Relationship between solid state structure and solution stability of copper(ii)-hydroxypyridinecarboxylate complexes

Article abstract of DOI:10.1039/c9nj01469a

The complementary solid state/solution studies of the systematic series of bioactive ligands 3-hydroxy-1-methyl-4-pyridinecarboxylate (L1), 3-hydroxy-1,2,6-trimethyl-4-pyridinecarboxylate (L2), 4-hydroxy-1-methyl-3-pyridinecarboxylate (L3), 4-hydroxy-1,6-

Full text of DOI:10.1039/c9nj01469a

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Relationship between solid state structure
and solution stability of copper(II)–
Cite this:DOI: 10.1039/c9nj01469a
hydroxypyridinecarboxylate complexes†
Nora V. May, *a G. Tamas Gal,a Zsolt Szentendrei,a Laszlo Korecz,b
´
´
´
´
´
b
c
a
Zoltan May,
Maria Grazia Ferlin,
Annalisa Dean,d Petra Bombicz
and
´
d
Valerio B. Di Marco
The complementary solid state/solution studies of the systematic series of bioactive ligands 3-hydroxy-
1-methyl-4-pyridinecarboxylate (L1), 3-hydroxy-1,2,6-trimethyl-4-pyridinecarboxylate (L2), 4-hydroxy-1-
methyl-3-pyridinecarboxylate (L3), 4-hydroxy-1,6-dimethyl-3-pyridinecarboxylate (L4), 4-hydroxy-1-(2-
hydroxyethyl)-6-methyl-3-pyridinecarboxylate (L5) and 4-hydroxy-1-(2-carboxyethyl)-6-methyl-3-
pyridinecarboxylate (L6) with copper(II) have been performed in order to design efficient chelating drugs
for the treatment of metal overloading conditions. Single crystals of [Cu(L1)2(H2O)]ꢀ3H2O (1) (monomer) with
axial water coordination, [Cu2(L2)4]ꢀ6H2O (2) and [Cu2(L3)4]ꢀ4H2O (3) (cyclic dimers), where pyridinolato and
carboxylato oxygens, respectively, act as linkers between adjacent copper complexes, [Cu(L4)2]nꢀ3H2O (4) (1D
polymer) and [Cu3(L5)6]ꢀ18H2O (5) (trimer), constructed using two square-pyramidal and one elongated
octahedral Cu(II) complexes have been determined by SXRD. The bidentate coordination mode of the ligands
has been found preferentially with cis arrangements in 1 and 2 and trans arrangements in 3–5. The solution
speciation and complex stability of aqueous solutions have been studied by pH-dependent electron
paramagnetic resonance spectroscopy resulting in the detection of solely monomeric [CuL]+ and [CuL2]
complexes. The stability order obtained for the [CuL]+ complexes could be correlated with the deprotonation
constants of their hydroxyl group (log bLH) reflecting that the higher acidity increases the complex stability in
the order L2 o L1 E L6 o L4 E L5 o L3. This stability order elucidates the different axial linkers in the
cyclic dimers 2 and 3. DFT quantum-chemical calculations support the effect of the electron distribution on
the established stability order.
Received 20th March 2019,
Accepted 5th June 2019
DOI: 10.1039/c9nj01469a
rsc.li/njc
drugs, imaging agents, or chelators. Hydroxypyridinecarboxylic
acid (HPC) derivatives have been proposed recently1–7 as potential
Introduction
In diverse fields of clinical practice, metal complexes of small chelating agents for Fe(III) and Al(III) due to their favourable
biomolecules are frequently used as bioactive compounds, e.g. properties which include low toxicity, no redox activity, complex
stability and probable oral bioavailability due to their low molecular
mass. The design of these compounds was based on deferiprone
a Research Laboratory of Chemical Crystallography, Research Centre for Natural
(1,2-dimethyl-3-hydroxypyridine-4-one) which is a worldwide used
´
¨ ´
Sciences Hungarian Academy of Sciences, Magyar tudosok korutja 2,
chelating drug for the treatment of iron overloading conditions.
In vitro studies showed that Cu(II) is the most competitive metal ion
which affects considerably the complex formation of deferiprone
with Fe(III)8–14 and the same can be expected to occur for HPCs also.
The investigation of the stability constants of HPCs towards Cu(II)
(and other possible competing ions such as Zn(II)) is necessary as
the displacement of essential metal ions by chelating drugs could
affect the biological processes dependent on these metals and may
cause toxicity. To this aim, complex formation studies were started
with some HPCs and Cu(II).2,15
H-1117 Budapest, Hungary. E-mail: may.nora@ttk.mta.hu
b Institute of Materials and Environmental Chemistry, Research Centre for Natural
´
¨ ´
Sciences Hungarian Academy of Sciences, Magyar tudosok korutja 2,
H-1117 Budapest, Hungary
c Department of Pharmacological Sciences, University of Padova, via Marzolo 1,
35131 Padova, Italy
d Department of Chemical Sciences, University of Padova, via Marzolo 1,
35131 Padova, Italy
† Electronic supplementary information (ESI) available: Crystal data and structure
refinement of crystals 1–5; selected data of bond lengths and angles and figures
about packing arrangements and crystal voids, comparison of concentration
distribution curves; experimental and calculated EPR spectra; results of DFT
calculations and statistical analysis. CCDC 1865730–1865734. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c9nj01469a
The X-ray diffraction method is one of the most powerful
techniques for the structural investigation of metal complexes.
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Though the crystallographic method can offer detailed and the toxic metal ion.7 Crystals of the bis-ligand copper HPC
accurate data on the structure of these complexes, it is limited complexes were prepared in all cases (except for L6), and their solid-
only to the solid state. In order to establish any structure– state structures were studied by single crystal X-ray diffraction
stability–activity relationships, the knowledge of the speciation, (SXRD). The Cu(II) complex formation with all ligands in aqueous
and of the most plausible chemical forms, in aqueous solution solution was studied using pH-dependent EPR spectroscopy at
is mandatory. Electron paramagnetic resonance (EPR) spectro- room temperature and in frozen solution (77 K). In order to
scopy is able to detect paramagnetic metal complexes in interpret the effect of the electron distribution on the complexation
solution equilibrium systems. A structural comparison obtained properties of HPCs, atomic charges and bond orders were calculated
at different phases can disclose features of the intramolecular by DFT quantum-chemical calculations using different basis sets.
and intermolecular interactions of the complexes, and reveal Correlations between the different parameters have been found by
possible structural transformation which can be crucial for both multivariate data analysis.
