Angewandte Research Articles Chemie www.angewandte.org How to cite: Angew. Chem. Int. Ed. 2023, e202310354 Synthetic Coordination Chemistry Hot Paper doi.org/10.1002/anie.202310354 Retrosynthetic Analysis Applied to Clip-off Chemistry: Synthesis of Four Rh(II)-Based Complexes as Proof-of-Concept Anna Broto-Ribas+, Sara Ruiz-Relaño+, Jorge Albalad,* Yunhui Yang, Felipe Gándara, Judith Juanhuix, Inhar Imaz,* and Daniel Maspoch* vibrant challenge for chemists.[1–3] Traditionally, the way that Abstract: Clip-off Chemistry is a synthetic strategy that chemists envision their synthesis is ultimately driven by our group previously developed to obtain new molecules bond formation steps (i.e. from simple starting materials to a and materials through selective cleavage of bonds. complex product)[4–7] or, to a lesser extent, by bond- Herein, we report recent work to expand Clip-off breaking.[8,9] We have recently developed an alternative Chemistry by introducing into it a retrosynthetic analysis synthetic approach, named Clip-off Chemistry, which pro- step that, based on virtual extension of the products poses using bond breaking as the core synthetic step.[10] Clip- through cleavable bonds, enables one to define the off Chemistry benefits from the rich repertoire of molecules required precursor materials. As proof-of-concept, we and materials synthesised by traditional methods by using have validated our new approach by synthesising and these as precursors that, once conferred with cleavable sites, characterising four aldehyde-functionalised Rh(II)- can generate new molecules and materials upon selective based complexes: a homoleptic cluster; a cis-disubsti- bond cleavage. tuted paddlewheel cluster; a macrocycle; and a crown. In a first attempt to demonstrate the feasibility of Clip- off Chemistry, we have recently applied this concept using reticular materials as the starting precursors. We reasoned that reticular materials such as metal–organic frameworks Introduction (MOFs)[11] and metal-organic polyhedra (MOPs)[12,13] would be ideal candidates for the following three reasons. Firstly, New molecules and materials are and will be key for our they are all formed by periodic structures, such that their society, so that their design and synthesis will still be a constituent organic linkers are perfectly ordered.[14,15] Sec- ondly, they are porous, so reagents can diffuse throughout their structures to reach all cleavable sites.[16–18] Finally, [*] A. Broto-Ribas,+ S. Ruiz-Relaño,+ Dr. J. Albalad, Y. Yang, Dr. I. Imaz, Prof. Dr. D. Maspoch Reticular Chemistry dictates that for a given structure, the Catalan Institute of Nanoscience and Nanotechnology (ICN2), constituents can be chemically functionalised pre- and/or CSIC and The Barcelona Institute of Science and Technology post-synthetically, without any loss in structural Campus UAB, Bellaterra, 08193 Barcelona (Spain) connectivity.[19–21] This idea translates to the ability to encode and the organic linkers of an existing reticular material with Departament de Química, Facultat de Ciències, Universitat Autòn- synthetic information by inserting into them cleavable oma de Barcelona (UAB) Cerdanyola del Vallès, 08193 Barcelona (Spain) groups without altering the linkers’ shape or directionality, E-mail: jorge.albalad@icn2.cat to ultimately enable the synthesis of analogous cleavable inhar.imaz@icn2.cat isoreticular structures.[22] In our first report, we inserted daniel.maspoch@icn2.cat olefinic groups as cleavable bonds in MOFs/MOPs, and then Dr. F. Gándara selectively and quantitatively cleaved those bonds by Materials Science Institute of Madrid (ICMM), Consejo Superior de ozonolysis. Thus, we demonstrated Clip-off Chemistry by Investigaciones Científicas (CSIC) synthesising two topologically distinct 3D MOFs (each from Calle Sor Juana Inés de la Cruz, 3, 28049 Madrid (Spain) a distinct MOF precursor) and one metal-organic macro- Dr. J. Juanhuix cycle (from a single precursor MOP).