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Published in final edited form as: Nat Chem. 2022 Dec 1;15(3):413–423. doi: 10.1038/s41557-022-01094-w

Dimeric and Trimeric Catenation of Giant Chiral [8+12] Imine Cubes Driven by Weak Supramolecular Interactions

Bahiru Punja Benke 1, Tobias Kirschbaum 1, Jürgen Graf 1, Jürgen H Gross 1, Michael Mastalerz 1,*
PMCID: PMC9986109  EMSID: EMS155921  PMID: 36456691

Abstract

Mechanically interlocked structures, such as catenanes and rotaxanes, are fascinating synthetic targets and some are used for molecular switches and machines. Today, the vast majority of catenated structures are built upon macrocycles and only a very few examples of three-dimensional shape-persistent organic cages forming such structures are reported. However, the catenation in all these cases was based on a thermodynamically favoured π-π stacking under certain reaction conditions. Here, we show that catenane formation can be induced by adding methoxy- or thiomethyl groups to one of the precursors during the synthesis of chiral [8+12] imine cubes, giving dimeric and trimeric catenated organic cages. To elucidate the underlying driving forces, we reacted eleven differently 1,4-substituted benzene dialdehydes with a chiral triamino tribenzotriquinacene under various conditions to study whether monomeric cages or catenated cage dimers are the preferred products. We find that catenation is mainly directed by weak interactions derived from the substituents rather than by π-stacking.

Since the first report of Wasserman in the early 1960s of a catenane as a statistical occurring by-product during a macrocyclization via acyloin condensation,1 the interest in interlocked molecular structures developed rapidly in the last decades,2,3 especially because such compounds build the fundamental knowledge for supramolecular switches and machines.4,5,6 Although Lüttringhaus and Schill introduced already rational synthetic approaches towards a number of interlocked structures in the 1960s,7 the real ignition of this research field began with the work by Jean-Pierre Sauvage and coworkers with a high-yielding catenane synthesis exploiting the templated coordination of two molecular strands by a metal ion before closing these to two interlocked macrocycles via Williamson ether synthesis.8,9 This concept of using a template was and still is the most frequently applied strategy for the synthesis of more complex interlocked structures such as Borromean rings,10 various knots,11,12,13,14 a Star of David catenane,15 poly[n]catenanes,16 or interlocked coordination cages.17,18,19,20,21 Besides ligand to metal ion coordination, weaker and less directing supramolecular interactions—such as hydrogen bonding or π-π stacking—have been used to arrange molecular precursors in the right fashion to synthesize interlocked structures.22

In contrast to the relative large number and diversity of interlocked coordination cages,18 there are still only a few examples of purely organic cage catenanes reported to date. The first example was reported by Beer et al.23 They exploited a template effect of sulfate anions, interacting with carbamate units to prearrange two tripodal precursor molecules in such a way that by the end-capping of these via a copper-mediated 1,3-dipolar cycloaddition a triply interlocked cage dimer was formed in 21% yield. One year later, in 2010, Cooper and coworkers described that by changing conditions for the synthesis of a [4+6] imine cage by adding catalytic amounts of trifluoroacetic acid to the reaction solution in acetonitrile or dichloromethane, these [4+6] imine cages form triply interlocked dimers,24 which was proven by single-crystal X-ray diffraction. It was suggested that π-π stacking most probably is the driving force for the catenane formation and if a competing aromatic solvent was present in certain amounts, this indeed suppressed the catenane formation. In 2014, the formation of a quadruply interlocked dimer of giant [12+8] boronic ester cage was described,25 which was clearly characterized by single-crystal X-ray diffraction. The only difference between the interlocked cage dimer and a corresponding monomeric [12+8] boronic ester cage26 published before is the position and length of solubilizing alkyl-chains in the molecular precursors, which led to the hypothesis that additionally weak dispersion interactions may be responsible for the catenane formation to overcome any entropic penalty. Similar but more distinct, this entropic penalty was balanced by dispersion interactions in the formation of a hydrocarbon cage and its catenated dimer made by alkyne metathesis.27 Depending on concentration of reacting monomers, the equilibrium between monomeric and interlocked cage could be shifted towards the one or the other metathesis product. The authors assumed that a triply interlocked structure is energetically more favored than a singly one due to a maximization of filled space. 2015, Li et al. exploited the hydrophobic effect to achieve an interlocked cage dimer via a hydrazone bond formation in water.28 Very recently, the group of Shaodong Zhang presented the formation of a triply interlocked catenane of a [2+3] imine cage.29,30 Again, it was concluded that the driving force is the energetic benefits of additional π-π stacking. In contrast to the before mentioned examples, here the dimer formation has been studied more detailed by kinetic NMR measurements and time-dependent mass spectrometry; however, no thermodynamic assumptions were corroborated by experiments. It is worth mentioning that Greenaway et al. described the unexpected formation of a bridged cage catenane, during large high-throughput screening.31

During our ongoing work on using chiral triamino tribenzotriquinacenes (TBTQs) in the condensation with aromatic aldehydes to study self-sorting of cages,32,33 we serendipitously found a substituent driven formation of dimeric and trimeric cage catenanes, which is described herein.

