Water-Soluble Bismuth(III) Polynuclear Tyrosinehydroximate Metallamacrocyclic Complex: Structural Parallels to Lanthanide Metallacrowns

Recently there has been a great deal of interest and associated research into aspects of the coordination chemistry of lanthanides and bismuth—elements that show intriguing common features. This work focuses on the synthesis and characterization of a novel bismuth(III) polynuclear metallamacrocyclic complex derived from aminohydroxamic acid, in order to compare the coordination ability of Bi3+ with the similarly sized La3+ ions. A polynuclear tyrosinehydroximate Bi(OH)[15-MCCu(II)Tyrha-5](NO3)2 (1) was obtained according to the synthetic routes previously described for water-soluble Ln(III)-Cu(II) 15-MC-5 metallacrowns. Correlations between structural parameters of Bi(III) and Ln(III) complexes were analyzed. DFT calculations confirmed the similarity between molecular structures of the model bismuth(III) and lanthanum(III) tyrosinehydroximate 15-metallacrowns-5. Analysis of the electronic structures revealed, however, stronger donor-acceptor interactions between the central ion and the metallamacrocycle in the case of the lanthanum analogue. Thermochromic properties of 1 were studied.


Introduction
Bismuth(III) complexes have received increased interest due to their high effectiveness in eradication of Helicobacter pylori, and also as potential antimicrobial and anti-leishmanial agents [1][2][3]. Up to now, many coordination bismuth(III) compounds with a large variety of ligands and coordination environments had been synthesized and explored in biomedical applications [4][5][6][7][8]. Recent interest in the use of alpha-emitting 213 Bi in nuclear medicine requires efficient Bi complexation, preferably within a macrocyclic cavity [9,10]. It is not surprising that research on the synthesis of biologically important ligands and their water-soluble complexes has received significant attention [11][12][13][14][15][16][17]. However, the chemistry of Bi(III) explored in this purpose to date is rather scarce, and the study of bismuth complexes in aqueous solutions is often difficult.
Bismuth is the heaviest stable element and is recognized as a relatively low toxic metal, although conversely, it sits in the Periodic table among the most toxic and radioactive elements including mercury, thallium, lead, and polonium [18]. Additionally, within group 15, antimony and arsenic compounds are generally of high toxic nature, whereas those of bismuth exhibit a significantly reduced A relevant aspect of this structure is that the ligand scaffold prefers early lanthanides characterized by the same charge and similar ionic radii as Bi 3+ . Recently, we have demonstrated the first metallamacrocyclic 15-MC-5 complex constructed from Cu 2+ and Bi 3+ metal centers and pyrazinohydroxamic moieties [29]. The single-crystal structure reveals the classic metallamacrocyclic 15-MC-5 configuration. The Bi 3+ ion is located at the center of the 15-MC-5 ring consisting of five [Cu(II)-N-O] repeating units. Following our interest in water-soluble Ln(III)-Cu(II) 15-MC-5 metallacrowns with aminohydroximate ligands [30][31][32][33][34], we describe here a general synthetic approach and comparable characterization of a new water-soluble metallamacrocyclic Bi(III)-Cu(II) 15-MC-5 complex derived from tyrosinehydroxamic acid.

Synthesis and Spectroscopic Aspects
Following a previously described synthetic procedure for water-soluble Ln(III)-Cu(II) 15-MC-5 metallacrowns [30,31] we employed the most frequently used two-step methodology with some modification. In the first step, α-tyrosinehydroxamic acid and Cu(CH 3 COO) 2 were mixed in water and, in the second step, Bi(NO 3 ) 3 was added to this solution (Scheme 2). It can be seen ( Figure 1) that the absorption spectra of the resulting complex 1 are similar to those of La complex. In the visible region a broad band with the maximum at 575 nm (ε = 395 M −1 cm −1 ), assigned to Cu(II) d-d transition, is responsible for the characteristic dark blue color, which is observed in all previously reported water-soluble Ln(III)-Cu(II) aminohydroximate complexes [23,24,30,31]. The yield of isolated crystalline 1 was 32%, in contrast to 85% of the lanthanum analogue, because of hydrolysis of Bi 3+ in water. Crystals of 1 suitable for the single-crystal X-ray diffraction experiment were obtained by recrystallization from water. It is worth mentioning that the stability of complex 1 in aqueous solutions was confirmed using UV-vis spectroscopy by recording absorption spectra at a pH value of about 7, important for biological studies (pH 6.8). No absorbance changes even after several days were recorded in either the intensity or the position of the absorption bands. Nevertheless, in contrast to the lanthanum complexes, in alkaline medium (greater than pH 8) the rapid hydrolysis of 1 occurs with the formation of an amorphous pale precipitate.

