The End of the Beginning of Mechanical Stereochemistry.

ConspectusStereochemistry 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 [2]catenanes and [2]rotaxanes 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.

The Final Stereogenic Unit of [2]Rotaxanes: Type 2 Geometric Isomers.

Mechanical stereochemistry arises when the interlocking of stereochemically trivial covalent subcomponents results in a stereochemically complex object. Although this general concept was identified in 1961, the stereochemical description of these molecules is still under development to the extent that new forms of mechanical stereochemistry are still being identified. Here, we present a simple analysis of rotaxane and catenane stereochemistry that allowed us to identify the final missing simple mechanical stereogenic unit, an overlooked form of rotaxane geometric isomerism, and demonstrate its stereoselective synthesis.

Facial Selectivity in Mechanical Bond Formation: Axially Chiral Enantiomers and Geometric Isomers from a Simple Prochiral Macrocycle.

In 1971, Schill recognized that a prochiral macrocycle encircling an oriented axle led to geometric isomerism in rotaxanes. More recently, we identified an overlooked chiral stereogenic unit in rotaxanes that arises when a prochiral macrocycle encircles a prochiral axle. Here, we show that both stereogenic units can be accessed using equivalent strategies, with a single weak stereodifferentiating interaction sufficient for moderate to excellent stereoselectivity. Using this understanding, we demonstrated the first direct enantioselective (70% ee) synthesis of a mechanically axially chiral rotaxane.

Steric Engineering of Rotaxane Catalysts: Benefits and Limits of Using the Mechanical Bond in Catalyst Design.

The mechanical bond is emerging as a novel design element in catalyst development. Here, we report a series of 1,1'-binaphthyl-2,2'-diol (BINOL) based catalysts in which the number of interlocked macrocycles is varied. Unsurprisingly, the macrocycles have a profound steric influence on the catalytic performance of these molecules. However, in the enantioselective transformations examined, the macrocycles are detrimental to catalyst stereoselectivity whereas in lactide polymerization, they increase the molecular weight of the polymeric product.

A Platform Approach to Cleavable Macrocycles for the Controlled Disassembly of Mechanically Caged Molecules.

Inspired by interlocked oligonucleotides, peptides and knotted proteins, synthetic systems where a macrocycle cages a bioactive species that is "switched on" by breaking the mechanical bond have been reported. However, to date, each example uses a bespoke chemical design. Here we present a platform approach to mechanically caged structures wherein a single macrocycle precursor is diversified at a late stage to include a range of trigger units that control ring opening in response to enzymatic, chemical, or photochemical stimuli. We also demonstrate that our approach is applicable to other classes of macrocycles suitable for rotaxane and catenane formation.

Non-equilibrium Steady States in Catalysis, Molecular Motors, and Supramolecular Materials: Why Networks and Language Matter.

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.

Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

A Co-conformationally "Topologically" Chiral Catenane.

Catenanes composed of two achiral rings that are oriented (Cnh symmetry) because of the sequence of atoms they contain are referred to as topologically chiral. Here, we present the synthesis of a highly enantioenriched catenane containing a related but overlooked "co-conformationally 'topologically' chiral" stereogenic unit, which arises when a bilaterally symmetric Cnv ring is desymmetrized by the position of an oriented macrocycle.

Direct Detection of Hydrogen Bonds in Supramolecular Systems Using 1H-15N Heteronuclear Multiple Quantum Coherence Spectroscopy.

Hydrogen-bonded supramolecular systems are usually characterized in solution through analysis of NMR data such as complexation-induced shifts and nuclear Overhauser effects (nOe). Routine direct detection of hydrogen bonding particularly in multicomponent mixtures, even with the aid of 2D NMR experiments for full assignment, is more challenging. We describe an elementary rapid 1H-15N HMQC NMR experiment which addresses these challenges without the need for complex pulse sequences. Under readily accessible conditions (243/263 K, 50 mM solutions) and natural 15N abundance, unambiguous assignment of 15N resonances facilitates direct detection of intra- and intermolecular hydrogen bonds in mechanically interlocked structures and quadruply hydrogen-bonded dimers─of dialkylaminoureidopyrimidinones, ureidopyrimidinones, and diamidonaphthyridines─in single or multicomponent mixtures to establish tautomeric configuration, conformation, and, to resolve self-sorted speciation.

An autonomous chemically fuelled small-molecule motor.

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.

Anion-π Catalysis Enabled by the Mechanical Bond.

We report a series of rotaxane-based anion-π catalysts in which the mechanical bond between a bipyridine macrocycle and an axle containing an NDI unit is intrinsic to the activity observed, including a [3]rotaxane that catalyses an otherwise disfavoured Michael addition in >60 fold selectivity over a competing decarboxylation pathway that dominates under Brønsted base conditions. The results are rationalized by detailed experimental investigations, electrochemical and computational analysis.

Using the Mechanical Bond to Tune the Performance of a Thermally Activated Delayed Fluorescence Emitter*.

