Novel and efficient templates for assembly of rotaxanes and catenanes

Abstract

Efficient templates play an important role in the construction of mechanically interlocked molecules such as catenanes and rotaxanes. This minireview presents a retrospective introduction on the traditional templates and highlights recent significant accomplishments in developing novel and efficient templates, especially active metal templates and radical templates, employed in the construction of rotaxanes and catenanes. The current status of this field is summarized and the scope and future prospects are also discussed in this minireview.

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1. Introduction

During the past few decades, research on mechanically interlocked molecules (MIMs), better known as rotaxanes and catenanes, has grown to an unprecedented level of activity, because of their interesting physical and chemical properties, applications in molecular electronics, potential as smart materials with adjustable surface properties and as components of molecular machinery.^1,2 Making these molecules, in which the components are connected mechanically rather than covalently, has become a challenging and appealing task, especially for chemists and materials scientists.

The initial attempts at making MIMs were based on either the statistical method³ depending on the chance of interlocking before covalent bond formation, or a chemical transfer strategy developed by Schill,⁴ in which covalent bond-directed synthesis was involved in multi-step reaction sequences. Although both of the two approaches are rarely used at this stage because of their low efficiency and tedious procedures in the preparation of MIMs, Schill's covalent bond-directed synthesis represents the first example of the use of a chemical template for the construction of MIMs and, most importantly, it inspired chemists to develop novel and efficient strategies for the synthesis of these kinds of molecules.

In the late 1980s and the early 1990s, with the development of supramolecular chemistry and a better understanding of the processes of host–guest molecular recognition,⁵ it became possible to take advantage of noncovalent intermolecular attractive forces, to develop the so-called “template-directed” synthetic methodology⁶ for mechanically interlocked species. Template-directed strategy has proven to be a very efficient synthetic approach for the construction of MIMs, such as rotaxanes and catenanes. The synthesis of the rotaxane and catenane becomes quite routine and a large variety of these intriguing compounds of ever increasing regularity and complexity have been reported.¹ Various traditional noncovalent templates have been developed and described.^1,2,6 Based on traditional templates such as metal–ligand templates⁷ and donor–acceptor templates,⁸ novel and efficient template methods such as active metal templation⁹ and radical templation¹⁰ have been developed recently. In this minireview, we would like to review the traditional noncovalent templates and highlight recent significant accomplishments in developing novel and efficient templates, especially active metal templation and radical templation involved in mechanical bond formation leading to rotaxanes and catenanes.

2. Traditional templates

Two distinct approaches, namely, the capping and clipping methods, were developed for the template synthesis of rotaxanes and catenanes, each of which is based on the high efficiency of the noncovalent templates.⁶ The mostly widely used noncovalent templates include metal–ligand,⁷ donor–acceptor,⁸hydrogen-bonding,¹¹ anion¹² and hydrophobic¹³ templation. In this section, we shall focus mainly on traditional templates reliant upon metal–ligand coordination and donor–acceptor interactions, which are important to the recent development of two novel and efficient templates, active metal template and radical template, respectively.

Metal–ligand templation was first introduced in 1983 by the Sauvage group.¹⁴ The metal can act as a multifunctional center that not only holds the organic building blocks together, but also keeps them in an appropriate orientation to fit the geometrical shape for the generation of the new mechanical bond between the ligands. As shown in Fig. 1a, the tetrahedral geometry of Cu(I) can hold two phenanthroline-containing moieties orthogonally and generate the necessary cross-over points for mechanical bond formation. A 6-coordinate metal template allowed the use of tridentate, terpyridine ligands, which were coordinated to Ru(II),¹⁵ shown in Fig. 1b. Leigh and co-workers¹⁶ extended the concept of Sauvage's tetrahedral Cu(I) template and developed a series of octahedral complexes between metal ions and two bis(2,6-diiminopyridine)-derived ligands for the subsequent formation of catenanes (Fig. 1c). Another system based on palladium complexes¹⁷ having 2,6-pyridinedicarboxamide-containing tridentate macrocyclic ligands was also developed (Fig. 1d). It should be mentioned that if one of the ligands shown in Fig. 1 is a macrocycle, formation of rotaxanes can be easily achieved by suitable functionalization of the other ligand, using stoppering or capping strategies.

Fig. 1 Widely used metal–ligand templates in the construction of rotaxanes and catenanes.

The group of Stoddart led the way in the use of donor–acceptor π–π interactions in the assembly of mechanically interlocked architectures.⁸ The donor–acceptor template employs aromatic stacking forces as the main supramolecular interaction that holds the components together in a certain spatial arrangement. The most frequently used donor and acceptor units and the corresponding macrocycles to form host–guest interations are shown in Fig. 2. For example, macrocycle BPP34C10 is a π-electron rich receptor unit for viologen that contains π-electron-deficient bipyridinium units. 1,4,5,8-Naphthalenetetracarboxylate diimide (NPI) and pyromellitic diimide (PMI) derivatives¹⁸ have also been developed as efficient acceptors for specific π-electron-rich receptor macrocycles. Cyclobis(paraquat-p-phenylene) (CBPQT⁴⁺) has turned out to be an excellent receptor for substrates containing π-electron rich aromatic rings such as 1,4-dioxyphenylene, 1,5-dioxynaphthalene (DNP) and tetrathiafulvalene (TTF) derivatives, and is now the most important π-electron-deficient ring for constructing switchable rotaxanes and catenanes. Based on these donor–acceptor interactions, rotaxanes, catenanes and more complex architectures have been constructed.⁸

Fig. 2 The widely used donors, acceptors and macrocycles as templates in the synthesis of rotaxanes and catenanes.

