Syntheses of three-dimensional catenanes under kinetic control.

Although catenanes comprising two ring-shaped components can be made in large quantities by templation, the preparation of three-dimensional (3D) catenanes with cage-shaped components is still in its infancy. Here, we report the design and syntheses of two 3D catenanes by a sequence of SN2 reactions in one pot. The resulting triply mechanically interlocked molecules were fully characterized in both the solution and solid states. Mechanistic studies have revealed that a suit[3]ane, which contains a threefold symmetric cage component as the suit and a tribromide component as the body, is formed at elevated temperatures. This suit[3]ane was identified as the key reactive intermediate for the selective formation of the two 3D catenanes which do not represent thermodynamic minima. We foresee a future in which this particular synthetic strategy guides the rational design and production of mechanically interlocked molecules under kinetic control.

While a number of catenanes consisting of multiple mechanically interlocked cyclic DNA (1, 2) and proteins (3, 4) have been found in living organisms, the creation of wholly synthetic analogs of these molecules—in an attempt to understand and harness their intrinsic physical, chemical, or biological properties—has inspired scientists for decades. The first chemical synthesis of a [2]catenane, which was reported in 1960 by Wasserman (5) using a statistical approach, was followed, in 1964, with the covalently directed templation of a [2]catenane involving more than 20 steps by Schill and Lüttringhaus (6). Since the early 1960s, the syntheses of catenanes progressed slowly, if hardly at all, during the subsequent 20 y. Over this period, catenane synthesis suffered from lengthy stepwise routes and/or low overall yields, resulting in only minuscule amounts of catenanes being produced and leaving their properties largely unexplored.

Using templation provided by metal ions to preorganize ligands into spatial arrangements that direct the formation of catenanes, Sauvage and coworkers (7) made a conceptual breakthrough in their synthesis in 1983. Since this time, much effort has been devoted to the development of new methodologies to effect the catenation of rings. These strategies have nearly always been accompanied (8, 9) by noncovalent bonding interactions, including, but not limited to, templation based on donor–acceptor (10), hydrogen-bonding (11, 12), and radical-pairing (13) interactions. The ever-expanding molecular-recognition toolbox, leading to efficient catenation, has enabled catenanes to become commonplace components in a variety of integrated systems, employing organic materials (14) and polymers (15) to fabricate molecular electronic devices (16) and create artificial molecular machines (17). Most of these catenanes, however, have been constructed from macrocyclic precursors, which are topologically two-dimensional (2D) in nature. The creation of catenanes composed of two or more three-dimensional (3D) cage-shaped components remains a challenge.

The formation of 3D catenanes (although all the catenanes are topologically 3D in nature, the term 3D catenanes used in this article refers specifically to catenanes consisting of multiple cage-shaped components) has relied on—with a few exceptions (18, 19)—self-assembly, in which the reversible formation of dynamic bonds acts as an error-checking mechanism to ensure the generation of thermodynamically favorable mechanically interlocked molecules (MIMs) in solution or during crystallization. The first example of the syntheses of 3D catenanes, which takes advantage of the dynamic metal–ligand coordinative bonds and hydrophobic interactions in water, was reported in 1999 by Fujita et al. (20). This approach has proved to be versatile for making metal-coordination-based 3D catenanes, as evidenced (21–36) by subsequent reports over the years. Besides metal–ligand interactions, several types of dynamic covalent chemistry, including the formation of imines (37, 38), boronic esters (39) and acylhydrazones (40), as well as alkyne metathesis (41), have been employed in the syntheses of 3D catenanes. Although these approaches are promising, the resulting catenanes oftentimes suffer from the use of precious metals in their syntheses and/or stability issues, limiting further applications. The development of new and efficient synthetic methodologies for the production of 3D catenanes remains a highly desirable pursuit.

Here, we present a facile strategy for the design and syntheses of a pair of 3D catenanes in one pot. The structures of both catenanes have been confirmed in both the solution and solid states. Moreover, mechanistic investigations reveal the importance of a suitane-based reaction pathway, in which a mechanically interlocked suit[3]ane with a trivial topology was identified as the reactive intermediate for the selective formation (Fig. 1) under kinetic control of the two 3D catenanes with nontrivial topologies.

Fig. 1.

