ChemComm This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online FEATURE ARTICLE View Journal | View Issue Surface chemistry of metal–organic polyhedra Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. Cite this: Chem. Commun., 2022, Jorge Albalad, *a Laura Hernández-López,b Arnau Carné-Sánchez *b and 58, 2443 Daniel Maspoch *bc Metal–organic polyhedra (MOPs) are discrete, intrinsically-porous architectures that operate at the molecular regime and, owing to peripheral reactive sites, exhibit rich surface chemistry. Researchers have recently exploited this reactivity through post-synthetic modification (PSM) to generate specialised Received 14th December 2021, molecular platforms that may overcome certain limitations of extended porous materials. Indeed, the Accepted 25th January 2022 combination of modular solubility, orthogonal reactive sites, and accessible cavities yields a highly DOI: 10.1039/d1cc07034g versatile molecular platform for solution to solid-state applications. In this feature article, we discuss representative examples of the PSM chemistry of MOPs, from proof-of-concept studies to practical rsc.li/chemcomm applications, and highlight future directions for the MOP field. 1. Introduction Frameworks (MOFs)4,5 and more recently, Covalent–Organic Frameworks (COFs)6,7 has garnered interest from both academia Research on porous materials dates back centuries but has only and industry, owing to their modular structures with well-defined bloomed over the past few decades. This is down to two microporous environments.8 These materials can be designed reasons: growing interest in their physical properties, and the reticularly with bespoke structural features (e.g., pore sizes, ability to rationally design them via bottom-up methods.1–3 windows, and inner functionalisation) that, together with strong A new generation of porous materials such as Metal–Organic bonding among constituent components,9 define the mechanical, chemical, and topological attributes of a given framework.10–12 a Centre for Advanced Nanomaterials and Department of Chemistry, The University Additionally, the structured building units retain a chemical of Adelaide, North Terrace, Adelaide, SA 5000, Australia. reactivity similar to that of their molecular counterparts; there- E-mail: jorge.albalad@adelaide.edu.au fore, the pore domains of framework can be further modified with b Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, Barcelona specific functionalities by post-synthetic modification (PSM).13–15 Institute of Science and Technology, Bellaterra 08193, Barcelona, Spain. E-mail: arnau.carne@icn2.cat, daniel.maspoch@icn2.cat By applying PSM to porous materials, researchers have been able c ICREA, 08010 Barcelona, Spain to blend specialised materials with previously unobtainable Jorge Albalad is an ARC-funded Laura Hernández López is currently Postdoctoral Researcher under the pursuing a PhD in Chemistry at the supervision of Prof. Christian ICN2 under the supervision of Prof. J. Doonan and Christopher Daniel Maspoch and Dr. Arnau J. Sumby at the University of Carné. She received her BSc degree Adelaide (Australia). He received in Nanoscience and Nanotechnology his BSc degree in Chemistry at the at Autonomous University of Autonomous University of Barcelona Barcelona (UAB) in 2017. In 2019, (UAB) in 2014. Then, he completed she got her MSc in Applied Materials his MSc in Industrial Chemistry and Chemistry from University of Introduction to Chemical Research Barcelona (UB). Her research (2015) and his PhD in Chemistry interest lies in understanding the Jorge Albalad (2019) at the same university, Laura Hernández-López reactivity and assembly of discrete conducting his research at the metal–organic polyhedra in solution. ICN2. His research focuses on the post-synthetic modification of metal– organic entities, with particular emphasis on the influence of molecular- level transformations to the macroscopic properties. This journal is © The Royal Society of Chemistry 2022 Chem. Commun., 2022, 58, 2443–2454 | 2443 View Article Online Feature Article ChemComm properties. Indeed, by bypassing the solvothermal synthetic amassed to date into the design of porous soluble platforms with conditions typically used for porous materials such as MOFs, unique functionalities. scientists can now incorporate highly-reactive and sensitive moieties into these materials.16–18 2. Morphology and structural features This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Recently, investigators have extended PSM to Metal–Organic Polyhedra (MOPs), which are discrete, intrinsically-porous of prototypical metal–organic architectures assembled through metal–linker coordination polyhedra bonds, similarly to MOFs.19,20 MOPs are an underrepresented family of porous materials whose unique attributes are not Structurally, MOPs are similar to the well-known coordination found in extended frameworks. Unlike their extended analogues, cages devised by the groups of Fujita,30,31 Stang,32,33 and Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. MOPs are generally bound in the solid state by weak cage-to-cage others. Thus, MOPs can be considered a subclass of such cages, interactions that can easily be disrupted to dissolve them.21 distinguished by showing permanent porosity in the solid state Thus, while these materials generally lack the long-range order and for their strong, typically metal–carboxylate, coordination effects that confer MOFs with robustness and high surface areas, bonds. Just like their extended MOF analogues, MOPs exhibit researchers can exploit their molecular nature to access a wide rich and versatile structural chemistry. However, the polyhedral library of solution-based PSM chemistry to precisely control their nature of MOPs provides structural attributes that are not solubility, processability, and solid-state packing.22–24 This in found in MOFs: (i) a single internal cavity, accessible through turn can generate unique porous materials with well-defined the cage’s windows; (ii) two well-defined surfaces (internal and surfaces poised for specific applications in homogeneous and external); (iii) finite, directional, orthogonal reactive sites interfacial regimes, where long-range order and diffusion throughout both surfaces (i.e. axial metal sites and organic kinetics have proven detrimental.25,26 functionalities); and (iv) modular solubility.34 Together, these In this feature article, we explain the influence of PSM on features confer MOPs with exquisite reactivity, matching that of MOPs and their molecular