Tailoring the local environment around metal ions: A solution chemical and structural study of some multidentate tripodal ligands

Article abstract of DOI:10.1039/c7dt00104e

Manganese(ii), copper(ii) and zinc(ii) complexes of four polydentate tripodal ligands (tachpyr (N,N′,N′′-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane), trenpyr (tris[2-(2-pyridylmethyl)aminoethyl]amine, tach3pyr (N,N′,N′′-tris(3-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane) and tren3pyr (tris[2-(2-pyridylmethyl)aminoethyl]amine)) were characterized in both solution and solid states. A combined evaluation of potentiometric, UV-VIS, NMR and EPR data allowed the conclusion of both thermodynamic and structural information about the complexes formed in solution. The four tailored polydentate tripodal ligands studied here exhibit a high thermodynamic stability, and a variety of coordination environments/geometries for the studied transition metal ions. Our data indicate that tachpyr is a more efficient zinc(ii) chelator and a similar copper(ii) chelator compared to trenpyr. Considering the higher number of N-donors and conformational flexibility of trenpyr, as well as the energy demanding switch to the triaxial conformation required for metal ion binding of tachpyr, the above observation is surprising and is very likely due to the encapsulating effect of the more rigid tachpyr skeleton. This relative binding preference of tachpyr for zinc(ii) may be related to the observation that zinc(ii) is one of the principal metals targeted by tachpyr in cells. In contrast, trenpyr is a considerably more efficient manganese(ii) chelator, since it acts as a heptadentate ligand in the aqueous Mn(trenpyr) complex. The crystal structures of copper(ii) and zinc(ii) complexes of tachpyr indicated important differences in the ligand conformation, induced by the position of counter ions, as compared to earlier reports. The closely related new ligands, tach3pyr and tren3pyr, have been designed to form oligonuclear complexes. Indeed, we obtained a three dimensional polymer with a copper(ii)/tren3pyr ratio of 11/6. Within this metal-organic framework, three distinctly different copper geometries can be identified: square pyramidal, trigonal bipyramidal and tetrahedral. Two square pyramidal and four trigonal bipyramidal copper centres create a hexanuclear subunit with a large inside cavity. These moieties are linked by tetrahedral copper(ii) centres, constructing the three-dimensional polymer structure. The formation of such polynuclear complexes was not detected in solution. Both tach3pyr and tren3pyr form only mononuclear complexes with square pyramidal and trigonal bipyramidal geometries, respectively.

Full text of DOI:10.1039/c7dt00104e

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Tailoring the local environment around metal ions: solution chemical and
structural study of some multidentate tripodal ligands
†
Ferenc Matyuskaa, Attila Szorcsikb, Nóra V. Mayc, Ágnes Dancsa, Éva Kovátsd, Attila Bényeie
and Tamás Gajdaa,b,*
a
Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Hꢀ
6720 Szeged, Hungary. Eꢀmail: gajda@chem.uꢀszeged.hu
b MTAꢀSZTE Bioinorganic Chemistry Research Group, Dóm tér 7, Hꢀ6720 Szeged, Hungary
c
Research Centre for Natural Sciences HAS, Magyar tudósok körútja 2, Hꢀ1117 Budapest,
Hungary
d
Institute for Solid State Physics and Optics, Wigner Research Centre for Physics HAS,
Konkoly Thege Miklós u. 29ꢀ33, Hꢀ1121 Budapest, Hungary
e Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, Debrecen
Hꢀ4032, Hungary
Abstract
Manganese(II), copper(II) and zinc(II) complexes of four polydentate tripodal ligands
(tachpyr (N,N’N’’ꢀtris(2ꢀpyridylmethyl)ꢀcis,cisꢀ1,3,5ꢀtriaminocyclohexane), trenpyr (tris[2ꢀ(2ꢀ
pyridylmethyl)aminoethyl]amine,
tach3pyr
(N,N’N’’ꢀtris(3ꢀpyridylmethyl)ꢀcis,cisꢀ1,3,5ꢀ
triaminocyclohexane) and tren3pyr (tris[2ꢀ(2ꢀpyridylmethyl)aminoethyl]amine)) were
characterized in both solution and solid states. Combined evaluation of potentiometric, UVꢀ
VIS, NMR and EPR data allowed concluding both thermodynamic and structural information
on the complexes formed in solution.
The four tailored polydentate tripodal ligands studied here offer high thermodynamic
stability, and a variety of coordination environment/geometry for the studied transition metal
ions. Our data indicate that tachpyr is more efficient zinc(II) and similar copper(II) chelator
than trenpyr. Considering the higher number of Nꢀdonors and conformational flexibility of
trenpyr, as well as the energy demanding switch to the triaxial conformation required for metal
ion binding of tachpyr, the above observation is surprising and is very likely due to the
encapsulating effect of the more rigid tachpyr skeleton. This relative binding preference of
tachpyr for zinc(II) may be related to the observation that zinc(II) is one of the principal metals
targeted by tachpyr in cells. In contrast, trenpyr is considerably more efficient manganese(II)
chelator, since it acts as a heptadentate ligand in the aqueous Mn(trenpyr) complex. The crystal
1

