Synthesis and Crystal Structure of Solvated Complexes of Copper(II

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Synthesis and crystal structure of solvated complexes of copper(II) with serine and phenanthroline and their solidstate-to-solid-state transformation into one stable solvate Darko Vušak, Biserka Prugove#ki, Dalibor Mili#, Marijana Markovi#, Ines Petkovi#, Marijeta Kralj, and Dubravka Matkovi#-#alogovi# Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01157 • Publication Date (Web): 04 Oct 2017 Downloaded from http://pubs.acs.org on October 4, 2017

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Crystal Growth & Design

Synthesis and crystal structure of solvated complexes of copper(II) with serine and phenanthroline and their solid-state-to-solid-state transformation into one stable solvate Darko Vušak,† Biserka Prugovečki,*,† Dalibor Milić, †,‡ Marijana Marković,¤,⸸ Ines Petković,†,# Marijeta Kralj,§ and Dubravka Matković-Čalogović*,† †

Division of General and Inorganic Chemistry, Department of Chemistry, Faculty of Science,

University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. ¤ Institute for Medical Research and Occupational Health, Ksaverska cesta 2, P. O. Box 291, 10001 Zagreb, Croatia. § Laboratory of Experimental Therapy, Division of Molecular Medicine, Bijenička 54, 10000 Zagreb, Croatia

ACS Paragon Plus Environment

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KEYWORDS: solvent exchange, porous structures, pi-interactions, supramolecular chemistry, solid-state transformations

ABSTRACT: Reactions of copper(II) sulfate with 1,10-phenanthroline, L-serine and a base were investigated under different solution-based and mechanochemical synthetic procedures. Six complexes with serine were obtained: [Cu(L-ser)(H2O)(phen)]2SO4·xH2O (x = 4, 6 or 10; 1·4H2O,

1·6H2O

and

ser)(CH3OH)(phen)]SO4·3H2O·CH3OH

1·10H2O),

[Cu(L-ser)(H2O)(phen)][Cu(L-

(1·2·3H2O·CH3OH),

[Cu(L-

ser)(CH3OH)(phen)]2SO4·xCH3OH (x = 2 or 2.5; 2·2CH3OH and 2·2.5CH3OH), and two without serine: [Cu(SO4)(phen)2]·xH2O (x = 4.5 or 6.75; 3·4.5H2O and 3·6.75H2O) (phen = 1,10-phenanthroline, L-ser = L-serinato). The X-ray crystal structure analysis of serine-containing complexes revealed extensive hydrogen bonding and π-interactions that link complex cations, sulfate anions and solvent molecules into 3D architectures. Most of the water/methanol solvent molecules in these porous compounds are found in channels, some in pockets connected to channels, and can be exchanged in vapours of the other solvent. Along with the solvent exchange, the solvent molecule apically coordinated to copper(II) is also exchanged in some transformations. By neat grinding, all serine-containing complexes transform into 1·6H2O. Quantum chemical calculations were done for compounds 1·4H2O and 1·6H2O in the gas phase and an aqueous (or methanol) surrounding. 1·6H2O and 3·4.5H2O showed pronounced antiproliferative activity toward human breast and lung tumour cell lines.


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INTRODUCTION Copper complexes with heterocyclic aromatic compounds have been studied extensively due to their diverse physical and chemical properties. In combination with different organic ligands, they have potential applications in biomedicine, industry, environment protection and materials science.1–4 Copper(II) complexes with 1,10-phenanthroline and its derivatives are of particular interest because of their various biological activity such as cytotoxic,5,6 antimicrobial,7 antibacterial,8–10 anti-Candida activities,11 DNA-binding and nuclease activity.12,13 It was found that amino acid/peptide based copper(II) compounds show efficient DNA cleavage under physiological conditions in the presence or absence of a reducing agent.14–16 Also, metal complexes are usually more active than ligands alone.17 Copper complexes with amino acids are often used as model systems for investigations of copper containing proteins and enzymes. Copper(II) complexes with 1,10-phenanthroline and L-α-amino acids (L-val, L-arg, L-leu and Lmet) possess superoxide dismutase-like activities.18,19 Moreover, ligands such as heterocyclic bases and amino acids are capable of taking part in the formation of non-covalent interactions, such as hydrogen bonds and π-interactions. As a consequence, many different architectures may emerge from self-assembly of the complexes,20–22 making them interesting systems for investigations in crystal engineering. Complexes with hydrogen bond acceptors and/or donors can form porous structures in which solvent molecules form 1D chains, 2D or 3D frameworks. In recent years, porous coordination compounds are materials of interest for their ability of recognition and adsorption of solvent or other guest molecules.23–26 Hence, these type of materials have potential applications in solvent storage or as catalysts.27 If one of the ligands in such porous material is chiral (e.g. an amino acid), it may also be used in enantioselective synthesis.28


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Only a few copper complexes containing L-serine were structurally characterized until the present day – mixed copper complexes with

29

L-histidine

and glycine,30 pure serine

complexes,31–33 and complexes with 1,10-phenanthroline and nitrate34 or chloride ions.8 It was found that copper complexes with amino acids, including L-serine, can be used for stereospecific reactions,35 which are important for investigations in biomimetic chemistry and can also be used as catalysts in organic synthesis.36,37 Most of the research including those complexes was done with a goal to reveal their biological activity. Along with our interest in essential metal complexes with amino acids, we are also interested in transformation of polymorphs and in structural changes that occur upon the change in their solvation state (sometimes called pseudopolymorphs and solvatomorphs). For some of these terms there was a polemic going on, especially for pseudopolymorphs.38,39 For description of our compounds we will use the term solvates as explained later. In this work we report synthesis, crystallization and crystal structures of six copper(II) complexes with 1,10-phenanthroline and L-serine ligands obtained from the water/methanol solvent system, and two copper(II) complexes with sulfate and 1,10-phenanthroline ligands. These two ligands were chosen having in mind a polar ligand and a nonpolar ligand and their ability to form different types of intermolecular contacts. The effects of grinding and solvent molecules exchange in solution and/or vapour were investigated in order to study solid-state-tosolid-state transformations. We report the in vitro biological activity on two human tumour cell lines, on human breast (MCF-7) and lung (H 460) tumour cells, and also the computational studies of the complex compounds in the gas phase and in simulated aqueous/methanol environment.


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EXPERIMENTAL SECTION Materials and methods Ethanol and methanol were purchased from Alkaloid, Skopje,

L-serine

and anhydrous

copper(II) sulfate from Acros Organics, copper(II) sulfate pentahydrate from Gram-Mol, Zagreb, sodium hydrogencarbonate from Kemika, Zagreb, 1,10-phenanthroline monohydrate from Merck, and were used without further purification. The CuSO4·H2O and anhydrous 1,10phenanthroline were prepared by heating the CuSO4·5H2O and 1,10-phenanthroline monohydrate, respectively (the X-ray powder diffraction of the bulk samples of CuSO4·H2O and 1,10-phenanthroline were performed and the diffraction patterns were consistent with the patterns calculated from single crystal data40,41). The CHN-microanalysis was carried out by a PerkinElmer 2400 Series II CHNS analyzer in the Analytical Services Laboratory of the Ruđer Bošković Institute, Zagreb, Croatia. FT-IR spectra were measured by a PerkinElmer Spectrum Two spectrometer equipped with Diamond UATR accessory in the spectral range between 4000 – 450 cm−1 with a resolution of 2 cm−1. Samples of 1·10H2O, 2·2CH3OH and 2·2.5CH3OH, which are unstable outside the solution, were kept moist with mother liquor during the measurement. Thermogravimetric measurements were performed using a simultaneous TGADTA analyzer (Mettler-Toledo TGA/SDTA851e) using alumina crucible in pure oxygen. The TGA results were developed by applying the Mettler STARe 9.01 software. DSC thermograms were recorded in a nitrogen atmosphere on a Perkin-Elmer Pyris Diamond DSC instrument using about 2 mg of a sample in Al-pans. Each heating run was performed in the temperature range 20 to 400 °C, at a rate of 20 °C min–1. A Retch MM200 grinder operating at 25 Hz frequency and a stainless steel jars (14 mL in volume; using stainless steel grinding ball of 8 mm in diameter) were used for the grinding experiments.