chemistry, highlighting the interesting MOFs, albeit within the molecular solution regime. Thus, MOPs properties conferred to MOPs via PSM that are not found in other can operate as highly-processable soluble hollow nanoparticles,35 common porous materials. Whilst MOPs have attracted some where the finite number of reactive sites enables stoichiometric interest as potential building blocks for the synthesis of extended control of their surface reactivity as well as reversible transition materials,27–29 that is beyond the scope of this article. In the first from solution phase to packed phase.36,37 Consequently, the section of the present article, we cover the fundamental structural functionalisation of MOPs can be characterised both in solution features of MOPs, aiming to facilitate visualisation of their surface (e.g. by NMR, mass-spectrometry, DLS) and the solid-state (e.g. by chemistry for the subsequent sections. Next, we discuss the X-ray diffraction/crystallography, infrared spectroscopy, gas principal challenges that researchers face for PSM of MOPs at sorption). their metal nodes and at their organic linkers, and cite significant We recognise that ensemble of structural details that we milestones in the chemistry at each site. In these sections, have provided on MOPs so far may be difficult to visualise for we mention examples of conceptual and practical value. Finally, some readers, especially for those new to the field. Thus, in this we look towards the future, identifying what we believe to be section, we provide a graphic representation of all the features the most important paths to follow for the next decade, in terms that we described above. Fig. 1 depicts the structure of a MOP of translating the wealth of chemical knowledge that has been from the prototypical M24L24 family, arguably the most studied Arnau Carné-Sánchez is a ‘‘La Daniel Maspoch is an ICREA Caixa’’ Junior Leader fellow at Research Professor at the Institut ICN2. He received his BSc degree in Català de Nanociència i Chemistry from the Universitat de Nanotecnologia (ICN2). He Barcelona (UAB) in 2008. In 2014 received his BS degree at the he got his PhD in Chemistry from the Universitat de Girona and his PhD UAB under the supervision of Prof. degree at the Universitat Autònoma Daniel Maspoch and Dr. Inhar Imaz. de Barcelona & Institut de Ciència In 2014 he joined Prof. Susumu de Materials de Barcelona. He Kitagawa and Prof. Shuhei worked as a postdoctoral fellow at Furukawa’s group in iCeMS at Northwestern University. His Kyoto University (Japan) under a research interests include reticular Arnau Carné-Sánchez JSPS postdoctoral fellowship. He is Daniel Maspoch materials (MOFs, COFs and MOPs) currently researching the synthesis and delivery systems. and reactivity of nano-sized molecular porous materials. 2444 | Chem. Commun., 2022, 58, 2443–2454 This journal is © The Royal Society of Chemistry 2022 View Article Online ChemComm Feature Article This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. Fig. 1 Schematic representation of the internal and external orthogonal reactive sites within the archetypical M24L24 metal–organic polyhedra. Left: The external surface (red) contains twelve axial open-metal sites that stem from the dimetallic M–M paddlewheel SBUs, as well as up to 72 organic functional groups from positions 4, 5, and 6 of the linker. The internal surface (blue) contains 12 axial open-metal sites and 24 organic functionalities that stem from position 2 of the linker. Right: The internal cavity of the cage (2.5 nm; yellow sphere) is accessible through two distinct windows: a trigonal one (diameter: 4.5 Å) and a square-shaped one (diameter: 6.6 Å). architecture to date.38 It comprises 12 divalent M–M paddle- groups, and cavities. Representative MOPs include the lantern- wheel clusters and 24 angular aromatic linkers perfectly spaced type (M2L4),41,42 tetrahedral (M4L4X+),43,44 and octahedral throughout the material, converging into a cuboctahedral (M6L12)45,46 families, among other, more complex variants with shape with an intrinsic inner cavity (diameter: 2.5 nm). The multiple components.26 Thus, researchers now have access to rigidity and directionality imposed from both subunits render a numerous possible molecular platforms with very distinct distinct geometry in which all vertices, edges, and facets can be attributes that offer potential for development of smart soluble chemically elucidated with atomic-level precision by adapting materials with molecular-level precision. Importantly, each the principles of reticular chemistry.39 Within the cage shown reactive site can be modified via PSM to exponentially increase in Fig. 1, one can clearly depict both an internal (blue) and the number of variables that scientists can tune to generate a external (red) MOP surface. These surfaces can be targeted massive library of functionally specialised MOPs for countless separately during the design, self-assembly, and PSM of the applications in solution or solid phase. cage. The inner surface is tagged with 12 spaced coordination centres that stem from the axial sites of each paddlewheel cluster. Likewise, 24 distinct organic functionalities point 3. Post-synthetic modification of inwards from position 2 in the aromatic ligand (bottom, left) metal–organic polyhedra and heavily influence both the hydrophobicity and sterics of the inner cavity. The inner metal sites and the organic functionalities Reflecting on the impressive features of MOPs, we are shocked can only be accessed by substrates small enough to fit through the that their PSM has remained rather underrepresented in the two windows (diameters: 4.5 Å and 6.6 Å) in the MOP structure literature, and that MOPs have been overshadowed by other (right), so that these sites/functionalities are mainly targeted competing porous materials. Nevertheless, we recognise that towards adsorption/separation of small substrates or gas-phase this may be partially explained by certain drawbacks inherent molecules.40 Alternatively, the external surface contains 12 to the earliest MOPs. Foremost among these is the structural independent axial metal sites, and the organic linkers confer this fragility exhibited by the first generation of Cu(II)-based MOPs, surface with up to 72 different functional sites that stem from which made them prone to degradation by moisture, heat, positions 4, 5 and 6 of the aromatic linkers (top, left), which nucleophiles, or acids. Accordingly, for years, researchers dictate the solubility of the cage. Consequently, if for simplicity, focused on