Graphical representation of a suit[3]ane-based strategy for the selective syntheses of the two 3D catenanes 26+ and 36+. The reaction of TPPT with TBPT gives a tricationic monomeric cage 13+, which can open up its entrances at elevated temperatures and allow the slippage of TBPT into the cavity of 13+ to produce [Suit[3]ane·TBPT]3+ as an intermediate. The subsequent reaction with TPPT from the bottom and top side of this intermediate affords the 3D catenanes 26+ and 36+, respectively. Since TPPT is relatively more bulky than TBPT, the formation of a similar [Suit[3]ane·TPPT]3+ intermediate is disfavored kinetically as a result of steric hindrance. Thus, the 3D catenane 46+ cannot be formed.

Results

One-Pot Syntheses of 3D Catenanes.

The syntheses of the monomeric cage 1·3CF3CO2 and the 3D catenanes 2⋅6CF3CO2 and 3·6CF3CO2 (Fig. 2) started from two readily accessible precursors (), namely 2,4,6-tris-[4-(4-pyridylmethyl)phenyl]-1,3,5-triazine (TPPT) and 2,4,6-tris-(4-bromomethylphenyl)-1,3,5-triazine (TBPT). Both TPPT and TBPT contain a triaryl triazine moiety, which tends to adopt a much flatter conformation compared with triaryl benzene (42) and favors [π···π] interactions (20). We began our investigation with the reaction between equimolar amounts of TPPT and TBPT at 50 °C for 3 d in N,N-dimethylformamide (DMF) in the presence of tetrabutylammonium iodide (TBAI) as a catalyst, followed by chromatographic purification, during which counterion exchange with trifluoroacetic acid (TFA) occurs to give the corresponding products. Although both starting materials were consumed, only trace amounts of 3D catenanes were obtained (, Entry 1). When we changed the solvent to acetonitrile (MeCN), however, the yields of the 3D catenanes 2·6CF3CO2 and 3·6CF3CO2 increased to 3% and 4%, respectively, most likely because MeCN sustains a larger solvophobic effect than DMF. This improvement in yields encouraged us to optimize this reaction by varying the solvent, temperature, reaction time and feeding ratio of the two reactants. The best result (, Entry 7) was obtained after several rounds of optimization in which the monomeric cage 1·3CF3CO2 and the [2]catenanes 2·6CF3CO2 and 3·6CF3CO2 were isolated in 41%, 23%, and 13% yields, respectively. The formation of another putative 3D catenane 4·6CF3CO2, however, was not observed under a wide range of conditions.

Fig. 2.

One-pot syntheses of the monomeric cage 1·3CF3CO2 and the 3D catenanes 2·6CF3CO2 and 3·6CF3CO2 from TPPT and TBPT using TBAI as a catalyst. The formation of another putative 3D catenane 4·6CF3CO2 was, however, not observed.

Structural Characterization.

The constitution of 1·3CF3CO2, and the co-constitutions of 2·6CF3CO2 and 3·6CF3CO2 were determined by 1H nuclear magnetic resonance (NMR) spectroscopy. The 1H NMR spectra of the 3D catenanes 2·6CF3CO2 (Fig. 3) and 3·6CF3CO2 (Fig. 3) differ significantly from that (Fig. 3) of the monomeric cage 1·3CF3CO2. After making assignments to all the resonances in the 1H NMR spectra of both 3D catenanes by employing a series of 2D NMR spectroscopic techniques (see for details), we found that the resonances in the 1H NMR spectra, corresponding to Ha (5.97 ppm) in 2·6CF3CO2, and Ha′ (6.01 ppm) and Hh (5.91 ppm) in 3·6CF3CO2, undergo significant upfield shifts when compared with those (8.58 ppm for Ha, 8.46 ppm for Hh) arising in the 1H NMR spectrum of 1·3CF3CO2. This observation is good evidence for the formation of MIMs, because once the triphenylenetriazine moiety is located within the cavity of the other cage component, the protons on the phenylene groups experience a strongly shielded magnetic environment. In contrast, the resonances corresponding to Hb, Hg, and Hh in 2·6CF3CO2 and Hb′, Hg′, Hh′, Ha, Hb, and Hg in 3·6CF3CO2 undergo relatively minor upfield shifts. This observation can be ascribed to the fact that these protons are located in less shielded magnetic fields. The resonances corresponding to all the protons on the pillars (Hc, Hd, He, and Hf in 2·6CF3CO2 and Hc, Hd, He, Hf, Hc′, Hd′, He′, and Hf′ in 3·6CF3CO2) undergo downfield shifts, an observation which can be explained by the fact that they are located in deshielded environments.