their biological functions and pharmaceutical formulations. In
the present paper, we introduce the synthesis of two new HPC
derivatives and compare the complexation properties of some
Experimental section
Chemicals
additional HPC derivatives to study the substituent effect on the
complexation properties with Cu(II) in the solid state and in
aqueous solution. The studied ligands are 3-hydroxy-1-methyl-4-
pyridinecarboxylate, 3-hydroxy-1,2,6-trimethyl-4-pyridinecarboxylate,
4-hydroxy-1-methyl-3-pyridine-carboxylate, 4-hydroxy-1,6-dimethyl-3-
pyridinecarboxylate, and the newly synthesised 4-hydroxy-1-(2-
hydroxyethyl)-6-methyl-3-pyridinecarboxylate and 4-hydroxy-1-(2-
carboxyethyl)-6-methyl-3-pyridinecarboxylate. These molecules
are known in the literature7 as DT1, DT8126, DQ1, DQ716,
DQ7167, and DQ7165, respectively. For brevity, in this paper
they are indicated with the shorter abbreviations L1, L2, L3, L4,
L5 and L6. Their structures in their zwitterionic forms are
reported in Scheme 1 (the charges are omitted throughout the
text for clarity). L1–L6, proposed as chelating agents for Fe and
Al, represent the most promising HPC derivatives, as reported
by Crisponi et al.7 These authors explained the different properties
of compounds L1 and L2 (4-hydroxy-derivatives) with respect to
L3–L6 (3-hydroxy-derivatives), and the particular properties of L5
and L6. 4-Hydroxy HPC can undergo keto–enol tautomerism,
whereas it is less pronounced in 3-hydroxy HPCs; L5 and L6
represent the in vivo products of possible esterified prochelators,
i.e. compounds with an enhanced ability to cross the gastro-
intestinal barrier (due to their larger lipophilicity) which, once
in vivo, can be deesterified to give more hydrophilic drugs
which are able to be decorporated once they have bound to
HPCs were synthesized as described in ref. 16–18, except L5 and
L6 which were synthesized according to the procedure reported
in the next section. The CuCl2 stock solution was prepared from
CuCl2ꢀ2H2O (Sigma-Aldrich) dissolved in doubly distilled water.
The concentration was checked by ICP-OES. NaOH, HCl and
buffer solutions used in pH adjustment were purchased from
Sigma-Aldrich.
Synthesis of compounds L5 and L6
Scheme 2 describes the synthetic routes carried out to obtain
final HPC derivatives L5 and L6. For this purpose, the common
intermediates P2 and P3 were prepared as previously reported.3,19
Briefly, the starting material 4-hydroxy-6-methyl-2-pyrone (P1) by
reacting with N,N-dimethylformamide dimethyl acetal in dioxane
yielded 60% of 3-(dimethylaminomethylene)-4-hydroxy-6-methyl-
2-pyrone (P2). The latter by treatment with 30% aqueous
ammonia furnished P3 (64% yield). The precursor pyridinic
compound P3 was reacted with acrylic acid under reflux to give
the corresponding N-carboxyethyl compound H2L6 (70% yield),
and the precursor pyrone compound P2 by reacting with ethanol-
amine at room temperature yielded the N-hydroxyethyl pyridinic
compound HL5 (80% yield).
Melting points were determined on a Gallenkamp MFB 595
010M/B capillary melting point apparatus, and are uncorrected.
Infrared (IR) spectra were measured on a PerkinElmer 1760
Scheme 2 Synthesis of ligands HL5 and H2L6: (a) N,N-dimethylformamide
dimethyl acetal, dioxane, 15 1C, 2 h; (b) 30% aqueous ammonia, dimethylamine,
1 M, HCl, rt; (c) acrylic acid, refluxing, 24 h; (d) ethanolamine, H2O, 4 h, rt, HCl.
Scheme 1 Molecular structure of the investigated ligands, shown in their
zwitterionic (neutral) forms.
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FTIR spectrometer using potassium bromide pressed disks. N (6.22%); found C (53.30%), H (5.38%), N (6.14%); HR MS
1
Values are expressed in cmꢁ1. H NMR spectra were recorded calcd: [MH+] C10H12NO5 226.0637; found 226.0683.
on Varian Gemini (200 MHz) and Bruker (300 MHz) spectro-
meters, using the indicated solvents. NMR data are reported as
d values (ppm) relative to tetramethylsilane as an internal
Synthesis of copper(II) complex crystals 1–5 and single crystal
structure determination
standard. Elemental analyses were performed using a Perkin- Single crystals suitable for X-ray diffraction experiment of
Elmer elemental analyser model 240B; results fell in the range compounds [Cu(L1)2(H2O)]ꢀ3(H2O) (1), [Cu2(L2)4]ꢀ6(H2O) (2),
of calculated values ꢂ0.4%. Mass spectra were obtained using a [Cu2(L3)4]ꢀ4(H2O) (3), [Cu(L4)2]nꢀ3(H2O) (4), and [Cu3(L5)6]ꢀ
Mat 112 Varian Mat Bremen (70 eV) mass spectrometer and 18(H2O) (5) were obtained from 10 mL water solution containing
Applied Biosystems Mariner System 5220 LC/MS (nozzle potential 1 mM CuCl2 and the investigated ligands in 2 mM concentration.
250.00). Starting materials as well as solvents were purchased from The pH was adjusted with NaOH to 7.0. Slow evaporation of the
Sigma (Milan, Italy).
