[4 + 4]-Imine Cage Compounds with Nitrogen-Rich Cavities and Tetrahedral Geometry

Organic imine cage compounds have found a variety of dif- ferent applications in several fields in materials science. To design tai-lor-made cages for corresponding applications, synthetic approaches to cages with tunable functionalities, sizes and shapes have to be found. Here we report a series ofcages with truncated cubic shape and tetrahe- dral geometry possessing nitrogen-rich cavities.


Results and Discussion
The desired cage compounds were synthesized by condensation reactions of methyl-trispyrrolyl-aldehyde 1 56 with equimolar amounts of the differently substituted triamines 2-Me, 2-Et, 2-OPr and 2-Br in chloroform at room temperature or 60°C (Scheme 1). Due to their solubility in common organic solvents, cage compounds 3-Me, 3-Et and 3-OPr were successfully isolated by recycling gel permeation chromatography (rec-GPC) in THF after 6 (3-Me and 3-Et) or 15  recycling cycles in yields between 10 and 18 % (for chromatograms, see the Supporting Information, SI).
Due to its low solubility, the purification of 3-Br by rec-GPC was not possible and attempts to remove impurities by recrystallization failed, so that minor impurities remained. The successful synthesis of the cages was verified by 1 H NMR spectroscopy by the disappearance of the signals of the aldehyde units of 1 (δ = 9.13 ppm) as well as of the amine units of 2-Me, 2-Et, 2-OPr and 2-Br (δ = 1.30 -1.63 ppm). Instead, signals of the imine protons of cages 3-Me, 3-Et, 3-OPr and 3-Br at δ = 8.15 -8.24 ppm were found (labeled as protons 7 in Figure 1a   Br; 2618.7568) representing the corresponding [4 + 4] condensates (Figure 1eh).
The low isolated yields of cages 3-Me, 3-Et and 3-OPr after rec-GPC purification can be rationalized by the formation of several other species as obvious by multiple peaks in the GPC-chromatograms (see the SI). MALDI-TOF MS analyses of the isolated fractions showed the 4 + 4 condensates as main components alongside minor impurities for each fraction. Nevertheless, 1 H NMR analyses revealed more complex patterns leading to the hypothesis of isomeric cage structures. To get further insight into possible cage isomers, we conducted quantum chemical calculations at the B3LYP/ 6 -31 G(d) level of theory and calculated the interconversion energy of a pro-chiral trispyrrol unit to elucidate whether these units lead to a potential mixture of diastereoisomeric cages ( Figure 2). Even considering the highest energy barrier between intermediate II and transition state III of 23.7 kJ/ mol would result in a rapid interconversion rate of 4.35·10 8 · s −1 and a half-life time of 1.59 ns, suggesting a fast interconversion in solution. This is further underlined by the comparably low relative energies of MMMM, MMMP, MMPP, MPPP and PPPP cages of 6.7 to 11.1 kJ/mol independent of the side chains (see SI), indicating again a fast interconversion excluding diastereomeric cages causing the several fractions obtained by rec-GPC. Another possibility is the formation of in-out-isomers referring to the central methylunits of the trispyrrols. The relative energies of the possible in-out-combinations show that the all-in isomers should represent > 98.5 % of the cages in a dynamic equilibrium in solution. Thus, it can be concluded that the different fractions obtained by rec-GPC contain different in-out isomers of the cages that are kinetically trapped.
For all isolated all-in cages, suitable crystals for singlecrystal X-ray diffraction (SCXRD) analyses have been obtained, unambiguously proving the molecular structures of the [4 + 4] cages ( Figure 3). The geometrical shapes can best be described as truncated cubes with tetrahedral symmetry. In all studied cases, the central methyl group of the trispyrrols is pointing into the cage cavities resulting in distances to adjacent phenyl rings of d Me-Ph = 1.2 -1.3 nm and outer diameters of d = 1.5 -1.6 nm. As previously observed, for 3-Me all ethyl substituents are conformationally stable and point outwards, whereas propoxy groups in 3-OPr point either out-or inwards.
