Organophosphorus compounds are used in many fields of medicine and agriculture and play a significant role in organic synthesis, catalysis, and biochemistry [1–6]. Phosphoryl-substituted phenols are known for their complexing, extraction, and ion-selective properties [7–13]. Among them, 2-hydroxyphenylphosphonic acids occupy a special place, since they are phosphoryl analogues of salicylic acid and can be considered as physiologically active substances (Scheme 1). 2-Hydroxy-5-ethylphenylphosphonic acid (H3L2) and its complex [Cu(H2L2)2(Н2О)2] exhibit analgesic activity [14, 15]. With low toxicity, the analgesic effect of the complex significantly exceeds the effect of analgin. The possibility of using drugs based on complexes of transition metals, such as platinum [16, 17], cobalt(II) [18], manganese(II/IV) [19], nickel(II) [20], and copper(II) [21–25], with organic ligands has been shown. Therefore, the synthesis of new organic compounds and their complexes, which often exhibit higher biological activity than the initial compounds [26–28], is an important area of research.

Scheme
scheme 1

1.

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We synthesized 2-hydroxy-5-methoxyphenylphosphonic acid (H3L1) and the complex [Cu(H2L1)2(Н2О)2], and determined its structure by X-ray structural analysis. The protonation constants of H3L1 acid and the stability constants of its complexes with Cu2+ in water were determined; the IR spectroscopy and thermogravimetry data are presented.

2-Hydroxyphenylphosphonic acids are rather inaccessible compounds [14, 29–31]. In the synthesis of H3L1 acid (Scheme 2), we used the technique, which we developed earlier [14]. Its main advantage is the final reaction with in situ generated trimethylbromosilane. The reaction proceeds practically without by-products formation.

Scheme
scheme 2

2.

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As the starting compound in the preparation of the organolithium component necessary to create the Ar-P bond, methoxymethyl ether 1 of 4-methoxyphenol was used, which reacts with butyllithium in a mixture of solvents tetrahydrofuran‒hexane (3 : 1) to form [2-(methoxymethoxy)-5-methoxyphenyl]lithium 2. The (EtO)2HL1 phosphonate in crystalline form was isolated with a high yield when equivalent amounts of compound 2 and diethyl chlorophosphate reacted in situ at ‒60 ± 5°C with following acid hydrolysis of the methoxymethyl protective group at room temperature. The reaction of (EtO)2HL1 with trimethyl chlorosilane in the presence of anhydrous sodium bromide in boiling acetonitrile resulted in the formation of bis(trimethylsilyl)phosphonate (TMSO)2HL1, which, without isolation, was hydrolyzed at room temperature with a mixture of ethanol and water to form H3L1 acid. This acid, unlike salicylic acid, is highly soluble in water, which is a key criterion for the selection of compounds promising in the drug development [32, 33].

Crystals of complex [Cu(H2L1)2(H2O)2] 3 were obtained by the reaction of copper(II) perchlorate with H3L1 acid. According to the results of the X-ray structural analysis, complex 3 has a centrosymmetric structure (Fig. 1).

Fig. 1.
figure 1

Structure of the complex [Cu(H2L1)2(H2O)2] (3). Bond lengths: Cu1-O1 1.9601(1), Cu1-O4 2.450(2), and Cu1-O6 1.9499(17) Å.

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The 4+2 coordination sphere is usual for Cu2+. The copper atom polyhedron is an axially elongated square bipyramid with oxygen atoms of phenolic and monodeprotonated phosphonic groups at the base and with oxygen atoms of water molecules at the vertices. As a result of the combined action of four hydrogen bonds, a 2D structure is formed (the layers are perpendicular to the a axis, Fig. 2). The structure of similar [Cu(H2L2)2(H2O)2] complex of 2-hydroxy-5-ethylphenylphosphonic acid was determined earlier [15]. The molecular structures of the two complexes are the same (accurate to OMe/Et), the parameters of the elementary cells are close [15] (Table 1), and the systems of hydrogen bonds are identical [15] (Table 2), however replacing Et with OMe leads to a noticeable decrease in the unit cell volume (2040 and 1892 Å3). This change is caused by intermolecular contacts of 3.56 and 4.17 Å in the compexes 3 and [Cu(H2L2)2(H2O)2], respectively, between O∙∙∙O (OMe) and C∙∙∙C (CH2Me) atoms connected to each other by the 21 axis (Fig. 2). Replacing Et with OMe leads not only to a shift of neighboring complexes relative to each other (Fig. 3a), but also to their half-turn (Fig. 3b).

