Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2019, 84, 9075−9086
2H‑Indazole Tautomers Stabilized by Intra- and Intermolecular Hydrogen Bonds Mark V. Sigalov,*,† Andrey V. Afonin,‡ Irina V. Sterkhova,‡ and Bagrat A. Shainyan‡ †
Department of Chemistry, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel Siberian Division of Russian Academy of Sciences, A. E. Favorsky Irkutsk Institute of Chemistry, 664033 Irkutsk, Russia
‡
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S Supporting Information *
ABSTRACT: 2-[(2H-Indazol-3-yl)methylene]-1H-indene-1,3(2H)-dione 6 and (E)-2-[(2H-indazol-3-yl)methylene]-2,3-dihydro-1H-inden-1-one 7 have been synthesized. In the crystal, the NH hydrogen atom of 6 is disordered between the N(1) and N(2) atoms with the population ratio of 0.69:0.31. Molecule 7 crystallizes in two tautomeric polymorphs: 7-1H tautomer (yellow) and 7-2H tautomer (red). Both 6 and 7 form centrosymmetric dimers in the crystal with the monomeric units linked by CO···H···N bifurcated hydrogen bonds in 6 and N−H···N hydrogen bonds in 7. According to 1H and 13C NMR data, in DMSO-d6 solution, the 6-1H tautomer predominates, whereas in less polar CDCl3 or CD2Cl2, the 6-2H tautomer is stabilized by a strong N−H···OC intramolecular hydrogen bond. Compound 7 in dimethyl sulfoxide (DMSO) or ethanol solutions exists in the form of 7-1H and 7-2H tautomers. On the example of the 7-2H tautomer, it was shown for the first time that the 2H tautomers of 3-substituted indazoles can be stabilized by an intermolecular hydrogen bond and may remain in aprotic solvents almost indefinitely. However, in the open air or in water, fast 2H → 1H tautomerization occurs. As follows from density functional theory calculations, the high stability of the 2H form in solution is due to the formation of centrosymmetric dimers, which are more stable than the corresponding dimers of the 1H tautomer.
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INTRODUCTION Investigation of tautomeric equilibria of heterocyclic compounds is of great interest to organic chemists for a number of reasons. Apart from fundamental implications for theoretical chemistry,1,2 the phenomenon of tautomerism is very important for biological activity since the latter depends on the tautomer-receptor specific interactions.3−5 Different tautomers also provide different hydrogen-bonding sites as ligands or in forming supramolecular networks.6 For a long time, it was generally accepted that irrespective of the aggregate state or medium,7 or substitution in the indazole ring,8 the 1H tautomer of indazole 1 is significantly more stable than its 2H-counterpart9−11 (Scheme 1). The lower stability of the 2H-indazole as compared with the 1H tautomer was explained by the loss in aromaticity in view of its quinoid structure.12 The theoretically estimated gas-phase energy difference amounts to 3.6 kcal/mol (MP2)13 or 5.3 kcal/mol (B3LYP)14 in favor of 1H-indazole. There have been attempts to shift the tautomeric equilibrium toward 2H-indazole by varying the substituents: the calculated energy difference between the
tautomers for 3-NO2 and 3-MeOC(O) derivatives decreased, although the 1H-indazole tautomer remained more stable.14 According to calculations, 2H tautomers of methyl 6Hpyrazolo[4,3-d][1,2,3]triazine-7-carboxylate 2 and methyl-2Hdibenzo[e,g]indazole-3-carboxylate 3 are stable (Scheme 2), Scheme 2. Theoretically Estimated (2, 3) and Experimentally Observed (4) Stable 2H-Indazole Derivatives
although no information on their synthesis is available. The first example of unprecedented stabilization of the 2H-indazole motif in osmium(IV) complex 4 was recently reported (Scheme 2).15 However, the isostructural ruthenium complex16 contains in its anionic part the 1H-indazole moiety as a ligand. Recently, we have shown that the inclusion of the indazole fragment into the 7-membered ring, closed by the N−H···O
Scheme 1. Indazole Tautomerism
Received: April 14, 2019 Published: June 26, 2019 © 2019 American Chemical Society
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DOI: 10.1021/acs.joc.9b01021 J. Org. Chem. 2019, 84, 9075−9086
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such centrosymmetric dimers containing strong intermolecular N−H···OC hydrogen bonds was shown by us earlier for pyrrolylidene derivatives of 1-indanone both in crystals and in solution.20 The formation of cyclic dimers in the case of the studied indazole derivatives can stabilize both the 1H- and 2H tautomers, as shown in Scheme 6.
C hydrogen bond in molecule 5, also stabilizes the 2H tautomer.17 However, it is still rather unstable as follows from easy Z,E-isomerization in compound 5, especially in polar solvents, leading to the rupture of the H-bond and to the reverse tautomerization to the 1H-form (Scheme 3).17 Scheme 3. Structure of Z,E and E,E Isomers of Compound 5
Scheme 6. Dimers of Compounds 6 and 7 Linked by N−H··· OC Hydrogen Bonds
In continuation of our attempts to stabilize the 2H tautomers of indazoles, we searched for more suitable compounds and investigated the possibility of stabilizing the 2H-indazole tautomer of 2-(indazol-3-yl)methylene-1H-indene-1,3(2H)-dione 6 by intramolecular hydrogen bonding, which is possible only in the 2H- but not in the 1H tautomer (Scheme 4).
Finally, in the case of compound 7, centrosymmetric dimers closed by N−H···N hydrogen bonds can also be formed for both the 1H- and 2H tautomers (Scheme 7).
Scheme 4. Tautomers of 2-(Indazol-3-yl)methylene-1Hindene-1,3(2H)-dione 6
Scheme 7. Dimers of Compound 7 Linked by N−H···N Hydrogen Bonds
For the sake of comparison, the adduct of 3-indazolcarbaldehyde with 1-indanone, (E)-2-[(1(2)H-indazol-3-yl)methylene]-2,3-dihydro-1H-inden-1-one 7, was synthesized and studied. Similar to 6, molecule 7 can exist in two tautomeric forms, neither of which can be stabilized by an intramolecular hydrogen bond with the carbonyl oxygen (Scheme 5).