solvent (about one or two months) resulted in green (1,2) or blue
4-Hydroxy-1-(2-hydroxyethyl)-6-methyl-3-pyridinecarboxylic acid (3,4,5) crystals. Single crystals were mounted on loops and trans-
(HL5). About 10 mL (d = 0.89 mg mLꢁ1, 74 mmol) of N,N- ferred to the goniometer. X-ray diffraction data were collected at
dimethylformamide dimethyl acetal was slowly added to a stirred 103 K (except 2 which was measured at 293 K) on a Rigaku RAXIS-
suspension of 4-hydroxy-6-methyl-2-pyrone (P1) (5 g, 40 mmol) in RAPID II diffractometer. The diffraction measurement was
10 mL of dioxane: the starting material dissolved and the solution performed with Mo-Ka radiation in all cases but one where a
became brown. The reaction mixture was held at a temperature of Cu-Ka source was used (crystal 3). The multi-scan absorption
15 1C for 2 h, when a precipitate formed. The precipitate was corrections (on crystal 2) were carried out using the CrystalClear20
collected, washed with cold dioxane and acetone, and dried in software and numerical absorption corrections in the cases of 1 and
vacuo. Yield 60% of 3-(dimethylaminomethylene)-4-hydroxo-6- 3–5 were done using NUMABS.21 Sir201422 and SHELXL23,24 under
methyl-2-pyrone (P2)3,19 (Scheme 2). About 1 g of 4-oxo-6-methyl- WinGX25 software were used for structure solution and refinement,
2-pyrone derivative P2 (5.58 mmol), dissolved in 10 mL of water, respectively. The structures were solved by direct methods. The
was added to 30 mL of ethanolamine. After 4 h at room models were refined by full-matrix least squares on F2. Refinement
temperature the solvent was evaporated and the remaining of non-hydrogen atoms was carried out with anisotropic temperature
solution was cooled and acidified to pH 3 with 1 M HCl. The factors. Atomic positions for water hydrogens were located in
formed precipitate was filtered and dried, yielding a nearly pure difference electron density maps, whereas all the other hydrogens
crystalline solid. Yield 80%; mp 199.8 1C; NMR (D2O, NaOD): d were placed in geometric positions. They were included in structure
2.49 (s, 3H, CH3), 3.45 (t, 2H, CH2CH2OH), 4.62 (t, 2H, CH2CH2OH), factor calculations but they were not refined. The isotropic displace-
6.70 (s, 1H, 5-H), 8.72 (s, 1H, 2-H) ppm; 13C NMR (DMSO): d 19.22 ment parameters of the hydrogen atoms were approximated from
(CH3), 54.32 (CH2CH2OH), 58.95 (CH2CH2OH), 114.71 (C-5), 118.91 the U(eq) value of the atom they were bonded to. The summary of
(C-3), 147.89 (C-2), 153.90 (C-6), 166.67 (C-4), 172.30 (COOꢁ) ppm; data collection and refinement parameters of complexes is
elemental analysis: calcd for C9H11NO4: C 54.82, H 5.62, N 7.10; collected in Table S1 (ESI†). Selected bond lengths and angles
found: C 52,91, H 5.49, N 6.88; HR MS calcd: [MH+] C9H12NO4 were calculated using PLATON.26,27 The graphical representation
198.07; found 198.12.
was done using the Mercury28 software and the editing of CIF
4-Hydroxy-1-(2-carboxyethyl)-6-methyl-3-pyridinecarboxylic acid files was done using the PublCif29 software.
(H2L6). About 1 g (5.58 mmol) of pyrone derivative P2 was
pH-Potentiometric studies
suspended in 30% aqueous ammonia (20 mL) and 1 mL of
NH(CH3)2. After stirring for 30 min at room temperature, the Acidity constants of the newly synthesised ligands (HL5 and
solution was evaporated under reduced pressure to about 1/3 of H2L6) were determined by pH-potentiometric titrations and
its volume, and the remaining solution was cooled (ice-bath) UV-vis measurements (if pKa o 2) using a procedure described
and acidified to pH 3 with 1 M HCl. The formed precipitate by Di Marco et al.30 Briefly, ligand solutions (5 ꢃ 10ꢁ4 to 2 ꢃ
was collected and dried yielding a solid product which was 10ꢁ3 m, m = mol kgꢁ1) were titrated with 0.1 m NaOH, which
re-crystallized from water to give the pure product. Yield 64% was previously standardized with 0.1 m HCl. A Metrohm 715
of 4-hydroxy-6-methylpyridine-3-carboxylic acid (P3).3 Into a Dosimat burette was used. The samples were in all cases
10 mL round-bottom flask, 0.236 g (1.54 mmol) of pyridine thermostated at 25.0 ꢂ 0.1 1C, and completely deoxygenated
derivative P3 and 1 mL of acrylic acid (14.59 mmol) were added by bubbling purified nitrogen for ca. 15 min before the measure-
and the suspension was heated under reflux for 24 h. The ments. The bubbling gas was also passed over the solutions during
formed precipitate was collected, washed with cold acetone and the titrations. The pH-metric titrations were performed in the pH
1
then dried in an oven. Yield 70%; mp 4300 1C dec; H NMR range of 2.0–11.0. The acidity constants were calculated using the
(D2O, NaOD): d 2.49 (s, 3H, CH3), 2.82 (t, 2H, CH2CH2COOH), PITMAP31 computer programme. UV-vis spectra were recorded at
4.36 (t, 2H, CH2CH2COOH), 6.70 (s, 1H, 5-H), 8.72 (s, 1H, 2-H) ppm; 25.0 ꢂ 0.1 1C, in 0.5 or 1 cm quartz cuvettes, using a PerkinElmer
13C NMR (DMSO): d 19.22 (CH3), 34.32 (CH2CH2COOH), 49.95 Lambda 25 diode array spectrophotometer, for solutions containing
(CH2CH2COOH), 114.71 (C-5), 118.91 (C-3), 147.89 (C-2), 153.90 each ligand alone at various pH values below 2. Calculations of the
(C-6), 166.67 (C-4), 172.30 (COOꢁ), 178.22 (CH2CH2COOH) ppm; stability constants were performed at the wavelengths displaying the
elemental analysis: calcd for C10H11NO5: C (53.33%), H (4.92%), highest absorbance variation with pH.
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EPR measurements and evaluation of the spectra
where g1, A1 and g2, A2 are the g and A tensors of the Cu(II) centres, D
is the dipolar interaction and J is the exchange interaction between
the two spin centres. The principal values and principal orientation
of g and A tensors can be treated identical or different and their
relative orientation can be characterized by the three Euler angles (a,
b and g). The relative position of the two centres is further described
by two polar angles (w, c) which define the position of the connector
line between the Cu(II) centres in the frame of g1.
Since the naturally occurring copper contains two isotopes,
63Cu and 65Cu, the EPR spectra were calculated as the sum of the
spectra of 63Cu and 65Cu weighted by their natural abundance
(69.17% and 30.83%, respectively). The quality of fit was char-
acterized by the noise-corrected regression parameter (Rj for the
jth spectrum) derived from the average square deviation (SQD)
between the experimental and the calculated intensities. The
details of the statistical analysis were published previously.32,34 The
hyperfine and superhyperfine coupling constants and the relaxation
parameters were obtained in field units (Gauss = 10ꢁ4 T).
All CW-EPR spectra were recorded using a BRUKER EleXsys
E500 spectrometer (microwave frequency B9.7 GHz, microwave
power 13 mW, modulation amplitude 5 G, modulation frequency
100 kHz). The pH-dependent isotropic EPR spectra were recorded at
room temperature (25 1C) in a circulating titration system. Two series
of EPR spectra were recorded in freshly prepared solutions contain-
ing 2 mM ligand and 1 mM or 2 mM CuCl2, in the pH range 2–8. At
higher pH values precipitation was detected in both cases. (By
adding acid to the solution the precipitate can be dissolved and
the previously measured EPR spectra could be recollected.) The ionic
strength I = 0.1 M was adjusted with KCl. The pH was measured
using a Radiometer PHM240 pH/ion Meter equipped with a
Metrohm 6.0234.100 glass electrode. A Heidolph Pump drive 5101
peristaltic pump was used for circulating the solution from the
titration pot through a capillary tube into the cavity of the
instrument. The titrations were carried out under a nitrogen atmo-
sphere. For several pH values a 0.10 mL of sample was taken out of
the stock solution and was measured individually in a Dewar
containing liquid nitrogen (at 77 K) to obtain frozen solution EPR
spectra. 0.02 mL of MeOH was added to the samples to avoid water
crystallization. Temperature-dependent EPR spectra were measured
using the same Bruker instrument. The measured 0.1 mL sample
contained 3.8 mM ligand L6 and 1.9 mM CuCl2 at pH = 5.71. Two
series of spectra were recorded: one from 150 K to 230 K in steps
of 5 K, and another between 150 and 190 K in steps of 2.5 K. The
temperature was adjusted with an accuracy of ꢂ0.1 K.