Fig. 2.
figure 2

Projections of the complex 3 structure along axes (a) a and (b) b.

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Fig. 3.
figure 3

(a) Comparison of packages of complexes 3 and [Cu(H2L2)2(H2O)2] in crystals and (b) mutual arrangement of two pairs of structures formed by complexes 3 (red) and [Cu(H2L2)2(H2O)2] (blue). The distances are minimized between Cu, P, and coordinated O atoms of (a) central and (b) left complexes of the two structures.

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Table 1. Main structural data and refinements of the complex 3 structure
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Table 2. Lengths and angles of hydrogen bonds in complex 3
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The assignment of several vibrational frequencies of donor groups in the spectra of H3L1 acid and [Cu(H2L1)2(H2O)2] complex, which allows us to judge the H3L1 coordination, was carried out taking into account previous spectral studies of H3L2 and [Cu(H2L2)2(H2O)2] [15].

The bands of stretching vibrations ν(С‒Н), ν(O‒H)Ph, and ν(О‒Н)Р in the IR spectrum of H3L1 acid lie in the range of wave numbers 4000‒2000 cm–1. The band ν(O‒H)Ph is shifted to the low-frequency region up to 3207 cm‒1 (~3600 cm‒1 in the spectrum of free phenol), which is caused by the participation of the phenolic group of acid H3L1 in the formation of hydrogen bonds characteristic of such compounds [34]; the ν(О‒Н)Р bands are low intensive.

Replacing Et with OMe leads to noticeable differences in the IR spectra of H3L1 and H3L2 acids in the range of 1250‒900 cm–1: in the spectrum of H3L1, compared to the spectrum of H3L2, there is a significant decrease in the intensity and an increase in the number of bands. The band of average intensity at 1219 cm–1, which is 11 cm–1 lower than in the spectrum of H3L2 [15], can be assigned to stretching vibrations ν(P=O) of the phosphoryl group, the frequency of which is determined by the electronegativity of substituents at the phosphorus atom. According to the assignments made for H3L2 [15], the band of average intensity at 1286 cm–1 refers to the ν(Ph‒O) absorption of the phenolic fragment. The intense bands at 1026 and 929 cm–1 in the H3L1 spectrum are caused by δ(POH) and ν(PO) vibrations of the phosphonic fragment.

The complex formation leads to a certain decrease of 3207→3190 cm–1 in the ν(O‒H)Ph frequency. Low-intensity blurred bands with maxima of about 2552 and 2248 cm–1 correspond to the ν(O‒H)P vibrations in the spectrum of the complex. In the IR spectrum of [Cu(H2L1)2(H2O)2] complex, a new ν(H2O) band, as compared with the spectrum of the free H3L1 acid, appears at 3359 cm–1, and a wide low-intensity δ(H2O) band appeared nearby 1713 cm–1.

The presence of the OMe donor group leads not only to a decrease in the unit cell volume and a change in the packaging of [Cu(H2L1)2(H2O)2] complex, compared to [Cu(H2L2)2(H2O)2], but also to a significant decrease in the frequency of the phosphoryl group stretching vibration ν(Р=О). In the IR spectrum of [Cu(H2L1)2(H2O)2], the ν(Р=О) vibrations correspond to the asymmetric band of higher than the average intensity at 1205 cm–1, which is 14 cm–1 lower compared to its position in the H3L1 spectrum, and is associated with the participation of the phosphoryl oxygen atom in the formation of hydrogen bonds. The formation of hydrogen bonds in [Cu(H2L2)2(H2O)2] complex also leads to a decrease in ν(Р=О), but it is not so significant (~5 cm–1) [15]. The frequency of the phenolic fragment vibrations ν(Ph‒O) in the spectrum of [Cu(H2L1)2(H2O)2] complex decreases slightly in comparison with the spectrum of the free H3L1 acid, and appears, in our opinion, as an average intensity band at 1257 cm–1. Intense bands near 1020 and 943 cm–1 are caused by δ(POH) and ν(PO) vibrations.

In terms of the number, intensity, and position of the main vibrational frequencies, the spectrum of [Cu(H2L1)2(H2O)2] complex is identical to the spectrum of [Cu(H2L2)2(H2O)2] complex, which points to the isostructurality of these compounds.

