Rearrangement of Imidazolidine to Piperazine Rings in the Presence of Dy^III †

Abstract

The formation of imidazolidines from secondary amines and aldehydes is well known. This small cycle can act as a nitrogen donor, and it is usually stable when it coordinates to metal ions. Sometimes, imidazolidines acting as ligands undergo breaking of the C-N bond when coordinating to the metal center, yielding related amines. However, the reorganization of the imidazolidine into a piperazine ring is quite an unusual process. In this work, we describe the transformation of a zinc complex with a ligand containing two imidazolidine moieties into a zinc complex with a piperazine fragment as donor, in the presence of a dysprosium salt.

1. Introduction

Nitrogen heterocycles are undoubtedly the most important structural motifs in medical chemistry and pharmaceuticals [1]. These include imidazolidines and piperazines [2], which are also potential ligands for the formation of metal complexes [3,4]. The stability of imidazolidine-based complexes greatly depends on the substituents attached to the nitrogen donors. Thus, there are many complexes with imidazolidine ligands that have been shown to be stable in solution, while others undergo hydrolysis very easily [5]. When this hydrolysis takes place, it typically cleaves the imidazolidine ring to transform the ligand into an amine [5]. However, in some cases, although very rare, the conversion of the imidazolidine ring into a piperazine heterocycle has also been described. To our knowledge, this transformation has only been described twice in the literature, and it took place in the presence of Cu^II ions [6,7]. In this work, we describe the conversion of a ligand containing two imidazolidine rings into one with a piperazine cycle, a reaction that occurs in the presence of a dysprosium(III) salt.

2. Materials and Methods

2.1. Materials and General Methods

All chemical reagents and solvents were purchased from commercial sources, and used as received without further purification. ¹H NMR spectra of 1 and 2·1.75H₂O were recorded on a Varian Inova 400 spectrometer, using DMSO-d₆ as solvent.

Single X-ray data for 2·1.75H₂O were collected at 100 K on a Bruker D8 VENTURE PHOTON III-14 diffractometer, employing graphite-monochromated Mo-kα (λ = 0.71073 Å) radiation. Multi scan absorption corrections were applied using SADABS [8]. The structure was solved using standard direct methods, employing SHELXT [9], and then refined using the full matrix least-squares techniques on F², using SHELXL [10] from the program package SHELX.

2.2. Syntheses

[Zn₃(L¹)(OAc)₂] (1): To a solution of pentaethylenehexamine (0.107 g, 0.461 mmol) in absolute ethanol (12 mL), Zn(OAc)₂·2H₂O (0.100 g) and an ethanolic (15 mL) solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (0.426 g, 1.844 mmol) were added. The mixture was stirred for 6 h at room temperature, and the solid that precipitated was separated through centrifugation, and dried in air. Yield: 0.125 g (19%). ¹H NMR (400 MHz, DMSO-d₆, δ in ppm): 2.09 (s, 6H, CH₃-COO⁻); 2.11–2.24 (m, 2H), 2.64–3.05 (m, 8H), 3.53–3.58 (m, 4H), 3.80–3.90 (m, 2H), 3.75–3.83 (m, 2H), 4.10–4.35 (m, 2H) (4H1+ 4H2 + 4H3 + 4H18 + 4H19); 3.48 (s, 6H, OCH₃); 3.63 (s, 6H, OCH₃); 3.69 (s, 1H), 3.73 (s, 1H) (H17 + H17’); 6.75 (s, 2H), 6.82-6.98 (m, 6H) (2H6 + 2H8 + 2H11 + 2 H13); 8.34 (s, 2H, 2H4).

[Zn₂L²(NO₃)₂]·1.75H₂O (2·1.75H₂O): To an acetonitrile (8 mL)/methanol (4 mL) solution of 1 (0.022 g, 0.016mmol), Dy(NO₃)₃∙6H₂O (0.011 g, 0.031 mmol) was added, and the resultant solution was stirred for 4 h at room temperature. Slow evaporation of the obtained solution yielded single crystals of [Zn₂L²(NO₃)₂]·1.75H₂O, suitable for single X-ray diffraction studies. Yield: 0.010 (66%) ¹H NMR (400 MHz, DMSO-d₆, δ in ppm): aliphatic protons: most of them hidden under the DMSO and water peaks; 3.71 (s, 6H, OCH3); 6.96 (s, 2H), 7.07 (s, 2H) (2H9 + 2H11); 8.51 (s, 2H, H7). Crystal data (at 100(2) K): tetragonal, I4₁/a, C₂₈H₃₈Br₂N₈O_11.75Zn₂, MW = 965.22, with a = 24.077(9) Å, b = 24.077(9) Å, c = 11.8202(6) Å, α = β = γ = 90^°, V = 6864.0(6) ų, Z = 8; R₁ = 0.0514 and wR₂ = 0.1241 (I > 2σI).