[10] Alba Synchrotron Light Facility Herein, we advance on the development of Clip-off Cerdanyola del Vallès, 08290 Barcelona (Spain) Chemistry by introducing the concept of retrosynthetic Prof. Dr. D. Maspoch analysis. In Organic Chemistry, retrosynthesis is a crucial ICREA process that allows defining the reactants and the chemical Pg. Lluís Companys 23, 08010 Barcelona (Spain) reactions needed to form a desired product (Figure 1a).[23–25] [+] These authors contributed equally to this work. This process starts by virtually dissecting stepwise the © 2023 The Authors. Angewandte Chemie International Edition product into simple and easily-accessible synthons. Each published by Wiley-VCH GmbH. This is an open access article under synthon is later chemically translated to suitable reagent the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any precursors, essentially building backwards the series of medium, provided the original work is properly cited and is not used chemical reactions that will be followed to synthesise the for commercial purposes. product. However, in Clip-off Chemistry, we cannot apply Angew. Chem. Int. Ed. 2023, e202310354 (1 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie Figure 1. (a) Schematic example of the retrosynthetic analysis of bond formation steps in Organic Chemistry. A target bond is virtually dissected into molecular synthons, which later get chemically translated into logical reagent substrates. (b) Schematic of retrosynthetic analysis in Clip-off Chemistry, used here to obtain the product [Rh2(3FBA)4]. In it, the final product is virtually extended via cleavable bonds into a logical structure (discrete or periodic), which later is structurally translated into suitable reported lattices from several structural databases. If required, a final step consisting of isoreticular conversion of the reported linkers into an alkene-tagged analogue can be performed. this style of retrosynthetic analysis, as it is ultimately based analytical techniques and single-crystal X-ray diffraction on bond breaking rather than bond formation steps. In fact, (SCXRD). we should conceive it in an opposite way: retrosynthesis in Clip-off Chemistry should start by virtually connecting the target product through cleavable bonds into an initial Results and Discussion molecule or material, which will be used as the sacrificial precursor to synthesise our target product via bond breaking We began with the synthesis of a homoleptic Rh Rh reactions (Figure 1b). paddlewheel cluster, as the simplest test-case scenario. As As proof-of-concept, we employed our retrosynthetic ozonolysis enables transformation of an olefinic bond into approach to design and synthesise four novel, aldehyde- either an aldehyde (under reductive conditions) or a functionalised, Rh(II) metal-organic materials: a homoleptic carboxylic acid (under oxidative conditions),[26] we envisaged paddlewheel cluster; a cis-disubstituted paddlewheel cluster; this cluster to be built up with four 3-formylbenzoate a triangular macrocycle; and a crown-like architecture. In (3FBA) ligands under strict control of the reaction con- each case, we followed a three-step process: firstly, retro- ditions (Figure 1b). Thus, our initial target product was a synthetic conversion of the target product into a suitable Rh Rh paddlewheel cluster of formula [Rh2(3FBA)4], which reticular precursor that contains olefinic bonds as future is functionalised with four aldehyde groups located at the cleavage sites; secondly, synthesis of that precursor; and meta position of each phenyl ring. Once we had defined the finally, cleavage of the olefinic bonds (by ozonolysis). We product, we conducted the retrosynthetic analysis by the characterised all four products through a battery of conceptual assembly of this cluster through cleavable Angew. Chem. Int. Ed. 2023, e202310354 (2 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie olefinic bonds (Figure 1b, extended synthon) into a suitable