Thermochromic Properties
Compound 1 exhibits interesting low-temperature thermochromism. Diffuse reflection spectra recorded in the range from −175 to +21 • C are shown in Figure 2. They show a monotonous shift toward near the IR region. To determine the absorption value from the diffuse reflection spectra, the spectra of the Kubelka-Munk function F(R) were calculated: where R is the diffuse reflection coefficient. The Kubelka-Munk function is directly proportional to the absorption coefficient k and inversely proportional to the scattering coefficient s of the powder, which is virtually independent on the wavelengths. Therefore, the shape of F(R) qualitatively approximates the absorption spectrum. The procedure described in [35] was applied to determine the value of the gap (E g ) of interband electronic transitions. In the range of the electronic transition, the dependence of the absorption coefficient α on the energy E has the form: where A and m are the constants of the electronic transition and E g is its energy. In this paper we used the Kubelka-Munk function F(R) as an approximation for α. This can be transformed into the following equation: which provides a simple way to determine E g , since the value of E g will correspond to the maximum of this function. As an example, the dependence obtained at −175 • C is given in Figure 3. ion in square planar and square pyramidal coordination environment. The first transition formally corresponds to the band gap and is temperature-dependent ( Figure 4). Such a behavior might reflect a decrease of the bond lengths under cooling [36], which increases the antibonding d x 2 -y 2 orbital energy and the width of the band gap (the HOMO-LUMO gap in an isolated complex). The temperature dependence of the other d-d-transitions is very weak. This can be caused by the π-admixture to the corresponding occupied d orbitals (they are π *-antibonding), which also results in an increase of their energies on cooling and reduces the band gap, therefore off-setting the influence of the raising d x 2 -y 2 energy on the electronic transitions.

Gd(H 2 O) 3 [15-MC Cu(II)Tyrha -5] [37]
M-O(oxime) 2.387 (7)  Note that the gadolinium atom in complex Gd(H 2 O) 3 [15-MC Cu(II)Tyrha -5](NO 3 ) 3 [37] is additionally coordinated by three oxygen atom of water molecules (two of which are located on one side in respect to Cu5 plane while the third on the other). In contrast to the lanthanide analogues, the Bi 3+ ion is additionally coordinated by only one oxygen atom of the hydroxide anion in an apical position. The Bi-O distance (2.047(7), 2.106(8) Å) is in excellent agreement with the literature data on the compounds with the Bi-OH bonds [38][39][40]. The nearest water molecules are at the distance of 2.920(8) and 2.996(8) Å from Bi in the A and B molecules, respectively. These values significantly exceed the sum of the ionic radius of Bi 3+ (1.03 Å) [21] and the van der Waals radius of the oxygen atom (1.55 Å) [41]. Thus, the coordination number of the bismuth atoms in both molecules is six, and the coordination environment is a pentagonal pyramid.
Two copper atoms additionally coordinate the water molecule in each of the independent molecules. One copper atom in each of the independent molecules has a strong interaction with the nitrate anion. Two A comparison of the related complex of bismuth with pyrazinohydroxamic acid [29] reveals significant differences in the crystal packing between these two compounds. The molecules of the bismuth complex with pyrazinohydroximate ligands form an infinite three-dimensional (3D) network due to N ... H interactions and π ... π stacking. Neighboring molecules are largely offset from each other and do not form dimeric motifs. In contrast, in complex 1, one copper atom of the metallacrown ring is additionally coordinated by the hydroxyl oxygen atom of a neighboring molecule. The Cu-O(Tyrha) distances are 2.762 (8)   Note that the crystal packing of complex 1 (Figure 7) is similar to that found in the gadolinium (III) tyrosinehydroximate complex [37]. Three water molecules are located inside the dimer cavity, both in complex 1 and in the gadolinium tyrosinehydroximate complex [37]. However, in the case of gadolinium, two water molecules are coordinated to Gd 3+ . Thus, the Gd-O bonds are almost perpendicular to the planes of the metallacrown rings. In turn, in complex 1, the water molecules are significantly displaced from such an ideal position. This leads to the Bi...Bi distance in the dimers in 1 (7.17 Å) being much shorter than the corresponding Gd...Gd distance (8.39 Å). The distances between the copper atom and the hydroxyl group of tyrosinehydroximate ligand of the neighboring metallacrown are also significantly shorter in complex 1 (Table 1). In turn, the distance between dimer particles is shorter in the gadolinium complex (d(Gd . . . Gd) = 8.52 Å) [37] than the Bi...Bi distances in complex 1 (9.24 Å).