Therefore, as follows from Schemes 6 and 7, stabilization of the indazole 2H tautomer of 6 may be not only due to intramolecular but also intermolecular hydrogen bonds.
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RESULTS AND DISCUSSION X-ray Structural Analysis. Single crystals of compounds 6 and 7 were obtained by vaporization from chloroform and ethanol, respectively. The molecular structures are depicted in Figure 1. Crystal data, data collection, and structure refinement details are summarized in Table S1 (Supporting Information). Principal bond distances, bond angles, and torsion angles are presented in Table S2, and hydrogen-bond characteristics, in Table S3. In the crystal, molecule 7 adopts the E-configuration. The same configuration was found for similar molecules.20,21 Besides, the indazole fragment and the indandione moiety in molecules 6 and 7 adopt the trans-arrangement with respect to the exocyclic double bond (Figure 1). The hydrogen atom H(2) [H(2′)] in molecule 6 is disordered between two positions: at N(1) and N(2) atoms with the N(1)H/N(2)H ratio of 0.69:0.31. In the 6-2H tautomer, a strong intramolecular hydrogen bond N−H···O is formed as proved by the intramolecular distance H(2′)···O(2) of 2.087 Å. Detection of the 6-2H form in the crystal is the first experimental proof of the existence of the 2H tautomer of indazole caused by the N−H···O intramolecular hydrogen
Scheme 5. Tautomers of (E)-2-[(1(2)H-Indazol-3yl)methylene]-2,3-dihydro-1H-inden-1-one 7
No geometric isomers with respect to the exocyclic CC bond are possible in molecule 6. According to experimental and theoretical estimations for a large series of compounds containing the pyrrole ring and having the intramolecular hydrogen bond N−H···OC closing the 7-membered ring, the hydrogen-bond energy amounts to 5−9 kcal/mol.18,19 Apparently, this energy gain outweighs the above-mentioned predominance of the more aromatic 1H tautomer. Stabilization of the 6-2H tautomer by a strong intramolecular N−H···OC hydrogen bond allows one to assume that the 7-2H tautomer can be stabilized also by intermolecular hydrogen bonds in cyclic dimers, provided that they are closed by the H-bonds of the same type. Indeed, the formation of 9076
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observed 7-α → 7-β gradual transformation upon standing is, apparently, the reason for the presence of both tautomeric forms in the crystal of the red form (vide supra). Note that polymorphism of 3-substituted indazoles was reported in the literature;28 however, the polymorphs were shown to differ in crystal packing, rather than in the position of the NH proton, both polymorphs being 1H-indazole derivatives. The crystal structure of 7 and 6 is similar. Both polymorphs, 7-α and 7-β, form centrosymmetric dimers in the crystal linked by two intermolecular N(2)−H(2)···N(1) and N(1)−H(1)··· N(2) hydrogen bonds (2.150 and 2.207 Å, respectively) forming the 6-membered ring motifs (Figure S5). The dimers form chains (Figure S6). NMR Spectroscopic Study: Spectral Evidence of 1H → 2H Tautomerism and Solvent Influence. The 1H NMR spectrum of 6 in CDCl3 is shown in Figure 2a. Its main feature is a large downfield shift of the NH proton (δ = 15.5 ppm), which is indicative of a strong hydrogen bond N−H···O and, probably, of the existence of the 6-2H tautomer in solution. However, this issue requires special consideration including additional data. The electronic structures of 1H- and 2H tautomers of indazole 1 are significantly different because of the less aromatic character of the latter form.12 This difference must be reflected in the 13C NMR spectra, so the comparison of 13C chemical shifts is a convenient and reliable way to distinguish between the 1H- and 2H tautomers of indazole derivatives. The 13C NMR spectrum of indazole 6 is shown in Figure S8, and the values of 13C chemical shifts are presented in Table S4. To develop criteria for establishing tautomeric forms, we have analyzed the 13C NMR data for a series of model benzenefused 5-membered heterocycles isostructural to the 1H- and 2H tautomers of indazole (Table S4). The most distinctive feature of the data in Table S4 is the upfield shift of the C-7 resonance to 109−111 ppm in compounds isostructural to the 1H tautomer, whereas C-7 in the isostructural analogues of the 2H tautomer resonates at 118−119 ppm. Besides, the C-7a resonances fall in the range of 135−140 ppm in the first series of compounds, whereas in the second one they fall within the range of 145−150 ppm. Hence, the δ(C-7) and δ(C-7a) chemical shifts of 120.4 and 150.1 ppm clearly show that 2-(indazol-3-yl)methylene-1H-indene1,3(2H)-dione 6 exists as the 2H tautomer stabilized by the N−H···O intramolecular H-bond. 3-Indazol-carbaldehyde 8, the starting compound for the synthesis of compounds 6 and 7, according to its chemical shifts δ(C-7) and δ(C-7a) (109.7 and 140.9 ppm, respectively), exists in the 1H tautomeric form. The transition from the 1H- to 2H-form in going from 8 to 6 is also proved by the 4.4 ppm downfield shift of the NH proton resonance, from 11.1 to 15.5 ppm (Figure 2a), suggesting the formation of a fairly strong N−H···O intramolecular H-bond (Scheme 5),18,20,29,30 which is possible only in the 6-2H tautomer. To obtain additional evidence of the proper assignment of tautomeric forms of indazoles 6 and 8, we compared the experimental and calculated δ(13C) values for the corresponding 1H- and 2H tautomers (Table S5). As follows from the data in Table S5, the mean absolute error (MAE) of the calculated δ(13C) values is much less for 6-2H than for 6-1H (0.9 and 5.6 ppm, respectively). On the contrary, MAE for the 8-1H tautomer is much less than for the 8-2H tautomer (1.6 and 5.5 ppm, respectively). This is an independent evidence of
Figure 1. Molecular structures of compounds 6 (mixture of 6-1H and 6-2H tautomers, proton disordered between N1 and N2 atoms) and 7 (mixture of 7-1H and 7-2H tautomers, polymorph 7-α) and pure 71H tautomer (polymorph 7-β) Oak Ridge thermal ellipsoid plot (50% probability level).
