# A Ditopic Calix[6]arene Ligand with N-Methyl-Imidazole and 1,2,3-Triazole Substituents: Synthesis and Coordination with Zn(II) Cations.

Benoit Colasson§, Marion Save§, Petr Milko,¶ Jana Roihová,¶‡ Detlef Schröder,¶ and Olivia Reinaud§*

Olivia.Reinaud@univ-paris5.fr

Received Date (will be automatically inserted after manuscript is accepted)

## ABSTRACT

<figure><img src="image_1.png" /></figure>

The first member of a new class of ditopic calix[6]arene has been synthesized, which is decorated with three N-methyl-imidazoles at the small rim and three 1,4-disubstituted-1,2,3-triazoles at the large rim. The coordination of a first Zn(II) cation selectively takes place at the small rim. Addition of a second equivalent results in the complexation of the three triazoles, providing a rare example of 1,2,3-triazole ligands embedded within a supramolecular system.

The versatility of calixarenes has been extensively used as their scaffolds present an hydrophobic aromatic core

which can be functionalized easily.¹ In the past few years, we have reported a series of calix[6]arenes with appended

<footnote>§ Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR CNRS 8601, Université Paris Descartes, 45 rue des Saints Pères, 75006 Paris, France.</footnote>

<footnote>¶ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Prague 6 (Czech Republic)</footnote>

<footnote>‡ Department of Organic Chemistry, Charles University in Prague, Faculty of Science, Hlavova 8, 12843 Prague 2 (Czech Republic)</footnote>
ligands on the small rim offering a biomimetic N₃ environment for a metal cation.² Incorporation of the metal center rigidifies the cavity of the calixarene and offers a labile coordination site pointing towards the inside of the cavity enabling host-guest recognition studies. We were interested in implementing novel functionalities onto the large rim which could be used either as new recognition sites or which could create a second coordination domain. The presence of the phenolic units on the small rim offers simple methods to functionalize this part of the calixarene. On the contrary, selective functionalization of the large rim remains challenging. Among the few reactions, ipso-nitration and ipso-sulfonylation have proven to be very useful.³ Ipso-nitration gives access to calixarene 2 on a large scale, making 2 a good precursor to explore new methods to decorate the large rim. We focused on the blooming CuI-catalyzed azide-alkyne cycloaddition (CuAAC)⁴ for two reasons: a) from the same calixarene building block 3, we

can rely on the high efficiency of the CuAAC to confer many different properties to the calixarenes; b) the presence of the 1,2,3-triazoles on the large rim can offer a second coordination site, allowing the synthesis of bimetallic complexes.⁵ The coordination chemistry of 1,4-disubstituted-1,2,3-triazoles has not yet been explored. To the best of our knowledge, only three recent papers deal with the use of triazole as a ligand.⁶ Few other papers report their use for catalysis without emphasis on the nature of the complexes involved.⁷ Here, we report the synthesis of a novel calixarene tris-imidazole ligand functionalized at the large rim with three triazole units. The coordination properties of this calixarene are described. Two binding sites have been shown to selectively interact with metal ions, thus giving a unique example of triazole ligands incorporated in a supramolecular system capable of host-guest recognition.

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Synthesis of the triazole calixarene 4, the monometallic zinc complex 5 and the bimetallic zinc complex 6.</figcaption></figure>

S is either a solvent molecule (CH₃CN) or water depending on the experimental conditions. Bottom left: tetracation region of the ESI mass spectrum of a diluted solution of [6⁴⁺,4CF₃SO₃⁻] in MeCN showing the isotope patterns for the tetracation [6(CH₃CN)]⁴⁺.

**Synthesis of triazole calixarene 4.** Calixarene 2 can be obtained on a gram scale. In order to generate calixarene 3 (Scheme 1), 2 was subjected to diazotation followed by nucleophilic substitution with sodium azide.⁸ After workup, calixarene 3 bearing three azido groups was obtained in quantitative yield. 3 was then reacted with tBu-4-(prop-2-ynyloxy)benzene⁹ under standard conditions for CuCAAC. 0.6 equivalent of the copper catalyst precursor were required for complete conversion. The ability of the three imidazole arms to coordinate either Cu(II) or Cu(I) and to form rather stable complexes may be the reason why the catalyst loading had to be increased. Calixarene 4 was obtained in 75% yield after

flash chromatography. The ¹H NMR spectrum of calixarene 4 in CD₃CN at 300K showed broad resonances due to slow conformational motions of the calixarene core on the NMR timescale. When the temperature was raised to 343K, sharp peaks were observed and indicated a C₃v symmetry (Figure S1).

