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Molecular Borromean Rings

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Science  28 May 2004:
Vol. 304, Issue 5675, pp. 1308-1312
DOI: 10.1126/science.1096914

Abstract

The realization of the Borromean link in a wholly synthetic molecular form is reported. The self-assembly of this link, which is topologically achiral, from 18 components by the template-directed formation of 12 imine and 30 dative bonds, associated with the coordination of three interlocked macrocycles, each tetranucleating and decadentate overall, to a total of six zinc(II) ions, is near quantitative. Three macrocycles present diagonally in pairs, six exo-bidentate bipyridyl and six endo-diiminopyridyl ligands to the six zinc(II) ions. The use, in concert, of coordination, supramolecular, and dynamic covalent chemistry allowed the highly efficient construction, by multiple cooperative self-assembly processes, of a nanoscale dodecacation with an approximate diameter of 2.5 nanometers and an inner chamber of volume 250 Å3, lined with 12 oxygen atoms.

An object of particular interest in knot theory is known as the Borromean rings (BRs). It occurs in low-dimensional topology and is comprised (Fig. 1A) of three interlocked rings such that scission of any one ring leads to the other two falling apart. Although this symbol can be traced (1) back to early Christian iconography and Norse mythology, its proliferation on crests and statues commissioned by the Borromeo family in 15th-century Tuscany sealed its etymological fate. In addition to the symbol's having made cultural inroads into art and theology and heraldry, the last century witnessed its emergence on the scientific horizon in particle physics (2) and magnetism (3), as well as in the formidable challenge (4, 5) it presents to synthetic chemists in search of its molecular expression. In the wake of Wasserman's first synthesis (6) of a compound—a [2]catenane—in which the molecules have two interlocked rings, the field of molecular topology has blossomed (79). Although more elaborate examples in chemical topology (10, 11) and topological stereochemistry (12, 13) have emerged (14, 15) in the shape of molecular knots, as well as catenanes, the BRs, with the exception of Seeman's seminal work (16) with single-stranded DNA, have proved to be elusive in a wholly synthetic molecular form (1719).

Fig. 1.

The Borromean rings (BRs) can be depicted in many ways, including a planar Venn representation (A) and a more informative orthogonal arrangement (B). At each of the six crossing points on this graph, it is possible to embed a templating feature [the silver spheres shown in (C)] to control the overall three-dimensional architecture in a molecular context. By employing transition metal ions to gather around themselves appropriate ligands in a prescribed fashion, one can envisage a relatively straightforward retrosynthetic disconnection of the BRs (D). The retrosynthesis in chemical terms (E) anticipates the use of an exo-bidentate bipyridyl ligand and an endo-tridentate diiminopyridyl ligand that is formed reversibly upon the reaction of DFP with DAB in a [2+2] macrocyclization. Molecular modeling (E, left) confirms that three such [2+2] macrocycles can be slotted together to form a highly stabilized assembly with a BR topology.

Conceptually, there are two extreme synthetic strategies for the construction of molecular Borromean links: (i) a stepwise synthesis wherein the three rings are slotted into place by successive templation (20) one at a time and (ii) a strict self-assembly protocol (21, 22) that brings the components of the three rings together in one step under comprehensive template-directed control (20). A ring-by-ring (2325) approach that is predominantly kinetically executed offers, in principle, access to a greater degree of structural diversity. Such an approach, however, courts the danger of being burdened by undesirable side reactions, particularly in the formation of the third and final ring of the Borromean links where the geometrical demands associated with both noncovalent and covalent bond formation are likely to be high.

By contrast, an all-in-one strategy, which combines the virtues of reversibility, proofreading, and the error checking we associate with supramolecular (26) and dynamic covalent (27) chemistry with the geometrical precision afforded by coordination chemistry (2830), allows the synthetic chemist to take up the gauntlet of assembling molecular BRs in the knowledge that thermodynamic control can be an efficient supplier of a complex product (27). Such a paradigm requires that each individual piece in the molecular self-assembly process is programmed so that the multiple molecular recognition between the pieces is optimized in a highly cooperative manner in the desired product. In our bid to facilitate the self-assembly of a BR compound, it was essential to ensure that cooperativity between π–π stacking interactions and coordination geometries was highly optimized. This crucial design element was satisfied computationally by molecular modeling. The manner in which the computer-aided design of the BR12+ dodecacation led directly to its synthesis in very high yields is rare in our own laboratories' experience.

