Hierarchical assembly of a Ti_24 metal-organic polyhedron via kinetic trapping of intermediates

Domain: physics
Published: 2026-02-03
Editorial outcome: major_revision

Abstract
The synthesis of high-nuclearity titanium metal-organic polyhedra (Ti-MOPs) has remained a formidable challenge due to the high oxophilicity and hydrolysis susceptibility of Ti4+ ions. Herein, we report a Ti24 MOP with a truncated octahedron (tro) topology, which represents the highest nuclearity Ti-MOP reported to date. Beyond structural characterization, we introduce a pathway intervention strategy using Ni2+ as a kinetic modulator to trap and structurally characterize two key intermediates—a Ti12 macrocycle and a Ti12 (6-4-6) module. These intermediates outline a hierarchical assembly pathway from simple precursors to Ti24 MOP. Furthermore, we demonstrate that this process is governed by a coordination lability gradient between Ti4+ and Ni2+, providing an effective strategy for directing supramolecular complexity. This Ti-MOP exhibits permanent microporosity, gas separation, and post-assembly modification capability. This work transforms a synthetic challenge into a strategic advantage, offering a blueprint for the rational assembly of complex metal-organic architectures.

Introduction
The programmable construction of metal-organic polyhedra (MOPs) represents a central goal in supramolecular chemistry1–7, driven by their potential for creating tailored nanocavities with applications in separation, catalysis, and sensing8–12. A significant barrier to achieving this goal is the inherent difficulty in probing self-assembly mechanisms, which typically involve high-energy intermediates13. While in situ techniques such as nuclear magnetic resonance (NMR)14,15, high-resolution mass spectrometry (HRMS)16, and fluorescence spectrum17 can track coordination processes in real time to some extent, they often lack the structural resolution needed to unambiguously identify intermediate species.

This challenge is particularly acute in titanium chemistry, where the high reactivity and oxophilicity of Ti4+ ions18–20 typically lead to the formation of thermodynamically stable titanium-oxo clusters (TOCs)21–25 or metal-organic frameworks (Ti-MOFs)26–30, rather than discrete Ti-MOPs31–34. Since Raymond’s pioneering report on tetrahedral Ti4 MOP in 199835, although certain progress has been made in this field, there are still fewer than 20 types of Ti-MOPs to date31. These structures still have the following limitations: i) low nuclearities (≤18 Ti atoms)34, ii) simplistic topologies such as tetrahedra and cubes36–38 (Fig. 1a), and iii) low modifiability. The lack of structural complexity and functional versatility in known Ti-MOPs highlights a significant gap in the field. Although our group has contributed to this area with the synthesis of a giant cage-like Ti oxo-cluster and several Ti-MOPs36,39–41, the development of high-nuclearity Ti-MOPs with sophisticated architectures remains a formidable challenge, owing to the difficulty in controlling Ti4+ ion reactivity and hydrolysis.

Herein, we have successfully synthesized and determined the crystal structure of FIR-151—a Ti24 MOP with tro topology. This high-symmetry cage not only represents the highest nuclearity Ti-MOP reported to date, but also demonstrates how the inherent challenges of titanium coordination chemistry can be overcome to achieve architectural complexity. The assembly pathway was elucidated through the structural characterization of two key intermediates: a Ti12 macrocycle (FIR-152) and a Ti12 (6-4-6) module (FIR-153). These structures provide direct evidence for a hierarchical assembly pathway (Fig. 1b), underpinned by a coordination lability gradient between Ti4+ and Ni2+. Furthermore, FIR-151 exhibits permanent porosity, selective gas adsorption, and post-assembly modification capabilities, demonstrating functional relevance. This work not only advances the understanding of titanium supramolecular chemistry but also establishes an effective strategy for achieving programmable synthesis in dynamic metal-organic systems.

Results
Squaric acid (H2C4O4) is frequently employed as an organic template to facilitate the ring expansion and assembly of macrocyclic compounds42. In existing titanium complexes, it has been observed that the C4O42– ligand coordinates with four Ti4+ ions to form a 4-membered ring module43,44. Such modules are often found in complex polyhedral structures, exhibiting topological types such as sod, rho, and lta. Here, we select Ti4+ ions and C4O42– ligands for assembly to construct polyhedral featuring intricate topological architectures. The reaction of Ti(OiPr)4 with H2C4O4 in the mixture solvent of acetic acid (CH3COOH)/acetonitrile (CH3CN) at 120°C led to the formation of yellow rhombic dodecahedral crystals of FIR-151 (FIR = Fujian Institute Research; Supplementary Fig. 1). Single-crystal X-ray diffraction (SCXRD) analysis reveals that FIR-151 crystallizes in the tetragonal P4/nmc space group with the formula as Ti24O24(C4O4)6(CH3COO)36 · guest (Supplementary Fig. 2 and Table S1). Its structure features a Ti24 MOP with a tro topology, representing the highest nuclearity Ti-MOP reported to date (Fig. 2a).

To elucidate the structure of FIR-151, we conducted a detailed analysis (Supplementary Fig. 3). Firstly, twelve Ti atoms are bridged by twelve μ2-O atoms to form a Ti12 macrocycle—marking what is, to the best of our knowledge, the first observation of such a Ti12 structure (Supplementary Table S2). This ring is capped by eighteen terminally coordinated CH3COO– ligands. Then, one C4O42– ligand positions within the central pore of the Ti12 ring, coordinating to four Ti atoms, leading to the formation of a Ti12 (6-4-6) module. Four additional C4O42– ligands occupy the remaining coordination sites on the Ti atoms within this module. The incorporation of C4O42– induces a conformational change in the Ti12 macrocycle, causing it to narrow and bend into a distinct roof-like architecture. This contrasts sharply with the planar or S-shaped configurations typically found in other wheel-type TOCs (Supplementary Fig. 4)25. The cage structure of FIR-151 can be viewed as a dimer of two Ti12 (6-4-6) modules via four shared C4O42– ligands (Fig. 2b and Supplementary Fig. 5). The assembly pathway of FIR-151, involving the dimerization of two curved Ti12 (6-4-6) modules, is reminiscent of the formation of iconic supramolecular structures such as the ‘tennis ball’ capsule45. In that system, two identical, curved organic subunits self-assemble through hydrogen bonds to form a closed spheroidal cavity capable of encapsulating guest molecules. The convergence of this geometric design principle across both organic hydrogen-bonded systems and inorganic MOPs underscores its universality for constructing closed-shell nanostructures from pre-organized, curved building blocks. As such, the overall assembly can be topologically represented as a truncated octahedron with the point symbol (46.68) (Fig. 2c). It is noteworthy that the square faces in the topological representation are realized as rectangles in the actual structure; this geometric distortion does not affect the topological classification. To the best of our knowledge, this structure provides an instance of a tro-type topology in Ti-MOP (Supplementary Table S3). The resulting structure measures approximately 18.7 × 18.7 × 20.2 Å3 and features a spherical inner cavity with a diameter of roughly 10.0 Å. Electrostatic potential (ESP) calculations reveal that FIR-151 is electrically neutral overall, yet features negatively charged open windows that favor interaction with cationic guest species (Supplementary Fig. 6). Moreover, these cages adopt a body-centered cubic close-packed arrangement in FIR-151 (Supplementary Fig. 7).

To deconvolute the pathway leading to this MOP, we designed a strategy to perturb the assembly equilibrium using kinetic trappers, aiming to stabilize and isolate metastable intermediates for structural characterization (Supplementary Fig. 8).

Intervention I: Trapping a macrocyclic precursor with Ni2+. Introducing NiCl2·6H2O into the reaction mixture leads to the isolation of yellow block-shaped crystals of FIR-152 (Supplementary Fig. 9). SCXRD analysis reveals that it crystallizes in the monoclinic space group P2/n. Its structure is represented by the formula [Ni(CH3CN)6]2+·[Ti12Ni2O6Cl4(C4O4)8(CH3COO)18(CH3CN)6]2– (Supplementary Table S4), and is built around Ti12 macrocycle—corresponding to intermediate 1 (Fig. 2d). Two NiCl3 clusters are positioned above and below the Ti12 macrocycle and are connected to it via three C4O42– ligands, forming a heterometallic MOP, FIR-152. The incorporation of the two NiCl3 clusters (Fig. 2e) results in a chair-like configuration of the Ti12 macrocycle ring. We propose that Ni2+ acts as a kinetic trap for this oligomeric species by modulating the local coordination thermodynamics, thereby stabilizing a critical nucleation intermediate along the assembly pathway.

Intervention II: Directing evolution with quaternary ammonium ions. When tetrabutylammonium bromide (TBAB) was introduced under otherwise identical reaction conditions, a structural rearrangement occurred, leading to the formation of orange hexagonal dipyramid crystals assigned as the isomeric phase FIR-153 (space group Cmcm, Supplementary Fig. 10 and Table S4). This compound features a Ti12 (6-4-6) modular structure (intermediate 2, Fig. 2f) in which the original 12-membered ring adopts a boat conformation. A central C4O42– ligand partitions the ring via coordination to four Ti4+ ions, while two NiCl3 clusters reposition to apical sites, linked by additional C4O42– ligands to form an isomeric MOP. Here, Ni2+ again serves to kinetically trap this reconfigured module. This transformation demonstrates how non-coordinating additives can profoundly influence the assembly landscape, steering the reorganization of a metastable intermediate into a non-pathway structural motif preceding the final MOP. The molecular structures of both intermediates, FIR-152 and FIR-153, were corroborated in solution by 1H NMR and small-angle X-ray scattering (SAXS) techniques (Supplementary Figs. 11–14).

To elucidate the assembly pathway of FIR-151, we employed a combination of solution-phase, structural, and reactivity analyses. Real-time SAXS monitoring revealed a continuous evolution of the maximum particle dimension (Dmax), as derived from the pair distance distribution function, P(r), from an initial ~6.7 Å through discrete states (~9.5 Å, ~17.0 Å) to the final ~19.1 Å (Supplementary Fig. 15). This progression is consistent with a multi-step assembly process rather than a single-step reaction. To gain atomic-level insight into potential intermediates along this pathway, we introduced Ni2+ ions as a kinetic trap, successfully isolating two key structural modules: the Ti12 macrocycle (FIR-152) and the Ti12 (6-4-6) module (FIR-153). Their precise structural complementarity provides a plausible geometric model for the progression towards the final cage. Critical reactivity tests further support this interpretation: while FIR-151 forms efficiently in the absence of Ni2+, the Ni2+-stabilized FIR-153 cannot be converted to the final product under identical conditions. This indicates that Ni2+ acts to trap and stabilize transient, on-pathway species, which would otherwise be unobservable. While each line of evidence—solution dynamics, structural correlation, and chemical reactivity—has inherent limitations, their convergence mutually supports a coherent, hierarchical assembly pathway from simple precursors to the complex Ti24 architecture.

