Solvent Drives Switching between Λ and Δ Metal Center Stereochemistry of M8L6 Cubic Cages.

An enantiopure ligand with four bidentate metal-binding sites and four (S)-carbon stereocenters self-assembles with octahedral ZnII or CoII to produce O-symmetric M8L6 coordination cages. The Λ- or Δ-handedness of the metal centers forming the corners of these cages is determined by the solvent environment: the same (S)-ligand produces one diastereomer, (S)24-Λ8-M8L6, in acetonitrile but another with opposite metal-center handedness, (S)24-Δ8-M8L6, in nitromethane. Van 't Hoff analysis revealed the Δ stereochemical configuration to be entropically favored but enthalpically disfavored, consistent with a loosening of the coordination sphere and an increase in conformational freedom following Λ-to-Δ transition. The binding of 4,4'-dipyridyl naphthalenediimide and tetrapyridyl Zn-porphyrin guests did not interfere with the solvent-driven stereoselectivity of self-assembly, suggesting applications where either a Λ- or Δ-handed framework may enable chiral separations or catalysis.

The chirality of metal–organic cages has enabled novel applications across different areas.[1] For instance, the stereochemistry of cages has been used to recognize and separate enantiomers from racemic mixtures through encapsulation or cocrystallization.[2] Enantiopure cages are also able to mimic the catalytic functions of enzymes,[3,4] promoting asymmetric transformations by shaping the chirotopic space around reactive intermediates.[5] Recently, chiral cages that emit circularly polarized luminescence (CPL) have also emerged as a novel platform for the modular design of CPL-active materials,[6] which are of potential use in optical information transfer and new display technologies.[7]

Different methods can be used to prepare enantiopure cages. One approach is the resolution of racemic cage mixtures,[8] which can be induced by chiral guests.[9] Alternatively, the direct self-assembly of enantiopure ligands around metal ions can produce stereochemically pure cages.[1] This method involves stereochemical information transfer from ligands to metal centers, which adopt preferentially a Δ or Λ configuration based upon ligand sterics.[10] As a consequence, coordination cages are formed in a diastereoselective manner. Among these enantiopure architectures are sandwiches,[11] helicates,[12] tetrahedra,[2e,4e,13] octahedra,[14] cubes,[15] knots,[16] and other structures.[1,17]

In cases that have been reported so far, one enantiomer of ligand leads to a single diastereomer of metal–organic assembly, with diastereoselective self-assembly minimally impacted by external factors.[18] Here we demonstrate the self-assembly of a single enantiopure ligand with octahedral metal ions to produce two distinct diastereomers of an MII8L6 cage, having metal centers with either a preferred Δ or Λ configuration, through a simple change of solvent.

Enantiopure porphyrin-containing fourfold-symmetric ligand A (Figure a) was synthesized from commercially available 5,10,15,20-tetrakis(pentafluorophenyl) porphyrin[19] as described in Supporting Information section S2. The amide-containing chiral directing groups, each bearing a carbon stereocenter with an a (S) configuration, were incorporated near the coordination sites. Based upon the original work of Lusby et al. on cages built from pyridyl-triazole-based ligands,[20] we envisioned that this design, together with the high rigidity of the porphyrin skeleton, would influence the metal center configurations during cage formation, resulting in diastereoselective cage formation.

Figure 1

(a) Diastereoselective self-assembly of ZnII8L6 and CoII8L6 cages 1 and 2 from chiral porphyrin ligand A. The chiral directing group R is highlighted in the gray box. (b) Partial 1H NMR spectrum of ZnII8L6 cage 1 (CD3CN, 500 MHz, 25 °C). (c) Partial wide-sweep 1H NMR spectrum of CoII8L6 cage 2 (CD3CN, 500 MHz, 25 °C).