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Synthetic procedures 1. Solution based synthesis Synthesis of bis[aqua(1,10-phenanthroline)(L-serinato)copper(II)] sulfate–water (1/4), 1·4H2O, and bis[aqua(1,10-phenanthroline)(L-serinato)copper(II)] sulfate–water (1/6), 1·6H2O. Copper(II) sulfate (0.125 g, 0.50 mmol) pentahydrate, 1,10-phenanthroline monohydrate (0.099 g, 0.50 mmol), L-serine (0.053 g, 0.50 mmol), NaHCO3 (0.042 g, 0.50 mmol), and mixture of water (7 mL) and methanol (3 mL) were mixed and heated for 15 minutes. After cooling, dark blue crystals of 1·4H2O and 1·6H2O suitable for X-ray structure analyses were formed. Synthesis of bis[aqua(1,10-phenanthroline)(L-serinato)copper(II)] sulfate–water (1/10), 1·10H2O, 1·6H2O and 1·4H2O. Solution of 1,10-phenanthroline monohydrate (0.40 g, 2.02 mmol) in ethanol (2 mL) was added dropwise to an aqueous solution (2 mL) of copper(II) sulfate pentahydrate (0.50 g, 2.00 mmol) and a pale blue precipitate was formed. After the addition of Lserine solution (0.21 g, 2.00 mmol) in hydrochloric acid (1 mL, c = 0.1 mol dm–3) an aqueous solution of ammonia (15 mL, c = 0.1 mol dm–3) was added dropwise. Dark blue suspension was refluxed for 30 minutes. Solution was left to evaporate slowly. After a few days, dark blue crystals of 1·10H2O and 1·4H2O suitable for X-ray structure analyses were formed. If the resulting solution was quickly evaporated, only 1·4H2O was formed. The X-ray powder diffraction of the bulk sample 1·4H2O were performed and the diffraction pattern was consistent with the pattern calculated from single crystal data (Figure S1 in the Supporting Information). Crystals of 1·10H2O decompose when taken out of solution. IR (ATR, for 1·10H2O): = 3600– 3000 cm–1 (O–H), 3230 cm–1 (N–H), 3126 cm–1 (N–H), 2928 cm–1 (C–H), 1651 and 1626 cm–1


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(C=O), 1600 cm–1 (C=N + ring stretching), 1523 cm–1 (C=C), 1432 cm–1 (C=N), 1398 cm–1 (C=O), 1360 cm–1 (CH2), 1066 cm–1 (C–O + C–N). Synthesis of 1·10H2O, 1·6H2O, 1·4H2O and bis(1,10-phenanthroline)(sulfato)copper(II)– water (1/4.5), 3·4.5 H2O. Solution of 1,10-phenanthroline monohydrate (0.70 g, 3.53 mmol) in ethanol (2 mL) was added dropwise to an aqueous solution (2 mL) of copper(II) sulfate pentahydrate (0.50 g, 2.00 mmol) and a pale blue precipitate was formed. After the addition of a solution of L-serine (0.30 g, 2.85 mmol) in hydrochloric acid (1 mL, c = 0.1 mol dm–3) an aqueous solution of ammonia (15 mL, c = 0.1 mol dm–3) was added dropwise. Dark blue suspension was refluxed for 30 minutes. Solution was left to evaporate slowly. After a few days dark blue crystals of 1·10H2O, 1·6H2O and 1·4H2O suitable for X-ray structure analyses were formed. Crystals were filtered off and after a few days X-ray quality pale blue crystals of 3·4.5H2O were formed in the filtrate. If the resulting solution was quickly evaporated, only 1·6H2O, 1·4H2O and 3·4.5 H2O were formed. Synthesis of 1·6H2O. Copper(II) sulfate pentahydrate (0.125 g, 0.50 mmol), 1,10phenanthroline monohydrate (0.099 g, 0.50 mmol), L-serine (0.053 g, 0.50 mmol), of NaHCO3 (0.042 g, 0.50 mmol) and mixture of water (3 mL) and methanol (7 mL) were mixed and heated in a beaker for 10 minutes. After cooling, dark blue crystals of 1·6H2O suitable for X-ray structure analyses were formed. Crystals were filtered off, the X-ray powder diffraction of the bulk sample was performed and the diffraction pattern is consistent with the pattern calculated from single crystal data (Figure S2 in the Supporting Information). IR (ATR): = 3600–3000 cm–1 (O–H), 3211 cm–1 (N–H), 3120 cm–1 (N–H), 3070–2800 cm–1 (C–H), 1634 cm–1 (C=O), 1595 cm–1 (C=N + ring stretching), 1521 cm–1 (C=C), 1432 cm–1 (C=N), 1398 cm–1 (C=O), 1345


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cm–1 (CH2), 1102 and 1046 cm–1 (C–O + C–N); elemental analysis calcd (%) for C30H44N6O18SCu2: C 38.50, H 4.74, N 8.98; found: C 38.16, H 4.38, N 8.86. Synthesis

of

[aqua(1,10-phenanthroline)(L-serinato)copper(II)][methanol(1,10-

phenantroline)(L-serinato)copper(II)] sulfate–methanol–water (1/1/3), 1·2·3H2O·CH3OH. Compound 1·6H2O (0.010 g, 0.011 mmol) or 1·4H2O (0.010 g, 0.011 mmol) was dissolved in methanol (1 mL) or methanol/water mixture (9:1 or 19:1 v/v, 1 mL). After a few days, blue crystals of 1·2·3H2O·CH3OH suitable for X-ray structure analyses were formed. Crystals of 1·2·3H2O·CH3OH decompose when taken out of solution. Synthesis of bis[methanol(1,10-phenanthroline)(L-serinato)copper(II)] sulfate–methanol (1/2), 2·2CH3OH. Copper(II) sulfate monohydrate (0.089 g, 0.50 mmol), anhydrous 1,10phenanthroline (0.090 g, 0.50 mmol), L-serine (0.053 g, 0.50 mmol), NaHCO3 (0.042 g, 0.50 mmol) and methanol (10 mL) were mixed and heated for 10 minutes. After one day, pale blue powder of dark blue crystals of 2·2CH3OH suitable for X-ray structure analyses were formed. Crystals of 2·2CH3OH decompose when taken out of solution. IR (ATR): = 3600–3000 cm–1 (O–H), 3224 cm–1 (N–H), 3132 cm–1 (N–H), 3100–2800 cm–1 (C–H), 1624 cm–1 (C=O), 1587 cm–1 (C=N + ring stretching), 1520 cm–1 (C=C), 1431 cm–1 (C=N), 1390 cm–1 (C=O), 1345 cm–1 (CH2), 1128, 1094 and 1029 cm–1 (C–O + C–N). Synthesis of bis(1,10-phenanthroline)(sulfato)copper(II)–water (1/6.75), 3·6.75H2O and 3·4.5H2O. Solution of 1,10-phenanthroline monohydrate (0.40 g, 2.01 mmol) in methanol (2 mL) was added to a solution of copper(II) sulfate pentahydrate (0.25 g, 1.00 mmol) in water (10 mL). Resulting solution was heated for 15 minutes and filtered off. After a few days, blue crystals of 3·4.5H2O and 3·6.75H2O suitable for X-ray structure analyses were formed.