The successful construction of a BR compound from individual pieces relies on the precise control of the six crossover points that can be identified in the Venn representation (Fig. 1A), where the like signs of the three outer nodes are opposite to those of the three inner nodes. Although these nodes define the topology of the final assembly, to conceive retrosynthetic disconnections it is advantageous to reorient the three interlocked rings so that they are mutually perpendicular in Cartesian space, as depicted in the orthogonal representation (Fig. 1B). With reference to any one of the three identical rings, the sequence of four alternating nodes (+/–/+/–) can manifest itself in the form of exo/endo/exo/endo binding sites in a wholly cross-complementary fashion. In a chemical context (Fig. 1C), transition metals can be embedded into these binding sites, thus ensuring complete three-dimensional control at all six such sites through a judicious choice of coordination geometry. Specifically, differentiation of the exo and endo binding sites at each of the six ring crossings can be established through the union (Fig. 1D) of bidentate and tridentate ligands around a five-coordinate metal ion. The requirements for flexibility and reversibility in the coordination spheres were met by using kinetically labile zinc(II) ions, each bound preferentially to one exo-bipyridyl and one endo-diiminopyridyl ligand. Ligands of this latter class have been used (28) to form macrocycles in the presence of metal-ion templates. It seemed propitious, therefore, to incorporate two of these endo-tridentate ligands, as a result of dynamic imine bond formation (27) between 2,6-diformylpyridine (DFP) and a diamine (DAB) harboring the incipient exo-bidentate ligands following a [2+2] macrocyclization (Fig. 1E).

Whereas in the absence of a metal-ion template, a complex mixture of polymeric and macrocyclic products is the likely outcome, introduction of zinc(II) ions is expected to template the formation of molecular BRs with maximal site occupancy (31) being honored. Molecular modeling (32) of the Borromean links, constructed from the appropriately interlocked arrangement of three of the [2+2] macrocycles, revealed only two molecular trinities stabilized by combinations of 12 π–π stacking interactions and 30 dative bonds, one with Ci (= S2) symmetry and the other, shown in Fig. 1E, with S6 symmetry.

Initial 1H nuclear magnetic resonance (NMR) spectroscopic investigations, conducted in a CD3OD solution containing equimolar amounts of DFP and DAB-H4·4TFA (TFA-trifluoroacetate), revealed that little or no reaction occurred at room temperature during several hours. Upon the addition of an equivalent of Zn(OAc)2 to the NMR tube, the spectrum changed dramatically, indicating that a reaction was occurring. To expedite the self-assembly process, the reaction mixture was heated under reflux for 3 days. Periodic monitoring of the 1H NMR spectrum revealed that equilibrium was reached after 2 days, affording predominantly (90%) one highly symmetrical entity. To isolate sufficient quantities of the major product for characterization, the reaction was repeated on a preparative scale, resulting in a pale yellow powder that was crystallized from MeOH/Et2O to yield a pure crystalline sample. Electrospray ionization mass spectrometric (ESI-MS) analysis of this sample revealed three major peaks at mass-to-charge (m/z) ratios of 1465, 1070, and 834, corresponding to [M–3TFA]3+, [M–4TFA]4+, and [M–5TFA]5+, respectively, a situation that is consistent with the proposed Borromean ring compound BR·12TFA.