The self-assembly of A (6 equiv) with zinc(II) bis(trifluoromethanesulfonyl)imide (Zn(NTf2)2, 8 equiv) in acetonitrile at 70 °C produced Zn8L6 cubic cage 1 as the uniquely observed product, with the metal centers adopting either all Δ- or all Λ-handedness (Figure a). Electrospray ionization mass spectrometry (ESI-MS) confirmed formation of a ZnII8L6 complex (Figure S18). Two sets of Hb, Hh, and Hi signals in the 1H NMR spectrum indicated that the cage consists of a pair of diastereomers. The well-separated signals allowed determination of the diastereomeric ratio (d.r.) to be 3.8:1 (Figure b). Diffusion-ordered spectroscopy (DOSY) NMR experiments confirmed the same diffusion coefficient for both diastereomers (Figure S14). In control experiments, a monomeric pyridyl-triazole ligand bearing the same chiral directing group reacted with Zn(NTf2)2 (Figures S77 and S78), forming a ZnL3 complex with significantly lower diastereoselectivity (d.r. = 1.3:1). These results indicated that the energy difference between the Zn8L6 diastereomers emerges as a consequence of higher-order assembly.

To demonstrate the generality of this method, cobalt(II) bis(trifluoromethanesulfonyl)imide was also employed in self-assembly (Figures c), leading to the formation of CoII8L6 cubic cage 2 in equally high yield and with similar diastereoselectivity (d.r. = 3.6:1).

Circular dichroism (CD) spectroscopy was used to gauge the diastereoselectivities of formation of zinc and cobalt cages 1 and 2 (Figure S20). Both 1 and 2 displayed clear negative Cotton effects in acetonitrile, with similar intensities in the region from 413 to 440 nm, corresponding to the Soret bands of the Zn-porphyrin walls. In accordance with previous observations[19,21] and the present NMR spectra (Figures and S22), we inferred that the major diastereomer for each cage has all eight metal centers with either Λ- or Δ-handedness, whereas the minor diastereomer has all metal centers with the opposite stereochemical configuration. Other diastereomers, containing both Λ and Δ metal vertices, were not observed by NMR.

Purple crystals suitable for analysis by single-crystal X-ray diffraction were obtained by slow diffusion of diethyl ether into acetonitrile solutions of the Zn8L6 and Co8L6 cages 1 and 2 (Figure ). The X-ray structures revealed six chiral ligands bridging eight octahedral ZnII or CoII centers in an O-symmetric cubic configuration, with all eight stereogenic metal centers adopting a Λ configuration surrounded by three (S)-bidentate chelating moieties. Within (S)24-Λ8-1, the metal–metal distances are 19.4 Å for ZnII centers forming adjacent vertices and 19.8 Å for the ZnII centers in facing porphyrins. For (S)24-Λ8-2, the corresponding CoII···CoII and ZnII···ZnII distances are 18.6 and 19.7 Å, respectively. The internal cavity volumes of (S)24-Λ8-1 and (S)24-Λ8-2 were calculated to be 2881 Å3 and 2906 Å3 respectively using the MoloVol program (Figure S74).[22,23]

Figure 2

(a) Crystal structure of (S)24-Λ8-Zn8L6 cage 1, highlighting a single (S,S,S)-Λ-Zn center. (b) Crystal structure of (S)24-Λ8-Co8L6 cage 2, likewise showing a single (S,S,S)-Λ-Co center. Disorder, hydrogen atoms, and H2O bound to the porphyrin ZnII centers are omitted for clarity.

We then investigated the parameters that can influence diastereocontrol in the self-assembly of cage 1. The concentration appeared to not impact the diastereomeric ratio, as the same d.r. of 3.8:1 was observed when the reaction of ligand A with Zn(NTf2)2 was carried out at ligand concentrations ranging from 1 to 8 mM (Figures S40 and S41).

We found the diastereoselectivity of self-assembly to be profoundly influenced by the choice of reaction solvent, however. In acetonitrile, we tentatively assign the major diastereomer of cage 1 as (S)24-Λ8-1, based on the observation that this diastereomer crystallized from acetonitrile. This diastereomer was obtained with a d.r. of 3.8:1 in acetonitrile, whereas in nitromethane the diastereomer with opposite metal handedness, (S)24-Δ8-1, was formed predominantly, with a d.r. of 1:6 (Figure a). Opposite Cotton effects observed in the CD spectra of cage 1 in acetonitrile and nitromethane also confirmed these divergent stereochemical outcomes (Figure c). At different ratios of these two solvents (CD3CN:CD3NO2), the diastereomeric ratio of cage 1 also differed (Figure b). Although good diastereoselectivity was observed in nitromethane, attempts at growing crystals of (S)24-Δ8-1 in nitromethane suitable for X-ray diffraction were unsuccessful.

