Topological Strain-Induced Regioselective Linker Elimination in a Chiral Zr(IV)-Based Metal-Organic Framework

Abstract

•Highly flexible 18-crown-6-ether functionality was embedded into a chiral Zr-MOF•An unprecedented solid-state topology transition behavior was observed•The transition process was captured by single-crystal and powder X-ray diffraction•The resultant chiral Zr-MOF can enantioseparate lansoprazole, with up to 98% ee Zr-carboxylate metal-organic frameworks (MOFs) are well known as structurally robust materials with strong coordination bonds that have been widely investigated in the MOF community since 2008. The robust coordination of these 3D materials makes topology transitions involving Zr–O bond cleavage and formation extremely challenging and rare. Here, we demonstrate that by introducing a highly flexible 18-crown-6-ether functionality into a homochiral Zr-MOF, we are able to target an unprecedented SC-SC topology transition by the virtue of topological strain. The transition, which occurs without any external stimuli and through a regioselective-linker-elimination process, was captured by single-crystal and powder X-ray diffraction studies. As a result, a highly porous and stable 3D phase with fluorite topology is attained that can be employed as a solid adsorbent for enantioadsorptive and solid-phase extractive separation of lansoprazole, with an excellent enantioselectivity. Zr-carboxylate metal-organic frameworks (MOFs) are structurally robust materials, in part due to their strong coordination bonds. The regioselective Zr–O bond cleavage and formation between 3D architectures are thus challenging and are heretofore unexplored. In this work, by introducing highly flexible 18-crown-6-ether functionalities into a homochiral Zr-MOF, we report an unprecedented topology transition in which a 4,10-connected framework undergoes a rapid solid-state transition into a thermodynamically more stable 4,8-connected analog by a regioselective-linker-elimination under ambient conditions. The transition process was unambiguously unraveled by single-crystal and powder X-ray diffraction studies, and we proposed a possible transition mechanism based on various control experiments and theoretical calculations. The excellent chemical stability and substantially expanded porosity and pore apertures endowed the transformed chiral MOF with an exceptional capacity for the enantioadsorptive and solid-phase extractive separation of the racemic drug molecule of lansoprazole with 98% ee and 93% ee, respectively. Zr-carboxylate metal-organic frameworks (MOFs) are structurally robust materials, in part due to their strong coordination bonds. The regioselective Zr–O bond cleavage and formation between 3D architectures are thus challenging and are heretofore unexplored. In this work, by introducing highly flexible 18-crown-6-ether functionalities into a homochiral Zr-MOF, we report an unprecedented topology transition in which a 4,10-connected framework undergoes a rapid solid-state transition into a thermodynamically more stable 4,8-connected analog by a regioselective-linker-elimination under ambient conditions. The transition process was unambiguously unraveled by single-crystal and powder X-ray diffraction studies, and we proposed a possible transition mechanism based on various control experiments and theoretical calculations. The excellent chemical stability and substantially expanded porosity and pore apertures endowed the transformed chiral MOF with an exceptional capacity for the enantioadsorptive and solid-phase extractive separation of the racemic drug molecule of lansoprazole with 98% ee and 93% ee, respectively. Metal-organic frameworks (MOFs), composed of metal ions/clusters and multitopic organic linkers, contain porous architectures that are reminiscent of those of zeolites.1Yaghi O.M. Kalmutzki M.J. Diercks C.S. Introduction to Reticular Chemistry: Metal-Organic Frameworks and Covalent Organic Frameworks. Wiley-VCH, 2019Crossref Scopus (207) Google Scholar, 2Zhou H.C. Long J.R. Yaghi O.M. Introduction to metal–organic frameworks.Chem. Rev. 2012; 112: 673-674Crossref PubMed Scopus (4484) Google Scholar, 3Howarth A.J. Liu Y. Li P. Li Z. Wang T.C. Hupp J.T. Farha O.K. Chemical, thermal and mechanical stabilities of metal–organic frameworks.Nat. Rev. 