Comparison of the 1H NMR spectrum of this crystalline material (Fig. 2B) with that of DAB-H4·4TFA (Fig. 2A) (both spectra recorded in CD3OD) reveals appreciable changes in the chemical shifts for the aromatic protons of the DAB fragment. Specifically, the resonances for H-e, H-f, H-g, and H-i are all moved upfield by as much as from 0.1 to 0.9 parts per million (ppm), indicating the occurrence of π–π stacking interactions, as predicted by the computational investigations carried out on the molecular Borromean ring (BR) surrogate. The averaged molecular symmetry (Th) of this compound, which is fluxional on the 1H NMR time scale at 50°C, is such that we would expect to see 1H NMR signals for only one quadrant of one of the [2+2] macrocycles, because all three rings are equivalent. Inspection of the 1H NMR spectrum shown in Fig. 2B reveals eight of the anticipated nine signals centered on δ 8.89 (H-c), 8.62 (H-a), 8.31 (H-b), 7.97 (H-i), 6.74/6.68 (H-e/f), 6.50 (H-g), and 4.84 (H-d). It is notable that the signal for H-g on the bipyridyl ligand is broad but that the signal for the vicinal H-h proton has merged into the baseline between δ 7 and 8 ppm. A spectrum recorded at 50°C indicates that the signal for H-g becomes much sharper, whereas that for H-h emerges out of the baseline and resonates as a broad singlet, centered on δ 7.90 ppm. This temperature-dependent behavior suggests that a (co)-conformational change might be occurring within the BR12+ dodecacation that is on the order of the 1H NMR time scale at room temperature.

Fig. 2.

The 1H NMR spectra (CD3OD, 298 K) of (A) the exo-bidentate ligand-containing starting material DAB-H4·4TFA (500 MHz), (B) the molecular Borromean rings BR·12TFA (600 MHz), and (C) an inseparable mixture of “empty” and “filled” Borromean rings, namely BR·12TFA and Zn@BR·14TFA, respectively (600 MHz). The letters a to i are defined for BR12+ with respect to the appropriate protons on the structural formulas shown in Fig. 1E. Primed letters represent the corresponding protons in Zn@BR14+.

The x-ray crystallographic analysis (33) of BR·12TFA reveals a molecular structure (Fig. 3, A to E) with S6 symmetry wherein the three rings have the topology of a Borromean link. Each of the three equivalent rings adopts a chairlike conformation and, consequently, the BR12+ dodecacation can be symmetry-related from half of one of the rings, which is 24.5 Å long from the tip of one pyridyl unit to the tip of the other. Molecular recognition is manifest in a mutually compatible manner. The three equivalent rings are held together by six Zn(II) ions, positioned 12.7 Å apart. They are each coordinated in a slightly distorted octahedral geometry to five N atoms (Zn–N bond lengths ranging from 2.10 to 2.24 Å with the cis N–Zn–N bond angles, ranging from 72.4° to 109.6°), with the sixth coordination site occupied by an O atom (Zn–O bond length of 2.06 Å and cis O–Zn–N bond angles, ranging from 89.0° to 99.3°) belonging to aTFA anion with a disordered trifluoromethyl group. The six equivalent bipyridyl ligands are sandwiched unsymmetrically between six pairs of phenolic rings, such that the π–π stacking distance is 3.61 Å in one direction and 3.66 Å in the other. The BR12+ dodecacation contains an inner chamber (34) of volume 250 Å3 lined with the van der Waals surfaces of 12 O atoms that are oriented in the form of a cuboctahedral array toward the center of the chamber, which contains species that give rise to nonresolved and diffuse electron density.

Fig. 3.

