Chiral Nanoscale Metal–Organic Tetrahedral Cages: Diastereoselective Self‐Assembly and Enantioselective Separation

Cage rage: Chiral tetrahedral cages are diastereoselectively self-assembled from enantiopure C2-symmetric biphenyl bis(β-diketonate) linkers and C3-symmetric octahedral Fe3+ or Ga3+ ions (see picture; Fe purple, C blue, O red; cavity shown as an orange sphere). The porous polyhedra exhibit metal-dependent chiroptical behavior and act as hosts for the crystallization separation of racemic alcohols with up to 99.5 % ee. The self-assembly of nanoscale molecular architectures that have inner cavities has received intense attention in the past decade.1, 2 Such hollow polyhedra can be synthesized by recognition-driven self-assembly of complementary subunits. A variety of high-symmetry cages and capsules with distinct geometries have been synthesized with the use of rigid, highly directional multibranched ligands to bind to coordinatively unsaturated metal complexes.2–4 In particular, starting with the pioneering work of Saalfrank et al.,3a a variety of MxLy cages have been assembled from octahedral metal centers and C2- or C3-symmetric bis- and tris(bidentate) catecholamide or β-diketonate ligands.3, 4 The resolution of racemic anionic M4L6 clusters by chiral cations has been described by Raymond and co-workers.4d The incorporation of chiral functionalities into such assembled entities can expand their utility in enantioselective processes.5, 6 Nevertheless, asymmetric processes based on chiral cavities still remain relatively unexplored, mainly because of the difficulty in synthesizing large chiral cages in optically pure forms.6 1,1′-Biphenyl derivatives with intrinsic C2 symmetry constitute a class of compounds that are widely employed in chiral recognition processes, in particular as auxiliaries in asymmetric synthesis.7 We report herein the self-assembly of homochiral tetrahedral cages from the biphenyl bridging ligand 5,5′,6,6′-tetramethyl-3,3′-diketone-2,2′-bis(methoxymethoxy)-biphenyl (H2L), and potentially C3-symmetric metal ions. The polyhedra can be used as hosts for crystallization separation of racemic alcohols with an enantioselectivity of up to 99.5 %. The enantiopure atropisomeric H2L was prepared in four steps in good overall yield (32 %) from the readily available chiral 5,5′,6,6′-tetramethyl-3,3′-di-tert-butyl-1,1′-biphenyl-2,2′-diol (Scheme 1). Reaction of H2L with MIII chloride (3:2 molar ratio) in DMF followed by layering the solution with methanol afforded the desired complexes M4L6 (M=Fe 1, Ga 2) in moderate yields. The formation of the tetrameric compounds was supported by ESI-MS, which showed prominent peaks for the desired tetramers [Fe4L6+H]+ and [Ga4L6+2 H]2+ at m/z 3370.6 and 1711.8, respectively. The IR spectra of both 1 and 2 showed bands characteristic of chelated acetylacetonate (acac) groups at 1575 cm−1. Synthesis of the ligand H2L and compounds 1 (Fe4L6) and 2 (Ga4L6). MOM=methoxymethyl. The 1H and 13C NMR spectra of 2 show well-resolved signals for a single ligand environment; most of these signals have a slight upfield shift with respect to the free ligand (Figure 1). The C2 symmetry of the biphenyl ligand is preserved in the complex, as could be deduced from the number of signals in the NMR spectra. The absence of the proton signal of Hacac at δ=16.71 ppm in the spectrum of H2L supports the complete metal–ligand complexation. The resonances of methyl protons of each acac group are equivalent on the NMR time scale, with a signal at δ=1.96 ppm in H2L, but the resonances become obviously nonequivalent with separate signals at δ=1.75 and 1.99 ppm in 2. All the proton signals are very sharp, which is indicative of the formation of discrete metal complexes rather than higher oligomeric species. Therefore, the formation of tetrameric species with differently configured metal centers can be excluded because the spectra would be more complicated as the ligand would lose its symmetry in this case. We thus believe that the self-assembly of chiral clusters based on H2L proceeded with high diastereoselectivity and only one single diastereomer was formed. The clusters possess an ideal tetrahedral symmetry, and contain metal centers with either ΔΔΔΔ or ΛΛΛΛ symmetry. 