Synthesis and structure of novel copper(II) complexes with pyrazole derived ligands and metal–ligand interaction in solution

Polyhedron 26 (2007) 2589–2596 www.elsevier.com/locate/poly

Synthesis and structure of novel copper(II) complexes with pyrazole derived ligands and metal–ligand interaction in solution Aleksander Kufelnicki a, Magdalena Woz´niczka a, Lilianna Che˛cin´ska b, Magdalena Miernicka c, El_zbieta Budzisz c,* a

Laboratory of Physical and Biocoordination Chemistry, Faculty of Pharmacy, Medical University of Ło´dz´, Muszyn´skiego 1, 90-151 Ło´dz´, Poland b Department of Crystallography and Crystal Chemistry, University of Ło´dz´, Pomorska 149/153, 90-236 Ło´dz´, Poland c Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy, Medical University of Ło´dz´, Muszyn´skiego 1, 90-151 Ło´dz´, Poland Received 11 December 2006; accepted 29 December 2006 Available online 13 January 2007

Abstract Two new ligands of the coumarin type have been synthesized and characterized by 1H, 13C NMR, IR and MS. The crystal and molecular structures of ligand 2, determined by the X-ray diffraction method, are presented. With copper(II) these ligands create solid complexes of the type CuLCl2, where L is 5-(2-hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)pyrazol-4-carboxylic acid methyl ester (2) or 3-methyl-1-(2-pyridinyl)-1H-chromene[4,3-c]pyrazol-4-on (3). The new copper(II) complexes have been characterized by elemental analysis and solid state FT-IR. The protonation constants of ligands 2 and 3 have been determined in 5% v/v 1,4-dioxane–water solution (25 C). The coordination modes in the complexes with copper(II) are discussed for 2 on the basis of potentiometric and UV–Vis data.  2007 Elsevier Ltd. All rights reserved. Keywords: Cu(II) complexes; Pyrazole derivatives; Crystal structure; M–L Interactions in solution

1. Introduction Copper plays a crucial role in several enzymes that catalyze oxidation/reduction reactions related to an antioxidant system of the organism [1]. This metal ion has also been found in many metalloproteins [2]. It takes part in a variety of processes in living organisms like development of embryos, formation of tissues, control of body temperature and nerve cell functions [3]. Therefore, improper copper homeostasis is connected with neurological disorders (Alzheimer’s disease [4], Parkinson’s disease [5]) and genetic disorders resulting in copper deficiency and excess (Wilson’s disease [6], Menkes disease [7]). Copper and its compounds have many medical applications. Copper(II) complexes such as acetate, aspirinate and salicylate have been used as analgesic, antipyretic, antiinflammatory and platelet antiaggregating agents. They have antioxidant *

Corresponding author. Tel.: +48 42 677 91 25; fax: + 48 42 678 83 98. E-mail address: [email protected] (E. Budzisz).

0277-5387/$ - see front matter  2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2006.12.043

activity and protect against some bad consequences of UV exposure. Binuclear complexes like Cu2(asp)4 exert additional activities, including antiulcer, anticancer, antimutagenic and antimicrobial ones [8]. The antitumor activity of copper(II) complexes has been explored in the last few decades [9]. The cytostatic activity of metal complexes (cisplatin) was noticed for the first time in the 1960s [10]. Unfortunately, cisplatin is highly toxic and its side effects have led to the search for new effective and safer metal complexes [11]. Copper(II) complexes may have less severe side effects and may overcome the acquired and inherited resistance to medicines based on platinum [12]. Copper complexes with thiosemicarbazone were amongst the first complexes tested for their anticancer activity [13]. Biological studies performed with some of them involved inhibition of cell proliferation and in vitro apoptosis tests in the human leukemia cell line U973. They also showed antimycotic, antiviral and antibacterial (including tuberculostatic) properties [14]. In recent years, 5-formylouracil thiosemicarbazone was