Comparative analysis of the intermediates and the final product with precise crystal structures allows us to propose a hierarchical assembly pathway: Ti12 macrocycle (intervention 1) → Reorganization → Ti12 (6-4-6) module (intervention 2) → Dimerization → Ti24 MOP (Fig. 3a). This mechanistic proposal is best regarded as a robust working hypothesis, substantiated by the convergence of multiple experimental observations within the current technical constraints. We acknowledge that definitive proof would require direct molecular-level tracking of the transient intermediates in solution. Nevertheless, this hypothesis provides a valuable structural and conceptual framework for understanding the complex self-assembly of high-nuclearity MOPs and paves the way for future investigations using advanced in situ techniques.

This work supplies an effective strategy that extends beyond a single case study: the strategic use of coordination lability gradients (Fig. 3b). The assembly is controlled by the differential kinetics between the highly labile Ti4+ ion, which drives dynamic reorganization, and the moderately labile Ni2+ ion, which acts as a kinetic trap to stabilize key intermediates at defined points along the pathway. This strategy of using a second metal ion to modulate the energy landscape of a primary assembly process offers an alternative approach to achieve structural complexity, and its broad utility awaits validation in other metal-organic systems.

The as-synthesized FIR-151 were further characterized using various analytical techniques to confirm their phase purity, thermal stabilities, optical bandgap, and photoactivity (Supplementary Figs. 16–22). FIR-151 exhibit high stability towards common organic solvents and some acids and bases (Supplementary Fig. 23), enabling investigation of its gas adsorption and separation properties. To evaluate its porosity, the solvent-exchanged sample (CH3CN) was activated under vacuum at 30°C for 12 h (Supplementary Fig. 24). N2 sorption isotherms measured at 77 K revealed a type I isotherm, confirming the microporous nature and permanent porosity of FIR-151 (Fig. 4a). The Brunauer–Emmett–Teller (BET) and Langmuir surface areas were calculated to be 703 and 859 m2·g–1 (Supplementary Fig. 25), respectively—significantly higher than those of most reported MOPs2,46. The total pore volume, estimated from the N2 uptake at a relative pressure of P/P0 = 0.998, is 0.322 cm3·g–1 (Supplementary Fig. 26). Density functional theory (DFT) pore size distribution analysis further indicated a predominant pore width of 7.5 Å (Fig. 4b).

Leveraging its high surface area, we further assessed FIR-151’s gas separation potential via CO2, C2H2, C2H4, and C2H6 sorption at 273 and 298 K (Fig. 4c, d, and Supplementary Figs. 27–31). FIR-151 exhibits a high CO2 uptake capacity of 79 cm3·g–1 at 273 K and 51 cm3·g–1 at 298 K, with an isosteric heat of adsorption (Qst) of 40 kJ·mol–1, indicating strong host-guest interactions within the pores. Furthermore, FIR-151 shows distinct gas uptake profiles for C2 hydrocarbons: under identical conditions, sorption capacities for C2H2, C2H4, and C2H6 were measured as 73, 53, and 35 cm3·g–1 at 273 K, and 60, 38, and 25 cm3·g–1 at 298 K, respectively. The corresponding Qst values are 32, 28, and 27 kJ·mol–1, reflecting differential binding affinities. The notable contrast in both uptake capacity and adsorption enthalpy among these gases underscores the potential of FIR-151 for highly selective gas separation. To quantitatively predict separation selectivity, ideal adsorbed solution theory (IAST) was employed based on the above adsorption results (Supplementary Figs. 32–37). As a result, the predicted selectivity for an equimolar C2H2/C2H6 (v/v = 50:50) mixture reaches 42 at 273 K and 53 at 298 K (Fig. 4e). In addition, FIR-151 also shows favorable selectivities for CO2/C2H6 (v/v = 50:50; 15 at 273 K and 9 at 298 K (Fig. 4f), outperforming most reported MOPs46–48. Furthermore, the structural integrity and permanent porosity of FIR-151 were confirmed by powder X-ray diffraction (PXRD) measurements after gas sorption and the reproducibility of two consecutive BET measurements (Supplementary Fig. 38). These results demonstrate how mechanistic understanding and controlled synthesis of MOPs can yield functional materials49.

Building on the structural insights of FIR-151, we explored its post-assembly modification potential to tailor material properties (Fig. 5a). Specifically, the replacement of acetate ligands in FIR-151 with methacrylate and benzoate to form FIR-154 and FIR-155, respectively. The successful ligand exchange was verified by 1H NMR spectroscopy (Supplementary Figs. 39, 40), while the retention of the intact MOP architecture in solution was confirmed by SAXS (Supplementary Figs. 41 and 42). Furthermore, PXRD spectra confirmed the phase purity of the modified MOPs in the solid state (Supplementary Figs. 43 and 44). SCXRD confirmed that both compounds retain the structural integrity of the parental Ti24 MOP (Supplementary Table S5). Furthermore, all three MOPs adopt a body-centered cubic close-packed arrangement (Fig. 5b–d). The introduction of benzoate groups in FIR-155 enhances the material’s hydrophobicity, as confirmed by contact angle measurements (Supplementary Fig. 45), and facilitates π-π stacking (3.68 Å) between MOPs in its body-centered cubic lattice. Concurrently, the incorporation of methacrylate groups in FIR-154 installs structurally confirmed polymerizable handles, establishing a rational molecular design for exploring chemical functionality tuning and serving as a building block for extended polymeric networks in future studies.

Methods
Synthesis of FIR-151
A mixture of Ti(OiPr)4 (0.325 mmol, 100 μL), H2C4O4 (0.1 mmol, 0.011 g), CH3CN (4 mL), and CH3COOH (1 mL) in a 25 mL Teflon-lined stainless-steel autoclave. Then, the mixture was heated at 120°C for 3 days. After cooling to room temperature, the yellow rhombic dodecahedral crystals were washed with a large amount of CH3CN, filtered, and stored in CH3CN (Yield: ∼13.1 mg, ca. 22% based on Ti). One of these crystals was used for X-ray crystallography.

Synthesis of FIR-152
A mixture of Ti(OiPr)4 (0.325 mmol, 100 μL), NiCl2·6H2O (0.2 mmol, 0.048 g), H2C4O4 (0.1 mmol, 0.011 g), CH3CN (4 mL), and CH3COOH (1 mL) in a 20 mL vial. Then, the mixture was heated at 80°C for 7 days. After cooling to room temperature, the yellow block-shaped crystals were washed with CH3CN and stored in CH3CN (Yield: ∼20.0 mg, ca. 33% based on H2C4O4). One of these crystals was used for X-ray crystallography.

Synthesis of FIR-153
A mixture of Ti(OiPr)4 (0.325 mmol, 100 μL), NiCl2·6H2O (0.2 mmol, 0.048 g), H2C4O4 (0.1 mmol, 0.011 g), tetrabutylammonium bromide (TBAB, 0.2 mmol, 0.062 g), CH3CN (4 mL), and CH3COOH (1 mL) in a 20 mL vial. Then, the mixture was heated at 80°C for 7 days. After cooling to room temperature, the orange hexagonal dipyramid crystals were washed with CH3CN and stored in CH3CN (Yield: ∼21.2 mg, ca. 35% based on H2C4O4). One of these crystals was used for X-ray crystallography.

Synthesis of FIR-154
FIR-151 crystals (0.005 g, 1.154 × 10-6 mol) were dissolved in a DMSO/CH3CN mixture (v/v = 1/9, 1 mL) under ultrasonication. Methacrylic acid (0.30 mmol, 25 μL) was then added, and the solution was heated at 80°C for 7 days. After cooling to room temperature, orange crystals of FIR-154 were collected by filtration, washed with CH3CN, and stored in CH3CN (Yield: ∼5.4 mg, ca. 89% based on FIR-151). One of these crystals was used for X-ray crystallography.

Synthesis of FIR-155
FIR-151 crystals (0.005 g, 1.154 × 10-6 mol) were dissolved in a DMSO/CH3CN mixture (v/v = 1/9, 1 mL) under ultrasonication. Benzoic acid (0.30 mmol, 0.036 g) was then added, and the solution was heated at 80°C for 7 days. After cooling to room temperature, yellow single crystals of FIR-155 were collected by filtration, washed with CH3CN, and stored in CH3CN (Yield: ∼6.5 mg, ca. 86% based on FIR-151). One of these crystals was used for X-ray crystallography.