**Coordination properties of calixarene 4.** The coordination of Zn(II) to calixarenes with the small rim functionalized with three N-methyl imidazoles is well-described.² The Zn(II) center has a tetrahedral geometry with a fourth neutral exogeneous ligand encapsulated inside the cavity. This feature leads to the possibility of performing various host-guest studies with the ditopic
system based on **4**. Therefore, we decided to use the diamagnetic Zn(II) cation in order to investigate the coordinating properties of calixarene **4** and especially the influence of the triazoles.

A UV-vis titration of a solution of calixarene **4** in CH<sub>3</sub>CN with Zn(ClO<sub>4</sub>)<sub>2</sub> was carried out (Figure 1). During the addition of the first equivalent of Zn(II), an isobestic point at 260 nm was observed. Upon addition of a second equivalent of Zn(II), the isobestic point disappeared concomitantly with a collapse of the band centered at 265 nm. Further additions of Zn(II) did not modify the spectrum. The profile of the absorbance at 250 nm vs. equiv Zn(II) clearly indicates two distinct binding events with high K<sub>a</sub> values (K<sub>a1</sub> > K<sub>a2</sub> = 3 x 10<sup>5</sup>, see the Supporting Information).

<figure><img src="image_3.png" /><figcaption>**Figure 1.** UV-vis titration of calixarene **4** (3.10<sup>-5</sup> M in CH<sub>3</sub>CN containing 10 mM Bu<sub>4</sub>NClO<sub>4</sub>, T = 293 K) with Zn(OH)<sub>2</sub><sub>6</sub>(ClO<sub>4</sub>)<sub>2</sub>.</figcaption></figure>

In order to identify the coordination sequence of two Zn(II) cations by calixarene **4**, the titration was monitored by ¹H NMR in CD<sub>3</sub>CN (Figures 2 and S2). Upon titration with the first equivalent of Zn(II), the formation of a single new species was observed. The spectrum shows sharp resonances due to the rigidification of the calixarene core upon complexation. The resonances corresponding to the protons on the imidazoles are split into two peaks and the δ shift of the OMe groups (3.64 ppm) shows that they point away from the cavity. These observations account for the formation of a monometallic zinc complex, **5**, with the zinc cation being coordinated to the imidazoles and to a solvent molecule (MeCN) that is included in the calixarene cavity, as in the parent system based on calixarene **1** (Scheme 1).² The second equivalent of Zn(II) led to the formation of compound **6**. The resonance of the triazole protons underwent downfield shift (Δδ = 0.46 ppm), whereas the imidazole signals remained unaffected.

This is fully consistent with coordination of the second metal center to the triazole units. While the first Zn(II) cation spatially preorganizes the three triazoles through a conformational freeze, the coordination of the second Zn(II) forces them to move further towards the C<sub>3</sub> axis of the macrocycle as shown by the upfield shift of their aromatic protons (Δδ = -0.20 ppm).

<figure><img src="image_4.png" /><figcaption>**Figure 2.** ¹H NMR (CD<sub>3</sub>CN, 300 K) of the titration of calixarene **4** with Zn(OH)<sub>2</sub><sub>6</sub>(ClO<sub>4</sub>)<sub>2</sub>. From bottom to top: before and after addition of 1, 2.25 and 4 equiv of Zn(II). ■ H<sub>triazole</sub>, ○ H<sub>Im</sub>, ▲ H<sub>ArrBu</sub>, ● H<sub>ph</sub>, ◊ H<sub>Artria</sub>, ▼ OCH<sub>2</sub> and CH<sub>2Im</sub>, □ CH<sub>2</sub>Ar, ■ OCH<sub>3</sub> and NCH<sub>3</sub>, ⊕ tBu</figcaption></figure>