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evaluated and its metal complexes, especially with copper(II), showed an enhanced biological activity with respect to the free ligand. One of these copper N-aroylN 0 -thioaroylhydrazines derivatives was able to inhibit cell proliferation and induce apoptosis [15]. Copper(II) complexes of a-ketoglutaric acid thiosemicarbazone also inhibited cell proliferation through the apoptosis mechanism [16]. Copper(II) complexes of thiosemicarbazones derived from acyl diazines showed cytotoxic activity against colon adenocarcinoma HT-29 cells and large and small lung carcinoma cells. They inhibit the enzyme ribonucleoside diphosphate reductase and affect the synthesis of DNA. One of these complexes is a potent inducer of apoptosis in Burkitt’s lymphoma cells [17]. Cu(II) complexes of thioaroylhydrazines derivatives show significant inhibition of 3H-thymidine and 3H-uridine incorporation into DNA and RNA in P-815 and L-929 tumor cells and have an effect on DNA synthesis. They inhibit tumor growth and that process is associated with induction of apoptosis in lymphocytes, but the detailed mechanism of inhibition is still unclear. The inhibition in tumor cell blastogenesis could be a direct result of the interaction of the metal complexes with DNA, thus interfering with the normal process of its replication. The inhibition of uridine incorporation suggests their influence on the activity of enzymes involved in DNA replication, especially DNA endonucleases causing DNA fragmentation [18]. Over recent years, increasing attention has been paid to pyrazoles, pyrimidines and related N-containing heterocyclic derivatives, which play an important role in many biological processes due to their coordinating ability for metal ions [19]. The studies have been stimulated by promising pharmacological [20], analytical [21] and agrochemical [22] applications. Pyrazoles and their complexes with metals, besides having antitumor activity, are analgesic and antiinflammatory agents, such as the pyrimidinopyrazole derivative – mepirizole [19]. Some mixed chelate copper-based drugs have exhibited greater antineoplastic potency than cisplatin in in vitro and in vivo studies of a variety of tumor cell lines [23]. Pyrazol-thioketone derivatives have antimicrobial activity. They inhibit growth of Staphylococcus aureus, Staphylococcus typhii, Candida albicans and Mycobacterium tuberculosis [24]. O-Hydroxyphenylopyrazoles are used as UV stabilizers, analytical reagents in the complexation of metal ions, analgesic agents and platelet aggregation inhibitors [21]. Diarylopyrazoloquinolinones have affinity for the benzodiazepine receptor and their activity is similar to that of diazepam [25]. Here we present the synthesis of the new chelating ligands 5-(2-hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)pyrazol-4-carboxylic acid methyl ester (2) and 3-methyl-1 -(2-pyridinyl)-1H-chromene[4,3-c]pyrazol-4-on (3), as well as their solid pyrazole complexes with Cu(II). Physical and the protolytic properties of the ligands as well as their interaction with Cu(II) in solution are also shown.

2. Experimental 2.1. Materials All substances were used without further purification. Chloroform-D solvent for NMR spectroscopy was obtained from Dr. Glaser AG Basel. Solvents for synthesis (toluene, methanol, dimethylformamide, acetone) were reagent grade or better and were dried according to standard methods. The melting points were determined using an Electrothermal 1A9100 apparatus and they are uncorrected. The IR spectra were recorded on a Pye-Unicam 200G Spectrophotometer in KBr and CsI. The 1H NMR spectra were registered at 300 MHz on a Varian Mercury spectrometer. The MS data were obtained on a LKB 2091 mass spectrometer (70 eV ionization energy). The MS-FAB data were determined on Finnigan Matt 95 mass spectrometer (NBA, Cs+ gun operating at 13 keV). For the new compounds satisfactory elemental analyses (±0.3% of the calculated values) were obtained using a Perkin–Elmer PE 2400 CHNS analyzer. 2.2. Synthesis of the ligands 2.2.1. Synthesis of 5-(2-hydroxybenzoyl)-3-methyl-1(2-pyridinyl)pyrazol-4-carboxylic acid methyl ester (2) 2-Hydrazinopyridin (5 mmol) in EtOH (5 mL) was added at room temperature to a solution of 2-methyl-4oxo-4H-chromene-3-carboxylic acid methyl ester (1) (5 mmol) in EtOH (10 mL). The mixture was refluxed for 1 h. The solid crude product, which precipitated after 24 h, was filtered off, dried and crystallized from ethanol. The pure compound was obtained as a white solid. Yield: 942 mg (61%), mp: 158.5–159.9 C. IR: mmax/cm1 3190 (OH); 1705 (C@O); 1613 (C@N) cm1. 1H NMR (CDCl3): d = 2.57 (s, 3H, C–CH3); 3.62 (s, 3H, O–CH3); 6.83–8.34 (m, 8H, aromat) ppm. 13C NMR (CDCl3): d = 14.55 (C–CH3); 51.53 (O–CH3); 164.46 (C@O) ppm. MS m/z: 309.0. Anal. found: C, 65.97; H, 4.67; N, 13.30. Calc. for C17H13N3O3 (309.311): C, 66.01; H, 4.89; N, 13.59. 2.2.2. Synthesis of 3-methyl-1-(2-pyridinyl)-1Hchromene[4,3-c]pyrazol-4-on (3) N-Methylhydrazin (0.5 mmol) was added at room temperature to a solution of 5-(2-hydroxybenzoyl)-3-methyl1-(2-pyridin)pyrazol-4-carboxylic acid methyl ester (2) (0.5 mmol) in MeOH (10 mL). The mixture was refluxed for 1 h. The solid product, which precipitated after 1 h, was filtered off, dried and crystallized from ethyl acetate. The pure compound was obtained as a white crystal solid. Yield: 88 mg (63%), mp: 202.8–205.1 C. IR: mmax/cm1 1742 (C@O); 1615 (C@N) cm1. 1H NMR (CDCl3): d = 2.71 (s, 3H, CH3); 7.41–8.76 (m, 8H, aromat) ppm. 13 C NMR (CDCl3): d = 13.32 (C–CH3); 158.12 (C@O) ppm. MS m/z: 278.0. Anal. found: C, 68.91; H, 3.51; N,