Results and Discussion

Synthesis and characterization of cage and catenanes

Inspired by Warmuth’s chiral cube,34 based on the condensation of eight molecules of cyclotriveratrylene (CTV) trisaldehyde and para-phenylene diamine, we intended to use a chiral TBTQ precursor instead, which is in contrast to the CTV structurally fixed and cannot racemise during cage formation. Indeed, the condensation of enantiopure triamino TBTQ (P)-135 with 2,4-dihydroxy terephthalaldehyde 2 under typical conditions we used before for similar systems (cat. TFA, CDCl3 room temperature)34,36 gave clean chiral [8+12] cage OH-cube in 88% isolated yield (Fig. 1) and was identified by NMR and mass spectrometry.

Figure 1. Synthesis and characterization of chiral OH-cube.

Figure 1

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a Schematic representation of the acid catalysed 24-fold imine condensation of chiral TBTQ amine 1 and 2,5-dihydroxy terephthalaldehyde 2 to OH-cube. Please note that the alkyl substituents of TBTQ are omitted on the cubic structure of OH-cube for clarity. Reactants and cube are also drawn as cartoons. Red balls represent the TBTQ units and blue struts the aldehyde or imine linker units. b 1H NMR spectrum (500 MHz, CD2Cl2, room temp.) of pure OH-cube. For assignment see atom labels in the molecular structure of OH-cube in panel a and Supplementary Section 2. c MALDI-TOF MS (DCTB) of pure OH-cube. The inset shows the comparison of measured and calculated isotopic patterns for OH-cube.

Originally we were interested in post-stabilizing the OH-cube by Pinnick-oxidation to turn imine bonds into amide bonds.37 As reported before, this does not work with the phenolic hydroxy groups present. To avoid a 24-fold post-synthetic Williamson etherification on OH-cube,38 we instead condensed TBTQ (P)-1 with dimethoxy terephthalaldehyde 3 under the same conditions (Fig. 2a). In contrast to the reaction with aldehyde 2, here the 1H NMR spectrum of the crude product was very complex with a large number of peaks in the aromatic as well as in the aliphatic region (Fig. 2b). The corresponding MALDI-TOF MS revealed that beside the [8+12] OMe-cube (m/z = 5623.21), a [16+24] condensation product (m/z = 11245.46) was generated and even a small peak with m/z = 16868.53 was detected (Fig. 2c), suggesting that a larger [24+36] species may have formed. Taking into consideration the complex 1H NMR spectra reported for triply interlocked cages before,24 it was assumed that these species are most likely catenated dimer (OMe-cube)2 and trimer (OMe-cube)3 rather than larger more symmetric and non-interlocked species. By applying recycling gel permeation chromatography (r-GPC) with dichloromethane as solvent, it was possible to separate the three compounds after multiple cycles (Fig. 2d, and Supplementary Section 8).

Figure 2. Synthesis and analysis of monomeric cage and dimeric and trimeric catenanes.

Figure 2

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a Schematic representation of the acid catalysed 24-fold imine condensation of 1 and 2 to OMe-cubes. b and c 1H NMR (600 MHz, CDCl3) and MALDI-TOF MS (DCTB) of crude reaction mixture of OMe-cubes. 1H NMR spectrum of the crude product was very complex but that the MALDI-TOF MS spectrum was relatively clear with three distinct peaks. Peaks in the MALDI-TOF MS are labelled with the structures of the products, and that the small peak for the trimeric catenane is highlighted and shown in inset. d r-GPC traces (solvent DCM) of the crude reaction mixture of OMe-cube, (OMe-cube)2 and (OMe-cube)3 clearly show three peaks.

As described in literature before, the equilibrium between monomeric and catenated cage shifts towards the latter by increasing the concentration of reactants and vice versa to the monomeric cage by decreasing it. Therefore, the reaction was performed at different concentrations (between 0.42 mM and 42.8 mM) and analyzed mainly by MALDI-TOF MS (Supplementary Table 1). As expected, with higher concentration more catenated compounds (OMe-cube)2 and (OMe-cube)3 were found and the concentration needs to be 0.42 mM or below to avoid the formation of those and to form monomeric cage OMe-cube exclusively. For comparison; reactions with dihydroxy terephthaldehyde 2 at various concentrations (up to 42.8 mM) did not give any catenated species and in each experiment only monomeric cage OH-cube was detected by 1H NMR spectroscopy (Supplementary Fig.398). It is worth mentioning that as soon as a chloroform or dichloromethane solution of monomeric cage OMe-cube was concentrated by rotary evaporation (50 °C, reduced pressure), the equilibrium immediately shifted towards the catenated products (OMe-cube)2 and (OMe-cube)3 as found by NMR and r-GPC analysis. On one hand, this clearly demonstrated the dynamic covalent chemistry character and thus thermodynamically driven formation of the catenane.39 On the other hand, it made the separation and characterization of monomeric cage OMe-cube more challenging.

