Synthesis and Structure of Macrocyclic Tetraimidazolium Salt Containing Propylene and m-Phenylene Linkers

Abstract

Macrocyclic tetraimidazolium salts 2 and 3 containing propylene and m-phenylene linkers were synthesized from diimidazole derivative 1 and 1,3-diiodopropane. The molecular structure of 3 was determined by single-crystal X-ray diffraction analysis, revealing an almost planar macrocyclic framework. DFT calculations identified three low-energy conformers of the tetracation in 3, suggesting conformational flexibility in solution.

1. Introduction

Macrocyclic polydentate ligands have been widely employed in the construction of multimetallic complexes, in which the macrocyclic framework fixes the metal centers and defines their intermetallic distances [1,2]. Macrocyclic tetraimidazolium compounds have been studied as macrocyclic N-heterocyclic carbene (NHC) ligands for multimetallic complexes and as receptors for anion recognition [3]. Murphy and Spicer reported the synthesis of the macrocyclic tetraimidazolium salt a, containing propylene linkers together with the corresponding dinuclear Ag and Cu complexes (Scheme 1) [4]. Subsequently, a variety of tetraimidazolium salts (b–g) have been reported as versatile precursors for the preparation of Ni, Cu, Ag, Au, and Ir complexes [5,6,7,8,9,10,11,12,13,14,15]. The length and flexibility of the linker connecting the imidazolium units, together with the nature of additional donor sites incorporated into the macrocyclic framework, play important roles in determining the structures and properties of the resulting multinuclear complexes. More recently, we reported a macrocyclic tetraimidazolium salt h containing a rigid m-phenylene carbon donor and flexible butylene linkers as a precursor to Rh complexes, bearing a CCC pincer coordination motif [16]. In our previous study, the conformational flexibility of the butylene linkers led to the formation of multiple conformational isomers. These findings prompted us to investigate the effect of replacing the butylene linker with a shorter propylene linker on the structure and conformational properties of the corresponding macrocyclic tetraimidazolium salt.

2. Results and Discussion

Macrocyclic tetraimidazolium salts are generally synthesized by the reaction of a diimidazole derivative with a dihaloalkane under high-dilution conditions. Accordingly, a MeCN solution (0.005 M) of 1,3-di(imidazol-1-yl)-4,6-dimethylbenzene (1) and 1,3-diiodopropane was refluxed for 7 days (Scheme 2). The ¹H NMR spectrum of the crude product showed several signals in the region of δ 9.55–9.80 ppm, attributable to imidazolium C2–H protons, including the signal of 2 at δ 9.62 ppm (Figures S1 and S5 in the Supporting Information). While the side products could not be identified, this observation suggested the formation of a mixture of imidazolium-containing species, possibly including oligomeric and macrocyclic products [5,11,17]. Although crystallization is commonly employed to isolate macrocyclic tetraimidazolium salts from such reaction mixtures, suitable crystallization conditions for the isolation of 2 could not be identified. On the other hand, the desired macrocycle 2 could be isolated by column chromatography on Al₂O₃ using an MeCN/H₂O mixture as the eluent, giving 2 in 22% yield.

Because suitable single crystals of 2 for X-ray diffraction analysis could not be obtained, the corresponding PF₆⁻ salt 3 was prepared by anion exchange. Treatment of 2 with KPF₆ in water afforded the PF₆⁻ salt 3 as a water-insoluble solid in 94% yield.

The ¹H NMR spectrum of 3 exhibited signals attributable to the imidazolium rings at δ 9.27 (4H), 8.22 (4H), and 8.12 (4H) ppm and to the benzene ring at δ 7.73 (4H) ppm arising from two overlapping aromatic protons. Signals arising from the propylene linkers were observed at δ 4.43 and 2.55 ppm with an integral ratio of 8H:4H. The ¹³C NMR spectrum of 3 displayed signals for imidazolium carbons at δ 137.2, 123.8, and 123.4 ppm and, for the benzene carbons, at δ 136.2, 135.0, 132.3, and 124.7 ppm. Signals for propylene linker carbons were observed at δ 46.4 and 30.8 ppm. These spectral features are consistent with a macrocyclic tetraimidazolium structure in solution.

The molecular structure of 3 was confirmed by single-crystal X-ray diffraction analysis using colorless single crystals obtained by the slow diffusion of diethyl ether into an MeCN solution (Figure 1a). The two m-phenylene units are arranged nearly parallel, resulting in an almost planar molecular geometry with pseudo-C_2h symmetry. The two imidazolium rings attached to each m-phenylene unit are oriented on opposite sides of the corresponding m-phenylene planes, with dihedral angles of 47.7(3) and 52.9(3)°, respectively. The cavity dimensions were evaluated using a space-filling model, which revealed a nearly square cavity of 3.8 × 3.6 Å (Figure 1b). Despite the shorter propylene linkers, the cavity is comparable in size to that of the previously reported macrocyclic imidazolium salt h [16], which contains butylene linkers (3.7 × 3.4 Å).

To investigate the conformational flexibility of the macrocyclic tetraimidazolium framework, DFT calculations were performed at the PBE0-D3/def2-TZVP//PBE0-D3/def2-SVP level of theory with the SMD solvation model for DMSO. The syn/anti conformer corresponds to the molecular geometry observed in the crystal structure, whereas the syn/syn and anti/syn conformers represent alternative conformations (Figure 2). The three conformers are distinguished by the relative orientations of the imidazolium units within and between the linkers connecting the m-phenylene units. The calculated Gibbs free energies of the three conformers differ by less than 0.20 kcal mol⁻¹. The cavity dimensions were evaluated using space-filling models. The syn/anti and syn/syn conformers possess nearly square cavities with dimensions of approximately 3.5 × 3.3 Å and 3.5 × 3.3 Å, respectively, whereas the anti/syn conformer exhibits a markedly elongated cavity of 4.6 × 2.4 Å. These results indicate that the macrocyclic tetraimidazolium framework is conformationally flexible, and the small Gibbs free energy differences between the conformers suggest that multiple conformations coexist in solution.