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15.17. Calc. for C16H11N3O2 (277.269): C, 69.30; H, 4.0; N, 15.16. 2.3. Synthesis of copper(II) complexes 4 and 5 2.3.1. Synthesis of complex 4 Copper(II) chloride (0.1 mmol) in MeOH (2 mL) was slowly added at room temperature to a solution of 5(2-hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)pyrazol-4-carboxylic acid methyl ester (2) (0.1 mmol) in MeOH (10 mL). The mixture was left at room temperature for 24 h. The yellow solid product which precipitated was filtered off and crystallized from acetonitryl. The pure compound was obtained as a yellow crystal solid. Yield: 36 mg (81%), mp: 197.4–199.1 C. IR: mmax/cm1 3221 (OH); 1717 (C@O); 455 (Cu–N); 295 (Cu–Cl) cm1. FAB-MS m/z: 443.0. Anal found: C, 46.01; H, 3.32; N, 9.41. Calc. for C17H15N3O3CuCl2 (443.35): C, 46.05; H, 3.41; N, 9.48. 2.3.2. Synthesis of complex 5 Copper(II) chloride (0.1 mmol) in ethyl acetate (3 mL) was slowly added at room temperature to a solution of 3-methyl-1-(-2-pyridinyl)-1H-chromene[4,3-c]pyrazol-4-on (3) (0.1 mmol) in ethyl acetate (10 mL). The green solid precipitated after a few minutes. The product was filtered off. The pure compound was obtained as a green crystal solid. Yield: 22 mg (53%), mp: 297–298 C. IR: mmax/cm1 1749 (C@O); 457 (Cu–N); 302 (Cu–Cl) cm1. FAB-MS m/z 412.0. Anal. found: C, 46.41; H, 2.62; N, 10.21. Calc. for C16H11N3O2CuCl2 (411.619): C, 46.68; H, 2.69; N, 10.21. 2.4. Potentiometric studies The protonation constants of ligands 2 and 3 were determined by pH-metric titration of 4 cm3 samples, at 25 ± 0.1 C. The total concentration of ligand 2 in each sample ranged within 3.75–6.25 · 104 mol dm3. For ligand 3 the concentration range amounted to 3.75– 6.25 · 104 mol dm3. Owing to the very low solubility in pure water, the mixed 5% v/v 1,4-dioxane–water solvent was used for ligands 2 and 3, respectively. The titrations were carried out with carbonate-free NaOH solution of known concentration (0.1 mol dm3). The value of pKw = 13.77 resulted from our acid–base calibrations in the same solvent. The hydrolysis constants of the aquoion were determined under the same conditions as in the titrations in the presence of ligand. The metal–ligand interaction was studied by pH-metric titration of the same volume, medium and temperature as described for the ligand alone. The ligand was in excess – the L:M molar ratio amounted to 4:1, 5:1 and 6:1 at a total metal concentration within 1.1–5.0 · 104 mol dm3. Cu(NO3)2 purum p.a. of Fluka AG was used. The standard solution was titrated with the disodium salt of EDTA in the presence of murexide.