bonding in spite of the presence of the free N(1) site in the molecule. In the crystal, molecules 6 form centrosymmetric dimers linked by two intermolecular C(8)O(2)···H(2)−N(2) bifurcated hydrogen bonds (Figure S1). 2H Tautomers of molecule 6 form centrosymmetric dimers also linked by two bifurcated hydrogen bonds with a stronger intramolecular component N(2)−H(2′)···O(2)C(8) (2.087 Å) and a weaker intermolecular component N(2)−H(2′)···N(1) (2.220 Å) (Figure S1). For compound 7, the yellow form was determined to be the 7-1H tautomer, whereas the red form showed disordering of the NH proton between the N(1) and N(2) nitrogen atoms, as in its analogue 6, in the ratio of 0.82:0.18 in favor of the 1H tautomer (Figure 1). As no intramolecular hydrogen bond can be formed in 7, the existence of the 7-2H tautomer is an experimental proof that the indazole 2H tautomers can be stabilized not only by intramolecular but also by intermolecular hydrogen bonding. When the solid sample of freshly prepared red crystals of 7 was exposed to open air overnight, the color turned yellow. Therefore, we face here the phenomenon of socalled tautomeric polymorphism, when the compound crystallizes in two forms differing in the position of a labile proton (most often OH or NH).22−26 Tautomeric polymorphism is considered as a very rare phenomenon.23 According to the accepted nomenclature,27 the metastable form of 7 (red crystals) should be referred to as polymorph 7-α and the stable form (yellow crystals) as polymorph 7-β. The 9077
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Figure 2. 1H NMR spectrum of compound 6 in CDCl3 (a) and in DMSO-d6 (b).
Scheme 8. Proton Transfer between the Pyridine and Indazole Rings in 6·Pyridine Complex
DMSO-d6 results in the equilibrium between the 1H- and 2H tautomers, which is shifted to the former. The 1H NMR spectrum of compound 6 in pyridine-d5 is quite different from those in CDCl3 or DMSO-d6: the aromatic protons of the 1,3-indandione moiety form an AA′BB′ spin system (Figure S12). This is indicative of fast (on the NMR time scale) rotation about the C-8−C-9 bond, which results in averaging the chemical shifts of the proton pairs H-11,14 and H-12,13. Besides, the NH signal disappears from the spectrum. The most probable reason for this effect is the fast NH proton exchange between indazole 6 and the pyridine molecules, lowering the order of the C-8−C-9 bond and, thereby, the barrier to rotation about this bond (Scheme 8). The fast proton exchange also broadens the NH signal. An intriguing observation was made when studying the NMR spectra of polymorphs 7-α (red, 7-2H tautomer) and 7β (yellow, 7-1H tautomer). Because of poor solubility in less polar solvents, the spectra were recorded in acetone-d6, ethanol-d6, CD3CN, DMSO-d6, and pyridine-d5 solutions. A general rule is that crystalline polymorphs become identical in solution.31 Surprisingly, the solutions of 7-α and 7-β in all
the existence of indazole 8 in the conventional 1H-form, whereas for indazole 6 the unusual 6-2H tautomeric form is favored. The 1H NMR spectrum of 6 undergoes drastic changes in going from CDCl3 to DMSO-d6 solution (cf. Figure 2a,b). Most remarkable is the appearance of two signals at 15.4 and 14.4 ppm integrated as 1:2 and belonging to two different NH groups (Figure 2b). Taking into account that DMSO-d6 only slightly weakens strong N−H···O intramolecular H-bonding20,29,30 and comparing these chemical shifts to those in CDCl3 (15.5 ppm, Figure 2a), the minor signal at 15.4 ppm (Figure 2b) can be assigned to the 6-2H tautomer. The position of the major signal is close to that of the NH proton of aldehyde 8 in DMSO-d6 (14.2 ppm, Figure S9), confirming its belonging to the 6-1H tautomer. The 13C NMR spectrum of 6 in DMSO-d6 (Figure S11a) provides an additional evidence of the presence of two tautomers in solution: both aforementioned characteristic signals of C-7 in the 1H tautomer and of C-7a in the 2H tautomer appear in the spectrum, at ca. 110 and 150 ppm, respectively. Therefore, dissolution of 6 in polar 9078
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Figure 3. Aromatic part of 1H NMR spectra of 7-2H (a) and 7-1H (b) tautomers in ethanol-d6.