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As a result, there are only a handful of reports where flexible Zr-MOFs were achieved by either the introduction of long and rotatable linkers20Deria P. Gómez-Gualdrón D.A. Bury W. Schaef H.T. Wang T.C. Thallapally P.K. Sarjeant A.A. Snurr R.Q. Hupp J.T. Farha O.K. Ultraporous, water Stable, and breathing zirconium-based metal–organic frameworks with ftw topology.J. Am. Chem. Soc. 2015; 137: 13183-13190Crossref PubMed Scopus (113) Google Scholar,21Krause S. Bon V. Stoeck U. Senkovska I. Többens D.M. Wallacher D. Kaskel S. A stimuli-responsive zirconium metal–organic framework based on supermolecular design.Angew. Chem. Int. Ed. Engl. 2017; 56: 10676-10680Crossref PubMed Scopus (50) Google Scholar or through the reduction of cluster connectivity.22Zhang Y. Zhang X. Lyu J. Otake K.I. Wang X. Redfern L.R. Malliakas C.D. Li Z. Islamoglu T. Wang B. Farha O.K. A flexible metal–organic framework with 4-connected Zr6 nodes.J. Am. Chem. Soc. 2018; 140: 11179-11183Crossref PubMed Scopus (102) Google Scholar Using these approaches, flexible Zr-MOFs are predominantly limited to undergoing structural swelling and/or contraction, a process commonly referred to as “gating” or “breathing,” where the overall topology remains undisrupted. Although flexibility often comes with the penalty of reduced structural robustness, Zr-MOFs are able to circumvent this drawback owing to their strong Zr–O bonds. However, the robust coordination makes topology transitions among 3D Zr-MOFs involving Zr–O bond cleavage and formation extremely challenging and rare. Thus far, only two examples have been reported. Užarević and colleagues demonstrated the first phase transition in Zr-MOFs in which the 12-connected porphyrinic Zr6-based MOF-525 underwent a dramatic topology transformation from its cubic phase to its hexagonal phase upon liquid-assisted grinding.23Karadeniz B. Žilić D. Huskić I. Germann L.S. Fidelli A.M. Muratović S. Lončarić I. 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The regioselective Zr–O bond cleavage and formation among 3D architectures that does not compromise the crystallinity is still unexplored as a consequence of the inevitable difficulties in controlling the location (regioselectivity) of any weakness in their crystal lattices. Monitoring and snapshotting such regioselectivity in a single-crystal to single-crystal (SC-SC) manner is highly sought after, yet, it has never been achieved in Zr-MOFs. In this work, we show that by introducing topological strain into a chiral 4,10-connected Zr6-based MOF with highly flexible 18-crown-6-ether functionalities, an unprecedented topology transition can be realized through a SC-SC manner in the solid state without any external stimuli. The transition process is accomplished by three sequential procedures: (1) regioselective linker deformation and Zr–O bonds cleavage, (2) ordered linker elimination and oriented crystal lattice contraction, (3) and finally Zr6 cluster dimerization and framework formation, as unequivocally revealed by SC X-ray crystallography. As a result of this transformation, a highly porous and stable 3D phase with 4,8-connected fluorite (flu) topology is attained that can be employed as a solid adsorbent for the highly efficient adsorption of electron-deficient cationic dye of methylene blue, as well as for the enantiospecific adsorption and separation of the large-sized racemic drug molecule of lansoprazole with up to 98% ee. Moreover, the resultant MOF can serve as the chiral solid-phase extractant to separate a racemic mixture of lansoprazole, achieving 93% ee within 4 h. To the best of our knowledge, this is the second example where chiral MOFs are successfully exploited in the solid-phase extraction (SPE) separation technologies,25Navarro-Sánchez J. Argente-GarcÍa A.I. Moliner-MartÍnez Y. Roca-Sanjuán D. Antypov D. CampÍns-Falcó P. Rosseinsky M.J. MartÍ-Gastaldo C. Peptide metal−organic frameworks for enantioselective separation of chiral drugs.J. Am. Chem. Soc. 2017; 139: 4294-4297Crossref PubMed Scopus (152) Google Scholar and the enantioselectivity presented herein is among the best in a broad class of stationary phases. The spiro-derived chiral 18-crown-6-ether functionalized tetracarboxylic linkers, S- and R-4,4′,6,6′-tetrakis(4-benzoic acid)-[7,7′-(1,1′-Spirobiindano)]-1,4,7,10,13,16-hexaoxahexadecane (S-H4L and R-H4L) (Figure 1A), were prepared with 56% overall yields starting from enantiopure S- or R-spinol, respectively. Solvothermal reactions of ZrCl4 with S-H4L or R-H4L in the presence of formic acid as the competing reagent in N,N-dimethylformamide (DMF) afforded colorless triangular crystals of [Zr6O4(μ3-OH)4(μ1-OH)(HCOO)(DMF)(H2O)2(L)2.5]. The enantiopure MOF was characterized by both SC and powder X-ray diffraction, with the latter confirming its phase purity. SC structural analysis clearly revealed that Spiro-CE-1 crystallizes in the orthorhombic chiral space group of C2221, with the asymmetric unit containing a whole formula unit. The Zr6O8 core, formed by six Zr atoms connected to each other by four μ3-O and four μ3-OH groups yielding a D2d symmetry (Figure S1), was connected to ten fully deprotonated L4- linkers, with two of the linkers coordinated in a monodentate fashion and the rest engaged in bidentate coordination. The coordination of the secondary building unit (SBU) was completed with one terminal μ1-OH, one formate ligand, one DMF molecule, and two water molecules (Figure 1A). Spiro-CE-1 contained narrow zig-zag channels with necked junctions along the c axis that have an aperture measuring 0.8 nm, which were suffused with highly flexible 18-crown-6-ether groups and disordered DMF molecules. Spiro-CE-2 was obtained by exposing fresh-prepared Spiro-CE-1 to air for 3–5 min. Spiro-OH was obtained by employing similar synthetic procedures as Spiro-CE-1, except that enantiopure 4,4′,6,6′-tetrakis(4-benzoic acid)-1,1′-Spirobiindano-7,7′-diol was used as ligand. Changes in the unit cell parameters arising from solvent effects are uncommon in Zr6-based MOFs with high connectivity. Therefore, we were surprised to observe a distinct peak shift in the powder X-ray diffraction (PXRD) patterns of the bulk Spiro-CE-1 upon removal from the solvent as compared with the simulated pattern from single-crystal data (Figure S8). This phenomenon can be indicative of solvent-evaporation-induced structural changes, which prompted us to further investigate our materials. Fortunately, the transformed phase, denoted as Spiro-CE-2, maintained high crystallinity, thus allowing us to collect good X-ray diffraction data for structural determination. SC analysis revealed that Spiro-CE-2 also crystallizes in the chiral C2221 space group, with half of the formula in the asymmetric unit. However, the c axis was found to be decreased by 31% and resulted in a 27% shrinkage in the unit cell volume when compared with Spiro-CE-1. Detailed structural analysis showed two edge-sharing Zr6O8 clusters in Spiro-CE-2 that were connected by two μ2-OH groups to generate a new Zr12O8(μ3-OH)8(μ2-OH)2 SBU, which has not been reported in MOFs and even in molecular complexes to date (Figure 1C). The novel SBUs were connected to eight L4- linkers, with two of them monodentately coordinated. The remaining Zr coordination sites were occupied by two formate ligands and terminal –OH/H2O groups to give the overall formula of [Zr12O8(μ3-OH)8(μ2-OH)2(μ1-OH)12(HCOO)2(H2O)14(L)2], which is indicative of a 1.5 linker loss per asymmetric unit. A close examination of the two structures revealed that Spiro-CE-2 is formed through the ordered regioselective linker elimination in the crystal lattice of Spiro-CE-1, while keeping the remaining segments nearly undisturbed (Figure 1). The massive linker loss and significant contraction of the unit cell volume from 47,325 Å3 (calculated density ρcalc = 0.889 g cm−3) to 34,475 Å3 (ρcalc = 0.719 g cm−3) lead to a highly open phase with large intercrossed channels with an edge length of 1.8 nm and distorted octahedral cavities with an approximate size of 1.8 × 1.8 × 2.9 nm3 (Figures 6A, 6B, S3, and S4). Calculations with PLATON26Spek A.L. Single-crystal structure validation with the program PLATON.J. Appl. Crystallogr. 