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The pH was measured with a Molspin Ltd. (Newcastle upon Tyne, England) automatic titration set and combined OSH 10-10 electrode (Metron, Poland). The total volume of the Hamilton microsyringe in the autoburette was 250 ll, the volume increments amounted to 0.0025 ml. The experiments were performed using MOLSPIN.EXE software. The electrode was calibrated in the log[H+] scale by titration of 0.005 M HNO3 (in 5% dioxane) with 0.1 M NaOH, temperature 25 C. Then concentration overall protonation constants blh = [LlHh]/[L]l[H]h were calculated by the SUPERQUAD computer program [26]. 2.5. X-ray measurements The light white single crystal of ligand 2 was used for measurement on an AFC5S Rigaku diffractometer [27]. X-ray intensities were collected using graphite monochromated Mo Ka radiation and the x scan technique. After each group of 150 reflections three standard reflections were monitored and insignificant (<2%) intensity fluctuation was observed. All data were corrected for Lorentz and polarization effect [28]. The structure of ligand 2 was solved by direct methods (SHELXS97 [29]) and refined on F2 by the full-matrix leastsquares technique (SHELXL97 [27]). All non-hydrogen atoms were refined anisotropically. During the refinement the atoms of the C13–C17 pyridyl ring were found to be disordered. Two components of the disorder were modelled, using rigid planar hexagons for the phenyl rings. Refinement of the site-occupation factors of the disordered atoms indicated that the two conformations were approximately equally occupied. Finally, the occupancies of the disordered atoms were fixed at 0.5 and similar restraints were applied to the atomic displacement parameters of those disordered atoms. The distances between atom pairs N2/C13A and N2/C13B were restrained to be equal, with ˚. an effective s.u. of 0.003 A Carbon-bonded H-atoms were included in calculated ˚ ) and constrained to ride on positions (C–H = 0.93–0.98 A their parent atoms with isotropic displacement parameters equal to 1.2Ueq(C) (or 1.5Ueq for methyl C atoms). The oxygen-bonded H-atoms (H3 and H41, H42 in the water molecule) were located from the difference map and refined isotropically. Selected crystal data and details of the structure refinement are collected in Table 2. Geometrical calculations and drawings were performed with PLATON [30].

Table 1 Selected IR bands for ligands 2, 3 and complexes 4, 5 m (cm1)

OH

–C@O

C@C

C@N

M–N–

M–Cl

2 3 4 5

3190

1705 1742 1717 1749

1613 1615 1615 1612

1543 1542 1554 1580

455 457

295 302

3221

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carboxylic acid methyl ester (1) and 2-hydrazinepyridin (1:1) in boiling methanol we have obtained 5-(2-hydroxybenzoyl)-3-methyl-1-(2-pyridin)pyrazol-4-carboxylic acid methyl ester (2) with a good yield (61%). This compound easily cyclizes under basic conditions to form 3-methyl1-(2-pyridinyl)-1H-chromene[4,3-c]pyrazol-4-on (3) (see Scheme 1). The physical data are given in Section 2.

Table 2 Crystallographic data, data collection and refinement for ligand 2 Ligand 2 Crystal data Chemical formula Mr Cell setting, space group ˚) a (A ˚) b (A ˚) c (A b () ˚ 3) V (A Z Dx (Mg m3) Radiation type Number of reflections for cell parameters h Range () l (mm1) Temperature (K) Crystal form, colour Crystal size (mm)

C17H15N3O3 · H2O 327.34 monoclinic, P21/c 13.945(3) 12.536(3) 16.497(5) 144.87(2) 1659.5(11) 4 1.310 ˚) Mo Ka (k = 0.7107 A 20 20.03–24.89 0.095 293(2) prism, white 0.50 · 0.35 · 0.25

Data collection Diffractometer Number of measured reflections Number of independent reflections Number of observed reflections Criterion for observed reflections hmax () Range of h, k, l

3.2. Synthesis of the complexes Complex 4, of the formula Cu(L)Cl2, was obtained by treatment of the corresponding ligand 2 with CuCl2 Æ 2H2O (in a 1:1 molar ratio) in methanol. Complex 5 was not formed in methanolic solution, most likely due to methanolysis (see Schemes 2 and 3) as we have isolated the free ligand 3. We have obtained complex 5 in the reaction of 3 and CuCl2 Æ 2H2O in ethyl acetate. Under this condition methanolysis or hydrolysis is not possible and the complex is formed. The IR spectra of the complexes are similar to those of the free ligands (see Table 1). The most characteristic bands are those at 1612 and 1580 cm1, attributable to the pyraz-

