Multiple Catenanes Derived from Calix[4]arenes

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Science  28 May 2004:
Vol. 304, Issue 5675, pp. 1312-1314
DOI: 10.1126/science.1096688


A multicatenane is described in which two belts consisting of four annelated rings attached to the wide rims of two calix[4]arenes are interwoven in such a way that each ring of one belt penetrates two adjacent rings of the other belt and vice versa. The key step of the synthesis of this [8]catenane is the exclusive formation of preorganized heterodimers between a multimacrocyclic tetraurea calix[4]arene and an “open-chain” tetraurea calix[4]arene containing eight ω-alkenyl groups. When a tetraurea calix[4]arene containing four alkenyl groups is used, a bis-[3]catenane is formed analogously.

Topologically interesting molecules represent a permanent challenge for synthetic chemists (1). Möbius strips (2), various knots (3), K5 molecules (4), or first steps toward Borromean rings (5) may be cited as a somewhat arbitrary selection of examples. The interest is justified not only by the potential application of such systems, which has already been demonstrated for rotaxanes (6) and catenanes in the areas of molecular devices [for reviews, see (79)] and information storage (10, 11), but also because, in nature, topologically nontrivial forms of DNA play a crucial role in the correct replication and translation processes (12). An increasing understanding of the preorganization of suitable precursor molecules by reversible bonds (“self-assembly”) is responsible for the rapid progress in this area.

We recently have shown that the preorganization of tetraurea calix[4]arenes (Scheme 1, formula 1) in hydrogen-bonded dimers (13) (Fig. 1) can be used to synthesize novel bis-[2]catenanes by metathesis reaction between alkenyl groups attached to the urea residues R (14). A “statistical approach” with homodimers (1)2 led to three possible topological isomers: bis-[2]catenanes (5 to 12%), doubly bridged mono-[2]catenanes (26 to 32%), and tetrabridged capsules (10 to 15%). However, the bis-[2]catenane is the only identified reaction product when heterodimers of prefabricated double-loop derivative 3 with a tetraurea of type 1 (bearing 5-hexenyloxy chains instead of 7-octenyloxy chains) are reacted (15). Here, we show how such double-loop derivatives 3 and analogous tetra-loop derivatives 4 (16) of calix[4]arenes can be used as building blocks for novel multicatenanes.

Fig. 1.

(A) Hydrogen-bonded dimer of a tetraurea calix[4]arene 1 or 2, showing the mutual orientation of the urea residues R. Ether groups are omitted for clarity. (B) Schematic representation of the synthesis of multicatenanes 5 and 6 by metathesis reaction of selectively formed heterodimers 1·4 and 2a·4 followed by hydrogenation (reactions a and b). While reaction d led to a complicated mixture of products, reaction c (which has not yet been checked) seems at least an alternative to a, although wrong connections between double bonds are possible for c in contrast to a.

Scheme 1.

Formula survey.

“Open-chain” tetraureas 1 and 2 exist as well-defined homodimers in aprotic solvents (Fig. 2A). Tetraureas of type 3 and 4 do not homodimerize (Fig. 2B), because this would necessarily lead to a sterically unfavorable overlap of the loops. Thus, a solution of a 1:1 mixture of 4 and 1 or 2 in apolar solvents contains exclusively the heterodimers 1·4 or 2·4 as the only species that can be detected by proton nuclear magnetic resonance (1H NMR) spectra (Fig. 2C), because this is the only way by which all urea functions can be involved in the usual belt of 16 NH···O=C hydrogen bonds (17).

Fig. 2.

1H NMR spectra (400 MHz) of (A) homodimer 2a2 (chloroform-d1); (B) ill-defined assemblies of 4; (C) heterodimer 2a·4; (D) [8]catenane 6 (all in dichloromethane-d2); (E) 6 (in THF-d8); (F to H) 6 (in pyridine-d5) at 25°C, 55°C and 100°C, respectively. Signals of the urea groups (α and β for the hydrogens of NH groups nonattached and attached to the calixarene moieties, respectively), signals of the calixarene aromatic hydrogens (γ, γ′), and signals of the methylene bridge protons ArCH2Ar (δ, δ′) are indicated; signals of solvents are marked with asterisks.

Metathesis reaction of such pseudorotaxane-like heterodimers (18) under the conditions described before (15, 19) leads (after hydrogenation) to a single reaction product 5 or 6, as schematically represented in Fig. 1B (reactions a and b).