Mono- and bimetallic complexes **5** and **6** were isolated by reaction of **4** with one and two equivalents of Zn(OTf)<sub>2</sub>, respectively. Elemental analyses account for two and four triflate counteranions, respectively, with water to complete the coordination sphere of the metals. Synthesis of **6** was also achieved with Zn(H<sub>2</sub>O)<sub>6</sub>(ClO<sub>4</sub>)<sub>2</sub>. In pure CD<sub>3</sub>CN, the ¹H NMR spectra of the two complexes were identical to those recorded in the course of the titration at 1 and 2 equiv of Zn(II). In a non-coordinating solvent such as CDCl<sub>3</sub>, the spectra of **5** and **6** showed broad peaks, whereas new upfield shifted resonance in each case was observed, at -0.20 ppm for **5** and 0.44 ppm for **6**. These observations indicate that the bimetallic complex, as with the monometallic complex, hosts an exchangeable nitrile guest in the calixarene cavity (this was confirmed by saturation transfer experiments). According to Dreiding models, coordination of the second metal ion to all three central nitrogen atoms N2 of the triazoles is hardly feasible, whereas coordination to the N3 atoms does not appear to induce any major steric distortion for either a 4- or a 5-coordinate Zn centers orienting its labile sites towards the microcavity provided by the triazole R substituents. Solvent molecules, and possibly one counter anion, are
most probably completing the coordination sphere of this
second Zn(II) center. These qualitative conclusions from
the NMR data are fully supported by electrospray
ionization (ESI) mass spectra of 6 dissolved in MeCN,
which show three major signals, all with the expected
isotope patterns: the dication 5 with MeCN bound, a
trication signal containing two Zn(II) cations, one triflate
counterion and one MeCN, i.e. [6(CH<sub>3</sub>CN)(CF<sub>3</sub>SO<sub>3</sub>)]<sup>4+</sup>,
and finally a clear signal due to the acetonitrile complex
of the free tetracation [6(CH<sub>3</sub>CN)]<sup>4+</sup> (see inset in Scheme
1). We further note that gaseous [6(CH<sub>3</sub>CN)]<sup>4+</sup> is one of
the few examples of highly multiply charged transition-
metal cations observed so far.<sup>10</sup>

<figure><img src="image_5.png" /><figcaption>**Figure 3.** High-field region of the ¹H NMR spectrum of 5 with encapsulated heptylamine (500 MHz, CDCl₃, 300 K) and plot of the Δδ shifts [Δδ = δ(free) - δ(encapsulated)] for the guest's protons as a function of their position relative to the nitrogen for the zinc(II) complex of calixarene 1 and calixarene 4.</figcaption></figure>

**Mapping the cavity.** Primary amines are good guests for calix[6]arene-based Zn(II) complexes.²ª When one equivalent of heptylamine was added to 5, a set of well-resolved peaks appeared in the high field region of the spectrum (Figure 3), accounting for its encapsulation in the calixarene cavity. Comparison of the shielding effect of the cavity between the mono zinc complex of calixarenes 4 and 1 clearly indicates that the functionalization of the large rim with substituted triazoles extends the cavity. Indeed, for positions 4 to 7 in the alkyl chain, the shielding effects for 5 are 0.5 to 1 ppm higher than for the Zn(II) complex of 1. In contrast, binding a second Zn²⁺ at the triazole site shortens the cavity. Indeed, whereas the addition of MeCN and EtOH into a CDCl₃ solution of the bimetallic complex led to their encapsulation into the calixarene core, their higher homologues (EtCN and PrOH) appeared to be too long and increasing their stoichiometry (vs. 6) only led to the decoordination of the triazole-Zn associated to their encapsulation in 5.

In conclusion, we have synthesized a new triazole
calixarene using the CuCAAC methodology. This
synthetic pathway opens the possibility of extending the

calixarene cavity and of implementing other functional
groups with fluorescent, redox or hydrophilic properties.
The presence of the three triazole ligands enables the
formation of a bimetallic Zn(II) complex that, despite the
closure of the cavity, can accommodate an exchangeable
nitrile guest. Complex 6 differs from the previously
reported calix[6]arene-based bimetallic complex, where a
H3O2- unit occupies the cavity and bridges the Zn(II)
centers. 5 In the present system, the second metal ion
orients its labile site in the opposite direction, being easily
accessible to exogenous binding, although protected by
the microenvironment defined by the triazole substituents.
Hence, whereas the mononuclear complex offers an
extended and tunable cavity for host-guest recognition,
the dinuclear complexes provide a novel platform for
studying biomimetic catalysis.

**Acknowledgment.** This research was supported by CNRS and Agence National pour la Recherche (Calixzyme Project ANR-05-BLAN-0003) and by the Grant Agency of the Academy of Sciences of the Czech Republic (KJB400550704).

**Supporting Information Available.** Experimental procedures, spectral data for compounds **3-6**. This material is available free of charge via the Internet at http://pubs.acs.org.

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