AFC-5S Rigaku 4038 3814 1703 I > 2r(I) 27.51 18 ) h ) 18 0 ) k ) 16 18 ) l ) 21

OH

OH

COOCH3

COOCH3

Refinement Refinement on R [F2 > 2r(F2)] wR (F2) S Number of reflections Number of parameters (D/r)max ˚ 3) Dqmax (e A ˚ 3) Dqmin (e A

+

F2 0.0584 0.1889 0.873 3814 258 0.000 0.661 0.470

N

CuCl2.2H2O

N

CH3

N

N

N

Cu

2 4

Scheme 2. Synthesis of complex 4.

O

O O

O CH3

3.1. Preparation of the ligands and their complexes N

It has been reported that certain copper(II) complexes catalyze radical formation while others seem to have antioxidant properties [31]. Their actual behavior depends upon the chemical environment and the nature of chelating agents. In the reaction of 2-methyl-4-oxo-4H-chromene-3-

CH3 +

CuCl2.2H2O

N

N

N +

H N

5

Scheme 3. Synthesis of complex 5.

CO2CH3 NH2NHCH3 N N

O

O

CH3

CH3 N N

N N 1

Cu Cl

3

NH2

CO2CH3 O

N

N

N

OH CH3

Cl

Cl

3. Results and discussion

O

CH3

N

2

Scheme 1. The synthesis of ligands 2 and 3.

3

Cl

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olyl m(C@C) and m(C@N) groups. The band at 3200 cm1 is characteristic of the OH group in ligand 2 and its complex 4. The IR spectra of the Cu complexes in the region 500–100 cm1 were also recorded and show well-defined bands corresponding to m(Cu–Cl) at 295 and 303 cm1. Bands attributable to m(Cu–N) at 455 and 457 cm1 are also present. The mC@N band observed for compound 2 at 1543 cm1 is shifted towards higher frequencies (to 1554 cm1) for complex 4. This observation can be explained by participation of the nitrogen atom in the coordination with the metal ions in the complex [32]. 3.3. Crystal and molecular structure of ligand 2 The molecular structure of ligand 2 is shown in Fig. 1. The molecule consists of four fragments: pyridyl and phenolic rings, methyl and carboxylate groups substituted on the pyrazole ring. The pyridyl rings have been found to be disordered (see Section 2.5). Both components of the disordered pyridyl rings are refined to be planar, the dihedral angle between their planes is 30(1). The pyrazole and benzene rings are also planar with a dihedral angle equal to 66(1). The bond lengths and angles listed in Table 3 are within the normal ranges, hence no detailed discussion is needed. The principal structural interest lies in the molecular interactions. Hydrogen-bonding geometries are listed in Table 4. The molecules of structure 2 are linked into two-dimensional layers by a combination of O–H  O and O–H  N hydrogen bonds. These layers are stacked along the [0 1 0] direction. Fig. 2 presents the hydrogen-bonding network projected on the ac plane. There are only weak C–H  O contacts between neighboring layers and no specific interactions are observed; in particular, aromatic p–p stacking interactions are absent from the structure of 2.

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Table 3 Selected geometric parameters for ligand 2 ˚) Bond lengths (A N1–N2 N1–C4 C3–C4 C3–C6 N2–C6 C6–C7

1.375(3) 1.324(7) 1.411(4) 1.378(7) 1.358(3) 1.479(4)

Bond angles () N2–N1–C4 N1–C4–C3 C4–C3–C6 C3–C6–N2

O3–C12 C4–C5 C1–C3 C1–O1 C1–O2 O2–C2

105.1(2) 110.5(2) 106.6(2) 105.5(2)

C6–N2–N1 C3–C1–O1 C3–C1–O2 C1–O2–C2

Table 4 Hydrogen-bonding geometry for ligand 2 ˚) ˚) D–H (A H  A (A i

O3–H3  O4 O4–H41  N1ii O4–H42  O1 C9–H9  O3iii

0.98(3) 0.92(3) 0.91(7) 0.93

1.73(3) 2.04(4) 1.98(8) 2.56

1.355(3) 1.495(9) 1.468(4) 1.211(8) 1.329(4) 1.454(4) 112.3(2) 124.0(3) 114.1(5) 115.4(2)

˚) D  A (A

D–H  A ()

2.696(3) 2.923(4) 2.880(7) 3.302(4)

169(6) 161(6) 170(4) 137

Symmetry codes: (i) x, 1/2  y, z  1/2; (ii) x  1, 1/2  y, z  1/2; (iii) 1  x, 1/2 + y, 1/2  z.