Despite these findings, we were able to develop a synthetic protocol to isolate OMe-cube in 85% yield, avoiding long reaction times, certain concentration and temperature thresholds and exploiting the low solubility of the cage in acetonitrile (Supplementary Section 2). To our delight, by changing the solvent to 1,1,2,2 tetrachloroethane (TCE), monomeric cage OMe-cube can be synthesized even at higher concentration (5.4 mM), without the necessity of GPC separation, in 76% yield (Fig. 3a). On the other hand, running the reaction of 3 and 1 in dichloromethane instead of CHCl3 at 10.7 mM concentration and 80 °C for 3 days allowed us to push the equilibrium towards the tricatenane (OMe-cube)3, which was isolated in 80% yield (Fig. 3a). The best results for the dimeric cage (OMe-cube)2, was achieved, when dialdehyde 3 and triamine 1 were reacted at 10.7 mM scale. However, (OMe-cube)2 still needed to be separated by r-GPC from OMe-cube and (OMe-cube)3 at 35 °C to be obtained in 46% isolated yield (Fig. 3a).

Figure 3. Selective synthesis and characterisation of OMe-cube, (OMe-cube)2 and (OMe-cube)3.

Figure 3

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a Schematic representation of the acid catalysed 24-fold imine condensation of 1 and 3 in different solvents for the selective formation of OMe-cube, (OMe-cube)2 and (OMe-cube)3. For reaction details, see Supplementary Section 2. b, d, f r-GPC-traces (solvent DCM) of pure OMe-cube, (OMe-cube)2 and (OMe-cube)3 show retention times 27.7, 25.9 and 25.4 minutes respectively which are consistent with their sizes. Depicted is the 1st cycle for each. c, e, g corresponding MALDI-TOF mass spectra of pure OMe-cube, (OMe-cube)2 and (OMe-cube)3 showing exclusively single peak for each species. h, i, 1H NMR spectra (600MHz, 295 K, CD2Cl2) of pure OMe-cube and (OMe-cube)2. J 1H NMR spectra (700 MHz, 375 K, Toluene-d8) of pure (OMe-cube)3.

Mechanistic investigation of monomeric cage to dimeric catenane reaction

To get some more mechanistic information of catenane formation, the transformation of OMe-cube to (OMe-cube)2 was studied in more detail. Kinetic NMR experiments indicated that full equilibrium between OMe cube (c0 = 1.35 mM, CDCl3) and (OMe-cube)2 was achieved after approx. 800 mins (k1 = 10.5 ± 0.4 M-1s-1), if catalytic amounts of TFA are present (Supplementary Fig. 506). In the absence of acid, no conversion at all was detected even after 24 hrs (Supplementary Fig. 507). By mixing a 15N-labelled cage *OMe-cube in a 1:1 stoichiometry with nonlabelled OMe-cube under reaction conditions (cat. TFA, CDCl3) and analyzing the mixture after 3 days by TIMS-TOF MS revealed that all units (TBTQ and linkers) are fully scrambling to a statistical mixture, suggesting that during catenane formation all TBTQ units must be disconnected from the cage scaffolds at a certain stage, opening the cages for catenation (Supplementary Figs. 508 & 509).

Structural analysis of cage and dimeric and trimeric catenanes

The GPC purified fractions were again separately injected into r-GPC that shows three distinct peaks each of nearly Gaussian shape with retention times of 25.4 min (1st fraction), 25.9 min (2nd) and 27.7 minutes (3rd) were detected (Figs. 3b, d and f). MALDI-TOF MS analysis of each fraction (Figs. 3c, e, and g) now show single peaks exclusively at m/z = 16868.69 (1st fraction), m/z = 11245.57 (2nd fraction) and m/z = 5623.24 (3rd fraction) which exactly fit to a [24+36], a [16+24] and a [8+12] species. The 1H NMR spectrum (Fig. 3h) of the 3rd fraction was very simple, showing signals comparable to OH-cube and in combination with the mass spectrum (Fig. 3c) this compound was clearly identified as the monomeric chiral [8+12] OMe-cube. By diffusion-ordered NMR spectroscopy (DOSY) in deuterated dichloromethane at 295 K only one trace was detected with a diffusion coefficient of D = 3.09·10-10 m2s-1 which corresponds according to the uncorrected Stokes-Einstein equation to a solvodynamic radius of rS = 16.9 Å (Supplementary Fig. 308). In contrast to the relatively simple 1H NMR spectrum of monomeric OMe-cube (Fig. 3h), that of the [16+24] species was much more complex (Fig. 3i). Nevertheless, despite the large number of signals, most of them were sharp and did not superimpose, allowing a more detailed analysis of the structure (Fig. 4a and for detail structural analysis see Supplementary Section 13). By 2D NMR experiments, eight different types of imine-protons and eight different methoxy-protons were identified (Figs. 4b and 4c). This is exactly the number expected for a triply interlocked cage dimer (see cartoon in Fig. 4h.) Other possible catenanes such as a singly interlocked dimer (Fig 4g, twelve imine peaks) or quadruply interlocked dimer (Figure 4i, six imine peaks) can clearly be ruled out. By DOSY NMR in dichloromethane at 295 K only one trace of signals for (OMe-cube)2 confirmed that this is a single species. The diffusion coefficient D = 2.67·10-10 m2s-1 corresponds to a solvodynamic radius of 19.6 Å (Supplementary Fig. 309). This is slightly larger than for OMe-cube (16.9 Å) which is consistence with its slightly larger size.

