Metal complexes with N-(trifluoromethylbenzyl)iminodiacetate chelators (x-3F ligands). Part I. Copper(II) chelates of p-3F, m-3F, and o-3F with or without imidazole-like ligands

Eight Cu(II) complexes with N-(p-, m- or o-trifluoromethylbenzyl)iminodiacetate chelators (x-3F ligands) have been synthesized to promote C–F/H interligand interactions involving the F3C-group: {[Cu(μ2-p-3F)(H2O)]·3H2O]}n (1), [Cu(m-3F)(H2O)2] (2), [Cu(p-3F)(Him)(H2O)] (3), [Cu(m-3F)(Him)(H2O)] (4), [Cu(o-3F)(Him)(H2O)] (5), [Cu2(p-3F)2(H5Meim)2(H2O)2] (6), [Cu(m-3F)(H5Meim)(H2O)] (7), and [Cu(o-3F)(H5Meim)(H2O)] (8) [Him and H5Meim = imidazole and the “remote” tautomer 5-methylimidazole, respectively]. The compounds were studied by single-crystal X-ray diffraction, FT-IR, electronic spectra and coupled thermogravimetric + FT-IR methods. The conformation of the iminodiacetate chelating moiety (IDA group) is fac-NO + O(apical) in 1 and mer-NO2 in 2–8. The fac-IDA conformation observed in 1 is related to its polymeric structure and the coordination of a O’-carboxylate donor, from an adjacent complex unit, trans to the Cu–N(IDA) bond. The mer-IDA conformation in 2 is in agreement with similar compounds with an aqua ligand trans to the corresponding Cu–N(IDA) bond. As expected, the ternary complexes 3–8 feature a mer-IDA conformation. Some of the studied complexes exhibit disorder in the –CF3 group and C–H⋯F interligand interactions along with conventional N–H⋯O and O–H⋯O interactions. The thermal decomposition of all studied compounds under air flow produces variable amounts of trifluorotoluene. Graphical Abstract


Introduction
Fluorinated compounds have gained technical [1], chemical [2], and therapeutic [3][4][5] relevance. It is easy to find them in a large variety of daily life products. The fluorine is characterized by small size, high electronegativity, low polarizability, and bond strength. The replacement of hydrogen by fluorine in organic compounds alters their physical, chemical, and biological properties [6]. Fluorine can promote different inter-and/or intra-molecular interactions, such as C-F⋯H, C-F⋯F, or C-F⋯π [6][7][8][9]. These interactions are normally weak, such as van der Waals forces, nevertheless they have proved to be important in defining the molecular and/or crystal structure of different compounds [6,8,9]. In contrast, fluorine directly bonded to electron-withdrawing aromatic rings does not participate in such interactions. The role of fluoromethyl moieties attached to aromatic rings seems to be also different and are indeed assumed to have the ability of taking part in C-F⋯H, C-F⋯F, or C-F⋯π interactions [10].
Herein, the synthesis of three N-(x-trifluoromethylbenzyl)iminodiacetate(2-) ligands, with x-being p-, m-, or o-substitution in x-3F ligands, is reported. In addition, the corresponding binary and ternary copper(II) complexes, involving one N-heterocyclic imidazole-like ligand, were also studied. The formulas of the ligands used in this work are shown in scheme 1. This work involves two main aims. First, to evaluate the structure of the obtained compounds. Special attention is paid to the conformation of the chelating iminodiacetate moiety (IDA) both in binary and ternary compounds. Second, to investigate the involvement of the trifluoromethyl group in intermolecular interactions and their role in the crystal architecture. Therefore, single-crystal X-ray diffraction is a crucial tool [11][12][13][14][15]. Syntheses of the metal complexes have been carried out in water or in methanol:water mixtures. Considering the active H-donor character of the N-H group of imidazole ligands, we anticipate structural frameworks where a competition or cooperation between O-H⋯O and/or N-H⋯O interactions as well as C-F⋯H, and related weak interactions, will be operative [6][7][8][9]. In addition, the tautomerism of H(4/5)-methylimidazole (HMeim) offers possibilities to isolate the "remote isomer" (more stable, with H5Meim) and/or the "adjacent isomer" (more hindered, with H4Meim) in the corresponding ternary complexes [16,17].