2003; 36: 7-13Crossref Scopus (15734) Google Scholar a with probe radius of 1.8 Å showed that Spiro-CE-2 had a higher solvent-accessible volume than Spiro-CE-1 (69.4% versus 53.3%). From a purely topological point of view of Spiro-CE-1, the Zr6 clusters and L4- ligands served as 10-connected and 4-connected nodes, respectively. With this combination, we could now form the first example among Zr-MOFs of a simplified 4,10-connected 3D net with the point symbol of {417·624·84}2{45·6}2{46}3 (Figure 1B). In contrast, the 4,8-connected net with the fluorite (flu) topology of Spiro-CE-2 could be obtained when considering the Zr12 clusters as 8-connected nodes (Figures 1C and S2). Spiro-CE-2 could alternatively be described as the rare 4,5-connected binodal tcs topology (Figure S2), where the Zr12 clusters could be further deconstructed into two interconnected Zr6 nodes. It should be noted that MOFs with flu topology are generally recognized as thermodynamically stable and highly porous.27Zhang M. Chen Y.P. Bosch M. Gentle III, T. Wang K. Feng D. Wang Z.U. Zhou H.C. Symmetry-guided synthesis of highly porous metal–organic frameworks with fluorite topology.Angew. Chem. Int. Ed. Engl. 2014; 53: 815-818Crossref PubMed Scopus (160) Google Scholar,28Tan Y.X. Yang X. Li B.B. Yuan D. Rational design of a flu-type heterometallic cluster-based Zr-MOF.Chem. Commun.(Camb). 2016; 52: 13671-13674Crossref PubMed Google Scholar To obtain detailed information regarding the transition process, a series of experiments were carried out on Spiro-CE-1 under different conditions. First, to rule out the possibility that the transition occurred in solution before being taken out from the reaction system, we extended the initial solvothermal reaction to 1 week while remaining at 393 K. The unchanged PXRD pattern indicated that no transition occurred during the reaction process (Figure S9). Moreover, the freshly prepared crystals of Spiro-CE-1 maintained their structural integrity even after being immersed in DMF for 1 month (Figure S9). Second, we removed the freshly prepared crystals of Spiro-CE-1 from various solvents (DMF, acetone, or CH2Cl2) under ambient conditions and found that they completely transformed to the open phase of Spiro-CE-2 within 3–5 min. This process was effectively accelerated or decelerated at elevated or cryogenic temperatures, respectively. Notably, while the transition process proceeded smoothly at 220 K, it was completely prohibited below the freezing point of DMF (212 K). Third, we unambiguously elucidated that the transition process occurred in a SC to SC manner by performing in situ optical microscopy and single-crystal X-ray diffraction studies on an individual crystal. To achieve a steady and slow transition rate, the SC X-ray diffraction was performed at 220 K. SC-XRD patterns showed continuous peak shifts and three consecutive metastable intermediates (Figure 2A). Optical microscopy images showed an apparent crystal size reduction (Figure 2B, inset), which is in accordance with the contraction of the unit cell volume. The c axis gradually decreased from 64.585 to 44.637 Å with the three intermediates of 60.169, 52.660, and 48.352 Å, leading to an overall unit cell volume shrinkage of 12,850 Å3. Importantly, we successfully obtained the crystal structure of the first intermediate (denoted as Spiro-CE-α) and the unit cell parameters of the subsequent two intermediates (denoted as Spiro-CE-β and Spiro-CE-γ). Despite our efforts to collect good diffraction data of Spiro-CE-β and Spiro-CE-γ, we were unsuccessful due to their highly disordered structures, as illustrated by the diffuse scattering in all the collected image frames (Figure S12). SC structure analysis of Spiro-CE-α revealed that this intermediate has same 3D topology as Spiro-CE-1, in which each Zr6 cluster is bonded to ten linkers. However, further comparison of the two structures indicated that one of the bidentately coordinated Zr–O bonds in Spiro-CE-1 is monodentately coordinated in Spiro-CE-α, with the corresponding linker showing severe deformation where the dihedral angle of spiro backbone changes from 78.8° to 89.7°, as depicted in Figures 3 and S6. This noteworthy movement evidently brings the two adjacent Zr6 clusters closer to each other and would conceivably further induce the domino-like linker elimination and Zr6 cluster dimerization. Given that the solid-state transition process occurs at 220 K, the DMF solvent cannot evaporate at such a low temperature, which excludes the commonly recognized solvent evaporation mechanism where elevated temperatures are needed to liberate guest solvent molecules. Therefore, we speculated that the main driving force in our transition system was the subtle topological strain in the crystal lattice of Spiro-CE-1. Moreover, the highly flexible 