solvents except pyridine gave different 1H NMR spectra as clearly seen in Figure 3 on the example of the spectrum in ethanol-d6. To the best of our knowledge, this is the first observation of different spectra of tautomeric polymorphs in solution. Furthermore, samples 7-α and 7-β keep their color upon dissolution. The wavelength of the absorbed color has been known to increase when the highest occupied molecular orbital (HOMO)−lowest unoccupied molecular orbital (LUMO) energy gap decreases.32 According to our B3LYP/6-311+ +G(d,p) calculations, the HOMO−LUMO energy gap in the 7-2H tautomer becomes lower by 0.55 eV compared with that of the 7-1H tautomer (3.25 vs 3.80 eV). This corresponds to a change in the color of the substance on going from compound 7-α to compound 7-β from yellow to red (Figure S24). The olefinic proton signal in the proton spectra of 7-1H and 7-2H tautomers recorded in all used solvents excluding DMSO-d6 (see below) appears at 7.9−8.2 ppm as a characteristic triplet due to long-range coupling with the endocyclic methylene group (4JHH ∼ 2 Hz, Figure 3 and refs 20, 21). Such a downfield resonance is indicative of the Econfiguration of both tautomers of 7 in solution. Additional evidence of the E-configuration of tautomers 7-1H and 7-2H comes from the two-dimensional nuclear Overhauser spectra (Figure S15): the cross-peaks between the CH triplet and the H-4 multiplet of the indazole moiety unambiguously prove that they are spatially close to each other, which is possible only in the E-configuration with trans-orientation of the C-8− C-9 and C-3−C-4a double bonds. The trends revealed by the analysis of the 13C spectra of model compounds (Table S4) can be used to interpret the 13C spectra of compounds 7-yellow and 7-red (Figures S16 and S18, respectively). The key parameters allowing the assigning
of 7-red and 7-yellow to specific tautomers are the C-7 and C7a chemical shifts. These values (118.2 and 151.0 ppm in 7red, and 111.1 and 141.0 ppm in 7-yellow) unequivocally prove the 2H tautomeric structure of 7-red and 1H-structure of 7-yellow. The assigned 13C chemical shifts together with the calculated ones can be found in Table S6. As follows from the data of Table S6, the calculated 13C chemical shifts for tautomers 7-2H and 7-1H match well with the experimental ones for 7-red and 7-yellow. In this regard, it should be noted that we have faced an amazing effect when recording the 1H and 13C NMR spectra of the freshly prepared solution of 7-red in DMSO-d6. The signals of the CH2 group completely disappeared. Besides, the olefinic proton became a singlet (instead of a triplet) at 7.94 ppm, and a 1:1:1 triplet of the CH2D group in CD3SOCH2D appeared alongside the CHD2 quintet of the solvent. Remarkably, no exchange occurs in 7-1H, nor it was found in other solvents used is this study. The only reasonable explanation seems to be deuterium exchange with the CD3 groups of DMSO-d6 (Figures 4a and S17, S18). In nondeuterated DMSO, the signals of the CH2 group of compound 7-red are present in both the 1H (4.25 ppm, Figure 4b) and 13C NMR (35.1 ppm, Figure S18b) spectra, thus proving the deuterium isotope exchange as the reason for the observed spectral changes in DMSO-d6. An additional evidence of the deuterium exchange was obtained from highresolution mass spectrometry (HRMS) data (see the Experimental Section): the molecular masses of 7-red isolated from the reaction mixture and the one dissolved in DMSO-d6 differ by 3 amu, indicating the deuterium exchange in the CH2 and NH groups in 7-red. A tentative mechanism shown in Scheme 9 includes repetitive cycles of deprotonation of the indazole moiety by dimethyl sulfoxide (DMSO) as a base, 1,59079
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Figure 4. 1H NMR spectra of compound 7-red in DMSO-d6 (a) and in nondeuterated DMSO (b).
Scheme 9. Tentative Mechanism of the Deuterium Isotope Exchange in 7-2H with DMSO-d6
deprotonation as compared with 7-1H. An alternative mechanism without complete deprotonation but proceeding through the solvate complex with DMSO also cannot be ruled out. In this case, the DMSO molecule coordinated to the N(2)−H proton can interact with the CH2 group of the indanone ring, whereas when coordinated to the N(1)−H
proton transfer from the indanone CH2 group to N-2, and deuteration of the formed carbanion. An intriguing question is why the observed deuterium exchange occurs in the 7-2H but not in the 7-1H tautomer. Within the proposed mechanism, this can be explained by a higher acidity of the former tautomer facilitating its 9080
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Figure 5. 1H NMR spectrum (CDCl3) of 7-Z, obtained by UV irradiation of 7-1H in ethanol.
the solvent, and recorded the spectrum of the yellow residue in CDCl3 (Figure 5). In the 1H NMR spectrum (CDCl3) of the solid obtained after UV irradiation of the ethanol solution of tautomer 7-1H with subsequent solvent evaporation, besides the triplet signal of H-8 at 7.34 ppm, a broad singlet of the NH proton appeared at 15.7 ppm, indicating the formation of a strong N−H···O intramolecular hydrogen bond (Figure 5), which can be formed only in the Z-isomer. This experiment provides independent evidence of 7-E → 7-Z transformation upon UV irradiation followed by proton transfer from N-1 to N-2 (Scheme 10).
proton, it is spatially inaccessible. So, irrespective of the mechanism, the deuterium exchange is more feasible in the 72H tautomer. In time, tautomer 7-2H is converted to 7-1H. Thus, solid 72H, when exposed to open air overnight, becomes yellow and shows the 1H NMR spectrum identical to that of 7-1H. The same result was observed when the solution of 7-red was poured into water. However, in a sealed NMR tube, the spectrum of 7-2H in DMSO remained unchanged for a long time (Figure S23; see the next section for a more detailed theoretical analysis). After heating the solution of tautomer 72H in DMSO-d6 for 1 h at 170 °C, pouring into water, filtering, and drying, the product was also shown to be pure 7-1H. These experimental findings allow one to understand the appearance of two tautomers in the X-ray crystal structure of 7red. Whereas the NMR spectra of 7-red registered immediately after its isolation from the reaction mixture showed the presence of only one form, its crystallization from ethanol solution in open air took several days. During this time, the 2H tautomer was partly transformed into the 1H tautomer. While the NMR spectra of 7-2H (red) and 7-1H (yellow) tautomers in DMSO-d6 or in ethanol-d6 are different (Table S6, Figures 3 and S13, S17), both forms give the same spectrum in pyridine-d5 (Figures S19 and S20), which, judged from the δ(C-7) and δ(C-7a) values in the 13C spectra, belongs to the 7-1H tautomer. Apparently, this is due to the fast reversible transfer of the indazole NH proton in 7 to the pyridine molecule (as shown in Scheme 8 for compound 6) shifting the equilibrium to the more stable 7-1H tautomer. As typical representatives of chalcones, isomers 7-1H and 72H can undergo photoinduced E → Z-isomerization.20,21 Indeed, after UV irradiation of ethanol-d6 solution of 7-1H for 2 h, the signals of the E-isomer disappeared, and a new set of signals appeared corresponding to the Z-isomer. Its structure was proved by the presence of a triplet of the olefinic proton at 7.34 ppm (4JHH = 2.4 Hz), which is close to that in other heterocyclic chalcones having the Z-configuration.17,20,21,33−35 The NH signal could not be seen in this experiment because of H/D exchange with the solvent. To avoid this exchange, we performed the irradiation in nondeuterated ethanol, removed
Scheme 10. Photoinduced E → Z-Isomerization of 7-1H
The 7-2H → 7-1H isomerization was chemically proved by converting both red and yellow forms to the same 1-Ac derivative 9 by the reaction with acetyl chloride (Scheme 11). The structure of 9 was evident from its 1H and 13C NMR spectra (Figures S21 and S22); the chemical shifts of the key heterocyclic carbons C-7 and C-7a are very close to those of 1acetyl-indazole.36 Theoretical Analysis. The energetic preference of 1Hwith respect to the 2H tautomer of indazole varying from 3.6 to 5.3 kcal/mol in favor of the former (vide supra) is reversed for compound 6 and at the B3LYP/6-311++G(d,p) level of theory amounts to 9.8 kcal/mol in favor of the 6-2H tautomer. Evidently, this is due to a short (1.800 Å) and, hence, very strong intramolecular N−H···O hydrogen bond making 6-2H more stable than 6-1H having no such hydrogen bond. The intramolecular hydrogen bonding also strongly increases the conjugation in the OC−CC−CC chain in the 6-2H tautomer having a s-cis-s-trans-configuration, as compared with the OC−CC−CN in the 6-1H tautomer with the s-ciss-cis-configuration, as can be clearly seen from the comparison 9081
DOI: 10.1021/acs.joc.9b01021 J. Org. Chem. 2019, 84, 9075−9086
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Figure 6. Optimized geometry of 6-1H and 6-2H in vacuum (upper row), in DMSO (middle row), and of their solvate complexes 6-1H·DMSO and 6-2H·DMSO in vacuum (bottom row).