Besides the solvate 3-Et α crystallized from dichloromethane and hexane (cubic, P a 3 ̅) and cage 3-OPr (orthorhombic, A ba 2), all obtained structures crystallized in the triclinic space group P1 ̅. Due to steric repulsion, each trispyrrol unit adopts a chiral C 3 -symmetrical conformation (for the sake of simplicity, we name them here M or P orientation), which can interconvert quickly by rotation around the C-C single bonds to the central carbon atom. Thus, each trispyrrol unit is prochiral leading to overall five possible cage isomers due to their tetrahedral symmetry. The solid-state structures of 3-Me, 3-Et β , 3-OPr and 3-Br adopt single enantiomeric MMMM or PPPP orientation, an effect comparable to the assembly of face-orientated polyhedra derived from prochiral building blocks as reported by Caoʼs group (Table 1 and Figure 5). 57,58 Since four out of eight "faces" of the synthesized truncated cubes possess helical chirality, the cages can be understood as semi-face-orientated polyhedra.    Table 1). In both cases face-toface π-π-stacking motifs are found on one face of each cage with distances of d π-π = 3.43 Å (3-Br) or 3.48 Å (3-Me) (Figure 4). The residual faces interact, e.g., via C -H⋯π interactions in the case of 3-Me with d C -H⋯π = 2.99 Å (Figure 4c). This interaction is mimicked in 3-Br by C-Br⋯π interactions of d C-Br⋯π = 3.26 Å (Figure 4f), leading in both cases to enantiopure layers within the crystallographic ab-planes (Figure 5f).
Changing the solvent diffused into saturated solutions of 3-Et from methanol (leading to 3-Et β with enantiopure cages) to hexane or if the crystals were grown by slow evaporation of a CDCl 3 solution of 3-Et, solvates 3-Et α and 3-Et γ are obtained showing the MMMP and PPPM isomers exclusively ( Figure 5).
In the case of 3-OPr, packing in the orthorhombic space group A ba 2, similar layers as in 3-Me and 3-Br are found in the crystallographic bc-plane with one-dimensional channels along the c-axis filled with methanol and water molecules (see Table 1, Figure 5, Figure 6 and discussion below). For 3-Et, the homochiral solvate 3-Et β , as well heterochiral solvate 3-Et γ , form layered structures as well, while 3-Et α crystallizes in the cubic space group P a 3 ̅ and the enantiomeric cages MMMP-3-Et and PPPM-3-Et can be found in an alternating order in all three dimensions (Figure 5f).
The nitrogen-rich inside of the cagesʼ cavities should be a perfect environment for polar guests. Crystallizing 3-Me using CHCl 3 and methanol led to 12 enclathrate-ordered methanol molecules in defined H-bonded arrays interacting with the pyrrol-imine subunits via synergetic H-bonds of d N-H⋯O = 2.00 Å and d O-H⋯N = 2.11 Å (Figure 6ac). This alignment generates a "shell" of methanol molecules by the interaction of the highly polar OH-groups and the inner surface of the cage leaving the methyl groups pointing to the inside of the cage creating a more nonpolar environment. Inside this nonpolar pocket, exactly one molecule of CHCl 3 can be found to be interacting via van-der-Waals interactions (Figure 6a).
While Russian-doll alignments with three spheres have been realized on a molecular level; [59][60][61][62] to the best of our knowledge, the structure discussed here is the first organic cage compound with two of these spheres being two different solvents. Furthermore, seven more methanol and one water molecule fill the inter-cage voids in the crystalline packing. For 3-Et β , 10 methanol molecules are found in similar alignments as discussed for 3-Me (Figure 6), yet due to disorder the residual solvent molecules had to be SQUEEZED. Ten methanol molecules are also found in the cavity in 3-OPr (Figure 6d). This time the residual voids are filled with ten water molecules which align in a chain-like fashion along the crystallographic a-axis (Figure 6d). Due to fast exchange, the H-atoms of the water molecules were not crystallographically found and a detailed discussion of the hydrogen bonding pattern is not possible.

Conclusions
To summarize, we have constructed four cage molecules based on a trispyrroltrialdehyde. While 3-Me, 3-Et and 3-OPr have been successfully isolated and fully characterized, 3-Br was mainly investigated by SCXRD. A detailed study of six single-crystal X-ray structures in total revealed that the prochiral trispyrroltrialdehyde orient in homoenantiomeric   PPPP and MMMM cages in four cases and only cage 3-Et can be found in the heteroenantiomeric MMMP and PPPM form in two solvates in the solid state. Furthermore, the nitrogen-rich interior of the cages is able to interact with polar molecules such as methanol or water and defined alignments like methanol shells or hydrogen-bonded chain-like structures were obtained. These findings can be beneficial for applications of the cages in the selective binding of polar guests or proton conductivity. [63][64][65] Furthermore, the nitrogen-rich cavity can be used as a cage ligand for transition metal ions or clusters. [66][67][68][69] Funding Information We  (shown as capped-stick models in white with one molecule shown as space-fill model in element colors) with ten methanol molecules (shown as capped-stick model in element colors) and ten water molecules (shown as a space-fill model in red without hydrogen atoms).