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Synthesis of bis[methanol(1,10-phenanthroline)(L-serinato)copper(II)] sulfate–methanol (1/2.5), 2·2.5CH3OH. Anhydrous copper(II) sulfate (0.080 g, 0.50 mmol), anhydrous 1,10phenanthroline (0.090 g, 0.50 mmol), L-serine (0.053 g, 0.50 mmol), NaHCO3 (0.042 g, 0.50 mmol), and methanol (10 mL) were mixed and heated in autoclave for 30 minutes at 120 °C. After a few days, dark blue needles of 2·2.5CH3OH were formed. Crystals of 2·2.5CH3OH decompose when taken out of solution. IR (ATR): = 3600–3000 cm–1 (O–H), 3237 cm–1 (N– H), 3125 cm–1 (N–H), 3070–2800 cm–1 (C–H), 1650 and 1625 cm–1 (C=O), 1587 cm–1 (C=N + ring stretching), 1521 cm–1 (C=C), 1432 cm–1 (C=N), 1384 cm–1 (C=O), 1351 cm–1 (CH2), 1072 cm–1 (C–O + C–N). 2. Mechanochemical synthesis Synthesis of 1·6H2O. Copper(II) sulfate pentahydrate (0.062 g, 0.25 mmol), copper(II) hydroxide (0.024 g, 0.25 mmol),

L-serine

(0.053 g, 0.50 mmol) and 1,10-phenanthroline

monohydrate (0.099 g, 0.50 mmol) were weighted into a stainless-steel milling jar and 1 – 3 drops of water (or methanol) was added. Milling was performed at room temperature for 30 minutes. The X-ray powder diffraction of the bulk sample was performed and the diffraction pattern is consistent with the patterns calculated from single crystal data (Figure S3 in the Supporting Information). Neat grinding with the same reactants resulted in an unknown phase. Synthesis of 3·4.5 H2O. Experimental procedure is the same as the previous one, for compound 1·6H2O, but L-serine and NaHCO3 were not used. Experiments were performed with 2 drops of methanol as well as the solvent-free experiment. Milling was performed at room temperature for 20 minutes (LAG experiment) or 80 minutes (NG experiment). The X-ray powder diffraction of the bulk sample was performed and it is consistent with the patterns


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calculated from single crystal data (Figure S4 in the Supporting Information); elemental analysis calcd (%) for C48H50N8O17S2Cu2: C 47.96, H 4.19, N 9.32; found: C 47.80, H 3.97, N 9.22.

Crystallography Single crystal X-ray diffraction The single crystal X-ray diffraction data were collected by ω-scans on an Oxford Diffraction Xcalibur 3 CCD diffractometer with graphite-monochromator using MoKα radiation (λ = 0.71073 Å) at 293 K (1·4H2O, 1·6H2O, 1·10H2O, 3·4.5H2O), 150 K, 1·10H2O, 2·2CH3OH, 2·2.5CH3OH, 3·6.75H2O), 120 K (1·2·3H2O·CH3OH) and 100 K (1·6H2O). Data collection and reduction was performed using CrysAlis software package.42 Crystal structures were solved and refined using the programs integrated in the WinGX system.43 The structures were solved by the direct methods using SHELXS program,44 and refined by the full-matrix least-squares method based on F2 against all reflections using SHELXL-97 program.44 All non-hydrogen atoms were refined anisotropically. Most of the hydrogen atoms were placed at calculated positions, except for the hydrogen atoms belonging to the solvent molecules and disordered parts of structures. Hydrogen atoms of the coordinated and crystallization water molecules were located in difference Fourier map and fixed to coordinates or fixed to O–H distances of 0.85(1) Å and H–H distances of 1.39(2) Å. In the complexes 1·2·3H2O·CH3OH, 2·2CH3OH and 2·2.5CH3OH the methyl hydrogen atoms in methanol molecules and hydroxyl hydrogen atoms were located from the electron density maxima, constrained to idealized geometry, and only the torsion angles were refined (HFIX 137 for methyl and HFIX 147 for hydroxyl hydrogen atoms). In the disordered sulfate ions the bond lengths and angles were restrained at S−O distances d = 1.470(1) Å and O−O distances d = 2.400(2) Å. Geometry parameters were calculated using


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PLATON.45 Drawings of the structures were prepared by ORTEP46 and MERCURY47 programs. The crystallographic data are summarized in Table S1 and S2, in the Supporting Information. Hirshfeld surfaces were calculated in CrystalExplorer.48 The voids occupied by water molecules were calculated by the Hydrate Analyzer program, and those occupied by methanol molecules by Voids program, both in MERCURY47 (probe radius 1.2 Å). Pictures of the crystals are those obtained during data collection. Drawings of the crystals were made by the WinXMorph49 program. Powder X-ray diffraction The powder X-ray diffraction data were collected on a PANalytical X'Change powder diffractometer in the Bragg-Brentano geometry using CuKα radiation (λ = 1.54056 Å) at room temperature. Samples were contained on Si sample holder. Patterns were collected in the range of 2θ = 5 – 50° with the step size of 0.01° and at 0.5 s per step. Powder X-ray diffraction data were collected and visualized using the HighScore Plus program.50 The powder diffraction data of unstable compounds were collected on a laboratory PANalytical X’Pert Pro diffractometer in the reflection geometry mode with the X’Celerator detector, using CuKα radiation. The sample was contained on a Si sample holder and covered with a Kapton foil. Solvent exchange experiments Interconversion 1·6H2O ↔ 1·4H2O Crystalline powder of 1·6H2O was left to stand in air for several months and the change in structure was monitored by XRPD. Diffraction patterns were collected in the range of 2θ = 5 – 50° with the step size of 0.02° and exposure of 1.0 s per step. Aging in air and solvent exchange; transformation 2·2CH3OH → 1·6H2O


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Crystals of 2·2CH3OH were left to stand in air. Diffraction pattern was measured each minute for 10 minutes in 2θ range 6.5 – 15°, and then every few hours and days in 2θ range 3 – 40° with step size 0.008°. Aging in methanol vapour; transformation 1·6H2O → 2·2CH3OH Crystals of 1·6H2O were placed in an Eppendorf tube which was in a larger container containing methanol. Sample was placed on Si holder with a few drops of methanol and sealed with a Kapton foil. Diffraction pattern was measured each minute for 10 minutes in 2θ range 6.5 – 15°, and then every few hours in 2θ range 3 – 40° with step size 0.008°. Aging in methanol solution; transformations to 2·2CH3OH Crystals of 1·6H2O were placed in saturated solution of the compound 2·2CH3OH and left to stand for one to three days. Samples of such prepared crystals were placed on Si sample holder along with the solution and sealed with a Kapton foil to prevent solvent evaporation and crystallization of other compounds. Diffraction patterns were collected from 3° to 40° (2θ) with a step size of 0.008°. Humidity control Crystals of 1·6H2O were ground with a mortar and pestle, and it was confirmed by XRPD of the bulk sample that the sample was pure. Samples of powder were placed in empty vials, which were then placed in containers with saturated solutions of different inorganic compounds with fixed relative humidity: sodium hydroxide, potassium acetate, magnesium chloride, potassium carbonate, magnesium nitrate, cobalt(II) chloride, sodium nitrate and potassium chloride.51 Samples were monitored by using XRPD. Diffraction patterns were collected in range of 2θ = 3 – 40° with step size 0.008°. Quantum Chemical Calculations (Gaussian09, DFT)


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The stationary points [i.e., the minimum structures] and relative energies of complexes 1·4H2O, 1·6H2O, 1·10H2O, 1·2·3H2O·CH3OH, and 2·2CH3OH, were calculated using the unrestricted density functional theory method with the B3LYP52 hybrid density functional, with the empirical dispersion correction energy term53–56, named B3LYP-D3. The all electron def2TZVP basis set57 was also tested for selected experimental molecular and crystal structure coordinates. Def2-TZVP is a balanced basis set on all atoms at the triple-ζ level including polarization.57 To account for the relativistic effects of copper inner-shell electrons, the relativistic pseudopotential MDF10 for Cu58,59 was applied together with def2-TZVP. MDF10 is a multi-configuration Hartree−Fock adjusted relativistic pseudopotential with perturbative corrections added from Dirac−Hartree−Fock results.58,59 Altogether, the method and basis set combination describing the results was named B3LYP-D3/BS1. After having tested a selection of several method/basis set combinations before, and when taking into account the computational time and effort spent, B3LYP-D3/BS1 was chosen as suitable for our calculations. Cations [Cu(L-ser)(phen)] and [Cu(L-ser)(H2O)(phen)] are positively charged with a spin multiplicity of 2. Complexes containing the sulfate anion are electrically neutral molecules with a spin multiplicity of 1 or 3. Singlet states were energetically higher than the triplet ones and were therefore excluded from the computations. To verify whether the optimized geometries were local minima, frequency calculations were performed to ensure the absence of imaginary frequencies. All geometries were optimized without symmetry constraints. For some of the optimized gas phase geometries of 1·4H2O, 1·6H2O, 1·10H2O, 1·2·3H2O·CH3OH, and 2·2CH3OH, the equilibrium geometries were also computed in an aqueous medium by using the implicit solvent effects (the dielectric constant for water ε = 78.3553 and for methanol ε = 32.613). Solvent effects were modelled with the integral equation