of the bond lengths in the two fragments (Figure 6, upper row). Taking into account nonspecific solvation using the polarizable continuum model (PCM) model in a polar solvent (DMSO) decreases this energy difference by 4.4 kcal/mol, to 5.4 kcal/mol, due to higher polarity of tautomer 6-1H (2.35 D) as compared with 6-2H (1.62 D), although the latter still remains energetically preferable. The length and, hence, the strength of the intramolecular hydrogen bond in tautomer 62H are practically not affected in going from gas to solution (Figure 6, middle row). In contrast, specific solvation of the NH group in 6 via the formation of solvate complexes with DMSO with the N−H··· OS hydrogen bonds returns the situation to that in unsubstituted indazole. DMSO forms a very strong intermolecular hydrogen bond with the N1−H proton in the 6-1H tautomer (1.702 Å, Figure 6, bottom row), which makes complex 6-1H·DMSO to be 3.9 kcal/mol more stable than complex 6-2H·DMSO. This energy difference is only slightly less than that between the 1H- and 2H indazoles themselves (4.9 kcal/mol). In complex 6-2H·DMSO, the H-bond with DMSO is much weaker (1.948 Å), so, the intramolecular Hbond is retained. The formed bifurcated hydrogen bond has a substantially elongated (from 1.800 to 2.164 Å) and, hence, weaker intramolecular as compared with the intermolecular
component. The reason for higher stability of complex 6-1H· DMSO is the shortest and, hence, the strongest intermolecular H-bond (1.702 Å), as well as its higher aromaticity. The formation of the H-complex also affects the degree of conjugation between the indandione and the indazole moieties, taking as a criterion of conjugation the difference between the lengths of the exocyclic CC bond and the C−C bond between the CH olefinic carbon and the C-3 atom of the indazole ringthe lesser the difference, the stronger the conjugation. In the 6-1H tautomer, it equals to 0.082 Å and in 6-2H it is 0.046 Å; however, in the solvate H-complexes of the two tautomers with DMSO, this difference is smaller than in 61H, 0.066 and 0.061 Å, indicating stronger conjugation. Finally, nonspecific solvation (estimated from calculations of H-complexes with DMSO in the same solvent) slightly weakens the strong intermolecular hydrogen bond in complex 6-1H·DMSO (from 1.702 to 1.710 Å) but strongly loosens the intermolecular H-bond in complex 6-2H·DMSO (from 1.948 to 2.267 Å, Figure S25). The second component of the bifurcated hydrogen bond in the latter complex is strengthened (from 2.164 to 2.005 Å), but, in total, taking into account both components, the NH proton in the complex in solution is less H-bonded than that in the gas phase. Complex 6-1H·DMSO is 1.9 kcal/mol more energetically favorable (Figure S25), 9082
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Figure 7. Interconversion of the 7-1H and 7-2H tautomers.
suggesting that the effect of solvent polarity is more pronounced in the case of complex 6-2H·DMSO. For tautomers 7-1H and 7-2H, the calculated energy preference of the former is 4.5 kcal/mol, which seems to be in disagreement with the formation of the two forms in the synthesis. Since both tautomers exist in the E-configuration, only the formation of dimers in solution, linked by strong intermolecular hydrogen bonds, may explain the results of the NMR spectroscopy study (vide supra). The formation of dimers of 7-1H linked by two N−H···N intermolecular bonds leads to the energy gain of 7.2 kcal/mol. Dimerization of 7-2H in the same manner is accompanied by a significantly larger energy gain (10.8 kcal/mol, Figure 7). This is due to the shorter intermolecular distance H···N in the latter dimer (2.040 vs 2.065 Å). The energy of dimerization of 7-2H is 3.6 kcal/mol higher than that of 7-1H, which notably counterbalances the advantage of 7-1H over 7-2H. The formation of dimers of compound 7 is the most probable reason why the two tautomers show different spectra upon dissolution. Interconversion of 7-1H and 7-2H tautomers occurs by redistribution of the components of the two N−H··· N hydrogen bonds in the dimers in Figure 7. Such a transfer of two protons needs activation to overcome the energy barrier and so the process must take time. Calculation of barriers is a special task; roughly, it can be estimated by calculating the structures corresponding to synchronous or asynchronous transfer of NH protons in the dimers of tautomers 7-1H and 72H in Figure 7. The symmetric structure corresponding to the NH protons fixed in the middle between the two nitrogen atoms lies 45 kcal/mol above the dimer of 7-2H, whereas the transfer of only one NH proton, with the rest of the dimer being optimized, gives the structure lying 18 kcal/mol lower. Therefore, the value of 27 kcal/mol can be considered as the upper limit of the real activation barrier; using the PCM model with DMSO as the solvent lowers the barrier by 1 kcal/mol. Specific solvation may decrease it further. Finally, let us consider the aforementioned transformation of 7-2H to 7-1H, which occurs on standing in air or, instantly, in water (see the Experimental Section). The most probable reason for this conversion is the formation of the complex of two 7-2H molecules with two H2O molecules incorporated between the monomers and linked to them by four hydrogen bonds (Figure 8). The calculated energy of formation of such a complex amounts to 33 kcal/mol; so, the centrosymmetric dimeric complex of 7-2H can be easily destroyed by water, in full agreement with experimental observations. It can be assumed that the conversion of 7-2H to 7-1H in this complex
Figure 8. Optimized geometry of complex 7-2H·H2O.
occurs via intramolecular proton transfer through water bridges, but this issue is beyond the scope of this paper.