reticular material. To facilitate identification of the desired reticular material, we searched the Cambridge Crystallographic Data Centre (CCDC) database (ConQuest v. 2022.3.0, CCDC, Cambridge, UK)[27] for structures that would contain such an extended synthon. To this end, we followed a stepwise search protocol that can be applied to retrosynthetic analysis of any metal-organic product in Clip-off Chemistry. In Step 1, one searches for structures containing the exact extended synthon (in our case, the synthon comprising a Rh(II) paddlewheel cluster extended via olefinic cleavable bonds). If that is unsuccessful, then one proceeds to Step 2: expanding the search to encompass analogous synthons made with any metal ion. Finally, if that also fails, the one can do Step 3: an even broader search, of structures containing a simplified synthon (in our case, a paddlewheel cluster of any metal, extended via any organic atom). Note here that Steps 2 and 3 involve the use of isoreticular chemistry to synthesise the suitable precursor material, converting the linkers of any successful search into alkene- based analogues, and/or substituting the identified metal ions with the desired ones. In our search for [Rh2(3FBA)4], steps 1 and 2 failed. However, in Step 3, we found five suitable structures (Figure 1b): one Cu(II)-based double- wall triangular macrocycle;[28] one Cu(II)-based octahedral MOP;[29] one Cu(II)-based square-like MOP;[30] several lantern-type MOPs made of different metal ions [including Rh(II)];[31] and one extended two-dimensional Cu(II)-based MOF.[32] Among these structures, we selected the lantern- Figure 2. (a) Schematic of the Clip-off synthesis of the homoleptic paddlewheel [Rh2(3FBA)4] cluster from [Rh2(L1C)2]2. Representations of type MOP as our candidate precursor, as it was both the [Rh2(L1C)2]2 (left) and [Rh2(3FBA)4] (right) corresponding to their X-ray simplest and the only one containing Rh(II) ions. This crystal structures. Axial capping agents (pyridine derivatives, solvents) inspired us to design a similar lantern-type MOP embedded and H atoms were omitted for clarity. (b) MALDI-ToF spectrum of with alkene bonds, by substituting the reported 3,3’- [Rh2(L1C)2]2. (c) ESI-MS spectrum of [Rh2(3FBA)4]. (d) Digested 1 phenylenebis(ethyne-2,1-diyil)dibenzoic acid linker with one H NMR spectra of [Rh2(3FBA)4] (red) and its molecular component, containing olefinic bonds, the (E)-3,3’-(1,3- 3FBA (blue). phenylenebis(ethene-2,1-diyl))dibenzoic acid linker (L1C; Figure 1b). The precursor lantern-type MOP of formula [Rh2(L1C)2]2 was obtained by solvothermal synthesis in N’N- analysis confirmed the formation of the product, with an dimethylacetamide (DMA) at 100 °C. The formation of this experimental molecular weight of [m/z] = 824.9 (simulated MOP was confirmed by MALDI-ToF spectrometry (exper- [m/z] for [Rh2(3FBA)4 + Na + ] + = 824.9, Figure 2c, Fig- imental [m/z] = 1884.9; simulated [m/z] for [Rh4(L1C)4 + H + ure S7). 1H NMR analysis of the digested precipitate showed ] + = 1886.2) and 1H NMR spectroscopy (Figures S5–S6, a quantitative loss of the starting L1C signals in [Rh2(L1C)2]2 ESI†). Crystallisation of the green powder by vapour (HC=CH δ � 7.4 ppm, Figure S11), as well as a proportional diffusion of diethyl ether into a DMA solution containing 4- formation of new signals perfectly matching those expected tert-butylpyridine yielded parallelepiped-shaped purple crys- for 3FBA (CHO δ = 10.2 ppm, Figure 2d). Concurrently, 1 tals from which SCXRD analysis revealed the expected H NMR analysis of the acidic supernatant from the lantern-type structure (Figure 2a, left). ozonolysis reaction revealed 1,3-benzenedicarboxaldehyde With the precursor in hand, we carried out the as the only side-product (Figure S11). ozonolysis in a DMA/DMSO (1:0.7 v/v) mixture under a Having demonstrated the feasibility of retrosynthetically flow of ozone (10.4 mmol/h) at 0 °C for 15 minutes in the designing reticular precursors by