Theoretical Calculations
To  (Table 3). In the tyrosinehydroximate ligands, adjacent C-N im and C-O bonds are characterized by higher values of the electron density (r c ) and ellipticity ε at the (3,-1) critical points (0.358-0.362 a.u. and 0.099-0.289, respectively, Table 2). This indicates a π-delocalization among the N im , C, and O carb atoms in the hydroximate chelates with the π-contributions into the C-N im bonds being higher (ε = 0.277-0.289) than those for C-O (ε = 0.099-0.107). Ellipticity values of 0.175-0.195 calculated for the aromatic C-C bonds in the C 6 H 4 OH fragments are intermediate between those for C-N im and C-O. Ellipticity values of 0.059-0.070 obtained for the N-O single bonds suggest some p,π-conjugation between the oxime oxygen lone pair and the delocalized πsystem. Additionally, p,π-conjugation is expected to occur for C-O(H) bonds in the substituents (ε = 0.077-0.078). The C-C bonds in the hydroximate chelates (1.517-1.523 Å) are shorter than typical single C-C bonds (1.54 Å). Taking into account calculated ellipticity values of 0.104-0.107 one can assume the σ,π-conjugation (hyperconjugation) effect. Such interaction is also inherent in the single C-C ring bonds (1.508-1.510 Å) between the H 2 C and C 6 H 4 OH fragments of the substituents (ε = 0.043-0.049). For comparison: C-C R bonds between the hydroximate chelates and the substituents without σ,π-conjugation are characterized by the 1.547-1.552 Å lengths and ellipticity values close to zero (0.018-0.021). Among the copper(II) coordination bonds the interactions with the imine nitrogen atoms of the tyrosinehydroximate ligands are estimated as the strongest ones with calculated energies of 59.9-61.3 kcal/mol ( Table 3) 3+ is also predicted by the Bader QT AIM approach at the PBE/x2c-TZVPall//SR-PBE/rL2 level (+1.911e on Bi and +2.041e on La). On the basis of our calculations, one can conclude that accumulation of the density at the axial positions of the Bi 3+ ion together with its decreased positive charge prevents filling the Bi 3+ coordination sphere by the solvent molecules. This leads to the more effective bonding with the HO − negative ion in 1 (as well with Cl − in the pyrazinohydroximate complex [29]). As a result, the Bi 3+ ion in the complex is characterized by the lower coordination number as compared with the La(III) 15-metallacrowns-5 where the La 3+ central ion bears four H 2 O molecules at the axial positions [33]. Accordingly, the higher DED accumulation in the axial positions of the Bi 3+ ion induces weakening of the Bi-O ox donor-acceptor interactions in comparison with the La-O ox contacts that has been described above.

Materials and Methods
All chemicals were reagent-grade and were used as received from Sigma Aldrich without further purification. The C, H, and N elemental analyses were performed by the Microanalytical laboratory of IOMC on Euro EA 3000 Elemental Analyzer. Electronic absorption spectra were recorded with the Perkin Elmer Lambda 25 UV/Vis spectrophotometer at room temperature, at 200-1100 nm. IR spectra were obtained on a Perkin Elmer 577 spectrometer and recorded from 4000 to 450 cm −1 as a Nujol mull on KBr plates. 1 H NMR spectra were recorded on BrukerAvance III 400 MHz spectrometer. Samples were dissolved in high purity D 2 O (Sigma Aldrich, St Louis, MO, USA), and the chemical shifts were referenced to the solvent peak. Diffuse reflection spectra were measured with a spectrophotometric system consisting of a Kolibri-2 spectrometer (VMK "Optoelectronika," Novosibirsk, Russia), an FCR-7UV400-2-ME reflection/backscattering probe (Avantes, The Netherlands), and an AvaLight-DHS light source (Avantes, The Netherlands) [35]. The spectra were recorded in the 400-1000 nm range. BaSO 4 powder was used as a reference for 100% reflection. Temperature measurements of the reflection spectra were performed from −175 • C to room temperature at 20 temperature points.