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structures of copper(II) and zinc(II) complexes of tachpyr indicated important differences in
the ligand conformation, induced by the position of counter ions, as compared to earlier
reports.
The closely related new ligands, tach3pyr and tren3pyr have been designed to form
oligonuclear complexes. Indeed, we obtained a three dimensional polymer with
copper(II)/tren3pyr ratio of 11/6. Within this metalꢀorganic framework three distinctly different
copper geometries can be identified: square pyramidal, trigonal bipyramidal and tetrahedral.
Two square pyramidal and four trigonal bipyramidal copper centres create a hexanuclear
subunit with a large inside cavity. These moieties are linked by tetrahedral copper(II) centres,
constructing the three dimensional polymer structure.
The formation of such polynuclear complexes were not detected in solution. Both
tach3pyr and tren3pyr form only mononuclear complexes with square pyramidal and trigonal
bipyramidal geometry, respectively.
1
† Electronic supplementary information available: H NMR spectra of the ligands,
crystallographic data, figures depicting the arrangement of hydrogen bonds and unit cells, UVꢀ
VIS, EPR, MS spectra and speciation curves of the complexes studied, proposed mechanism
as well as saturation kinetic data for the hydrolysis of bnpp. See DOI : ???.
2

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Introduction
The favourable and preorganized spatial distribution of donor atoms in tripodal ligands
has been long time recognised1 and applied to develop for example structural/functional
models of metalloproteins2ꢀ6 or supramolecular assemblies.7 Polydentate (n > 4) tripodal
ligands are generally synthesized by derivatization of (tri/tetra)dentate tripodal platforms, such
as cis,cisꢀ1,3,5ꢀtriaminocyclohexane (tach), trisꢀ(2ꢀaminoethyl)amine (tren) or nitrilotriacetic
acid (nta). Such modifications may provide additional donor site(s), may influence the steric
environment around the metal centre or may help to introduce further metal binding site(s) in
order to create polynuclear complexes. Accordingly, these polydentate tripodal ligands are
efficient metal sequestering agents,8 artificial receptors,9 metal ion sensors10 or artificial
enzymes.11,12
Tachpyr (N,N’N’’ꢀtris(2ꢀpyridylmethyl)ꢀcis,cisꢀ1,3,5ꢀtriaminocyclohexane) and trenpyr
(tris[2ꢀ(2ꢀpyridylmethyl)aminoethyl]amine) are versatile polydentate tripodal ligands (Scheme
1). Tachpyr and trenpyr bind strongly to most transition metal ions.13ꢀ22 The Fe(II/III) and
Mn(II/III) complexes of trenpyr are highly active SODꢀmimicking compounds.13,14 Tachpyr
and some of its derivatives are promising chelators of 64/67Cu for radiotherapeutic uses.23,24
Moreover, both tachpyr and trenpyr, as well as some of their methylꢀsubstituted analogues, are
cytotoxic metal chelators with potential antiꢀtumor activity.17,25ꢀ28 Tachpyr induces inhibition of
ferritin synthesis,25 and triggers activation of the CHK kinases, leading to cellꢀcycle arrest in
G2, a radiosensitive phase of the cell cycle.26 The intracellular chelation of zinc as well as iron,
but not copper, may play a fundamental role in the apoptosis induced by tachpyr and its
derivatives. Accordingly, the apoptotic caspases 9 and 3 was blocked in cells preꢀtreated with
either iron or zinc.27,28
Although both tachpyr and trenpyr have been designed for efficient metal ion binding,
and a number of crystal structures are available for their metal complexes,13ꢀ22 thermodynamic
data on the stability of these complexes are very scarce. To our knowledge, no solution
equilibrium or detailed solution structural study is reported for tachpyr, and in the case of
trenpyr stability constants are available only for the Cu(II) and Zn(II) complexes at I = 1M.20,21
Due to the favourable position of pyridine nitrogens of tachpyr and trenpyr, these
ligands encapsulate the metal ions by fused chelate rings, which is probably one of the main
reasons of their efficient metal binding ability. This encapsulating effect is not present in the
cases of 3ꢀpyridylmethylꢀsubstituted derivatives of tach and tren (tach3pyr and tren3pyr, see
Scheme 1). Although the positions of pyridine nitrogens in these ligands are not appropriate for
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the coordination to metal ions already bound to the tripodal platform, it may be advantageous
in the construction of oligonuclear complexes. Indeed, the position of the pyridine nitrogens in
tach3pyr and tren3pyr may allow the formation of supramolecular structures or metalꢀorganic
frameworks. In addition, the steric and aromatic properties of pyridine rings of tach3pyr and
tren3pyr can be also advantageous to develop enzyme mimics. The Cu(tach)(OH) complex is
an efficient model of hydrolytic enzymes,29ꢀ32 but it readily transforms into the inactive
dihydroxoꢀbridged [Cu2(tach)2(OH)2] dimer.29 Nꢀalkylation of tach suppress the formation of
the inactive dimer species, therefore these complexes efficiently promote the hydrolysis of both
bis(4ꢀnitrophenyl) phosphate (bnpp)33 and DNA.32 In the Cu(II)ꢀtach3pyr system the formation
of the inactive dimer would be unfavourable, too, and the nonꢀcoordinating pyridine rings may
enhance the substrate binding to the hydrolytically active species.
To this end, beside tachpyr and trenpyr we also synthesized two new tripodal ligands
(tach3pyr and tren3pyr, Scheme 1). Here, we report the characterization of their Mn(II), Cu(II)
and Zn(II) complexes in both solution and solid state.
N
N
N
N
N
N
NH
NH
NH
NH
NH
NH
tachpyr
tach3pyr
N
N
N
N
N
N
NH
NH
N
NH
NH
HN
HN
N
tren3pyr
trenpyr
Scheme 1. Schematic structures of the studied ligands
4

