Template‐Controlled Synthesis of Polyimidazolium Salts by Multiple [2+2] Cycloaddition Reactions

Abstract The tetrakisimidazolium salt H4‐2(Br)4, featuring a central benzene linker and 1,2,4,5‐(nBu‐imidazolium‐Ph‐CH=CH‐) substituents reacts with Ag2O in the presence of AgBF4 to yield the tetranuclear, oktakis‐NHC assembly [3](BF4)4. Cation [3]4+ features four pairs of olefins from the two tetrakis‐NHC ligands perfectly arranged for a subsequent [2+2] cycloaddition. Irradiation of [3](BF4)4 with a high pressure Hg lamp connects the two tetra‐NHC ligands through four cyclobutane linkers to give compound [4](BF4)4. Removal of the template metals yields the novel oktakisimidazolium salt H8‐5(BF4)8. The tetrakisimidazolium salt H4‐2(BF4)4 and the oktakisimidazolium salt H8‐5(BF4)8 have been used as multivalent anion receptors and their anion binding properties towards six different anions have been compared.


Introduction
Coordination-driven self-assembly is currently one of the most effective strategies for the rational construction of discrete supramolecular coordination complexes (SSCs). [1] This synthetic methodbenefits from the richchemistry provided by transition metals and from the extensive libraryo fo rganic ligands, which properly combined can produce two-and three-dimensional metallosupramolecular structures for advanced applications. In most supramolecularc ompounds,t he donor groups are restricted to those brought in by the original constituent ligands. However,t here are metallosupramolecular systemst hat are amenablet oc ovalent post-assembly modification( PAM) reactions, facilitating the modification of the ligandst hat determine the architectureo ft he metallosupramolecular assembly after it has formed. [2] PAMs trategies appliedt om etallosupramolecular assemblies offer new pathways for the generation of supramolecular architectures with tailoredf unctionalities. However,t his strategy is underexplored compared to the wide-spread use of post-synthetic modification methods that are currently known for the tailoring of metal-organic frameworks (MOFs). [2b, 3] The relative lack of attention to PAMm ethods for discrete metallosupramolecular structures is arguably due to the more fragile and dynamic nature of self-assembled coordination complexes, [2a] which hampers access to effective covalent bond formation within the assemblies. For aP AM reaction to be useful it must preserve the metallosupramolecular structure and should not interfere with the metal-ligandb onds. Recently,l igands featuring various N-heterocyclic carbene (NHC) donors have appeared as promisingl igandsf or the design of metallosupramolecular assemblies that can be utilized for PAM processes.D ue to the stabilityo ft he MÀC NHC bond,p oly-NHCderived metallosupramolecular architectures can be as stable or even more stable than supramolecular architectures derived from Werner-type ligands. [2b,c, 4] PAMm ethods appliedt os elected M-poly-NHC assemblies include oxidative CÀCc oupling reactions. [2c] In addition, photochemically induced [2+ +2] cycloaddition reactions using silver(I)o rg old(I) complexes bearing terminal N-olefin-substituted poly-NHCs have recently been developeda sa ne ffective PAMs trategy for the connection of poly-NHC ligands. [5] Thiss trategy enabled the synthesis of tetrakisimidazolium macrocycles [5d,e] from terminal olefin substituted bisimidazolium salts and of hexakis-, [5c] nonakis-and