connecting the products presence of dimethyl sulphide (DMS, 0.3 mL) as reducing through cleavable bonds, we decided to extend our approach agent. The DMSO was required to protect the axial Rh(II) to the synthesis of a product that we expected to be more metal sites from ozone by coordination. The products were difficult to obtain using traditional synthetic methods. Thus, precipitated out and filtered off and crystallised from our second target was the cis-geometric isomer of the acetone/water by slow evaporation (see ESI for details). Rh Rh paddlewheel cluster coordinated by two 3FBA Encouragingly, SCXRD of the resulting crystals confirmed ligands and two 4FBA (where 4FBA is 4-formylbenzoate) the formation of the expected [Rh2(3FBA)4] cluster (Fig- ligands. This new cluster, of formula [Rh2(3FBA)2(4FBA)2], ure 2a, right), with a yield of 96 %. Mass spectrometric is functionalised with two aldehyde groups at the meta Angew. Chem. Int. Ed. 2023, e202310354 (3 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie position and two at the para position of the phenyl rings, as reasoned that if we could design suitable cleavable linkers shown in Figure 3a. Indeed, such a product is quite for each position (i.e. equatorial and axial), we would be challenging to obtain through bottom-up assembly, as it able to obtain our target product via Clip-off Chemistry. would likely produce a statistical combination of homoleptic After virtually extending the product, we decided to employ and mixed-linker Rh-paddlewheel clusters, whether mono-, the linkers (E)-3,3’-stilbenedicarboxylic acid (L2C) and (E)- di-, or tri-substituted.[33,34] Furthermore, trans clusters are far 4,4’-(1,3-phenylene-bis(ethene-2,1-diyl))dibenzoic acid (L3C) more common in the literature than cis clusters, further as the best candidates to generate the moieties 3FBA and increasing the complexity of obtaining our target product by 4FBA, respectively, through ozonolysis (Figure 3a). traditional methods.[35,36] Thus, we challenged our Clip-off We synthesised the MOP of formula [Rh2(L2C)(L3C)]6 Chemistry for the synthesis of this new cis-[Rh2(3FBA)2- through a solvothermal reaction of L2C, L3C and rhodium (4FBA)2] cluster in high yields and phase purity. Analysis of acetate. Unfortunately, our attempts to obtain single crystals the target product shows that the starting precursor must suitable for SCXRD were unsuccessful. Nonetheless, we contain at least two distinct cleavable linkers, with alkene were able to characterise the digested solid by 1H NMR groups in the meta positions and para positions, respectively, spectroscopy, which confirmed the formation of a single relative to the carboxylate sites. Additionally, both linkers entity comprising a 1 : 1 linker ratio (Figure S12). We must be connected to Rh Rh nodes in a cis conformation confirmed the formation of [Rh2(L2C)(L3C)]6 by MALDI- (Figure 3a). After searching for suitable candidates, we ToF spectrometry: the spectrum contained a broad peak found the perfect precursor in a family of heteroleptic centred at [m/z] = 5530.3, which agrees with the expected MOPs (Figure 3a).[37–39] These heteroleptic MOPs are built mass of [m/z] = 5524.6 for the targeted formula [Rh12(L2C)6- from two different linker groups, distributed regularly into (L3C)6 + H + ] + · 6 DMSO (Figure S13). Ozonolysis of [Rh2- axial and equatorial positions around 6 paddlewheel nodes. (L2C)(L3C)]6 in DMA/DMSO/DMS mixture (1:0.7:0.3 v/v/v) Closer analysis of their structure revealed that the linkers under the same conditions at 0 °C for 15 minutes resulted in are homogeneously distributed as two pairs of cis-distributed quantitative alkene bond cleavage, and [Rh2(3FBA)2- bridges in between clusters, thereby making them perfect (4FBA)2] was obtained in 92 % yield. Slow evaporation of a candidates for our cis-cluster synthesis. Therefore, we solution of the product in a mixture of MeCN/H2O (1 : 1 v/v) Figure 3. (a) Schematic representation of the retrosynthetic