Fig. 2. The hydrogen-bonding layer in 2 projected on the ac plane. The B component of the disordered atoms and H-atoms not participating in the hydrogen-bonding have been omitted for clarity. [Symmetry codes: (i) x, 1/2  y, z  1/2; (ii) x  1, 1/2  y, z  1/2].

3.4. Determination of protonation constants

Fig. 1. The molecular structure of ligand 2 with the atom numbering scheme. The second component of the disordered pyridyl ring (C13B– C17B) has been omitted for clarity. Displacement ellipsoids are drawn at the 40% probability level and H atoms are shown as small spheres of arbitrary radii.

As a result of the protonation constants, it follows that ligand 2 behaves as a triprotonated molecule, whereas ligand 3 is indicative of two functional groups. The stepwise protonation constants log K reported here (Table 5) may be compared with the corresponding values of relatively simple heterocyclic compounds – corresponding to the groups found in ligands 2 and 3.

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Table 5 Experimental conditions of potentiometric titrations and values of overall protonation constants of 2 and 3 at 25 C Ligand 2

Ligand 3

3 3.1–11.0 9.31(2)a 13.36(2)b 16.78(3)c 3.36 2.57 9.31

2 3.0–5.5 3.99(1)d 7.33(1)e 0.31 7.20

4.04

3.99

ML

ML 2 ML 3

40

20

M

4

6

8

10

pH

3.42

3.34 3.58 [35]

Solvent: 5% v/v 1,4-dioxane–H2O. Standard deviations in parentheses. The literature data correspond to the same temperature. L in the case of ligand 2 denotes the form with deprotonated phenol OH. a Equilibrium: L + H+ LH. b Equilibrium: L þ 2Hþ LH2 þ . c Equilibrium: L þ 3Hþ LH3 2þ . d Equilibrium: L + H+ LH+. e Equilibrium: L þ 2Hþ LH2 2þ .

3.5. Determination of stability constants (ligand 2) In the case of ligand 2 with a deprotonated phenol ring (L), the metal renders accessible six coordination sites (Table 6). The three consecutive equilibria are accepted in the refinements although none of the assumed bridged dimeric species has been found suitable in the model. NPyridine and N-pyrazole are the most probable electron pair donors, giving rise to highly favourable five-membered chelate rings. At lower pH, however, when the OH group is undissociated, only a complex with a L:M ratio of 2:1 could be confirmed (Fig. 3).

Table 6 Experimental conditions of potentiometric titrations and values of overall stability constants of ligand 2 at 25 C Ligand 2 Number of titrations Range of log[H+] log b101 log b102 log b110 log b120 log b130 log b122 r v2

60

0

5.22[34] log K (N, Me-pyrazole)

80

MH -2

9.79 [33] log K (N, pyridine)

ML2H2 % formation relative to M

Number of titrations Range of log[H+] log b11 log b12 log b13 r v2 log K (OH, phenol)

100

5 3.8–10.1 7.22(6)a 13.36(2)b 7.31(4)c 12.27(2)d 15.72(3)e 26.05(3)f 1.06 5.64

Solvent: 5% v/v 1,4-dioxane–H2O. Standard deviations in parentheses. a Equilibrium: Cu2þ CuH1 þ þ Hþ . b Equilibrium: Cu2+ CuH2 + 2H+. c Equilibrium: L + Cu2+ CuL+. d Equilibrium: 2L + Cu2+ CuL2. e Equilibrium: 3L þ Cu2þ CuL3  . f Equilibrium: 2L þ 2Hþ þ Cu2þ CuL2 H2 2þ .

Fig. 3. Species distribution in a solution containing M = Cu from Cu(NO3)2 and L = ligand 2 at a 1:4 molar ratio. Solv. 5% v/v 1,4dioxane–water. CCu = 3.4 · 104 mol dm3. Temperature 25 C.