Although the introduction of various noncovalent templates pioneered by Sauvage,⁷ Stoddart⁸ and others^11–13 has made the preparation of MIMs much more feasible and efficient than before, it still remains necessary and challenging to develop novel and efficient templates for the construction of such topologically intriguing molecules.

3. Active metal templates

Based on the traditional metal templates, Leigh and coworkers were inspired by the principles of transition metal catalysis chemistry and developed a novel and efficient template, namely, active metal templation.⁹ In this approach, the metal has a dual function, not only acting as a template to hold the organic building blocks together in a specific orientation, but also catalyzing the covalent bond formation that captures the interlocked structure, compared with the traditional metal templates, in which the metal ion is generally passive during the formation of MIMs. Key to the active metal template concept is the coordination of a metal ion to a macrocycle within its cavity. The metal ion is chosen for catalyzing and promoting covalent bond formation to capture the mechanically interlocked structures. The concept was first demonstrated^19a using the Cu(I)-catalyzed 1,3-cycloaddition of organic azides with terminal alkynes, a so-called ‘click’ reaction, to assemble [2]rotaxaneR1 in good yield (57%), as shown in Fig. 3. Since then a large number of rotaxanes were prepared with various macrocycles and thread components using this approach¹⁹ and mechanism of the CuAAC active template synthesis of rotaxanes was thoroughly investigated.^19b

Fig. 3 Structure of a [2]rotaxane assembled by using an active template CuAAC approach.

The concept has already been extended to other transition metals, such as palladium(II)-catalyzed reactions.²⁰ As shown in Fig. 4, the host macrocycleM1 is first coordinated with Pd(II) to form the trans-chloride ligands of M1–Pd(II), followed by subsequent substitution with terminal acetylide units in such a way that the ligands are coordinated to the square planar Pd(II) through the cavity of the macrocycle to generate trans-M2–Pd(II). Then trans-M2–Pd(II) undergoes a trans-to-cisisomerization of the alkyne ligands to form cis-M2–Pd(II), which has a “threaded” structure in which the two alkyne ligands are linearly linked with Pd(II). Subsequent reductive elimination of the cis-orientation species can occur to form the diyne rotaxane R2 and Pd(0). It should be noted that the scope of this strategy was also investigated. The formation of [2]rotaxaneR2 occurred in 61% yield by using a stoichiometric quantity of Pd(II). More exciting results were gained by introducing I₂ and O₂ to oxidise the Pd(0) back to Pd(II)in situ to make the active metal template catalytically turn over. In this case, using a sub-stoichiometric (5%) quantity of Pd(II) gave a 90% yield of rotaxaneR2, even more efficient than the stoichiometric reaction.

Fig. 4 Pd(II)-mediated active metal template synthesis of [2]rotaxaneR2.

The concept of the active metal template was also applied to a simple multicomponent assembly process utilizing Ni-catalyzed sp³-carbon-to-sp³-carbon homocoupling of unactivated alkyl bromides in the synthesis of an alkyl chain axle [2]rotaxane.^21a The mechanistic pathway involved in the preparation of [2]rotaxaneR3 is shown in Fig. 5. The macrocycleM3 is first coordinated with NiCl₂ to form M3–NiCl₂L, which undergoes reduction by Zn to yield a Ni(0) species M3–NiL. Subsequent oxidative addition of the alkyl bromide S to the generated M3–NiL results in the formation of the Ni(II)-alkyl species M3–I, which is reduced to the Ni(I) intermediate M3–II by Zn. The second oxidative addition of another equivalent of the alkyl bromide S to M3–II yields M3–III that has a “threaded” structure. Then M3–III undergoes reductive elimination to give [2]rotaxaneR3 in a moderate yield. Besides Ni-catalyzed homocoupling of alkyl bromides to construct rotaxane, Leigh and coworkers also extended this active template concept to the Lewis acid-catalyzed Diels–Alder cycloaddition to prepare rotaxanes and metal-ion-switchable molecular shuttles.^21b It should be noted that although the active metal template shows an excellent efficiency in the preparation of rotaxanes, the construction of catenanes using this approach still remains challenging. Only few examples of catenanes²² have been reported using the active metal template approach, because of their unique structures and difficulty in practice for an intramolecular ring closure.

Fig. 5 Ni-catalyzed sp³-carbon-to-sp³-carbon homocoupling of unactivated alkyl bromides in the synthesis of the [2]rotaxaneR3.