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formalism of polarizable continuum model (PCM)60 as it is implemented in Gaussian 09 suite of programs (keyword SCRF = PCM).61–64 The solute cavity was created via a set of overlapping spheres by using the Universal force field (UFF) atomic radii65 scaled by a factor of 1.1, and the density of surface elements was set to 5 Å–2. The representation of the solvent excluded surface by a scaled van der Waals surface based on the UFF atomic radii was chosen as the best choice for practicality and accuracy of the calculation of molecular properties.66 Except for the case of PCM calculations, all water and methanol molecules and a sulfate anion are explicitly included in the geometry optimization. Cell culturing H 460 and MCF-7 cells were cultured as monolayers and maintained in Dulbecco's modified Eagle medium (DMEM), supplemented with 10% fetal bovine serum (FBS), 2 mmol dm–3 Lglutamine, 100 U mL–1 penicillin and 100 µg mL–1 streptomycin in a humidified atmosphere with 5% CO2 at 37 °C. Proliferation assays The compounds were readily soluble in water (stock solutions were prepared in water at 8.4×10–3 mol dm–3 (1·6H2O) and 4×10–3 mol dm–3 (3·4.5H2O) and diluted with the cell culture medium on the day of testing.The panel cell lines were inoculated in parallel onto a series of standard 96-well microtiter plates on day 0, at 1×104 (H 460), or 3×104 cells mL–1 (MCF-7), depending on the doubling times of specific cell line. Test agents were then added in five 10-fold dilutions (10–8 to 10–4 mol dm–3) and incubated for a further 72 hours. Working dilutions were freshly prepared on the day of testing. After 72 hours of incubation the cell growth rate was evaluated by performing the MTT assay, which detects dehydrogenase activity in viable cells. The MTT Cell Proliferation Assay is a colorimetric assay system, which measures the reduction


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of a tetrazolium component (MTT) into an insoluble formazan product by the mitochondria of viable cells. For this purpose, the substance treated medium was discarded and MTT was added to each well at a concentration of 20 µg / 40 µL. After four hours of incubation the precipitates were dissolved in 160 µL of dimethyl sulfoxide (DMSO). The absorbance (OD, optical density) was measured on a microplate reader at 570 nm. The absorbance is directly proportional to the cell viability. The percentage of growth (PG) of the cell lines was calculated, as described previously. The results were expressed as IC50, a concentration necessary for 50% of inhibition. The IC50 values for each compound were calculated from dose-response curves using linear regression analysis by fitting the test concentrations that give PG values above and below the respective reference value (e.g. 50 for IC50). Each test point was performed in quadruplicate in at least two separate experiments.

RESULTS AND DISCUSSION The synthesized complexes discussed here are composed of complex cations of two different types (1 and/or 2) with sulfate counterions, or of a neutral complex molecule of type 3 (Scheme 1), all of them being solvates. In cations of types 1 and 2 the copper(II) ion is pentacoordinated by one N,O-donating L-serinato ligand and one N,N’-donating phenanthroline ligand in the basal plane and an apically coordinated water or methanol molecule. Complex molecule of type 3 is quite different since it does not contain a serine ligand but is coordinated by a sulfate and two phenanthroline ligands. We have obtained three different hydrates with cations of the type 1 and sulfate anions: [Cu(L-ser)(H2O)(phen)]2SO4·4H2O (1·4H2O), [Cu(L-ser)(H2O)(phen)]2SO4·6H2O (1·6H2O), and [Cu(L-ser)(H2O)(phen)]2SO4·10H2O (1·10H2O) (phen = 1,10-phenanthroline, Lser = L-serinato). Complex 1·2·3H2O·CH3OH contains both types of complex cations, 1 and 2,


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and

also

a

mixed

solvent

content

water/methanol:

Page 16 of 50

[Cu(L-ser)(H2O)(phen)][Cu(L-

ser)(CH3OH)(phen)]SO4·3H2O·CH3OH. We have also prepared two different solvates with the cation of type 2: [Cu(L-ser)(CH3OH)(phen)]2SO4·2CH3OH (2·2CH3OH) and [Cu(Lser)(CH3OH)(phen)]2SO4·2.5CH3OH (2·2.5CH3OH). The complexes containing cations of types 1 and 2 can, only in a wider sense, be considered as solvatomorphs since not only the solvent molecules water/methanol can be exchanged, but in the cases of transformation of 1 to 2 also the apically coordinated, weakly bound, solvent molecule is exchanged. We will therefore refer to these complexes using the more conventional and, in this case, more appropriate term different solvates, or different complexes if the change is also of the apically bound solvent molecule. The two complexes without serine are different hydrates of type 3 molecules (with a slightly different bonding of the sulfate ligand to the copper atom): [Cu(SO4)(phen)2]·4.5H2O (3·4.5H2O), and [Cu(SO4)(phen)2]·6.75H2O (3·6.75H2O).

Scheme 1. Three types of the prepared copper(II) cations/complexes. Synthesis Complexes were synthesized by using different solution-based and mechanochemical techniques (Scheme 2). In order to explore the role of solvent in the formation of crystal structures, different methanol/water ratios were used in the solution-based syntheses.


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Solution based synthesis of complexes having cations type 1 and 2 Reaction of copper(II) sulfate pentahydrate, 1,10-phenanthroline monohydrate, L-serine and a base resulted in five different complexes, depending on the ratio of reactants, used technique, and especially on the solvent methanol/water ratio. Compounds 1·10H2O, 1·6H2O and 1·4H2O were obtained from aqueous solutions. It was noticed that the method for concentrating the solution had a great impact on the resulting product. 1·10H2O crystallized only by slow evaporation of the solution at room temperature or at 4 °C (in a partially covered beaker; after a few days), followed by crystallization of 1·6H2O and 1·4H2O from a more saturated solution. If saturation was reached by fast evaporation (uncovered beaker or heating), 1·10H2O did not form, and a mixture of 1·4H2O and 1·6H2O, or pure 1·4H2O was obtained. When an excess of 1,10-phenanthroline monohydrate and L-serine was used in the synthesis, 1·10H2O crystallized first, followed by 1·4H2O and 1·6H2O, and then 3·4.5H2O if slow evaporation was used for saturating, whereas a mixture of 1·6H2O, 1·4H2O and 3·4.5H2O crystallized in the case of fast evaporation. These complexes can be separated if the solution is monitored during crystallization. They can be recognized by their crystal habit (Tables S1 and S2 in the Supporting information) and shades of blue colour (dark blue, for 1·10H2O, blue for 1·6H2O and 1·4H2O, and light blue 3·4.5H2O). Unfortunately, 1·4H2O and 1·6H2O cannot be distinguished by their crystal habits or colour.


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Scheme 2. Synthesis of compounds 1·4H2O, 1·6H2O, 1·10H2O, 1·2·3H2O·CH3OH, 2·2CH3OH, 2·2.5CH3OH, 3·4.5H2O and 3·6.75H2O. Packing diagrams show only complex cations, type 1 (blue) and 2 (red, yellow, orange, brown), and molecules of type 3 (green). Hydrogen atoms and serine side chains are omitted. Crystallographically independent cations in the structures are shown in light/dark colour of the appropriate cation/molecule type. In 2·2.5CH3OH there are four independent cations which are shown in red/yellow/orange/brown colour. The room temperature structure of 1·10H2O is shown, not the low-temperature superstructure.