The interaction of 3 with copper(II) during the titration was very weak in spite of the protolytic properties of the nitrogen functions being quite similar to 2 (Table 5). This resulted in a visible precipitation already at pH  5. As can be seen in Fig. 3 the MH1 monohydroxo complex is completely overhelmed by a dihydroxo MH2 complex and the formation of significant amounts of the MH2 complex occurs essentially at pH > 8.5. 4. Spectrophotometric studies of the Cu(II)–ligand interaction With a L:M molar ratio of 4:1, due to high concentrations of the metal (1.25 · 103 mol dm3), the experiments needed for this method were made in 1,4-dioxane–water solutions (10% v/v). The basicity of the solution was enhanced by adding small portions of 0.1 M NaOH of known density (20–40 ll) to a sample with an initial volume of 2.4 cm3. The accurate number of millimoles was evaluated by weighing the cell after each addition. As can be seen in Fig. 4, a rise in absorbance occurred already at pH  4. With alkalization the solution became more and more yellow (up to dark-yellow) until pH = 8.63 when the precipitation disturbed further absorption measurements. As it is well known for hexacoordinate Cu(II) compounds [36,37] in a tetrahedral environment, the crystal field splitting leads to three transitions (both for a tetragonal bipyramid elongated along the z-axis – ground state 2 B1g and for the shortened bipyramid – ground state 2A1g). Accordingly, in our spectra we may propose to assign the broad maximum at 700 nm (shifting from 730 to 707 nm) as the lowest energy band. The second band, initially only an inflection, becomes visible at higher pH, at ca. 430–440 nm, together with the rising complex formation, whereas the third band is probably masked by the highly intensive tail below 400 nm (Fig. 4). The very high intensity (e exceeding 104) indicates the tail of a strong charge transfer band. Moreover, the rise of absorbance within the observed tail makes it impossible to observe

A. Kufelnicki et al. / Polyhedron 26 (2007) 2589–2596

These data can be obtained free of charge via http:// www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +(44) 1223-336-033; or e-mail: [email protected].

1

absorbance

0.8 0.6 5 4

0.4

9

6

8

Acknowledgements

3 7

2

0.2 1

0 200

2595

300

400

500

600

700

800

900

-0.2

Financial support from the Medical University of Ło´dz´: Grant No. 503-3066-2 to E. Budzisz and 503-3014-2 to the Laboratory of Physical and Biocoordination Chemistry is gratefully acknowledged.

wavelength (nm)

Fig. 4. Absorption spectra in a solution containing Cu(NO3)2 and ligand 2 at a 1:4 molar ratio (starting from the aquo-ion; curve 1). Solv. 10% v/v 1,4-dioxane–water CCu = 1.25 · 103 mol dm3. Curves 2–9 denote the spectra scanned after adding a consecutive portion of acid. pH: 2 – 4.07; 3 – 4.32; 4 – 4.68; 5 – 5.26; 6 – 6.92; 7 – 7.94; 8 – 8.63. Curve 9 – precipitation.

the blue shift of the much weaker d–d band near 430 nm – the shift is slightly towards longer wavelengths. 5. Conclusions In this paper, we have shown a simple and convenient route for the synthesis of new chelating ligands and their copper(II) complexes. The newly synthesized ligands 2 and 3 create neutral complexes of the general type MLCl2. The molecular structure of ligand 2, which crystallizes as a monohydrate, has been confirmed by X-ray analysis. The crystal packing of 2 consists of two-dimensional layers generated by hydrogen bonds. Between these layers weak C–H  O contacts are observed. The complexing properties of 2 with Cu(II) in solution could be related to the phenol 2-hydroxy group. In alkali medium, the ionization of this group, introducing an additional negative charge, enhances the donor properties of the potential nitrogen functions (pyridine and Me-pyrazole) by an inductive effect. As a result the refinements confirm the presence of three consecutive complexes (ML, ML2 and ML3) where the chelate rings use up to all six coordination sites. On contrary, in more acidic medium (pH 4–6) only one of the potential coordination modes was accepted: the ML2H2 species with undissociated OH. The lack of inductive effects in the case of 3 leads to a very weak interaction with the metal in solution, which in connection with the low first hydrolysis constant of Cu(II)aq. (as follows from Table 6: log KOH = log b10–1 = 7.22) results in precipitation at relatively low pH. Studies on the biological activity (cytotoxicity) of the synthesized compounds are in progress. 6. Supplementary material CCDC 621681 contains the supplementary crystallographic data for the compound referred in this paper.

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