Solvent exchange and activation of FIR-151
Freshly prepared FIR-151 was soaked in CH3CN at room temperature for 7 days to exchange the guest CH3COOH. Subsequently, the samples were activated under dynamic vacuum at 30°C for 12 h. This temperature ensured the complete removal of the solvents, meanwhile excluding the possibility of FIR-151 decomposition.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This work reports a significant breakthrough in the synthesis of high-nuclearity titanium metal-organic polyhedra (Ti-MOPs).\nThe authors have not only synthesized a record-high nuclearity Ti-MOP but, more importantly, unveiled a novel 'pathway\nintervention' strategy with broad implications for the field of supramolecular assembly. I think this is an excellent and\nimpactful work that can be published in Nature Communications after minor revision.\n1. The authors propose a compelling mechanism where the differential kinetics between Ti4+ and Ni2+ ions control the\nassembly pathway. To strengthen the generalizability of this concept, could the authors comment on the selection criteria for\nthe kinetic trap metal ion? Specifically, what is the rationale for choosing Ni2+ over other moderately labile ions (e.g., Co or\nCu)?\n2. The authors state that the sample was activated at 30 °C under vacuum to evaluate porosity. Please provide the\nexperimental basis for the selection of activation temperature. Comparative gas sorption data should be included to\nsubstantiate that 30 °C is optimal for achieving complete activation and maximum porosity, as opposed to higher\ntemperatures, which may induce pore collapse or degradation.\n3. Please double-check the consistency of compound labels (e.g., FIR-151, FIR-152, FIR-153) and the corresponding\nintermediate numbers (Intermediate 1 and Intermediate 2) throughout all figures and the main text for clarity.", "reviewer_2": "This manuscript reports the synthesis, structural characterization, and further functionalization of a Ti24-based metal-organic\npolyhedron (MOP), designated as FIR-151. A notable strength of this work lies in the intriguing structure of Ti24-MOP, which\nresembles that of the well-known molecular \"tennis ball\"—a hydrogen-bonded capsule. The authors also make a valuable\ncontribution by clearly demonstrating that non-coordinating additives can exert a profound influence on the assembly\nstructures during synthesis; leveraging these additives, they successfully captured two intermediates and proposed a\nlogically reasonable assembly mechanism for FIR-151. Furthermore, the experimental data provided comprehensively\ncharacterize the material’s physicochemical properties, and the manuscript is generally well-organized. However, several\nissues requiring revision were identified. The manuscript is recommended for publication in Nature Communications after\naddressing the following suggestions.\n1. Page 4, line 82, the authors describe FIR-151 crystals as “yellow rhombic dodecahedral” and cite Supplementary Fig. 1 in\nsupport. However, this Supplementary Fig. 1 (an SEM image) only exhibits the morphology (rhombic dodecahedral shape)\nof the crystals, not their color (yellow). In fact, the photograph in Fig. 5 clearly shows the FIR-151 crystals with the perfect\nyellow rhombic dodecahedral appearance, making it the more appropriate reference for the authors’ description.\nAdditionally, the caption of Supplementary Fig. 1 contains a minor error: the term “images” should be revised to “image” (as\nthe figure only includes one SEM image).\n2. For Figure 2a, the four front-side Ti4+ cations form a rectangle with long edges oriented vertically. In contrast, for Figure\n2b, the front-side rectangle formed by 4 Ti-vertices has its long edges oriented horizontally. So the cage structures in the two\nfigures do not align in the same topological orientation.\n3. The caption of Supplementary Fig. 3 should explicitly emphasize that the depicted process represents a proposed\nassembly route. While the proposed route is logically reasonable, it should be clarified that this assembly process has not\nbeen directly observed experimentally.\n4. The formation mechanism of Ti24-MOP is particularly interesting, as it resembles that of the well-known molecular \"tennis\nball\"—a hydrogen-bonded capsule (Angew. Chem. Int. Ed., 1993, 32 (12): 1699).\n5. Supplementary Fig. 7b appears problematic. It contains numerous vertices that are not connected to the central node,\nwhich makes it difficult to identify the 8-connected mode as described. Additionally, the figure fails to clearly exhibit the cubic\nstructure corresponding to body-centered cubic (BCC) packing.\n6. The authors refer to Ti24-MOP as a truncated octahedral-type MOP. However, according to the structure shown in Fig. 2b,\nthe front-facing shape is a rectangle rather than a square—a key feature that deviates from the typical truncated octahedron.\nThus, it may be more accurate to term this structure a pseudo-truncated octahedron.\n7. Page 8, line 151, the content of this paragraph, when paired with Fig. 3, is somewhat confusing. Specifically, it appears\ninconsistent with the actual synthesis process: the synthesis of Ti24-MOF does not require Ni2+ for intermediate stabilization\nor trapping, nor does it require TBAB as a template for intermediate configuration.\n8. Supplementary Fig. 8, two issues are noted. Firstly, the figure itself does not include the subpanel labels (e.g., (a)/(b)) as\ndescribed in its caption. Secondly, the abbreviation “TBTA” in the figure (or caption, as applicable) should be corrected to\n“TBAB”.\n9. Page 9, line 171, the authors state that FIR-151 exhibits high stability in various organic solvents and cite Supplementary\nFig. 16. However, this figure only shows the cell parameters of the MOP in acetonitrile, not in multiple organic solvents, thus\nfailing to support the claim of stability across a range of solvents.\n10. Page 9, line 179, the description of the method used to obtain the pore volume is somewhat confusing. The authors state\nthat the pore volume was determined via a single-point method; however, they cite Supplementary Fig. 19—a figure that\npresents a pore volume curve with multiple data points (rather than a single-point result) and appears to show cumulative\npore volume, not the single-point pore volume referenced in the text. This creates a clear inconsistency between the stated\nmeasurement method and the supporting figure.\n11. The authors measured C2H4 adsorption isotherms for Ti24-MOP (Supplementary Fig. 20) but did not mention them in\nthe main text. Moreover, these C2H4 isotherms were not plotted together with the isotherms of other gases. This is\ninconsistent with Supplementary Fig. 25, which includes all four gas types in the Qst curves.\n12. Page 12, line 219, prior to discussing the interactions between MOPs, the authors should first clearly describe the key\nreaction outcomes: specifically, the replacement of the original acetate ligands in FIR-151 MOP with methacrylate ligands\n(yielding FIR-154) and with benzoate ligands (yielding FIR-155). This foundational information is necessary to\ncontextualize the subsequent discussion of MOP interactions.\n13. The sentence above Fig. 5, the authors propose that the polymerizable groups in FIR-154 hold potential for chemical\nfunctionality tuning, while the aromatic groups in FIR-155 may enable physical property tuning. To further validate these\npromising hypotheses, could the authors consider conducting additional simple demonstration experiments based on these\ntwo functionalized Ti24-MOPs? Such experiments would effectively strengthen the support for the proposed tuning potential\nand enhance the persuasiveness of this section.", "reviewer_3": "The paper reports the synthesis of a Ti₄₂ MOP (FIR-151) with a truncated octahedral topology—the largest and most\ncomplex titanium metal-organic polyhedron (Ti-MOP) reported to date. The authors claim to have elucidated its hierarchical\nself-assembly pathway through kinetic trapping of two intermediates (FIR-152 and FIR-153) using Ni²⁺ as a modulator. They\nfurther demonstrate porosity, gas separation, and post-assembly modification.\nIn my opinion, the work is synthetically impressive, but there are several major concerns, specifically conceptual and\nexperimental points, that I would like the authors to address prior to the acceptance of this manuscript.\nMajor points to be addressed/discussed:\n1. The claim of a hierarchical assembly pathway from Ti₁₂ → Ti₁₂(6-4-6) → Ti₂₄ relies primarily on isolated crystallographic\nsnapshots. However, there is no direct in situ spectroscopic evidence connecting these hypothetic reaction intermediates to\nspecies that form in solution during a one-pot reaction to obtain the final product. The so-called reaction intermediates,\nunless otherwise proven, might represent parallel or side-products that can be synthesized through off-pathway routes,\nand not on the main assembly route. The authors must provide solution tracking (e.g. NMR, Mass Spectrometry, SAX, etc.) of the\nmain reaction path to prove that FIR-152 and 153 are reaction intermediates and not off-track side products. And most\nimportantly, could the authors confirm if they attempted synthesize FIR-151 under solvothermal conditions in the presence of\nFIR-153 and Ni ions?\n2. Reported BET area (703 m² g⁻¹) and IAST selectivity values are impressive for a molecular specie, but need a few error\nanalysis. The activation temperature is set at 30ºC, which is unusually low, and might not ensure complete solvent or\nambient moisture removal. Furthermore, no PXRD data is given after activation, and thus we cannot confirm that the sample\ndoes not suffer a structural rearrangement upon activation. Can the authors show PXRD and BET reproducibility after at\nleast 2 activation/re-solvation cycles?\n3. FIR-151 is said to be “stable in various organic solvents,” but no data on water or acidic/basic stability are shown. Since\nTi4+ ions are prone to hydrolytic susceptibility, the authors need to show the stability of all the species in such media for\nproperly assessing their potential.\n4. In the literature, several Ti-MOPs with varying titanium nuclearities have been reported, and their bulk molecular integrity\nand purity are typically verified using spectroscopic techniques such as 1H/13C NMR, DOSY NMR, and mass spectrometry.\nTherefore, this manuscript should be supplemented with NMR and MALDI-MS or ESI-MS data for all newly synthesized\ntitanium structures (FIR-151, FIR-152, FIR-153, FIR-154, and FIR-155) to confirm their bulk composition and phase purity. A\nsingle crystal structure only proves the structure of one crystal, not for the whole bulk sample.\nMinor points to be addressed:\n1. The yield of all new structures should be provided.\n2. In the Supplementary Information, the PXRD pattern shown in Supplementary Figure S33 for the as-synthesized sample\ndisplays significantly fewer and weaker diffraction peaks compared with the simulated pattern. The authors should clarify the\nreason for this discrepancy and discuss whether it arises from preferred orientation, partial crystallinity, or sample\ndegradation.\n3. In the Supplementary Information, Supplementary Figure S34 shows that the as-synthesized PXRD pattern exhibits\nadditional diffraction peaks that are not present in the simulated pattern. The authors should explain the origin of these\ndiscrepancies—as those could indicate the presence of mixed phases or impurities. Additional molecular characterization,\nas mentioned in major Point 4, should be conducted to all species to confirm phase purity.\n4. As stated in Section 2: Instruments and Characterizations of the Supplementary Information (lines 79–80), several\nspectroscopic techniques, including FT-IR, 1H NMR, and 13C NMR, are listed as part of the characterization methods.