Theoretical and statistical calculations
Density functional theory (DFT) computations were performed
for HPC ligands in their fully deprotonated forms (L2ꢁ for L6
and Lꢁ for all the other ligands) using the ORCA package.35–39
Calculations were carried out in vacuum and in water by using the
conductor-like screening model (COSMO)40 with the dielectric
constant of water. All the geometry optimizations were performed
using the B3LYP41,42 hybrid functional. The two basis sets, split-
valence pulse polarization (SV(P))43 and cc-pVTZ,44,45 were compared.
Multivariate data analysis was performed on the matrix of solution
stability, EPR spectroscopic, SXRD and DFT data in order to reveal
correlations between these parameters. All statistical evaluations
were accomplished using the software Statistica 13.1 (Dell Inc.)46
The room-temperature CW-EPR spectra were simulated by
the ‘‘two-dimensional’’ method using the 2D_EPR software.32 Each
component curve was described by the isotropic EPR parameters g0,
AC0u copper (ICu = 3/2) and A0N nitrogen (IN = 1) hyperfine coupling.
The relaxation parameters a, b, and g defined the line widths
through the equation sMI = a + bMI + gMI2, where MI denotes the
magnetic quantum number of the paramagnetic metal ions. The
concentrations of the complexes were varied by fitting their for-
mation constants, b(MpLqHr), defined for the general equilibrium
pM + qL + rH " MpLqHr as b(MpLqHr) = [MpLqHr]/[M]p[L]q[H]r, where
M denotes the metal ion and L the completely deprotonated ligand.
The anisotropic EPR spectra recorded at 77 K were analysed
individually with the EPR software,33 which gives the anisotropic
EPR parameters gx, gy, gz (g tensor), ACxu, AyCu, AzCu (copper hyperfine
tensor) and ANx , AyN, ANz (nitrogen superhyperfine tensor). The
orientation-dependent line width parameters were used to set up
each component spectra.
Results
Proton dissociation processes of the ligands in solution
The protonation steps of the HPC ligands have been determined
by pH-potentiometry, either in the present study (L5 and L6) or in
previous ones (all other HPCs16–18). The constants are collected in
Table 1. All ligands have two detectable deprotonation steps
(Scheme 3). The first deprotonation (pKa1) is generally assigned to
the aromatic –COOH proton; it happens at very low pH (pKa1 o 1)
and it has therefore been obtained by UV-vis measurements. In the
case of L6 this deprotonation could not be detected, and the first
Temperature-dependent EPR spectra were simulated individually
by using the EPR software.33 The EPR spectra of the dimer complex
were simulated by a module of the same software developed for
calculating the EPR spectra of coupled spin systems (biradicals and
paramagnetic dimers).58 The EPR spectrum was calculated by the
complete diagonalization of the Hamiltonian of a two-spin system:
Table 1 Stability constants of ligand species H2L and HL determined by
UV-Vis spectroscopy and pH-potentiometrya
Ligand
lg b(H2L)
lg b(HL)
Ref.
L1
L2
L3
L4
L5
L6
6.91(5)
8.7(1)
6.08(1)
6.67(1)
6.25(1)
9.99(2)
6.6326(8)
8.06(1)
5.9578(6)
6.295(1)
6.109(3)
6.34(1)
16
17
16
18
~
~
~
~
~ ~
HSH ¼ H ꢃ g^1 ꢃ S1 ꢀ mB þ H ꢃ g^2 ꢃ S2 ꢀ mB þ JS1S2
This work
This work
ꢀ
ꢁ
~
^
^
þ D 2Sz1Sz2 ꢁ Sx1Sx2 ꢁ Sy1Sy2 þ S1 ꢃ A1 ꢃ I1
a
Uncertainties (SD) are shown in parentheses. For the charges of the
~
^
^
þ S2 ꢃ A2 ꢃ I2
L1–L6 species see Scheme 1.
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chelate coordination of the two L1 ligands in cis arrangements.
The coordination of the two ligands is asymmetrical, the angle
between the pyridine ring N2–C16 and the equatorial coordination
plane (defined by atoms O2–O3–Cu1–O12–O13) is 4.271, as well as
the Cu1–O12 and Cu1–O13 distances are 1.9258(14) Å and
1.9156(14) Å, respectively. The pyridine ring of the other ligand
(N1–C2) deviates from the equatorial plane by 14.331, and the
Cu1–O2 and Cu1–O3 distances are somewhat longer, 1.9564(14)
and 1.9349(13) Å, respectively. The axial position is occupied by
a water molecule with a long Cu–O4 distance of 2.2340(14) Å.
The complex [Cu2(L2)4]ꢀ12H2O (2) formed a cyclic dimer
where each copper ion is coordinated by [Oꢁcarb,Oꢁ] chelate
rings in cis positions in the equatorial plane, and the deproto-
nated hydroxyl groups form a bridge to the adjacent copper ion
in the axial direction (the Cu1–O3ax distance is 2.406(2) Å), and
vice versa (Fig. 2). The two Cu(L2)2 moieties are related by an
inversion centre. The pyridine rings N1–C6 and N12–C16 are
almost parallel to each other (the angle between the planes is
2.811); however they form an angle with the equatorial plane
which is 25.371 with the ring N1–C6 and 22.561 with N12–C16.
Similar cyclic dimer structures with the bridge formation of the
phenolato groups were found in the case of some mixed ligand
[Cu2(Sal)2(2,20-bpy)2] (Sal = salicylato, bpy = bipyridyl) complexes
(ref. codes REPJAY,48 MAHMOY,49 DIFQAK,50 XANHUP,51
EMOJOG,52 NALLUJ53). The copper–copper distances vary from
3.168(1) Å to 3.265(4) Å in the reported structures, and the value
of 3.231(1) Å obtained in crystal 2 falls in this range.