Complex 3·4.5H2O does not contain L-serine although it was also in excess in the reaction mixture. It was noticed that crystals of 1·10H2O decompose if exposed to air, and were the least stable among complexes with the cation of type 1, however, these needle-like crystals were the largest, even up to 2 cm in length. Possibly, the saturation concentration for 1·10H2O is easily missed upon fast evaporation, or there is no nucleation and crystal growth at elevated temperatures. If the solution was always concentrated by fast evaporation, or even if the beaker was not covered, this solvate would have been missed. Upon addition of methanol to the reaction solution (methanol/water 3:7 v/v) a mixture of 1·6H2O and 1·4H2O was obtained. Pure 1·6H2O was synthesized from a higher concentration of methanol (methanol/water 7:3 v/v). If pure methanol was used (there is still water present from hydrates of copper(II) sulfate and phenanthroline), the methanol molecule coordinated the copper ion in some complex cations and a mixture of 1·6H2O and 1·2·3H2O·CH3OH crystallized. 1·4H2O and 1·6H2O cannot be recrystallized from methanol or methanol/water (9:1 or 19:1 v/v), but instead crystals of 1·2·3H2O·CH3OH are obtained. Nevertheless, it is a good way to


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obtain this pure mixed complex with cations of types 1 and 2. Complexes 2·2CH3OH and 2·2.5CH3OH with coordinating methanol (type 2) were synthesized solvothermally from methanol solutions using anhydrous 1,10-phenanthroline. The only distinction between the synthetic procedures was the different hydration state of copper(II) sulfate: the monohydrate gave 2·2CH3OH, while the anhydrous compound resulted in 2·2.5CH3OH (which is the least stable of all complexes). 3·4.5H2O was obtained as the coproduct in both cases. It was observed that pure 2·2CH3OH can be obtained if either 1·6H2O or 2·2.5CH3OH is left to stand in a saturated methanolic solution. In this way, crystals of 2·2CH3OH grow in the solution at the expense of crystals of the starting solvate.

Mechanochemical synthesis of 1·6H2O One-pot mechanochemical synthesis was also performed for synthesis of 1·6H2O by using the liquid-assisted grinding method (LAG) with water or methanol as the liquid. When NaHCO3 was used as the base, Na2SO4·10H2O formed as the by-product (Paragraph 3. Mechanochemical synthesis in the Supporting Information). Pure 1·6H2O was synthesized by the LAG method when copper(II) hydroxide was used as the base. In this process, the self-assembly of complex cations is achieved through coordination of three different ligands to the metal ion. They are further interconnected through formation of π-interactions between phenanthroline rings and an extensive hydrogen bonding framework involving polar ligands, water molecules and sulfate ions. It has to be noted that all complexes containing serine transform to 1·6H2O upon neat grinding, as will be discussed later. Synthesis of complexes having molecules of type 3


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The two complexes without serine, 3·4.5H2O and 3·6.75H2O, were synthesized by heating copper(II) sulfate pentahydrate and 1,10-phenanthroline monohydrate in an aqueous solution. 3·4.5H2O was synthesized mechanochemically by one-pot synthesis using neat grinding (NG) or liquid assisted grinding method (LAG) and it was obtained in a pure form. Infrared spectroscopy The IR spectrum of 1·6H2O (Figure S5 in the Supporting Information) shows a broad band in the area 3600 – 3000 cm–1 corresponding to asymmetrical and symmetrical O–H stretching and indicates a wide array of hydrogen bonds as expected from the crystal structure of the complex due to presence of L-serine and crystallization water molecules. Bands appearing at 3211 cm–1 and 3120 cm–1 are attributed to asymmetrical and symmetrical stretching of N–H bonds in Lserine, while bands in the range 3070 – 2800 cm–1 are attributed to stretching of the C–H bonds. Absence of bands attributed to bending of –NH3+ in the range 2100 – 1900 cm–1 suggests that the amino group of L-serine is deprotonated. Bands characteristic for the carboxylate group are shifted toward lower wave numbers, compared to pure -serine in the anionic form,67 hence asymmetrical and symmetrical stretching appears at 1634 cm–1 and 1398 cm–1, respectively. Asymmetrical stretching of C–N bonds and phenanthroline rings stretching is observed at 1595 cm–1. Bands at 1521 and 1432 cm–1 are attributed to stretching of C–C and C–N bonds in the phenanthroline rings.68 Compounds 1·10H2O, 2·2CH3OHand 2·2.5CH3OH exhibit IR spectra similar to that of 1·6H2O (Paragraph Infrared spectroscopy and Figures S6, S7 and S8 in the Supporting Information.)

Thermogravimetric and DSC analysis


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In the TGA experiment in pure oxygen, 1·6H2O decomposes in a wide temperature range, from 50 °C to approximately 600 °C (Figure S9 in the Supporting Information). The first step occurs between 50 °C and 100 °C and corresponds to loss of 6 water molecules (11.37%; calculated: 11.35%). Mass loss in the area between 110 and 170 °C corresponds to the loss of the two remaining water molecules (3.90%; calculated: 3.85%). Since higher temperature is needed for those two water molecules to exit the structure, it can be concluded that crystallization water molecules exit in the first step, as they are weakly bound, followed by coordinating water molecules. Next several steps in range 250–600 °C overlap and correspond to the loss of serine, phenanthroline and SO2 (67.77%; calculated: 67.61%). The complex completely decomposes to copper(II) oxide, as confirmed by XRPD (Figure S10 in the Supporting Information). A similar decomposition mechanism is observed for 1·4H2O (Paragraph Thermogravimetric analysis and Figure S11 in the Supporting Information). DSC of 1·6H2O revealed two broad endothermic peaks corresponding to two dehydration events, the first one in the range from 73 °C to 99 °C, with a shoulder at 78 ºC and a maximum at 90 ºC, and the second one from 114 °C to 173 °C with a maximum at 159 °C. In another experiment, cooling was done after both events followed by heating. There were no events upon cooling after the first peak and heating to the second one whose onset was at a slightly higher temperature. Cooling and heating within the range of the second maxima showed no events, therefore pointing to an irreversible change which is in agreement with water loss. Sharp endothermic peaks at 202 °C and 351 °C correspond to the decomposition of ligands. DSC analysis was performed for 1·10H2O as well. Several endothermic peaks appear in the range 50 – 187 °C and correspond to the loss of water molecules. Peaks at 193 °C and 343 °C probably correspond to the same decomposition processes as for 1·6H2O.


22

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Other solvates could not be analysed by TGA and DSC due to their instability or inability to isolate them as pure solids. Crystal structures Compounds with the chiral L-serinato ligand crystallize in non-centrosymmetric space groups, while those without L-serine crystallize in a centrosymmetric space group (Tables S1 and S2 in the Supporting Information). All of the

L-serine

complexes have a distorted square-pyramidal geometry around the

copper(II) ion while in the complexes without L-serine the central copper(II) ions exhibit either a distorted octahedral or a highly distorted square-pyramidal/trigonal-bipyramidal coordination sphere (Table S3 in the Supporting Information). ORTEP plot of the asymmetric unit of 1·2·3H2O·CH3OH with the omitted crystallization solvent molecules is given in Figure 1. It is shown as a representative of both cation types 1 and 2. ORTEP plots of the molecular structures of 1·4H2O, 1·6H2O, 1·10H2O, 2·2CH3OH, 2·2.5CH3OH, 3·4.5H2O and 3·6.75H2O are given in Figures S12 – S14 in the Supporting Information. Complexes with cations of type 1 and 2 The asymmetric unit of L-serine complexes contains complex cations and sulfate anions in the 2:1 ratio, and crystallization solvent molecules (Figures S12 and S13 in the Supporting Information). Bond lengths and angles within the copper coordination polyhedra are similar in all complex cations. There is a small variation in Cu–NL-ser and Cu–Nphen [1.971(8) – 2.003(7) Å and 1.982(6) – 2.004(9) Å, respectively], both being longer than the basal Cu–O distances [1.917(7) – 1.964(2) Å]. The apical distances Cu–O (O from the coordinated water or methanol molecules) represent the largest ones within the distorted square-pyramid indicating the Jahn-Teller effect.


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Cu–Owater distances are in the range from 2.196(6) to 2.306(6) Å and are similar to Cu–Omethanol distances which are in the range from 2.215(3) to 2.301(7) Å.

Figure 1. ORTEP drawing of asymmetric unit of 1·2·3H2O·CH3OH. Displacement ellipsoids of non-hydrogen atoms are drawn at the 50% probability level. Solvent molecules are omitted for clarity. The atom numbering scheme in all complexes is the following: phenathroline – N1,C2C9,N10,C11-C14; serine O1,O2,C,CA,CB,OG (A, B, G standing for α, β, γ, respectively). When more than one molecule is present in the asymmetric unit one molecule gets an additional number 1 (others 2, 3 etc.): N11, C12-C19, N110, C111-C114; O11, O12, C1, C1A, C1B, O1G.

