Synthesizing interlocked molecules dynamically

As the complexity of mechanically interlocked molecular architectures increases, it is important to understand the underlying principles, such as molecular recognition and self‐assembly processes, that govern the practice of template‐directed synthesis necessary to create these particular compounds. In this review, we explain the importance of dynamic processes in the synthesis of mechanically interlocked compounds. We show how many different dynamic covalent bonds have been used in the synthesis of rotaxanes, catenanes, and other higher‐order mechanically interlocked compounds, with the goal of revealing the state of the art in dynamic covalent chemistry. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 136–154; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20173     

Hypervalent Iodine Based Reversible Covalent Bond in Rotaxane Synthesis

Reversible covalent bonds play a significant role in achieving the high‐yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel approach for the fast and simple preparation of interlocked molecules, combining the dynamic bond character of bis(acyloxy)iodate(I) anions with macrocyclic bambusuril anion receptors. The proof of principle was demonstrated on rotaxane synthesis, with near‐quantitative yields observed in both the classical and “in situ” approach. The rotaxane formation was confirmed in the solid‐state and solution by the X‐ray and NMR studies. Our novel approach could be utilized in the fields of dynamic combinatorial chemistry, supramolecular polymers, or molecular machines, as well inspire further research on molecules that exhibit dynamic behavior, but owing to their high reactivity, have not been considered as constituents of more elaborate supramolecular structures.     

A Shape‐Persistent Quadruply Interlocked Giant Cage Catenane with Two Distinct Pores in the Solid State

Discrete interlocked three‐dimensional structures are synthetic targets that are sometimes difficult to obtain with “classical” synthetic approaches, and dynamic covalent chemistry has been shown to be a useful method to form such interlocked structures as thermodynamically stable products. Although interlocked and defined hollow structures are found in nature, for example, in some viruses, similar structures have rarely been synthesized on a molecular level. Shape‐persistent interlocked organic cage compounds with dimensions in the nanometer regime are now accessible in high yields during crystallization through the formation of 96 covalent bonds. The interlocked molecules form an unprecedented porous material with intrinsic and extrinsic pores both in the micropore and mesopore regime.     

Template-directed synthesis of multiply mechanically interlocked molecules under thermodynamic control

The template-directed construction of crown-ether-like macrocycles around secondary dialkylammonium ions (R2NH2+) has been utilized for the expedient (one-pot) and high-yielding synthesis of a diverse range of mechanically interlocked molecules. The clipping together of appropriately designed dialdehyde and diamine compounds around R2NH2+-containing dumbbell-shaped components proceeds through the formation, under thermodynamic control, of imine bonds. The reversible nature of this particular reaction confers the benefits of "error-checking" and "proof-reading", which one usually associates with supramolecular chemistry and strict self-assembly processes, upon these wholly molecular systems. Furthermore, these dynamic covalent syntheses exploit the efficient templating effects that the R2NH2+ ions exert on the macrocyclization of the matched dialdehyde and diamine fragments, resulting not only in rapid rates of reaction, but also affording near-quantitative conversion of starting materials into the desired interlocked products. Once assembled, these "dynamic" interlocked compounds can be "fixed" upon reduction of the reversible imine bonds (by using BH3.THF) to give kinetically stable species, a procedure that can be performed in the same reaction vessel as the inital thermodynamically controlled assembly. Isolation and purification of the mechanically interlocked products formed by using this protocol is relatively facile, as no column chromatography is required. Herein, we present the synthesis and characterization of 1) a [2]rotaxane, 2) a [3]rotaxane, 3) a branched [4]rotaxane, 4) a bis [2]rotaxane, and 5) a novel cyclic [4]rotaxane, demonstrating, in incrementally more complex systems, the efficacy of this one-pot strategy for the construction of interlocked molecules.     

Cooperative self-assembly: producing synthetic polymers with precise and concise primary structures