Figure 4. NMR spectroscopic analysis and assignment of (OMe-cube)2.

Figure 4

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a Full 1H NMR (600 MHz, CD2Cl2) spectrum of (OMe-cube)2. Partial 1H NMR (600 MHz, CD2Cl2) showing eight different types of b imine peaks and c methoxy peaks of (OMe-cube)2. d NOESY spectrum showing cross peaks between imine proton B and methoxy proton d. e NOESY spectrum showing cross peaks between methoxy protons b and d. f NOESY spectrum showing cross peaks between highly shielded aliphatic protons of propyl chains and methoxy protons e and f. g cartoon of the singly catenated cubes highlighting the 12 different magnetically equivalent imine protons respectively. h cartoon of the triply interlocked catenated cube highlighting the 8 different magnetically equivalent imine protons. The colour code and assignment are the same as in b and c. i cartoons of the quadruply interlocked catenated cubes highlighting the 6 different magnetically equivalent imine protons respectively.

The trimeric interlocked cage (OMe-cube)3 shows at room temperature much less resolved multiple broad peaks in the 1H NMR spectrum (Supplementary Fig. 72) in contrast to dimer (OMe-cube)2. However, in toluene-d8 at 375 K a much better resolved spectrum was obtained, showing sets of 12 magnetically different peaks, such as 12 imine protons and 12 signals of the terminal CH3 group of the propyl chains (Figs 5a-5c, Supplementary Figs. 88- and 89). This excludes a syn-distal connectivity (36 imine peaks; Fig 5c, for models see, Supplementary Fig. 522) as well as a syn-proximal connectivity at two adjacent corners at the central cube (here 72 imine peaks are expected; Fig. 5d, for models see, Supplementary Fig. 523). For both a chain-like anti-connected catenane (OMe-cube)@(OMe-cube)@(OMe-cube) as well as for an interwoven catenane [(OMe-cube)@(OMe-cube)]@(OMe-cube) the same number—12—of magnetically different peaks are expected, as has been found (for models, see Supplementary Figs. 520 & 521). However, since the trimeric catenane (OMe-cube)3 is still very soluble under reaction conditions and no traces of larger oligomers such as tetrameric and pentameric cages (OMe-cube)4 or (OMe-cube)5 are found by mass spectrometry, it seems to be more likely that the interwoven catenane [(OMe-cube)@(OMe-cube)]@(OMe-cube) (Fig. 5a) and not the chainlike anti conformed catenane (OMe-cube)@(OMe-cube)@(OMe-cube) (Fig. 5b) has formed. If it would be the latter motif, we would expect at least some formation of longer oligomers, which is not the case. On the other hand, an interwoven tetrameric catenane is simply not possible for steric reasons, which once more would explain the absence of larger species and thus favors this motif for the trimeric catenane [(OMe-cube)@(OMe-cube)]@(OMe-cube). DOSY NMR of (OMe-cube)3 again shows a single trace with a diffusion coefficient D = 2.64·10-10 m2s-1. The calculated solvodynamic radius of 19.8 Å (Supplementary Fig. 310) was found to be almost similar with the dicatenane (OMe-cube)2 (19.6 Å) once more suggesting a tightly packed interlocked structure. In DOSY NMR spectra of a 1:1 stoichiometric mixture of pure (OMe-cube)2 and OMe-cube)3 (Supplementary Fig. 512) the difference between the diffusion coefficient values is very small further supporting the more dense interwoven catenane [(OMe-cube)@(OMe-cube)]@(OMe-cube) model.

Figure 5. NMR spectroscopic analysis and assignment of (OMe-cube)3.

Figure 5

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a Full 1H NMR (700 MHz, 375 K, Toluene-d8) spectrum of (OMe-cube)3. Partial 1H NMR (700 MHz, 375 K, Toluene-d8) showing twelve different types of b imine peaks and c methyl peaks of (OMe-cube)3. Cartoons of the d [(OMe-cube)@(OMe-cube)]@(OMe-cube), e (OMe-cube)@(OMe-cube)@(OMe-cube), f syn-distal and g syn-proximal trimeric catenanes highlighting the 12, 12, 36 and 72 different magnetically equivalent imine protons in different colour codes respectively.