shielding MOPs within confined environments,47–49 one limits the total permutation to a single reaction per position, which meant that they could learn very little about the surface then this one cage could contain up to 36 moieties on its internal chemistry of these materials. surface and up to 84 moieties at its external one. Importantly, each In the following sections, we review the most remarkable moiety is perfectly defined, both directionally and structurally, examples of surface functionalisation of MOPs at both the within the cage’s backbone. internal and external surfaces, grouping the examples by the The aforementioned structural analysis can be extended to subunit targeted and the type of chemistry employed in each the entire repertoire of (over fifteen) reported MOP structures, case (Fig. 2). We underscore how the development of alternative each of which contains distinct metal nodes, linkers, functional modification protocols, and the assembly of more-robust This journal is © The Royal Society of Chemistry 2022 Chem. Commun., 2022, 58, 2443–2454 | 2445 View Article Online Feature Article ChemComm This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. Fig. 2 Schematic representation of the surface reactivity of the archetypical M24L24 metal–organic polyhedra. S refers to solvent and Nu refers to a nucleophile. cages—including those of MOPs based on Rh(II), Cr(II), Mo(II), (Fig. 3a). The authors harnessed the reversible nature of their or Zr(IV)—have together enabled researchers to use more- MOPs, successfully exchanging the initial MOP linkers with attractive chemistries to develop functional MOP platforms structurally-diverse dicarboxylate variants to obtain a set of func- for diverse applications. tionalised isostructural MOPs. The successful exchange was based on two major driving forces that include the equilibrium displace- 3.1. Post-synthetic modification of MOPs at their metal ment with saturated linker solutions and the precipitation of the centres products from solution. Moreover, they were able to change Unlike most molecular platforms, MOPs present two defined the cage topology, by selecting a substituting ligand with an domains at their periphery: one comprising organic groups appropriate bending angle for ligand-exchange. Thus, they first from the linkers; and one comprising inorganic groups from converted their initial lantern-type cages to cuboctahedral cages, the coordination clusters that extend throughout the lattice. which they subsequently converted to octahedral cages (Fig. 3b). In the latter, one can distinguish two distinct types of positions Unfortunately, performing PSM on the equatorial positions around the metal nodes: one type, which helps hold the cage in paddlewheel MOPs threatens the chemical stability of together; and another type (open-metal site), which does not, but the structure, as uncontrolled ligand substitutions, whether is available and is prone to coordinate extraneous nucleophiles. partial or complete, can induce hydrolytic or defect-promoted For example, in a four-connected, dimetallic paddlewheel node, degradation.54,55 Accordingly, for PSM of MOPs at their inorganic there are four equatorial coordination positions (M-COO) that are sites, researchers have prioritised targeting the accessible axial directly involved in the MOP formation, and two axial labile sites sites under conditions that do not interfere with the cage’s that generally accommodate weakly-bound solvent molecules. Both integrity. Even the simplest cage containing paddlewheel nodes types of positions are amenable to PSM. Importantly, they can be features accessible open-metal sites that exhibit a strong affinity targeted independently under distinct reaction conditions.50 towards electron-donating nucleophiles and, consequently, can Zhou and co-workers were the first to demonstrate the accommodate those nucleophiles within its structure. These feasibility of reacting the equatorial positions in Cu(II)-based PSMs entail ligand-exchange in solution, as said axial positions paddlewheel MOPs through a ligand-exchange approach.51 are inherently occupied by solvent molecules. When electron- These positions are directly implicated in the coordination- donating nucleophiles with higher affinities compete for these driven self-assembly of MOPs under solvothermal conditions. coordination sites, the solvent molecules of poor nucleophilicity Such assembly requires a certain degree of bond lability, as it can be replaced. Therefore, the exploitation of open-metal sites in facilitates the formation of thermodynamically-favoured, MOPs is strongly influenced by the solvent in which the MOPs defect-free assemblies.52,53 Certainly, the equatorial metal–linker have been dissolved, which can drastically affect the properties bonds are not ‘‘blocked’’ after formation of the MOP, and and consequently, the reactivity of solvated cages both in solution their dynamic reactivity can be further exploited through PSM and in the solid state. Recent work highlights the strong influence 2446 | Chem. Commun., 2022, 58, 2443–2454 This journal is © The Royal Society of Chemistry 2022 View Article Online ChemComm Feature Article the lability of Cu(II)-, Zn(II)-, and Co(II)-based nodes in solution has precluded further work on the potential of their coordinative binding-sites. Interestingly, researchers have extensively demonstrated that the presence of mild N-donor nucleophiles This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. (e.g. primary amines, pyridine derivatives, or imidazole derivatives) induces the decomposition of certain MOPs into discrete clusters, via ligand-exchange between the N-donor and MOP bridging-ligands.54 Accordingly, investigators have recently begun to focus on assembling more-robust MOP architectures built from non-labile, equatorial, metal–linker bonds. Among these, we Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. would like to highlight here the rich surface-functionalisation chemistry of Rh(II)-based MOPs that are isostructural to the archetypical Cu(II) paddlewheel analogues. Rh(II)-based MOPs were first presented by the groups of Su (in 2015) and Furukawa (in 2016), who reported unprecedented thermal and chemical robustness in these materials.58,59 This enhanced stability relies on a combination of chemically-inert equatorial positions in the paddlewheel, and strong intermetallic Rh–Rh bonds. Remarkably, although the equatorial position of the dirhodium paddlewheel is ‘‘chemically locked’’, its axial metal sites remain highly reactive, albeit without