Chemicals
Blue-greenish Cu 2 CO 3 (OH) 2 , imidazole, 4(5)-methylimidazole, chloroacetic acid, methanol, and KOH were supplied by Merck, Aldrich or Acros. p-, m-and o-(Trifluoromethylbenzyl) amines were purchased from Alfa Aesar. All reagents and solvents were used as received. Caution: all the solutions used to prepare the chelating ligands in their acid form (section 2.2) were prepared with CO 2 -free distilled water.

Synthesis of chelating ligands
In a three-necked round bottom flask, chloroacetic acid (0.12 mol, 11.34 g) was dissolved in 150 mL of water, placed in an ice-salt bath (temperature < 0°C) under N 2 stream and stirred. KOH (0.29 mol, 16.3 g) was dissolved in 50 mL of cool water (about 0°C) and then added dropwise to the chloroacetic solution. To the alkaline solution of potassium chloroacetate, a 5-mL ethanol solution of x-(trifluoromethylbenzyl)amine (x = p-, m-or o-, 0.0571 mol, 10 g) was dropwise added. The three-necked flask with the resulting reaction mixture was then placed inside a water bath at 85°C, maintaining regular stirring and N 2 flow during 4 h. After condensation, the pH of the mother liquor was~11-12. This solution was cooled in ice, neutralized with HCl 6N, and concentrated in a Büchi evaporator (~50°C) to a volume of 100 mL. After that, the solution was cooled again and finally acidified to pH~2-2.5 to induce precipitation of a white powder corresponding to the N-(x-trifluoromethylbenzyl)iminodiacetic acids (H 2 p-3F, H 2 m-3F or H 2 o-3F). The H 2 x-3F products (C 12 H 12 F 3 NO 4 , MW 291.22) were collected in several fractions by filtration, washed with cool water, acetone and ether, and air-dried. Yields were ca. 50-60%. NMR and FT-IR spectra of the organic products are shown in Supplementary Material (SM1 and SM2.1, respectively). The aforementioned procedure of acidification must be carried out with care, gradually reducing the addition of acid after the mother liquors have pH~7. This is especially critical in the case of the H 2 o-3F acid, where the solution becomes turbid near neutrality. For instance, when the mother liquor of H 2 o-3F acid is cooled in an ice bath close to pH 7, precipitation of a different white product is induced. This product was collected by filtration, washed with cool water and iPrOH, and dried under air flow.  (1). In a Kitasato flask, Cu 2 CO 3 (OH) 2 (0.15 mmol, 33.2 mg) was reacted with H 2 p-3F acid (0.3 mmol, 87.4 mg) in 50 mL of water, heating (~50°C), and stirring for 1.5 h. The resulting clear blue solution was left to cool at room temperature and then filtered, without vacuum, on a crystallizing dish. The solution was allowed to stand at room temperature, covered with a film to control the evaporation. After one week, blue needle-like crystals were collected. These crystals were recrystallized in 30 mL of a methanol:water mixture (2 : 1). After one month, blue square crystals were obtained. Relevant bands FT-IR (cm −1 ) and assignments: [Cu(m-3F)(H 2 O) 2 ] (2). A similar synthesis to that described for 1 was performed using H 2 m-3F acid (0.3 mmol, 87.4 mg), instead of H 2 p-3F acid, and methanol as solvent. After one week, a white precipitate was collected. The solution was filtered on a small crystallizing dish and allowed to evaporate at room temperature, covered with a plastic film. [Cu(m-3F)(Him)(H 2 O)] (4). A similar synthesis to that described for 3 was carried out using H 2 m-3F acid (0.3 mmol, 0.0874 g) instead of H 2 p-3F acid. Blue square crystals were obtained in one week. Relevant bands FT-IR (cm −1 ) and assignments: ν as (H 2 O)~3400, [Cu 2 (p-3F) 2 (H5Meim) 2 (H 2 O) 2 ] (6). In a Kitasato flask, Cu 2 CO 3 (OH) 2 (0.15 mmol, 0.0332 g) was reacted with H 2 p-3F acid (0.3 mmol, 0.0874 g) in 50 mL of a MeOH : H 2 O mixture (10 : 1), heating (~50°C), and stirring. Two hours later, a clear blue solution was obtained. Once the solution cooled to room temperature, H5Meim (0.3 mmol, 0.0246 g) was slowly added to the binary chelate solution and the reaction mixture was stirred for 1 h. The resulting solution, intense blue, was filtered without vacuum on a crystallizing dish and covered with plastic film to control the evaporation. One week later, blue square crystals were collected. Relevant bands FT-IR (cm −1 ) and assignments: [Cu(m-3F)(H5Meim)(H 2 O)] (7). A similar synthesis to that described for 5 was carried out using H 2 m-3F acid (0.3 mmol, 0.0874 g) instead of H 2 p-3F acid. In one week, blue rhomboid crystals were collected. Relevant bands FT-IR (cm −1 ) and assignments: ν as ( FT-IR (SM2.2-SM2.4) and electronic spectra (diffuse reflectance, SM3) of all copper(II) complexes are provided in Supplementary Material.