It is worth mentioning that for OH-cube, OMe-cube, (OMe-cube)2 as well as (OMe-cube)3 and other cage catenanes described below innumerous large single-crystals from various solvents have been obtained. Unfortunately, even with synchrotron radiation no resolution has been obtained to elucidate the solid-state structures.

Investigation in driving force for catenation

We were interested to get further insight into the driving force of the unique catenation of methoxy cage OMe-cube to dimer (OMe-cube)2 and even to trimer (OMe-cube)3 and why we do not see any such catenation for the hydroxyl substituted OH-cube under any concentration. Due to the triply interlocked catenation of dimer (OMe-cube)≡OMe-cube) in favour of a possible singly interlocked dimer (OMe-cube)-(OMe-cube), the aforementioned π-π stacking as driving force, found for almost all other yet in literature described interlocked organic cages, was excluded (see above), otherwise singly interlocked catenation should have been formed preferably. In addition for OH-cube a higher tendency of dimerization would have been expected than for OMe-cube, because intramolecular H-bonding of the hydroxyl imine is stiffening the π-backbone and strongly enhances intermolecular π-π stacking.40 This assumption is strengthened by the fact that under various reaction conditions (different acid concentration, different concentration of reactants, different solvents, different and elevated temperature, different reaction times (up to several months!)) no substantial catenane formation was found for OH-cube (see Supplementary Figs. 398, 400, 401 and 510). A kinetic formation driven by precipitation was also ruled out, because the reaction mixture of 1, 2 and OH-cube were at all times clear solutions.39 Furthermore, mixing OH-cube and 15N labelled *OH-cube in a 1:1 ratio and treating this mixture under reaction conditions, shows by TIMS-TOF MS two highest peaks at m/z = 5297.56 (corresponding to OH-cube-15N12) and at m/z = 5320.54 (corresponds to (OH-cube-15N12+Na) suggesting a complete scrambling even in solution, supporting the thermodynamically formation of OH-cube and that it is not a kinetic trap (Supplementary Figs. 510 &511).41

Since π-stacking was ruled out as driving force, we first hypothesized that dipole-dipole interactions (so-called Keesom interactions)42 of the methoxy groups may be responsible for the catenation, as e. g. found in single crystals of methoxy-substituted π-systems (d(MeO⋯CH3O) = 3.1 Å).43 In this respect, it is worth mentioning that the bridged cage catenane reported by Greenaway et al., when originally achieving cages based on dimethoxy terephthaldehyde 3,31 could rely on such weak interactions, although a closer look at the X-ray structure show the same methoxy-methoxy interaction motif, albeit with a larger distance between the functional groups of d(MeO⋯CH3O) = 3.5 Å (Supplementary Fig. 513). Conformational analysis by DFT calculations (Supplementary Section 19) of OMe-cube as well as NOESY cross peaks between imine CH and the aromatic TBTQ protons revealed a low barrier of rotation of the linker units at room temperature, which is also present in the triply interlocked dimer (OMe-cube)2 allowing the mechanically interlocked molecule to adopt conformations that have three such methoxy-methoxy interactions (Fig. 6c). According to this assumption (Supplementary Figs. 513d & e), one methoxy group per dialdehyde unit should be enough to foster catenation and indeed reacting dialdehyde 12 (with only one methoxy group present) with triamine 1 in DCM clearly gave catenated (H/OMe-cube)2, as determined by MS (Supplementary Fig. 345).

Figure 6. Summary of cage and catenanes with twelve different dialdehyde linkers.

Figure 6

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a Reactions of various dialdehydes with TBTQ triamine 1, giving cages (left side) or catenated cages (right side). b Summary of interactions resulting in catenane formation or their exclusion. c Possible conformational arrangement of the two interlocked cages with spatial arrangement of methoxy groups interacting via weak dipole–dipole forces (green dotted lines). d Gibb’s enthalpy for catenation events determined by NMR spectroscopy. §Yields are given for optimized reactions.

If methoxy groups are absent, no catenane formation should occur. Thus triamine 1 was reacted with non-substituted terephthalaldehyde 4 (Fig. 6a) under different conditions (various solvents, Supplementary Fig. 405) and no catenane formation was observed. Pure H-cube was isolated in 90% from THF. By adding two methyl substituents instead of two methoxy groups to the aldehyde (5) still almost no catenane formation is observed by 1H NMR (Supplementary Fig. 406) and monomeric Me-cube is formed in 84% yield. As soon as the alkyl substituents at the dialdehyde precursor (6) get longer (here ethyl), the possibility of intermolecular dispersion interactions44 (Fig. 6b) is slightly increased and now some catenane (Et-cube)2 was found by 1H NMR spectroscopy as well as MS (Supplementary Fig. 407) besides monomeric Et-cube (which still is the main product). Comparing the different results of Me-cube versus Et-cube, based on the simple elongation of the alkyl chains by one methylene unit each, electronic effects to foster π-π-stacking can again be ruled out, because the methyl- as well as the ethyl-substituents have almost the same Hammett parameters (σm(Me) = -0.07; σm(Et) = -0.07; σp(Me) = -0.17; σp(Et) = -0.15).45 As for OMe-cube and (OMe-cube)2, the ratio of catenane (Et-cube)2 versus monomeric cage Et-cube was also strongly solvent dependent for the reaction of triamine 1 and aldehyde 6 and in THF the amount of catenane was higher than e.g. in CHCl3 and both compounds (monomer and catenane) were selectivity achieved by adjusting the conditions. The reaction in CHCl3 at room temperature gave monomeric cage Et-cube in 75% isolated yields, whereas running the reaction in THF gave after separation 35% of the catenated dimer (Et-cube)2 in pure form.

To further exclude pure electronic effects for a probable π-stacking, we reacted triamine 1 with diethoxy- and diisopropoxy dialdehydes 7 and 8, (Fig. 6a) where the substituents have comparable Hammett parameter as in dimethoxy dialdehyde 3 (σm(OMe) = 0.12; σm(OEt) = 0.10; σm(OiPr) = 0.10), but are of different steric demand. Whereas for the diethoxy dialdehyde 7 some catenane formation of (OEt-cube)2 was observed, for diisopropoxy dialdehyde 8 no catenane (OiPr-cube)2 was observed by 1H NMR spectroscopy (Supplementary Figs. 408 & 409), supporting once more the hypothesis that the catenane formation is mainly driven by weak interactions derived from the substituents rather than by π-stacking and in case of the latter steric repulsion is stronger than the weak attraction (Fig. 6b, Charton steric parameter for Me, Et, and iPr are νMe = 0.52; νEt = 0.56; νiPr = 0.76).46

By increasing these weak interactions, the equilibrium may be shifted towards the interlocked structures. By using dimethylthioether 9 in the condensation with triamine 1 in CDCl3 almost exclusively the triply interlocked catenated dimer (SMe-cube)2 was formed (Fig. 6a and Supplementary Fig. 410). Harsher conditions were needed to push the system to the trimeric cage (SMe-cube)3, which was isolated in 58% yield by using dichloromethane as a solvent in combination with elevated temperature (80 °C, screw-capped vessel, 4 days). By 2D NMR spectroscopy, the same linear and interwoven catenation motif was found as for (OMe-cube)3 (Supplementary Fig. 495). Switching the solvent system to TCE, monomeric SMe-cube was isolated in 80% yield. Again, to rule out electronic effects based on the thioalkyl substituent donating to the π-system of the aromatic dialdehyde, di-tert-butylthioether substituted dialdehyde 10 with two sterically demanding tert-butyl groups was investigated in the reaction (νMe = 0.52 vs νtBu = 1.24).46 As expected, only clean monomeric SC(CH3)3-cube was formed and isolated in 75% yield (Supplementary Fig. 411). Finally, we investigated the reaction of dibromo dialdehyde 11 with triamine 1, to see whether halogen bond formation47 can also induce catenation. Although the mass spectrum of the reaction mixture in CD2Cl2 showed a pronounced peak at m/z = 13591.6, which is the double amount of the monomeric Br-cube (m/z = 6796.4), in the correlated 1H NMR spectrum only small detectable peaks of any interlocked species are present besides mainly those signals of pure monomeric Br-cube (Supplementary Fig. 412). However, in contrast to all other reactions, here a precipitate was formed of very low solubility, which may contain insoluble (Br-cube)2.

Thermodynamic studies

To correlate the weak interactions responsible for catenation, the systems where catenation occurred have been studied by concentration dependent NMR spectroscopy (Supplementary Section 12), to estimate the Gibb’s enthalpy of cage to catenane transformation. With ΔG298 = -26.7 kJ/mol the reaction of 2 SMe-cube → (SMe-cube)2 is about 6 kJ/mol higher as for the methoxy cages 2 OMe-cube → (OMe-cube)2, ΔG298 = -20.8 kJ/ mol) and almost 10 kJ/mol higher than found for the ethoxy cages 2 OEt-cube → (OEt-cube)2, ΔG298 = -15.7 kJ/mol) (Fig. 6d), Unfortunately, in CDCl3 the amount of (Et-cube)2 besides Et-cube was too small to determine reliable numbers by this method. As mentioned above several times, the chosen solvents had clear impacts on whether catenation occurred or not. Therefore, we looked at the van’t Hoff-plots of temperature dependent 1H NMR measurements of the equilibria 2 OMe-cube ↔ (OMe-cube)2 and 2 SMe-cube ↔ (SMe-cube)2 to get further insights whether the processes of catenation are enthalpy or entropy driven reactions. In both investigated cases the catenation is an entropy-driven reaction (ΔSOMe = +114.3 J·K-1mol-1 and ΔSSMe = +185.3 J·K-1mol-1), rather than an enthalpically driven reaction (ΔHOMe = +13.1 kJ·mol-1 and ΔHSMe = +29.4 kJ·mol-1), which also explains the temperature-dependency of the reaction. It further suggests that solvophobic effects48 are dominating the catenation process at least in the investigated solvent systems. These solvophobic effects are dependent on polarity of side-chains,49,50 as it is here the case and need to be investigated further for such systems.

