Ultramacrocyclization in water via external templation

Condensing a dihydrazide and each of a series of cationic bisaldehyde compounds bearing polymethylene chains in weakly acidic water produces either a macrocycle in a [1 + 1] manner or its dimer namely a [2]catenane, or their mixture. The product distribution is determined by the length of the bisaldehydes. Addition of cucurbit[8]uril (CB[8]) drives the catenane/macrocycle equilibria to the side of macrocycles, by forming ring-in-ring complexes with the latter. When the polymethylene unit of the bisaldehyde is replaced with a more rigid p-xylene linker, its self-assembly with the dihydrazide leads to quantitative formation of a [2]catenane. Upon addition of CB[8], the [2]catenane is transformed into an ultra-large macrocycle condensed in a [2 + 2] manner, which is encircled by two CB[8] rings. The framework of this macrocycle contains one hundred and two atoms, whose synthesis would be a formidable task without the external template CB[8]. Removal of CB[8] with a competitive guest leads to recovery of the [2]catenane.


Introduction
Synthesis of macrocyclic compounds represents one of the major focuses in the eld of supramolecular chemistry. 1 When the sizes of the rings become larger, their production becomes more challenging, given that macrocyclization of rings containing more atoms implies more entropy loss. High dilution conditions 2 and/or addition of feasible guest templates 3 have proven to be efficient approaches to suppress or avoid oligomeric or polymeric byproducts. However, these approaches become less useful in the case that the sizes of macrocyclic products are ultra-large, especially for those rings containing more than one hundred atoms. In addition, nding a feasible internal guest template to t within the cavity of an ultra-large macrocycle becomes more difficult, despite a few exceptions. 4 Our group 5 and others 6 discovered that hydrazone condensation represents an ideal dynamic covalent reaction that is amenable to use in water. A variety of [2]catenanes, 5a,d-f rings, 5c,d,6d,e and cages 5b,g were self-assembled in aqueous media, thanks to the reversible nature of hydrazone that allows the systems to perform error checking. In addition, cucurbit[8]uril (CB[8]) 7c,e,g,i,k was observed as a host that is able to accommodate a two p-electron guest, driven by the hydrophobic effect and dipole-cation interactions in the case of cationic guests such as pyridinium derivatives. We thus envision that by taking advantage of the marriage of dynamic covalent chemistry 5,6,8 and external templation based on CB[8] rings, 7 we might be able to self-assemble an ultra-large macrocycle. Here, by condensing a dihydrazide and a dicationic bisaldehyde containing a polymethylene chain in water, rings with medium sizes containing y to sixty atoms in their framework were self-assembled in a [1 + 1] manner as the major products. When the polymethylene chain becomes longer, the macrocycles start to undergo equilibration with their dimerized form namely [2] catenanes, driven by the hydrophobic effect. In the presence of CB[8], the macrocycle- [2]catenane equilibria shied to the side of macrocycles, each of which was accommodated within the cavity of a CB[8] ring, forming a set of [2]pseudorotaxanes. The formation of these ring-in-ring complexes 9 is favored by the CB [8]-pyridinium interactions between the host and the guest. When the poly-methylene chain in the bisaldehyde was changed to a more rigid p-xylene unit, its self-assembly with the dihydrazide linker resulted in the exclusive formation of a [2]catenane in close to a quantitative yield, thanks to the dynamic nature of hydrazone bonds that allows error checking. Addition of CB[8] led to decomposition of this [2]catenane. However, the putative [2]pseudorotaxane was not obtained as occurred in the case of the aforementioned polymethylene counterparts. This is probably on account of the p-xylene linker, which renders the [1 + 1] macrocycle too large to t within the CB[8] cavity. Instead, the bisaldehyde and bishydrazide underwent condensation in a [2 + 2] manner, forming an ultra-large macrocycle that was encircled by two CB[8] rings. This macrocycle contains more than one hundred atoms in its framework, whose formation would be rather challenging without the external template CB [8] rings. Upon removal of the CB[8] by adding a competitive guest, the ultra-large macrocycle underwent decomposition, regaining the [2]catenane.
Upon addition of an equimolar amount of CB[8] to a D 2 O solution of a 1 : 1 mixture of 2 (2.5 mM) and each of 1x 2+ $2Br À (x ¼ a, b, c, d and e; 2.5 mM) in the presence of DCl ( Fig. 1 and Scheme S8 †), a set of [2] , c, d and e) were observed to form as the predominant products. The yields of (1x 2+ $2)3CB[8] (x ¼ a, b, c, d and e) (counteranions could be either Cl À or Br À ) were determined to be 80%, 74%, 88%, 90% and 85% ( Fig. S62A, S63A, S64A, S65A and S66A †), respectively, calculated by using an internal standard in the corresponding 1 H NMR samples. The structures of these [2] pseudorotaxanes were fully characterized by both 1 H NMR spectroscopy and mass spectrometry (Fig. S6, S7, S15, S16, S25, S26, S33, S34, S42 and S43 †). The 1 H NMR spectra of both (1a 2+ $2) and (1a 2+ $2)3CB[8] are shown in Fig. 2D. The resonances corresponding to the protons b and c in the guest undergo remarkable upeld shis, indicating that the CB[8] host encircles the phenylene units in the 1a 2+ residue, driven by the hydrophobic effect. As a comparison, the phenylene units in the 2 residue are located outside the pocket of CB[8], as indicated by the downeld shis of the corresponding protons. CB [8] chooses to reside on the phenylene units in the 1a 2+ residue Fig. 1 Structural formulae of a series of dicationic bisaldehydes 1x 2+ (x ¼ a, b, c, d and e) and a bishydrazide 2. A series of dicationic macrocycles (1x 2+ $2) (x ¼ a, b, c and d), as well as a set of tetracationic [2]catenanes (1x 2+ $2) 2 (x ¼ c, d and e) were self-assembled by combining each of the bisaldehydes and the bishydrazide in water. Addition of CB[8] into each of these self-assembly products led to formation of a series of [2] pseudorotaxanes (1x 2+ $2)3CB[8] (x ¼ a, b, c, d and e). Charges are balanced by Cl À or Br À counteranions, which are omitted here for the sake of clarity. The yields shown are determined by 1 H NMR spectroscopy. It seems that the counterions have little impact on the self-assembly.
instead of those in 2, because of the cation-dipole interactions between the CB[8] host and the pyridinium cations in the 1a 2+ residue of the macrocyclic guest. The host/guest association and dissociation occurred at a relatively slow rate on the timescale of 1 H NMR spectroscopy, as indicated by the observation that the two protons of CB[8] become chemically inequivalent in the 1 H NMR spectrum of (1a 2+ $2)3CB[8] (Fig. 2D). Addition of an equimolar amount of CB[8] to the corresponding pre-selfassembled [2]catenanes also produced the same [2]pseudorotaxane products, indicating that the corresponding [2]pseudorotaxanes (1x 2+ $2)3CB[8] (x ¼ a, b, c, d and e) are thermodynamic products, instead of kinetically trapped ones. Apparently, the formation of [2]pseudorotaxanes is more favored by dipole-cation interactions resulting from CB[8], compared to the homo [2]catenanes.