analysis conducted for the synthesis of the cis-disubstituted [Rh2(3FBA)2(4FBA)2] cluster via Clip-off Chemistry, from which the precursor [Rh2(L2C)(L3C)]6 was identified. (b) Single-crystal structure of [Rh2(3FBA)2(4FBA)2]. (c) Digested 1 H NMR spectra of [Rh2(3FBA)2(4FBA)2] (red) versus those of its molecular components: 3FBA and 4FBA (blue). (d) ESI-MS spectrum of [Rh2(3FBA)2(4FBA)2]. Angew. Chem. Int. Ed. 2023, e202310354 (4 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie afforded plate-shaped crystals suitable for SCXRD (Fig- ure 3b). Synchrotron diffraction data confirmed the integrity of Rh Rh paddlewheel clusters after ozonolysis, and the quantitative cleavage of both linkers into the expected product. SCXRD data revealed an experimental 50 : 50 occupancy distribution between the 3- and 4-substituted FBA ligands, corresponding to an overlay of an average of superimposed cis-clusters in different orientations (Fig- ure S14). NMR analysis of the digested product revealed a 1 : 1 ratio of 3FBA and 4FBA ligands (Figures 3c, S15). Likewise, ESI-MS analysis of the products showed a single entity with the expected molecular weight attributed to [Rh2(3FBA)2(4FBA)2] (experimental [m/z] = 836.9, simu- lated [m/z] for [[Rh2(3FBA)2(4FBA)2] + Cl ] = 836.9; Figur- es 3d, S16). Analysis of the acid supernatant used to precipitate the product did not reveal any residual traces of free rhodium ions, thereby confirming the inert character of the metal cluster upon ozone exposure (Table S5). Addi- tionally, 1H NMR analysis of the supernatant showed exclusively the presence of 1,3-diformylbenzene (side prod- uct expected from the reductive ozonolysis of L3C), thus ruling out any potential linker exchange/substitution around the Rh Rh node (Figure S19). Reflecting on the aforementioned heteroleptic MOP precursor, which contains two different linkers, we envi- sioned that in such MOPs, we could mix cleavable linkers with inert ones. We reasoned that this combination could follow either of two distinct routes. In the first one, the inert linker would occupy the equatorial positions, such that clipping of the precursor should generate a crown-shaped product (Figure 4a). In the second case, the axial sites would be resistant to ozone and therefore, clipping should generate a macrocyclic product (Figure 5a). In both cases, we restricted our search for the suitable precursors to those reported in this family of heteroleptic MOPs, from which we identified two previously reported MOPs: [Rh2(L2C)(NDC)]6 Figure 4. (a) Schematic of the Clip-off Chemistry synthesis of the (where NDC = 2,7-naphthalenedicarboxylic acid), to provide crown-shaped [Rh2(3FBA)2(NDC)]6 complex, using the [Rh2(L2C)(NDC)]6 the crown; and [Rh2(tBuBDC)(L2C)]6 (where tBuBDC = 5- MOP as precursor. Representations of [Rh2(L2C)(NDC)]6 (left) and tert-butylisophthalic acid), to give the macrocycle. [Rh2(3FBA)2(NDC)]6 (right) correspond to their X-ray crystal structures. We synthesised the first heteroleptic MOP precursor (b) Digested 1H NMR spectra of the [Rh2(L2C)(NDC)]6 precursor (dark with inert equatorial positions from a mixture of L2C and red) and the crown (red), versus those of their molecular components: NDC. SCXRD analysis and spectroscopic characterisation NDC (black) and 3FBA (blue). (c) MALDI-ToF spectra of the [Rh2(L2C)- (NDC)]6 precursor (dark red) and the synthesised crown (red). of the product confirmed the formation of the targeted heteroleptic cage of formula [Rh2(L2C)(NDC)]6, with six cleavable axial L2C linkers and six inert equatorial NDC moieties (Figure 4a, Figures S20–S21). [Rh2(L2C)(NDC)]6 protons at δ = 8.19 ppm, 7.92 ppm, 7.85 ppm and 7.52 ppm) was treated with ozone for 20 minutes under the standard by digestion 1H NMR (Figure 4b). Instead, the 1H NMR reductive conditions. The product was collected by filtration spectrum revealed the characteristic signals of NDC (phenyl after precipitation, washed with water, and obtained in 70 % protons at δ = 