compromising the integrity of the nodes. Thus, these sites can readily accommodate a plethora of coordinative nucleophiles, the most-widely studied of which are N-donors, although nucleophiles with other donor atoms (e.g. S-donors, P-donors, O-donors) can establish similar coordination bonds. The pioneering work of the Su and Fig. 3 (a) Schematic of the equatorial lability of dimetallic M–M paddle- Furukawa groups thus paved the way for researchers to explore wheel nodes. (b) The combination of Cu(Ac)2 and the corresponding linker molecular functionalisation of the open-metal sites of MOPs. in mixed solvents at room temperature affords multiple Cu-based MOPs Our (Maspoch) group and the Furukawa group were the first to with labile equatorial positions. To modify the external surface of the interrogate the axial sites in Rh(II)-based MOPs and established resultant MOPs, the labile bonds can be subjected to linker-exchange the basic chemistry of these understudied platforms. Our research chemistry. This entails mixing an excess of the new ligand(s) with the (soluble) parent MOP in a suitable solvent at room temperature. Adapted confirmed that up to twelve pyridine-based linkers could be with permission from ref. 51. selectively attached to the external axial Rh–Rh sites of the cage. Thus, we demonstrated that these porous molecular platforms could be functionalised at their axial sites with diverse of coordinating solvent molecules on the sorption properties42,56 coordinating linkers of different polarity, charge, and chirality. and crystal packing57 of MOPs, and illustrates how the same cage Consequently, certain intrinsic physicochemical properties of can exhibit drastically different attributes owing to its intrinsic these materials (i.e. solubility, hydrophilicity, and chirality) could solvatomorphism. Likewise, the coordination-based reactivity of be selectively modulated in a controlled and reversible way, MOPs with accessible open-metal sites can be either enhanced or without compromising their inner porosity. Through this completely masked by carefully selecting the reaction medium. approach, it was possible to modulate the solubility of multiple Strongly coordinating solvents (e.g. DMSO or DMF) generally Rh(II)-based MOPs in a broad spectrum of solvents, encompassing occlude the unoccupied nodes in the cage, which might restrain non-polar (diethyl ether), halogenated (DCM & chloroform), polar their reactivity. Fortunately, this occlusion is not permanent: aprotic (DMF & DMSO), and protic (H2O & alcohols) solvents, by coordinated solvent molecules can be replaced by a strategically- tagging the open-metal sites with suitable pyridine derivatives. chosen coordinating moiety of interest that will promote the Interestingly, the hybrid nature of MOP surfaces confers these formation of stronger coordination bonds. Non-coordinating materials with well-defined orthogonal positions that can be solvents (e.g. alkanes or alcohols) will augment the reactivity of targeted independently and reversibly without compromising the cage due to their weak interaction with the open-metal sites, the other active sites in the cage, whether internal or external but might induce the self-aggregation of the cages in solution. (Fig. 4).24 This approach allows for further chemistry at the MOP Overall, researchers seeking to maximise the potential of MOPs as surface, which would otherwise be precluded by the insolubility of molecular platforms should first anticipate the influence of the the parent MOP in the desired solvent. As proof of concept, we solvent(s) to be used before studying the reactivity of the MOP(s) covalently functionalised an OH-functionalised cuboctahedral in question. Rh(II)-based MOP (named OH-RhMOP, of formula [Rh2(5-OH- The examples that we cited above laid the foundation for the bdc)2]12, where 5-OH-bdc = 5-hydroxy-1,3-benzenedicarboxylate) open-metal site chemistry and reactivity of MOPs. Unfortunately, in a solvent in which the cage was insoluble and thus, unreactive. This journal is © The Royal Society of Chemistry 2022 Chem. Commun., 2022, 58, 2443–2454 | 2447 View Article Online Feature Article ChemComm organic substrates by coordinating them to a suitable MOP platform, such that the entire MOP-bound substrate molecules dissolve in a media where the substrate molecules alone would normally be insoluble. This approach is best suited for MOPs that This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. contain pendant organic groups that can heavily influence their solubility profile, such as long aliphatic chains or charged polar groups, despite the coordination of small molecules to the axial sites. In 2021, this technique was implemented for the solubilisation of strongly hydrophobic or hydrophilic pyridines into aqueous or non-polar phases, respectively. Specifically, we used Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. fully-deprotonated OH-RhMOP (named ONa-RhMOP; vide infra), a water-soluble species, to dissolve the strongly hydrophobic substrate 4-pyridinylboronic acid in water. Conversely, we used a hydrophobic MOP with 24 aliphatic chains (named C12-RhMOP) to dissolve the strongly hydrophilic substrate 4-aminopyridine into CHCl3 (Fig. 4).60 This strategy can be implemented into separation systems, as the MOP-bound substrate molecules can be easily separated from the corresponding unbound substrate molecules, thanks to its differentiated solubility. Therefore, molecules can be separated according to their capacity to coordinate to Rh(II)-based MOPs, which is influenced by the basicity and steric hindrance of their constituent coordinating heteroatoms.61 This approach could prove highly valuable for diverse applications, including currently low-yielding catalytic reactions that are limited by solubility restraints of the reagents and/or catalysts. Thus, we believe that further refinement of this coordinative solubilising methodology will enable researchers to surpass the solubility constraints in homogeneous organic chemistry. 