Figures 2 and 3 show overlapped cations of types 1 and 2, respectively, from all structures. All symmetrically independent cations are shown. The cation containing Cu1 will be referred to as cation(Cu1); the same type of notation is used for all other cations (cation(Cu2) etc.). The two basal N atoms from 1,10-phenanthroline, and N and O atoms from the L-serinato ligand, were used for overlaying the cations. The apically coordinated solvent molecules were found to be on both sides of the basal plane thus resulting in the two types of diastereomers.


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Figure 2. Overlapped cations of type 1 from all structures. Colour of the cation(Cu1) and cation(Cu2), respectively, together with the orientation of the apical water molecule are given in parentheses: 1·4H2O (light blue – up, cyan – down), 1·6H2O (blue – down, dark blue – down) and 1·10H2O (room temperature data, violet – up, pink – down), 1·2·3H2O·CH3OH (cation(Cu1) purple – down).

Figure 3. Overlapped cations of the type 2 from all structures. Orientation of the apical methanol molecule is given in parentheses. Cation(Cu2) in the structure of 1·2·3H2O·CH3OH is coloured red (up), cation(Cu1) in 2·2CH3OH is coloured brown (up), cations(Cu1)–(Cu4) in 2·2.5CH3OH are coloured dark brown (up), orange (down), orange-red (up) and yellow (down), respectively.


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As can be seen from these two figures, the copper atom is displaced from the mean basal coordination plane. The average distance of the copper atom from the plane is 0.177 Å in type 1 cations, being greater than in type 2 cations (average distance of 0.143 Å, Table S4 in the Supporting Information). The greatest displacement is in 1·4H2O amounting to 0.295 Å. In the L-serinato

ligand rotations around single bonds enable flexibility, in contrast to 1,10-

phenanthroline, especially the rotation about the Cβ–Oγ bond enables efficient intermolecular hydrogen bonding through the hydroxyl group. The hydroxyl group in the coordinated methanol is always oriented to the same side as the serine amino group, both forming hydrogen bonds toward sulfate anions (for “top” views of the overlapped cations of types 1 and 2 see Figures S15 and S16, in the Supporting Information). In the asymmetric units of complexes with type 1 cations there are two independent cations (except in the low temperature polymorph of 1·10H2O where there are four). One of the independent cations has the apical water molecule and the H(Cα) atom from the serine ligand on the opposite sides of the basal plane (assigned “up”), while in the other cation they are on the same side (“down”), see Figures 2 and 3, and the packing diagrams in Scheme 2. So, the two independent cations are oriented up and down in 1·4H2O and 1·10H2O but both down in 1·6H2O. In the mixed complex 1·2·3H2O·CH3OH the cation of type 1 is down and type 2 is up. In 2·2CH3OH there is only one cation of type 2 (up) while in 2·2.5CH3OH two are up and two down. These orientations were found to be important for the solid-state transformations described below. Supramolecular frameworks in complexes with cations of types 1 and 2 Hydrogen bond frameworks and porous channels


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A common feature in the crystal structures having cations of types 1 and 2 are hydrogen bonds and π-interactions (see the packing diagrams in Figure 4). The structures contain many potential hydrogen bond donors and acceptors enabling extensive hydrogen bonding. Sulfate ions are involved in strong charge-assisted hydrogen bonds with cations (Tables S5 and S6 in the Supporting Information). N–H···Osulfate hydrogen bonds are present in all of the complexes ranging from 2.784(5) to 3.232(11) Å, as well as O–H(coordinated solvent molecule)···Osulfate in the range 2.665(9) – 2.935(11) Å. Sulfate ions are also hydrogen bonded to solvent molecules. Also, serine ligands form hydrogen bonds linking amino groups with hydroxyl groups of the adjacent complex cations [N–H···Ohydroxyl 2.803(4) – 3.187(12) Å]. Each sulfate anion links four complex cations in all complexes except in the most hydrated 1·10H2O where it links three. In this way, the cations and anions are interconnected into double-chains parallel to the a-axis in 1·6H2O and in 1·2·3H2O·CH3OH, and parallel to the b-axis in 2·2CH3OH and 2·2.5CH3OH, whereas in 1·4H2O and 1·10H2O puckered planes are formed parallel to (101). Hydrogen bonds with solvent molecules and π-interactions connect the chains or planes into three-dimensional porous networks (Figure 4). The endless channels in all of these structures enable exchange of solvent molecules. π-interactions All of the L-serine compounds form infinite double chains through π-interactions of the neighbouring 1,10-phenanthroline rings (Scheme 2 and Figure 4). Average interplanar distance between the overlapping aromatic rings is influenced by the type of the coordinated solvent molecule. Aqua complexes have shorter interplanar distances [3.34(8) – 3.40(4) Å] in comparison to the methanol complexes [3.53(8) and 3.8(3) Å], while the mixed water/methanol complex lies in between with the average distance 3.47(4) Å (Tables S7 – S14 in the Supporting


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Information). These differences are probably the result of the steric hindrance of methanol. The central phenanthroline rings have the shortest centroid–centroid distances in all of the structures (Figure S17 and Tables S15–S22 in the Supporting Information). The dihedral angle between stacked phenanthroline rings in 2·2CH3OH is the largest, 17.06(5)°, and it is the only complex that has only one cation in the asymmetric unit, so the two-fold axes generate all cations up (see packing diagrams in Scheme 2). In 1·4H2O the dihedral angles are 1.8(4) – 7.7(4)°, while in other complexes the phenanthroline rings are almost parallel [1.3(6) – 3(2)°] (Tables S7 – S14 in the Supporting Information).


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Figure 4. Transformation of 1·4H2O, 1·10H2O, 1·2·3H2O·CH3OH, 2·2CH3OH and 2·2.5CH3OH into 1·6H2O by neat grinding. Packing diagrams show channels and voids occupied by solvent molecules. Packing of 1·6H2O is down the a-axis. Voids occupied by water molecules are shown in blue, those containing mixed water/methanol solvent molecules are shown in blue/orange, while those containing solvent methanol molecules are shown in orange colour. In 1·4H2O and 1·6H2O the hydrogen bonds are shown by dark blue to light blue lines


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indicating shorter to longer distances. In other complexes they are shown in blue. Methanol molecules are not shown in the voids. Further investigation of π-interactions is given by the analysis of Hirshfeld surfaces (mapped over dnorm) for 1,10-phenanthroline ligands in the complex cations. Analysis of close contacts is given in Table S23 and paragraph Analysis of Hirshfeld surfaces in the Supporting Information. The bond C–H···Ocarboxyl is present in all structures (Figure 5) except in 1·10H2O where a water molecule lies between the phenanthroline and carboxyl group.

Figure 5. Hirshfeld surface of the phenantroline ring in 2·2CH3OH. Close contact C17– H17···O11 is shown in red colour on the Hirshfeld surface.

