Synthesis of a novel aminobenzene-containing hemicucurbituril and its fluorescence spectral properties with ions

A novel hemicucurbituril-based macrocycle, alternately consisting of amidobenzene and 2-imidazolidione moieties was designed and synthesized. Based on the fragment coupling strategy, nitrobenzene-containing hemicucurbituril was firstly prepared facilely under alkaline environment, and reduction of the nitro groups produced the desired amidobenzene-containing hemicucurbituril. As an original fluorescent chemosensor, it exhibited strong interactions with Fe3+ over other metal cations. The experimental evidence of fluorescence spectra suggested that a 1:1 complex was formed between this macrocycle and Fe3+ with an association constant up to (2.1 ± 0.3) × 104 M−1. Meanwhile, this macrocycle showed no obvious or only slight enhancement of the fluorescence intensity with selected anions.

Although cucurbiturils with their rigid hydrophobic cavities have found broad application in host-guest chemistry, they suffer from insolubility, difficulty in derivatization, and lack of Scheme 1: The evolution of hemicucurbituril analogs.

chromophores. Hemicucurbit[n]urils (HQ[n]
) and relevant derivatives [24] represent as a sub-group of the cucurbituril family [25], possessing much more flexible structures than Q[n]s, and are generally characterized by an electroneutral cavity and a negative electro-potential portal. Comparing the coordination properties of HQ[n]s with that of Q[n]s, Buschmann [26] observed that HQ [6] 2 (Scheme 1) formed complexes only with Ni 2+ , Co 2+ , and UO 2 2+ with extremely low affinity, which may be caused by the poor solubility of HQ [6] 2 in aqueous solution and its universal "alternate" conformation. Most modified hemicucurbiturils 3 (Scheme 1) have been template synthesized [27] in succession by modified imidazolidiones, including bambusurils [28][29][30], cyclohexylhemicucurbiturils [31], and semithiobambusurils [32]. On the other hand, in previous works, authors discussed the ability of the derivatives for accommodating ions at submicromolar concentrations always by means of NMR spectroscopy [33]. Nevertheless, sensing by UV-vis or fluorescence spectra was hard to realize, for there is no chromophore in the frameworks. While hemicucurbit[n]urils with improvement in solubility, they still remain poor in derivatization. These adverse properties have impeded the development of hemicucurbit[n]urils to some extent.
Herein, we wish to report our endeavor in the facile synthesis of a new hemicucurbituril homologue, aminobenzene-containing hemicucurbituril 4 (Scheme 1). It was assumed that the amino groups could act as reactive sites for derivatization, at the same time allowing for formation of coordination or hydrogen bonds with guests, and the aminobenzene unit as a chromophore could improve the optical properties. With this novel macrocycle in hand, the interactions with some metal cations have been initially studied. Among the metal cations examined, the fluorescence intensity of macrocycle 4 quenched significantly when adding the corresponding equivalents of Fe 3+ and Cu 2+ . Notably, this macrocyclic host molecule formed 1:1 complexes with Fe 3+ in DMF with an association constant up to (2.1 ± 0.3) × 10 4 M −1 , which was contrary to those of hemicucurbiturils. As observed by fluorescence titration experi-