The quest to construct mechanically interlocked polymers, which present precise monodisperse primary structures that are produced both consistently and with high efficiencies, has been a daunting goal for synthetic chemists for many years. Our ability to realise this goal has been limited, until recently, by the need to develop synthetic strategies that can direct the formation of the desired covalent bonds in a precise and concise fashion while avoiding the formation of unwanted kinetic by-products. The challenge, however, is a timely and welcome one, as a consequence of, primarily, the potential for mechanically interlocked polymers to act as dynamic (noncovalent) yet robust (covalent) new materials for a wide array of applications. One such strategy which has been employed widely in recent years to address this issue, known as Dynamic Covalent Chemistry (DCC), is a strategy in which reactions operate under equilibrium and so offer elements of "proof-reading" and "error-checking" to the bond forming and breaking processes such that the final product distribution always reflects the thermodynamically most favourable compound. By coupling DCC with template-directed protocols, which utilise multiple weak noncovalent interactions to pre-organise and self-assemble simpler small molecular precursors into their desired geometries prior to covalent bond formation, we are able to produce compounds with highly symmetric, robust and complex topologies that are otherwise simply unobtainable by more traditional methods. Harnessing these strategies in an iterative, step-wise fashion brings us ever so much closer towards perfecting the controlled synthesis of high order main-chain mechanically interlocked polymers. This tutorial review focuses (i) on the development of DCC-namely, the formation of dynamic imine bonds-used in conjunction with template-directed protocols to afford a variety of mechanically interlocked molecules (MIMs) and ultimately (ii) on the synthesis of highly ordered poly[n]rotaxanes with high conversion efficiencies.     

Template-directed synthesis employing reversible imine bond formation

The imine bond--formed by the reversible condensation of an amine and an aldehyde--and its applications as a dynamic covalent bond in the template-directed synthesis of molecular compounds, will be the focus of this tutorial review. Template-directed synthesis--or expressed another way, supramolecular assistance to covalent synthesis--relies on the use of reversible noncovalent bonding interactions between molecular building blocks in order to preorganise them into a certain relative geometry as a prelude to covalent bond formation to afford the thermodynamically preferred product. The use of this so-called dynamic covalent chemistry (DCC) in templated reactions allows for an additional amount of reversibility, further eliminating potential kinetic products by allowing the covalent bonds that are formed during the template-directed reaction to be 'proofread for errors', thus making it possible for the reaction to search out its thermodynamic minimum. The marriage of template-directed synthesis with DCC has allowed chemists to construct an increasingly complex collection of compounds from relatively simple precursors. This new paradigm in organic synthesis requires that each individual piece in the molecular self-assembly process is preprogrammed so that the multiple recognition events expressed between the pieces are optimised in a highly cooperative manner in the desired product. It offers an extremely simple way of making complex mechanically interlocked compounds--e.g., catenanes, rotaxanes, suitanes, Borromean rings and Solomon knots--from relatively simple precursors.     

Template-directed dynamic synthesis of mechanically interlocked dendrimers

The versatility and efficiency of dynamic covalent chemistry (DCC) has been exploited in the convergent synthesis of mechanically interlocked dendrimers that are based upon the mutual recognition expressed between secondary dialkylammonium ions and crown ether-like macrocycles. Reversible imine bond formation is employed to clip two acyclic fragments, one of them a diformylpyridine unit bearing a dendritic side chain, and the other a complementary dianiline in the shape of the di(o-aminophenyl)ether of tetraethylene glycol, around each arm of a tritopic trisammonium ion core, thereby affording a branched [4]rotaxane. This template-directed strategy has been demonstrated to work in very high yields (>90%) with successive generations (G0-G2) of a modified Fréchet-type dendritic wedge attached to the 4-position of the diformylpyridine unit. Reduction of these dynamic dendritic systems is achieved upon treatment with borane.THF and results in kinetically stable compounds. The inherent modularity of the overall process should allow for the rapid and straightforward access to many other analogous mechanically interlocked systems in which either the branched core or the dendritic periphery can be modified to suit the needs of any given application of these molecules. Indeed, the dynamic nature of the initial thermodynamically mediated assembly could be utilized in order to amplify particular products from a potential library as a result of a selective recognition process.     

Dynamic covalent polymers

This Highlight presents an overview of the rapidly growing field of dynamic covalent polymers. This class of polymers combines intrinsic reversibility with the robustness of covalent bonds, thus enabling formation of mechanically stable, polymer‐based materials that are responsive to external stimuli. It will be discussed how the inherent dynamic nature of the dynamic covalent bonds on the molecular level can be translated to the macroscopic level of the polymer, giving access to a range of applications, such as stimuli‐responsive or self‐healing materials. A primary distinction will be made based on the type of dynamic covalent bond employed, while a secondary distinction will be based on the consideration whether the dynamic covalent bond is used in the main chain of the polymer or whether it is used to allow side chain modification of the polymer. Emphasis will be on the chemistry of the dynamic covalent bonds present in the polymer, in particular in relation to how the specific (dynamic) features of the bond impart functionality to the polymer material, and to the conditions under which this dynamic behavior is manifested. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3551–3577.     