Both compounds were isolated in >50% yield after a simple purification by column chromatography and recrystallization. Their unprecedented multicatenane structure was unambiguously proved by electrospray ionization mass spectrometry (20) and 1H and 13C NMR. Compound 6, especially, shows in apolar solvents the usual S8 symmetry of a homodimer of type (1)2 with two (and only two) singlets for NH protons and two (and only two) meta-coupled doublets for the aryl protons of the calixarene; thus, all of the phenolic units are identical, but the two sides of each unit are different. Three different meta-coupled triplets for the 3,5-dialkoxyphenyl groups attached to the urea functions are observed, because these units can not freely rotate around the urea N–C bond. This picture is typical for capsular dimers of tetraurea calix[4]arenes and is caused by the directionality of the carbonyl groups in the hydrogen-bonded belt, which is stable on the NMR time scale (Fig. 2D).

In the catenane 5, two bridges are missing, and thus the calix[4]arene units are not identical anymore. The spectrum of 5 shows four NH signals of strong hydrogen-bonded urea protons (21), four pairs of meta-coupled doublets, and four pairs of doublets with geminal coupling for the ArH and ArCH2Ar protons of the calixarene. This spectral picture (22) corresponds to the C2 symmetry expected for a kinetically stable orientation of the C=O groups in the hydrogen-bonded belt of the urea functions. While catenane 6 is achiral (S8 symmetry), catenane 5 is chiral (C2 symmetry) as a result of this directionality. Changing it leads to the opposite enantiomer.

Multicatenane 6 consists of two (conically shaped) belts of four annelated rings attached to the wide rims of two calix[4]arenes, which are interwoven in such a way that each ring of one belt penetrates two adjacent rings of the other belt and vice versa. Multiple interlocking systems of much higher complexity are found in nature. The overall structure of the HK97 capsid is stabilized by catenation of giant peptide macrocycles on the surface of an icosahedral particle of 660 Å diameter (23). The structure of 6 was determined definitely by x-ray analysis (Fig. 3) (24). The molecule has crystallographic C2 symmetry, with an axis going through the poles of the capsule formed by the two calix[4]arenes. Despite the relatively high R1 value (high because of the size of 6 and the quality of the crystal), the interlocked rings connecting the aromatic units of the two calix[4]arenes were unambiguously found. Additionally, the two tetraurea calix[4]arenes are held together by the usual belt of hydrogen bonds between eight interpenetrating urea functions. N-O distances (in Å) are Nα-O: 2.879, 2.817, 2.781, and 2.795; Nβ-O: 3.222, 3.223, 3.214, and 2.960. Thus, the typical capsular structure of such tetraurea dimers is retained.

Fig. 3.

Space-filling representation of the molecular structure of 6 in the crystalline state. (Left) Top view. Methoxy groups of one calix[4]arene are pointing toward the reader. (Right) Side view. The two multimacrocyclic calix[4]arenes are colored blue and red. Hydrogen atoms are omitted for clarity.

Hydrogen bonds within tetraurea dimers of 1 or 2 are broken in tetrahydrofuran-d8 (THF-d8), and only the simpler spectra of monomeric C4v-symmetrical calix[4]arenes are found. For 5 and 6, however, the 1H NMR spectrum is not simplified, and its lowfield part shows in principle the same pattern as in dichloromethane-d2 (Fig. 2E). The picture is not changed upon heating up to 55°C. In the more powerful hydrogen-bond-breaking solvent pyridine-d5, the rotation of the hydrogen-bonded belt in 6 is still slow on the NMR time scale at 25°C, because two broad but clearly distinguishable signals of the calix[4]arene aromatic protons (γ, γ′) and two signals of ortho-protons for tri-substituted aromatic groups, attached to urea functions, are found (Fig. 2F). Even at 100°C (Fig. 2H), the complete coalescence of these signals is not yet reached (25). Obviously, the intertwining of the two molecules makes the complete solvation of the urea functions and their free rotation around the Ar-NH σ-bonds impossible. Nevertheless, the exchange of the included guest is still possible (20).

In contrast to catenane 6, catenane 5 with two “missing” alkyl loops shows broad unresolved signals for aromatic moieties and urea groups in pyridine-d5 at 25°C. At high temperature (100°C), however, the observed pattern for NHα signals (three singlets in the ratio 2:1:1) and for the signals of calixarene methylene bridges ArCH2Ar (three pairs of doublets in the ratio 2:1:1) is in accordance with the time-averaged C2v symmetry expected for the case where the hydrogen-bonded belt changes its directionality quickly on the NMR time scale (22).

Molecules of types 5 and 6 appear to be unprecedented in their connectivity. Considering just the interlocked rings, the molecules can be regarded as bis-[3]catenane, and [8]catenane, respectively. The principle discussed and described above for their synthesis implies the selective heterodimerization of a bis- or tetra-loop tetraurea calix[4]arene with a reactive open-chain tetraurea calix[4]arene. We are convinced that this principle can also be applied to tetraurea derivatives with other loops, to other ring closure reactions, and to the formation of novel rotaxanes.

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