Hetero-Diels–Alder Reaction between Singlet Oxygen and Anthracene Drives Integrative Cage Self-Sorting

A ZnII8L6 pseudocube containing anthracene-centered ligands, a ZnII4L′4 tetrahedron with a similar side length as the cube, and a trigonal prism ZnII6L3L′2 were formed in equilibrium from a common set of subcomponents. Hetero-Diels–Alder reaction with photogenerated singlet oxygen transformed the anthracene-containing “L” ligands into endoperoxide “LO” ones and ultimately drove the integrative self-sorting to form the trigonal prismatic cage ZnII6LO3L′2 exclusively. This ZnII6LO3L′2 structure lost dioxygen in a retro-Diels–Alder reaction after heating, which resulted in reversion to the initial ZnII8L6 + ZnII4L′4 ⇌ 2 × ZnII6L3L′2 equilibrating system. Whereas the ZnII8L6 pseudocube had a cavity too small for guest encapsulation, the ZnII6L3L′2 and ZnII6LO3L′2 trigonal prisms possessed peanut-shaped internal cavities with two isolated compartments divided by bulky anthracene panels. Guest binding was also observed to drive the equilibrating system toward exclusive formation of the ZnII6L3L′2 structure, even in the absence of reaction with singlet oxygen.

Self-sorting processes in chemical systems 1 enable multiple structures to form from a common pool of subunits, potentially exercising their functions in parallel within the same solution.Understanding these processes can shed light on the complex self-assembly pathways in natural systems, 1a as well as enabling the design of chemical systems that serve useful purposes. 2Artificial self-sorting systems have been developed where subunits are bound together by hydrogen bonds, 3 metal-ligand coordination, 4 aromatic stacking interactions, 5 and electrostatic attraction. 6oordination cages can be produced in self-sorting systems, where selectivity is driven by thermodynamic and geometric parameters. 7These cages can undergo structural changes in response to different stimuli, 8 such as post-assembly modification. 9s shown in Figure 1, Zn II 8L6 pseudo-cubic cage 1 and Zn II 4L6 tetrahedral cage 2 self-assembled from trigonal subcomponent A and anthracene-centered tetragonal subcomponent B, respectively.As a consequence of the matching side lengths of A and B, mixing solutions of 1 and 2, led to the emergence of a third cage, trigonal-prismatic 3, 7a in equilibrium with the other two.
Singlet oxygen ( 1 O2) reacted with the anthracene-containing B residues within both 1 and 3, generating the hetero-Diels-Alder endoperoxide product. 10This post-assembly modification 9 impacted the relative stabilities of the members of the system, favoring the oxidized trigonal prismatic cage 4, and thus tilting the system towards integrative self-sorting.1a, 1b, 6 This modified trigonal prism 4 was observed to thermally revert to the precursor system following retro-Diels-Alder removal of O2 thermally, thus allowing for reversible switching between the mixed and integratively self-sorted states of the system.
The bulky anthracene panels of trigonal prismatic coordination cages 3 and 4 separated the internal cavity into two isolated compartments.Neutral guest molecules were encapsulated in the trigonal prisms 3 and 4, but not in pseudo-cube 1 or tetrahedron 2. Reaction with 1 O2 thus set in a cascade of events that resulted in guest binding, as the system of cages reconfigured.
In the absence of 1 O2, the strong binding of adamantane within 3 also reconfigured the 1 + 2 ⇌ 2 × 3 equilibrium.This binding stabilized 3, favoring its formation.Adamantane binding thus served as an alternative signal triggering the system to integratively self-sort.