3. Materials and Methods

3.1. General Instrumentation

1,3-di(imidazol-1-yl)-4,6-dimethylbenzene (1) was prepared according to the literature methods [18]. ¹H and ¹³C NMR spectra were recorded on a JEOL ECA (400 MHz for ¹H and 100 MHz for ¹³C) spectrometer (JEOL Ltd., Tokyo, Japan). Chemical shifts were reported in δ (ppm) relative to the residual signals at δ_H 2.50 and δ_C 39.52 ppm for DMSO-d₆. Elemental analyses were recorded on a Perkin Elmer 2400II (PerkinElmer Inc., Norwalk, CT, USA). X-ray diffraction data were collected on a Rigaku XtaLAB Synergy R diffractometer (Rigaku Co., Tokyo, Japan). The structure of 3 was solved using SHELXT-2018/2 and refined by full-matrix least-squares on F² using SHELXL-2018/3 [19,20]. The crystallographic calculations were performed using the Yadokari-XG software package (Revision 983) [21]. ORTEP drawings were prepared using ORTEP-3 for Windows (Ver. 2020.1) [22]. Disorder was observed for the F atoms of the PF₆ anions, and the site occupancies of the disordered components were refined to 0.92/0.08 and 0.86/0.14, respectively. DFIX restraints were applied to selected P–F bond lengths of the disordered PF₆ anions. The F atoms of the minor components were refined isotropically. CCDC 2576310 contains crystallographic data for 3. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures, accessed on 27 July 2026.

3.2. Synthesis of 2

A solution of 1,3-diiodopropane (2.181 g, 7.34 mmol) and 1,3-di(imidazol-1-yl)-4,6-dimethylbenzene (1.674 g, 7.02 mmol) in acetonitrile (1400 mL) was heated under reflux for 7 days. After removal of the solvent, the residue was washed with acetone, acetonitrile, and methanol. The resulting material was purified by column chromatography on basic alumina with acetonitrile/H₂O (10:1) as an eluent to give a colorless solid of 2 (841 mg, 0.787 mmol, 22%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 4H), 8.64 (s, 2H), 8.24 (s, 4H), 8.14 (s, 4H), 7.70 (s, 2H), 4.44 (t, J = 7.2 Hz, 8H), 2.72 (septet, J = 7.0 Hz, 4H), 2.38 (s, 12H). ¹³C NMR (100 MHz, DMSO-d₆) δ 137.7, 135.6, 134.8, 132.2, 125.2, 123.5, 123.2, 46.4, 30.2, 17.0. Anal. Calcd for C₃₄H₄₀I₄N₈∙H₂O: C, 37.59; H, 3.90; N, 10.31. Found: C, 37.44; H, 3.47; N, 10.17.

3.3. Synthesis of 3

To a solution of 2 (558 mg, 0.522 mmol) in H₂O (40 mL), KPF₆ (755 mg, 4.10 mmol) was added. After being stirred at room temperature for 19 h, the resulting precipitate was filtered. The crude product was washed with H₂O to give a colorless solid of 3 (561 mg, 0.492 mmol, 94% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 4H), 8.22 (s, 4H), 8.12 (s, 4H), 7.73 (s, 4H), 4.43 (t, J = 6.2 Hz, 8H), 2.55 (septet, J = 7.1 Hz, 4H), 2.39 (s, 12H). ¹³C NMR (100 MHz, DMSO-d₆) δ 137.2, 136.2, 135.0, 132.3, 124.7, 123.8, 123.4, 46.4, 30.8, 16.9. Anal. Calcd for C₃₄H₄₀F₂₄N₈P₄: C, 35.80; H, 3.53; N, 9.82. Found: C, 36.02; H, 3.14; N, 9.97.

Crystal data for 3: C₃₄H₄₀F₂₄N₈P₄ (FW 1140.62), T = 108 K, λ = 0.71073 Å, monoclinic, space group P₂₁/c, a = 9.6610(3) Å, b = 9.4016(3) Å, c = 24.3810(9) Å, β = 98.315(3)°, V = 2191.22(13) ų, Z = 2, D_calc = 1.729 g/cm³, μ = 0.315 mm⁻¹, F(000) = 1152, reflns collected = 19190, indep reflns = 5432, params = 352, GOF on F² = 1.038, R1/wR2 (I > 2σ(I)) = 0.0560/0.1533, R1/wR2 (all data) = 0.0673/0.1610.

3.4. Calculations

Geometry optimizations were performed in DMSO using the PBE0 hybrid density functional [23]. The def2-SVP basis set was employed for all atoms [24]. Dispersion effects were included using Grimme’s D3 dispersion correction [25], and solvent effects were treated using the SMD solvation model [26]. Single-point energy calculations were subsequently carried out at the PBE0-D3/def2-TZVP level using the same solvation model and the optimized geometries. All calculations were performed using Gaussian 16, Revision C.02 [27].

4. Conclusions

In summary, new macrocyclic tetraimidazolium salts 2 and 3 incorporating propylene and m-phenylene linkers were synthesized and fully characterized. The molecular structure of 3 was determined by single-crystal X-ray diffraction analysis, revealing an almost planar macrocyclic framework with a nearly square cavity. DFT calculations revealed that several low-energy conformers are accessible in solution, reflecting the conformational flexibility of the macrocyclic tetraimidazolium framework.