Dynamic covalent chemistry

Dynamic covalent chemistry relates to chemical reactions carried out reversibly under conditions of equilibrium control. The reversible nature of the reactions introduces the prospects of "error checking" and "proof-reading" into synthetic processes where dynamic covalent chemistry operates. Since the formation of products occurs under thermodynamic control, product distributions depend only on the relative stabilities of the final products. In kinetically controlled reactions, however, it is the free energy differences between the transition states leading to the products that determines their relative proportions. Supramolecular chemistry has had a huge impact on synthesis at two levels: one is noncovalent synthesis, or strict self-assembly, and the other is supramolecular assistance to molecular synthesis, also referred to as self-assembly followed by covalent modification. Noncovalent synthesis has given us access to finite supermolecules and infinite supramolecular arrays. Supramolecular assistance to covalent synthesis has been exploited in the construction of more-complex systems, such as interlocked molecular compounds (for example, catenanes and rotaxanes) as well as container molecules (molecular capsules). The appealing prospect of also synthesizing these types of compounds with complex molecular architectures using reversible covalent bond forming chemistry has led to the development of dynamic covalent chemistry. Historically, dynamic covalent chemistry has played a central role in the development of conformational analysis by opening up the possibility to be able to equilibrate configurational isomers, sometimes with base (for example, esters) and sometimes with acid (for example, acetals). These stereochemical "balancing acts" revealed another major advantage that dynamic covalent chemistry offers the chemist, which is not so easily accessible in the kinetically controlled regime: the ability to re-adjust the product distribution of a reaction, even once the initial products have been formed, by changing the reaction's environment (for example, concentration, temperature, presence or absence of a template). This highly transparent, yet tremendously subtle, characteristic of dynamic covalent chemistry has led to key discoveries in polymer chemistry. In this review, some recent examples where dynamic covalent chemistry has been demonstrated are shown to emphasise the basic concepts of this area of science.     

Dynamic Covalent Synthesis of Donor–Acceptor Interlocked Architectures in Solution and at the Solution:Surface Interface

Despite advances in the range of mechanically interlocked architectures that can be synthesized and operated as supramolecular machines, motors and sensors in solution, in many cases their synthesis is laborious and expensive requiring long multistep pathways with extensive purification at each stage. Dynamic covalent chemistry has been shown to overcome problems with traditional kinetically controlled synthetic approaches that often afford low yields of interlocked architectures due to irreversible formation of non‐interlocked by‐products. Herein, we describe the use of reversible disulfide exchange reactions as a means to assemble catenanes and rotaxanes in organic solutions. Moreover, the application of this thermodynamic approach to assemble interlocked architectures at the solution:surface interface, specifically polymer resins, is discussed.     

Dynamic imine chemistry

Formation of an imine--from an amine and an aldehyde--is a reversible reaction which operates under thermodynamic control such that the formation of kinetically competitive intermediates are, in the fullness of time, replaced by the thermodynamically most stable product(s). For this fundamental reason, the imine bond has emerged as an extraordinarily diverse and useful one in the hands of synthetic chemists. Imine bond formation is one of a handful of reactions which define a discipline known as dynamic covalent chemistry (DCC), which is now employed widely in the construction of exotic molecules and extended structures on account of the inherent 'proof-reading' and 'error-checking' associated with these reversible reactions. While both supramolecular chemistry and DCC operate under the regime of reversibility, DCC has the added advantage of constructing robust molecules on account of the formation of covalent bonds rather than fragile supermolecules resulting from noncovalent bonding interactions. On the other hand, these products tend to require more time to form--sometimes days or even months--but their formation can often be catalysed. In this manner, highly symmetrical molecules and extended structures can be prepared from relatively simple precursors. When DCC is utilised in conjunction with template-directed protocols--which rely on the use of noncovalent bonding interactions between molecular building blocks in order to preorganise them into certain relative geometries as a prelude to the formation of covalent bonds under equilibrium control--an additional level of control of structure and topology arises which offers a disarmingly simple way of constructing mechanically-interlocked molecules, such as rotaxanes, catenanes, Borromean rings, and Solomon knots. This tutorial review focuses on the use of dynamic imine bonds in the construction of compounds and products formed with and without the aid of additional templates. While synthesis under thermodynamic control is giving the field of chemical topology a new lease of life, it is also providing access to an endless array of new materials that are, in many circumstances, simply not accessible using more traditional synthetic methodologies where kinetic control rules the roost. One of the most endearing qualities of chemistry is its ability to reinvent itself in order to create its own object, as Berthelot first pointed out a century and a half ago.     