Scheme 3 Deprotonation steps of HPCs showed on ligand H2L1.
deprotonation is due to the aliphatic –COOH (pKa1 E 3.5). The
second deprotonation (denoted as pKa2 or log b(LH), between 6 and
8) is always due to the –OH group which is in an intramolecular
hydrogen bond with the deprotonated –COOꢁ group. The inductive
effect of the positively charged –NR+ groups has an impact on the
pKa1 and pKa2 values being relatively low. Further effects (see also
Crisponi et al.7), like the keto–enol tautomerism of the OH group
(typical and well known for 2- and 4-hydroxypyridines47), and
electron-donating effects of methyl substituents can modify the
pKa2 values of HPCs (in keto–enol tautomerism ring aromaticity is
lost and a pyridinone derivative is formed, see also Scheme S1,
ESI†). As a result of all these complex effects, different electron
distribution can emerge on the donor carboxylate and hydroxyl
oxygens of the different HPC ligands which will determine their
complex stability in solution and their coordination properties
in solid state, described in this paper.
The solid state structure of the bis-ligand copper complex of
L3, similarly to L2, resulted in a cyclic dimer [Cu2(L3)4]ꢀ4H2O (3)
(Fig. 3). However unlike L2, the two L3 coordinate in trans
arrangements, and it is the non-coordinated carboxylate oxygen
(O11), instead of the pyridinolato oxygen, which binds to the
neighbouring Cu(II) centre forming a syn–anti carboxylato bridge
in an equatorial–axial coordination mode. The two [Cu(L3)2]
moieties are symmetrical by an inversion centre. The axial
Cu1–O11 distance is 2.614(3) Å which is significantly longer
than the axial bond in the complex [Cu2(L2)4].
Solid state results of the bis-ligand complexes 1–5
Molecular structures. The bis-ligand copper(II) complexes
are predominant in aqueous solution at pH B 7 from which the
neutral [CuL2] complex could be crystallized for all the ligands
(except for ligand L6). Though identical donor groups resulted
in the same [Oꢁcarb, Oꢁ][Oꢁcarb, Oꢁ] coordination modes, a
variety of different solid state structures could be detected for
these bis-ligand complexes. A variety of structures were obtained
first because the two ligands can adopt cis or trans configuration
and also because the fifth (axial) coordination place can be
occupied in many different ways. Thus the [CuL2] moieties
formed mononuclear, binuclear, trinuclear complexes and poly-
nuclear 1D chains, as well. The summary of data collection and
refinement parameters can be found in Table S1 (ESI†).
The copper–copper distance is 5.266(2) Å in the cyclic dimer 3;
however a much closer copper–copper distance, 3.835(1) Å, emerged
between adjacent copper dimers above each other (Fig. S3, ESI†).
In [Cu(L1)2(H2O)]ꢀ3(H2O) (1), Cu1 adopts a square-pyramidal
environment as shown in Fig. 1, with the O2,O3 and O12,O13
Fig. 1 ORTEP view of [Cu(L1)2(H2O)] in crystal 1 with thermal displace-
ment ellipsoids drawn at the 50% probability level. Hydrogen atoms and
waters of crystallisation are omitted for clarity. Some selected bond
lengths and angles are given in Table S2 while Fig. S1 (ESI†) shows the
crystal packing arrangements.
Fig. 2 ORTEP view of [Cu2(L2)4] in crystal 2 with thermal displacement
ellipsoids drawn at the 30% probability level. Hydrogen atoms and waters
of crystallization are omitted for clarity. Some selected bond lengths and
angles are collected in Table S2 and packing arrangements are shown in
Fig. S2 (ESI†).
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EBIVAO).55 It is worth mentioning that in both cases the
salicylic acid is substituted with strong electron-attracting NO2
or Cl groups which significantly change the electron density on
the donor oxygens.
In the crystal of L4, the bis-ligand copper moieties establish
a 1D polymer chain [Cu(L4)2]nꢀ3H2O (4) (Fig. 4). The arrange-
ment of the ligands is trans similarly to L3. The Cu1 atom is
penta-coordinated with a highly similar arrangement as in 3
but the cyclic dimer could not be formed very likely because the
C9 methyl protons would be in sterically hindered by the C18
methyl protons in the case of a cyclic dimer structure. While in
3 the two copper centres have parallel arrangements, in 4 the
neighbouring centres are turning outward so that the carboxylate
oxygen O11 can coordinate a third copper ion axially. The angle
between the two planes of the neighbouring copper centres
defined by the four oxygen and copper atoms is 51.21. The angles
between the equatorial plane and the pyridine ring planes N1–C6
and N11–C16 are 19.661 and 31.601, respectively, which are also
much higher than in 4. Compared with 3 where the centres are
related by an inversion centre, the monomer units are related by
a 21 screw axis in 4, leading to a 1D helical structure. The same
bridging mode (1D framework) was found in the Mn(II) complex
of 4-hydroxynicotinic acid (ref. code SAKYOT56), where the metal
centre is hexa-coordinated with a more symmetrical octahedral
geometry.
In L5 a hydroxyethyl group is bound to the pyridine nitrogen,
and the crystallization process with copper(II) produced crystal
[Cu3(L5)6]ꢀ18H2O (5) (Fig. 5). Trimer [Cu3(L5)6] units construct
the crystal with a relatively high amount of water inclusion
(9 water of crystallization/asymmetric units). The three coordination
centres represent two different coordination arrangements.
The asymmetric unit contains half of the trimer arranged by
an inversion centre at the position of Cu2. All three centres are
coordinated by the [Oꢁcarb,Oꢁ] groups in trans positions in the
basal plane. The outward coppers are bound by one side chain
OH groups axially, generating a square-pyramidal geometry,
whereas the central copper is coordinated by two side chain OH
groups resulting in an elongated octahedral environment. The
axial bond is significantly shorter in the square pyramid (Cu1–
O24: 2.285(2) Å, see Table S2, ESI†) than in the elongated
octahedron (Cu2–O14: 2.427(2) Å).
Fig. 3 ORTEP view of [Cu2(L3)4] in crystal 3 with thermal displacement
ellipsoids drawn at the 50% probability level. Hydrogen atoms and waters
of crystallization are omitted for clarity. Selected bond distances and
angles can be found in Table S2 and packing arrangements are shown in
Fig. S3 (ESI†).
The pyridine ring planes are almost planar to the equatorial plane
(formed by the atoms O2–O3–Cu1–O12–O13); the deviation is
5.741 related to the ring N1–C6 and 8.931 related to N11–C16.