We report the characterization of rotaxanes based on a carbazole-benzophenone thermally activated delayed fluorescence luminophore. We find that the mechanical bond leads to an improvement in key photophysical properties of the emitter, notably an increase in photoluminescence quantum yield and a decrease in the energy difference between singlet and triplet states, as well as fine tuning of the emission wavelength, a feat that is difficult to achieve when using covalently bound substituents. Computational simulations, supported by X-ray crystallography, suggest that this tuning of properties occurs due to weak interactions between the axle and the macrocycle that are enforced by the mechanical bond. This work highlights the benefits of using the mechanical bond to refine existing luminophores, providing a new avenue for emitter optimization that can ultimately increase the performance of these molecules.

Rotaxane CoII Complexes as Field-Induced Single-Ion Magnets.

Mechanically chelating ligands have untapped potential for the engineering of metal ion properties. Here we demonstrate this principle in the context of CoII -based single-ion magnets. Using multi-frequency EPR, susceptibility and magnetization measurements we found that these complexes show some of the highest zero field splittings reported for five-coordinate CoII complexes to date. The predictable coordination behaviour of the interlocked ligands allowed the magnetic properties of their CoII complexes to be evaluated computationally a priori and our combined experimental and theoretical approach enabled us to rationalize the observed trends. The predictable magnetic behaviour of the rotaxane CoII complexes demonstrates that interlocked ligands offer a new strategy to design metal complexes with interesting functionality.

AT-CuAAC Synthesis of Mechanically Interlocked Oligonucleotides.

We present a simple strategy for the synthesis of main chain oligonucleotide rotaxanes with precise control over the position of the macrocycle. The novel DNA-based rotaxanes were analyzed to assess the effect of the mechanical bond on their properties.

Rotaxane-Based Transition Metal Complexes: Effect of the Mechanical Bond on Structure and Electronic Properties.

Early work by Sauvage revealed that mechanical bonding alters the stability and redox properties of their original catenane metal complexes. However, despite the importance of controlling metal ion properties for a range of applications, these effects have received relatively little attention since. Here we present a series of tri-, tetra-, and pentadentate rotaxane-based ligands and a detailed study of their metal binding behavior and, where possible, compare their redox and electronic properties with their noninterlocked counterparts. The rotaxane ligands form complexes with most of the metal ions investigated, and X-ray diffraction revealed that in some cases the mechanical bond enforces unusual coordination numbers and distorted arrangements as a result of the exclusion of exogenous ligands driven by the sterically crowded binding sites. In contrast, only the noninterlocked equivalent of the pentadentate rotaxane CuII complex could be formed selectively, and this exhibited compromised redox stability compared to its interlocked counterpart. Frozen-solution EPR data demonstrate the formation of an interesting biomimetic state for the tetradentate CuII rotaxane, as well as the formation of stable NiI species and the unusual coexistence of high- and low-spin CoII in the pentadentate framework. Our results demonstrate that readily available mechanically chelating rotaxanes give rise to complexes the noninterlocked equivalent of which are inaccessible, and that the mechanical bond augments the redox behavior of the bound metal ion in a manner analogous to the carefully tuned amino acid framework in metalloproteins.

Chemical Consequences of the Mechanical Bond: A Tandem Active Template-Rearrangement Reaction.

We report the unexpected discovery of a tandem active template CuAAC-rearrangement process, in which N2 is extruded on the way to the 1,2,3-triazole product to give instead acrylamide rotaxanes. Mechanistic investigations suggest this process is dictated by the mechanical bond, which stabilizes the CuI -triazolide intermediate of the CuAAC reaction and diverts it down the rearrangement pathway; when no mechanical bond is formed, the CuAAC product is isolated.

Efficient Multicomponent Active Template Synthesis of Catenanes.

We describe a simple and high yielding active template synthesis of [2]catenanes. In addition to mechanical bond formation using a single premacrocycle bearing an azide and alkyne moiety, our method is also suitable for the co-macrocyclization of readily available bis-alkyne and bis-azide comonomers and even short alkyne/azide components which oligomerize prior to mechanical bond formation.

Synthesis and Characterisation of a Paramagnetic [2]Rotaxane Based on a Crown Ether-Like Wheel Incorporating a Nitroxide Motif.

The synthesis of the new nitroxide crown ether 8 and its use as the wheel in a bistable [2]rotaxane, containing dialkylammonium and 4,4'-bipyridinium recognition sites, is reported. The synthesis of 8 was achieved by the sequential addition of substituted phenyl groups to a nitrone derivatives leading to the preferential formation of the cis stereoisomer. Due to charge-dipole interactions between the nitroxide unit and the bipyridinium moiety, it was possible to probe the movement of the macrocycle between the two molecular stations of the [2]rotaxane after addition of a base by measuring the nitrogen hyperfine splitting in the corresponding EPR spectra. The equilibrium constant for the complexation of dibenzyl viologen by the macrocycle 8 was also determined by EPR titration.

Metal ions in the synthesis of interlocked molecules and materials.

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.

Chelating Rotaxane Ligands as Fluorescent Sensors for Metal Ions.

Although metal-ion-binding interlocked molecules have been under intense investigation for over three decades, their application as scaffolds for the development of sensors for metal ions remains underexplored. In this work, we demonstrate the potential of simple rotaxanes as metal-ion-responsive ligand scaffolds through the development of a proof-of-concept selective sensor for Zn2+ .