction network for motor operation, composed of directional, futile, and slip cycles. Using derivatives of the motor where the final conformational step in the 360 degrees rotation is either very slow or completely blocked, the phenylpyrrole diacid becomes enantiomerically enriched, allowing the kinetic gating of the individual steps in the catalytic cycle to be measured. The chiral carbodiimide fuel that produces the highest directionality gives 13% enantiomeric excess (e.e.) for the anhydride-forming kinetically gated step, while the most effective chiral hydrolysis promoter generates 90% e.e. for the kinetically gated hydrolysis step. Combining the best-performing fuel and hydrolysis promoter into a single fueling system results in a 92% e.e.. Under a dilute chemostated fueling regime (to avoid N-acyl urea formation at high carbodiimide concentrations with pyridine N-oxide hydrolysis promoters), the motor continuously rotates with a directionality of similar to 24:1 (i.e., a backward rotation for every 24 forward rotations) with a catalytic efficiency of >99% and a fuel efficiency of 51%.

We report the deletion of nitrogen atoms from multiple template sites in rotaxanes, catenanes, and a molecular knot. Nitrogen extrusion from secondary amines in the backbone of the interlocked structures is achieved using O-diphenylphosphinylhydroxylamine (DPPH), forming carbon-carbon bonds while largely maintaining the integrity of the original mechanical bonding. We find that DPPH gives improved yields (up to 51%) for nitrogen atom deletions from template sites in rotaxanes compared to an anomeric amide nitrogen-deletion reagent and overcomes a major substrate limitation in that, using DPPH, only one of the substituents of the secondary amine in the rotaxane axle needs to be radical-stabilizing. Multiple template site nitrogen atom deletions were accomplished from a range of mechanically interlocked architectures, despite the potential for dethreading, unlinking, and/or strand uncrossing during each successive deletion event. Highlights include the deletion of two template sites from a doubly threaded [3]rotaxane (37% yield) and [3]catenane (45%), quadruple N-deletion of amines from both rings of a [2]catenane (33%), and six N-deletions from the six amine groups in a molecular trefoil knot (7%). The combination of skeletal editing with template synthesis provides a general strategy for synthesis that significantly increases the structural diversity of interlocked molecules that are potentially accessible.

We report on the metal‐free active template synthesis of crown ether–peptide rotaxanes. A 24‐crown‐8 ring is sufficiently small that the side chains of canonical branched amino acids act as barriers that trap the macrocycle on the particular glycine residue used to assemble the rotaxane. The resulting crown ether–tripeptide rotaxane can subsequently be extended from either or both N‐ and C‐termini of the axle. Three distinct positional isomers of a heptapeptide [2]rotaxane containing three glycine units were selectively synthesized, and in each case the unique position of the crown ether on the peptide axle was confirmed by 1 H nuclear magnetic resonance spectroscopy and tandem mass spectrometry. The three positional isomers adopt different conformations in the region adjacent to the trapped macrocycle, and have different chemical stabilities and secondary interactions in comparison to the unthreaded peptide axle. The crown ether does not inhibit enzymatic proteolysis over the entire length of the heptapeptide–axle rotaxanes, but rather provides significant protection from degradation for the three to four residues local to the encapsulated region. The strategy opens a pathway to new analogs of naturally occurring mechanically interlocked peptides.

An early love of construction toys led the Scottish chemist to thread molecules together, opening up a new field of chemistry. An early love of construction toys led the Scottish chemist to thread molecules together, opening up a new field of chemistry.

We report on a head-to-tail dual molecular motor consisting of two (identical) motor units whose pyrrole-2-carboxylic rings are turned in contra-rotary (i.e., disrotatory) fashion about a common phenyl-2,5-dicarboxylic acid stator. The motors directionally rotate via information ratchet mechanisms, in which the hydration of a carbodiimide (fuel) to form urea (waste) is catalyzed through the chemomechanical cycle of a motor unit, resulting in directional rotation about a biaryl C-N bond. The head-to-tail arrangement of the motor units produces coaxial contra-rotation of the end groups while the central phenyl ring of the axis remains dynamically unbiased. The electron-rich nature of the phenyl stator contributes to rotary catalysis by the dual-motor (and therefore motor rotation itself) being ∼7× faster than the parent 1-phenylpyrrole-2,2-dicarboxylic acid single-motor when operated under identical conditions, and 90× faster than the single-motor operated using the originally reported reaction conditions. Under batch-fueled operation (i.e., all of the fuel present at the start of motor operation), the dual-motor rotates at an initial rate of 0.43 rotations per minute (rpm). Chemostating the fuel concentration by syringe pump addition produced sustained repetitive contra-rotation at a rate of 0.24 rpm for a period of 100 min. The demonstration of chemically fueled continuous contra-rotation on a time scale of 2-4 min per rotation significantly advances the chemistry and mechanics of artificial catalysis-driven molecular machinery.