Thermogravimetric study of [Cu(H2L1)2(H2O)2] complex showed that its multi-stage thermal decomposition begins with the gradual removal of water molecules. On the DTG curve, two corresponding endothermic effects are observed at 76 and 128°C, which could not be separated. Full removal of two water molecules is completed by 151°C (calculated 7.12%, found 7.14%). A further increase in temperature to 400°C leads to a gradual decomposition of the compound.

The protonation constants of H3L1 acid were determined by the potentiometric titration method (Table 3). The resulting values of the constants of H3L1 and H3L2 acids [15] are close to each other, the confidence intervals of the corresponding constants overlap. The value of the second constant log K2 of H3L1, as in the case of H3L2, is close to the value of the second constant for unsubstituted 2-hydroxyphenylphosphonic acid (H3L3) (6.19±0.12 (H3L1), 6.36±0.37 (H3L2) [15], and 6.46 (H3L3) [35]). The lower acidity of H3L1 and H3L2 (log K3 2.64±0.14 and 3.20±0.74 [15], respectively) compared to H3L3 (log K3 1.66 [35]) may be caused by the presence of donor ethyl and methoxy groups, which affect the ionization of the phosphonic group and change the hydration of acid molecules. Intramolecular hydrogen bonding, characteristic of such compounds and confirmed by the IR spectroscopy data, leads to a decrease in the acidity of the phenolic group in H3L1 and H3L2 acids (log K1 11.42±0.08 and 11.58±0.24 [15]) compared with the values of log K1 10.03 and 10.56 for 3- and 4-hydroxyphenylphosphonic acids, respectively [35].

Table 3. Stepwise and total protonation constants of H3L1 acid in water at 298 K and ionic strength 0.1 M KCla
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The species distribution diagram for H3L1 acid depending on pH is shown in Fig. 4. At a physiological pH value of 7.4, the HL2– anion predominates in water, as also in H3L2 acid [15]. In the pH range from 3 to 5.5, the acid is mainly in the form of H2L‒ anion.

Fig. 4.
figure 4

Species distribution diagram for H3L1 acid as a function of pH in water at 298 K, ionic strength 0.1 M, and analytical concentration 2.0 mM. For simplicity, charges are not included in the formulas of acid anions.

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Stability constants of copper(II) complexes with deprotonated forms of H3L1 acid were determined by the potentiometry method using the CHEMEQUI program (Table 4). According to the species distribution diagram for the Cu2+ complexes with H3L1 acid (Fig. 5), the complex of the composition Cu : L = 1 : 2 is formed in solution. The complex of the composition 1 : 1 is formed in a much smaller amount (similar to the complex formation of Cu2+ with H3L2 acid [15]).

Table 4. Stepwise and total stability constants of Cu2+ complexes with H3L1 acid in water at 298 K and ionic strength 0.1 M KCl
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Fig. 5.
figure 5

Species distribution diagram for the Cu2+ complexes with H3L1 acid as a function of pH in water at 298 K, ionic strength 0.1 M, and initial concentrations of reagents 0.49 (H3L1) and 0.24 (Cu2+) mM. Percentage α of equilibrium ion concentrations relative to the total Cu2+concentration: (1) Cu2+, (2) CuL–, (3) CuL24–, (4) CuL(OH)2–, and (5) CuL2(OH)5–.

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The first of the stability constants log K1 8.34±0.02 and log K2 7.88±0.20 of the CuL– and CuL24–complexes appeared to be significantly lower than the corresponding constants of Cu2+ complexes with salicylic acid (log K1 10.83 and log K2 8.05 [36, 37]) and lower than those with H3L2 acid (log K1 8.91±0.06 and log K2 8.39±0.08 [15]). This seems to be caused by the fact that, according to structural data, the phenolic oxygen of H3L1 and H3L2 acids practically does not participate in the complex formation {the length of the Cu‒OPh bonds of 2.450(2) and 2.448(3) Å [15] is significantly longer than the length of the Cu‒OP(O)(OH)Ph bond 1.960(1) and 1.967(3) Å [15], respectively} in contrast to 4-methoxysalicylic acid {the Cu‒OPh bond length 1.899 Å and that of Cu‒OC(O)Ph 1.889 Å [38]}. The differences in the stability of the CuL and CuL2 complexes of H3L1 and H3L2 acids can be explained by the influence of the methoxy group (H3L1) and ethyl substituent (H3L2), which changes the free energy of acid hydration and the phosphonic group acidity.