3. Results and Discussion

3.1. Synthesis and Spectroscopic Characterization

The trinuclear zinc complex 1 was obtained using a template method, by mixing pentaethylenehexamine and 5-bromo-2-hydroxy-3-methoxybenzaldehyde in the presence of zinc acetate, as summarized in Figure 1.

The addition of dysprosium(III) nitrate to an acetonitrile/methanol solution of 1 yields the dinuclear zinc complex 2·1.75H₂O (Figure 1), which contains the new [L²]²⁻ donor with a piperazine ring. This heterocycle seems to come from the initial imidazolidine rings present in the [L¹]⁴⁻ ligand in 1, through a hydrolysis and rearrangement process. This transformation, although uncommon, has been previously described for copper(II) complexes [6,7] but, as far as we know, it has never been reported in the presence of a lanthanoid ion. Both complexes were characterized using ¹H NMR spectroscopy. In addition, 2·1.75H₂O has been unequivocally identified by single X-ray diffraction studies.

The ¹H NMR spectrum of 1 shows one singlet at 8.4 ppm (2H), assigned to the imine protons, and one singlet (2H) and one multiplet (6H) between 6.75 and 6.98 ppm, in agreement with the existence of four aromatic rings, which are not all equivalent. This confirms the tetracondensation of the amine and the aldehyde. Furthermore, the presence of two singlets at ca. 3.7 ppm points to the existence of two inequivalent imidazoline protons (H17 and H17’ in Figure 1), in agreement with previous results [11], and this reinforces the tetracondensation. In addition, it should be noted that only one set of signals is present in the ¹H NMR spectrum of 1, in agreement with the existence of only one species in solution, and this spectrum does not show any evidence of hydrolysis.

In the case of 2·1.75H₂O, the ¹H NMR spectrum in DMSO-d₆ (Figure 2) clearly shows the existence of two equivalent imine moieties (singlet at 8.5 ppm), and just two equivalent aromatic rings (two singlets at 6.96 and 7.07 ppm), without any other peak in the aromatic region, indicating the high purity of this species.

Thus, the comparison of this spectrum with that of 1 shows the disappearance of four aromatic protons, according to the removal of two aromatic rings in 2·1.75H₂O with respect to 1. Unfortunately, most of the aliphatic protons of 2·1.75H₂O are hidden by the DMSO and water peaks, but, despite this, the ¹H NMR spectrum is in complete agreement with the formation of the new piperazine donor.

Accordingly, the ¹H NMR studies suggest that both complexes are stable in solution, and, therefore, that the transformation of complex 1 into 2·1.75H₂O is mediated by the presence of the dysprosium(III) nitrate.

3.2. Single X-ray Diffraction Studies

Single crystals of [Zn₂L²(NO₃)₂]·1.75H₂O (2·1.75H₂O) were obtained as detailed above. An ellipsoid diagram for 2 is shown in Figure 3, and the main distances and angles are recorded in

Table 1. Main bond distances (Å) and angles (°) for 2·1.75H₂O.

Zn1—O1	1.971 (4)	Zn1—N1	2.072 (5)
Zn1—O10	2.367 (6)	Zn1—N2	2.155 (5)
Zn1—O11	2.233 (5)	Zn1—N3	2.160 (5)
Zn1···Zn1 #1	5.943 (1)
O1—Zn1—N2	169.64 (18)	N3—Zn1—O10	143.84 (19)
N1—Zn1—O11	148.21 (18)	O11—Zn1—O10	54.68 (18)

^#1 −x + 1, −y, −z − 1.

.

The unit cell of 2·1.75H₂O contains neutral dinuclear [Zn₂L²(NO₃)₂] molecules and water as solvate. [Zn₂L²(NO₃)₂] has an inversion center, which makes both halves of the molecule equivalent. In this complex, the new dianionic ligand [L²]²⁻ acts as a dinucleating octadentate donor, providing an N₃O (N_imine, N_amine, N_piperazine and O_phenolate) environment for each Zn^II ion, with the methoxy oxygen atoms remaining uncoordinated. The metal centers reach their coordinative saturation with a nitrate group, linked in a bidentate chelate mode. Accordingly, both Zn^II ions are hexacoordinated, with distances and bond angles that agree with a distorted octahedral geometry. It should be emphasized that the distortion of the octahedron is considerable, since an angle close to 55° is observed (Table 1), a value much lower than what would be expected, but that is quite typical for bidentate chelate nitrates [12]. Both zinc ions are bridged through the NCCN fragment of the piperazine ring, which adopts a chair conformation, leading to a Zn···Zn intramolecular distance of ca. 5.9 Å. The dinuclear [Zn₂L²(NO₃)₂] units are connected between them through hydrogen bonds, where only the amine nitrogen atoms (N2) and the water solvate are implicated, and the shortest Zn···Zn intermolecular distance in this arrangement is ca. 8.09 Å.

4. Conclusions

This work reports the uncommon conversion of an imidazolidine ligand into a piperazine donor in the presence of a dysprosium(III) salt. Accordingly, herein is described the first piperazine heterocycle isolated from an imidazolidine ligand in the presence of a lanthanoid metal ion.