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CONCLUSIONS 2-[(2H-Indazol-3-yl)methylene]-1H-indene-1,3(2H)-dione 6 and (E)-2-[(2H-indazol-3-yl)methylene]-2,3-dihydro-1Hinden-1-one 7 were synthesized. The X-ray structural analysis showed that the hydrogen atoms in compound 6 are disordered between the two nitrogen atoms of the indazole motif, N(1) and N(2), indicating the existence of the hitherto elusive 2H tautomer of indazole. The apparent reason for stabilization of the 6-2H tautomer is the formation of a strong N(2)−H···OC intramolecular hydrogen bond of 2.087 Å length, which is impossible in the 1H tautomer. The comparison of the 13C NMR spectra of compound 6 with those of model compounds shows that it exists as the 2H tautomer; the calculated 13C chemical shifts for the 6-1H and 6-2H tautomers support this conclusion. The presence of a strong N−H···O intramolecular hydrogen bond stabilizing the 6-2H tautomer is proved by the downfield shift of the NH signal in CDCl3 of 6 to 15.5 ppm. In DMSO-d6, however, the 6-1H and 6-2H are in equilibrium with the ratio of 2:1 in favor of the former due to formation of the N−H···O intermolecular hydrogen bond with the solvent. Compound 7 crystallizes in two forms, yellow and red, with different crystal structures. The yellow form is the 1H tautomer, and the red crystals showed disordering of the NH proton between the N(1) and N(2) nitrogen atoms. The freshly prepared red solid 7 changed their color to yellow on 9083
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molecule, and δref is the experimental value of 13C chemical shift in benzene (128.37).46 Synthesis. 2-[(2H-Indazol-3-yl)methylene]-1H-indene-1,3(2H)dione 6. First, 0.157 g (1.07 mmol) of 1,3-indandione and 0.157 g (1.07 mmol) of 3-indazolcarbaldehyde were stirred in 5 mL of glacial acetic acid; then, 3 drops of conc. HCl were added, the mixture was refluxed for 25 min, and finally cooled. The formed precipitate was filtered, washed with water, and air-dried. Orange solid, yield 0.130 g (44 %), mp > 300°C (decomp.) Anal. calcd for C17H10N2O2: C 74.44; H 3.67; N 10.21. Found: C 74.31; H 3.71; N 10.26. 1H NMR (500.13 MHz, CDCl3, δ ppm): 15.40 br., (1H, NH); 8.19 s (1H, CH); 8.14 m (1H, HAr), 8.08 m (3H, HAr), 7.92 m (2H, HAr), 7.54 m (2H, HAr). 13C{1H} NMR (125.76 MHz, CDCl3, δ ppm): 192.0; 189.4; 150.1; 141.5; 140.6; 135.8; 135.4; 131.3; 127.3; 126.8; 125.4; 125.3; 123.6; 123.4; 120.4; 119.1. (E)-2-[(2H-Indazol-3-yl)methylene]-2,3-dihydro-1H-inden-1-one (7-Red) and (E)-2-[(1H-Indazol-3-yl)methylene]-2,3-dihydro-1Hinden-1-one (7-Yellow). Base-Catalyzed Aldol Condensation. To 0.20 g (1.52 mmol) of 1-indanone and 0.22 g (1.52 mmol) of 3indazolcarbaldehyde in 10 mL of ethanol was added 1 mL of 1 M aqueous KOH; the mixture heated at reflux for 1 h, and then left overnight in a refrigerator. The red precipitate formed was filtered and air-dried. The filtrate was poured into cold water to give a yellow solid, which was filtered and air-dried. 7-red: Yield 0.21 g (53 %), mp 265−267 °C. (ESI+)-HRMS: calcd for C17H12N2OH (M + H)+ 261.1022, found 261.0998. 1H NMR (500.13 MHz, ethanol-d6, δ ppm): 8.22 t (1H, J = 1.9 Hz, CH); 7.95 dt (1H, J = 7.3, 1.1 Hz); 7.90 br.d (1H, J = 7.3 Hz); 7.75 br.d (1H, J = 7.7 Hz); 7.70 dt (1H, J = 8.1, 1.1 Hz); 7.66 td (1H, J = 7.7, 1.1 Hz); 7.46 td (1H, J = 7.3, 1.1 Hz); 7.22 m (1H); 7.14 t (1H); 4.33 br (2H). 13C{1H} NMR (125.76 MHz, DMSO-d6, δ ppm): 192.5; 151.1; 150.3; 140.2; 140.1; 133.4; 127.6; 127.4; 126.7; 125.9; 124.9; 123.1; 121.7; 119.8; 118.1; 116.1; 35.0. The solution of freshly prepared 7-red in DMSO-d6 was subjected to HRMS analysis: (ESI+)HRMS: calcd for C17H9D3N2OH (M + H)+ 264.1211, found 264.1205; calcd for C17H9D3N2ONa (M + Na)+ 286.1030, found 286.1025. 7-yellow: Yield 0.15 g (38 %), mp 280−282 °C. (ESI+)-HRMS: calcd for C17H12N2OH (M + H)+ 261.1022, found 261.0999. 1H NMR (500.13 MHz, ethanol-d6, δ ppm): 8.07 t (1H, CH, J = 2.2 Hz); 8.03dt (1H, J = 8.2, 0.8 Hz); 7.93 br.d (1H, J = 7.7 Hz); 7.74 m (2H); 7.66 dt (1H, J = 8.5, 0.8 Hz); 7.51 m (1H); 7.47 ddd (1H, J = 8.2, 6.9, 1.1 Hz); 7.32 ddd (1H, J = 7.7, 6.9, 0.8 Hz), 4.32 d (2H, J = 2.2 Hz). 13C{1H} NMR (125.76 MHz, DMSO-d6, δ ppm): 193.7; 150.8; 141.1; 141.0 138.3; 135.5; 135.3; 128.0; 127.3; 127.1; 124.3; 124.0; 122.2; 121.3; 120.0; 111.2; 34.2. Acid-Catalyzed Aldol Condensation. A mixture of 1-indanone 0.132 g, (1 mmol), 3-indazolcarbaldehyde 0.160 g (1.1 mmol), and two drops of conc. H2SO4 in 1,4-dioxane (10 mL) was heated at reflux for 2 h. The mixture was cooled, poured into cold water, the precipitate formed filtered off, washed with water, and dried. The yellow solid obtained in this synthesis is the only product and, according to NMR 1H and 13C, is identical to the 7-yellow product obtained from the base-catalyzed condensation. Yield 0.18 g (69%). (E)-2-((1-Acetyl-1H-indazol-3-yl)methylene)-2,3-dihydro-1Hinden-1-one (9). Acetyl chloride (0.2 mmol) was slowly added to a solution of 7-red (50 mg, 0.2 mmol) and Et3N (0.2 mL) in dichloromethane (5 mL) and stirred for 1 h. The reaction mixture was washed with aq HCl (1 M, 5 mL) and aq NaOH (2 M, 5 mL). The organic layer was dried with Na2SO4, and the solvent was evaporated to give 9 as the yellow solid, yield 32 mg (55%). Anal. calcd for C19H14N2O2: C 75.48; H 4.67; N 9.27; found: C 75.42; H 4.73; N 9.32. 