\nHowever, these corresponding spectra are not provided in the manuscript or Supplementary Information. The authors should\nensure that all characterization methods mentioned are properly documented and supported with the relevant experimental\ndata and spectra (see Major point 4).", "reviewer_4": "This study stands as a perfect example of how to combine structural innovation with profound mechanistic elucidation. The\nsuccessful synthesis of the Ti24 MOP with truncated octahedron topology is itself a remarkable achievement, given the\nsignificant synthetic challenges of Ti4+ chemistry. By employing Ni2+ ions as kinetic modulators, they have achieved what\nmany thought impossible: the crystallographic characterization of two key intermediates—a Ti12 macrocycle and a Ti12 (6-\n4-6) module. This provides unprecedented, atomic-level insight into the hierarchical assembly pathway. The methodology of\nexploiting coordination lability gradients to trap intermediates offers a generalizable blueprint for studying self-assembly\nprocesses across diverse metal-ligand systems. The additional demonstration of permanent porosity and post-assembly\nmodification further enhances the practical impact of these findings. Therefore, I would like to recommend the manuscript for\npublication in Nature Communications, after addressing the following revisions.\nComment 1. Was the 'pathway intervention' strategy attempted with other transition metal ions? If so, please summarize the\noutcomes in the supplementary information. Were similar intermediates observed, or did other metals lead to different\nproducts or no modulation at all?\nComment 2. It is crucial to confirm the structural integrity of Ti24 MOP after gas sorption. Please provide the PXRD data of\nFIR-151 after gas adsorption in the supplementary information will strongly demonstrate its stability for potential applications.\nComment 3. In Fig. 5b-d, please clearly indicate in the figure captions that the non-covalent interactions between MOPs\n(such as hydrogen bonds or π-π interactions) are highlighted with green dotted lines. This clarification is crucial for guiding\nreaders in interpreting crystal stacking diagrams.\nComment 4. In Supplementary Tables S1 and S3, please provide the complete chemical names for all ligand abbreviations\nto ensure clarity and thereby enhance the accessibility and utility of the presented data.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature\nCommunications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career\nResearchers who co-review manuscripts."}, "author_response": "Response to Reviewer #1\nThis work reports a significant breakthrough in the synthesis of high-nuclearity titanium metal-\norganic polyhedra (Ti-MOPs). The authors have not only synthesized a record-high nuclearity\nTi-MOP but, more importantly, unveiled a novel 'pathway intervention' strategy with broad\nimplications for the field of supramolecular assembly. I think this is an excellent and impactful\nwork that can be published in Nature Communications after minor revision.\n1. The authors propose a compelling mechanism where the differential kinetics between Ti4+\nand Ni2+ ions control the assembly pathway. To strengthen the generalizability of this concept,\ncould the authors comment on the selection criteria for the kinetic trap metal ion? Specifically,\nwhat is the rationale for choosing Ni2+ over other moderately labile ions (e.g., Co or Cu)?\nResponses: The reviewer raises a fundamental point regarding our choice of metal ion, which\nallows us to elaborate on the design principles behind the kinetic trap. The choice of Ni2+ was\nindeed deliberate, based on its unique positioning in what we might call the \"coordination\nlability landscape\".\nWhile several borderline acids like Co2+ or Cu2+ could in principle interact with the\nsquarate ligand, our working hypothesis was that Ni2+ would provide the optimal kinetic\nprofile—its ligand exchange rate is slow enough to form metastable complexes that can be\ncrystallized, yet sufficiently dynamic to allow incorporation during the Ti4+-driven assembly.\nThis creates the perfect conditions for intervention without a complete pathway shutdown.\nThe control experiments the reviewer might be wondering about strongly support this\nreasoning. When we substituted Cu2+ or Co2+ under otherwise identical conditions, the reaction\nproceeded directly to the final Ti MOP without any observable intermediate trapping. These\n24\n\"negative\" results are actually quite telling:\nWith Co2+, we believe its faster ligand exchange kinetics prevent the formation of a stable\nenough trap to halt the assembly process. For Cu2+, while it shares the borderline acid\nclassification, its tendency toward Jahn-Teller distortion leads to preferred geometries that\nappear incompatible with the specific coordination environments required in our intermediate\nstructures.\nSo in essence, Ni2+ emerged as the unique candidate that provided just the right\ncombination of moderate lability, geometric flexibility, and binding affinity to make the kinetic\ntrapping strategy work. This understanding gives us a valuable set of criteria to consider when\nextending this approach to other metal-organic systems.\n2. The authors state that the sample was activated at 30 °C under vacuum to evaluate porosity.\nPlease provide the experimental basis for the selection of activation temperature. Comparative\ngas sorption data should be included to substantiate that 30 °C is optimal for achieving\ncomplete activation and maximum porosity, as opposed to higher temperatures, which may\ninduce pore collapse or degradation.\nResponses: Thank you for the reviewers' suggestions. The selection of 30 °C as the activation\ntemperature for FIR-151 is not random. We screened different activation temperatures from 30\nto 120 °C and found that as the activation temperature increased, the adsorption uptakes\ngradually decreased, possibly due to pore collapse caused by higher temperatures\n(Supplementary Figure S24a). Similarly, we also compared the TGA results of as-synthesized,\nafter CH CN exchange, and activated at 30 °C for FIR-151 (Supplementary Figure S24b). This\n3\ncomparison further confirmed that 30 °C is the optimal activation temperature for this\ncompound.\nSupplementary Figure S24. (a) N -sorption isotherms at 77 K for FIR-151 with different\n2\nactivation temperatures. (b) TG curves of as-synthesized, after CH CN exchanged, and\n3\nactivated (30 °C) FIR-151.\n3. Please double-check the consistency of compound labels (e.g., FIR-151, FIR-152, FIR-153)\nand the corresponding intermediate numbers (Intermediate 1 and Intermediate 2) throughout\nall figures and the main text for clarity.\nResponses: Thanks very much for the kind suggestions. We have carefully reviewed and\nunified all compound labels and the corresponding intermediate numbers across the text and\nfigures to ensure consistency.\nResponse to Reviewer #2\nThis manuscript reports the synthesis, structural characterization, and further functionalization\nof a Ti -based metal-organic polyhedron (MOP), designated as FIR-151. A notable strength of\n24\nthis work lies in the intriguing structure of Ti -MOP, which resembles that of the well-known\n24\nmolecular \"tennis ball\"—a hydrogen-bonded capsule. The authors also make a valuable\ncontribution by clearly demonstrating that non-coordinating additives can exert a profound\ninfluence on the assembly structures during synthesis; leveraging these additives, they\nsuccessfully captured two intermediates and proposed a logically reasonable assembly\nmechanism for FIR-151. Furthermore, the experimental data provided comprehensively\ncharacterize the material’s physicochemical properties, and the manuscript is generally well-\norganized. However, several issues requiring revision were identified. The manuscript is\nrecommended for publication in Nature Communications after addressing the following\nsuggestions.\n1. Page 4, line 82, the authors describe FIR-151 crystals as “yellow rhombic dodecahedral” and\ncite Supplementary Fig. 1 in support. However, this Supplementary Fig. 1 (an SEM image)\nonly exhibits the morphology (rhombic dodecahedral shape) of the crystals, not their color\n(yellow). In fact, the photograph in Fig. 5 clearly shows the FIR-151 crystals with the perfect\nyellow rhombic dodecahedral appearance, making it the more appropriate reference for the\nauthors’ description. Additionally, the caption of Supplementary Fig. 1 contains a minor error:\nthe term “images” should be revised to “image” (as the figure only includes one SEM image).\nResponses: Thank you for your valuable suggestions. To ensure the correct sequencing of\nfigures in the manuscript, we have added a new photo of the FIR-151 crystal exhibiting a\nyellow rhombic dodecahedron morphology in Supplementary Fig. 1, so as to better clarify the\ndescription related to crystal appearance. We sincerely apologize for the error in the title of\nSupplementary Fig. 1. In the revised version, we have thoroughly reviewed and improved the\nlanguage for accuracy and appropriateness.\nSupplementary Figure S1. (a) Photograph and (b) SEM image of the FIR-151 single crystal.\n2. For Figure 2a, the four front-side Ti4+ cations form a rectangle with long edges oriented\nvertically. In contrast, for Figure 2b, the front-side rectangle formed by 4 Ti-vertices has its\nlong edges oriented horizontally. So the cage structures in the two figures do not align in the\nsame topological orientation.\nResponses: We are grateful to the reviewers for their meticulous attention to detail. The\ninconsistent direction of the front-side Ti rectangles of the cage structure shown in Figs. 2a\n4\nand 2b were caused by our oversight when drawing these figures. We have made adjustments\nto Fig. 2b to ensure that the Ti rectangles at its front end are consistent with the direction in\nFig. 2. a, Molecular structure of FIR-151. b, Topological representation of FIR-151, with\nspheres denoting Ti atoms (vertices) and rods representing Ti-Ti edges. The Ti (6-4-6) module\n12\nis highlighted in red.\n3. The caption of Supplementary Fig. 3 should explicitly emphasize that the depicted process\nrepresents a proposed assembly route. While the proposed route is logically reasonable, it\nshould be clarified that this assembly process has not been directly observed experimentally.\nResponses: We are grateful to the reviewers for their important clarification. We have revised\nthe title of Supplementary Fig. 3 to clearly indicate that the process shown represents one of\nthe proposed assembly routes. We will emphasize that although this specific assembly sequence\nis logically reasonable, it has not yet been directly observed in experiments.\nWe have revised the title of Supplementary Fig. 3 as follows: The proposed assembly route of\nthe FIR-151. (a) Ti O macrocycle. (b) Ti macrocycle: Ti O (CH CO ) . (c) Ti (6-4-6)\n12 12 12 12 12 3 2 18 12\nmodule: Ti O (C O )(CH CO ) . (d) Dimerization: 2Ti O (C O )(CH CO ) . (e)\n12 12 4 4 3 2 18 12 12 4 4 3 2 18\nTruncated octahedron: Ti O (C O ) (CH CO ) . Color codes: blue/green, Ti; red, O; gray, C.\n24 24 4 4 6 3 2 36\nThis assembly process has not been directly observed experimentally.\n4. The formation mechanism of Ti -MOP is particularly interesting, as it resembles that of the\n24\nwell-known molecular \"tennis ball\"—a hydrogen-bonded capsule (Angew. Chem. Int. Ed.,\n1993, 32 (12): 1699.\nResponses: We sincerely thank the reviewer for this exceptionally insightful comment. We\nfully agree that the formation mechanism of Ti MOP—which proceeds through the\n24\ndimerization of two curved macrocycles—bears a striking and conceptually significant\nresemblance to the self-assembly of the classic \"tennis ball\" molecular capsule reported by\nRebek and co-workers.