Cucurbitimines – imine cages with concave walls

Abstract

The variety of shape-persistent organic cages by imine bond formation has tremendously enlarged in recent years by using different building blocks (aldehydes and amines) in the condensation reactions. Here, we describe the use of a kinked tetraldehyde to generate pumpkin-shaped cages with concave walls, similar to cucurbiturils.

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Introduction

The synthesis of shape-persistent organic cage compounds, applying dynamic covalent chemistry (DCC) has developed in recent years tremendously fast and enabled the access of a large variety of defined molecular structures of different sizes, geometries and functions.^1–6 Although a few examples of boronic ester cages, or those based on disulphide formation or other DCC reactions are known,^{7–18,19–21,22–26} no doubt, the vast majority of shape-persistent organic cages is relying on the use of multiple imine condensation reactions,¹ which bear the advantage to be transformed further to convert these to chemically robust cages,^27–31 which is for the other type of DCC reactions difficult or even impossible.³² Among those imine cages, shapes, such as trigonal prisms,^33–35 tetrahedra,^36–39 truncated tetrahedra,^40,41 cubes,^42–46 tetrapods,⁴⁷ adamantoids^48–50 and even more complex structures^51–57 have been realized as well as tubular structures, based on linear tetraaldehydes.^58–61,62

Here we introduce [3 + 6] imine cages based on the condensation of triptycene tetraaldehydes with 1,2-cyclohexyldiamines. Due to the inherent 120° angle of the triptycene blades, the resulting imine cage contains concave π-walls giving the overall structure the shape comparable to those of cucurbiturils,^63–67 thus we call the compounds cucurbitimines (Fig. 1).

Fig. 1 Schematic representation of literature-known tubular [3 + 6] imine cages (left)^58–61 and the cucurbitimines presented herein. Please note that any further functional groups or substituents present in the molecular structures have been omitted for clarity.

Results and discussion

A key-step in the achievement of cucurbitimines is the synthesis of a triptycene-based tetraaldehyde precursor, having on two aromatic blades two aldehyde units each and at the third one none. Therefore, we developed a route where electron density of one blade was diminished by turning it into a phenazine unit and in addition allowed us to install long solubilizing hexyl-sidechains (Scheme 1). To achieve this first synthetic goal, hexamethoxytriptycene 1 was partially oxidized to the quinone 2^68–70 and condensed with phenylene diamine 3⁷¹ to give phenazine 4 in 79% yield.⁷² The next step is the introduction of the aldehyde groups. Finally, the tetraaldehyde precursor was achieved by a three-step-method, which was based on the fourfold chloromethylation to 5 (60% yield), followed by basic substitution of chlorine by hydroxyl groups to give tetra benzylic alcohol 6 in 77% yield, which was then oxidized with pyridinium chloro chromate (PCC) to give tetraaldehyde 7 in 85% yield. All compounds have been fully characterized, including single crystal structure analysis by X-ray diffraction for 4 and 5 (for details, see ESI†).

Scheme 1 Synthesis of tetraaldehyde 7. (i) conc. HNO₃, DCM, AcOH, 5 min, 91%; (ii) CHCl₃, AcOH, 80 °C, 7 h, 79%; (iii) ClCH₂OCH₃, CH₃SO₃H, 80 °C, 16 h, 60%; (iv) Cs₂CO₃, dioxane/water (1 : 1 v/v), 140 °C, 3d, 77%; (v) PCC, Celite, DCM, r.t., 6 h, 85%.

With tetraaldehyde 7 in hand, condensation reactions with (R,R)-1,2-cyclohexyldiamine 8 were investigated under various conditions (Scheme 2). Solvents, such as MeOH, MeCN, DCM, THF, toluene or CHCl₃ were used and the reactants with the addition of a small amount of TFA (2 mol%) were stirred at room temperature or under reflux. Although in all cases the [3 + 6] cucurbitimine cage was formed, as detected by MALDI-TOF mass spectrometry (m/z = 2739), the corresponding ¹H NMR spectra revealed that only in DCM the purity of the crude material was high enough to allow isolation and purification of the cage 9 in 10% yield. However, the best results were achieved by layering solutions of the two reactants and let them diffuse into each other, which has been widely used by Cooper et al.^37,73,74 Although in contrast to their cages, which usually crystallized during formation, here the reaction mixture still kept a clear solution. Nevertheless, by this method we were able to isolate cucurbitimine cage (R,R)-9 in 49% yield by applying separation with recycling-GPC (gel permeation chromatography,) besides 5% of the larger [4 + 8] cage (R,R)-10 (m/z = 3653). Using the enantiomeric (S,S)-1,2-cyclohexyldiamine gave basically the same results and here the cages (S,S)-9 and (S,S)-10 have been isolated in 54% and 5% yield (Fig. 2). It is worth to mention, that the calculated heats of formation (PM3) for the trimeric cage 9 is ΔH_f = 751 kJ mol⁻¹ (250.3 kJ mol per unit) and for tetrameric cage 10 ΔH_f = 975 kJ mol⁻¹ (243.3 kJ mol per unit) are very similar, if compared per unit (ΔΔH_f = 7 kJ mol⁻¹). Thus a more equal distribution would be excepted, if the cage products are in thermodynamically equilibrium. Since it is not the case in combination with all the observations made under various reaction conditions, it is concluded, that the cages 9 are rather kinetically controlled products than thermodynamically ones.