Crystal structure determinations
Suitable crystals were prepared for X-ray diffraction by immersion in perfluoropolyether, as protecting oil for manipulation, and mounted on a MiTeGenMicromounts™ under inert conditions. These samples were used for data collection. Data were collected with a Bruker D8 Venture diffractometer (120.0 K for 1 and 100.0 K for 2-8). Data were processed with APEX2 [18] and corrected for absorption using SADABS [19]. The structures were solved by direct methods [20], which revealed the position of all non-hydrogen atoms. These atoms were refined on F 2 by a full-matrix least-squares procedure using anisotropic displacement parameters. All hydrogens were located in difference Fourier maps and included as fixed contributions riding on attached atoms with isotropic thermal displacement parameters 1.2 times those of the respective atom. Geometric calculations were carried out with PLATON [21], and drawings were produced with OLEX2 [22] and MERCURY [23]. A summary of crystal data as well as structure and refinement parameters is given in table 1.

Other physical measurements
NMR spectra have been recorded on a 300 MHz 1H Varian Inova-TM spectrometer at room temperature. Chemical shifts (δ) are quoted in parts per million (ppm) and are referenced to the residual solvent peak (deuterium oxide). FT-IR spectra (KBr pellets) were recorded on a Jasco FT-IR 6300 spectrometer. Electronic (diffuse reflectance) spectra were obtained in a Varian Cary-5E spectrophotometer. Thermogravimetric (TG) analyses were carried out under dry air flow (100 mL/min), from RT-800°C, at 10°C/min in a Shimadzu thermogravimetric analyzer (TGA)-50H instrument, coupled to a FT-IR Nicolet Magma 550 spectrometer. A series of 20-35 FT-IR spectra were time-spaced recorded during each TG experiment. These spectra enable the qualitative identification of the gasses evolved during the experiment. The TG experiments always start after stabilization of the balance, i.e., once reached a stable weight for each sample is placed under dry air flow. It should be emphasized that, under these conditions, compounds can lose a variable amount of water before each TG experiment actually starts. The fitting of the formula and the starting material is assumed to be correct if the experimental and the calculated data for the final residue (expected to be CuO in the studied metal complexes) are in agreement within the experimental error, ≤1%.

Results and discussion
3.1. Molecular and/or crystal structure of binary copper(II) chelates (1 and 2)       5). It seems reasonable to state that the steric hindrance caused by the ortho-trifluoromethyl group in 5 and 8 is mainly tied to larger and more linear intermolecular (imidazole)N-H⋯O(carboxylate) interactions, compared to the corresponding compounds having p-3F or m-3F chelators.