X-ray Crystallographic Studies
The X-ray diffraction data for 1 were collected on Bruker D8 Quest diffractometer (graphite-monochromator, MoK α -radiation, ω-scan technique, λ = 0.71073 Å, T = 100(2) K). The intensity data were integrated by using the SAINT program [44]. The SADABS program [45] was used to perform area-detector scaling and absorption corrections. The structure was solved by dual method [46] and was refined on F 2 using all reflections with the SHELXTL package [47]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in calculated positions and refined in the riding-model (U iso (H) = 1.5U eq (O) in OH-groups and U iso (H) = 1. These data can also be obtained free of charge at www.ccdc.cam.ac.uk/structures from the Cambridge Crystallographic Data Centre.

Computational Methodology
Our quantum chemical investigations of the [M(15-MC Cu(II)Tyrha -5)] 3+ complexes (M = Bi, La) are based on the Density Functional Theory (DFT), the topological analysis of the electron density function, and studies of the Deformation Electron Density (DED) distribution. Full geometry optimizations of the complexes were performed with the Priroda 15 [48,49] software employing the PBE functional [50] in conjunction with the four-component one-electron scalar relativistic (SR) approximation to the full Dirac equation where all spin-orbit terms are neglected. For all atoms we used the original all-electron relativistic correlation-consistent rL2 basis set of the triple-ζ polarized quality [51], which is an analogue of the well-known cc-pVTZ. The complexes were treated as high-spin sextet systems without symmetry constraints. For the SCF convergence criterion, a value of 10 -6 was assigned. Tolerance on the gradient achieved in the geometry optimizations is 10 -5 . For accuracy of the integration grid, a value of 10 -8 per atom was used. Harmonic vibrational frequencies were calculated to ensure the optimized stationary points to be local minima without negative eigenvalues. Assignment of the "print=+density" keyword in the Priroda 15 code allowed us to obtain values of the electron density (r c ) at the critical points and corresponding eigenvalues λ 1 , λ 2 , and λ 3 of the hessian A(r c ). Thus, Laplacian∇ 2 (r c ) and ellipticity ε values at the critical points were calculated with the Equations (4) and (5) [52]: One of the important applications of the topological analysis is the estimation of interatomic interaction energies (E int ) on the basis of the Espinosa correlation [53]. Initially, Equation (6) was proposed for hydrogen bond energy calculations. Later, its usage was extended to coordination bonds in metal complexes [54,55]. We calculated values of the potential electron energy density V(r c ) at the critical points with the Equation (7) based on the approximation of the kinetic electron energy density [56] and the virial theorem [52]: Calculations of atomic charges by the Bader approach [52] were performed employing the Sculpt basin integration algorithm implemented in the AIMAll software [57]. The DED maps and isosurfaces were obtained with the Multiwfn code [58,59] using the wave functions computed with the Gaussian 09 package [60]. Corresponding Single Point Energy calculations were carried out for the molecular geometries optimized before with the Priroda 15 software. The PBE functional and the all-electron triple-ζ polarized x2c-TZVPall basis set [61] were applied at the Gaussian 09 calculations. Additionally, the ultrafine integration grid and default SCF convergence criteria without symmetry constraints were assigned ("Int = UltraFine" and "NoSymm" keywords in the Gaussian 09 code). The wave functions of the complexes were proven to be stable by the tests for the SCF solutions stability.

Conclusions
The identical charge and ionic radii of Bi 3+ and La 3+ cations open up the possibility for the development of Bi(III)-based metallacrowns. Based on this analogy, we have designed and isolated a novel example of Bi(III)-Cu(II) hydroximate metallamacrocyclic complex of the 15-MC-5 type. The single crystal X-ray diffraction measurements confirmed the classic metallamacrocyclic 15-MC-5 configuration with the neutral ring consisting of five [Cu(II)-N-O] repeating units, and the five hydroximate oxygen atoms encapsulating a Bi 3+ ion within the central cavity. Scalar relativistic DFT investigations predict similarity between molecular structures of the model bismuth(III) and lanthanum(III) tyrosinehydroximate 15-metallacrowns-5. At the same time analysis of the electronic structures reveals stronger donor-acceptor interactions between the central ion and the metallamacrocycle in the case of the lanthanum analogue. The larger density accumulation at the axial positions in the pentagonal pyramid ligand environment around the Bi 3+ ion explains the preferential coordination of the negatively charged OH − ion instead of the solvent molecule, as well as the exceptional six-coordinated geometry. Coordination of both Bi(III) and La(III) ions is characterized by significant π-contributions to the interactions with the metallamacrocycle. To conclude, we have prepared a new interesting bismuth(III) metallacrown complex, which may not only enrich the structure diversity of both metallacrowns and bismuth coordination compounds, but also offers another approach to discovery of new polynuclear metallamacrocyclic complexes with unconventional structures and properties.