1H NMR spectra of a) 2 and b) H2L in CDCl3. The proton signal of Hacac of H2L is shown as inset. The singlet signal at 7.26 ppm corresponds to CDCl3. A single-crystal X-ray diffraction study on 1 and 2 unambiguously revealed the formation of nanosized chiral, porous clusters.8 Both 1 and 2 crystallize in chiral trigonal P3 space group, and the asymmetric unit is formed from one-third of each of three cages. Each tetrameric cluster has noncrystallographic tetrahedral symmetry constructed from four C3-symmetric metal centers and six C2-symmetric (S)-L ligands (Figure 2). Within each polyhedron, the metal centers adopt a nearly idealized octahedral geometry by coordinating three chelated acac anions from three different ligands with reasonable metal–oxygen distances. Although the tris(bidentate) coordination at each metal center can form either a Δ or Λ configuration, the overall structure of the cluster when composed of chiral (S)-L may be homochiral ΛΛΛΛ-fac. Each of the six ligands possesses the same handedness of chirality and coordinates to two metal centers through its two chelating acac groups with an average metal–metal separation of approximately 12.0 Å for both 1 and 2. This arrangement of metal ions and coordination ligands thus leads to a molecular tetrahedron with the vertices occupied by the metal ions and the edges of the L ligands. The two phenyl rings of the L ligands are twisted along the pivotal CC bond at the 1,1′-positions with dihedral angles of 74.1–81.5° for 1 and 76.8–79.1° for 2; the bulk of the biphenyl moieties point away from the cavity of the molecular tetrahedron to give rise to a porous cluster. a) View of the molecular structure of 1 and b) its space filling model. (purple Fe, blue C, red O; the cavity is highlighted by a yellow sphere). A space-filling representation of 1 and 2 clearly shows the formation of a porous, nanosized cage with wide apertures (Figure 2 b). The overall sizes of the clusters are approximately 24.1 Å, while the aperture on each face has approximate diagonal distances of 7.0×7.0 Å. Each cage of both 1 and 2 has an open cavity that has an approximate volume of 1800 Å3 and is accessible to guest molecules. The packing of tetrahedral clusters in 1 and 2 leads to an occupation of around 33 % of the total volume by guest molecules.9 Clusters 1 and 2 are rare examples of homochiral molecular polyhedra that bear additional inwardly directed functional groups that have been crystallographically characterized.10 The electronic spectrum of H2L is characterized by two π–π* transitions of diketone and biphenyl groups at 283 and 238 nm, respectively. These π–π* transitions occur at 276 and 241 nm for 1 and 303 and 239 nm for 2 (Figure 3). In addition, there are two new bands around 461 and 369 nm for 1, which probably arise from ligand-to-metal charge transfer (LMCT) and metal-to-ligand charge transfer (MLCT) processes, respectively. CD (top) and UV/Vis (bottom) spectra of 1 and 2 in THF. The CD spectra of 1 and 2, which are formed from S- and R-enantiomers of H2L, are mirror images of each other, thus demonstrating their absolute configuration and enantiopurity. The CD spectra of (S)- and (R)-1 each exhibit an acac π–π* band at 302 nm and an MLCT band at 374 nm, as well as a bisignate LMCT band at 493 and 428 nm. The exciton coupling of two identical phenyl chromophores11 results in the corresponding positive and negative exciton splitting patterns centered at 250 nm for (S)- and (R)-1. The CD spectra of (S)- and (R)-2 show a phenyl π–π* band at 240 nm and do not show exciton coupling of the phenyl groups, whereas intense positive and negative exciton splitting patterns of acac groups centered at 296 nm were observed for (S)- and (R)-2, respectively. Based on the exciton chirality method for the absolute configuration assignment of tris(acac) metal complexes,12 the positive exciton pattern indicates that each Ga center in (S)-2 is in the Λ form, which is consistent with the crystal structure; the negative pattern indicates each Ga center in (R)-2 is in the Δ form. The configuration of the newly formed stereogenic metal centers is thus controlled by the configuration of the biphenyl platform. Exciton coupling of acac chromophores can be clearly observed for 2, as they may be free from overlapping transitions,11c as evidenced by the significant red shift of their π–π* transition in the absorption spectra. Upon addition of 2-butanol to apohost 2 in CHCl3, the expected formation of the kinetically stable host–guest complex could not observed by 1H NMR spectroscopy. However, the inclusion of 2-butanol could be readily achieved through cocrystallization of the evacuated host and racemic alcohols in CHCl3 at room temperature (Scheme 2). The desorbed 2-butanol from (S)-1 was analyzed by using GC on a chiral support, which showed that the enantiomeric excess (ee) value was 98.8 %, and the absolute configuration of (S)-2-butanol was confirmed by comparison of the retention time with that of a reported sample.13e Similar enantioselective inclusion behavior was observed for racemic 3-methyl-2-butanol, whereby (R)-1 exhibited remarkable selective inclusion of the R enantiomer over