Syntheses and dynamics of donor-acceptor [2]catenanes in water

A subset of mechanically interlocked molecules, namely, donor-acceptor [2]catenanes, have been produced in aqueous solutions in good yields from readily available precursors. The catenations are templated by strong hydrophobic and [π···π] stacking interactions, which serve to assemble the corresponding supramolecular precursors, prior to postassembly covalent modification. Dynamic (1)H NMR spectroscopic investigations performed on one of these [2]catenanes reveal that the pirouetting motion of the butadiyne-triethylene glycol chain occurs with a dramatically lower activation enthalpy, yet with a much higher negative activation entropy in water, compared to organic solvents. The preparations of mechanically interlocked molecules in water constitute the basis for the future development of complex functional molecular machinery in aqueous environments.     

Strategies and tactics for the metal-directed synthesis of rotaxanes, knots, catenanes, and higher order links

More than a quarter of a century after the first metal template synthesis of a [2]catenane in Strasbourg, there now exists a plethora of strategies available for the construction of mechanically bonded and entwined molecular level structures. Catenanes, rotaxanes, knots and Borromean rings have all been successfully accessed by methods in which metal ions play a pivotal role. Originally metal ions were used solely for their coordination chemistry; acting either to gather and position the building blocks such that subsequent reactions generated the interlocked products or by being an integral part of the rings or "stoppers" of the interlocked assembly. Recently the role of the metal has evolved to encompass catalysis: the metal ions not only organize the building blocks in an entwined or threaded arrangement but also actively promote the reaction that covalently captures the interlocked structure. This Review outlines the diverse strategies that currently exist for forming mechanically bonded molecular structures with metal ions and details the tactics that the chemist can utilize for creating cross-over points, maximizing the yield of interlocked over non-interlocked products, and the reactions-of-choice for the covalent capture of threaded and entwined intermediates.     

Dynamic Diselenide Bonds: Exchange Reaction Induced by Visible Light without Catalysis

Dynamic covalent bonds are extensively employed in dynamic combinatorial chemistry. The metathesis reaction of disulfide bonds is widely used, but requires catalysis or irradiation with ultraviolet (UV) light. It was found that diselenide bonds are dynamic covalent bonds and undergo dynamic exchange reactions under mild conditions for diselenide metathesis. This reaction is induced by irradiation with visible light and stops in the dark. The exchange is assumed to proceed through a radical mechanism, and experiments with 2,2,6,6‐tetramethylpiperidin‐1‐yloxyl (TEMPO) support this assumption. Furthermore, the reaction can be conducted in different solvents, including protic solvents. Diselenide metathesis can also be used to synthesize diselenide‐containing asymmetric block copolymers. This work thus entails the use of diselenide bonds as dynamic covalent bonds, the development of a dynamic exchange reaction under mild conditions, and an extension of selenium‐related dynamic chemistry.     

Dynamic covalent gels assembled from small molecules: from discrete gelators to dynamic covalent polymers

Dynamic covalent chemistry has emerged recently to be a powerful tool to construct functional materials. This article reviews the progress in the research and development of dynamic covalent chemistry in gels assembled from small molecules. First dynamic covalent reactions used in gels are reviewed to understand the dynamic covalent bonding. Afterwards the catalogues of dynamic covalent gels are reviewed according to the nature of gelators and the interactions between gelators. Dynamic covalent bonding can be involved to form low molecular weight gelators. Low molecular weight molecules with multiple functional groups react to form dynamic covalent cross-linked polymers and act as gelators. Two catalogues of gels show different properties arising from their different structures. This review aims to illustrate the structure-property relationships of these dynamic covalent gels.     