1H NMR (500.13 MHz, CDCl3, δ ppm): 1H NMR (500.13 MHz, CDCl3, δ ppm): 8.53d, J = 7.7 Hz, 1H; 8.00 m, 2H; 7.94 t, J = 2.2 Hz, 1H; 7.71 t, J = 7.0 Hz, 1H; 7.67 m, 2H; 7.51 m, 2H; 4.32 d, J = 2.2 Hz, 2H; 2.97 s, 3H. 13C{1H} NMR (125.76 MHz, CDCl3, δ, ppm): 194.0; 171.2; 150.4; 146.2; 140.4; 139.6; 138.1; 135.2; 129.8; 127.7; 126.9; 126.4; 125.1; 124.6; 119.8; 118.8; 115.7; 33.9; 23.2.
standing, indicating the existence of compound 7 in the form of the α- (red, N(2)−H) and β-tautomeric (yellow, N(1)−H) polymorphs. The existence of tautomer 7-2H in spite of its lower stability as compared with 7-1H is most probably due to a higher energy of its dimerization that notably counterbalances the higher stability of the monomer of 7-1H over that of 7-2H. The α- and β-polymorphs of compound 7 give different NMR spectra in DMSO-d6, indicating slow transformation of the 7-2H to 7-1H tautomer. This first experimental observation of different NMR spectra in solution for two polymorphs was explained by the fact that the isomerization includes the transfer of the NH protons from the N(2) to N(1) atom in the dimers of compound 7 linked by intermolecular N···H···N hydrogen bonds, occurring with the activation barrier. In contrast, in pyridine-d5, the two polymorphs give the same 1H NMR spectrum due to fast reversible proton exchange between the indazole moiety of 7 and a strongly basic molecule of the solvent. Tautomer 7-1H undergoes simultaneous photoinduced E → Z isomerization and 7-1H → 7-2H tautomerization, as proved by the appearance after UV irradiation of its ethanol solution of a downfield signal at 15.7 ppm, belonging to the NH proton involved in the strong N−H···O intramolecular hydrogen bond in the Z-isomer.
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EXPERIMENTAL SECTION
Experimental Methods. Crystal data of 6 were collected on a Bruker D8 Venture diffractometer with Mo Kα radiation (λ = 0.71073) using φ and ω scans. Crystal data of 7 were collected on an XtaLAB Synergy, Dualflex, HyPix diffractometer with Cu Kα radiation (λ = 1.54184) using ω scans. The structures were solved and refined by direct methods using the SHELX programs set.37 Data were corrected for absorption effects using the multiscan method (SADABS). Nonhydrogen atoms were refined anisotropically by the SHELX program.37 CCDC 1831601 (6), 1858366 (7-α), and 1858367 (7-β) contain supporting crystallographic data for this paper. Crystal data, details of intensity measurements, and structure refinement for 6 and 7 are given in the Supporting Information (Tables S1 and S2). The 1H and 13C NMR spectra were recorded at working frequencies 500 MHz (1H) and 125 MHz (13C); the chemical shifts are reported in parts per million relative to tetramethylsilane; the solvents were CDCl3, DMSO-d6, ethanol-d6, and pyridine-d5; the concentration of samples was 0.01 M. The 1H and 13C NMR signals were assigned using correlation spectroscopy, heteronuclear multiple quantum correlation, and heteronuclear multiple bond correlation experiments. The X-ray data for compound 6 were obtained using the resources of the Baikal Analytical Center of Joint Use of the SB RAS. The HRMS data for compound 7 were obtained on the mass analyzer ESI Orbitrap. Computational Methods. Quantum-chemical calculations were performed with the Gaussian09 software package.38 Geometry optimization was carried out using the B3LYP hybrid functional39,40 and the 6-311G++(d,p) basis set.41 The solvation effects were accounted for by using the polarizable continuum model (PCM)42,43 and DMSO as the solvent. The 1H and 13C shielding constants were calculated by the GIAO method44,45 at the same theory level. The δ values of theoretical 13C chemical shifts were calculated as the difference between the 13C shielding constants in benzene and in molecule 3 according to eq 1.46 δcalc X = σref − σX + δref
(1)
where δcalcX is the calculated 13C chemical shift in the molecule in question, σref is the calculated 13C shielding constant in benzene (49.7), σX is the calculated 13C shielding constant in the studied 9084