There is only one copper structure reported so far with a similar
carboxylato-bridged dimer in the literature which is a mixed
ligand complex of [Cu2(3,5-{(NO2)Sal})(2,20-bpy)2] ((NO2)Sal =
3,5-dinitrosalicylate, ref. code CIHQUG)54 where the copper–
copper distance was found to be 4.93(1) Å. A similar zinc complex
could also be found where a carboxylate oxygen instead of
the phenolato oxygen is bridging two zinc centres in a syn–anti
coordination mode in the coordination polymer [Zn(TCSA)
(4,40-bpy)0.5(DMF)]n (TCSA = 3,5,6-trichlorosalicylate, ref. code
Fig. 4 ORTEP view of the [Cu(L4)2]nꢀ3H2O coordination polymer in
crystal 4 with thermal displacement ellipsoids drawn at the 50% probability
level. Hydrogen atoms and lattice water molecules are omitted for clarity.
Selected bond lengths can be found in Table S2 and packing arrangements
in Fig. S4 (ESI†).
Fig. 5 ORTEP views of [Cu3(L5)6]ꢀ18H2O in crystal 5 with thermal displacement ellipsoids drawn at the 50% probability level. Hydrogen atoms and lattice
water molecules are omitted for clarity. Selected bond lengths can be found in Table S2 and packing arrangements in Fig. S5 (ESI†).
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Fig. 6 Packing arrangements in crystals (a) [Cu(L1)2(H2O)]ꢀ3H2O (1), (b) [Cu2(L2)4]ꢀ12H2O (2), (c) [Cu2(L3)4]ꢀ4H2O (3), (d) [Cu(L4)2]nꢀ3H2O (4), and
(e) [Cu3(L5)6]ꢀ18H2O (5) viewed from crystallographic axes b (a), a (b and c), and c (d and e). Building units are framed.
Packing arrangements of the crystals 1–5. In all crystal be detected by microwave radiation. This technique is extremely
structures waters of crystallization are placed in voids of different sensitive to the chemical surrounding of the unpaired electron
size and they connect the molecules through Ow–Hꢀ ꢀ ꢀO and providing unique local structural information. Due to hyperfine
C–Hꢀ ꢀ ꢀOw connections. In all lattices the building blocks (mono- interactions with copper (ICu = 3/2) the EPR line splits into four
mers, dimers or trimers) are arranged in a way that the copper lines. At room temperature, the isotropic parameters can be
basal plane together with the pyridine rings is parallel to the obtained (g0, A0), as the molecular motions average out the
neighbouring molecular units (Fig. 6).
orientation dependent EPR parameters. This simple description
In 1 the molecules are arranged in planes where the axially and low number of fitted parameters allow us to fit all the
coordinated water molecules are directed up and down alter- measured pH-dependent spectra together, by varying the EPR
nately. The complexes form chains by C–Hꢀ ꢀ ꢀO hydrogen bonds parameters and formation constants (logb) of the components
between the methyl protons and the neighbouring carboxylate by using the simulation program ‘‘2D_EPR’’.32,34 The main
and water oxygens (Fig. S1, ESI†). In 2 intermolecular hydrogen advantage of using this technique is that relevant structural
bonds with water molecules and pꢀ ꢀ ꢀp (off-centred parallel) and speciation data can be gained under ambient conditions
stacking interactions between the pyridine rings play an important (aqueous solution and room temperature). The EPR spectral
role in the stabilisation of the 2D layers. The water molecules form series is collected by an in situ titration performed in a
a 5-membered ring with Ow–Hꢀ ꢀ ꢀOw interactions between the circulating system to keep the EPR measuring conditions fixed.
molecular columns (Fig. S2, ESI†). In the case of crystal 3, the two Additional details concerning the coordination modes can be
water molecules located in the asymmetric unit are mirrored by gained from the frozen solution EPR spectra obtained at 77 K.
an inversion centre to form a square which connects the columns This evaluation (using the ‘‘EPR’’ program33) results in the
formed by the dimeric units (Fig. S3, ESI†). In 4, the 1D polymer anisotropic parameters (gx, gy, gz, and Ax, Ay, Az), which allow a
chains and water channels are arranged in columns (Fig. 6 more detailed analysis of the complex structures. In this case,
and Fig. S4, ESI†) while in crystal 5 the water of crystallization the molecules are randomly oriented in the sample, but their
(18 molecules/trimer units) and the complex molecules form positions are fixed during the measurement. The combination of the
layers (Fig. S5, ESI†).
two methods was used previously to investigate several copper(II)–
small bioligand complexes.58,59 Two series of pH-dependent EPR
spectra were recorded for each Cu(II)–HPC equilibrium system, one
Complex formation in solution
The complexation properties of HPC ligands in solution have at an equimolar metal-to-ligand ratio and another at two-fold ligand
been followed by electron paramagnetic resonance (EPR) spectro- excess both in aqueous solution at room temperature and at 77 K.
scopy. EPR is a powerful method for investigating paramagnetic
The simulation of the spectra resulted in the formation
copper(II) complexes. The principle of the measurement is that constants collected in Table 2 and the isotropic and anisotropic
the degenerated energy levels of the spin states can be resolved by EPR parameters of the detected species shown in Table S3
an external magnetic field and transitions between the levels can (ESI†). A series of measured and simulated EPR spectra of the
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Table 2 Stability constants of HPC–copper(II) complexes determined by
room temperature EPR (I = 0.10 M KCl, 25 1C in water); values are reported
as log b(MpLqHr). Various derived constants are also given for comparisona
ligand excess, which can be assigned to [Cu2L4]. In all copper(II)–L
equilibrium systems the complex [CuLH] could not be detected at
room temperature, but it appeared in frozen solutions except
for L2 for which this species could not be detected at low
temperature either.
The comparison of the distribution curves and isotropic EPR
spectra of [CuL] and [CuL2] complexes of all the measured
ligands are shown in Fig. S8 and S9 (ESI†), respectively. In Fig. 8
the distribution diagram is shown for the Cu(II)–L3 system, as a
typical example. The figure shows the formation of the compo-
nents at two different temperatures (295 K and 77 K). We would
like to note that even though the freezing of the EPR tubes in
liquid nitrogen takes only a couple of seconds, we can observe
that the complex equilibrium is shifted by 0.5 pH units to higher
pH upon freezing. The protonated complex [CuLH] appeared,
and the formation of [CuL] and [CuL2] increased at low tem-
L1
L2
L3
L4b
L5
L6c
lg b(CuL)
lg b(CuL2)
lg b0(CuL)d
5.87(2) 6.63(4) 6.34(1) 6.47(1) 6.32(1) 6.13(1)
10.07(4) 10.51(5) 11.04(1) 11.25(1) 10.64(1) 11.17(1)
3.24
2.57
6.38
3.73
4.38
10.48
5.34
4.17
10.30
5.15
4.21
9.92
5.18
3.63
10.11
5.16
lg b0(CuL2)d 8.63
pM (pH = 5)e 4.28
a
Uncertainties (SD) are shown in parentheses; for the charges of L1–L6
b
see Scheme 1. Values determined by pH-potentimetry from ref. 57:
log b(CuL) = 6.63(2) log b(CuL2) = 12.03(2). Protonated complexes have
c
also been determined with log b(CuLH) = 10.07(1) and log b(CuL2H) =
d
15.61(1). Calculated apparent stability constants at pH = 4.0 for CuL,
and at pH = 6.0 for CuL2 by the equation b0 = b/aH, where aH = 1 +
P
P
e
b
LHi[H]i. pM = ꢁlog( [MpHr]) at pH = 5.0, cM = 1.0 mM, cL = 1.0 mM.
