All chemists are familiar with the idea that, at equilibrium steady state, the relative concentrations of species present in a system are predicted by the corresponding equilibrium constants, which ...are related to the free energy differences between the system components. There is also no net flux between species, no matter how complicated the reaction network. Achieving and harnessing non-equilibrium steady states, by coupling a reaction network to a second spontaneous chemical process, has been the subject of work in several disciplines, including the operation of molecular motors, the assembly of supramolecular materials, and strategies in enantioselective catalysis. We juxtapose these linked fields to highlight their common features and challenges as well as some common misconceptions that may be serving to stymie progress.
Conspectus Stereochemistry has played a key role in the development of synthetic chemistry for the simple reason that the function and properties of most molecules, from medicine to materials ...science, depend on their shape and thus the stereoisomer used. However, despite the potential for rotaxanes and catenanes to display unusual forms of stereochemistry being identified as early as 1961, this aspect of the mechanical bond remained underexplored and underexploited; until 2014 it was only possible to access chiral rotaxanes and catenanes whose stereoisomerism is solely attributable to the mechanical bond using chiral stationary phase high performance liquid chromatography, which limited their production on scale and thus inhibited the investigation of their properties and applications. Furthermore, the stereogenic units of such molecules and analogues were often poorly described, which made it hard to fully articulate both what had been achieved in the field and what problems were left to solve. Relatively recently, methods to access rotaxanes and catenanes that display mechanical stereochemistry selectively have been developed, making these intriguing structures available for study in a range of prototypical applications including catalysis, sensing, and as chiral luminophores. In this Account, we briefly discuss the history of mechanical stereochemistry, beginning in 1961 when the potential for mechanical stereoisomerism was first identified, before defining how mechanical stereochemistry arises from a structural point of view. Building on this, using simple stereochemical arguments, we confirm that the complete set of unique stereogenic units of two-component rotaxanes and catenanes have finally been identified and categorized unambiguously, with the last being identified only in 2024. After pausing to discuss some of the stereochemical curiosities that arise when molecules contain both covalent and mechanical stereogenic units, and the potential for stereoisomerism to arise due to co-conformational movement, we use our stereochemical framework to summarize our efforts to develop conceptually general approaches to 2catenanes and 2rotaxanes containing all of the possible mechanical stereogenic units. In particular, we highlight how the nature of a mechanical stereogenic unit affects the available strategies for their stereoselective synthesis. We finish by highlighting recent prototypical chemical applications of interlocked molecules that rely on their mechanical stereochemistry, before discussing future directions and challenges. Taken together, we propose that the transition of such molecules from being hard to make and poorly described, to being available in high stereopurity using clearly articulated methodological and stereochemical concepts suggests that the field is finally maturing. Thus, we are now coming to the end of the beginning of mechanical stereochemistry. The stage is now set for such molecules to play a functional role in a range of areas, indeed in any chemical or physical application where control over molecular shape is required.
Research on mechanically interlocked molecules has advanced substantially over the last five decades. A large proportion of the published work focusses on the synthesis of these challenging targets, ...and the subsequent control of the relative position of the covalent sub-components, to generate novel molecular devices and machines. In this
Feature Article
we instead review some of the less discussed consequences of mechanical bonding for the chemical behaviour of catenanes and rotaxanes, and their application in synthesis, including striking recent examples of molecular machines which carry out complex synthetic tasks.
We highlight some of the less discussed consequences of mechanical bonding for the chemical behaviour of catenanes and rotaxanes, including striking recent examples where molecular motion controls chemical reactions.
The active template approach to interlocked molecules takes advantage of the ability of metal ions to both organize precursor fragments for mechanical bond formation and to mediate the final covalent ...bond-forming reaction that captures the interlocked structure. Since its inception just a decade ago, this new methodology has expanded rapidly from a single reaction for rotaxane synthesis to a range of metal-mediated bond formations for the synthesis of complex interlocked molecules. In this Review, we introduce the active template concept, its key advantages for the synthesis of interlocked molecules and outline recent advances that have been made using this technology. We will conclude with comments about future directions and challenges.The active template approach to interlocked molecules uses metal ions to both pre-organize reaction components and catalyse the final covalent bond formation that captures the interlocked structure. This Review looks at the history of the method, its application in the synthesis of ever more complex interlocked molecules and future directions.
The use of metal ions to template the synthesis of catenanes by Sauvage and co-workers was a pivotal moment in the development of the field of interlocked molecules. In this Review Article we shall ...examine the different roles metal-ligand interactions play in modern syntheses of interlocked molecules and materials, with a particular focus on seminal contributions and the advantages and disadvantages of employing metal ligand interactions.
We discuss the various roles that metal ions play, and their advantages, in the synthesis of mechanically interlocked materials.