18-crown-ether-6 moieties may trigger the transition process by providing sufficient initial energy through drastic vibrations, resembling a domino effect. To verify our deduction, we carefully performed a series of structural analyses, control experiments, and theoretical calculations. We began by carefully comparing the three structures, which revealed remarkable deformations of the 18-crown-6-ether moieties (Figure S5), implying their intense vibration during the transition process. Next, we demonstrated that the transition rates of Spiro-CE-1 were the same, regardless of the solvent types (DMF, acetone, and CH2Cl2) in the pores, further suggesting that the guest solvent evaporation was not the main driving force for the transition. In addition to experimental results, density functional theory (DFT) calculations (Figure S21) on the SBUs of Spiro-CE-1 and Spiro-CE-2 at 298 K demonstrated that the generation of Zr12 SBU was more thermodynamically favorable, as the reaction enthalpy (ΔrH) and Gibbs free energy (ΔrG) for this reaction were −103.4 and −20.7 kcal mol−1, respectively. Finally, to probe the role that the flexible 18-crown-6-ether functional group had on the phase transition, we prepared a new chiral tetracarboxylic spiro-based ligand with the 7.7′-positions modified with hydroxyl groups (Figure S7). After assembly with ZrCl4 under similar solvothermal conditions, we obtained a chiral Zr6-based MOF (Spiro-OH) that crystallized in the same C2221 space group with similar unit cell parameters as Spiro-CE-1. SC X-ray analysis indicated that the less sterically hindered hydroxyl groups lead to the formation of a 4,12-connected framework, in which the axial two carboxylic groups were monodentately bonded to the Zr6 cluster (Figure S7). Nonetheless, the resultant 3D structure of Spiro-OH is akin to that of Spiro-CE-1, with the only difference being the additional bonded linkers and the functional groups present on the linkers (Figure S7). Therefore, we additionally studied the transition behavior of Spiro-OH under our previously investigated conditions. Spiro-OH remained structurally robust and showed no phase transition, even under harsh conditions as confirmed by PXRD measurements (Figure S7), which suggests that the flexible 18-crown-6-ether functionalities played a crucial role in Spiro-CE-1 phase transition. Inspired by the well-established affinity between 18-crown-6-ether groups and K+ ions,29Sam D.J. Simmons H.E. Crown ether chemistry. Substitution reactions of potassium halide and potassium hydroxide complexes of dicyclohexyl-18-crown-6.J. Am. Chem. Soc. 1974; 96: 2252-2253Crossref Scopus (117) Google Scholar we looked to fix the 18-crown-6-ether moieties of Spiro-CE-1 through post-synthetic chelation, thereby restricting its vibrational motion. After optimizing the reaction conditions, the host-guest adducts of Spiro-CE-1-K were obtained by immersing Spiro-CE-1 crystals in saturated methanol solution of KBF4 at 333 K for 24 h. Inductively coupled plasma optical emission spectrometry (ICP-OES) analyses gave the K/Zr ratio of 0.43, which matched well with the theoretical value of 0.42 as calculated based on the formula. Although we have collected several sets of diffraction data of the post-synthetically modified crystals using synchrotron radiation, we were unsuccessful in locating the K+ ions in the crystal structure. The activated Spiro-CE-1-K gave a Brunauer-Emmett-Teller (BET) area of 450 m2 g−1 (Figure S16). With these results in hand, we set out to study the transition behavior of Spiro-CE-1-K at both room temperature and 373 K. The nearly unchanged PXRD patterns under both conditions are indicative of the formation of a stable framework (Figure S11), alluding to the importance of the vibrational motion of the linkers in the phase transition of the MOF. Taking note of these studies, we propose a transition mechanism associated with flexible 18-crown-6-ether initiators. As shown in Figure 4, the flexible 18-crown-6-ether groups may behave as molecular rotors,30Conyard J. Addison K. Heisler I.A. Cnossen A. Browne W.R. Feringa B.L. Meech S.R. Ultrafast dynamics in the power stroke of a molecular rotary motor.Nat. Chem. 2012; 4: 547-551Crossref PubMed Scopus (127) Google Scholar reminiscent of molecular machines that can vibrate inside the crystal lattice. However, their