A mechanically interlocked bundle

The prototype of an artificial molecular machine consisting of a trisammonium tricationic component interlocked with a tris(crown ether) component to form a molecular bundle with averaged C(3v) symmetry has been designed and synthesized. The system is based on noncovalent interactions, which include 1) N(+)-H...O hydrogen bonds; 2) C-H...O interactions between the CH(2)NH(2) (+)CH(2) protons on three dibenzylammonium-ion-containing arms, which are attached symmetrically to a benzenoid core, and three dibenzo[24]crown-8 macrorings fused onto a triphenylene core; and 3) pi...pi stacking interactions between the aromatic cores. The template-directed synthesis of the mechanically interlocked, triply threaded bundle involves post-assembly covalent modification, that is, the efficient conversion of three azide functions at the ends of the arms of the bound and threaded trication into bulky triazole stoppers, after 1,3-dipolar cycloaddition with di-tert-butylacetylenedicarboxylate to the extremely strong 1:1 adduct that is formed in dichloromethane/acetonitrile (3:2), on account of a cluster effect associated with the paucivalent adduct. Evidence for the averaged C(3v) symmetry of the molecular bundle comes from absorption and luminescence data, as well as from electrochemical experiments, (1)H NMR spectroscopy, and mass spectrometry. The photophysical properties of the mechanically interlocked bundle are very similar to those of the superbundle that precedes the formation of the bundle in the process of supramolecular assistance to covalent synthesis. Although weak non-nucleophilic bases (e.g., nBu(3)N and iPr(2)NEt) fail to deprotonate the bundle, the strong tBuOK does, as indicated by both luminescence and (1)H NMR spectroscopy. While deprotonation undoubtedly loosens up the interlocked structure of the molecular bundle by replacing relatively strong N(+)-H...O hydrogen bonds by much weaker N-H...O ones, the pi...pi stacking interactions ensure that any structural changes are inconsequential, particularly when the temperature of the solution of the neutral molecular bundle in dichloromethane is cooled down to considerably below room temperature.     

Shape‐Persistent Organic Cage Compounds by Dynamic Covalent Bond Formation

One area of supramolecular chemistry involves the synthesis of discrete three‐dimensional molecules or supramolecular aggregates through the coordination of metals. This field also concerns the chemistry of supramolecular cage compounds constructed through the use of such coordination bonds. To date, there exists a broad variety of supramolecular cage compounds; however, analogous organic cage compounds formed with only covalent bonds are relatively rare. Recent progress in this field can be attributed to important advances, not least the application of dynamic covalent chemistry. This concept makes it possible to start from readily available precursors, and in general allows the synthesis of cage compounds in fewer steps and usually higher yields.     

Mechanically Interlocked Single‐Wall Carbon Nanotubes

Extensive research has been devoted to the chemical manipulation of carbon nanotubes. The attachment of molecular fragments through covalent‐bond formation produces kinetically stable products, but implies the saturation of some of the C? C double bonds of the nanotubes. Supramolecular modification maintains the structure of the SWNTs but yields labile species. Herein, we present a strategy for the synthesis of mechanically interlocked derivatives of SWNTs (MINTs). In the key rotaxane‐forming step, we employed macrocycle precursors equipped with two π‐extended tetrathiafulvalene SWNT recognition units and terminated with bisalkenes that were closed around the nanotubes through ring‐closing metathesis (RCM). The mechanically interlocked nature of the derivatives was probed by analytical, spectroscopic, and microscopic techniques, as well as by appropriate control experiments. Individual macrocycles were observed by HR STEM to circumscribe the nanotubes.     

MCR XVI. Mathematical support for combinatorial chemistry

The algebra of the s- and r-vectors is an adequate formal tool to describe chemical objects in an abstract way. Compounds as well as reactions are represented, including all constitutional and configurational aspects. The stereochemistry of simple organic molecules as well as those of metal-organic compounds may be described in a unique way. Ionic bonds, covalent bonds, aromatics, and electron-deficiency compounds can formally be described without loss of information. Even reaction types and the flow of electrons can be described by this algebra. The biggest benefit of this approach is its intrinsic group theoretical structure. This does not bother the chemist for its use but allows a computer to handle and structure huge amounts of chemical data. This is especially important for combinatorial chemistry, which deals with huge sets of chemically distinct molecules, the so-called molecular libraries.     

Mechanically Interlocked [2]Rotaxane Aerogels with Tunable Morphologies and Mechanical Properties

Mechanical bonds have been utilized as promising motifs to construct mechanically interlocked aerogels (MIAs) with mechanical adaptivity and multifunctionality. However, fabricating such aerogels with not only precise chemical structures but also dynamic features remains challenging. Herein, we present MIAs carrying dense [2]rotaxane units, which bestow both the stability and flexibility of the aerogel network. Owing to the stable chemical structure of a [2]rotaxane, MIAs possessing a precise and full-scale mechanically interlocked network could be fabricated with the aid of diverse solvents. In addition, the dynamic nature of the [2]rotaxane resulted in morphologies and mechanical performances of the MIAs that can be dramatically modulated under chemical stimuli. We hope that the structure–property relationship in MIAs will facilitate the development of mechanically interlocked materials and provide novel opportunities toward constructing smart materials with multifunctionalities.