3.2. Post-synthetic modification of MOPs at their organic linkers Having overviewed the PSM of MOPs at their metal centres, we now turn to their organic linkers. From a strictly chemical perspective, soluble coordination cages should not behave any Fig. 4 Schematic of the molecule-to-MOP and MOP-to-molecule transfer differently than the simplest aromatic molecule: in both cases, the of properties via coordination of organic molecules to the external axial sites of Rh(II)-based MOPs. Top: The solubility of insoluble MOP platforms can be organic reactivity is shaped by the presence of functional groups. modulated via a coordinative solubiliser method, whereby the anchoring Thus, the richer the reactivity of those appendices, the broader the of (up to twelve) pyridinyl nucleophiles modifies the surface properties. scope of possible bond formation and the wider the range of Bottom: Conversely, the solubility of organic substrates can be modified by accessible surface-modification techniques. Unfortunately, the anchoring them to the surface of suitable MOP platforms that have well- chemistry of MOPs is not always as straightforward as that of defined solubility profiles. organic molecules: consequently, PSM of MOPs at their organic sites faces two major hindrances that arise from the supramole- By selectively coordinating twelve suitable pyridine derivatives to cular nature of the MOP backbone. Firstly, the functional groups the axial Rh–Rh sites, we were able to dissolve the cage in the incorporated within the linkers must be able to tolerate the optimal reaction solvent for subsequent etherification of the conditions to synthesise the cage, which can range from room hydroxyl groups with allyl bromide. Next, we selectively removed temperature crystallisation to solvothermal couplings in basic the coordination-based solubilising groups from the axial sites by media.62 Secondly, the reaction conditions available for covalent a mild acid wash to obtain the functionalised material as a functionalisation are restricted to those that do not affect other precipitate. elements in the structure, particularly the labile equatorial Just as the properties of a MOP cage can be tuned by attached M–COO bonds.54 Fortunately, organic chemistry is replete with coordinated moieties, as explained above, the opposite is also true: reactions to reliably assemble, cleave, or rearrange covalent bonds certain MOP properties can be transferred to surface-coordinated under mild conditions that can be safely applied to fragile MOP molecules. Accordingly, MOP surfaces can be coordinatively func- platforms. Most of the reported covalent PSMs of MOPs have tionalised for reasons other than modulation of physicochemical revolved around condensation reactions (e.g. formation of ester, properties of the MOP. For example, MOP-to-molecule transfer of imine, or amide bonds),57,63,64 click chemistry (azide-alkyne properties can be exploited to direct the solubility of important cycloadditions),65,66 or alkene polymerisation.22,67,68 2448 | Chem. Commun., 2022, 58, 2443–2454 This journal is © The Royal Society of Chemistry 2022 View Article Online ChemComm Feature Article One of the first examples of the covalent PSM of a MOP was reported in 2010 by the group of Zhou, who performed a Huisgen cycloaddition reaction between an alkyne-functionalised cuboctahedral Cu(II)-based MOP (named C2H2-CuMOP, of This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. formula [Cu2(5-C2H2-bdc)2]12, where 5-C2H2-bdc = 5-ethynyl-1,3- benzenedicarboxylic acid) and azide-terminated polyethylene glycol (PEG) chains. Despite the fragility of the mother cage in aqueous media, the combination of reagents in situ led to formation of water-stable, PEG-grafted cages with up to four hydrophilic, polymeric, PEG side-chains at the periphery.65 Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. Intriguingly, the authors later employed these PEG side-chains to encapsulate and release anti-cancer drugs in physiological media. In 2016, Kitagawa et al. reported the first-ever quantitative surface-functionalisation (24 positions) of another Cu(II)-based cuboctahedral MOP, using dithiobenzoate or trithioester moieties (of formula [Cu2(5-Z-SCS-bdc)2]12, where 5-Z-SCS-bdc = 5- dithiobenzoate-1,3-benzenedicarboxylic acid, or 5-trithiobutane- 1,3-benzenedicarboxylic acid, respectively). They grafted up to 24 polymeric arms around the MOP core by direct coupling with monomeric building blocks via soft Reversible-Addition- Fragmentation Chain Transfer (RAFT) polymerisation, without compromising the integrity of the cage. These results offered a rational strategy for the synthesis of highly-processable MOP-based star polymer materials with controlled grafting of multiple side-chains.69 Fig. 5 Covalent PSM of OH-RhMOP under interfacial conditions. React- Although researchers can access new and exciting MOP ing OH-RhMOP with at least 24 mol eq. of NaOH in H2O affords the reactions through mild covalent chemistry, if they truly wish quantitative deprotonation of the terminal hydroxyl groups within the to exploit MOPs as functional platforms, then they must cage, forming a 24-charged, water-soluble species. ONa-RhMOP reacts address the lability of M–COO equatorial bonds. Indeed, under interfacial conditions (aqueous/non-polar organic solvents), or although a diverse array of MOPs derivatised with broadly under pyridine-assisted solution, with multiple substrates to afford PSM of the cage in high yields. (b) Synthesis and PSM of internal NH2 moieties in reactive moieties (e.g. hydroxyl, alkyl, or alkynyl groups) is the lantern-type OMe-CuMOP(L)-NH2. Despite the nucleophilicity of the now available, only a mere fraction of their potential reactivity amine groups, the cage can be assembled without having to mask the can be harnessed for surface chemistry due to stability concerns. reactive sites, thanks to steric constraints. After cage assembly, the free In particular, the chemistry of hydroxyl-functionalised MOPs is NH2 groups retain their reactivity, and can be subsequently reacted with limited by their instability under basic conditions, which are the acetic anhydride to afford the mono-substituted amide product; further amide formation is prevented by sterics. Reproduced (adapted) with most common reaction conditions for quantitative formation of permission of ref. 24 (Copyright 2019 American Chemical Society) and ether or ester bonds. In fact, the cuboctahedral OH-CuMOP 72 (Copyright Royal Society of Chemistry). suffers spontaneous phase-transition upon exposure to N-based bases or even simply to water;70 consequently, it has not been subjected to deprotonation or PSM by this type of chemistry at its non-polar organic solvents) for esterification and etherification surface. Interestingly, this limitation was circumvented by reacting (Fig. 5a).24 Remarkably, OH-RhMOP endured the quantitative a hydroxyl-functionalized lantern-type Cu-MOP (named OH- deprotonation of its hydroxyl groups with excess NaOH, which CuMOP(L), of formula [Cu2(OH-L)2]2, where OH-L= 3,30 -(5- generated a water-soluble platform with 24 negative