Complexes of type 3 Complexes of type 3 (in 3·4.5H2O and 3·6.75H2O) are neutral molecular species with two bidentate phenanthroline molecules and one sulfate anion coordinated to the central Cu(II) cation. The asymmetric unit in both 3·4.5H2O and 3·6.75H2O consists of two independent complex molecules and water molecules of crystallization (Scheme 2 and Figure S14 in the Supporting Information). The sulfate anion coordinates in a monodentate mode in both


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molecules of 3·6.75H2O and in one molecule of 3·4.5H2O, while in the other molecule of 3·4.5H2O the sulfate ion is a bidentate ligand. The coordination spheres of the three penta-coordinated copper(II) ions were analysed by the descriptor τ5. It indicated a highly distorted square-pyramidal coordination of the copper ion in molecule(Cu1) in 3·4.5H2O, and a trigonal-bipyramidal coordination sphere for both molecules in 3·6.75H2O (Table S3 in the Supporting Information). The bond distances within the polyhedra of the pentacoordinated copper ions (Table S23 in the Supporting Information) fall in the range of several reported mononuclear [Cu(SO4)(phen)2] complexes.52,69,70 Only one central copper(II) ion exhibits a distorted octahedral coordination, (molecule(Cu2) in 3·4.5H2O, where a weak second

Cu-O

interaction

of

2.448(5)

Å

is

found,

similar

to

those

in

[Cu(SO4)(C5H6N2)2(C3H7NO)2].71 In both crystal structures the molecules are connected by extensive pattern of hydrogen bonds which include coordinated sulfate ion and water molecules of crystallization (Table S24 in the Supporting Information). The crystal structures are also governed by the stacking interactions between the phenanthroline moieties with the closest centroid–centroid distances being 3.560(4) Å and 3.4179(15) Å in 3·4.5H2O and 3·6.75H2O, respectively (Tables S25–S27 in the Supporting Information). Hirshfeld analysis of the phenanthroline rings is given in Figure S19 and Table S28 in the Supporting Information. Solid-state-to-solid-state transformations Neat grinding and solvent exchange experiments were done for all L-serine complexes, and were monitored by XRPD. Powder diffraction patterns corresponding to the solved structures enabled assignation of most of the transformation products (Figures S20 and S21 in the Supporting Information). However, there were some unknown and unstable phases which were


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assigned as intermediate phases (IM). These transformations, unfortunately, could not be monitored by Raman spectra in situ due to fluorescence (there were no suitable maxima). Transformation of all serine complexes to 1·6H2O by neat grinding All of the L-serine complexes gave the same diffraction pattern upon neat grinding – the one corresponding to 1·6H2O. This process resulted in loss of methanol molecules and/or absorption of water vapour from the atmosphere (Figure 4). These transformations can be accomplished by neat grinding in a mortar within a minute. Interconversion 1·6H2O ↔ 1·4H2O It was noticed that upon grinding of 1·4H2O for XRPD, the powder pattern of 1·6H2O was obtained (Scheme 3a). This transformation into a more hydrated complex was quite unexpected since upon grinding energy is brought to the system and solvent is usually lost. The extra two water molecules per asymmetric unit are acquired from the air. We couldn't conclude about the existence of intermediate phases since the forms could not be differentiated by their crystal habits or color and the XRD measurement took longer than seconds. Along with acquisition of two solvent water molecules per asymmetric unit, a change of the coordination of the apical water molecule from up to down occurs in cation(Cu1) (see Figure 6). There is also a change in the orientation of the side chain of serine. Orientation of cation(Cu2) remains unchanged. For this change to occur, a slight rotation of cation(Cu1) should happen, along with rotation of the sulfate ion, and uptake and rearrangement of solvent water molecules. The cations move in such a way that dihedral angles between phenanthroline rings decrease, and also the slippage between the centroids decreases. The two unit cells are similar (see the Experimental section). The apical water O13 in 1·4H2O is at a distance of 4.80 Å from the neighbouring Cu1. Since the bond length Cu1–O13 is 2.200(2) Å in 1·6H2O, the shift of O13 in the transformation 1·4H2O →


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1·6H2O amounts to approx. 2.6 Å, or even less (green arrows in Figure 6), having in mind the slight rotation and shift of cation(Cu1). The nearest water molecule is probably not involved in this transformation since it is at a longer distance to Cu1. The same shift distance of O13 is found for the transformation 1·6H2O → 1·4H2O. This transformation was observed when 1·6H2O was left in air at temperatures below approx. 20 °C. The reversed process was also observed when 1·4H2O was left in air at higher humidity and temperature. Contrary to the fast transformations upon neat grinding the transformations that occur in air are slow (months).

Figure 6. Transformations 1·4H2O ↔ 1·6H2O in the solid state. The possible shifts of O13 during these transitions are indicated by green arrows (both of these shifts amount to approx.


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2.5–2.6 Å). O1W is further away and probably not shifting to coordinate the adjacent Cu(II). Distances (in Å) from O1W to Cu1 and O13 are shown in green colour.

An experiment was set up to test whether the compounds are sensitive to the atmospheric humidity. It was found that in the humidity range of approximately 23% to 85% 1·6H2O was the most stable solvate, while at lower humidity levels, < 10%, it loses water molecules converting to an unknown less-hydrated phase. Diffractograms of the resulting solvates are shown in Figure S22 in the Supporting Information. These results show that the transformation is extremely slow. When 1·6H2O was left in water vapour, a mixture of 1·6H2O, 1·4H2O and an unknown phase(s) was observed (Figure S23 in the Supporting Information). However, after a few days, it absorbed so much water that it completely dissolved.


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Scheme 3. Solid state transitions (interconversions) of 1·4H2O, 1·6H2O, 1·2·3H2O·CH3OH, 2·2CH3OH and 2·2.5CH3OH. Diffractograms: a) of crystalline powder (1·4H2O) obtained when 1·6H2O was left to stand in air for five months (red); of 1·6H2O after NG of the same sample of 1·4H2O (black); b) of 2·2CH3OH and 2·2.5CH3OH crystals in their mother liquor,


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and diffractograms of 2·2CH3OH upon exposure to air; c) of samples obtained after exposure of 1·6H2O to methanol vapours. IM is assigned to different intermediate phase(s) which were not identified. Peaks marked with an asterisk (*) correspond to 1·2·3H2O·CH3OH, while peaks marked with a circle (°) correspond to complex 2·2CH3OH. Polymorphic transitions of 1·10H2O 1·10H2O is unstable outside the solution, so the room temperature single-crystal X-ray diffraction data had to be collected from a crystal in a capillary. Packing of the ions and water molecules in the crystal structure is different from those of 1·4H2O and 1·6H2O and, if left in air, the crystal decomposes into an unknown compound, while upon grinding 1·6H2O is obtained. X-ray data collection of 1·10H2O at 150 K showed doubling of the a-axis (it is the caxis in the low temperature data; Figures S24 and S25 in the Supporting Information). Simulation of precession images h0l and 0kl showed low intensity diffraction maxima at l = 2n+1 (n = 0, 1 to 7). The low temperature polymorph is thus a superstructure with four molecules in the asymmetric unit. There was no ordering of the disordered sulfate upon this transition. This transition is reversible and occurs at about 220 K (monitored by appearance of additional diffraction spots while lowering the temperature by 10 K, starting from 240 K). Aging in air and solvent exchange; transformation 2·2.5CH3OH → 1·6H2O By aging in air, 2·2.5CH3OH rapidly loses solvent methanol molecules (a PXRD pattern can only be obtained if it is left in mother liquor) and transforms into 2·2CH3OH followed by intermediate phase(s). Transformation then follows the same mechanism as the transformation of 2·2CH3OH. When starting from 2·2CH3OH transformation into intermediate phase(s) and 1·2·3H2O·CH3OH was found (Scheme 3b). After 1 hour 2·2CH3OH was completely gone and 1·2·3H2O·CH3OH remained along with intermediate phase(s). After 3 days 1·6H2O started to


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form. Even after 14 days the intermediate phase(s) were present, slowly decomposing to 1·6H2O. Aging in methanol vapour; transformation 1·6H2O → 2·2CH3OH When 1·6H2O is left in methanol vapour, an intermediate phase is formed rapidly (Scheme 3c). In 1 min there is only a small amount of 1·6H2O left. The solid state transformation to 1·2·3H2O·CH3OH proceeds through intermediate crystalline and amorphous phases and then continues to 2·2CH3OH which starts to appear after 2.5 days. Aging in methanol solution; transformations to 2·2CH3OH If either 1·6H2O or 2·2.5CH3OH is left to stand in a saturated methanolic solution crystals of 2·2CH3OH are obtained. In 2 – 3 days, crystals of 2·2CH3OH start to grow slowly consuming crystals of the other present solid phase. Transformation occurs with an amorphous intermediate phase (Figures S26 and S27 in the Supporting Information). Crystal habit Crystal faces were indexed for all serine complexes (Figure 4). We were interested to find the direction of solvent channels in crystals by analysing the crystal habit. In most serine complexes the channels extend along the shortest dimension of the crystal. 1·10H2O is the only complex where the channels extend along the longest crystal dimension (needle). However, the channels in this very hydrated complex are the widest ones among the serine complexes, the water molecules are lost within a minute and the crystal cracks and decomposes. Quantum Chemical Calculations Since only cation(Cu1) in both 1·4H2O and in 1·6H2O is involved in interconversion 1·4H2O → 1·6H2O, where it transforms from the up to down diastereomer, we calculated the equilibrium gas-phase and aqueous structures of both isomers and compared them with the experimental X-


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ray molecular structures in 1·4H2O and 1·6H2O (Figure 7). Both calculated overall geometries of the down cation are more similar to the experimental X-ray structure found in 1·6H2O than it is the case for the up cation in 1·4H2O (Table S29 in the Supporting Information). When implicitly accounting for water medium using polarizable continuum model (PCM), we showed that the equilibrium DFT/B3LYP-D3 structure of the up cation(Cu1) is only 1.26 kJ mol–1 more stable than its down isomer (Table S30 in the Supporting Information). Since the energy difference between these two diastereomers is low, they are easily interchangeable. More information on the quantum chemical calculations on these and other described complexes is given in Tables S31 – S36 in the Supporting Information.