vibration is restricted in solvated pores; accordingly, the generated weak energy is unable to trigger the topological strain in Spiro-CE-1. Once removed from the solvent, the equilibrium of solvent molecule ingress and egress is disrupted, thus greatly facilitating the vibration of 18-crown-6-ether rotors. The vibrational motion leads to rapid guest exclusion and the liberation of solvent molecules from the pores additionally accelerates and reinforces the vibration of the rotors. Consequently, the dramatic vibration of 18-crown-6-ether moieties provides enough energy to trigger the topological strain and ultimately induce the rapid topology transition. Solid-state circular dichroism (CD) spectra of Spiro-CE-2 made from S and R enantiomers of H4L are mirror images of each other, indicative of this MOF’s enantiomeric nature (Figure S13). N2 adsorption/desorption experiments of pretreated Spiro-CE-2 at 77 K showed a type I isotherm (Figure 5D) with a Brunauer-Emmett-Teller (BET) area calculated to be 1,230 m2 g-1, which is close to the simulated result (1,440 m2 g-1) based on the accessible surface area program.31Düren T. Millange F. Férey G. Walton K.S. Snurr R.Q. Calculating geometric surface areas as a characterization tool for metal-organic frameworks.J. Phys. Chem. C. 2007; 111: 15350-15356Crossref Scopus (440) Google Scholar Thermogravimetric analysis (TGA) of the evacuated Spiro-CE-2 showed no weight loss in the temperature range 313–603 K and framework decomposition starting at about 603 K (Figure S14). The chemical stability of Spiro-CE-2 was examined thoroughly by PXRD, N2 sorption, and dye uptake measurements after treatment in boiling water, 0.01 M NaOH (aq.) at room temperature (RT), and 8 M HCl (aq.) at RT for 1 week. As shown in Figure 5C, the PXRD patterns remained intact after these treatments, suggesting that no phase transition or framework collapse occurred. Furthermore, permanent porosity was retained in all conditions for Spiro-CE-2, as evidenced by N2 sorption measurements (Figure 5D). To evaluate the porosity of Spiro-CE-1 and Spiro-CE-2 in solution, we performed dye uptake experiments. Due to the ubiquitous distribution of electron-rich 18-crown-6-ether groups in the framework, we chose the electron-deficient cationic methylene blue (MB) (15.6 × 6.8 Å2) as the model dye (Figure S17). As shown in Figure 6A; Table S7, Spiro-CE-2 can adsorb 4.5 MB per formula unit in MeOH, compared with 0.7 for Spiro-CE-1, indicating that Spiro-CE-2 has ample interspaces to accommodate large guest molecules. Additionally, after the above-mentioned treatments, Spiro-CE-2 still adsorbed 3.0/3.1/3.9 MB per formula unit, respectively, indicative of its structural integrity. Spiro-CE-2 could not be recovered to Spiro-CE-1, even after the addition of extra chiral ligands into the DMF solution containing Spiro-CE-2 crystals, as verified by PXRD, which corroborated that this phase was the thermodynamically favored product (Figure S10).Figure 6Adsorption Behaviors of Spiro-CE-1 and Spiro-CE-2Show full caption(A) UV-vis curves of MB adsorption after different treatments. Inset: Image showing the color change of Spiro-CE-2 after MB sorption (left) and the optimized molecular structure and size of MB (right).(B) UV-vis curves of lansoprazole adsorption, with an inset picture of the molecular structure and size of lansoprazole.(C) Cartoon illustration of the enantioselective adsorptive separation of lansoprazole with S-Spiro-CE-2. The yellow triangles are indicative of S-Spiro-CE-2.(D) Cartoon illustration of enantioselective SPE separation of lansoprazole with R-Spiro-CE-2. The yellow triangles are indicative of R-Spiro-CE-2 and the R/S circles are indicative of the chiral configuration of lansoprazole molecule.