Fig. 3.

Structural elucidation of 1·3CF3CO2, 2·6CF3CO2 and 3·6CF3CO2 by 1H NMR (500 MHz, 298 K, CD3OD) spectroscopy. 1H NMR spectra of (A) 2·6CF3CO2, (B) 1·3CF3CO2, and (C) 3·6CF3CO2. The resonances corresponding to Ha (5.97 ppm) in 2·6CF3CO2, Ha′ (6.01 ppm) and Hh (5.91 ppm) in 3·6CF3CO2 show significant upfield shifts compared with those (8.58 ppm for Ha and 8.46 ppm for Hh) in 1·3CF3CO2. This observation is good evidence for the formation of MIMs, in which the inside protons are shielded by the other cage component.

Both 3D catenanes 26+ and 36+ are achiral and belong to the point group, D3 and C3, respectively. The catenane 36+ belongs to the same point group as its noninterlocked precursor 13+ for the simple reason that all six pyridinium units in 36+ point in the same direction, resulting in no changes in symmetry elements. In the case of 2, however, the three pyridinium units in one cage component point in the opposite direction relative to those in the other cage, introducing three additional C2 axes. As a consequence, this 3D catenane has a higher symmetry and belongs to the D3 point group. Because σ symmetry elements are present in both co-constitutional isomers 2 and 3—in which the two mechanically interlocked components adopt staggered co-conformations—the dihedral angles in the different cage components are all 60° as a result of minimizing Coulombic repulsions between the six pyridinium units.

Single crystals (suitable for X-ray crystallography) of each of the 3D catenanes were obtained by slow vapor diffusion of iPr2O into the corresponding MeOH solution at 252 and 298 K for 2·6CF3CO2 and 3·6CF3CO2, respectively. The solid-state structure of the monomeric cage 13+, which was also determined, showed a separation distance of 7.0 Å between the roof and the floor of the cage (). The single-crystal structures confirm (Fig. 4) unambiguously the formation of the two 3D catenanes, each consisting of two identical mechanically interlocked cage components. From the perspective views (Fig. 4 ), the efficient quadruple stacking of the aromatic platforms was observed for both 26+ and 36+. Side-on views (Fig. 4 ) revealed efficient [π···π] interactions between the two adjacent triphenylenetriazine platforms with plane-to-plane distances ranging from 3.3 to 3.5 Å in both 26+ and 36+. It is worthy of note that the separation distance (3.5 Å) between the inner triphenylenetriazine platforms of 26+ is slightly longer than that (3.4 Å) present in 36+, possibly because the repulsive interactions of positive charges in 26+ are stronger than those in 36+. From the plan view (Fig. 4) of 26+, it is found that the triazine cores of the two cage components are displaced slightly with respect to each other. This perturbation is, however, not present in the structure (Fig. 4) of 36+. We speculate that the differences in relative geometries of the cage components might result from the crystal packing preference at different temperatures. When crystals of 26+ were grown at low temperature (252 K), the crystals obtained were those with increased noncovalent bonding interactions between the two mechanically interlocked components. This interpretation is consistent with the fact that [CH···π] interactions, in addition to [π···π] interactions, are present in 26+ as revealed (43, 44) by an independent gradient model (IGM) analysis ().

Fig. 4.

X-ray single-crystal structures of the 3D catenanes 26+ and 36+. The two mechanically interlocked, identical cages are shown in royal blue and pale blue. Perspective views of (A) 26+ and (B) 36+ as stick representations with the corresponding semitransparent space-filling representations superimposed upon them. Side-on views of (C) 26+ and (D) 36+ as stick representations showing the plane-to-plane distances between two adjacent platforms. The distances are found to be 3.3 Å to 3.5 Å (i.e., ideal for [π···π] interactions). Plan views of (E) 26+ and (F) 36+ as stick representations showing the “dihedral angles”. Irrelevant protons, CF3CO2− counterions and solvent molecules are omitted for the sake of clarity.

Mechanism.