dodekakisimidazolium [5a] cages from C 3 -symmetric polyimidazolium precursors, respectively.T he preparation of these cagetype polyimidazolium salts is of particulari nterest, given that imidazolium salts are considered privilegeda nion receptors due to their strong affinity to anions through (CÀH) + ···X À interactions,w hich combineh ydrogen bonding with favourable electrostatic interactions. [6] Multivalent binding interactions between ah ost/receptor and ag uest requires that the receptor possessesm ore than one bindings ite connected through suitable spacers. [7] Multivalency is used by nature to achieve strong, yet reversible in-teractions and normally enhances binding at the molecular scale. As ar esult,t he design of multivalent scaffold architectures has enormous potentialf or the development of efficient receptors for various substrates. One of the advantages of synthetic multivalent receptors is that they possess as et number of defined bindings ites so that as eries of host-guest complex interactions may be examined in detail. [7d] In this contribution we describe the preparation of an ovel octakisimidazolium salt obtainedi natemplate-controlled synthesis starting from at etrakisimidazolium salt. This offered the unique opportunity to comparet he properties of the tetrakis-and octakisimidazolium salts as multivalent anion receptors.
Addition of NH 4 Cl to am ethanols olution of [4](BF 4 ) 4 generated ap recipitate of AgCl and the octakisimidazolium salt H 8 -5(Cl) 8 .A nion exchange with NH 4 BF 4 yieldedH 8 -5(BF 4 ) 8 in an overall yield of 76 %( Scheme 2). Salt H 8 -5(BF 4 ) 8 wasc haracterized by 1 Ha nd 13 C{ 1 H} NMRs pectroscopy and by mass spectrometry (see the Supporting Information). The resonances at d = 9.70 and at d = 134.7 ppm in the 1 Ha nd 13 C{ 1 H} NMR spectra, respectively,c onfirmed the demetallationa nd formation of the octakisimidazolium salt. The resonances for the imidazolium H2 and C2 atoms fall, as expected, in the range previously recorded for the related resonances in the tetrakisimidazolium salt H 4 -2(BF 4 ) 4 .T he resonances fort he cyclobutane protonsi n cation H 8 -5 8 + were detecteda st wo singlets at d = 5.10 and 5.19 ppm, only slightly shifted upfield from the equivalent resonances in [4](BF 4 ) 4 (d = 5.32 and 5.18 ppm). The ESI mass    The preparation of the polyimidazolium salts H 4 -2(BF 4 ) 4 and H 8 -5(BF 4 ) 8 offers ag ood opportunity to compare their capabilities as multivalent anion receptors. The recognitiona nd binding properties of the anions in the two salts were studied by 1 HNMR titration experiments monitoring selected proton signals of the receptors upon addition of the tetrabutylammonium salts of the investigated anions. All titrations studies were carried out in [D 6 ]DMSO. For the study we selected six anions of different geometry and charge density,namely chloride, bromide, nitrate, benzoate, adenosine triphosphate (ATP À )a nd 2-(4-isobutylphenyl)propionate (IBF À ). The last two anions were selected in an effort to demonstrate the relevance of the two polyazolium salts as receptors of anions with biological and medicali nterest (2- (4-isobutylphenyl)propionic acid is ibuprofen, H-IBF). Generally,a ddition of solutions containing the anions induceds ignificant perturbations in the 1 HNMR spectra of the polyimidazolium hosts.
As an illustrative example, Figure 4s hows the 1 HNMR spectra of H

