First Example of Fluorinated Phenanthroline Diamides: Synthesis, Structural Study, and Complexation with Lanthanoids

An efficient approach to the synthesis of diamides of 4,7-difluoro-1,10-phenanthroline-2,9-dicarboxylic acid was elaborated. Direct nucleophilic substitution with 4,7-dichloro-1,10-phenanthroline precursors opened access to difluoro derivatives in high yield. As a result, four new fluorinated ligands were prepared in up to 88% yield. Their structure was proved by a combination of spectral methods and X-ray data. A set of lanthanoid complexes was prepared to demonstrate the utility of new ligands. The structure of the complexes was studied in solid state (IR-spectroscopy, X-ray diffraction) and in solution (NMR-spectroscopy).


Introduction
Currently, nuclear power plays very important role in global electricity production. However, the resulting high-level wastes (HLW) are a deterrent to the further development of this industry [1]. Known approaches to recycle the HLW involve the use of nitrogencontaining ligands capable of forming organosoluble complexes with f -elements. One of the most popular and widely studied classes of such compounds are heterocyclic amides [2]. 2,9-Diamides of 1,10-phenanthroline dicarboxylic acid are unique polydentate N,O-ligands. Their structure contains "soft" coordination centers (aromatic nitrogen atoms) and hard coordination centers (carbonyl oxygen atoms) simultaneously ( Figure 1) [3][4][5]. The complexing and extraction properties of these ligands can be varied by changes in the structure of substituents in both the amide function and the phenanthroline core. On the other hand, such structural diversity permits fine-tuning of the ligand properties. Recently, serious attention has been paid to such phenanthroline diamides which have various substituents in the aromatic core, such as chlorine atoms [6][7][8][9], alkoxy groups [3,10], and others.
The presence of two chlorine atoms opens the way to further modification of ligands using nucleophilic substitution reactions. This approach may be of use for reducing the Brönsted basicity of the synthesized ligands. However, the presence of chlorine atoms is undesirable in terms of the resistance of the extractants to radiolysis [11,12].
The introduction of fluorine atoms into the target molecule changes such parameters as lipophilicity, solubility, binding to receptors, metabolism, membrane permeability, acidbase characteristics, conformational properties of compounds, resistance to oxidants, and environmental influences. All these unique features are used as a working tool in the creation of new medicines and materials [13][14][15][16][17]. Furthermore, the replacement of chlorine atoms with fluorine atoms can be considered as one of the possible ways to increase the radiation resistance, since the C-F bond strength (115.7 kcal/mol) is significantly higher than the C-Cl bond energy (77.2 kcal/mol). The incorporation of a fluorine atom into a strictly defined position of an organic molecule is one of the key problems in the synthetic chemistry of fluorine-containing compounds. Due to the progress in the field of selective fluorination, trifluoromethylation, and the introduction of small fluorinated fragments into the target structure, many practical tasks have been seriously developed [18][19][20][21][22][23][24][25][26].
Despite the exceptional importance of fluorinated heterocyclic compounds, only a few examples of fluorinated 1,10-phenanthrolines have been described to date. Thus, some 5fluoro substituted 1,10-phenanthrolines were prepared [27] by Skraup-Debner-Miller reaction using the corresponding fluorinated derivatives of 2-nitroaniline. In [28], the synthesis of copper coordination compounds based on 5-fluoro-and 5,6-difluorophenanthrolines was reported and it was shown that such complexes have a cytotoxic effect on cancer cells, while their toxicity to healthy cells (fibroblasts) is lower. 5,6-difluorophenanthroline has been also prepared [29] by electrolysis of 1,10-phenanthroline using a triethylamine hydrofluoric acid complex (Et 3 N·6HF) as a fluorinating agent. Recently [30], 2-fluoro-1,10phenanthroline was obtained in 89% yield from the corresponding chlorine-containing precursor by exposure to a 20-fold excess of KF in the presence of 3 equiv. of 18-crown-6 in a DMSO medium at 110 • C for 96 h. Later [31], isomeric 5-fluoro-1,10-phenanthroline was synthesized by a similar method. 3,8-difluoro-5,6-diphenyl-1,10-phenanthroline [32] was prepared in 58% yield by the Rh(III)-catalyzed reaction of 2,2 -bipyridine N-oxides with internal alkynes. Palladium complexes of phenanthroline fluorinated at 4-position were obtained and luminescence properties of both ligands and their complexes were studied [33]. Some 4-fluorinated derivatives of 1,10-phenanthroline were prepared using intramolecular cyclization of fluorine-containing building blocks [34]. In spite of some progress in the field of fluorinated phenanthrolines, there are no efficient and general methods for their synthesis. It is important to note that to date there are no examples of 1,10-phenanthroline-2,9-dicarboxylic acid diamides containing fluorine atoms in the aromatic cores. This paper is devoted to the study of the synthesis of 4,7-difluorinated phenanthrolines starting from the corresponding dichloro derivatives. The nucleophilic substitution of chlorine for fluorine [35] using cesium or potassium fluorides have been demonstrated as an efficient approach to fluorine-containing N-heterocycles [36]. The advantages of this method are the economy of the fluorinating agent and the ability to work without strict exclusion of air and moisture.

Synthesis and Structure of Fluorinated Phenanthrolinediamide
We used 4,7-dichloro derivatives of phenanthrolinediamides 4 as precursors for the synthesis of fluorinated phenanthrolinediamides. The currently known method for synthesis of 4 is a multistage transformation based on 4,7-dichloro-2,9-dimethylphenanthroline 1, which, in turn, can be obtained by a well-known method from Meldrum acid and ortho-phenylenediamine (Scheme 1) [8]. We started our research by studying the nucleophilic substitution of chlorine atoms in 4,7-dichloro-2,9-dimethylphenanthroline 1 using potassium and cesium fluorides as nucleophiles (Scheme 2). We carried out numerous model experiments to find the conditions for this transformation using various solvents, fluorinating agents, and reaction times. Periodic monitoring of the reaction was performed by NMR spectroscopy. The data obtained indicate that the reaction proceeds completely within 24 h in the case of large excess of a calcined cesium fluoride in dry DMSO at a temperature of 110 • C. Signals of initial phenanthroline 1, intermediate monofluorinated phenanthroline 5, as well as the desired fluorine-containing phenanthroline 6 can be distinguished due to significant difference in chemical shifts of 1, 5, and 6. Figure 2 shows a typical spectral pattern for a reaction mixture of these products upon isolation from the reaction mixture after 8 h of heating at 110 • C. In accordance with the selected conditions, fluorinated phenanthroline 6 was obtained in a yield of 33%. The product is a yellowish powder, noticeably soluble in dichloromethane, chloroform, acetone, and other organic solvents. Traces of moisture negatively affect the yield of 6 due to competitive nucleophilic substitution of halogen atoms with water to form hydroxy derivatives. Isolation and purification of compound 6 is complicated due to its tendency to sublimate. In addition, the intermediate product 5 has similar chromatographic mobility and solubility.
Thus, it became necessary to find another, more effective approach to fluorinated phenanthroline diamides. We decided to study nucleophilic substitution for chlorinated diamides 4a-d. These diamides were prepared using literature methods [8]. We obtained compound 4c for the first time (see the Experimental part and ESI). Ligand 4c is a white powder, highly soluble in chloroform, dichloromethane, ethyl acetate, acetone, and benzene. Due to the amide rotation of [37] substituents, the NMR spectra of compound 4c are predictably complicated. Nevertheless, it is possible to achieve reasonable spectra in C 6 D 6 ( Figure 3). Next, we started investigation of nucleophilic fluorination of 4a-d. Taking into account the results obtained during the fluorination of compound 1, we selected CsF as the fluorinating agent and dry DMSO as the solvent. It was found, using 19 F NMR monitoring of the reaction mixture, that 4 h of heating at 80 • C leads to complete conversion of 4a-d ligands. As a result, we isolated fluorinated ligands 7a-d as white or yellowish powders in 74-88% yields. Some characteristics of these substances are given in Table 1.  Table 1 were predicted using ACD/LogP software.
Detailed analytical data and detailed synthesis techniques are given in the experimental part and ESI. The structure of fluorinated ligands was unambiguously confirmed by the X-ray data on the example of compounds 7a and 7c. The bond lengths and angles in 7a and 7c are similar to each other and close to the expected values for this class of compounds. The amide groups in both ligands in crystal are almost orthogonal to phenanthroline core indicating the absence of any conjugation between these two moieties ( Figure 4). In both molecules, C=O groups of amide fragments are oriented in opposite direction with pseudo torsion angles ca 180 • .
In both 7a and 7c crystals, molecules are involved in centrosymmetric dimers by stacking interaction with interplane distance equal to 3.4 Å ( Figure 5).  The structures of the newly synthesized diamides 4c and 7a-d were studied in solutions using multinuclear NMR. n-Bu substituted diamide 7a and pyrrolidine derived compound 7b demonstrates relatively fast rotation along the "Phen"-C(O) bonds at 25 • C on the NMR time scale; therefore, the spectra contain narrow signals. In their turn, diamides 4c, 7c, and 7d contain aromatic substituents in the amide fragments and demonstrates slow rotation around the "Phen"-C(O) bonds. As a result, 7a-d exist in solutions as mixtures of conformers, interconversions of which are strongly temperature dependent. The signals in the NMR spectra of these diamides at 25 • C are strongly broadened, but become narrow as the temperature rises to 60 • C. As an example, 1 H NMR spectra of 7c in benzene-d 6 at 25 • C and 60 • C are shown in Figure 3. This phenomenon has already been studied by us earlier on the example of diamides of a similar structure [7,9]. The full assignment of the signals in the NMR spectra was done using 2D and 19 F NMR spectroscopy methods [9].
Fluorine-containing phenanthrolinediamides 7a-d are supposed to be investigated in liquid-liquid extraction experiments for the separation of f -elements. Within the framework of this work, we obtained a series of complex compounds of ligand 7a with nitrates of some lanthanoids (La, Nd, Eu and Lu).

Preparation of Complexes with Nitrates of REE
Previously, we obtained a series of complexes of some lanthanoids with the TBuPhen ligand ( Figure 6) which has no fluorine atoms in the structure. We decided to compare electronic properties of nonfluorinated ligand TBuPhen and 7a. For this aim, electrostatic potential (ESP) maps at PBE0/def2-TZVP theoretical level for both ligands in optimized geometries were calculated. ESP maps in two projections shown in Figure 7 (a single potential scale from −0.025 to +0.025 conventional units). Natural bond orbitals (NBO) charges of some atoms for optimized geometries TBuPhen and 7a are given in Table 2. All quantum chemical calculations were performed using Gaussian16 [38] software package at PBE0-D3/def2-TZVP level of theory. Hybrid PBE0 [39,40] functional and Weigend def2-TZVP [41] basis set has recommended itself as a highly accurate method for modeling small organic molecules [42,43]. Grimme's D3 dispersion correction has been used to better estimation of non-covalent interactions [44]. Tight optimization criteria and ultrafine grids were used in each calculation.
ESP maps and calculated charges at the carbonyl oxygens and phenanthroline nitrogens look very similar. However, the corresponding basicity of fluorinated and nonfluorinated derivatives can differ significantly which is very important for the formation of complexes with lanthanoids and the extraction properties of the ligands. For example, pKa of parent pyridine is 5.25. The corresponding value for 4-fluoropyridine is 4.15. pKa for TBuPhen and 7a calculated in a similar manner are 0.54 and −1.22.
The synthesis of complexes of 7a with nitrates La, Nd, Eu, and Lu was carried out by analogy with the method of obtaining TBuPhen complexes [45]. For detailed procedure, see the Experimental part. Their structures were investigated in solid form by IR spectroscopy and X-ray diffraction. The structure of complex compounds 7a•Ln(NO 3 ) 3 was studied by IR spectroscopy and X-ray diffraction in the solid state and by NMR spectroscopy (2D, 1 H, 13 C, 19 F). In the IR spectra of the obtained complexes, there is a shift in the vibrations of the C=O band compared to the value for the ligand by 25-31 cm −1 (Table 3). Attention is drawn to the fact that a decrease in the atomic radius of lanthanoid leads to a decrease in the value of ∆ν(CO). The structure of the complexes 7a•La(NO 3 ) 3 , 7a•Nd(NO 3 ) 3 , and 7a•Eu(NO 3 ) 3 was investigated by X-ray diffraction. Complexes 7a•La(NO 3 ) 3, 7a•Nd(NO 3 ) 3 , and 7a•Eu(NO 3 ) 3 were obtained as isostructural solvates with two acetonitrile molecules. Considering that complexes are isostructural, we will discuss hereinafter the neodymium complex 7a•Nd(NO 3 ) 3 as the most accurate one (Figure 8). The variation of Ln-X bonds in the isostructural series coincides well with the expected lanthanoid contraction [45]. The phenanthroline core acts as a tetradentate ligand. Coordination of lanthanoid cation occurs by binding to two amide oxygen atoms and two nitrogen atoms of the heterocyclic core. The coordination number of lanthanoid ions is supplemented to 10 by three bidentate nitrate anions. The coordination polyhedron of lanthanoid can be described as sphenacorona J87 according to SHAPE 2.1 [46,47]. The mutual arrangement of N-(n-Bu) 2 groups with respect to the phenantroline core is determined by the conformation of the 5-memered LnO(1)C(11)C(2)N(1) and LnO(2)C(21)C(9)N(10) cycles. The latter are both characterized by the envelope conformation with a deviation of corresponding oxygen atom in the same direction. As a consequence, the average N-(n-Bu 2 ) planes are shifted to the same direction with respect to the plane of phenanthroline ring. The deviation of Nd(1) from the plane of coordinated sites of the ligand (N(1), N(10), O(1), and O(2)) is equal to 0.41 Å. The conformation of n-Bu groups is close to all-trans.
Considering that the coordination sphere and coordination number in 7a•Ln(NO 3 ) 3 are identical to TBuPhen•Ln(NO 3 ) 3 [45], it was interesting to estimate the extent to which the introduction of fluorine atoms to phenantroline core affects the Ln-X bonds in the complexes.
As one can see from the selected bond lengths and angles for Nd complexes with ligands 7a and TBuPhen the introduction of fluorine atoms to the ligand leads on the one hand to the elongation of Nd-N bonds, but on the other hand to the similar decrease in the lengths of the Nd-O bonds (Table 4). Thus, it is reasonable to propose that overall interaction energy for particular lanthanoid ion with ligand in the case of 7a and TBuPhen can be almost the same. The introduction of fluorine atoms does not lead to a significant change in the distribution of bond lengths in the phenanthroline core. Comparison of the bond lengths in ligand 7a and the corresponding complex also shows that the change of lengths of the N-C bonds is almost negligible upon coordination. Finally, we can mention that bond lengths C-C of amide with phenanthroline is insensitive to the conjugation and is governed by the steric repulsion. Indeed, the variation of C(9)-C(21) and C(2)-C(11) in complex and pure ligand is on average 0.005 Å, while in complex amide is coplanar to phenanthroline ring and in 7a is orthogonal to it. Table 4. Selected bond lengths and angles for Nd complex with 7a and TBuPhen ligands.
NMR spectroscopy also provides valuable information on the structure of the obtained complexes 7a•Ln(NO 3 ) 3 in CDCl 3 solution. The application of 2D NMR methods makes it possible to make complete attributions in all registered spectra of the complexes. Fragmental views of 1 H NMR spectra are shown in Figure 11. As it may be seen from Figure 11, the presence of lanthanoids strongly affects the shifts of phenanthroline protons in a multidirectional manner depending on the lanthanoid. The full spectral data are given in the experimental part and ESI (Figures S36-S59). In the future, we plan to study in detail the extraction properties of the synthesized fluorinated phenanthroline diamides.

Materials
Chemical reagents such as La(NO 3 ) 3 ·6H 2 O, Nd(NO 3 ) 3 ·6H 2 O, Eu(NO 3 ) 3 ·6H 2 O, Lu(NO 3 ) 3 ·xH 2 O, and other inorganic/organic reagents and solvents were of analytical grade. Water content x in lutetium nitrate was determined as x = 3. Deuterated solvents CDCl 3 and C 6 D 6 for NMR spectra registration were purchased from commercial sources and used without further purification. All syntheses were performed in an argon inert atmosphere. Dimethyl sulfoxide and dichloromethane were purified by distillation over calcium hydride prior to use. Acetonitrile, chloroform, and diethyl ether for the synthesis of complexes were purified according to known procedures.

Methods
The Log P values given in Table 1 were predicted using ACD/LogP software (Advanced Chemistry Development, Inc., Toronto, ON, Canada).
NMR spectra were recorded using standard 5 mm sample tubes on an Agilent 400-MR spectrometer (Agilent Technologies, Santa Clara, CA, USA) with operating frequencies of 400.1 MHz ( 1 H), 100.6 MHz ( 13 C), and 376 MHz ( 19 F). The ROESY spectrum was recorded on an Agilent 400-MR spectrometer using a standard ROESYAD pulse sequence with a mixing time of 200 ms and an acquisition time of 150 ms. IR spectra in the solid state were recorded on a Nicolet iS5 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) using an internal reflectance attachment with diamond optical element attenuated total reflection (ATR) with a 45 • angle of incidence. The resolution is 4 cm −1 ; the number of scans is 32 HRMS ESI mass spectra were recorded on a LCMS-IT-TOF (Shimadzu, Japan) in the negative and positive ion modes. Resolution of the instrument is >10,000 according to the manufacturer. LabSolution software (version 3.80.410, Shimadzu, Kyoto, Japan) was used to acquire and process MS data.
Single crystals of 7a and 7c were obtained upon slow isothermal (25 • C) recrystallization of corresponding substances from hexane, single crystals of complexes 7a•La(NO 3 ) 3 , 7a•Nd(NO 3 ) 3 and 7a•Eu(NO 3 ) 3 were obtained upon slow isothermal (25 • C) crystallization of corresponding substances from acetonitrile. The crystallographic data were collected using Quest D8 diffractometer (Bruker, Munich, Germany) equipped with a Photon-III area-detector (shutterless ϕand ω-scan technique), using Mo Ka-radiation. The intensity data were integrated by the SAINT program and corrected for absorption and decay by SADABS. Structures were solved by direct methods using SHELXT and refined against F2 using SHELXL-2018. Analysis of anisotropic displacement parameters and Fourier density synthesis revealed that in 7a•La(NO 3 ) and 7c, the alkyl groups and NO 3 and La ion are disordered by two positions. The refinement of two positions of carbon atoms were performed with the EADP and DFIX constraints. The positions of hydrogen atoms were calculated and refined in the riding model. Crystal data, data collection, and structure refinement details are summarized in Table S1.
A solution of 4.43 g (25 mmol) of 4-butyl-N-ethylaniline and 3.5 mL of triethylamine (25 mmol) in 10 mL of dichloromethane was added at -10 • C with stirring to a suspension of 3.74 g (10 mmol) 4,7-dichloro-1,10-phenanthroline-2,9-dicarboxylic acid in 25 mL of dichloromethane. Then, the reaction mixture was allowed to heat up to room temperature and stirred overnight. Then, the reaction mixture was allowed to heat up to room temperature and stirred overnight. Next, the reaction mixture was diluted with 50 mL of dichloromethane, washed with water (2 × 50 mL), dried over sodium sulfate and the solvent was distilled. The residue was washed with hexane and recrystallized from a hexane/ethyl acetate mixture. After drying, the product was obtained in the form of a slightly colored powder. Tetramethylammonium chloride (0.23 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.25 mmol) in an argon atmosphere were placed in a three-necked flask equipped with a stirrer and a thermometer. Then, dry dimethyl sulfoxide (30 mL) and 4,7-dichloro-1,10phenanthroline-2,9-dicarboxylic acid (2.0 mmol) were added. The mixture was heated to 80 • C and stirred until the reaction mixture became homogeneous. After that, pre-hardened cesium fluoride (20 mmol) was added and stirred at the same temperature for 4 h. Upon completion of the reaction, the mixture was poured into ice, then extracted in 3 portions of 50 mL of methylene chloride. Dried over sodium sulfate, concentrated, and purified by column chromatography. N 2 ,N 2 ,N 9 ,N 9 -tetrabutyl-4,7-difluoro-1,10-phenanthroline-2,9-dicarboxamide (7a).

Conclusions
Thus, nucleophilic substitution of chlorine atoms was found to be effective for obtaining diamides of 1,10-phenanthroline-2,9-dicarboxylic acid containing fluorine atoms at positions 4 and 7. New fluorinated phenanthrolinediamides 7a-d were synthesized in high yield using DMSO as a solvent and cesium fluoride as a fluorinating agent. The method permits preparation of both N,N,N ,N -tetraalkyl and N,N -dialkyl-N,N -diaryl diamides. The structure of all the obtained ligands was investigated by spectral methods, including 2D and 19 F NMR spectroscopy and X-ray for ligands 7a and 7c. A set of complex compounds with nitrates La, Nd, Eu, and Lu was prepared using ligand 7a as a model. The structure of these complexes has been studied both in solutions and in the solid state. X-ray diffraction analysis of the complexes showed that in the case of La, Nd, and Eu nitrates, these complexes are isostructural, the metal atom is associated with 4 coordination centers of the ligand and three bidentate nitrate groups, reaching a coordination number of 10. The exact structure of the lutetium complex may differ from the complexes with light lanthanoids. We plan to study the features of the structure of this complex in detail.