8.74 ppm and 8.08 ppm) and those of 3FBA yield after crystallisation via ether vapour diffusion to a (aldehyde proton at δ = 10.07 ppm; phenyl protons at δ = THF solution containing 4-tert-butylpyridine. The resultant 8.41 ppm, 8.21 ppm, 8.13 ppm and 7.73 ppm). Moreover, the crystals were characterised by SCXRD, using synchrotron integrated spectrum indicated an 3FBA/NDC acid-proton diffraction data that was collected at a maximum resolution ratio of 2 : 1, consistent with the formula expected for the of 1.3 Å, suggesting the synthesis of the [Rh2(3FBA)2- crown (Figure S22). The formation of the Rh(II)-based (NDC)]6 crown (Figure 4a). The formation and phase purity crown was unambiguously corroborated by MALDI-TOF of the targeted [Rh2(3FBA)2(NDC)]6 crown functionalised (Figure 4c), which showed the molecular weight increase with aldehyde groups was further confirmed by spectro- expected for a product of formula [Rh12(3FBA)12(NDC)6 + scopic analysis, revealing the lack of all the characteristic H + ] + (experimental [m/z] = 4300.2 expected [m/z] = 4306.8, peaks of L2C (olefinic protons at δ = 7.45 ppm; and aromatic Figure S23); in comparison to the [Rh2(L2C)(NDC)]6 precur- Angew. Chem. Int. Ed. 2023, e202310354 (5 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie nolysis at 0 °C for 30 minutes under reductive conditions, which cleaved the MOP structure into two identical halves, with a yield of 65 %. Indeed, although we could not solve its crystal structure, we confirmed formation of the expected metal-organic Rh-macrocycle by comparing 1H NMR spec- tra of the starting [Rh2(tBuBDC)(L2C)]6 with that of the ozonated product (Figure 5b). The 1H NMR spectrum lacked all the characteristic peaks of L2C (olefinic protons at δ = 7.45 ppm; and phenyl protons at δ = 8.18 ppm, 7.90 ppm, 7.84 ppm and 7.53 ppm). However, it revealed the character- istic signals of tBuBDC (phenyl protons at δ = 8.30 ppm and 8.16 ppm; and tert-butyl protons at δ = 1.31 ppm) and those of 3FBA with the expected 1 : 2 ratio (Figure S29). This integrated spectrum indicated the quantitative transforma- tion into a Rh-macrocycle. This was supported by MALDI- TOF analysis (Figure 5c) where the spectrum of the reaction product showed only the macrocycle [Rh6(3FBA)6- (tBuBDC)3 + H + ] + [m/z] = 2173.0 (simulated [m/z] = 2172.9, Figure S30) and nothing for the [Rh2(tBuBDC)(L2C)]6 start- ing material [M + H] + ([m/z] = 4651.5). Moreover, no shift in the low-energy UV/Vis absorption band I (λmax) at 592 nm was consistent with no change in Rh(II) coordination mode and there was no significant trace of Rh in the supernatant from ICP-OES analysis, confirming a clean and chemo- selective alkene cleavage (Table S5, Figure S33). Conclusion In summary, we have expanded our paradigm of Clip-off Chemistry to include a new step of retrosynthetic analysis. Unlike retrosynthesis in Organic Chemistry, which is based on the virtual dissection of bonds, retrosynthesis in Clip-off Chemistry entails virtually extending the product into a Figure 5. (a) Schematic of the Clip-off Chemistry synthesis of the logical periodic material through cleavable bonds. As proof- triangular [Rh2(tBuBDC)(3FBA)2]3 macrocycle, using the MOP [Rh2- of-concept, we employed our new retrosynthesis analysis in (tBuBDC)(L2C)]6 as precursor. The representation of [Rh2(tBuBDC)- the Clip-off synthesis of four unprecedented, aldehyde- (L2C)]6 (left) corresponds to its X-ray crystal structure, whereas those of functionalised Rh(II)-based structures: a homoleptic cluster; [Rh2(tBuBDC)(3FBA)2]3 (right) are graphic models. (b) Digested a cis-disubstituted cluster; a macrocycle; and a crown-like 1 H NMR spectra of the [Rh2(tBuBDC)(L2C)]6 precursor (dark red) and architecture. Specifically, we used retrosynthesis to define the macrocycle (red) versus those of their molecular components: tBuBDC (black) and 3FBA (blue). (c) MALDI-ToF spectra of the the Rh-based MOP precursors functionalised with cleavable [Rh2(tBuBDC)(L2C)]6 