Figure 3

(a) Solvent-dependent self-assembly of Zn8L6 cage 1 to form two diastereomers (d.r. = (S)24-Λ8-1:(S)24-Δ8-1). (b) Partial 1H NMR spectra (CD3CN or CD3NO2, 500 MHz, 25 °C) of Zn8L6 in different solvent ratios: (i) CD3CN, d.r. = 3.8:1; (ii) CD3CN:CD3NO2 = 7:3, d.r. = 2.2:1; (iii) CD3CN:CD3NO2 = 1:1, d.r. = 1:1.6; (iv) CD3CN:CD3NO2 = 3:7, d.r. = 1:2.6; (v) CD3NO2, d.r. = 1:6. (c) CD spectra of Zn8L6 in MeCN and MeNO2 at the same concentrations. A PM3 molecular model of a (S,S,S)-Λ-Zn center was minimized using the SCIGRESS software package,[24] whereas the (S, S, S)-Δ-Zn center is from the crystal structure.

In control experiments, ligand A displayed no Cotton effects in either solvent (Figure S10). It was also observed that removing acetonitrile through evaporation, and subsequently adding nitromethane, switched the diastereoselectivity from 3.8:1 to 1:6 after 2 h at 70 °C (Figure S30). Removal of nitromethane and readdition of acetonitrile restored the diastereomeric ratio to 3.8:1 after 10 min at 25 °C. These observations indicated that Δ-Zn ⇄ Λ-Zn interconversion is reversible, with the equilibrium position governed by the solvent. Λ-Zn centers within 1 were thus favored in acetonitrile, whereas Δ-Zn centers were preferred in nitromethane.[25,26] Predominantly (S)24-Δ8-1 (d.r. = 1:2.4) was observed to form in acetone (Figure S24), as with nitromethane.

The impact of reaction temperature on diastereocontrol was also examined. The self-assembly of cage 1 was performed at elevated temperatures from 80 to 120 °C. Immediately after cooling to 25 °C, 1H NMR spectra were measured. The results showed that the diastereoselectivities remained the same as those of experiments carried out at 70 °C in both acetonitrile (d.r. = 3.8:1) and nitromethane (d.r. = 1:6).

The acetonitrile solution of 1 was stored at 25 °C for 6 months with no changes observed in the diastereomeric ratio. Variable temperature 1H NMR experiments indicated minimal temperature-dependent diastereomer interconversion in acetonitrile (Figure S38). In contrast, a temperature-dependent interconversion was observed in the nitromethane solution of 1 (Figure S38). After self-assembly in MeNO2, a diastereomeric ratio of (S)24-Λ8-1:(S)24-Δ8-1 = 1:6 was observed. After 7 days at 25 °C, an equilibrium diastereomeric ratio of (S)24-Λ8-1:(S)24-Δ8-1 = 1:1.5 was reached; reequilibration back to the original diastereomeric ratio of 1:6 occurred following heating of the diastereomeric mixture of cages.

Variable temperature 1H NMR experiments enabled the construction of a van ’t Hoff plot, which provided thermodynamic insight into the temperature-dependent diastereomer interconversion in nitromethane (Figure S39). The conversion of (S)24-Λ8-1 into (S)24-Δ8-1 in nitromethane was revealed to be an endothermic and entropically favored process, with ΔH = 24.6 ± 0.8 kJ mol–1 and ΔS = 83.1 ± 2.4 J K–1 mol–1. The Δ-Zn centers of (S)24-Δ8-1 may thus possess slightly more conformational freedom than in the case of diastereomeric (S)24-Λ8-1, which may contain more strongly bound, but less free, Λ-Zn centers. These effects are likely to be small for each individual vertex, but the effects of the 24 pendent stereocenters cooperatively tip the thermodynamic balance from one diastereomeric form to the other.

The van ’t Hoff analysis also provided possible mechanistic insight into the solvent-controlled Δ-Zn ⇄ Λ-Zn interconversion. Based on the different hydrogen-bond acceptor abilities of acetonitrile (β = 40) and nitromethane (β = 6),[27] we inferred that the better hydrogen-bond acceptor acetonitrile may restrict the conformational freedom of a metal vertex by accepting hydrogen bonds from the amide group, thus favoring the Λ-Zn configuration.