Conclusions

We observed the formation of dimeric and trimeric cage catenane based on the weak interactions of the substituents of the constituent1,4-benzene dialdehydes. Whereas π-stacking as driving force was ruled out, Keesom and London dispersion interactions between the substituents as well as with the solvent were considered. Changing the methoxy groups to less polar ethyl groups decreased catenane formation significantly. In cases where there is only a methyl- or no substituent at the dialdehyde, the intermolecular forces are too weak to foster catenane formation. Finally, dialdehydes with thiomethyl substituents were beneficial to catenane formation and indeed a clear reaction to (SMe-cube)2 was observed, having a difference of |ΔG°| of approx. 6 kJ/mol for catenane formation than the (OMe-cube)2. Solvent effects play a crucial role in the cases where dimeric and trimeric catenation was observed. Both systems (with OMe and SMe substituents) showed the same trends. In TCE, monomeric cages OMe-cube and SMe-cube were formed selectively, whereas in dichlormethane at elevated temperatures the clean formation of trimeric catenanes (OMe-cube)3 and (SMe-cube)3 were observed. Comparing the coherence energy densities (ced’s) of the solvents (TCE = 98.0 cal/cm3 vs. DCM = 93.7 cal/cm3) in combination of the data from van’t Hoff plot analysis revealed, that solvophobic effects may play a major role, since reactions toward catenated cages are entropically favoured.

This motif of weak dispersion interactions in combination with solvophobic effects as driving force for catenation of shape-persistent organic cages allow to further study the influence of subtle structural changes in combination with chosen solvents as reaction media to understand events of dynamic covalent chemistry of larger and more complex structures as well as to construct e.g. poly[n]catenated cages with n > 3, e.g. for cages of higher molecular volumes.

Methods

Synthesis of (OMe-cube)2

To a solution of TBTQ 1 (20 mg, 0.043 mmol) and 2,5-dimethoxy-terephthaldehyde 3 (12.6 mg, 0.0649 mmol) in deuterated chloroform (4 mL) in a screw-capped 8 mL glass vial, a catalytic amount of TFA (0.4 μL, 0.0052 mmol) was added and the reaction mixture was stirred at RT for 3 days. Afterwards, the crude reaction mixture was washed with aq. K2CO3 solution (0.25 M, 3 × 2 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting red colored solid was immediately dissolved in dichloromethane and purified by recycling gel permeation chromatography (r-GPC) (DCM, 35°C, 5 mL/min) to give 14 mg (46%) of (OMe-cube)2 as a yellow solid. Mp: 315°C (decomposed); 1H NMR (600 MHz, CD2Cl2): δ = 8.90 (s, 6H, HC=N), 8.87 (s, 6H, HC=N), 8.85 (s, 12H, HC=N), 8.82 (s, 6H, HC=N), 8.78 (s, 6H, HC=N), 8.65 (s, 6H, HC=N), 8.38 (s, 6H, HC=N), 8.03 (s, 6H, Ar-H), 7.88 (s, 6H, Ar-H), 7.79 (s, 6H, Ar-H), 7.71 (s, 6H, Ar-H), 7.69 (12H, Ar-H), 7.53 (d, 3J = 8.4 Hz, 6H, TBTQ Ar-H), 7.41 (d, 3J = 8.4 Hz, 6H, TBTQ Ar-H), 7.38 (d, 3J = 8.4 Hz, 6H, TBTQ Ar-H), 7.36-7.32 (m, 6H, TBTQ-Ar-H & Ar-H), 7.27 (s, 6H, TBTQ-Ar-H), 7.24 (s, 12H, Ar-H, TBTQ-Ar-H), 7.21 (s, 6H, TBTQ-Ar-H), 7.19 (s, 6H, TBTQ Ar-H), 7.17-7.14 (m, 6H, TBTQ-Ar-H), 7.08 (d, 3J = 8.4 Hz, 6H, TBTQ-Ar-H), 7.03-6.97 (m, 18H, TBTQ-Ar-H), 6.89 (s, 6H, TBTQ-Ar-H), 6.83 (d, 3J = 8.4 Hz, 6H, TBTQ-Ar-H), 6.78 (d, 3J = 8.4 Hz, 6H, TBTQ-Ar-H), 6.77 (d, 3J = 8.4 Hz, 6H, TBTQ-Ar-H), 6.72 (s, 6H, TBTQ-Ar-H), 6.59 (d, 3J = 8.4 Hz, 12H, TBTQ-Ar-H), 6.26 (d, 3J = 7.8 Hz, 6H, TBTQ-Ar-H), 4.04 (s, 18H, OCH3), 3.94 (s, 18H, OCH3), 3.90 (s, 18H, OCH3), 3.86 (s, 18H, OCH3), 3.82 (s, 18H, OCH3), 3.67 (s, 18H, OCH3), 3.11 (s, 18H, OCH3), 2.85 (s, 18H, OCH3), 2.30-1.74 (m, 96H, -CH2CH2CH3) 1.71 (s, 30H), 1.64 (s, 18H), 1.35-1.09 (m, 84H, -CH2CH2CH3), 1.0-0.90 (m, 126H, -CH2CH2CH3), 0.77-0.72 (m, 12H, -CH2CH2CH3), 0.48 (t, 3J = 7.2 Hz, 18H, -CH2CH2CH3); 13C NMR (151 MHz, CD2Cl2): δ = 156.5, 155.7, 155.3, 155.2, 155.0, 154.6, 154.31, 154.26, 154.2, 153.9, 153.8, 153.1, 152.7, 152.5, 152.6, 152.3, 152.2, 150.1, 149.8, 149.64, 149.6, 149.5, 149.4, 149.3, 149.1, 146.7, 146.6, 146.4, 146.1, 146.0, 145.5, 145.4, 129.0, 128.9, 128.6, 128.55, 128.49, 127.8, 125.0, 124.6, 124.42, 124.36, 124.2, 124.0, 119.8, 119.7, 119.4, 119.04, 118.96, 118.8, 118.5, 118.4, 118.1, 117.5, 117.3, 116.1, 116.0, 111.2, 110.2, 109.83, 109.77, 109.63, 109.58, 73.5, 73.2, 73.0, 67.39, 67.35, 67.33, 67.23, 67.18, 66.9, 56.71, 56.68, 56.65, 56.61, 56.6, 56.4, 56.1, 55.4, 41.8, 41.2, 41.1, 41.0, 21.3, 21.1, 21.0, 20.9, 20.8, 20.3, 15.5, 15.4, 15.32, 15.29, 15.0, 14.9; FT-IR (neat, ATR): v (cm-1) = 2999 (w), 2957 (m), 2925 (m), 2870 (m), 2853 (m), 1734 (w), 1616 (m), 1593 (m), 1492 (s), 1482 (s), 1465 (s), 1410 (s), 1373 (m), 1211 (s), 1140 (m), 1043 (s), 974 (w), 882 (m), 821 (m), 701 (w); UV/Vis (CH2Cl2): λmax (nm) = 296, 406; MALDI-TOF (DCTB): m/z [M]+ calcd. for C752H768N48O48: 11245.94, found 11245.57. Elemental analysis calcd. for C752H768N48O48·33CH2Cl2: C 67.11, H 5.98, N 4.79, found C 66.94, H 5.91, N 4.86.