Scheme 2 Synthesis of cucurbitimines. (i) DCM, 2 mol% TFA, r.t., 7d, yields: (R,R)-9 (49%); (R,R)-10 (5%); (S,S)-9 (54%); (S,S)-10 (5%).

Fig. 2 Recycling-GPC chromatogram of the reaction of 7 with (S,S)-8. For experimental details, see ESI.† Please note that in between the peak at 150 min and 160 min, the compounds responsible for the broad peak were removed.

In the ¹H NMR spectra of enantiopure cages 9, the most characteristic peaks are found in the aromatic region (Fig. 3). Whereas triptycene bridgehead protons overlap with the outer phenazine protons (7.84 ppm), the inner ones resonate at 7.67 ppm. The imine protons show a large difference in chemical shifts. The peak at 9.26 ppm are assigned to the imine protons closer to the triptycene bridgeheads, the peak at 8.70 ppm corresponds to the imine protons pointing towards the outer rim of the cage. The larger cages 10 are unfortunately not stable enough to be fully purified by GPC or other means and still contain some minor impurities, as detected by ¹H NMR spectroscopy (see ESI†). By DOSY experiments, diffusion coefficients of D = 4.3 × 10⁻¹⁰ m² s⁻¹ for the cages 9 were determined, which corresponds to a solvodynamic radius of r_s = 1.1 nm and fits well to the outer diameter of the molecule found by single-crystal X-ray diffraction (vide infra). For [4 + 8] cage 10 a diffusion coefficient of D = 3.4 × 10⁻¹⁰ m² s⁻¹ was measured, thus the solvodynamic radius was a bit larger (r_s = 1.4 nm) and fits to the radius of the molecular model (see below).

Fig. 3 ¹H NMR spectrum (700 MHz, CD₂Cl₂) of cage (R,R)-9. # residual CH₂Cl₂.

For cage (R,R)-9 single-crystals for X-ray diffraction were grown from diffusion of n-pentane into a saturated solution of the cage in DCM (Fig. 4). The compound crystallizes in the orthorhombic space group P2₁2₁2 and contained one enclathrated DCM molecule inside the cavity and disordered electron density (according to 8 DCM molecules per asymmetric unit) inside the formed extrinsic channels (Fig. 4d and e). The cages pack window-to-window with a closest distance of two methoxy units of d(C⋯OMe) = 3.47 Å (Fig. 4b), which is a hint for some week dipole–dipole interactions (Keesom interactions) as found before for methoxy-substituted π-extended heteroarenes.⁷⁵ Due to the relative small window, pores are isolated, e.g. for gases with kinetic diameters >2.2 Å, if one assumes a static structure in the crystals.⁷⁶ By the second dominant packing motif (CH⋯π interactions) between the cyclohexyl moieties and the aromatic phenazine backbones (Fig. 4c) extrinsic one-dimensional channels are formed containing disordered solvate (DCM) molecules (Fig. 4d and e). Up to now, these have not been tried to be activated for gas sorption, because we are more interested in the molecular structure as defined host for supramolecular host-guest chemistry.

Fig. 4 Single crystal X-ray structure of cage (R,R)-9. (a) single molecule from top; (b) window-to-window packing; (c) packing by CH-π interactions of aromatic phenazine units and aliphatic cyclohexyl ring; (d) and (e) calculated pores with a probe radius of 1.82 Å. For (b) and (c) hydrogen atoms have been omitted for clarity. In (d) an (e) the red surface is the solvent accessible surface and yellow the inaccessible surface.