charges hydroxy-1,3-phenylene)-bis(ethyne-2,1-diyl)dibenzoic acid) with at its periphery. We then coupled this charged platform hydrophobic alkyl anhydrides in the presence of an esterification with various organic moieties (acyl chlorides, anhydrides, catalyst at room temperature in DMF. Using these very mild alkyl halides, etc.) in high yields, under conditions that conditions, the authors were able to quantitatively transform would completely disintegrate any Cu(II)-based analogue. More the pendant hydroxyl groups of OH-CuMOP(L) into alkyl-ester recently, the group of Bloch applied similar chemistry to Cr(II) side-chains, which drastically enhanced the solubility and stability and Mo(II)-based MOPs to obtain functionalised platforms that of the cage in organic solvents.71 would be inaccessible via direct synthesis.63 Adamant to overcome the aforementioned limitations of To further enhance the versatility of MOPs, researchers OH-functionalised MOPs, our group, in close collaboration must develop alternative pathways to expand the catalogue of with the group of Furukawa, investigated the chemistry of the surface functional groups, especially those that are normally Rh(II) analogue, OH-RhMOP.59 Specifically, we explored incompatible with the conditions for cage synthesis. For example, the possibility of functionalising OH-RhMOP under standard linkers with free coordinating moieties such as primary amine interfacial conditions (biphasic system made of aqueous and (–NH2) or carboxylic acid (–COOH) groups have been challenging This journal is © The Royal Society of Chemistry 2022 Chem. Commun., 2022, 58, 2443–2454 | 2449 View Article Online Feature Article ChemComm to incorporate into MOP structures due to their nucleophilicity They exploited the affinity of copper(II) acetate towards nitrogen- and their affinity for metal sources, both of which can disrupt the donors to protect the axials sites with bulky monodentate auxiliary assembly of the MOP. One way to circumvent these issues is to use ligands, rendering the first-ever M24L24 NH2-functionalised ligands with sterically-hindered amine groups, which essentially MOP (NH2-CuMOP, of formula [Cu2(5-NH2-BDC)2]12, where This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. renders them those non-coordinative. For instance, Klosterman 5-NH2-bdc = 5-amino-1,3-benzenedicarboxylate) (Fig. 6a).73 More and co-workers functionalised the inner cavity of a lantern-type recently, our group reported the use of covalent protecting groups MOP named OMe-CuMOP(L)-NH2, of formula [Cu2(L)2]2, where to incorporate sensitive moieties at the external surface of MOPs. L = 3,30 -((2-amino-5-methoxy-1,3-phenylene)-bis(ethyne-2,1-diyl)- Through a two-step synthesis involving temporary masking of dibenzoic acid) via direct assembly of Cu(II) precursors and a linker the linker functional groups prior to the assembly of the with free NH2 groups. The position of the amine groups on the cage, followed by chemoselective deprotection, we obtained the Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. linker made them too sterically hindered to interfere with the Cu(II) first-ever cuboctahedral Rh(II)-based MOPs with 24 appended ions during the cage assembly, yet sufficiently reactive with small NH2 or COOH moieties (named NH2-RhMOP and COOH-RhMOP, molecules that had entered the lantern-type cavity. The authors of formulae [Rh2(5-NH2-bdc)2]12 and [Rh2(5-COOH-bdc)2]12, respec- demonstrated this concept by reacting the lantern cage with acetic tively, where 5-COOH-bdc = 1,3,5-benzenetricarboxylate) (Fig. 6b).74 anhydride in DMF to yield the mono-functionalised amide product. These two examples established the basis for incorporating reactive Molecular modelling corroborated the experimental results, groups at the surface of MOPs independently of their stability, as the indicating that the inclusion of a second acetate is disfavoured protecting group and the deprotection step can each be adapted to due to sterics (Fig. 5b).72 address concerns over chemical compatibility or stability.75,76 Unfortunately, to synthesise MOPs that contain free amines Indeed, this strategy was later employed by Bloch et al. to control at their external surface, researchers cannot employ the steric the self-condensation of a new family of lantern Cu-MOPs with hindrance approach described above, because of the high external NH2 groups, via controlled deprotection of Fmoc groups, degree of exposure of these coordinating groups within the which afforded products ranging from isolated cages to crystalline bent-linker structure. To date, two opposing methodologies self-condensation crystalline networks.77 have been developed to circumvent the nucleophilicity of free An alternative way to develop NH2-tagged MOPs is based on amino groups during MOP synthesis, both of which entail the using hard-metal sources with no affinity for such reactive use of protecting groups to temporarily mask undesired groups (e.g. Zr(IV)-based MOPs). In this case, exploitation of reactivity. The group of Yaghi was the first to introduce free surface NH2 groups enables the use of PSM pathways with amino groups onto the surface of MOPs, by developing a higher degrees of stoichiometric control, since the risk of self- protocol that blocked the axial reactivity of Cu(II) precursors. condensation is precluded. In 2018, Yuan, Zhao and colleagues Fig. 6 (a) Nucleophile-based masking of the axial sites of copper(II) acetate with tert-butyl glycine ester affords the synthesis of the cuboctahedric NH2-CuMOP instead of evolving to extended products. (b) Protecting group-based strategy for the synthesis of NH2- and COOH-tagged Rh(II)-based MOPs, unobtainable via direct synthesis. A selective deprotection pathway affords the quantitative deprotection of the cages without compromising their integrity, and revealing new functionality poised for further PSM steps. (c) Top: Scheme for the PSM of NH2-ZrMOP(T) with up to 6 sites per cage. Bottom: ESI-TOF-MS-based process-tracing of the PSM products of a Mannich reaction with formaldehyde and methanol after (1) 1 min; (2) 20 min; (3) 50 min; (4) 120 min; (5) 600 min; (6) 1400 min. Reproduced (adapted) with permissions of ref. 73, 74 and 78. Copyright 2008/2018 American Chemical Society – 2019 Royal Society of Chemistry. 