Different structural and superstructural representations of the BR12+ dodecacation(s) in the solid state as deduced from x-ray crystallography carried out on single crystals of BR·12TFA. In the case of the illustrations of the single BR12+ dodecacation, the three equivalent macrocycles are featured, as tubular and space-filling representations, in the three primary colors, green, red, and blue. The six Zn(II) ions are depicted in silver. (A) Tubular representation viewed down the S6 (and collinear C3) axis of BR12+ (B) Space-filling representation of A, showing the pore with a diameter of 2.08 Å in BR12+, which leads to an inner chamber. (C) Space-filling representation of BR12+, highlighting the mutually orthogonal arrangement of the three interlocked macrocycles adopting chairlike conformations wherein the distance from the tip of one pyridyl ring to the other, in any given macrocycle, is 24.5 Å. Multiple π–π stacking interactions are evident to the extent that all six equivalent bipyridyl ligands are sandwiched between six pairs of flanking phenolic rings, such that the plane-to-plane separations are 3.61 Å in one direction and 3.66 Å in the other. In addition, there are six [C–H···π] interactions (H···π distance 2.78 Å) between H-h on all of the bipyridyl ligands and the faces of the six pyridyl rings. The coordination sphere around each of the six equivalent Zn(II) ions exhibits distorted octahedral geometry, with a single TFA anion (not shown) occupying the sixth coordination site in all cases. (D) A stick representation of BR12+, upon which are superimposed a platonic solid (i.e., the silver octahedron with its vertices defined by the six Zn(II) ions and having edges that are all equal to 12.7 Å) and a slightly distorted Archimedean solid [i.e., the red cuboctahedron with its vertices defined by 12 O atoms (each 5.1 Å distant from the centroid of BR12+) that line the inner chamber of BR12+ and with a volume of ∼250 Å3]. (E) Space-filling representation of the hexagonal array of six individual columnar stacks of three BR12+ dodecacations clustered around a central column viewed down the c direction of the crystal lattice, showing the TFA anions (red and blue) coordinated to the Zn(II) ions. Neighboring BR12+ dodecacations are held together by intermolecular π–π stacking interactions (3.31 Å) between matching pairs of pyridyl rings. The small channels that run through the center of the superstructures are separated by 22.5 Å, and the large channels, which are 4.2 Å in diameter, are filled with Zn(II)-coordinated TFA anions (not shown) and separated from each other by 13.0 Å. (F) Space-filling representation of three interdigitated BR12+ dodecacations present in superstructural columns that run through the crystal in the c direction. Each BR12+ (green) in the columnar array is linked above (purple) and below (blue) itself by six [C–H···O=C] hydrogen bonds (with a [H···O] distance of 2.52 Å), which arise from an interaction between H-g in one BR12+ and the carbonyl oxygen atom of a Zn(II)-bound TFA anion in the neighboring BR12+. The distance within the columns between the centers of repeating BR12+ dodecacations is 16.3 Å.

At a supramolecular level, the BR12+ dodecactions are arranged (Fig. 3E) in hexagonal arrays with close (3.31 Å) intermolecular π–π stacking interactions between pairs of pyridyl rings in adjacent dodecacations, which form (Fig. 3F) columnar arrays in the orthogonal c direction that are stabilized by six [C–H···O=C] interactions between each BR12+ dodecacation, the centers of which are 16.3 Å apart. The six cylindrical channels that surround each column have a diameter of 4.2 Å and are filled with [ZnTFA4]2– counterions.

When the self-assembly process was repeated in 95% ethanol, we noted (Fig. 4) the appearance of additional peaks in the ESI mass spectrum at m/z 1563 and 1143 corresponding to [M–3TFA]3+ and [M–4TFA]4+, respectively, a situation that can be explained if an additional Zn·2TFA is associated with BR·12TFA. We propose that the central electron-rich cavity, decorated with 12 donor O atoms, and so qualitatively reminiscent of Cram's spherands (35), hosts the seventh Zn(II) ion. This hypothesis is supported by an 1H NMR spectrum (Fig. 2C) that shows an additional set of signals—some of which correspond to protons (H-c/c′, H-b/b′, and H-a/a′) on the periphery of the molecule and overlap with those for BR·12TFA— attributable to another highly symmetrical species that we propose is Zn@BR·14TFA, i.e., a seventh Zn(II) ion occupies the central electron-rich cavity of BR12+. Of further importance is that resonances corresponding to the protons H-i′ and H-g′, located much closer to the core of the molecule, are influenced most in their chemical shifts by the incarcerated guest.

Fig. 4.

(A) The ESI mass spectrum of a mixture of BR·12TFA and Zn@BR·14TFA. (B) The expanded isotopic distribution pattern for [M–4TFA]4+, which correlates well with the calculated distribution shown in (C).

The ability to produce gram quantities of highly soluble hosts that can locate a range of different transition metals in an insulated octahedral array around an inner heteroatom-lined chamber, which can provide a welcoming home for many different guest species, suggests numerous ideas in which these BR compounds could be exploited as highly organized nanoclusters in a materials setting such as spintronics (36) or in a biological context such as medical imaging (37).

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Materials and Methods

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