\nIn response, we have incorporated this analogy into the discussion section of our revised\nmanuscript to better contextualize our work within the broader field of supramolecular\nchemistry. This comparison serves to highlight a fundamental and convergent design principle:\nthat curved subunits can spontaneously close into hollow, spherical architectures to maximize\ninteractions and minimize energy. Although the \"tennis ball\" is stabilized by hydrogen bonds,\nwhereas our Ti MOP relies on robust coordination bonds, the underlying geometric\n24\nrequirement for closure is profoundly similar. We believe this perspective not only enhances\nthe conceptual appeal of our work but also suggests exciting future directions, such as exploring\nthe host-guest chemistry of this inorganic \"nanocage\" in a manner analogous to its organic\ncounterparts.\nWe are again grateful to the reviewer for pointing out this connection, which has\nsignificantly strengthened the narrative of our manuscript. The following paragraph has been\nadded to the revised manuscript:\n\"The cage structure of FIR-151 can be viewed as a dimer of two Ti (6-4-6) modules via\n12\nfour shared C O 2– ligands (Fig. 2b and Supplementary Fig. 5). The assembly pathway of FIR-\n4 4\n151, involving the dimerization of two curved Ti (6-4-6) modules, is reminiscent of the\n12\nformation of iconic supramolecular structures such as the 'tennis ball' capsule43. In that system,\ntwo identical, curved organic subunits self-assemble through hydrogen bonds to form a closed\nspheroidal cavity capable of encapsulating guest molecules. The convergence of this geometric\ndesign principle across both organic hydrogen-bonded systems and inorganic MOPs\nunderscores its universality for constructing closed-shell nanostructures from pre-organized,\ncurved building blocks.\"\n5. Supplementary Fig. 7b appears problematic. It contains numerous vertices that are not\nconnected to the central node, which makes it difficult to identify the 8-connected mode as\ndescribed. Additionally, the figure fails to clearly exhibit the cubic structure corresponding to\nbody-centered cubic (BCC) packing.\nResponses: We thank the reviewer for pointing out the potential ambiguity in Supplementary\nFig. 7b. We report herein isolated cages exhibiting a truncated octahedral topology. Although\nthese discrete cages lack direct inter-cage connections, we analyzed their spatial arrangement\nby treating each cage as a spherical node. Our analysis shows that each node is equidistant from\nits eight immediate neighbors. Therefore, when each node is treated as having eight\nconnections, the entire lattice exhibits a body-centered cubic (bcu) topology. This confirms a\nbcu close-packing mode, as opposed to the simple cubic (pcu) packing that was mistakenly\nindicated by the initial visualization.\nThe original figure did not effectively convey this specific topological perspective. We\nhave therefore replaced it with an improved version that explicitly highlights the central cage\nand its eight topological neighbors, which now unambiguously illustrates the bcu packing\narchitecture. We believe this revision resolves the previous visual ambiguity.\nSupplementary Figure S7. (a) Packing of the cages in FIR-151. (b) An individual cage is\ndefined as an 8-connected node and the resulting simplified 8-connected bcu topology.\n6. The authors refer to Ti -MOP as a truncated octahedral-type MOP. However, according to\n24\nthe structure shown in Fig. 2b, the front-facing shape is a rectangle rather than a square—a key\nfeature that deviates from the typical truncated octahedron. Thus, it may be more accurate to\nterm this structure a pseudo-truncated octahedron.\nResponses: We are grateful to the reviewer for this insightful comment regarding the facial\ngeometry of our Ti -MOP. The reviewer is correct in observing that the faces are rectangular,\n24\nwhich indeed represents a geometric deviation from a perfectly regular truncated octahedron.\nWe would like to clarify that our classification is based on the underlying topology of the\ncage. In topology, the precise shape (square vs. rectangle) is not distinguished; the critical factor\nis the connectivity. Our cage comprises eight hexagonal and six square faces, matching the\ndefining topology of a truncated octahedron. The rectangular shape arises from ligand-induced\ngeometric constraints, a common phenomenon that does not change the core topological\nidentity. We have added a sentence in the revised manuscript to explicitly note this geometric\ndistortion for clarity.\n‘As such, the overall assembly can be topologically represented as a truncated octahedron\nwith the point symbol (46.68) (Fig. 2c). It is noteworthy that the square faces in the topological\nrepresentation are realized as rectangles in the actual structure; this geometric distortion does\nnot affect the topological classification. To the best of our knowledge, this represents the first\nexample of a tro-type topology in Ti-MOPs (Supplementary Table S3).’\n7. Page 8, line 151, the content of this paragraph, when paired with Fig. 3, is somewhat\nconfusing. Specifically, it appears inconsistent with the actual synthesis process: the synthesis\nof Ti -MOP does not require Ni2+ for intermediate stabilization or trapping, nor does it require\nResponses: We sincerely thank the reviewer for raising this important point, which highlights\na key aspect of our experimental design that requires clarification. The reviewer is correct that\nthe standard one-pot synthesis of Ti -MOP proceeds efficiently without the need for Ni2+ or\nWe wish to emphasize that these additives were specifically introduced for our\nmechanistic investigation to trap and stabilize intermediate species. Our reasoning was that\nthey serve as \"chemical freezers\", halting the reaction at defined points and allowing us to\nisolate fleeting intermediates that cannot be detected under standard synthetic conditions. A\nkey finding is that these isolated intermediates are completely inert and do not react further to\nyield the final Ti -MOP, indicating they represent \"frozen\" snapshots of the process rather than\n24\ntrue synthetic precursors. Consequently, Fig. 3 is meant to portray the underlying assembly\nmechanism as deduced from these snapshots, and it does not reflect the actual procedure for\npreparing the final compound. We deeply appreciate the reviewer's feedback, which has\nenabled us to make this critical distinction clear.\n8. Supplementary Fig. 8, two issues are noted. Firstly, the figure itself does not include the\nsubpanel labels (e.g., (a)/(b)) as described in its caption. Secondly, the abbreviation “TBTA” in\nthe figure (or caption, as applicable) should be corrected to “TBAB”.\nResponses: Thank you for the reviewer's suggestions. We have made corresponding\nmodifications to Supplementary Fig. 8, marked the subpanel labels (e.g., (a)/(b)), and modified\nthe TBTA in the figure to TBAB (abbreviation for tetrabutammonium bromide).\nSupplementary Figure S8. (a) The molecular structure of FIR-152 is based on a Ti\n12\nmacrocycle with a chair conformation. (b) The molecular structure of FIR-153 is based on a\nTi (6-4-6) module with a boat conformation.\n12\n9. Page 9, line 171, the authors state that FIR-151 exhibits high stability in various organic\nsolvents and cite Supplementary Fig. 16. However, this figure only shows the cell parameters\nof the MOP in acetonitrile, not in multiple organic solvents, thus failing to support the claim of\nstability across a range of solvents.\nResponses: Thank you for this correct observation. We added the cell parameters of FIR-151\nafter immersion in other different organic solvents (such as n-hexane, acetone, ethyl acetate,\nTHF, and chloroform) to the supporting information (updated to Supplementary Figure S23a-\nf) to further verify the statement about its solvent stability.\nReviewer-Only Figure 1. Unit cell parameter of FIR-151 after soaking in different organic\nsolvents: (a) CH CN, (b) n-hexane, (c) acetone, (d) ethyl acetate, (e) THF, (f) chloroform at\n3\nroom temperature for 7 days.\n10. Page 9, line 179, the description of the method used to obtain the pore volume is somewhat\nconfusing. The authors state that the pore volume was determined via a single-point method;\nhowever, they cite Supplementary Fig. 19—a figure that presents a pore volume curve with\nmultiple data points (rather than a single-point result) and appears to show cumulative pore\nvolume, not the single-point pore volume referenced in the text. This creates a clear\ninconsistency between the stated measurement method and the supporting figure.\nResponses: We are grateful to the reviewer for this insightful comment regarding the\nmethodological description of the pore volume. In response, we have clarified the text to\ndistinguish between two distinct pieces of data: 1) the total pore volume, which is a single value\nestimated from the adsorption uptake at P/P = 0.998, and 2) the cumulative pore volume curve\n0\nin Supplementary Fig. 19, which is a distribution profile derived from DFT calculations. The\nHorvath-Kawazoe method was cited in error and has been removed.\nThe revised text on Page 9, line 179 for: \"The total pore volume, estimated from the N\n2\nuptake at a relative pressure of P/P = 0.998, is 0.322 cm3·g-1.\" This revision ensures the\n0\nmethodology is precisely described and resolves the inconsistency with the figure.\n11. The authors measured C H adsorption isotherms for Ti -MOP (Supplementary Fig. 20)\n2 4 24\nbut did not mention them in the main text. Moreover, these C H isotherms were not plotted\n2 4\ntogether with the isotherms of other gases. This is inconsistent with Supplementary Fig. 25,\nwhich includes all four gas types in the Q .st\nResponses: We sincerely thank the reviewer for this excellent observation and for pointing out\nthe inconsistency in our data presentation. We have integrated the C H sorption data into Fig.\n2 4\n4c and 4d of the revised manuscript, allowing for direct comparison with the other gases. This\nintegration ensures logical consistency with the Q curves in updated Supplementary Fig. 31,\nst\nwhich already includes all four gas types.\nFig. 4 Porosity and gas separation selectivity of FIR-151. a, N -sorption isotherms at 77\ntheory (DFT) analysis. c, The sorption isotherms of FIR-151 for CO , C H , C H , and C H\n2 2 2 2 4 2 6\nat 273 K. d, The sorption isotherms of FIR-151 for CO , C H , C H , and C H at 298 K. e,\n2 2 2 2 4 2 6\nThe IAST selectivities of FIR-151 for C H /C H (50/50, v/v) mixtures at 1 bar. f, The IAST\n2 2 2 6\nselectivities of FIR-151 for CO /C H (50/50, v/v) mixtures at 1 bar.\n2 2 6\n12. Page 12, line 219, prior to discussing the interactions between MOPs, the authors should\nfirst clearly describe the key reaction outcomes: specifically, the replacement of the original\nacetate ligands in FIR-151 MOP with methacrylate ligands (yielding FIR-154) and with\nbenzoate ligands (yielding FIR-155). This foundational information is necessary to\ncontextualize the subsequent discussion of MOP interactions.\nResponses: We thank the reviewer for this constructive suggestion. We have revised the\nmanuscript to first clearly describe the key ligand exchange reactions—specifically, the\nreplacement of acetate ligands in FIR-151 with methacrylate and benzoate to form FIR-154\nand FIR-155, respectively—before discussing the interactions between MOPs.