The active template synthesis of mechanically interlocked molecular architectures exploits the dual ability of various structural elements (metals or, in the case of metal-free active template synthesis, particular arrangements of functional groups) to serve as both a template for the organisation of building blocks and as a catalyst to facilitate the formation of covalent bonds between them. This enables the entwined or threaded intermediate structure to be covalently captured under kinetic control. Unlike classical passive template synthesis, the intercomponent interactions transiently used to promote the assembly typically do not 'live on' in the interlocked product, meaning that active template synthesis can be traceless and used for constructing mechanically interlocked molecules that do not feature strong binding interactions between the components. Since its introduction in 2006, active template synthesis has been used to prepare a variety of rotaxanes, catenanes and knots. Amongst the metal-ion-mediated versions of the strategy, the copper(I)-catalysed alkyne-azide cycloaddition (CuAAC) remains the most extensively used transformation, although a broad range of other catalytic reactions and transition metals also provide effective manifolds. In metal-free active template synthesis, the recent discovery of the acceleration of the reaction of primary amines with electrophiles through the cavity of crown ethers has proved effective for forming an array of rotaxanes without recognition elements, including compact rotaxane superbases, dissipatively assembled rotaxanes and molecular pumps. This Review details the active template concept, outlines its advantages and limitations for the synthesis of interlocked molecules, and charts the diverse set of reactions that have been used with this strategy to date. The application of active template synthesis in various domains is discussed, including molecular machinery, mechanical chirality, catalysis, molecular recognition and various aspects of materials science.

Conformational dynamics are increasingly recognized as an important contributor to enzyme catalysis but are often overlooked in synthetic catalyst design. Here, we experimentally demonstrate faster catalysis by conformational selection caused by stochastic interconversion of two conformations of a catenane-based organocatalyst. The dependencies of the reaction rates on the relative positioning of the catalyst components during different stages of the catalytic cycle enable the dynamic organocatalyst to achieve order -ofmagnitude rate accelerations over static or predominantly singleconformer analogs. The dynamic rate acceleration results in the emergent property of the organocatalyst acting as a directionally rotating motor. In demonstrating that conformational dynamics can overcome linear scaling relationships, these findings have implications for theories of enzyme catalysis and artificial catalyst design. The link between faster catalysis and directionally biased conformational dynamics may suggest that "motor molecules"could have first arisen in primitive form due to prebiotic evolutionary pressure to achieve faster catalysis.

Removing the nitrogen atom from secondary amines while simultaneously linking the remaining fragments is a powerful form of late-stage skeletal editing. Here, we report its use for the deletion of the nitrogen atom of the dibenzylammonium template used to assemble crown ether rotaxanes. The reaction uses an anomeric amide that activates secondary amines to generate a carbon-carbon bond that replaces the amine nitrogen. Despite the potential for dethreading of the intermediate diradical pair, the nitrogen atom was successfully deleted from a series of rotaxane axles as long as the macrocycle could access coconformations that did not inhibit the reaction of the amine group. The skeletally edited interlocked molecules were obtained directly from the parent crown ether-dibenzylammonium rotaxanes in modest yields (23-36%) and characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. One skeletally edited rotaxane shows a network of weak CHO hydrogen bonds between the crown ether and benzylic methylene groups of the axle in the solid state, in place of the crown ether-ammonium binding motif used to assemble the parent, unedited, rotaxane.

We report the synthesis of a right-handed (Δ-stereochemistry of strand crossings) trefoil knot from a single molecular strand containing three pyrazine-2,5-dicarboxamide units adjacent to point-chiral centers and six pyridine moieties. The oligomeric ligand strand folds into an overhand (open-trefoil) knot through the assistance of coordinatively dynamic Co(II) "chaperones" that drive the formation of a three-metal-ion circular helicate. The entangled structure is kinetically locked by oxidation to Co(III) and covalently captured by ring-closing olefin metathesis to generate a trefoil knot of single topological handedness. The stereochemistry of the strand crossings in the metal-coordinated overhand knot is governed by the stereochemistry of the point-chiral carbon centers in the ligand strand. The overhand and trefoil knots were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Removal of the metal ions from the knot, followed by hydrogenation of the alkene, yielded the wholly organic trefoil knot. The metal-free knot and parent ligand were investigated by circular dichroism (CD) spectroscopy. The CD spectra indicate that the topological stereochemistry of the knot has a greater effect on the asymmetry of the chromophore environment than do the point-chiral centers of the strand.