precursor (dark red) and the synthesised macro- alkene bonds that would be required for the subsequent cycle (red). Clip-off synthesis of each target in high yield. We exten- sively characterised all four products. Considering this new retrosynthetic approach, and the fact that bond-breaking sor (experimental [m/z] = 4116.7; expected for [Rh12(L2C)6- can be applied both selectively and quantitatively to (NDC)6 + H + ] + [m/z] = 4116.4). Finally, analysis of the precursors of different dimensionalities (from 3D to 0D), we supernatant (Table S5, Figure S26) did not reveal any anticipate that Clip-off Chemistry will complement existing rhodium ions or free 3FBA moieties, thus confirming the synthetic methodologies to ultimately inform the design and selectivity of the method. synthesis of new molecules and materials. In our final example, we synthesised a heteroleptic MOP precursor, the one exhibiting ozone-inert axial positions, using tBuBDC and L2C linkers. SCXRD analysis of the Acknowledgements product revealed a heteroleptic MOP cage of formula [Rh2(tBuBDC)(L2C)]6, composed of six paddlewheel Rh Rh We thank Alba Cortés for her help with MALDI-MS SBUs connected through six axial tBuBDC linkers and six measurements. This work has received funding from the equatorial L2C linkers poised for Clip-off Chemistry (Figur- European Union’s Horizon 2020 research and innovation es 5a, S27–28). Thus, a solution of [Rh2(tBuBDC)(L2C)]6 in program under grant agreement No 101019003; the Grant DMA/DMSO/DMS (1:0.7:0.3 v/v/v) was subjected to ozo- Ref. PID2021-124804NB-I00 funded by MCIN/AEI/ Angew. Chem. Int. Ed. 2023, e202310354 (6 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie 10.13039/501100011033/ and by “ERDF A way of making [18] A. J. Gosselin, C. A. Rowland, E. D. Bloch, Chem. Rev. 2020, Europe”; and the Catalan AGAUR (project 2017 SGR 238). 120, 8987–9014. It was also funded by the CERCA Programme/Generalitat [19] T.-Y. Luo, S. Park, T.-H. Chen, Prerna, R. Patel, X. Li, J. I. Siepmann, S. Caratzoulas, Z. Xia, M. Tsapatsis, Angew. Chem. de Catalunya. ICN2 is supported by the Severo Ochoa 2022, 134, e202209034. Centres of Excellence programme, Grant CEX2021-001214- [20] A. M. Bumstead, I. Pakamorė, K. D. Richards, M. F. Thorne, S, funded by MCIN/AEI/10.13039.501100011033. F.G. ac- S. S. Boyadjieva, C. Castillo-Blas, L. N. McHugh, A. F. Sapnik, knowledges funding from the Spanish Research Agency D. S. Keeble, D. A. Keen, R. C. Evans, R. S. Forgan, T. D. (PID2021-123287OB-I00). Y.Y. acknowledges the China Bennett, Chem. Mater. 2022, 34, 2187–2196. Scholarship Council for scholarship support. [21] J. Albalad, H. Xu, F. Gándara, M. Haouas, C. Martineau- Corcos, R. Mas-Ballesté, S. A. Barnett, J. Juanhuix, I. Imaz, D. Maspoch, J. Am. Chem. Soc. 2018, 140, 2028–2031. [22] V. Guillerm, H. Xu, J. Albalad, I. Imaz, D. Maspoch, J. Am. Conflict of Interest Chem. Soc. 2018, 140, 15022–15030. [23] E. J. Corey, Pure Appl. 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Version of record online: ■■■, ■■■■ Angew. Chem. Int. Ed. 2023, e202310354 (7 of 7) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202310354 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Angewandte Research Articles Chemie Research Articles Synthetic Coordination Chemistry In Clip-off Chemistry, a retrosynthetic analysis step based on virtual extension A. Broto-Ribas, S. Ruiz-Relaño, J. Albalad,* of the products through cleavable bonds Y. Yang, F. Gándara, J. Juanhuix, I. Imaz,* enables defining the required precursor D. Maspoch* e202310354 materials. As proof-of-concept, this new approach is used to synthesize four Retrosynthetic Analysis Applied to Clip-off aldehyde-functionalised Rh(II)-based Chemistry: Synthesis of Four Rh(II)-Based complexes: a homoleptic cluster; a cis- Complexes as Proof-of-Concept disubstituted paddlewheel cluster; a macrocycle; and a crown. Angew. Chem. Int. Ed. 2023, e202310354 © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH