First Trifluoromethylated Phenanthrolinediamides: Synthesis, Structure, Stereodynamics and Complexation with Ln(III)

The first examples of 1,10-phenanthroline-2,9-diamides bearing CF3-groups on the side amide substituents were synthesized. Due to stereoisomerism and amide rotation, such complexes have complicated behavior in solutions. Using advanced NMR techniques and X-ray analysis, their structures were completely elucidated. The possibility of the formation of complex compounds with lanthanoids nitrates was shown, and the constants of their stability are quantified. The results obtained are explained in terms of quantum-chemical calculations.


Introduction
Amides of 1,10-phenanthroline-2,9-dicarboxylic acid are an important type of tetradentate ligands widely used in modern coordination chemistry. Ligands of this type are capable of forming strong complexes with large cations (ionic radius ≈ 1 Å) in highly acidic media due to the combination of soft nitrogen centers and hard oxygen centers (within the framework of the HSAB concept) in the coordination node. These ligands have large size of the coordination cavity and relatively low Brønsted basicity [1]. Varying the structure of amide fragments and the substituents in the heterocyclic core enables "fine tuning" of the ligand to the requirements of the guest cation. As a result, such an approach is very fruitful in the design of efficient catalytic and solvent extraction systems. In particular, highly selective phenanthroline extractants have been developed for the separation of lanthanoids and minor actinides (Am, Np, Cm) [2][3][4][5], which is one of the most urgent and difficult problems in the development of a closed fuel cycle in nuclear power industry. The high coordinating ability of phenanthroline derivatives towards transition metals made them attractive platforms on which the coordinated metal can serve as a Lewis acid binding site for various substrates. That is why functionally substituted phenanthrolines are increasingly used in asymmetric catalysis (see reviews [6][7][8][9][10][11][12][13]). In recent years, a large number of lanthanoid and rare-earth elements complexes with chiral donor ligands have been obtained [13][14][15]. For example, a scandium complex of C 2 -symmetric phenanthroline derived diol has been successfully used in the enantioselective ring opening of epoxides and amination of β-ketoesters [16]. Recently, the synthesis of some representatives of It should be noted that the application of fluorinated compounds is an important trend of modern chemistry and materials science. In particular, the incorporation of fluorine into the target molecule is recognized as an effective tool in the development of new drugs and materials science. Many important characteristics, such as lipophilicity, metabolism, membrane permeability, binding efficiency and bioavailability can be altered by the inclusion of fluorine. Fluorinated materials have much higher resistance to oxidation, light degradation and hydrolysis. The unification of fluorine chemistry and heterocycle chemistry is especially fruitful for opening new horizons in the synthetic organic chemistry [25][26][27]. Another important advantage providing by the presence of fluorine in a molecule is possibility to use 19 F NMR. Nowadays, this method became a very powerful tool for various structural studies including complex natural objects. This is due to such advantages of 19 F NMR as 100% abundance of 19 F isotope, very broad chemical shifts span (800 ppm) and high sensitivity of this method. Incorporation of CF 3 -groups significantly simplified the study of the stereodynamics of these compounds using 19 F NMR.

Synthesis, Structure and Stereodynamics of Ligands 1 and 2
Synthesis of the "parent" pyrrolidine-derived ligand was first published in 2004 [28]. Later, some properties of this compound were revealed [29].
Starting from (±)-2-(trifluoromethyl)pyrrolidine [30], we obtained new phenanthroline ligands 1 and 2. Then we started their structural study. Both compounds were characterized by combination of spectral methods and high-resolution mass spectrometry. They are white powders, readily soluble in dichloromethane, chloroform, acetone and moderately soluble in acetonitrile and hexane. In spite of simple structure of prepared diamides 1 and 2, their NMR spectra were surprisingly complicated in CDCl 3 solution at room temperature (Figures S1 and S2 in Supplementary Materials) even taking into account that mixtures of diastereomers are under study. The 19 F-NMR spectrum of 1 (Figure 2a) contains a set of 8 signals of CF 3 groups the doublet splitting of which is due to the 3 J 19F,1H spinspin coupling. Simpler picture is observed in the spectrum of the heteronuclear double resonance 19 F-{ 1 H} (Figure 2b). Eight singlets of CF 3 groups of different intensities are clearly seen in it. Eight signals of CO-groups are also present in the carbonyl region of the 13 C-NMR spectrum of 1 (Figure 2c). Such complex 19 F and 13 C-NMR spectra indicate that the internal rotation along Phen-CO bonds in diamides 1 and 2 in solutions at 23 • C occurs as a fast process in the NMR time scale, while the rotation along the amide bonds N-C=O is completely inhibited. Thus, diamides 1 and 2 in this respect behave similarly to other ligands of this type that we studied earlier [23]. As a result, three rotamers along the amide bonds (A-C) (Figure 3), differing in the orientation of -CHCF 3 fragments relative to the phenanthroline backbone, which coexist in solutions, give separate signals in the NMR spectra. Note that processes of this type in arylcarboxamides are well documented [31][32][33][34]. In contrast to symmetric structures A and C, the rotamer B contains two non-equivalent CF 3 -groups in the structure. This consideration allows us to explain very well the observed complicated spectra. To have deeper insight in the equilibrium between rotamers of ligand 1, we decided to separate diastereomers in pure form. The quantitative separation of diastereomers of ligand 1 was carried out by HPLC in the acetonitrile/water system. The chromatogram contains two closely spaced peaks with an intensity ratio of 2:3 (see Figure S50 in Supplementary Materials). At slow isothermal concentration of the acetonitrile solution of the second fraction, crystals of the racemate of 1 suitable for X-ray were obtained ( Figure 4). Depending upon the crystal growth procedure, we were able to investigate two racemic crystal forms of ligand 1, which corresponds to isomer 1A and the hydrate of isomer 1B with one water molecule. The analysis of these two forms clearly shows that they are differ by orientation of pyrrolidine ring in respect to phenanthroline. In 1A and 1B·H 2 O the C=O groups are in trans orientation in respect to nitrogen atoms of phenanthroline while the CF 3 -C-N-C=O torsion angles in 1A and 1B·H 2 O differ. In 1 CF 3 -C groups in both pyrrolidine substituents are in syn-periplanar orientation in respect to C=O groups while in 1B·H 2 O one pyrrolidine group is syn-periplanar while the other is in the antiperiplanar orientation. The variation of mutual orientation of the trifluoromethylated pyrrolidine almost does not affect the bond lengths distribution in amide fragment (see Table 1) but leads to different weak interactions between the trifluoromethylated pyrrolidine and nitrogen of phenanthroline ring. As one can see in the case of 1A N(1) and N(10) atoms participate in formation of the weak contacts with CH 2 group of pyrrolidine ring while in 1B·H 2 O one of C-H . . . N contacts is formed by more acidic C-HCF 3 group. Basing on the geometric parameters one can propose that latter contact with H . . . N distance equal 2.16 Å should be stronger than those (2.36 Å) in 1A and thus such conformation should be more stable.
At the same time, we cannot exclude that stabilization of the conformation in 1B·H 2 O is the consequence of crystal packing effects ( Figure 5). Analysis of crystal packing have revealed that both molecules participate in the formation of infinite stacks with comparable interplane separation (3.38 vs. 3.40 Å) but slightly different area of overlap.
In order to estimate the relative stability of the conformations of the molecule in 1A and 1B·H 2 O we performed DFT (PBE/def-2-TZVP) calculations. The geometry of 1A was optimized using the very tight optimization criteria and empirical dispersion corrections on the total energy [35] with the Becke-Johnson damping (D3) [36]. The optimization of 1A lead to the geometry that is almost identical to those in 1B·H 2 O (see Table 1). Thus, we can assume that this geometry corresponds to global minimum. In order to estimate the possible way of conformation transformation from 1B·H 2 O to the conformation in 1A we check two possible opportunities and performed the relaxed potential energy scan along the Phen-C=O and O=C-N-C-CF 3 torsion angles (step equal to 10 • ). The barrier to rotation for the first coordinate is equal to 14 kcal/mol while for the other it can be as much as 24 kcal/mol. Upon the relaxed scan we have found the additional minimum which geometry is almost identical to those observed in 1A (see Table 1). The difference in energy of these two conformers is only 1.04 kcal/mol.  Aiming at estimating the energy of C-H . . . N contacts in two conformers we have used the topological analysis of the electron density distribution function ρ(r) within Bader's quantum theory of "Atoms in Molecule" (QTAIM) theory [37]. Using the AIM formalism, one can distinguish the binding interatomic interactions from all other contacts. When the distribution of ρ(r) in molecule or crystal is known, one can answer the question whether the bonding interaction is present or not by the search of the bond critical point (3,-1) and predict the energy of weak intermolecular interactions (Econt) with high accuracy on the basis of the potential energy density function v(r) -the correlation suggested by Espinosa et al. (CEML) [38]. Recently, the physical interpretation of CEML was suggested [39].
According to the critical point (CP) search of ρ(r), CP (3,-1) in conformers in 1A and 1B·H 2 O are located not only for all expected bonds but also for weak C-H . . . The energy of H . . . H and H . . . F interaction in both conformers is comparable and vary in the range of 0.4-0.9 kcal/mol. In their turn, the energy of C-H . . . N contacts is higher and equal to ca. 3.2 and 4.6 kcal/mol for CH 2 and CF 3 CH group. As one can see, the difference in energy of this interactions is very close to the estimated difference of the conformers' energy. Thus, the stabilization of conformation is mainly governed the intramolecular H-bond and, although the difference in energy of two conformers is negligible, the conformation obtained in 1B·H 2 O was also observed in the case of meso-2B, which crystallized without any solvate molecules (Figure 7). The interesting feature of 2B is that, due to presence of chlorine substituent, the formation of stacking interaction (with interplane distance ca. 3.3 Å) is accompanied by the Cl . . . π interaction (Figure 8). As expected, the 19 F NMR spectrum of racemic 1 (Figure 9) is simpler, and consists of 4 doublets in the region from -73.9 ppm up to -74.8 ppm. The spectrum of rotamer B should contain two signals of nonequivalent CF 3 groups of equal intensity, while rotamers A and C should have in their 19 F NMR spectra by one doublet each since both CF 3 groups of these rotamers are equivalent. These considerations made it possible to distinguish signals from rotamer B but do not allow the two remaining doublets to be assigned ( Figure 9). The assignment of signals of two different CF 3 -groups of rotamer B (B1 and B2) in the spectrum of racemate was unambiguously confirmed by EXSY 19 F NMR ( Figure 10).
The slow exchange of the positions of CF 3 -groups is observed due to hindered internal rotation along the amide bonds in EXSY spectrum. As a result, the spectrum contains off-diagonal peaks between signals linked to each other by one exchange act. Such peaks are present only between the A→C, B1, B2→C doublets since only one rotation around the amide bond is required for the transitions between these rotamers. The EXSY spectrum at short mixing times has no B1→B2 cross-peaks because two acts of exchange are required for such transition. Consequently, peaks B1 and B2 belong to rotamer B which is realized in the crystal ( Figure 6). Next, the influence of temperature on the ligand 1 rotamers equilibrium was studied in toluene-d 8 . Rising of temperature results in increase of content of rotamers A and C (Table 2) in the equilibrium mixture. A significant increase in the rate of rotation around the amide bonds is clearly observed above 40 • C. As a result, it is possible to observe in the spectra a gradual broadening and merging of signals from rotamers of each of the diastereomers with increasing of temperature, and two very broad signals are seen at 75 • C ( Figure 11).
The potential energy surfaces of rotamers A-C of both diastereomers are rather complex. There are several very close local minima differing in dihedral angles for Phen-CO bonds (the difference in free energies is ±0.5 kcal/mol) near the global minima. The structures corresponding to the global minima are shown in Figure 12.
As it can be seen, all rotamers A-C have practically similar stability in the gas phase, but they differ significantly in their dipole moments. Therefore, it is possible to expect that the equilibrium between rotamers can be shifted by solvent polarity change. Indeed, measurement of spectra in four different solvents (toluene, chloroform, acetone and nitrobenzene) confirmed our proposal. Rising the polarity of the solvent leads to an increase in the content of the most polar rotamers A and B, while the content of non-polar rotamer C decreases (Table 3).   Based on these data, one can assign the signals of rotamers A and C. As a result, we have clear understanding of spectral data for mixture of rotamers A-C. The results obtained for a solution in toluene fall out somewhat from the general dependence. This means that, although the polarity of the solvent is the main factor determining the equilibrium position, other factors, such as the solvent ability to form hydrogen bonds, should be also considered.
We were unable to obtain crystals of the meso-form of 1 suitable for X-ray studies. However, having solved the problem of assigning the signals of the rotamers of the racemic 1, it was possible to make the unambiguous assignment of the signals of rotamers of the meso-form as well. The 19 F-{ 1 H}-NMR spectrum in CDCl 3 is given in Figure 2b. Two singlets of equal intensity at -73.75 ppm and -74.81 ppm are related to rotamer B (72% at 21 • C). Two singlets at -73.73 ppm and -74.19 ppm belong to rotamers A and C (14% each at 21 • C). The assignment of signals in this spectrum was done according to two-dimensional NMR spectra (see Figures S9-S13 in Supplementary Materials).
Having established the approach for structure elucidation applied for ligand 1, we were able to determine the structure and composition of diastereoisomers of diamide 2 using a combination of 1 H, 13 C and 19 F NMR spectra (Table 4). The 19 F NMR spectra of mixture of diastereomers of diamides 1 and 2 are substantially similar (Figures 2 and 13). As a result, it possible to distinguish all groups of lines in the spectrum of diamide 2 related to rotamers A-C for both the meso-form and the racemate. All 8 singlets of CF 3 -groups belonging to 6 rotamers are present in the 19 F-{ 1 H}-NMR spectrum in CDCl 3 ( Figure 13). The ratio of two diastereomers of compound 2 is 2:3 according to the integration data. Thus, ligands 1 and 2 have the same ratio of diastereomers.

Complexation of Ligands 1 and 2 with Ln(III) Nitrates
The prepared amides 1 and 2 are highly attractive ligands for various cations. Based on ligand 1, we obtained a series of complexes with nitrates of La, Nd, Eu, and Lu. It was expected that such interaction can lead to complexes of both 1:1 and 2:1 L:Ln stoichiometry. Using acetonitrile as a solvent for this reaction we were able to synthesize L·Ln(NO 3 ) 3 complexes. Complexes of diamide 1 with nitrates La (III), Nd (III), Eu (III), and Lu (III) of 1:1 composition were isolated from solutions in acetonitrile in solid form as light-colored powders. We studied all these complexes using IR and 19 F NMR spectroscopy. The coordination of the metal leads to a bathochromic shift of the ν C=O stretching vibration band in the IR spectrum by 42 cm −1 in the lanthanum complex. This shift rises with an increase in the atomic number of the cation to reach 49 cm −1 for Lu complex. Some characteristics of 1·Ln(NO 3 ) 3 complexes are given in Table 5.  Figure 14). Due to formation of coordination bonds, the amide rotation stops in these cases. This results in two doublet signals are observed in each spectrum which belongs to a complex of racand mesoforms, respectively. Having confirmed the possibility of the formation of complexes for the ligands obtained we measured the stability constants by the UV-Vis spectrophotometric titration method. The stability constants were determined by spectrophotometric titration in the UV-visible region (Table 6, Figure 15).   Additionally, we obtained electrostatic potential (ESP) maps at B3LYP/G-31G(d,p) theoretical level (Gaussian 16 [40]) for both ligands. ESP maps in two projections are given in Figure 16 (a single potential scale from −0.01 to +0.015 conventional units). The introduction of chlorine in a phenanthroline system leads to a significant change in electron density of the molecules.
Merz-Kollman (ESP) charges of some atoms for optimized geometries of 1 and 2 are shown in Table 7.
Thus, less effective complexation of 2 with lanthanoids can be associated with the decreased charges at amide oxygens and phenanthroline nitrogens of 2 in comparison to diamide 1, because it leads to weaker ionic component to Ln-O and Ln-N bonds.

Methods
NMR spectra were recorded at room temperatures (if otherwise not stated) using standard 5 mm sample tubes on Agilent 400-MR spectrometer equipped with OneNMR and ATB probes with operating frequencies of 400.1 MHz ( 1 H), 100.6 MHz ( 13 C) and 376.0 MHz ( 19 F). The concentrations of ligands and their complexes were 20 g·L −1 . For NMR of racemic 1 the concentration was 1 g·L −1 . Deuterated solvents for NMR spectra were purchased from commercial sources and used without further purification.
IR spectra were recorded on FTIR spectrometer Nicolet iS5 (Thermo Scientific) using an internal reflectance attachment with diamond optical element -attenuated total reflection (ATR) with 45 • angle of incidence. Resolution 4 cm −1 , the number of scans is 32.
HRMS ESI (+) mass spectra were recorded on the MicroTof Bruker Daltonics and Orbitrap Elite instruments.
The crystallographic data was collected using Bruker Quest D8 diffractometer equipped with a Photon-III area-detector (shutterless φand ω-scan technique), using Mo K a -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 F 2 using SHELXL-2018.
Detailed crystallographic data provided here in the Supplementary Materials. UV−Vis spectra were recorded at the temperature 25.0 ± 0.1 • C in the wavelength region of 200−400 nm (0.5 nm interval) on a Shimadzu UV 1800 spectrophotometer controlled by LabSolutions UV−Vis software with thermostatic attachment (Shimadzu TCC-100) using quartz cuvettes with an optical path length of 10 mm. A stock solution of the ligand was prepared (ca. 10 −4 mol/L) by dissolving respective ligand in CH 3 CN, and then a working ligand solution (ca. 10 −5 mol/L) was prepared from the initial solution. A working titrant solution (10 −3 mol/L) was prepared by dissolving corresponding lanthanoid (III) nitrate hydrate Ln(NO 3 ) 3 ·6H 2 O (Ln = La, Nd, Eu, Lu) in CH 3 CN. Acetonitrile (CH 3 CN; 99.95%, HPLC grade, Panreac AppliChem) was dried over molecular sieves (zeolite KA, 3 Å, balls, diameter 1.6−2.5 mm, production HKC Corp., Hong Kong) prior to use. The titration was carried out by adding 2 µL aliquots of the working metal cation solution to 2 mL of the working ligand solution in the titration cell. The titration continued until no obvious change was observed in the spectra. The stability constants of the Ln(III) complexes were calculated using the HypSpec2014 program.

Synthesis of Diamides
A solution of (±)-2-(trifluoromethyl)pyrrolidine (12.5 mmol) and 1.74 mL of triethylamine (12.5 mmol) in 10 mL of methylene chloride was added at -10 • C under vigorous stirring to a suspension of 5 mmol of the corresponding chloride in 50 mL of methylene chloride. Then the reaction mixture was allowed to reach room temperature followed by refluxing for 4 h. Next, the reaction mixture was diluted with 50 mL of methylene chloride, washed with water (2 × 50 mL), dried over sodium sulfate, and the solvent was distilled off. The residue was purified by recrystallization from a mixture of hexane/ethyl acetate or by silica gel column chromatography (eluent: hexane/acetone = 7/3), obtaining the desired product in the form of a white or slightly colored solid.

Synthesis of Complexes 1·Ln(NO 3 ) 3
A solution of lanthanoid nitrate (0.1 mmol) in dry acetonitrile (1 mL) was added dropwise to a solution of L (0.1 mmol) in chloroform (1 mL). After that the reaction mixture was concentrated in vacuo (~20 Torr) to 1/5 of the initial volume and treated with diethyl ether (2 mL). The resulting precipitate of the complex was filtered, washed with a fresh portion of ether, dried in air, then at 80 • C at~2 Torr.

Quantum Chemistry Computations
Quantum chemistry computations were performed with the Gaussian 16, Revision C.01 program [40] using the density functional theory (PBE0) [42] and the def-2-TZVP basis set. Topological analysis of the ρ(r) function, calculations of the v(r bcp ) and integration over interatomic zero-flux surfaces were performed using the AIMAll program. [43] All expected critical points were found and the whole set of critical points in each system satisfies the Poincaré-Hopf rule.
Molecular geometries have been fully optimized (tolerance on gradient: 10 −7 au) at PBE/L1 [44] level of theory using a PRIRODA-19 program developed by Laikov [45]. All stationary points on the potential energy surface (PES) were checked by vibrational analysis and none of them had imaginary frequencies.
Geometries of both ligands were optimized at B3LYP/6-31G(d,p) theoretical level, after that ESP maps were calculating using Gaussian 16 program [40].

Conclusions
To summarize, first trifluorinated phenanthrolinediamides 1 and 2 were synthesized using 2-CF 3 -pyrrolidine. Both new ligands are formed as a mixture of diastereomers-meso-(R,S) and rac-(R,R and S,S) in a 2:3 ratio. The structure of racemic 1 was determined by X-ray. A detailed study of the 1 H, 13 C and 19 F NMR spectra as well as EXSY and ROESY techniques in solvents of different polarities and at different temperatures were performed for both ligands. It was found that each of the diastereomers in solutions exists in the form of three rotamers caused by hindered rotation along the amide bonds. The ratio of rotamers in equilibrium mixtures is determined by the polarity of the solvents and the temperature. The structures of diastereomers and rotamers for ligand 1 were calculated by the density functional theory. It was shown that both diamides 1 and 2 are efficient ligands to form complexes with lanthanoids nitrates (La, Nd, Eu, Lu) in acetonitrile media. The stability constants of the complexes were determined by spectrophotometric titration. It was found that ligand 1 can form complexes of 1:1 and 2:1 composition, whereas less basic ligand 2 forms only 1:1 complexes.