2450 | Chem. Commun., 2022, 58, 2443–2454 This journal is © The Royal Society of Chemistry 2022 View Article Online ChemComm Feature Article published the first process-tracing study on the stepwise PSM what exciting possibilities will arise from exploring surface of a NH2-tagged Zr(IV)-based MOP (NH2-ZrMOP(T), of formula functionalisation of robust MOPs with alkyne, NH2, or other [Zr3(CP)3(2-NH2-bdc)]44+, where CP = cyclopentadienyl and equally reactive groups now that the full repertoire of 2-NH2-bdc = 2-amino-1,4-benzenedicarboxylate). The authors chemistry is becoming accessible, beyond the mere use of mild This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. employed ESI-TOF Mass Spectrometry to unambiguously condensation pathways. determine the molecular formula of their cages at different stages of PSM, which comprised Mannich reaction of the free NH2 groups with formaldehyde and methanol. The mass spectra 3.3. Post-synthetic ion-exchange/metathesis confirmed the sequential stoichiometric formation of amino– MOPs with a charged backbone can undergo PSM by an methyl methoxy side-chain products throughout the PSM, from a additional type of reactivity, which is based on salt metathesis. Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. mono-functionalised cage to a quantitatively tagged (six side- Akin to the behaviour of charged inorganic nanoparticles,82 the chains) one (Fig. 6c).78 Importantly, the authors not only type of counter ions on the surface of nano-sized molecules contributed to the field by elucidating stoichiometric control influence their surface chemistry and consequently, their over MOP surface chemistry, but also achieved a milestone behaviour in solution (i.e. solubility and reactivity). For example, towards the processability and manipulation of these materials Nitschke et al., among other groups, have elegantly employed by controlled switching from the solid-state to solution via PSM. ion-exchange reactions to alter the solubility of coordination Finally, we would like to highlight that covalent PSM is not cages.83–85 the only post-synthetic strategy that can be applied to modify In addition to modifying charged MOPs, researchers can the chemistry of MOP linkers. As in MOFs, the introduction of now confer neutral MOPs with charge. For example, although stimuli-sensitive moieties in the cage backbone in MOPs can the backbone of paddlewheel-based MOPs is neutral, these yield platforms whose structure responds stimuli such as MOPs can be conferred with charge through the strategic use changes in temperature, light, or solvent.79 In 2014, Zhou of pendant pH-responsive groups that, upon protonation et al. synthesised the first example of stimuli-responsive MOP (or deprotonation), become positively (or negatively) charged. (srMOPs), which they functionalised with azobenzene groups. For instance, strong acids such as sulfonic acid can be easily The cage exhibited UV-irradiation-induced isomerisation from deprotonated to yield the corresponding negatively-charged the insoluble trans-conformer to the soluble cis-conformer, sulfonate groups. Through this approach, Zhou et al. synthesised whereas irradiation with blue light reversed this process to the first negatively-charged MOP with formula (named SO3X- precipitate out the trans-conformer. Impressively, the authors CuMOP, of formula X24[Cu2(5-SO3-bdc)2]12, where X = Li(I) or were able to trap guest molecules inside the srMOPs, and then Na(I)).51 Later, Bloch et al. used SO3X-CuMOP as a charged selectively release the guest molecules upon cis-to-trans and monomer to synthesise porous salts.86,87 However, the trans-to-cis isomerisation, laying the groundwork for a new amenability of SO3X-CuMOP in to solution-phase metathesis class of optically-responsive soluble platforms.80 More recently, has not yet been studied, probably due to its structural fragility Bloch et al. exploited this concept to engineer a series of in solution, especially in water. self-sorting lantern-type cages composed of rotationally isomeric Alternatively, our group has shown that the 24 hydroxyl ligands with different porosity profiles. The authors were able to groups at the periphery of OH-RhMOP could be quantitatively selectively prepare the most favourable cage isomers from deprotonated with NaOH to afford the negatively-charged among the 34 configurationally-distinct MOPs possible, by ONa-RhMOP, of formula Na24[Rh2(5-O-bdc)2]12. The resultant applying different crystallisation steps based on solubility and negatively-charged species with 24 hydrophilic Na+ cations on crystal-packing effects. They thus obtained crystallographic evi- its surface proved to be highly soluble and stable in an aqueous dence of three distinct C2h-symmetric MOPs, with two of these alkaline solution, whereas the parent OH-RhMOP was only comprising different ligand conformations within the same cage soluble in aliphatic alcohols. The deprotonation of the surface assembly. In the solid-state, the respective cage configurations hydroxyl groups was both fast and quantitative, enabling us to were locked, allowing the authors to probe the respective solid- perform it in situ to transfer the Rh-MOPs from an organic state transformations and porosity profiles of each conformer.81 phase (1-butanol) into an aqueous phase. Importantly, we were We believe that the above examples reflect how covalent also able to do the reverse transfer. Additionally, ONa-RhMOP chemistry and other chemistries of organic subunits are the was not only responsive towards a change in pH but also most powerful post-synthetic techniques with which to modify to cation-exchange reactions. Thus, it was possible to the surface of MOPs and convert them into a specialised quantitatively exchange the 24 Na(I) ions with organic hydro- platform. Recent advances regarding the overall stability of phobic cations, such as cetyltrimethylammonium (CTA), to MOPs, in combination with techniques that introduce yield a MOP with formula CTA24[Rh2(5-O-BDC)2]12 that was functionality by eschewing aggressive synthetic conditions, have highly soluble in polar organic solvents (Fig. 7a). Furthermore, enabled researchers to functionalise MOPs with unprecedented this cation exchange reaction could also be triggered in situ to diversity. The recent development of Zr(IV)- or Rh(II)-based MOPs, transfer the Rh-MOPs from an aqueous phase to an organic among other, less-represented sources of strong metals, has phase (i.e. chloroform or 1-butanol). Remarkably, the pH- and enabled researchers to revisit post-synthetic chemistries that cation-triggered phase transfer steps could be coupled in a were once incompatible with the platforms. Only time can tell triphasic system to induce the autonomous transport of This journal is © The Royal Society of Chemistry 2022 Chem. Commun., 2022, 58, 2443–2454 | 