the S enantiomer. The ee value of the desorbed guests was 99.5 %. On the basis of microanalysis and thermogravimetric analysis (TGA), the inclusion complexes, which were not particularly soluble in common organic solvents, can be formulated as 1⋅(2-butanol)3 and 1⋅(3-methyl-2-butanol)3. The chiral nature of the included molecule is determined by the handedness of host, as further evidenced by the remarkable inclusion preference of (R)-1 for the R enantiomer of 2-butanol over the S enantiomer (99.2 % ee). Control experiments indicated that the ligand H2L itself can not resolve the enantiomers of 2-butanol under otherwise identical conditions. Selective inclusion of (S)-2-butanol by ΛΛΛΛ-1. Although many artificial hosts have been developed for chiral recognition of alcohols in the solid state, there are few examples of the highly enantioselective inclusion of small alcohols.13 In particular, in the case of secondary alcohols, it is difficult to recognize chirality because the subtle structural difference between the enantiomers as methyl groups and hydrogen atoms attached to the chiral carbon atom have to be discriminated. In this case, success may result from the combination of the chiral cage with the amphiphilic cavity interior that is lined with flexible methoxymethyl ethers; this combination leads to bioanalogous interaction of the host with guest species during the crystallization process.13g Attempts to obtain single crystals of the inclusion adducts have been unsuccessful. Further investigations on the resolution behavior and resolution of other racemic organic species are in progress. In conclusion, we have presented the diastereoselective self-assembly of chiral neutral metal–organic cages and demonstrated their highly enantioselective abilities to resolve small racemic alcohols by crystallization inclusion. Further work is aimed at enlarging the open channels and further functionalization of the interiors of the cages through modifications of organic linkers for enantioselective processes. Synthesis of 1 and 2: A solution of FeCl3 (10.8 mg, 0.067 mmol) in DMF (1 mL) was added dropwise to a solution of (S)- or (R)-H2L (52.6 mg, 0.1 mmol) in DMF (4 mL) at room temperature. The resulting solution turned dark purple and was stirred for 10 minutes, after which time the solution was layered with methanol. After two weeks, dark-red crystals of 1 suitable for X-ray crystallography were collected by filtration, washed with ethanol and ether, and dried in air. Yield: 57 %. IR (KBr): =2918 (b), 1575 (vs), 1443 (s), 1357 (s), 1271 (w), 1155 (m), 1081 (w), 1030 (m), 970 (w), 935 (w), 817 (w), 699 (w), 682 (w), 602 (w), 449 cm−1 (w); elemental analysis calcd (%) for C192H292Fe4N4O76 ([Fe4L6]⋅4DMF⋅24H2O): C 56.30, H 7.19; found: C 56.01, H 7.14. The guest molecules could be removed by heating in vacuum to further confirm the composition of the apohost [Fe4L6]: calcd (%) for C180H216Fe4O48: C 64.13, H 6.46; found: C 63.98, H 6.40. (S)- and (R)-2 were synthesized by following a similar method. Yield: 51 %. IR (KBr): =2918 (b), 1575 (vs), 1443 (s), 1357 (s), 1271 (w), 1155 (m), 1081 (w), 1030 (m), 970 (w), 935 (w), 817 (w), 699 (w), 682 (w), 602 (w), 449 cm−1 (w); elemental analysis calcd (%) for C192H284Ga4N4O72 ([Ga4L6]⋅4 DMF⋅20 H2O): C 56.53, H 7.02; found: C 56.60, H 7.00. The guest molecules were also removed by heating, and the resulting apohost characterized: 1H NMR (400 MHz, CDCl3): δ=1.75 (s, 6 H), 1.99 (s, 6 H), 2.03 (s, 6 H), 2.25 (s, 6 H), 2.85 (s, 6 H), 4.36–4.40 (t, 4 H), 6.97 ppm (s, 2 H); 13C NMR (400 MHz, CDCl3): δ=17.1, 20.2, 27.6, 27.8, 56.4, 98.1, 111.1, 130.6, 132.3, 132.8, 133.7, 135.9, 152.4, 190.5, 194.2 ppm. Elemental analysis calcd (%) for C180H216Ga4O48: C 63.09, H 6.35; found: C 62.92, H 6.33. Crystallization separation experiment: Racemic 2-butanol (4 mL) or 3-methyl-2-butanol (4 mL) was added dropwise to a solution of the apohost 1 (40 mg) in dry CHCl3 at room temperature. The resulting solutions were allowed to evaporate slowly; the inclusion solids formed after two days. The solid were filtered and washed with diethyl ether to remove surface solvent molecules. The guest alcohols were removed from the inclusion solids of 1⋅(guest)3 by washing with MeOH. Elemental analysis calcd (%) for the adduct C192H246Fe4O51 (1⋅(2-butanol)3): C 64.18, H 6.90; found: C 64.28, H 6.87. Calcd (%) for the adduct C195H252Fe4O51 ([Fe4L6]⋅(3-methyl-2-butanol)3): C 64.42, H 6.99; found: C 64.32, H 6.90. Optical purity of the guests was determined by GC using a Chiral-G-TA capillary column (ASTEC Company; 30 m×0.25 mm internal diameter). Other experimental details are given in the Supporting Information. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.