Results and Discussion
Because of the relatively strong nucleophilicity of the amino group in aniline, the synthesis could become complicated when aminobenzene is directly used as the starting substrate. Thus, the study was commenced with the synthesis of the nitrobenzene-containing hemicucurbituril 9 based on a fragment coupling strategy (Scheme 2). For this purpose, 1,3-bis(bromomethyl)-5-nitrobenzene, which was easily obtained by reduction of 5-nitroisophthalic acid with NaBH 4 and BF 3 ·Et 2 O followed by subsequent bromination with PBr 3 [46] and 2-imidazolidinone (6) were used as building blocks. By controlling the molar ratio of 5 and 6 at 1:10 or 6:1 and the reaction conditions, products 7 and 8 were readily accessible with 25.3% yield and 30.0% yield based on starting compounds 5 and 6, respectively (Scheme 2). With the trimers 7 and 8 in hand, the reaction conditions for the [3 + 3] macrocyclic condensation were examined.
Due to the low solubility of compound 7, the subsequent reactions were conducted in DMF. With two equivalents of Cs 2 CO 3 as the base and with or without an additive (Table 1, entries 1-4), no desired product was isolated. When the base was changed to NaH, to our delight, the macrocycle 9 was obtained even without any additive with 26.0% yield (Table 1, entry 5).
As is known that the template plays an important role in the cyclization, some additives were examined in combination with NaH as the base for improving the yield (Table 1, entries 6-9). For the synthesis of hemicucurbituril derivatives in a previous study, halide ions usually facilitated the cyclization [27]. However, halide ions had no effect on the current process ( Macrocycle 9 was obtained as a yellowish solid and dissolving it in a mixture of dichloromethane and methanol, a yellowish crystal was obtained by gradually evaporating the solvent, which was suitable for X-ray diffraction analysis. As shown in Figure 1, the nitrobenzene-containing hemicucurbituril 9 adopted a square-cavity conformation. Notably, three nitrobenzene units shared nearly a plane. It should be highlighted that macrocycle 9 gave concise proton and carbon signals in the 1 H and 13 C NMR spectra, respectively. As displayed in Figure S6 (Supporting Information File 1), only two sets of proton peaks and four sets of carbon peaks corresponding to aromatic portions of the aforementioned macrocycle, in addition to two sets of proton peaks corresponding to bridged methylene and methylene of imidazolidinone components were observed at rt. This indicated that the formed macrocycle is highly symmetric in solution.
After successful construction of macrocycle 9, the aminobenzene-containing hemicucurbituril 4 was obtained by reduction of the nitro groups in 9 with Fe powder in H 2 O/EtOH at 86 °C for 2 h with 40.1% yield (Scheme 2). Similar to the macrocyle 9, the NMR spectra of aminobenzene-containing hemicucurbituril 4 ( Figure S7, Supporting Information File 1) revealed that the compound is also highly symmetric. It is worth mentioning, that the macrocycle 4 is the first example of an aminobenzenecontaining hemicucurbituril analog.   With the novel macrocycle 4 in hand, initial experiments were conducted to explore its properties on recognizing metal cations. The fluorescence titration of macrocycle 4 with a series of selected cations (Figure 2), including Ag + , Na + , NH 4 + , Cu 2+ , Co 2+ , Cr 3+ , Fe 3+ , Ni 2+ , and Mn 2+ (nitrate salts were used as cation sources) in DMF resulted in different degrees of quenching of the fluorescence emission of host 4. The results are collected in Figure 3 as the corresponding fluorescence quenching efficiency which was quantified using the equation where I is the fluorescence intensity response of the aminobenzene-containing hemicucurbituril 4 in the ammonium salts were used as anion source) were also tested tentatively by fluorescence titration ( Figure 5). The overwhelming majority of aromatic molecules follow the heavyatom effect rule [48]. However, it was surprisingly found that the coordination of selected anions, such as halide ions, especially the heavier iodide ion, to the macrocyclic sensor, slightly enhanced the fluorescence emission in CH 2 Cl 2 /CH 3 OH 4:1 (v/v) at 298 K, instead of quenching the fluorescence as predicted by the classic heavy-atom effect. The corresponding fluorescence enhancement efficiency of selected anions is collected in Figure 6.

Conclusion
In summary, we have presented a novel type of hemicucurbituril derivative modified with aminobenzene. Based on the fragment coupling strategy, the nitrobenzene-containing hemicucurbituril 9 was synthesized by nucleophilic substitution reaction with two fragments 7 and 8. The desired aminobenzene-containing hemicucurbituril 4 was achieved by reduction of the corresponding nitrobenzene-containing hemicucurbituril 9. In the initial host-guest study, this novel macroycle 4 exhibited strong interaction with Fe 3+ and formed a 1:1 complex with the association constant of K a = (2.1 ± 0.3) × 10 4 M −1 . In another perspective, the presence of the coordination of selected anions to the macrocyclic sensor enhanced the fluorescence emission in various degree, extremely contrary to the classic heavy-atom effect caused by a heavy atom. In general, this macrocyclic sensor showed high fluorescence quenching efficiency toward Fe 3+ and Cu 2+ over other cations and generally low fluorescence enhanced efficiency with selected anions.
Overall, the fluorescence response properties of aminobenzenecontaining hemicucurbituril and its readily modifiable nature, provide a convenient platform for the exploration on host-guest interaction and supramolecular systems. Its applications and modifications are being pursued in our laboratory, and the results will be reported in due course.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data and copies of spectra.