\n13. The sentence above Fig. 5, the authors propose that the polymerizable groups in FIR-154\nhold potential for chemical functionality tuning, while the aromatic groups in FIR-155 may\nenable physical property tuning. To further validate these promising hypotheses, could the\nauthors consider conducting additional simple demonstration experiments based on these two\nfunctionalized Ti -MOPs? Such experiments would effectively strengthen the support for the\n24\nproposed tuning potential and enhance the persuasiveness of this section.\nResponses: We thank the reviewer for this valuable suggestion to experimentally validate the\nfunctional tuning potential of our modified MOPs, which aligns perfectly with our own\nresearch trajectory.\nIn response, we have performed contact angle measurements, which clearly show that the\nbenzoate-functionalized FIR-155 exhibits significantly enhanced hydrophobicity compared to\nthe parent FIR-151. This result now stands as direct experimental evidence supporting our\nclaim of tunable physical properties (Supplementary Fig. S45).\nRegarding the polymerizable nature of FIR-154, its molecular structure was specifically\ndesigned to serve as a building block for extended polymeric networks. Validating this chemical\nfunctionality is a key objective of our ongoing research. The scope of the current study is to\nestablish the synthetic platform and elucidate the assembly mechanism. Within this context, we\nprioritized the synthesis and meticulous structural characterization of FIR-154, which provides\nthe essential proof-of-concept for the incorporation of polymerizable handles. The dedicated,\nlarge-scale synthesis and subsequent exploration of its polymeric material properties represent\na distinct and significant research endeavor that naturally follows this foundational work.\nWe are confident that the confirmed physical property tuning in FIR-155, combined with\nthe rationally designed and structurally confirmed reactive site in FIR-154, provides a\ncompelling and robust foundation for our post-assembly modification strategy as presented in\nthis manuscript.\nSupplementary Figure S45. Contact angle measurements. Water contact angles measured on\npowder samples of FIR-151 (31 °) and FIR-155 (64°). The contrast in wettability stems from\ntheir surface ligands—hydrophilic acetate for FIR-151 versus hydrophobic benzoate for FIR-\n155.\nResponse to Reviewer #3\nThe paper reports the synthesis of a Ti MOP (FIR-151) with a truncated octahedral\n24\ntopology—the largest and most complex titanium metal-organic polyhedron (Ti-MOP)\nreported to date. The authors claim to have elucidated its hierarchical self-assembly pathway\nthrough kinetic trapping of two intermediates (FIR-152 and FIR-153) using Ni2+ as a modulator.\nThey further demonstrate porosity, gas separation, and post-assembly modification.\nIn my opinion, the work is synthetically impressive, but there are several major concerns,\nspecifically conceptual and experimental points, that I would like the authors to address prior\nto the acceptance of this manuscript.\nMajor points to be addressed/discussed:\n1. The claim of a hierarchical assembly pathway from Ti → Ti (6-4-6) → Ti relies\n12 12 24\nprimarily on isolated crystallographic snapshots. However, there is no direct in situ\nspectroscopic evidence connecting these hypothetic reaction intermediates to species that form\nin solution during a one-pot reaction to obtain the final product. The so-called reaction\nintermediates, unless otherwise proven, might represent parallel or side-products that can be\nsynthesized through off-pathway routes, and not on the main assembly route. The authors must\nprovide solution tracking (e.g. NMR, Mass Spectrometry, SAXS, etc.) of the main reaction\npath to prove that FIR-152 and 153 are reaction intermediates and not off-track side products.\nAnd most importantly, could the authors confirm if they attempted synthesize FIR-151 under\nsolvothermal conditions in the presence of FIR-153 and Ni ions?\nResponses: We sincerely thank the reviewer for the insightful comments and rigorous\nstandards, which have prompted us to reassess our mechanistic interpretation with greater\ncaution and precision. We fully understand your concern regarding the completeness of the\nmechanistic evidence chain, and we would like to clarify, within the scope of our current\nexperiments, the evidential value and reasonable limits of our mechanistic hypothesis. We\nacknowledge that directly observing transient species in Ti4+ systems remains inherently\nchallenging. To address this, we employed multiple complementary experimental approaches.\nFirst, solution-phase SAXS monitoring (Supplementary Fig. S15) revealed a continuous\nevolution in particle size (D ) from ~6.7 Å through discrete intermediates (~9.5 Å and ~17.0\nmax\nÅ) to a final value of ~19.1 Å, suggesting a stepwise rather than a single-step assembly process\n(Chem. Soc. Rev. 2011, 40, 1006). Second, using a Ni2+ stabilization strategy, we successfully\nisolated two structurally complementary modules, the Ti macrocycle and Ti (6-4-6) unit,\n12 12\nwhose geometrical matching provides a reasonable structural rationale for the formation of the\nfinal Ti cage. Third, reactivity tests demonstrated that FIR-151 can be efficiently obtained\n24\nunder Ni2+-free solvothermal conditions, whereas the Ni2+-stabilized FIR-153 cannot be\nconverted under identical conditions, highlighting the critical kinetic trapping effect of Ni2+ in\ncapturing transient intermediates (Chem. Soc. Rev. 2017, 46, 3431).\nTogether, these three sets of independent observations—from dynamic evolution,\nstructural correlation, and reactivity behavior—mutually support a coherent picture of a\nmultistep assembly process (Chem. Rev. 2014, 114, 9645). We fully recognize that each line of\nevidence has its limitations: SAXS data lack molecular specificity; the proposed ‘structural\ncomplementarity’ is primarily geometrical rather than quantitatively proven; and the reactivity\ntests could, in principle, admit multiple interpretations. Nevertheless, the convergence of these\nobservations points to a structurally correlated and kinetically interpretable multistep assembly\npathway, in which the system likely proceeds through several stabilized intermediate states\ntoward the final structure.\nWe are transparent in acknowledging that the current data do not constitute definitive\nproof of the mechanism but rather represent a technically constrained, yet informative,\nexploration of a complex self-assembly process. The proposed hierarchical pathway should\ntherefore be regarded as a reasonable and testable working hypothesis, valuable for providing\na structural framework and experimental basis for subsequent investigations. We fully agree\nwith the reviewer that direct molecular-level evidence—such as in situ spectroscopic tracking\nor theoretical modeling—will be essential to further verify and refine this mechanism.\nDespite these limitations, we believe that the present study offers meaningful structural\ninsights and experimental references for understanding the intricate self-assembly behavior of\ntitanium-oxo systems. We will explicitly clarify the inferential nature and scope of our\nmechanistic discussion in the revised manuscript and look forward to advancing this\nhierarchical assembly model through more advanced techniques in future work.\nSupplementary Figure S15. Ex-situ SAXS monitoring of FIR-151 assembly. (a)\nExperimental SAXS diffraction signal and (b) interatomic distance distribution function P(r) at\nvarious reaction times.\n2. Reported BET area (703 m2 g-1) and IAST selectivity values are impressive for a molecular\nspecie, but need a few error analysis. The activation temperature is set at 30ºC, which is\nunusually low, and might not ensure complete solvent or ambient moisture removal.\nFurthermore, no PXRD data is given after activation, and thus we cannot confirm that the\nsample does not suffer a structural rearrangement upon activation. Can the authors show PXRD\nand BET reproducibility after at least 2 activation/re-solvation cycles?\nResponses: Thank you for the reviewers' suggestions. We have conducted additional\nexperiments to fully address these concerns, as summarized below and supported by new data\nin the Supplementary Figs. S24 and S38.\n1. Optimization of activation temperature: The selection of 30 °C as the activation temperature\nwas the result of a systematic screening process. As shown in the Reviewer-Only Figure 2a,\nN -sorption isotherms were measured for samples activated at temperatures ranging from 30 °C\n2\nto 120 °C. The results clearly demonstrate that the adsorption capacity progressively decreases\nwith increasing activation temperature, suggesting potential pore collapse or framework\ndamage at elevated temperatures. This confirms that 30 °C is indeed the optimal and sufficient\ncondition for activating FIR-151. The effectiveness of the 30 °C activation protocol is further\ncorroborated by TGA data (Reviewer-Only Figure 2b). The analysis confirms the complete\nremoval of solvent molecules after activation at this temperature.\n2. Confirmation of reproducibility and cyclic stability: The BET surface area measured after\nthe second cycle remains nearly identical to the initial value (Reviewer-Only Figure 2c),\naffirming the reproducibility of the porosity and the stability of the framework through multiple\ncycles. Furthermore, the PXRD pattern of FIR-151 after gas adsorption shows that most of the\nmain peaks are well consistent with the simulated pattern (Reviewer-Only Figure 2d).\nReviewer-Only Figure 2. (a) N -sorption isotherms at 77 K for FIR-151 with different\n2\nactivation temperatures (from 30 to 120 °C). (b) TG curves of as-synthesized, after CH CN\n3\nexchanged, and activated (30 °C) FIR-151. (c). N -sorption isotherms at 77 K for FIR-151 with\n2\ntwo consecutive cycles. (d) The PXRD pattern of FIR-151 after gas adsorption.\n3. FIR-151 is said to be “stable in various organic solvents,” but no data on water or acidic/basic\nstability are shown. Since Ti4+ ions are prone to hydrolytic susceptibility, the authors need to\nshow the stability of all the species in such media for properly assessing their potential.\nResponses: We thank the reviewer for the insightful comment. Our tests confirm the instability\nof FIR-151 in water, with direct evidence from SCXRD showing significant changes in its unit\ncell parameters after immersion. To address stability in acidic/basic media, we evaluated FIR-\n151 in organic acids and bases (acetic acid, triethylamine, and N, N-dimethylaniline). SCXRD\nresults confirm the framework remains intact under these conditions. These new data have been\nadded to the Supplementary Fig. S23.\nReviewer-Only Figure 3. Unit cell parameter of FIR-151 after soaking in (a) water (12 h),\n(b) acetic acid (7 d), (c) N, N-dimethylaniline (12 h), and (d) triethylamine (12 h) at room\ntemperature.\n4. In the literature, several Ti-MOPs with varying titanium nuclearities have been reported, and\ntheir bulk molecular integrity and purity are typically verified using spectroscopic techniques\nsuch as 1H/13C NMR, DOSY NMR, and mass spectrometry. Therefore, this manuscript should\nbe supplemented with NMR and MALDI-MS or ESI-MS data for all newly synthesized\ntitanium structures (FIR-151, FIR-152, FIR-153, FIR-154, and FIR-155) to confirm their bulk\ncomposition and phase purity. A single crystal structure only proves the structure of one crystal,\nnot for the whole bulk sample.\nResponses: We would like to express our gratitude to the reviewers for their critical comments\nregarding the necessity of verifying the bulk purity and molecular integrity of our newly\nsynthesized Ti-MOPs. We fully agree that comprehensive characterization beyond SCXRD is\ncrucial. To directly address this point, we conducted a comprehensive and systematic\ncharacterization study. Convergent evidence from multiple complementary techniques now\nsupports the bulk composition, phase purity, and structural integrity of all compounds (FIR-\n151 to FIR-155). Our comprehensive research methods and main findings are summarized as\nfollows.