2451 View Article Online Feature Article ChemComm Unlike paddlewheel-based MOPs, Zr-MOPs are intrinsically charged, owing to their trinuclear zirconocene clusters. Zr-MOPs are generally balanced by Cl ions,44 which makes them soluble in polar solvents, including water.78 In a pioneering This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. example, the Cl ions in a Zr-MOP of formula Cl4[Cp3Zr3m3- O(m2-OH)3(Me2-bdc)6] (where Me2-bdc is 2,5-dimethyl-1,4- benzenedicarboxylic acid) could be quantitatively exchanged by larger anions such as triflate (OTf), and that by doing so, the solubility of the resulting cage in methanol is significantly greater than that of the parent MOP.86 This example nicely illustrates the Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. possibility of leveraging the zirconocene-cluster counterion as an additional source of reactivity to selectively tune the properties of Zr-MOPs in solution. Overall, salt metatheses are rapid and quantitative reactions that can dramatically change the surface chemistry of MOPs, and consequently, enable in situ tuning of their solubility and reactivity. We believe that the synergistic combination of ionic exchange reactions, the inherent porosity of MOPs, and their coordination and/or covalent reactivity, is especially attractive for the development of novel vehicles for molecular transport, separation, and phase-transfer catalysts. 4. Outlook and perspectives Researchers were initially slow to advance the field of MOPs, given their widespread preference for other materials with more-robust bulk properties, such as MOFs. Nevertheless, the chemistry of MOPs has gradually matured, proving to be as attractive and precise as that of other porous materials. In fact, MOPs are poised to take the spotlight for applications in which the long-range structure or insolubility of their extended counterparts can prove detrimental.88,89 For example, MOPs hold great potential for the development of new porous liquids. The surface reactivity of MOPs can be leveraged for versatile functionalisation to confer Fig. 7 (a) Reversible pH-triggered (blue arrows) and cation exchange- triggered (orange arrows) phase transfer of OH-RhMOP after quantitative MOPs with unusual properties, such as melting (e.g. polymer melts) deprotonation of surface hydroxyl groups in water. (b) The pH- and cation- or solubility in bulky solvents (e.g. ionic liquids), to generate new triggered phase transfer steps were coupled in a triphasic system, to trigger type 1 or 2 porous liquids, respectively.90 The molecular nature of autonomous transport of OH-RhMOP through three immiscible solvent media, MOPs, their defined cavities, and their open-metal sites, amenable from a 1-butanol phase into water and finally, into chloroform. Reproduced to rich and selective coordination chemistry, together allow for the with permission of ref. 60. Copyright 2019 American Chemical Society. synthesis of new metal–organic porous liquids with potential as working fluids for tasks such as separation, catalysis, or storage. OH-RhMOP from the 1-butanol phase into the aqueous phase We believe that the stability and solubility of certain robust and finally, into the chloroform phase (Fig. 7b).60 MOPs in physiological pH should inspire researchers to explore We believe that the synthesis of charged MOPs through using MOPs for biomedical applications. Given the surface protonation/deprotonation reactions could be extended to chemistry of MOPs, we envision conjugation of them to bio- other MOPs containing pH-sensitive pendant groups such as molecules (e.g. peptides, proteins, or even DNA) by conventional amines, sulphonic acids, or carboxylic acids. However, these click chemistry or condensation chemistry. Similarly, we reason functionalised MOPs would have to be sufficiently robust to that MOPs could be used for Drug Delivery, by incorporating withstand the pH required for the protonation/deprotonation. drug molecules onto the MOP surface and/or entrapping them Alternatively, one could use pH-independent charged pendant within the MOP cavities. In this regard, the proven capacity of groups such as imidazolium rings or tetrasubstituted amines to MOPs to solubilise hydrophobic molecules in water could prove develop positively charged MOPs. Importantly, such charged invaluable for engineering delivery vehicles for drugs with poor groups can also be incorporated within the axial sites of water-solubility. This use of MOPs would merge the benefits of paddlewheel-based MOPs via coordination chemistry, using inorganic or MOF nanoparticles, with those of molecular charged N-donor or S-donor nucleophiles.34 systems, by combining rich surface chemistry, defined cavities, 2452 | Chem. Commun., 2022, 58, 2443–2454 This journal is © The Royal Society of Chemistry 2022 View Article Online ChemComm Feature Article and stoichiometric reactivity. These combined features would Acknowledgements enable highly versatile delivery vehicles that could be charac- terised at the molecular level, thus enabling facile study of their This work was supported by the Spanish MINECO (project structure-property relationships. RTI2018-095622-B-I00) and the Catalan AGAUR (project 2017 This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. We are confident that the surface of MOPs is an excellent SGR 238). It was also funded by the CERCA Programme/Gen- platform at which to localise and arrange active molecules eralitat de Catalunya and through a fellowship (LCF/BQ/PR20/ while keeping them in solution. The possibility of localising 11770011) from the ‘‘la Caixa’’ Foundation (ID 100010434). chromophores on the surface of a MOP, either through covalent ICN2 is supported by the Severo Ochoa programme from the or coordinative linkages, would enable the synthesis of solutions Spanish MINECO (Grant No. SEV-2017-0706). with optical properties in which the distance and symmetry Open Access Article. Published on 25 January 2022. Downloaded on 10/31/2022 11:26:19 AM. between the dyes would be controlled to regulate or suppress their energy transfer processes. This approach would circumvent the use References of solid scaffolds to regulate energy transfer processes between 1 K. Otsubo, Y. Wakabayashi, J. Ohara, S. Yamamoto, H. Matsuzaki, dyes, thus enhancing the liquid processability of optical materials. H. Okamoto, K. Nitta, T. Uruga and H. Kitagawa, Nat. Mater., 2011, However, the full potential of MOPs for practical applications 10, 291–295. 2 F. Dai, J. Zai, R. Yi, M. L. Gordin, H. 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