Supplementary Material

Computational Data
Pubchem
SI
xyz coordinates

Acknowledgements

The authors like to thank the European Research Council ERC in the frame of the consolidators grant CaTs n DOCs (grant no. 725765). We further would like to thank Dr. Julian Holstein (Universität Dortmund, Germany), Dr. Sven M. Elbert, Margit Brückner and Dr. Frank Rominger, (all Ruprecht-Karls-Universität Heidelberg) and Prof. Dieter Fenske (Karlsruhe Institute of Technology) for their efforts in getting single-crystal X-ray structures of the here described cages and catenanes. Support by the state of Baden-Württemberg through bwHPC and the German Research Foundation (DFG) through grant no INST 40/5751 FUGG (JUSTUS 2 cluster) is acknowledged.

Footnotes

Author Contributions

B.P.B. found the catenation reaction. M.M. and B.P.B. conceived and planned the project. B.P.B. did all the experimental work. M.M. and B.P.B. analysed and interpreted the results. T.K. performed quantumchemical calculations. J.G. was responsible for the NMR experiments, especially in helping elucidating the structure of catenanes. J.G. measured all mass spectra. M.M. and B.P.B. prepared the manuscript, which was edited by all authors.

Competing interests

The authors declare no competing interests.

Data availability

All data supporting the findings of this study are available within the paper and its Supporting Information. The original experimental data to this paper has been deposited in the repository heiDATA and can be downloaded via https://heidata.uni-heidelberg.de/privateurl.xhtml?token=96ab88cd-5fc2-4b2c-b836-522dab565ba2

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Computational Data
EMS155921-supplement-Computational_Data.doc (49.9MB, doc)
Pubchem
EMS155921-supplement-Pubchem.cdx (1.4MB, cdx)
SI
EMS155921-supplement-SI.pdf (32.4MB, pdf)
xyz coordinates
EMS155921-supplement-xyz_coordinates.zip (33.8MB, zip)

Data Availability Statement

All data supporting the findings of this study are available within the paper and its Supporting Information. The original experimental data to this paper has been deposited in the repository heiDATA and can be downloaded via https://heidata.uni-heidelberg.de/privateurl.xhtml?token=96ab88cd-5fc2-4b2c-b836-522dab565ba2

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