4. Radical templates

Radical cation dimerization is widely used in traditional organic synthesis. Investigation of such systems was hindered because of their inherent instability and high reactivity. Kim et al.²³ reported that dimers of radical cations, such as the methyl viologen (MV^•+) and tetrathiafulvalene (TTF^•+) cation radicals, could be threaded into the cavity of neutral hosts to form stable supramolecular host–guest complexes, providing a new control element for driving molecular motion in electrochemically driven molecular machines. For example, Stoddart and co-workers have recently demonstrated that the radical–cation dimerization can be employed to control the shuttling motion of the macrocycle component in an electrochemically driven tristable rotaxane²⁴ with three recognition sites and moreover, highly stable tetrathiafulvalene radical dimers can be achieved in a series of [3]catenanes.²⁵

The radical–radical dimerization interaction also offers the possibility of a new template for assembly of interlocked molecules. As shown in Fig. 6, 1,1’-dialkyl-4,4’-bipyridinium viologen dications V²⁺ and CBPQT⁴⁺, which can act as π-electron-deficient guests and hosts in the field of donor–acceptor of MIMs, respectively, are highly repulsive components and show no binding affinities with each other. However, after reduction of the two components, they become attractive species. The viologen radical cation (V^•+) can form a strong supramolecular host–guest inclusion complex with the reduced diradical dicationic species of CBPQT⁴⁺ due to the radical–radical interaction arising from the attraction between viologen radical cations.²⁴

Fig. 6 The formation of a stable supramolecular host–guest inclusion complex between a viologen and the bis-viologen ring upon reduction.

Based on this novel interaction type, Stoddart and co-workers reported the first example of a [2]rotaxane¹⁰ constructed via radical template-directed synthetic strategy by employing a ruthenium-ligand complex as an electron transfer photocatalyst to generate the necessary radical cation components. Tris(2,2′-bipyridine) dichlororuthenium(II) hexahydrate, known as [Ru(bpy)₃]²⁺, was selected as the reducing agent because of its highly efficient reduction of viologen units via a well-known photoinduced charge transfer process, when activated by visible light. Triethanolamine (TEOA), acting as a sacrificial electron donor, can prevent back electron transfer from the reduced bipyridinium radical cations to the ruthenium species. As shown in Fig. 7, the viologen derivative AV²⁺ with two terminal azide moieties and the CBPQT⁴⁺ were simultaneously reduced to their corresponding radical cations in the presence of [Ru(bpy)₃]²⁺ and an excess of TEOA upon irradiation with visible light and formed a stable supramolecular inclusion complex. Using a threading-followed-by-stoppering strategy, the reduced species R4^3(•+) of the [2]rotaxane was formed as a result of copper-free azide-alkyne 1,3-dipolar cycloaddition between the terminal azides on the inclusion complex and di-tert-butyl acetylenedicarboxylate. The radical cation rotaxaneR4^3(•+) can be oxidized to the target rotaxaneR4 by atmospheric oxygen in a moderate isolated yield (35%). This is the first example of mechanical bond formation between repulsive species employing radical dimer interaction as the recognition motif.

Fig. 7 The radical template-directed synthesis of the [2]rotaxaneR4.

5. Conclusions

The research area of molecular machines is a multi-disciplinary field and it requires a high level of combination of synthetic, physical and materials chemistry if function-oriented molecules are to result.^1,2 In this minireview, we have highlighted recent accomplishments in developing novel and efficient templates employed in the construction of rotaxanes and catenanes. In the active metal strategy, the metal not only functions as a directional scaffold to position the components in the appropriate geometry as in the traditional approach, but also promotes covalent bond formation to capture the interlocked structure that the traditional one cannot.⁹ By taking a cue from extensively studied donor–acceptor templation, the radical template synthetic strategy, makes use of the combination of templation and radical–radical interactions and offers an opportunity for chemists to overcome the reliance on the traditional template-directed procotols.¹⁰ Both the active metal template and the radical template approach represent a change in methodology for the assembly of MIMs in which the intercomponent interactions can be as weak as possible, even repulsive in their ground states.^9,10 It can be envisaged that more complicated structures, including knots and other topologically complex assemblies besides rotaxanes and catenanes, could be constructed employing these novel methodologies.

Acknowledgements

The authors would like to thank the NSFC/China (20902024 and 20972053), National Basic Research 973 Program (2011CB808400). D. Qu thanks the Foundation for the Author of National Excellent Doctoral Dissertation (200957), Shanghai Pujiang Talent Program (10PJ1402700), Fok Ying Tong Education Foundation (121069), Shanghai Chenguang project (09CG26), SRFDP (20090074120017), Fundamental Research Funds for the Central Universities (WJ1014001) and the Scientific Committee of Shanghai for funds. H. T. appreciates Prof. J. F. Stoddart and Prof. J.-P. Sauvage very much for their helpful discussion and valuable comments. Mr. G. Barin, Mr. M. E. Belowich, Mr. H. Li and Dr R. S. Forgan are acknowledged for useful suggestions and for careful reading and correction of the manuscript.

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