Mechanistic investigations into the synthetic strategy, not only provided insight into the formation of 2·6CF3CO2 and 3·6CF3CO2, but more importantly also shed light on what we believe to be new design principles for the syntheses of 3D catenanes in general. Theoretically, three different catenanes () can be formed by the reaction of TPPT with TBPT, including 26+, 36+, and another C3-symmetric 3D catenane 46+ with all the positive charges pointing outward. The theoretical formation probabilities of 26+, 36+, and 46+ were calculated () to be 25%, 50%, and 25%, respectively. Density functional theory (DFT) calculations reveal () that the relative energies of 26+, 36+, and 46+ are 20.8, 11.5, and 0 kcal/mol, respectively. Although 46+ has the lowest relative energy, no product corresponding to this 3D catenane was observed under all the conditions explored ()—suggesting that the formation of the 3D catenanes 26+ and 36+ is not taking place under thermodynamic control, which has been proposed for the formation of other 3D catenanes reported in the literature for approaches involving both metal coordination (20–36) and dynamic covalent chemistry (37–41).

Given the fact that the monomeric cage 13+ was isolated in a good yield—41% under the optimized conditions—and the plane-to-plane separation distance in the solid-state structure of 13+ is 7.0 Å— —we propose a suitane-based mechanism based on the near-perfect cofacial [π···π] stacking interactions between the suit 13+ and an aromatic torso (). We assume that the first step in the formation of the 3D catenanes 26+ and 36+ is the generation of a monomeric cage 13+, which opens up its entrances at elevated temperatures and allows the slippage of TBPT into the cavity of 13+ to produce [Suit[3]ane·TBPT]3+ as an intermediate. The subsequent reaction with TPPT from the bottom and top side of this intermediate affords the 3D catenanes 26+ and 36+, respectively (reaction pathway A in ). Because TPPT is relatively more bulky than TBPT, the formation of a similar [Suit[3]ane·TPPT]3+ intermediate is disfavored kinetically as a result of steric hindrance. Thus, neither 36+ nor 46+ can be formed by the reaction pathway B ().

In order to verify the proposed hypothesis, a mixture of 1·3Br and TBPT was stirred (Fig. 5) at 80 °C for 4 d in MeCN in the presence of TBAI. The crude reaction mixture was analyzed by 1H NMR spectroscopy () and two doublets were identified at 9.50 (J = 7.0 Hz) and 6.36 ppm (J = 8.2 Hz). This observation suggests that a [Suit[3]ane·TBPT·3Br] intermediate with TBPT trapped inside the cavity of 1·3Br has been formed. Whereas, in a control experiment using TPPT instead of TBPT to perform the same reaction (), neither downfield nor upfield-shifted doublets can be detected in the 1H NMR spectrum (), indicating that TPPT is not able to slip into the cavity of 1·3Br to form the [Suit[3]ane·TPPT·3Br] intermediate under the same reaction conditions.

Fig. 5.

Mechanistic study. (A) Generation of the reactive intermediate [Suit[3]ane·TBPT·3Br] and subsequent counterion exchange to give Suit[3]ane·TBPT·3CF3CO2. This compound, however, can be easily hydolyzed at room temperature so only mass spectrum was recorded. (B) Capturing of the reactive intermediate [Suit[3]ane·TBPT·3Br] by reacting it with pyridine in the presence of TBAI to form Suit[3]ane·TPyPT·6CF3CO2, which is stable during column purification using H2O and MeCN as the eluent and can be fully characterized.

In an attempt to obtain convincing evidence for the proposed mechanism, we tried to isolate and characterize the reaction intermediate [Suit[3]ane·TBPT]3+. After counterion exchange with TFA (Fig. 5), the crude mixture containing Suit[3]ane·TBPT·3CF3CO2 was purified by reversed-phase column chromatography and analyzed by high resolution electrospray ionization mass spectrometry (ESI-MS). The mass spectrum (Fig. 6) of Suit[3]ane·TBPT·3CF3CO2 exhibited prominent peaks at m/z = 505.1028 (calculated for [Suit[3]ane·TBPT]3+ m/z = 505.1022) and 814.1469 (calculated for [Suit[3]ane·TBPT·CF3CO2]2+ m/z = 814.1462), confirming the formation of the proposed suit[3]ane intermediate. Characterization of Suit[3]ane·TBPT·3CF3CO2 by NMR spectroscopy was, however, not successful because this compound was found to hydrolyze over time at room temperature. Further evidence of the water-labile nature of Suit[3]ane·TBPT·3CF3CO2 was provided by ESI-MS analysis ().

Fig. 6.