Cages 1 and 2 were synthesized individually via subcomponent self-assembly, as shown in Figure 1a, where dynamic coordinative (N→Zn) and covalent (C=N) bonds formed during the same overall process.Subcomponent A was synthesized from commercially available anthracene-9,10-diboronic acid bis(pinacol) ester (SI section 2.1).The reaction of A (6 equiv) with zinc(II) bis-(trifluoromethanesulfonyl)imide (Zn(NTf2)2, 8 equiv) and 2formylpyridine (24 equiv) in acetonitrile at 70 °C produced Zn II 8L6 cubic cage 1. Electrospray ionization mass spectrometry (ESI-MS) confirmed the Zn II 8L6 composition (Figure S11, S12), in line with diffusion-ordered spectroscopy (DOSY) NMR measurements (Figure S10), which provided a hydrodynamic radius of 20.9 Å.The reaction of commercially-available subcomponent B (4 equiv) with 2formylpyridine (12 equiv) and Zn(NTf2)2 (4 equiv) provided cage 2, following published procedures.Single crystals of cage 1 suitable for analysis by X-ray diffraction were obtained by slow diffusion of diethyl ether into an acetonitrile solution.The solid-state structure (Figure 2a) revealed six anthracene ligands bridging eight octahedral Zn II in an S6-symmetric framework, with four metal centers adopting a Λ configuration, and the other four adopting a Δ configuration. 12Within cage 1, the metal-metal distances between adjacent vertices range from 14.8 Å to 16.4 Å.The bulky anthracene panels protrude into the cage cavity, leaving only a small cavity volume of 9.0 Å 3 , calculated using MoloVol 13 (Figure S88).
Cages 1 and 2 were mixed in acetonitrile and heated at 65 °C for 24 hours.The formation of trigonal prismatic cage 3 was observed through integrative self-sorting, 1b in equilibrium with the narcissistic products 1 and 2 (Figure 1).The presence of all three products was confirmed by 1 H NMR, DOSY spectra (Figure S14, S15) and ESI-MS (Figure S16, S17).Two-dimensional NMR techniques provided structural information consistent with a D3-symmetric trigonal prismatic framework for cage 3 (Figure S52-S55).DFT calculations were undertaken using Gaussian 16 program 14 to obtain an energy-minimized structure for cage 3, shown in Figure 2c.This structure gave conformations of the three bulky anthracene panels that projected inwards, separating the internal cavity into two isolated compartments.We then investigated the [4+2] hetero-Diels-Alder reaction between anthracene and 1 O2 involving both anthracene-based cubic cage 1, and the self-sorted system containing cages 1, 2 and 3. Pioneering work employing this reaction in supramolecular structures has been conducted by the groups of Stang, 15 Shionoya 16 and Bibal, 17 involving structural transformations of host species and changes of their binding affinities.Building upon this work, cage 1 was mixed with the photosensitizer methylene blue (MB, 0.05 equiv) in acetonitrile.This solution was irradiated (max = 630 nm) for 2 hours at room temperature under air (Figure 1).After irradiation, the anthracene moieties of the cages were found to have reacted to form endoperoxides, generating oxidized cubic cage 5, as shown in Figure 3b.ESI-MS and 1 H NMR analyses confirmed complete 1 → 5 transformation (Figures S28, S36, S37).Comparison of the 1 H NMR spectra of cages 1 and 5 revealed the same number of signals, but with different chemical shift values (Figures S3,  S28), which implied that the S6 symmetry of the framework was maintained.The structure of cage 5 was further confirmed by 2D NMR spectroscopy (Figure S31-S35), and it was also minimized by DFT calculation (Figure 2b, see supporting information Section 7).
Next, we applied the same oxidation conditions to the mixture of cages 1-3.All anthracene panels in this geometric self-sorting system also underwent complete transformation into endoperoxides after irradiation.The hetero-Diels-Alder reaction triggered integrative self-sorting, resulting in the exclusive formation of oxidized trigonal prismatic cage 4, the formulation of which was confirmed by 1 H NMR and ESI-MS (Figure S18, S26, S27).DFT geometry minimization provided a structure for oxidized trigonal prismatic cage 4 (Figure 2c) that was again consistent with 2D NMR spectra (Figures S21-25), which reflected C3 point symmetry.
As the cycloaddition reaction between 1 O2 and anthracene is thermally reversible, 15,17 we studied the recovery of parent cage 1 from oxidized 5 (Figure S38).This transformation occurred after heating 5 in acetonitrile at 120 °C under microwave irradiation for 2 h.Trigonal prismatic cage 4 also underwent deoxygenative retro-cycloaddition, transforming back into the initial mixture of 1-3 following microwave heating.After five cycles of photooxygenation/cycloreversion, NMR integration indicated that 84% of the oxidized trigonal prism was formed, relative to the amount initially present (Figures 3e, S40).