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(11) Stadlbauer, W. Indazoles. In Science of Synthesis; Neier, R., Ed.; Georg-Thieme-Verlag Stuttgart: New York, 2002; pp 227−324. (12) Martínez, A.; Vázquez, M.-V.; Carreón-Macedo, J. L.; Salcedo, R.; Sansores, L. E. Benzene fused five-membered heterocycles. A theoretical approach. Tetrahedron 2003, 59, 6415−6422. (13) Catalán, J.; de Paz, J. L. G.; Elguero, J. Importance of aromaticity on the relative stabilities of indazole annular tautomers: an ab initio study. J. Chem. Soc., Perkin Trans. 2 1996, 57−60. (14) Alkorta, I.; Elguero, J. Theoretical estimation of the annular tautomerism of indazoles. J. Phys. Org. Chem. 2005, 18, 719−724. (15) Büchel, G. E.; Stepanenko, I. N.; Hejl, M.; Jakupec, M. A.; Keppler, B. K.; Arion, V. B. En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2]″>En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2]. Inorg. Chem. 2011, 50, 7690−7697. (16) Bravo, J.; Bolano, S.; Gonsalvi, L.; Peruzzin, M. Coordination chemistry of 1,3,5-triaza-7-phosphaadamantane (PTA) and derivatives. Part II. The quest for tailored ligands, complexes and related applications. Coord. Chem. Rev. 2010, 254, 555−607. (17) Sigalov, M. V.; Shainyan, B. A.; Chipanina, N. N.; Oznobikhina, L. P. Molecular structure, intramolecular hydrogen bonding, solventinduced isomerization, and tautomerism in azolylmethylidenederivatives of 2-Indanone. Eur. J. Org. Chem. 2017, 1353−1364. (18) Afonin, A. V.; Vashchenko, A. V.; Sigalov, M. V. Estimating the energy of intramolecular hydrogen bonds from 1H NMR and QTAIM calculations. Org. Biomol. Chem. 2016, 11199−11211. (19) Afonin, A. V.; Sterkhova, I. V.; Vashchenko, A. V.; Sigalov, M. V. Estimating the energy of intramolecular bifurcated (threecentered) hydrogen bond by X-ray, IR and 1H NMR spectroscopy, and QTAIM calculations. J. Mol. Struct. 2018, 1163, 185−196. (20) Sigalov, M.; Shainyan, B.; Chipanina, N.; Oznobikhina, L.; Strashnikova, N.; Sterkhova, I. Molecular structure and photoinduced intramolecular hydrogen bonding in 2-pyrrolylmethylidene cycloalkanones. J. Org. Chem. 2015, 80, 10521−10535. (21) Sigalov, M. V.; Shainyan, B. A.; Sterkhova, I. V. Photoinduced Intramolecular Bifurcate Hydrogen Bond: Unusual Mutual Influence of the Components. J. Org. Chem. 2017, 82, 9075−9086. (22) Chierotti, M.; Ferrero, L.; Garino, N.; Gobetto, R.; Pellegrino, L.; Braga, D.; Grepioni, F.; Maini, L. The Richest Collection of Tautomeric Polymorphs: The Case of 2-Thiobarbituric Acid. Chem. Eur. J. 2010, 16, 4347−4358. (23) Cruz-Cabeza, A. J.; Groom, C. R. Identification, classification and relative stability of tautomers in the cambridge structural database. CrystEngComm 2011, 13, 93−98. (24) Nath, N. K.; Kumar, S. S.; Nangia, A. Neutral and Zwitterionic Polymorphs of 2-(p-Tolylamino)nicotinic Acid. Cryst. Growth Des. 2011, 11, 4594−4605. (25) Delaney, S. P.; Witko, E. M.; Smith, T. M.; Korter, T. M. Investigating Tautomeric Polymorphism in Crystalline Anthranilic Acid Using Terahertz Spectroscopy and Solid-State Density Functional Theory. J. Phys. Chem. A 2012, 116, 8051−8057. (26) Long, S.; Zhang, M.; Zhou, P.; Yu, F.; Parkin, S.; Li, T. Tautomeric Polymorphism of 4-Hydroxynicotinic Acid. Cryst. Growth Des. 2016, 16, 2573−2580. (27) McGauley, S. E.; Marangoni, A. G. Static Crystallization Behavior of Cocoa Butter and Its Relationship to Network Microstructure. In Physical Properties of Lipids; Marangoni, A. G.; Narina, S. S., Eds.; Marcel Dekker, Inc.: New-York, Basel, 2002; Chapter 4, pp 85−123. (28) Garcia, M. A.; Lopez, C.; Claramunt, R. M.; Kenz, A.; Pierrot, M.; Elguero, J. Polymorphism vs. desmotropy: the cases of 3-phenyland 5-phenyl-1H-pyrazoles and 3-phenyl-1H-indazole. Helv. Chim. Acta 2002, 85, 2763−2776. (29) Sigalov, M.; Shainyan, B.; Chipanina, N.; Ushakov, I.; Shulunova, A. Intra- and intermolecular N−H···O hydrogen bonds in pyrrolyl derivatives of indane-1,3-dione − experimental and theoretical study. J. Phys. Org. Chem. 2009, 22, 1178−1187.
The same procedure was applied to 7-yellow (50 mg) to give 45 mg (78%) of yellow solid, which according to NMR spectra have the structure of 1-acetyl derivative 9.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01021. Crystallographic data for compound 6 (CIF) Crystallographic data for compound 7-red (CIF) Crystallographic data for compound 7-yellow (CIF) X-ray diffraction structural data, NMR data, and Cartesian coordinates of optimized molecular structures (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Mark V. Sigalov: 0000-0002-7609-9030 Bagrat A. Shainyan: 0000-0002-4296-7899 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS I.V.S. and B.A.S. are grateful to the Russian Foundation for Basic Research for financial support (Grant No. 19-03-00036). REFERENCES
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