\n1. NMR spectroscopy:\n(1) 1H NMR: We successfully obtained high-quality 1H NMR spectra for all five compounds.\nAll spectra exhibited sharp and well-resolved signals, with chemical shifts and integral ratios\nconsistent with the expected cage structure, providing fundamental evidence for their bulk\nchemical composition and purity in solution.\n(2) Other one-dimensional/two-dimensional NMR: In response to the reviewer's specific\nmention of cage structural integrity, we conducted 13C NMR and DOSY experiments.\nIn 13C NMR, due to the low mass fraction of the squaric acid ligand and the limited\nsolubility of these samples, even after long-term acquisition (>12 hours), the characteristic\nsignal of the squaric acid ligand was not observed. However, the signals of all other organic\nligands (acetic acid, methacrylic acid, benzoic acid, acetonitrile) were clearly identifiable and\ncould be identified.\nCrucially, we performed DOSY NMR on the representative compound FIR-155, and the\nspectrum showed consistent diffusion coefficients, confirming the presence of monodisperse\ncage structures in solution and ruling out the possibility of other impurities.\n2. Mass spectrometry analysis:\nWe fully recognize the value of mass spectrometry data. We extensively attempted both\nESI-MS and MALDI-TOF MS under various conditions, including changes in solvents,\nconcentrations, ionization parameters, and matrices. Despite these systematic efforts, we were\nunable to detect any complete molecular ions of the MOPs. Instead, we consistently observed\nonly fragment signals with low mass-to-charge ratios—a result that recurred across all\ncompounds and techniques. This strongly indicates a fundamental challenge: the inherent\ninstability of such high-nuclearity MOPs under the vacuum and ionization conditions required\nfor mass spectrometry. Our claim of \"extensive effort\" is supported by a rigorous (though\nultimately unsuccessful) experimental process. Spectra from these attempts are available upon\nrequest.\n3. Small-angle X-ray scattering (SAXS):\nTo directly and clearly probe the size and integrity of the MOPs in solution, we performed\nSAXS measurements.\nFor FIR-151, FIR-152, and FIR-153, the maximum particle size (D ) derived from the\nmax\npair distance distribution function P(r) is consistent with the crystallographic data. For the\nsynthetically modified MOPs (FIR-154 and FIR-155), the SAXS data confirm that they exist\nas discrete, monodisperse cage structures, and their sizes match the framework after structural\nmodification. This technique provides direct validation that the complete MOP structure is\nmaintained for all compounds in the solution state, effectively bridging the solid-state (SCXRD)\nand solution-phase (NMR) data.\n4. Verification of phase purity:\nThe powder X-ray diffraction (PXRD) patterns of the bulk samples of FIR-154 and FIR-\n155 are in excellent agreement with their simulated SCXRD patterns, confirming phase purity\nin the solid state. Slight differences in peak intensity can be attributed to common effects in\npowder samples, such as preferred orientation.\nIn summary, despite inherent technical challenges that prevented us from obtaining\nconventional 13C NMR data for the squaric acid ligands in the structure and, most notably,\ncomplete mass spectrometry data for all MOPs, we have effectively addressed the reviewers'\nconcerns through a multidimensional characterization strategy. This comprehensive and\ncomplementary dataset demonstrates the bulk molecular integrity and high purity of the\nreported Ti-MOPs.\nSupplementary Figure S17. 1H NMR of FIR-151.\nSupplementary Figure S11. 1H NMR of FIR-152.\nSupplementary Figure S12. 1H NMR of FIR-153.\nSupplementary Figure S39. 1H NMR of FIR-154.\nSupplementary Figure S40. 1H NMR of FIR-155.\nReviewer-Only Figure 4. 1H-1H DOSY NMR of FIR-155.\nSupplementary Figure S13. (a) Experimental SAXS diffraction signal and (b) interatomic\ndistance distribution function P(r) of FIR-152 at 100 M.\nSupplementary Figure S14. (a) Experimental SAXS diffraction signal and (b) interatomic\ndistance distribution function P(r) of FIR-153 at 100 M.\nSupplementary Figure S41. (a) Experimental SAXS diffraction signal and (b) interatomic\ndistance distribution function P(r) of FIR-154 at 100 M.\nSupplementary Figure S42. (a) Experimental SAXS diffraction signal and (b) interatomic\ndistance distribution function P(r) of FIR-155 at 100 M.\nMinor points to be addressed:\n1. The yield of all new structures should be provided.\nResponses: Thank you for your comment. We have provided the yields of all new structures in\nthe table below, and they have also been included in the synthetic schemes in the revised\nmanuscript.\nReviewer-Only Table 1. The yield of compounds FIR-151-155.\nFIR-151 FIR-152 FIR-153 FIR-154 FIR-155\nyield 13.0 mg, 22% 20.2 mg, 33% 21.5 mg, 35% 5.4 mg, 89% 6.5 mg, 86%\n2. In the Supplementary Information, the PXRD pattern shown in Supplementary Figure S33\nfor the as-synthesized sample displays significantly fewer and weaker diffraction peaks\ncompared with the simulated pattern. The authors should clarify the reason for this discrepancy\nand discuss whether it arises from preferred orientation, partial crystallinity, or sample\ndegradation.\nResponses: We thank the reviewer for raising this critical point regarding the discrepancy in\nthe PXRD pattern shown in the revised Supplementary Figure S39. The observed reduction in\nthe number and intensity of diffraction peaks in the original data is primarily attributed to the\ndesolvation and subsequent cracking of the sample during measurement. Specifically, FIR-154\nundergoes rapid CH₃CN loss upon exposure to the ambient atmosphere, leading to a partial\ncollapse of the crystal lattice and a degradation of diffraction quality. This phenomenon is well-\ndocumented in similar metal-organic polyhedra (e.g., Angew. Chem. Int. Ed. 2011, 5, 1046–\n1051). To preserve its crystallinity during analysis, we measured the PXRD pattern of FIR-154\nwhile maintaining the sample in a CH CN-solvated state. The results confirm that FIR-154\n3\nretains good crystallinity, with key diffraction peaks matching the simulated pattern, thereby\nvalidating the synthesized structure.\nSupplementary Figure S43. PXRD patterns of simulated and as-synthesized FIR-154.\n3. In the Supplementary Information, Supplementary Figure S34 shows that the as-synthesized\nPXRD pattern exhibits additional diffraction peaks that are not present in the simulated pattern.\nThe authors should explain the origin of these discrepancies—as those could indicate the\npresence of mixed phases or impurities. Additional molecular characterization, as mentioned\nin major Point 4, should be conducted to all species to confirm phase purity.\nResponses: We thank the reviewer for highlighting the discrepancy in the PXRD pattern, which\nis a critical indicator of phase purity. In response, we meticulously re-synthesized the\ncompound, paying particular attention to the reaction conditions and work-up procedures. The\nPXRD pattern of the newly synthesized batch now exhibits excellent agreement with the\nsimulated one, and the previously observed extraneous peaks are entirely absent (see updated\nSupplementary Fig. S44).\nWe attribute the initial minor impurities to subtle, unoptimized parameters in the early synthesis\nprotocol, such as slight variations in stirring efficiency or crystallization kinetics. The\nreproducibility of the high-quality pattern from the new batch confirms that these impurities\nare not intrinsic to the material's structure and that the phase-pure product can be reliably\nobtained. This result robustly confirms the phase purity of the target material.\nFurthermore, as comprehensively addressed in our response to Major Point 4, we have provided\nadditional molecular characterization data (including ¹H NMR) for all species. These data\ncollectively and consistently verify the chemical composition and phase purity of the\nsynthesized compounds.\nSupplementary Figure S44. PXRD patterns of simulated and as-synthesized FIR-155.\n4. As stated in Section 2: Instruments and Characterizations of the Supplementary Information\n(lines 79–80), several spectroscopic techniques, including FT-IR, 1H NMR, and 13C NMR, are\nlisted as part of the characterization methods. However, these corresponding spectra are not\nprovided in the manuscript or Supplementary Information. The authors should ensure that all\ncharacterization methods mentioned are properly documented and supported with the relevant\nexperimental data and spectra (see Major point 4).\nResponses: We thank the reviewer for highlighting this omission. We sincerely apologize for\nthis oversight. The missing spectral tests, such as 1H NMR spectra, have now been included in\nthe supplementary information.\nResponse to Reviewer #4\nThis study stands as a perfect example of how to combine structural innovation with profound\nmechanistic elucidation. The successful synthesis of the Ti MOP with truncated octahedron\n24\ntopology is itself a remarkable achievement, given the significant synthetic challenges of Ti4+\nchemistry. By employing Ni2+ ions as kinetic modulators, they have achieved what many\nthought impossible: the crystallographic characterization of two key intermediates—a Ti\n12\nmacrocycle and a Ti (6-4-6) module. This provides unprecedented, atomic-level insight into\n12\nthe hierarchical assembly pathway. The methodology of exploiting coordination lability\ngradients to trap intermediates offers a generalizable blueprint for studying self-assembly\nprocesses across diverse metal-ligand systems. The additional demonstration of permanent\nporosity and post-assembly modification further enhances the practical impact of these findings.\nTherefore, I would like to recommend the manuscript for publication in Nature\nCommunications, after addressing the following revisions.\nComment 1. Was the 'pathway intervention' strategy attempted with other transition metal ions?\nIf so, please summarize the outcomes in the supplementary information. Were similar\nintermediates observed, or did other metals lead to different products or no modulation at all?\nResponses: We thank the reviewer for this insightful question, which gets to the heart of our\nstrategy. We are happy to summarize our investigations into other transition metal ions. Our\nselection of Ni2+ was guided by its unique position in the coordination kinetics landscape,\nwhich we reasoned would provide the optimal balance for effective pathway intervention.\nWhile several borderline acids (like Co2+ or Cu2+) could theoretically bind the squarate ligand,\nNi2+ exhibits intermediate lability—its ligand exchange rate is slow enough to form metastable\ncomplexes that can be crystallized, yet sufficiently dynamic to allow its incorporation during\nthe Ti4+-driven assembly process. This rationale is strongly corroborated by control\nexperiments. When we used Cu2+ or Co2+ under identical conditions, the reaction proceeded\ndirectly to the Ti MOP without any observable trapped intermediates. We interpret these\n24\n\"negative\" results as highly informative: Co2+ typically exhibits faster ligand exchange kinetics\nthan Ni2+, likely preventing it from forming a stable enough trap to halt the assembly. Cu2+,\nwhile also a borderline acid, is prone to Jahn-Teller distortion, which often leads to preferred\ngeometries (e.g., square planar or distorted octahedral) that may be incompatible with the\nspecific coordination environment required within our intermediate architectures. Therefore,\nNi2+ was not merely an arbitrary choice but the one that uniquely provided the right\ncombination of moderate lability, geometric compatibility, and binding affinity to effectively\nperturb, without completely shutting down, the dynamic assembly pathway. This understanding\nprovides a valuable criterion for extending this strategy to other systems.