By contrast, the 2 + 5 → 2 × 4 transformation (Figure 3d) was found not to be reversible between 25 °C and 65 °C, consistent with high thermodynamic stability of 4 relative to 2 and 5 (Figure S43).The relative energetic favorability of structure 4 was also supported by DFT calculations (Figures S85, S86).DFT structures also suggested that the bent anthracene endoperoxide moieties reduced hindrance inside the cage, further stabilizing cage 4 (Figure S84).The host-guest properties of trigonal prismatic cages 3 and 4 were then investigated (Figure 4).In cages 3 and 4, the bulky meridional anthracene units were designed to separate the internal cavity into two isolated compartments, resembling a 'peanut' structure. 19The internal cavity volumes were calculated by MoloVol 13 to be 308.9Å 3   S57, S70 and S73), where the encapsulated guest and host were observed to diffuse at the same rate.Intriguingly, some terpenoid natural products such as verbenone (G3), (1S)-(-)-camphor (G4) and (-)-beta pinene (G5), which are similar in size to norbornane, were also observed to encapsulate within both 3 and 4 (Figures 4b, S59-S66, S75-S83), also in slow exchange on the NMR timescale.
Synthetic receptors have been shown to adjust their binding sites to better bind guests.8b Thus, we also studied guestencapsulation-induced structural transformation in the equilibrium mixture of cages 1, 2 and 3.The addition of G1 to this mixture prompted re-equilibration, resulting in the formation of only cage 3 containing G1 (Figure 4c). 1 H NMR integrations indicated the formation of host-guest complex 2 .G13, which was also confirmed by ESI-MS, with no signals observed corresponding to cages 1 and 2. The hostguest complex 2 .G13 was characterized by 2D NMR spectroscopy (Figures S52-S55).
Entropy changes associated with guest encapsulation may help drive reconfiguration of the system.The freeing of solvent from the cavity of a cage provides an entropic driving force for guest binding.The entropy change associated with guest binding within 3 could thus result in the stabilization of heteroleptic 3 as opposed to homoleptic 2 and 1, which do not bind guest G1.
Using the reversible cycloaddition of 1 O2 to anthracene to reconfigure a self-sorting system may thus open new possibilities for signal transduction within systems of cages, potentially involving guest uptake and release.The incorporation of enantiopure anthracene ligands may also enable the dynamic control of the chirotopic internal cavities of these coordination cages for potential applications of enantioselective guest recognition and separation. 20 11

Figure 1 .
Figure 1.(a) Self-assembly and structural transformation of pseudo-cubic cage 1 and tetrahedral cage 2 from tetramine A and triamine B, respectively; (b) Construction of trigonal prismatic cage 3 and its transformation into cage 4 via hetero-Diels-Alder reaction with photo-generated 1 O2; (c) Schematic illustrating how the ligands panel the faces of cages 1-4.Single crystals of cage 1 suitable for analysis by X-ray diffraction were obtained by slow diffusion of diethyl ether into an acetonitrile solution.The solid-state structure (Figure2a) revealed six anthracene ligands bridging eight octahedral Zn II in an S6-symmetric framework, with four metal centers adopting a Λ configuration, and the other four adopting a Δ configuration.12Within cage 1, the metal-metal distances between adjacent vertices range from 14.8 Å to 16.4 Å.The bulky anthracene panels protrude into the cage cavity, leaving only a small cavity volume of 9.0 Å 3 , calculated using MoloVol 13 (FigureS88).Cages 1 and 2 were mixed in acetonitrile and heated at 65 °C for 24 hours.The formation of trigonal prismatic cage 3 was observed through integrative self-sorting, 1b in equilibrium with the narcissistic products 1 and 2 (Figure1).The presence of all three products was confirmed by 1 H NMR, DOSY spectra (FigureS14, S15) and ESI-MS (FigureS16, S17).Two-dimensional NMR techniques provided structural information consistent with a D3-symmetric trigonal prismatic framework for cage 3 (FigureS52-S55).DFT calculations were undertaken usingGaussian 16 program 14   to obtain an energy-minimized structure for cage 3, shown in Figure2c.This structure gave conformations of the three bulky anthracene panels that projected inwards, separating the internal cavity into two isolated compartments.