Conclusion
In summary, by combining the corresponding bishydrazide and a set of cationic bisaldehydes bearing polymethylene chains in aqueous media, a series of [1 + 1] macrocycles were self-assembled, accompanied with the corresponding dimers namely [2]catenanes. The product distribution was determined by the length of the polymethylene chains in the bisaldehyde precursors. That is, the longer chains favor the formation of [2] catenanes, while the shorter ones favor the macrocycles more. Upon addition of CB[8], the macrocycles form a set of [2] pseudorotaxanes, driving the catenane/macrocycle equilibria to the side of macrocycles. When the polymethylene units in the bisaldehyde compounds are replaced by a p-xylene unit, the putative [1 + 1] condensed ring is too large to t within the ring of CB [8]. Instead, an ultra-large macrocycle was self-assembled in a [2 + 2] manner, which was encircled by two CB[8] rings that act as the external templates. The framework of the ultra-large ring contains more than one hundred atoms, whose synthesis would be thermodynamically disfavored in the absence of the external template, namely CB [8]. We envision that the success in formation of a ring-in-rings complex would be taken advantage of in the synthesis of more complex architectures, such as Borromean rings. Such trials are ongoing in our laboratory.

Data availability
Data for this paper, including the synthesis, structural characterization are available at ESI. †

Conflicts of interest
There are no conicts to declare.