1:2 Cu(II)–L3 equilibrium system and the corresponding calculated perature. In order to compare the stability of the Cu(II)–HPC
component spectra are shown in Fig. 7. The spectra recorded in complexes, the apparent formation constant and pM values
equimolar solution for the same system are shown in Fig. S7 (ESI†). have been calculated (see Table 2). Clearly, the 3-hydroxy-4-
In solutions containing Cu(II) and either L1, L2, L3, L4 or L5, the pyridinecarboxylate derivatives (3HPCs) show much lower stabi-
[CuL] and [CuL2] complexes were detected besides the Cu(II)aqua lity than 4-hydroxy-3-pyridinecarboxylate derivatives (4HPCs),
species. For all the obtained complexes, the stability values are and there are some significant differences between 4HPCs, as
much lower than those of deferiprone–copper(II) complexes well: L6 has the lowest stability, L5 and L4 are almost identical,
(lg b(CuL) = 10.3(9), lg b(CuL2) = 19.2(6)).12 In the solutions and L3 forms the strongest Cu(II) complexes (Fig. S10, ESI†).
containing Cu(II) and L6, the protonated complexes [CuLH]
The frozen-solution EPR spectra of the complexes could be
and [CuL2H] were also detected owing to the protonated carboxy- fitted by assuming the usual elongated octahedral geometry of
ethyl side chain. With this ligand, in frozen solutions, besides Cu(II) complexes (Fig. 7d). For the description of the spectra of
the mono complexes, dimer species were observed at a two-fold [CuL] and [CuLH] complexes, g and A tensors with axial
Fig. 7 (a and c) pH-dependent series of experimental (black) and simulated (gray) EPR spectra recorded in the Cu(II)–L3 system at cCu = 1 mM and
cL = 2 mM (a) at room temperature and (c) in frozen solution (77 K). (b and d) Component curves obtained by the simulation of (b) room temperature and
(d) frozen solution spectra.
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Fig. 8 Concentration distribution curves of Cu(II) complexes formed in the presence of metal ions and L3 at (a) cCu = cL = 1 mM and (b) cCu = 1 mM,
cL = 2 mM obtained from the simulation of room temperature (lines) and frozen solution (77 K) (scatters) EPR spectra.
symmetry were used; however for [CuL2] the axial symmetry was structural parameters, based on which the Cu(II)–Cu(II) distance
not sufficient, and a rhombic symmetry has been taken into and the orientation of the two g-tensors relative to each other
account. EPR parameters are in good agreement with the can be proposed. Identical Cu(II) centres with an almost parallel
increasing ligand field in the order of [CuLH] o [CuL] o equatorial plane (all three Euler angles are zero), with polar
[CuL2], since g-values decreased and A-values increased (Table angles of w = 301 and c = 01 and dipolar coupling D = 380 G,
S3, ESI†). The suggested coordination modes are shown in were obtained. For the g- and A-tensor values, data obtained for
Scheme S2 (ESI†). In the case of [CuL2], a mixture of cis or the mono complexes have been used: gx = 2.057, gy = 2.066,
trans coordination isomers can be supposed in solution, but gz = 2.331, Ax = 12.8 G, Ay = 12.0 G, Az = 150.1 G. For the exchange
the difference is probably below the experimental error, and coupling, the estimation of J 4 1500 G can be given, because
EPR spectra could be satisfactorily described with one component. under this value a doublet peak originating from this inter-
In the case of L6 a dimerization process has been found in frozen action should have been detected under the experimental
solution. In the presence of a ligand excess a well-resolved dimer conditions. From the dipolar coupling, the Cu(II)–Cu(II) dis-
spectrum of ferromagnetically coupled copper centres could be tance of 3.82 Å can be calculated and from w = 301 slightly
measured (Fig. 9) which can be assigned to [Cu2L4]. The half-field shifted copper centres above each other could be suggested.
peak, measured at 1600 G, can be attributed to a double quantum The crystal structures of [Cu2(L3)4] and [Cu2(L2)4] resulted in
transition (DMS = 2) of a coupled-spin system (Fig. 9a). The very similar Cu(II)–Cu(II) distances (3.231(1) and 3.835(1) Å) and
measured spectrum was described by the superposition of dimeric angles (w B 301) suggesting that the secondary interactions
and monomeric species (Fig. 9c and 9b). The dimer spectrum detected in the solid state can also appear in frozen solution.
was simulated by the exact solution of the Hamiltonian, using The dimerization process has been followed by temperature-
EPR software.60 This exact description resulted in effective dependent EPR spectra (Fig. S11, ESI†) which indicated that the
appearance of the ferromagnetically coupled dimeric species is
reversible with temperature and it is detectable only below
180 K. A small amount of a similar dimer could be detected in
the case of ligand L1 as well (Fig. S12, ESI†). At room temperature,
in solution, line broadening or diminishing of EPR signals would
have been expected in the case of dimer formation, but none of
these effects were found under our measuring conditions. We can
suggest that in the case of dissolution of the solid [CuL2] crystals in
a 1–2 mM concentration, oligomers dissociate and only monomers
are obtained.
Discussion
It is supposed that both the solid state coordination arrangements
and the solution stability are related to the electron distribution
on the donor oxygen atoms of the ligands. To compare this
Fig. 9 EPR spectra recorded in Cu(II)–L6 solution at 77 K, pH = 5.71, cL
=
for the different HPCs, Mulliken charge density61 and Mayer
bond order62–64 values have been calculated for the fully deproto-
nated ligands (L2ꢁ for L6 and Lꢁ for all the others) after geometry
optimization by density functional theory (DFT). The B3LYP
3.80 mM, cCu= 1.9 mM: (a) experimental (black) and simulated (gray) curves
with an enlargement in the inset, (b) calculated EPR spectra of the
monomer complex [CuL2], (c) calculated EPR spectra of dimeric species
[Cu2L4], and (d) description of the orientation of the two copper centres.