It is worth to compare the molecular dimensions of the cavity of the cucurbitimines 9 with the cucurbiturils (Fig. 5). The distance between two oxygens of adjacent veratrole units is between 3.8 and 4.6 Å. The distance of two adjacent triptycene bridgehead carbons is 7.6 Å. The height of the molecule (distance between two eclipsed oxygens of the upper and the lower rim) is between 9.0 and 9.2 Å. By applying the SwissPDB viewer⁷⁷ a pore volume of 177 ų was calculated. Most interestingly, these dimensions are somewhat larger than the 115 ų we calculated for cucurbit[6]uril (CB6) with the same program, but comparable to those reported in literature (164 ų).⁶⁵ In CB6 the diameter of two opposite oxygens at the rims is 3.9 Å, the inner distance of two opposite carbons is with 5.8 Å smaller than in cage 9 and the height is very similar (9.1 Å).

Fig. 5 Comparison of molecular pore volumes of cucurbitimines (R,R)-9 (left) and (R,R)-10 (right) with those of CB6 (top middle) and CB8 (bottom middle)., generated with SwissPDBviewer.⁷⁷ For details, see ESI.†

For the [4 + 8] cages 10 we were not successful to grow suitable crystals for a detailed analysis by X-ray diffraction. However, cage 9 is very rigid and thus shape-persistent and the experimental structure determined by X-ray diffraction fits nearly perfectly to the calculated model (PM6). Thus we take the PM6 model of the larger cage 10 for comparison with cucurbiturils. As in cucurbiturils the height is the same for all members of the family, the height is here also the same for cage 10 and cage 9 (9.1 Å). Due to the higher symmetry, the distance between two opposite oxygens at one rim can be measured. With 9.0 Å it is significantly larger than e.g. for cucurbituril[8] CB8 (6.9 Å). The inner diameter (distance between two opposite triptycene bridgehead carbons) is 12.0 Å. The calculated void volume is with 368 ų similar to what we estimated for CB8 with the PDB viewer (351 ų) but substantially smaller than reported in literature (479 ų).⁶⁵ Furthermore we calculated the electron density distribution, which is similar to curcurbiturils, but less pronounced (see ESI†), so the curcubitimines may show a similar host–guest behaviour as the cucurbiturils.^65,66,78,79 Whereas all initial tests to incorporate ammonium compounds into the cavity did not show any uptake, it was realized that neutral molecules are found in the molecular void. As described above, by X-ray crystallography one DCM molecule was found in the interior of cage 9, and as soon as it is purified by recycling-GPC with THF as eluent, one molecule of THF is bound inside, when analysed by ¹H NMR in toluene-d8 (Fig. 6). The peak at −0.84 ppm is clearly assigned to the eight THF protons of THF inside the cavity. The corresponding peaks of (R,R)-9 of the host–guest complex are highlighted in blue. In Fig. 6 (top spectrum) already a second set of cage protons are detected (magenta colored peaks), that are shifted all slightly upfield. By time these increase in intensity (Fig. 6, bottom, whereas those of the THF@(R,R)-9 complex decrease. Besides that, free THF is found (1.45 and 3.56 ppm), thus we conclude that THF most likely got exchanged by toluene-d8. The exchange is very slow at room temperature (more than 2 d) but can be accelerated to less than 1 h at 100 °C.

Fig. 6 (a) Exchange of host molecules from THF@(R,R)-9 to toluene-d8@(R,R)-9. (b) ¹H NMR spectrum (700 MHz) of freshly prepared THF@(R,R)-9 in toluene-d8. (c) same sample after exchange of THF guest by toluene-d8. Note, that in the upper spectrum some toluene-d8@(R,R)-9 has formed.

Conclusions

Based on a triptycene tetraaldehyde a new type of imine cages has been introduced that have a similar shape than cucurbiturils. Therefore, these imine cages are named cucurbitimines. Initial studies demonstrate, that small neutral guests are bound inside the cavity and that their exchange (here THF by toluene) is kinetically suppressed due to the small window sizes of the opening. By increasing the temperature, the exchange of guest molecules can be accelerated. This behaviour is quite similar to that of the cucurbiturils. In contrast to those, the here discussed cucurbitimines are much better soluble in organic solvents and, which for cucubiturils is quite rare,⁸⁰ are chiral, opening up new possibilities for classical host–guest chemistry, but also for separation of volatile chiral compounds.⁸¹ Furthermore, we will look for possibilities to get the larger members of the family ([5 + 10] and higher) to open up new vistas in supramolecular chemistry simply by enlarging the windows – as has been done before for cucurbiturils.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the European Research Council ERC in the frame of the consolidators grant CaTs n DOCs (grant no. 725765). Jochen C. Lauer and Tobias Kirschbaum (both Ruprecht-Karls-Universität Heidelberg) are acknowledged for their helpful discussions.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2072797 (4), 2072798 (5), and 2072799 ((R,R)-9). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo00478f

‡ Current address. Institut für Organische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany

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