We then turned our attention to the exploration of the host–guest properties of cage 1. Although porphyrin-containing metal–organic capsules have exhibited extensive fullerene-binding abilities,[28] cage 1 was not observed to encapsulate C60, C70 and their covalent adducts (Figure S73). This observation may be attributable to the large inner cavity (2881 Å3) of 1 and the distance between parallel faces (19.8 Å), which preclude extensive stacking interactions between the host cage and guest fullerenes.[19]

Metal-porphyrin-containing supramolecular architectures have been used to bind pyridine-containing guests, driven by the coordination of pyridine nitrogen donors to porphyrin metal centers.[29] Taking advantage of such coordination-mediated host–guest chemistry, bidentate 4,4′-dipyridyl naphthalenediimide guest G1, with a N···N distance of 15.4 Å, was investigated. The mixture of equimolar amounts of G1 and 1 in acetonitrile led to the formation of host–guest complex G1⊂1 (Figure , left). This complex (d.r. = 3.5:1) retained the stereochemical configuration of the parent cage 1 (d.r. = 3.8:1) (Figure S42).

Figure 4

Simplified representation of the stereoretentive encapsulation of pyridine-containing guests by Zn8L6 cage 1. Reaction conditions: encapsulation of G1 in acetonitrile (70 °C, 16 h); encapsulation of G1 in nitromethane (70 °C, 16 h); encapsulation of G2 in acetonitrile (MW, 150 °C, 1.5 h).

Encapsulation of G1 also occurred in nitromethane, furnishing G1⊂1 with a lower diastereoselectivity (d.r. = 1:3.2) than was observed in the case of the empty cage (d.r. = 1:6) (Figure S51). The encapsulation of G1 by 1 thus proceeds in a stereoretentive manner, as further confirmed by CD spectroscopy (Figure S50). The guest nonetheless influences the stereochemistry of the host metal vertices, particularly in nitromethane, leading to altered diastereomeric ratios.

Cage 1 was also observed to bind tetrapyridyl Zn-porphyrin G2, which measures 15.3 Å between opposing pyridyl nitrogen atoms, in acetonitrile (Figure , right). Host–guest complex G2⊂1 was formed with a diastereomeric ratio of G2⊂(S)24-Λ8-1:G2⊂(S)24-Δ8-1 = 3:1 (Figure S58). Although cage 1 was not observed to encapsulate G2 in nitromethane, which we attribute to the insolubility of G2 in nitromethane, dissolution of G2⊂1 in this solvent gave G2⊂(S)24-Δ8-1 with a diastereoselectivity (d.r. = 1:2.9) again favoring the opposite metal-center handedness than in acetonitrile (Figure S66).

The encapsulation of G2 segregated the cavity of cage 1 into two symmetry-equivalent cells, enabling the binding of smaller guests that were previously not competent guests for cage 1.[29c]G2⊂1 was observed to internally bind 4,4′-bipyridine between central and exterior zinc sites (Figure S71).

The coordination-driven self-assembly of an enantiopure tetratopic ligand with either ZnII or CoII thus provided a straightforward strategy for the diastereoselective preparation of M8L6 cubic cages, which share the same (S) ligand stereochemistry but vary in the Λ- or Δ-handedness of their metal vertices. This metal-vertex handedness was switched by the solvent. Although the diastereoselectivities achieved in the present case are modest, this study may lead to the discovery of new methods by which the handedness of chiral coordination cage frameworks could be switched through a change in the environment, with no need for additional synthesis. The ability to bind pyridine-containing guests to form chiral coordination architectures such as G1⊂1 and G2⊂1 diastereoselectively may enable the creation of new caged metalloporphyrin catalysts capable of generating either enantiomer of a chiral product,[3,29] which may become practically useful following the further improvements in diastereoselectivity noted above. Given that the Δ stereochemical configuration is entropically favored, future work to improve diastereoselectivity will focus on the incorporation of more flexible chiral side chains, which may enhance this entropic preference. This phenomenon of solvent-driven stereochemical switching may be general to cages with pyridyl-triazole ligands[20] bearing chiral side chains, enabling the design of cages that are capable of selectively binding either enantiomer of a newly synthesized product, thus enabling new methods of chiral purification. Future studies will explore this solvent-driven phenomenon in cages built from ditopic, tritopic, and pentatopic ligands.