Characterization of the suit[3]ane intermediate. (A) Mass spectrum of Suit[3]ane·TBPT·3CF3CO2. The labeled m/z signals correspond to those of species that lose different numbers (3, 2) of CF3CO2− counterions. The corresponding theoretical peaks (blue) of [Suit[3]ane·TBPT]3+ and [Suit[3]ane•TBPT·CF3CO2]2+, shown in the expanded spectra, were found to be consistent with the experimental peaks (red). (B) 1H DOSY NMR spectrum (600 MHz, 298 K, CD3OD) of Suit[3]ane·TPyPT·6CF3CO2 revealed a single diffusion coeffiecient (D = 4.19 × 10−6 cm2 s−1) for all of its proton resonances. This observation confirms that all these resonances belong to a single molecule.

In order to overcome the problem of isolating and characterizing the reactive intermediate, we reacted (Fig. 5) it with pyridine to obtain a stable compound (i.e., Suit[3]ane·TPyPT·6CF3CO2), which was isolated and fully characterized. The diffusion-ordered spectroscopy (DOSY) NMR spectrum (Fig. 6) of Suit[3]ane·TPyPT·6CF3CO2 revealed a single diffusion coefficient (D = 4.19 × 10−6 cm2 s−1) for all of its proton resonances. This observation confirms that all these resonances belong to a single molecule. The structure of Suit[3]ane·TPyPT·6CF3CO2 was also confirmed by mass spectrometry (). All these computational results and experimental evidence support the proposed suit[3]ane-based mechanism for the selective formation of the 3D catenanes 26+ and 36+.

Conclusions

We have shown that two 3D catenanes, namely 26+ and 36+ with nontrivial topologies, can be synthesized in 23% and 13% yields, respectively, by a sequence of facile SN2 reactions in one pot. Each of these two 3D catenanes is composed of two mechanically interlocked triangular prisms and comprises six pyridinium pillars. On account of the Coulombic repulsions between these pyridinium units, neither 26+ nor 36+ represents the most thermodynamically favored product. It is noteworthy that another putative isomeric catenane, namely 46+, which is able to locate its six positively charged pyridinium nitrogen atoms in a relatively remote manner, is more thermodynamically stable than either 26+ or 36+. Mechanistic studies, however, revealed that a suit[3]ane—containing a triangular component with three benzylbromide units (TBPT) that becomes mechanically interlocked within the cavity of a C3-symmetric cage-shaped component—represents the key reactive intermediate for the selective formation of the 3D catenanes 26+ and 36+. In contrast, the formation of the putative suit[3]ane containing TPPT is disfavored kinetically because of the large steric hindrance preventing its formation. The fact that the suit[3]ane containing TPPT is not formed during the reaction means that the 3D catenane 46+ cannot be obtained under kinetic control. Considering the well-developed methodologies (45–50) for the construction of suitanes, this suit[3]ane-based strategy opens up what we believe to be new opportunities for synthesizing 3D catenanes and other topologically nontrivial molecules (51–54) which do not correspond to thermodynamic minima. Such co-conformations are unlikely to be obtained by previously reported methods (20–41) that rely on dynamic bond formation.

Materials and Methods

All reagents were purchased from commercial suppliers (MilliporeSigma or Fisher) and used without further purification. TPPT and TBPT were synthesized according to protocols described previously (20, 55) with slight modifications (56).

Syntheses of 1•3CF3CO2/2•6CF3CO2/3•6CF3CO2.

A catalytic amount of TBAI (2.5 mg, 6.9 µmol, 0.2 eq.) was added to a suspension of TPPT (20.0 mg, 34.3 µmol, 1.0 eq.) and TBPT (25.0 mg, 42.9 µmol, 1.25 eq.) in anhydrous MeCN (40 mL) under a N2 atmosphere. The reaction mixture was heated at 80 °C and stirred for 5 d. After evaporation to remove all the solvent, TFA (2 mL) and MeOH (10 mL) were added to the residue and the resulting mixture was stirred for an additional 30 min. The concentrated residue was loaded onto a CombiFlash chromatography system and purified on a C18 reversed-phase column using a mixture of 0.1% vol/vol TFA in H2O and 0.1% vol/vol TFA in MeCN. Fractions containing the product were combined and concentrated. The crude product was then subjected to purification on a preparative reversed-phase HPLC system with H2O/MeCN (67/33, vol/vol, both containing 0.1% vol/vol TFA) as the eluent, affording 1·3CF3CO2 (17.9 mg, 41% yield), 2·6CF3CO2 (10.0 mg, 23% yield) and 3·6CF3CO2 (5.7 mg, 13% yield) as white solids.