Thus, we synthesized 2-hydroxy-5-methoxyphenylphosphonic acid (H3L1) with a sufficiently high yield, which allowed us to prepare trial batches of this compound necessary for biological research. For the first time the obtained complex [Cu(H2L1)2(Н2О)2] was characterized by the methods of X-ray structural analysis, IR spectroscopy, and thermogravimetry. The protonation constants of the acid in water are significantly influenced by the intramolecular hydrogen bond and the methoxy group. The H3L1 acid, as well as the 2-hydroxy-5-ethylphenylphosphonic acid (H3L2), forms with Cu2+ water-soluble CuL– and CuL24– complexes. Since the results of biological studies have shown that [Cu(H2L2)2(Н2О)2] complex has a high analgesic activity [15], our planned studies of biological activity of [Cu(H2L1)2(Н2О)2] complex are very promising.

EXPERIMENTAL

All reactions involving [2-(methoxymethoxy)-5-methoxyphenyl]lithium 2 were carried out in a dry argon atmosphere. The 1H and 31Р NMR spectra were recorded on a Bruker SHR-200 spectrometer. Melting temperatures were measured on a Boetius PHMK 05 device. Elemental analysis was performed on a C, H, N analyzer (Carlo Erba Strumentazione) and an IRIS Advantage (Thermo Jarrell Ash) atomic emission spectrometer with inductively coupled plasma. The IR absorption spectra were recorded in the range of 4000-550 cm–1 by the FTIR spectroscopy method on a Nexsus Nicolet spectrometer. Thermogravimetric studies were carried out on a SDT Q600 derivatograph in the temperature range 20–600°C at a heating rate of 4 deg/min in argon current.

Diethyl ether of 2-hydroxy-5-methoxyphenyl-phosphonic acid [(EtO)2HL1]. To a solution of [2-(methoxymethoxy)-5-methoxyphenyl]lithium 2 obtained by the reaction of 40 mL of 2.5 N solution of n-butyllithium in hexane with 21.5 g (130 mmol) of 4-methoxyphenol methoxymethyl ether 1 [39, 40] in 130 mL of THF, 22 g (130 mmol) of diethylchlorophosphate was added at –60±5°. Then the temperature of the reaction mixture was raised to 20°C. The mixture was stirred for 1.5 h, and the solvent was removed in vacuum. To the residue, 100 mL of saturated KH2PO4 solution was added, extraction with CHCl3 (2×50 mL) was carried out, the extract was washed with water (3×50 mL), dried with Na2SO4, and the solvent was removed in vacuum. To the residue, 100 mL of an 1 : 1 mixture of concentrated HCl and EtOH, was added and left overnight, then poured into 300 mL of water, and extracted with CHCl3 (3×50 mL). The extract was washed with water (3×50 mL), dried with Na2SO4, and the residue was distilled in vacuum. Yield 26.30 g (78%), bp 134–136°C (1 mmHg), mp 58–60°C (heptane). 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.32 t (6H, 2ОCH2CH3, 3JHH 7.0 Hz), 3.74 s (3Н, ArOCH3), 4.05 m (4Н, 2ОСН2СН3), 6.85 m (2НAr), 6.89 m (1НAr), 9.67 s (1Н, ОН). 31P{1H} NMR spectrum DMSO-d6–CCl4, 1 : 3): δР 21.61 ppm. Found, %: C 50.88; H 6.19; P 11.95. C11H17O5P. Calculated, %: C 50.77; H 6.59; P 11.90.

2-Hydroxy-5-methoxyphenylphosphonic acid (H3L1). To a solution of 1.50 g (5.8 mmol) of (EtO)2HL1 ether in 15 mL of anhydrous acetonitrile, 1.18 g (11.6 mol) of NaBr and 1.28 g (11.9 mmol) of Me3SiCl were added. The reaction mass was boiled for 6 h. The hot solution was filtered, the solvent was evaporated. The residue was dissolved in 20 mL of aqueous ethanol (1 : 1), kept for 12 h at room temperature, and the solvent was evaporated in vacuum. To the residue, 10 mL of CH2Cl2 was added, the precipitate was filtered and dried in vacuum (12 h, 10 mmHg). Yield 0.8 g (67 %), mp 148–149°C (mp 158–159°C [29]). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.70 s (3H, СН3ОAr), 6.88 m (3НAr). 31P{1H} spectrum (DMSO-d6): δР 16.83 ppm. Found, %: C 41.54; H 4.63; P 15.01. C7H9O5P. Calculated, %: C 41.19; H 4.44; P 15.17.