) 8 upon titration with [NBu 4
+ ](IBF À ). The spectra illustrate how the resonance fort he eight equivalent acidic imidazolium protons (H2) is shiftedp rogressively downfield upon addition of increasing amountso fI BF À .T ogether with this, one of the resonances due to the remaining protons of the imidazolium ring (H5) is slightly downfield shifted, while the resonance fort he othero ne (H4) moves slightly upfield ( Figure 4). These observations strongly suggest that the interaction of the IBF À anion with H 8 -5 8 + mainly happensa tt he periphery of the host, with am aximum participation of the imidazolium rings via ah ydrogen bonding interaction of the acidic imidazoliump rotons with the anion.
The determination of the binding constants between the anions and H 8 -5 8 + was performed by globaln on-linear regres-sion analysis of the 1 HNMR titrationd ata. [12] For the titrations using H 4 -2(BF 4 ) 4 as the host, the stoichiometry of the host:guest complexes formed was best fitted to a1 :2 stoichiometry (two anionsb ound to the tetrakisimidazolium receptor). This assumption was based on the analysis of the binding isotherms resulting from the titrations of host H 4 -2(BF 4 ) 4 with all six anions. In all cases, the 1:2s toichiometry gave the best distribution of residuals, compared to a1 :1 stoichiometry. [12b] The 1:2s toichiometry was also supported by the Job plot analysis (see the Supporting Information for details). This observation indicates that the binding can be described as the hydrogen bondingi nteraction of each anion with two imidazolium moieties of the receptor.
For the experiments performed with H 8 -5(BF 4 ) 8 ,t he Job plot analyses suggested as toichiometry that could vary between 1:3o r1 :4 (the maximum c values assumed values between 0.20-0.25). We are perfectly aware that the Job plot analysis has serious limitations, particularly when referred to modelso f high stoichiometry, [13] but in this case and considering the results obtained for the titrations with H 4 -2(BF 4 ) 4 ,t he 1:4s toichiometry in which two arms of the receptor are bound to each anion seems to be the most plausible one.
For the determination of the binding constants, a1:2 stoichiometry model wasu sed for both the tetrakisimidazolium and the octakisimidazolium salts. The 1:4( or 1:3) modelsw ere not used fore valuatingt he titrations with H 8 -5(BF 4 ) 8 due to the limitations of the regression analysis used to process the data obtained from 1 HNMR titrations. For the determination of the constantsw ea lso considered two different variants of the 1:2 binding model,d epending on whethert he two stepwise binding constantsa re linked (thusa ssuming an on-cooperative binding mode, in which K 11 = 4K 12 ), or not (cooperative, K 11 ¼ 6 4K 12 ). [7a] This is an important point to consider,b ecause it determines how many parameters will need to be fitted during the regression fitting process, [14] and this can be used to assess the reliability of the result.
As can be seen from the data in Table 1, the binding constants obtained for the tetrakisimidazoliums alt H 4 -2(BF 4 ) 4 ,d id not differ much regardless of whether we used ac ooperative or non-cooperative binding model (entries 1-6). This allows us to assume that the bindingo ft he anions followedanon-cooperative binding model, and this wast he model that we used for the determination of the association constantsw hen the octakisimidazolium salt H 8 -5(BF 4 ) 8 was used (entries 7-12). The data reflect that the affinitiess hown for chloride are higher than that shown for bromide, in agreement with the larger basicity of the former one. Both receptors show larger affinities for carboxylates and ATP À .T he two carboxylate anions (benzoate and IBF À )e xhibited ar ather similar affinity and the binding constant shown for ATP À was the largest found for both receptors, therefore showingl arge selectivity for this anion.T he larger affinitieso bserved for phosphate anions when polyazolium receptors are used have been observed before. [15] It is importantt op oint out, that fora ll anions tested, we found that the affinities for the octakisimidazolium receptor H   8 were between 3-8 times larger than those obtained when H 4 -2(BF 4 ) 4 was used.

Conclusions
In summary,w eh ave demonstratedt he templates ynthesis of the novel octakisimidazolium salt H 8 -5(BF 4 ) 8 from two tetrakisi-midazolium buildingb locks H 4 -2(BF 4 ) 4 .T he intermediate octakis-NHCc omplex [4](BF 4 ) 4 with four cyclobutane linkersf eatures two non-planar central benzene groups. The tetrakisand the octakisimidazolium saltsw ere tested as multivalent receptors of six different anions, including two with relevant biological and medical significance (ATP À and IBF À ). From our study,w ec oncluded that the octakisimidazolium salt exhibited al arger binding affinity for all six anions tested. Given that we did not find reasonst oc onclude that the stepwise binding of the anionsf ollowed ac ooperative model, we believe that the enhancement of the binding affinity should be ascribed to the larger electrostatic attraction produced between the anionic guests and the octacationic octakisimidazolium receptor compared to the tetracationict etrakisimidazolium one. With our work we proved that the template-controlled preparation of polyimidazolium salts offersaunique opportunity to generate multivalent receptors with enhanced recognition abilities.

Experimental
Full details of synthesis and characterisation can be found in the Supporting Information.