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) UV-vis curves of MB adsorption after different treatments. Inset: Image showing the color change of Spiro-CE-2 after MB sorption (left) and the optimized molecular structure and size of MB (right). (B) UV-vis curves of lansoprazole adsorption, with an inset picture of the molecular structure and size of lansoprazole. (C) Cartoon illustration of the enantioselective adsorptive separation of lansoprazole with S-Spiro-CE-2. The yellow triangles are indicative of S-Spiro-CE-2. (D) Cartoon illustration of enantioselective SPE separation of lansoprazole with R-Spiro-CE-2. The yellow triangles are indicative of R-Spiro-CE-2 and the R/S circles are indicative of the chiral configuration of lansoprazole molecule. Given the advantages of the intrinsic chirality of Spiro-CE-2, rich potential recognition sites, and good stability, we foresaw that it could be utilized as a solid adsorbent for enantiospecific recognition and separation.32Corella-Ochoa M.N. Tapia J.B. Rubin H.N. Lillo V. González-Cobos J. Núñez-Rico J.L. Balestra S.R.G. Almora-Barrios N. Lledós M. Guell-Bara A. et al.Homochiral metal−organic frameworks for enantioselective separations in liquid chromatography.J. Am. Chem. Soc. 2019; 141: 14306-14316Crossref PubMed Scopus (52) Google Scholar To implement this hypothesis, we chose lansoprazole, a chiral drug molecule used for gastric ulcers,33Lai K.C. Lam S.K. Chu K.M. Wong B.C.Y. Hui W.M. Hu W.H.C. Lau G.K.K. Wong W.M. Yuen M.F. Chan A.O.O. et al.Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use.N. Engl. J. Med. 2002; 346: 2033-2038Crossref PubMed Scopus (553) Google Scholar as our substrate due to its similar size (16.1 × 7.2 Å2) to MB (Figure S17). As a result, it can be readily accommodated inside the cavities of Spiro-CE-2. As illustrated in Figures 6B and S18, Spiro-CE-2 can adsorb about 3.7 lansoprazole molecules per formula unit in MeOH with fast adsorption kinetics. In contrast, Spiro-CE-1 only allowed for surface adsorption, thus precluding any possibility for efficient separation. With these results in hand, we evaluated the adsorption enantioselectivity. After careful optimization of the adsorption conditions, 98% ee was achieved using S-Spiro-CE-2 (94 mg, 0.025 mmol) in 3 mL dry MeOH containing 0.4 mmol racemic lansoprazole at 277 K, with the R enantiomers being in excess. The chiral nature of the product was dominated by the handedness of the sorbent, as evidenced by the separation performed by R-Spiro-CE-2 yielding the S enantiomer over the R enantiomer. Spiro-CE-2 can be recycled at least five times without compromising its enantioselectivity (Figure S19) while still retaining its high crystallinity and porosity (Figures 5C and 5D). The slight decrease of N2 uptake after five runs was ascribed to the residual lansoprazole molecules in the cavities that could not be fully removed through solvent washing. The uniform crystal morphology and size (Figure S19) and excellent performance of Spiro-CE-2 in the enantioadsorptive separations prompted us to evaluate its potential use as a chiral stationary phase (CSP) for the SPE separation of lansoprazole. As shown in Figure 6D, the fully evacuated R-Spiro-CE-2 (50 mg, 13.3 mmol) was packed into a polypropylene cartridge, and a racemic mixture of lansoprazole (10 mg, 0.027 mmol) was eluted in 2 mL dry MeOH at 0.5 mL/h with the assistance of a syringe pump. High-performance liquid chromatography (HPLC) analysis of the resulting extract showed 93% ee, with the R enantiomers being in excess, confirming the ability of R-Spiro-CE-2 to preferentially trap S enantiomers. The slight decrease in enantioselectivity is ascribed to the inefficient packing of the MOF crystals. Moreover, the MOF cartridge can be reused for at least two additional runs without any significant loss of enantioselectivity (Figure S20). Thus, our results highlight the potential application of Spiro-CE-2 for the enantioselective separation of racemic lansoprazole. In summary, we have achieved an unprecedented topology transition in a conventionally stable chiral Zr6-based MOF by introducing a highly flexible 18-crown-6-ether moiety into a unique C2 symmetric spiro-based linker. The dramatic vibration of 18-crown-6-ether moieties in the solid state was believed to trigger the topological strain and resulted in the regioselective linker deformation and elimination. Moreover, the topology transition led to the formation of a highly porous and stable fluorite network that shows outstanding performances in the enantiospecific separation of lansoprazole with both adsorptive and SPE technologies. This work not only probes the limits to which a stable Zr6-based SC material can undergo ordered linker elimination while still maintaining both the microscopic and macroscopic crystallographic integrity but also brings new design principles for the production of novel crystalline materials.