Chelating ligand conformation of the IDA group in 1-8 and related copper(II) iminodiacetates
Another aspect to be discussed in this work concerns the conformation of the iminodiacetate moiety within the x-3F chelating ligands. This question must be addressed differently regarding binary and ternary complexes. Table 5 summarizes examples of mononuclear and binuclear copper(II) chelates where the IDA moiety exhibits a fac-NO + O(apical) conformation, with the two metal-glycinate rings nearly perpendicular to each other and sharing the Cu-N bond. The fac-tridentate conformation of the chelator yields two short and one long coordination bonds within the 4 + 1 or 4 + 1 + 1 metal surrounding (square pyramidal or asymmetrical elongated octahedron, respectively). This conformation is directly related to the Jahn-Teller distortions caused by the 3d 9 electronic structure of copper(II) centers. The fac-NO + O(apical) IDA conformation is usually found in polymeric compounds where the Cu-N(IDA) and the O'-carboxylate donors (with O'-being an O-carboxylate appertaining to the chelator of one adjacent metallic center) are trans to each other. This is the case for 1 (figure 1). Note that in table 5, three different kinds of polymers are found as follows: (i) polymers having their own iminodiacetate ligand; (ii) complexes with binucleating chelators (such as HDTA, with a 1,6-hexamethylene spacer, or p-PhDTA, with a p-phenylene spacer); (iii) and also 1,3-thiazolidine-2,4-dicarboxylate (1,3-thiadc, a C,C'-disubstituted IDA chelator). One compound out from this general trend is the binary Cu(II) chelate of N-carboxymethyl-S-prolinate(2-) (cm-S-Pro, a N,C-disubstituted IDA ligand). In this case, the Cu-N(IDA) bond and one aqua ligand (instead of an O'-carboxylate donor) are trans to each other. Abbreviations for some chelators and groups: p-(tfm)Bz, p-(trifluoromethyl)benzyl; HDTA, 1,6-hexamethylenedianinotetraacetate (4-) ligand; C6-alkyl, n-hexamethylene spacer; p-PhDTA, p-phenylenediamine-N,N,N',N'-tetra-acetato(4-) ligand; p-phenylene, 1,4-phenylene spacer, 1,3-thiadc, 1,3-thiazolidine-2,4-dicarboxylato(2-) ligand; 1,3-thia, 1,3-thiazolidine; cm-S-Pro, N-(carboxymethyl)-S-prolinato(2-) ligand. Table 6 summarizes structural information on binary copper(II) compounds where the IDA moiety of the chelator adopts a mer-NO 2 conformation, that is two nearly coplanar Cu-glycinate rings that share the Cu-N bond. This IDA conformation is more frequent than the fac-NO + O(apical). The mer-NO 2 conformation is found in a remarkable variety of binary monomeric or polymeric compounds, with 4 + 1 and 4 + 1 + 1 copper(II) coordination. It is noticeable that the IDA-mer-NO 2 conformation is always present in molecular compounds with Cu(II) coordination type 4 + 1 having two aqua ligands. Compound 2 agrees with this criterion (figure 2). The mer-NO 2 conformation is also present in polymeric compounds where the Cu-N(IDA) bond and an aqua ligand are trans to each other, and an additional aqua or a neighboring O'-carboxylate is on the apical/distal coordination site. Other binary Cu(II) compounds showing the IDA-mer-NO 2 conformation are polymers where the chelators have two bridging carboxylate groups or a tridentate carboxylate group. Regarding ternary complexes, the IDA-mer-NO 2 conformation is also well documented. For instance, this conformation has been previously described for a variety of ternary copper(II) complexes having an iminodiacetate-like tridentate chelator and a coligand which supplies one N-heterocyclic donor per metal center. No exception has been reported to this structural correlation, including 3-8 (figures [3][4][5][6][7][8]. Other examples of ternary copper(II) complexes with typical N-heterocyclic ligands have benzimidazole [24], H(4/5)methylimidazole [16,17], 2,4-diaminopyrimidine [11], adenine [46] and related N-heterocyclic bioligands [13][14][15]47] such as hypoxanthine [48] or the synthetic acyclic-nucleoside acyclovir [49].