Mechanically interlocked molecules have a long and rich history as ligands thanks to the key role coordination chemistry has played in the development of high yielding passive template syntheses of ...rotaxanes and catenanes. In this Feature Article, we highlight the effect of the mechanical bond on the properties of metal ions bound within the sterically hindered environment of the macrocycle cavity, and discuss the emerging applications of interlocked ligands in catalysis, sensing and supramolecular materials.
We discuss the properties and potential future applications in catalysis, sensing and materials of ligands based on mechanically interlocked molecules.
We describe the first method for production of mechanically planar chiral rotaxanes in excellent enantiopurity without the use of chiral separation techniques and, for the first time, unambiguously ...assign the absolute stereochemistry of the products. This proof-of-concept study, which employs a chiral pool sugar as the source of asymmetry and a high-yielding active template reaction for mechanical bond formation, finally opens the door to detailed investigation of these challenging targets.
Mechanically interlocked molecules are perhaps best known as components of molecular machines, a view further reinforced by the Nobel Prize in 2016 to Stoddart and Sauvage. Despite amazing progress ...since these pioneers of the field reported the first examples of molecular shuttles, genuine applications of interlocked molecular machines remain elusive, and many barriers remain to be overcome before such molecular devices make the transition from impressive prototypes on the laboratory bench to useful products. Here, we discuss simplicity as a design principle that could be applied in the development of the next generation of molecular machines with a view to moving toward real-world applications of these intriguing systems in the longer term.
Rotaxanes are interlocked molecules in which a molecular ring is trapped on a dumbbell-shaped axle because of its inability to escape over the bulky end groups, resulting in a so-called mechanical ...bond. Interlocked molecules have mainly been studied as components of molecular machines, but the crowded, flexible environment created by threading one molecule through another has also been explored in catalysis and sensing. However, so far, the applications of one of the most intriguing properties of interlocked molecules, their ability to display stereogenic units that do not rely on the stereochemistry of their covalent subunits, termed “mechanical chirality,” have yet to be properly explored, and prototypical demonstration of the applications of mechanically chiral rotaxanes remain scarce. Here, we describe a mechanically planar chiral rotaxane-based Au complex that mediates a cyclopropanation reaction with stereoselectivities that are comparable with the best conventional covalent catalyst reported for this reaction.
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•We synthesized a mechanically planar chiral rotaxane for catalytically active gold ions•We demonstrate enantioselective catalysis with a mechanically planar chiral rotaxane•Our results suggest that mechanical stereochemistry has untapped potential in enantioselective catalysis
Molecules that exist in non-identical mirror image forms are referred to as chiral. Chirality can arise because of various molecular features in which atoms are held in fixed orientations that are themselves chiral, and typically such “stereogenic units” are maintained by direct bonds between atoms. Molecular chirality can also arise by threading a dumbbell-shaped molecule through a molecular ring to generate a rotaxane. However, these molecules have not been investigated significantly because until recently they were extremely hard to make in one mirror image form. Here, we report the first example of a catalyst based on such a “mechanically chiral” rotaxane. Catalysis with chiral molecules is extremely important in modern chemistry because it is one of the most efficient ways to make chiral molecules for applications in healthcare and other areas. Our results demonstrate that mechanically chiral molecules are a promising and underexplored platform for generating such catalysts.
We report an enantioselective catalyst based on a “mechanically chiral” rotaxane. Catalysis with chiral molecules is extremely important in modern chemistry because it is one of the most efficient ways to make chiral molecules for applications in many areas. Our results demonstrate, for the first time, that mechanically chiral molecules are a promising and underexplored platform for generating such catalysts. We achieve enantioselectivities for the AuI-catalyzed Ohe-Uemura cyclopropanation of benzoate esters comparable to previously reported covalent catalysts.
Molecular machines are among the most complex of all functional molecules and lie at the heart of nearly every biological process. A number of synthetic small-molecule machines have been developed, ...including molecular muscles, synthesizers, pumps, walkers, transporters and light-driven and electrically driven rotary motors. However, although biological molecular motors are powered by chemical gradients or the hydrolysis of adenosine triphosphate (ATP), so far there are no synthetic small-molecule motors that can operate autonomously using chemical energy (that is, the components move with net directionality as long as a chemical fuel is present). Here we describe a system in which a small molecular ring (macrocycle) is continuously transported directionally around a cyclic molecular track when powered by irreversible reactions of a chemical fuel, 9-fluorenylmethoxycarbonyl chloride. Key to the design is that the rate of reaction of this fuel with reactive sites on the cyclic track is faster when the macrocycle is far from the reactive site than when it is near to it. We find that a bulky pyridine-based catalyst promotes carbonate-forming reactions that ratchet the displacement of the macrocycle away from the reactive sites on the track. Under reaction conditions where both attachment and cleavage of the 9-fluorenylmethoxycarbonyl groups occur through different processes, and the cleavage reaction occurs at a rate independent of macrocycle location, net directional rotation of the molecular motor continues for as long as unreacted fuel remains. We anticipate that autonomous chemically fuelled molecular motors will find application as engines in molecular nanotechnology.
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