\nComment 2. It is crucial to confirm the structural integrity of Ti MOP after gas sorption.\ninformation will strongly demonstrate its stability for potential applications.\nResponses: We thank the reviewer for this important suggestion. To directly address the\nconcern regarding structural integrity after gas sorption, we have conducted the following\nexperiments (Supplementary Fig. S38). Firstly, two consecutive BET surface area\nmeasurements were performed, which yielded nearly identical values and confirmed the\nstability of the porous framework. Then, the PXRD pattern of FIR-151 after gas adsorption\nshows that most of the main peaks are well consistent with the simulated pattern, robustly\nsupporting its stability for potential applications.\nSupplementary Figure S38. (a). N -sorption isotherms at 77 K for FIR-151 with two\n2\nconsecutive cycles. (b) The PXRD pattern of FIR-151 after gas adsorption.\nComment 3. In Fig. 5b-d, please clearly indicate in the figure captions that the non-covalent\ninteractions between MOPs (such as hydrogen bonds or π-π interactions) are highlighted with\ngreen dotted lines. This clarification is crucial for guiding readers in interpreting crystal\nstacking diagrams.\nResponses: Thank you for your valuable suggestion. We have revised the captions for Figures\n5b, 5c, and 5d in the manuscript to clearly state that the green dashed lines indicate hydrogen\nbonds or π-π interactions between adjacent MOPs.\nComment 4. In Supplementary Tables S1 and S3, please provide the complete chemical names\nfor all ligand abbreviations to ensure clarity and thereby enhance the accessibility and utility\nof the presented data.\nResponses: Thank you for this suggestion. We have updated Supplementary Tables S1 and S3\nto include the full chemical names alongside all ligand abbreviations.\nSupplementary Table S1. Summary of Ti-MOPs with different titanium nuclearity.\nformula nuclearity Ref.\nTi O (C O ) (CH COO) •guest\n24 24 4 4 6 3 36\nTi O (C O ) (CH =C(CH )COO) •guest Ti this work\n24 24 4 4 6 2 3 36 24\nTi O (C O ) (C H COO) •guest\n24 24 4 4 6 6 5 36\nTi (HPO ) (iOPr) (μ -O) (BPDS) ] Ti 3\n18 3 6 42 3 6 3 18\n(NH ) (enH )[Ti O (PhCOO) (en) ] Ti 4\n4 4 2 18 27 24 9 18\n[Ti 16 ( 3 -OH) 2 ( 3 -O) 8 ( 2 -O) 6 ( 2 -OiPr) 8 (OiPr) 14 (DHB) 4 ] Ti 16 5\n(NH ) Ti O Sal HSal AC Ti 6\n4 2 14 12 10 14 2 14\nTi (OiPr) (TBC[4]) (Pdc) •14CH CN Ti 7\n12 12 6 6 3 12\nTi (OiPr) (TBC[4]) (Pip) •34CH CN Ti 7\n12 12 6 6 3 12\n[Ti (p-H bdha) (p-bdha) ] Ti 8\n8 2 8 4 8\nH [(CH ) NH ] [Ti L1 ]•(DMF)(CH CN) (H O) Ti 9\n4 3 2 2 2 8 12 3 4 2 2 8\n(Me NH ) [(Ti L2 )]·4(n-PrOH)·2(en)·6DMF Ti 10\n2 2 8 4 6 4\n[L3 Ti ]8− Ti 11\n4 4 4\nBPDS: [1,1'-biphenyl]-4,4'-disulfonic acid\nen: ethylenediamine\nDHB: 2,5-dihydroxybenzoic acid\nSal: Salicylic acid\nTBC[4]: tert-butylcalix[4]arene\nPdc: pyridine-3,5-dicarboxylic acid\nPip: 5-(pyridin-4-yl)isophthalic acid\np-bdha: N1,N4-dihydroxyterephthalamide\nDMF: N,N'-dimethylformamide\nL1: 2,6-dihydroxybenzoic acid\nL2: 4,4'-methylenebis(3-hydroxy-2-naphthoic acid)\nL3: N,N',N''-(benzene-1,3,5-triyl)tris(2,3-dihydroxybenzamide)\nSupplementary Table S3. Representative wheel-like TOCs: formula and nuclearity.\nformula nuclearity Ref.\nTi O (OOCC H ) Ti 12\n8 8 6 5 16 8\nTi (μ -O) (μ -O) (OiPr) (OMc) Ti 13\n9 3 2 2 6 4 16 9\n[Cy MeNH][Ti O (O CtBu) ] Ti 14\n2 10 11 2 19 10\nTi O (OH ) Pro Ti 15\n12 18 2 24 6 12\nK [Ti (μ-O) (HO ) (O ) (R,R-tart) ]⋅52H O Ti 16\n16 20 8 2 8 2 12 12 2 20\nTi (μ -O) (μ -O) (OCH CH O) (EtCOO) (OCH CH OH) Ti 17\n32 2 8 3 8 2 2 32 16 2 2 16 32\nOMc: methacrylic acid\nPro: L-Threonine\nR,R-tart: (2R,3R)-2,3-dihydroxysuccinic acid\nResponse to Reviewer #5\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nResponses: We thank all the reviewers for their insightful comments.\nAll the changes have been highlighted in blue in the revised manuscript and\nsupplementary information."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have addressed my questions and concerns. And I think I am fine with the acceptance for the manuscript.", "reviewer_2": "The authors have considered and well addressed the comments, and acceptance is recommended.", "reviewer_3": "I thank the authors for such a comprehensive and exhaustive explanation of our doubts and concerns. The manuscript has\nsubstantially improved its quality, and us such is close to being ready for acceptance.\nI still have, however, some concerns that I would like to raise, and hope the authors can provide a suitable answer.\n> Compound FIR-155 's characterization is inconsistent with the expected nature and structure of the MOP. First, the 1H\nNMR spectra in Fig.S40 shows a mixture of signals attributed to acetate, benzoic acid, squaric acid and acetonitrile.\nHowever, FIR-155 is synthesized through complete ligand exchange from acetate to benzoic acid, and thus the presence of\nacetate signals shows incomplete conversion and the presence of impurities.\n> In regards to all characterization, I would like to highlight that the presence of proton signals 4 and 5 in figures S39 and\nS40 highlights a partial disassembly of the MOP structures in DMSO solution. A fully stable MOP structure should not have\nthe signals of free acid protons (both carboxylic acids and squaric acid protons)\n> Finally, the authors should carefully check the figure references throughout the manuscript, as several ESI figures are not\nproperly labelled within the text (e.g., calling Fig S40 as Supplementary Fig 40).\nI would consider the manuscript ready for acceptance after fixing these minor issues.", "reviewer_4": "The authors have well addressed my concerns and I would like to recommend its acceptance for publication.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature\nCommunications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career\nResearchers who co-review manuscripts."}, "author_response": "Response to Reviewer #3\nI thank the authors for such a comprehensive and exhaustive explanation of our doubts and\nconcerns. The manuscript has substantially improved its quality, and us such is close to being\nready for acceptance. I still have, however, some concerns that I would like to raise, and hope\nthe authors can provide a suitable answer.\n> Compound FIR-155 's characterization is inconsistent with the expected nature and structure\nof the MOP. First, the 1H NMR spectra in Fig. S40 shows a mixture of signals attributed to\nacetate, benzoic acid, squaric acid and acetonitrile. However, FIR-155 is synthesized through\ncomplete ligand exchange from acetate to benzoic acid, and thus the presence of acetate signals\nshows incomplete conversion and the presence of impurities.\n> In regards to all characterization, I would like to highlight that the presence of proton signals\n4 and 5 in figures S39 and S40 highlights a partial disassembly of the MOP structures in DMSO\nsolution. A fully stable MOP structure should not have the signals of free acid protons (both\ncarboxylic acids and squaric acid protons).\nResponse: We thank the reviewer for raising these important points. Both the purity and the\nsolution-phase behavior of FIR-154 and FIR-155 have been re-examined through re-analysis\nof the original batches, additional purification, and measurements under solvent conditions\nrepresentative of our experimental workflow.\n(1) Impurity signals in the original ¹H NMR spectra\nWe agree that the earlier spectra displayed weak resonances assignable to residual carboxylic\nacids and acetate. These species originate from surface-adsorbed or lattice-included guests\nassociated with the ligand-exchange synthesis, rather than from the MOP framework itself.\nThis interpretation aligns with the single-crystal XRD data, which shows complete ligand\nexchange at the cage surface.\nTo isolate the framework signals exclusively, the original batches were subjected to a strict\nmulti-cycle washing protocol using anhydrous CH₃CN, a non-coordinating solvent that\nremoves guest molecules without perturbing the coordination structure.\nThe updated ¹H NMR spectra (Supplementary Figs. 39–40) show complete disappearance of\nall previously noted impurity peaks while all framework resonances remain unchanged. No\nnew signals appear after purification. This confirms that the earlier features originated from\nremovable guest species rather than structural defects, as the framework signatures are\nunaffected by the washing process.\n(2) Signals 4 and 5 and solution-phase behavior\nThe reviewer’s observation regarding signals 4 and 5 is well taken. Our re-analysis indicates\nthat their appearance in the initial spectra was caused by the use of pure DMSO-d₆, a strongly\ncoordinating solvent capable of inducing minor, reversible perturbations in metal–carboxylate\nenvironments. Such perturbations do not involve irreversible ligand dissociation.\nTo assess the species present under conditions relevant to our study, we re-recorded the spectra\nin CD₃CN containing only minimal DMSO-d₆ for solubility—the solvent environment\nemployed in our synthesis, crystallization, and SAXS experiments.\nIn this representative solvent system, signals 4 and 5 are absent. Only the resonances expected\nfor the intact cages are observed, and no signals corresponding to free ligand or decomposition\nproducts are detected.\nThese observations show that:\n The features observed in pure DMSO arise from solvent-induced coordination\nperturbations rather than structural dissociation.\n Under all chemically relevant conditions used in this work, the MOPs display\nspectroscopic signatures fully consistent with intact cages.\n No evidence for ligand liberation or framework decomposition was detected under any\nof the conditions relevant to our workflow.\nTherefore, the new results support the conclusions that:\n FIR-154 and FIR-155 are structurally pure; the initial impurity peaks were due to\nremovable guest species.\n The cages exhibit stable, intact spectroscopic signatures in the CD₃CN/DMSO-d₆\nenvironment central to synthesis and characterization.\n The earlier concerning signals were artifacts specific to pure DMSO and not\nrepresentative of the materials’ behavior under the experimental conditions used in this\nstudy.\nThe revised manuscript includes the updated spectra and corresponding clarifications. We\nappreciate the reviewer’s comments, which led to a clearer and more rigorous characterization.\nSupplementary Fig. 39. 1H NMR of FIR-154 (400 MHz, CD CN/dmso-d ; v/v=4/1).\n3 6\nSupplementary Fig. 40. 1H NMR of FIR-155 (400 MHz, CD CN/dmso-d ; v/v=4/1).\n3 6\n> Finally, the authors should carefully check the figure references throughout the manuscript,\nas several ESI figures are not properly labelled within the text (e.g., calling Fig S40 as\nSupplementary Fig 40). I would consider the manuscript ready for acceptance after fixing these\nminor issues.\nResponse: Thank you for noting the inconsistent labeling of ESI figures (e.g., Fig S40 vs.\nSupplementary Fig 40). We have now revised both the main text and the supplementary\nmaterial to adopt the consistent format “Supplementary Fig. XX” throughout and have verified\nall citations accordingly.\nAll the changes have been highlighted in blue in the revised manuscript and\nsupplementary information."}, {"round": 3, "reviewer_comments": {"reviewer_3": "After the revision of all the new provided data, I consider this manuscript to be well-suited for publication."}, "author_response": ""}]

Decision letter