Figure 4 .
Figure 4. a) DFT energy-minimized structures of 3 and 4 with the cavity volumes outlined in deep blue mesh; b) Guest molecules (G1-G5) were encapsulated by both 3 and 4; c) G1 induced conversion from 1 and 2 to form exclusively 2 .G1⊂3.The host-guest properties of trigonal prismatic cages 3 and 4 were then investigated (Figure4).In cages 3 and 4, the bulky meridional anthracene units were designed to separate the internal cavity into two isolated compartments, resembling a 'peanut' structure.19The internal cavity volumes were calculated by MoloVol 13 to be 308.9Å 3 and 279.1 Å3 for 3, and 258.6 Å 3 and 226.4 Å 3 for 4, respectively (Figures 4a, S87).Cages 3 and 4 both bound a series of alkanes, including adamantane (G1) and norbornane (G2) in slow exchange on the NMR time scale (Figures S44, S67).Encapsulation was further confirmed by DOSY NMR (Figures S49,S57, S70 and S73), where the encapsulated guest and host were observed to diffuse at the same rate.Intriguingly, some terpenoid natural products such as verbenone (G3), (1S)-(-)-camphor (G4) and (-)-beta pinene (G5), which are similar in size to norbornane, were also observed to encapsulate within both 3 and 4 (Figures 4b, S59-S66, S75-S83), also in slow exchange on the NMR timescale.Synthetic receptors have been shown to adjust their binding sites to better bind guests.8b Thus, we also studied guestencapsulation-induced structural transformation in the equilibrium mixture of cages 1, 2 and 3.The addition of G1 to this mixture prompted re-equilibration, resulting in the formation of only cage 3 containing G1 (Figure4c). 1 H NMR integrations indicated the formation of host-guest complex 2 .G13, which was also confirmed by ESI-MS, with no signals observed corresponding to cages 1 and 2. The hostguest complex 2 .G13 was characterized by 2D NMR spectroscopy (FiguresS52-S55).Entropy changes associated with guest encapsulation may help drive reconfiguration of the system.The freeing of Figure 4. a) DFT energy-minimized structures of 3 and 4 with the cavity volumes outlined in deep blue mesh; b) Guest molecules (G1-G5) were encapsulated by both 3 and 4; c) G1 induced conversion from 1 and 2 to form exclusively 2 .G1⊂3.The host-guest properties of trigonal prismatic cages 3 and 4 were then investigated (Figure4).In cages 3 and 4, the bulky meridional anthracene units were designed to separate the internal cavity into two isolated compartments, resembling a 'peanut' structure.19The internal cavity volumes were calculated by MoloVol 13 to be 308.9Å 3 and 279.1 Å3 for 3, and 258.6 Å 3 and 226.4 Å 3 for 4, respectively (Figures 4a, S87).Cages 3 and 4 both bound a series of alkanes, including adamantane (G1) and norbornane (G2) in slow exchange on the NMR time scale (Figures S44, S67).Encapsulation was further confirmed by DOSY NMR (Figures S49,S57, S70 and S73), where the encapsulated guest and host were observed to diffuse at the same rate.Intriguingly, some terpenoid natural products such as verbenone (G3), (1S)-(-)-camphor (G4) and (-)-beta pinene (G5), which are similar in size to norbornane, were also observed to encapsulate within both 3 and 4 (Figures 4b, S59-S66, S75-S83), also in slow exchange on the NMR timescale.Synthetic receptors have been shown to adjust their binding sites to better bind guests.8b Thus, we also studied guestencapsulation-induced structural transformation in the equilibrium mixture of cages 1, 2 and 3.The addition of G1 to this mixture prompted re-equilibration, resulting in the formation of only cage 3 containing G1 (Figure4c). 1 H NMR integrations indicated the formation of host-guest complex 2 .G13, which was also confirmed by ESI-MS, with no signals observed corresponding to cages 1 and 2. The hostguest complex 2 .G13 was characterized by 2D NMR spectroscopy (FiguresS52-S55).Entropy changes associated with guest encapsulation may help drive reconfiguration of the system.The freeing of