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functional41,42 was used under three different conditions: slope indicates that the ligand field decreases with the increasing
(1) SV(P) basis set43 in gas phase, (2) SV(P) basis set using acidity of the OH group. These results show that the complexation
the conductor-like screening model COSMO40 of water and properties of the studied HPCs are mainly influenced by the acidic
(3) cc-pVTZ44,45 using the same model COSMO (see Table S4, character of the OH group, whereas the nature of the carboxylate
ESI†). As we had now formation constants, EPR parameters, group has only little effects. This is further supported by the result
calculated charges and bond orders together with SXRD copper– of theoretical calculations. In all three calculations the Mayer bond
oxygen distances, all data were collected in a database and orders of the deprotonated hydroxyl C–Oꢁ bonds were in good
multivariate data analysis was performed using the Statistica correlation with the apparent formation constants of the complex
program package46 to reveal the relations between the obtained [CuL]. Fig. 10d shows the result of calculation (1) where R = 0.8744
values. By using this approach several significant (p o 0.05) was obtained. (Calculation (2) resulted in R = 0.8079 and calcula-
correlations have been found (see Table S5, ESI†) among which tion (3) in R = 0.8793.) The Mayer bond order values indicate that
four correlations are highlighted in Fig. 10. The correlation the C–Oꢁ bond is between a single and a double bound and the
between the deprotonation constants of the hydroxyl group double bound character has a continuous change according to the
(pKa2 ꢄ log b(LH)) and the apparent formation constant of electron donating effect of the different substituents. The different
complex CuL (log b0(CuL) calculated at pH = 4.0) is shown in electron density is also manifested in the C–O distances measured
Fig. 10a. The negative slope indicates that the lower the depro- in the crystals. These data are collected in Table S6 (ESI†) for all
tonation constants (higher acidity of the OH proton) the higher ligands which are in the asymmetric unit. When we compare
the formation constants of CuL. This is probably due to the the Cring–O3 distances of the different HPCs averaged over
strong intramolecular interaction between the OH proton and two (or three) structures measured in the asymmetric unit,
the adjacent carboxylate oxygen, so the deprotonation of this the obtained trend is L2 (1.307(6) Å) 4 L1 (1.303 Å) 4 L4
group necessarily precedes the binding of the copper ion. A (1.289(1) Å) 4 L5 (1.286(5) Å) 4 L3 (1.282(2) Å) which is in
significant correlation between the g0 values of complexes [CuL] agreement with the increasing Mayer bond order calculated by
and [CuL2] was also obtained (Fig. 5b). g0 (similarly to lmax
)
the DFT method. Several examples for fine-tuning the physical–
represents the ligand field around the Cu(II) ion, and it decreases chemical properties of complexes by substituent effects are known,
with increasing ligand field. It is an expected correlation that the such as the redox potential for iron(II)65,66 or copper(II)67 complexes
higher the ligand field in the mono-complex, the higher the ligand or the relaxivity and stability of Gd(III) contrast agents.68 This
field in the bis-complex. Interestingly, the order of the ligands in obtained substituent effect gives the possibility to optimize the
Fig. 5a and b is very similar, and as a consequence g0(CuL) and stability of HPC chelators with copper(II). The main difference
pKa2 also show a significant correlation (Fig. 5c). The negative between the obtained solution and solid state structures of
Fig. 10 Correlation between solution equilibrium, EPR spectroscopic and DFT data: (a) log b(LH) and log b0(CuL) (pH = 4.0), (b) g0 values of complexes
[CuL] and [CuL2] of the same ligands, (c) g0(CuL) and log b(LH) values and (d) log b0(CuL) (pH = 4.0) and the Mayer bond order of the C–Oꢁ bond
calculated by the DFT method.
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the bis-ligand copper(II) complexes is that in solution the same distribution on the detected stability order. According to this,
[Oꢁcarb,Oꢁ][Oꢁcarb,Oꢁ] coordinated monomer copper(II) complexes the copper(II) binding strength of the studied compounds follows
have been found for all HPCs (possibly with axial water coordi- the order L2 o L1 E L6 o L4 E L5 o L3. As a consequence, the
nation). However, in the solid state, a great structural variety deprotonated hydroxyl group loses the bridging role in the solid
has been detected owing to the fact that the axial position can state structures of 4HPCs.
be fulfilled in different ways: by a water molecule resulting in a
The present study illustrates the potential of combined solid
monomer complex (1), by the ligand oxygen of a neighbouring state/solution study of bioligand–copper(II) complexes by using
complex forming cyclic dimer structures (2 and 3) or by the single crystal X-ray diffraction together with EPR spectroscopy.
ligand side chain OH groups, in 5, resulting in this case a 5-, 6-, The understanding of the solid state and solution structures of
5-coordinated trimer complex. When the sterical hindrance small bioligand copper(II) complexes paves the way to design
prevents cyclic dimer formation in 4, a 1D polymer evolves. chelators with predicted coordination modes.
Interestingly, in the cyclic dimer of ligand L2 (2) it is the
pyridinolato oxygen which acts as the bridging atom; anyhow
in the case of ligand L3 (3) it is the carboxylato oxygen that plays
Conflicts of interest
this role. The nature of the axially coordinated donor atom
strongly depends on the electron distribution of the ligand
There are no conflicts to declare.
oxygen donors. The solution equilibrium studies and DFT
calculations revealed a systematic order in the acidic character Acknowledgements
of the OH group where the highest value was found in the case
The authors thank Prof. Antal Rockenbauer for valuable dis-
cussions about the EPR results and Prof. Ferenc Simon for EPR
measuring possibilities. This work was supported by the National
of the L3 and the lowest value in the case of the L2 (Fig. 10a)
ligands. If we compare the Mulliken gross atomic charges (see
Table S4, ESI†) for the deprotonated carboxyl (O1) and the
Research, Development and Innovation Office-NKFIH through
hydroxyl (O3) atoms in the different ligands we can see that
OTKA K115762 and K124544, by the J. Bolyai Research Scholar-
they are almost equal in the case of the 3HPC ligands; however
ship of the Hungarian Academy of Sciences (N. V. M.), and by the
O1 values are significantly more negative than O3 values in all
CPDA08390X ‘‘Progetto Ateneo’’ of the University of Padova.
4HPCs. It means that the more electronegative carboxylate
oxygen (O1) takes the bridging role over pyridinolate oxygen
(O3) in the L3 copper complex. By examining the crystal structures
of related cyclic dimers of salicylic acid, phenolato bridges can be
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mentioning that in 3HPC complexes only cis and in 4HPC
complexes only trans configuration of the ligands could be
detected in solid state which is probably also related to their
different electron distribution. Further investigations are planned
to understand the origin and nature of this cis/trans predominancy
in these copper(II) complexes.
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Conclusions
This work provides the systematic exploration of the influence
of electron distribution on the coordination properties of hydro-
xypyridinecarboxylate derivatives with copper(II) as potential
candidates in chelating therapy of metal overloading conditions.
In the solid state, the electron distribution in the ligand influences
both the type of the axial coordination of the metal centre and
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