Figure 7. Superposition of the experimental X-ray molecular structure (293 K; cation(Cu1), depicted in red) and the corresponding equilibrium geometries: calculated in the gas phase by using B3LYP-D3/BS1 (blue), and calculated in the aqueous surroundings by using the polarizable continuum model (PCM) for water and B3LYP-D3/BS1 (yellow). Biological assays


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The antiproliferative activities of 1·6H2O and 3·4.5H2O were tested on human breast (MCF-7) and lung (H 460) tumour cell lines using MTT test. Tested compounds showed pronounced antiproliferative activity toward both tumour cell lines (Table 1). The IC50 concentrations are comparable to two known antitumour compounds – etoposide and 5-fluorouracil. Compound 1∙6H2O showed strong, probably nonselective cytotoxicity in maximal tested concentrations, while compound 3∙4.5H2O is even more potent, showing concentration-dependent response (Figure S28, in the Supporting Information), which encourages further study on precise mechanism of its activity in these and other tumour cells. The activities tested in two tumour cell lines (MCF-7 and H 460) resulted with the IC50 values in the submicromolar to micromolar range, corresponding to the ones described in Santini et al.72 and Bravo-Gómez et al.73 The compounds can be described as potent cytotoxic agents. However, from the here-presented results no precise mechanism can be ascertained, including the slight difference in the two complex. Further mechanistic studies, such as DNA binding abilities, ROS generation, along with the influence on the cell cycle and the induction of apoptosis, should be performed. The slight difference in the activities between the two complexes could be the result of a better cell penetration. Table 1. IC50 valuesa, obtained by MTT test. IC50 / 10–6 mol dm–3 Compound MCF-7

H 460

1·6H2O

2 ± 0.08

2 ± 0.2

3·4.5H2O

0.6 ± 0.4

1 ± 0.2

Etoposide

1 ± 0.7

0.1 ± 0.04

5-Fluorouracil

2 ± 0.3

3 ± 0.3

a

Concentration that causes 50% inhibition of the cell growth.


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CONCLUSION Six new copper(II) complexes with serine and phenanthroline (1·4H2O, 1·6H2O, 1·10H2O, 1·2·3H2O·CH3OH, 2·2CH3OH, 2·2.5CH3OH) and two only with phenanthroline (3·4.5H2O and 3·6.75H2O) were synthesized by solution-based syntheses and two of them (1·6H2O and 3·4.5H2O) also by one-pot mechanochemical procedures. In the serine complex cation the copper(II) atom is coordinated by a serinato and a phenanthroline ligand in the equatorial plane, and apically by a solvent molecule, either a water molecule (in type 1 cation), or a methanol molecule (in type 2 cation). Two types of diastereomers are found for the cation regarding the position of the apically coordinated solvent molecule in relation to the chiral serinato-ligand (named up and down). In their crystal structures the cations, sulfate anions and solvent molecules are linked by hydrogen bonds and π-interactions into 3D porous networks. Solvent molecules are situated in the endless channels or in pockets connected to the channels. Analysis of the crystal habit and faces showed that the channels extend along the greatest crystal dimension only in the most hydrated complex 1·10H2O which has large solvent channels (along a needle-like crystal). All this is in favour of an easy exchange of solvent molecules: solvent and coordinated water molecules (type 1 complexes) are replaced by methanol when the complexes are left in methanol vapours; an opposite replacement occurs in type 2 complexes if they are left in air. These solidstate-to-solid-state transformations, of which some are very fast – in minutes, mostly proceed through some unidentified crystalline and amorphous intermediate phases since the crystal structures differ too much for a direct transformation. Transformation 1·4H2O → 1·6H2O necessitates acquisition of two solvent water molecules per asymmetric unit and a change of the coordination of the apical water molecule from up to down. For a transition to occur, an apically


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coordinated water molecule presumably shifts by approx. 2.6 Å and coordinates the neighbouring complex molecule from the uncoordinated side. Quantum chemical calculations, when implicitly accounting for a water medium using PCM, showed only a small difference amounting to 1.26 kJ mol–1 for the equilibrium DFT/B3LYP-D3 structures of the two diastereomers in 1·4H2O and 1·6H2O involved in the transformation. The porous structures enable easy exchange of solvent and rearrangement of ions and molecules explaining the transformation of all serine complexes, within a minute, into 1·6H2O by neat grinding using only a mortar and pestle. Also, the two diastereomers can be easily exchanged via transfer of apically coordinated solvent, when brought close enough during grinding. For 1·10H2O a polymorphic transition to a low-temperature superstructure (doubling of the unit cell) was found at approximately 220 K. A representative of a serine complex (1·6H2O) and a non-serine complex (3·4.5H2O) was tested on human breast (MCF-7) and lung (H 460) tumour cell lines using the MTT test. Both showed strong but nonselective cytotoxicity. ASSOCIATED CONTENT Supporting Information. The supporting material is available free of charge and contains crystallographic data, ORTEP drawings of crystal structures, hydrogen bond distances and angles, ring puckering analysis, powder X-ray diffraction patterns, Hirshfeld surface analysis, IR spectra, TGA curves, additional data obtained from quantum chemical calculations and biological asseys. AUTHOR INFORMATION Corresponding Author


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*E-mail: [email protected]; [email protected]. Tel: +385-1-4606347; +385-14606345. Fax: + 385-1-4606341

Present Addresses ‡ Institute of Biochemical Plant Physiology, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany. ⸸ Institute of Physical and Theoretical Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria. # Belupo d.d., Danica 5, 48000 Koprivnica, Croatia. Funding Sources The Croatian Science Foundation is kindly acknowledged for financially supporting grant no. IP2014-09-4274. ACKNOWLEDGMENT The authors are grateful to dr. Maja Devčić Bogdanović for measuring PXRD data on a PANalytical X’Pert Pro diffractometer, dr. Irina Pucić for measuring the DSC data and dr. Krunoslav Užarević for trials regarding Raman measurements. REFERENCES (1) Correaia, I.; Roy, S.; Matos, C. P.; Borovic, S.; Butenko, N.; Cavaco, I.; Marques, F.; Lorenzo, J.; Rodriguez, A.; Morento, V.; Pessoa, J. C. J. Inorg. Biochem. 2015, 147, 134−146. (2) Ma, T.; Xu, J.; Wang, Y.; Yu, H.; Yang, Y.; Liu, Y.; Ding, W.; Zhu, W.; Chen, R.; Ge, Z.; Tan, Y.; Jia, L.; Zhu, T. J. Inorg. Biochem. 2015, 144, 38−46.


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For Table of Contents Use Only Synthesis and crystal structure of solvated complexes of copper(II) with serine and phenanthroline and their solid-state-to-solid-state transformation into one stable solvate Darko Vušak, Biserka Prugovečki, Dalibor Milić, Marijana Marković, Ines Petković, Marijeta Kralj, and Dubravka Matković-Čalogović

TABLE OF CONTENTS Six solvated complexes of copper(II) with serine and phenanthroline have porous crystal structures with interchangeable solvent molecules. By neat grinding five of them transform to a single one. Water uptake is induced by structural changes when energy is brought to the system. All transformations occur at room temperature, and are reversible.


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Synthesis and Crystal Structure of Solvated Complexes of Copper(II

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