Vibrational and electronic spectra and thermal analyses by coupled TG + FT-IR spectroscopy
The infrared spectra of trifluoromethyl-aryl compounds exhibit at least three bands related to the F 3 C-group, expected at 1321 ± 9, 1179 ± 7, and 1140 ± 9 cm −1 . The origin of these bands has been controversial, probably because they are non-pure stretching bands. The last two bands can be essentially attributed to the ν as and ν d modes, while the absorption near 1321 cm −1 could be a combined band of the stretching and deformation modes of this group. The aforementioned bands appear in spectra of the four reported organic ligands at 1322 ± 11, 1178 ± 7, and 1125 ± 15, the latter value being out of the expected range (1140 ± 9 cm −1 ). The averaged values of these bands in the corresponding spectra of the copper (II) complexes are 1325 ± 10, 1167 ± 12, and 1134 ± 11 cm −1 . The band near 1325 cm −1 is similar in the spectra of both the organic ligands and the copper(II) complexes. In most of the metal complexes, the other two absorptions occur with a smaller difference in wavenumber (30-45 cm −1 ) compared to the organic ligands. The highest shift at lower frequencies was observed for the band near 1179 cm −1 .
The electronic (diffuse reflectance) spectra of studied compounds exhibit, as expected, a broad and asymmetric absorption with maxima ranging between 11.9 and 14.8 kK. Spectra of binary chelates 1 and 2 had their maxima below 14,000 cm −1 , whereas the maximum absorption in 3-8 (with one Him-like ligand instead of the proximal aqua ligand in the 4 + 1 Cu(II) coordination) was registered at 14,300-14,750 cm −1 . The O-aqua substitution by N-imidazole is performed in solutions where the H 2 O/imidazole molar ratio is 55.5 M/0.01 M. This is possible due to the strong affinity of the N-imidazole donor, a borderline Pearson base, to the copper(II) center, a borderline Pearson acid. Thus, the coordination of an imidazole instead of an O-donor increases the ligand field and for compounds with similar coordination geometry (type 4 + 1 in 1-8) consequently increases the ν max values, as indeed is observed (see SM3).
All compounds reported in this work, binary (1 and 2) and ternary compounds (3)(4)(5)(6)(7)(8), have also been studied by coupled TG + IR spectroscopy. Their thermal behavior can be exemplified in the spectra of 2 and 4. Detailed information on the TG + FT-IR measurements of both complexes as well as additional data from 1, 3, and 5-8 can be found in the Supplementary Material SM4. Compound 2 (see SM4.2 and table 7) decomposes in three rather different steps. The first step is mainly characterized by the loss of both aqua ligands (the FT-IR spectra recorded at this time also revealed the loss of some CO 2 ). Afterward, the decomposition of the m-3F organic ligand occurs in a quite sharp event (weight loss  3 and table 8) exhibits an overall aqua loss process (~4.8%) divided into two similar steps (Ia and Ib, with a~2.4% loss per step). Again, the corresponding FT-IR spectra revealed the loss of some CO 2 during this initial step. In this case, the formation of TFT is weakly observed (step 4) while that of TMA can be neglected. In contrast, the formation of the three N-oxides gasses (N 2 O, N 2 O and NO) are observed in the last step (370-500°C), mainly related to the decomposition of the 5-methylimidazole ligand. The weight of the final residue (about 600°C) agrees to that calculated for a non-pure CuO residue within an experimental error <1%.
The formation of different amounts of TMA and TFT is also observed in all the p-3F, m-3F and o-3F derivatives here reported. This fact strongly suggests that the decarboxylation of the x-3F chelators can be followed by the appropriate recombination process. This singularity should be only understood as one decomposition possibility, among others, also associated to the well-known thermodynamic stability of the C-F bonds. In this regard, similar TG experiments also revealed the formation of TMA during the thermal decomposition of Cu(II) complexes with N-methyl-IDA [46] or N-benzyl-IDA (unpublished results).

Concluding remarks
Binary 1 showed a polymeric nature and the iminodiacetate chelating moiety in fac-NO + O conformation. In contrast, 2-8 have a molecular nature and exhibit a mer-NO 2 conformation. All copper(II) complexes have in common the coordination of aqua ligands (1)(2)(3)(4)(5)(6)(7)(8). The formation of rather strong N-H⋯O and/or O-H⋯O interactions does not preclude the formation of C-H⋯F interactions (1,(4)(5)(6)(7). However, C-F/π or F⋯F interactions are missing. Appropriate comparisons revealed that the C-H⋯F interactions occur irrespective of (a) the dimensionality of the compounds (polymeric (1) or molecular (2-8) structures) and (b) the binary (1 and 2) or mixed-ligand nature (3-8) of the compounds. No further structural correlation was observed between the presence of C-F⋯H interligand interactions and the disorder on the trifluoromethyl group.