Complex [Cu(H2L1)2(Н2О)2] (3) was obtained by the reaction of equimolar amounts of H3L1 and Cu(ClO4)2·6H2O in water. Varying the ratio of reagents and performing the reaction in the presence of 1 eq. of NaOH did not affect the yield and composition of the resulting compound. The light blue crystals for the X-ray structural analysis were obtained by slow evaporation of the solution. The complex is slightly soluble in low-polar organic solvents and readily soluble in ethanol, DMFA, and DMSO. Found, %: C 33.43; H 4.14. C14H20CuO12P2. Calculated, %: C 33.26; H 3.96.

Potentiometric titration with the aim of determining the protonation constants of H3L1 acid and the stability constants of its complexes with copper(II) perchlorate was performed according to the method [41], using an OP-300 Radelkis potentiometer. To study the complex formation, chemically-pure grade copper(II) perchlorate hexahydrate was used.

Solutions of H3L1 acid were titrated with a standard 0.1 M NaOH solution at 298± 0.1 K and ionic strength 0.1 M with KCl. Three titrations including 41–60 points were performed in the pH range from 2.9 to 11.5; the initial analytical H3L1 concentration in the experiments was 0.96, 1.62, and 2.00 mmol/L. The values of the H3L1 protonation constants were obtained with the help of the CHEMEQUI program freely available on the server [42], using four algorithms EQ, SIMPLEX, MONTE-CARLO [43], and GENETIC ALGORITHM [44], which significantly increase the reliability of the calculated constants and reduce the influence of the detected correlations between the logarithms of the constants for these experiments. The average values of the protonation constants of H3L1 acid were determined from eight estimates of the constants obtained using two best titrations and four calculation algorithms. In all calculations of the constants, Hamilton’s R-factor (HRF) and the determination coefficient (R2det) were used as criteria for the agreement of the assumed set of equilibrium reactions in solution with experimental data [41]. For H3L1 acid, the HRF factor ranged from 0.62 to 1.11%, and the R2det coefficient ranged from 0.9990 to 0.9997.

Titration of H3L1 acid solutions with Cu(ClO4)2 was performed under similar conditions in the pH range from 3.4 to 11.3. The copper(II) cation forms stable hydroxides in water [44], therefore estimates of the complexation constants of Cu2+ with the acids under study were performed both taking into account the copper(II) hydrolysis reactions and without taking them into account. The stability constants of log βn for hydroxocomplexes in water, ‒6.29 and ‒13.10, for n = 1 and 2 in equilibria (1), respectively, were used in the calculations [44].

Cu2+ + nH2O = Cu2+(OH‒)n + nH+ , n = 1, 2. (1)

In the both variants, as in the calculation of the complexation constants of H3L2 with Cu(ClO4)2 [15], close values of constants with overlapping intervals of their standard deviations were obtained. The stability constants of copper(II) perchlorate complexes with H3L1 were estimated on the basis of three titrations, including from 47 to 52 points, with the analytical concentrations of acid and salt for each experiment of 0.62 and 0.31, 0.54 and 0.28, 0.49 and 0.24 mmol/L, respectively. The complexation constants of H3L1 with Cu(ClO4)2 were estimated using the CHEMEQUI program [42, 43] and four of its algorithms. The HRF factor varied from 0.56 to 0.80%, and the R2det coefficient – from 0.9994 to 0.9997. Thus, according to three titrations and four algorithms, 12 estimates of the constants were performed, according to which their average values were calculated. Sharply deviating values were excluded according to Thomson’s rule [45]. In the calculations of the constants of Cu2+ complex formation with protonated forms of the HnL(3–n)– (n = 0, 1, 2) ligand, the acid protonation constants were not varied, they were taken as earlier estimated in the previous three titrations of the initial acid.

The X-ray diffraction analysis of compound [Cu(H2L1)2(H2O)2] 3 was performed at the Center for Collective Use of N.S. Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences on a Bruker SMART APEX3 diffractometer [λ(MoKα) with a graphite monochromator] [46]. Absorption was taken into account by the semi-empirical equivalent method using the SADABS program [47]. The structure was determined by a combination of the direct method and Fourier syntheses. Hydrogen atoms were partially localized from the Fourier difference synthesis (O-H), and partially calculated from geometric considerations (C‒H). The structure was refined by a full-matrix anisotropic-isotropic least squares method (H atoms bound to O atoms). All calculations were performed using the SHELXS and SHELXL programs [48]. The experimental data for complex 3 were deposited in the Cambridge Structural Data Bank (CCDC 2102671).