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Materials and methods
Materials
All reagents were of analytical grade and used without further purification. Copper(II)
perchlorate solution were prepared from analytically pure compounds obtained from Sigmaꢀ
Aldrich and standardized complexometrically. A 0.1 M NaOH standard solution (Sigma) was
used for pH titrations. The compounds trisꢀ(2ꢀaminoethyl)amine (98%), pyridineꢀ2ꢀ
carboxaldehyde (99%), pyridineꢀ3ꢀcarboxaldehyde (98%) and cis,cisꢀl,3,5ꢀcyclohexaneꢀ
tricarboxylic acid (98%) was purchased from SigmaꢀAldrich and TCI, respectively. The
buffers MES 2ꢀ([Nꢀmorpholino]ethanesulfonic acid (MES), Nꢀ(2ꢀhydroxyethyl)piperazineꢀN’ꢀ
ethanesulfonic acid (HEPES) and 2ꢀ(cyclohexylamino)ꢀethanesulfonic acid (CHES) were
purchased from SigmaꢀAldrich. Tach×3HBr34 and trenpyr14,20 were prepared as previously
reported.
Synthesis of N,N’,N’’-tris(2-pyridylmethyl)-1,3,5-cis,cis-triamino-cyclohexane (tachpyr, L1)
Tachpyr was prepared by a slight modification of the previously reported method.34
Tach(HBr)3 (1.032 g, 2.775 mmol) was dissolved in H2O (5 mL) with NaOH (0.333 g, 8.325
mmol) to form a clear solution. Benzene (100 mL) was added and the water was removed by
azeotropic distillation with a DeanꢀStark trap. Pyridineꢀ2ꢀcarboxaldehyde (0.905 g, 8.45
mmol) was added during this process. After 24 h reflux the solvent was evaporated. The
resulting white imine was dissolved in MeOH (40 mL) and NaBH4 (1.09 g, 29 mmol) was
added in small portions. The reaction was stirred for 24 h, than the solvent was removed by
rotary evaporation. The residue was dissolved in CHCl3 (40 mL) and stirred vigorously with
40 mL aqueous 5% NaHCO3 solution. The layers were separated, and the CHCl3 solution was
further washed with saturated NaCl solutions (2 x 40 mL), then dried over Na2SO4. After the
filtration, the organic phase was treated with dry HCl gas to form the hydrochloric salt of the
ligand (tachpyr×4HCl). The product was washed with CHCl3 (60 mL) and dry Et2O (60 mL),
1
(1.37 g, 92%). The purity was checked by HꢀNMR in 10%ꢀ90% D2O/H2O at pH = 3.25
(8.52, d, 3H; 7.88, t, 3H; 7.47, d, 3H; 7.43, t, 3H; 4.42, s, 6H; 3.50, t, 3H; 2.71, d, 3H; 1.77,
dt, 3H, no other signals were detected, see Fig. S1 in Electronic Supporting Information).
(HR)ESIꢀMS m/z 403,2534, calculated for C24H31N6 [M+H]+ = 403.2532.
Synthesis of N,N’,N’’-tris(3-pyridylmethyl)-1,3,5-cis,cis-triamino-cyclohexane (tach3pyr, L2)
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The synthesis was similar as described above for tachpyr. The ligand was obtained as
1
hydrochlorid salt (tach3pyr×6HCl, yield 87%). Purity was checked by HꢀNMR in 10%ꢀ90%
D2O/H2O at pH = 3.0 (8.90, s, 3H; 8.79, d, 3H; 8.60, d, 3H; 8.02, dd, 3H; 4.58, s, 6H; 3.68, t,
3H; 2.83, d, 3H; 1.84, q, 3H). (HR)ESIꢀMS m/z 403,2608, calculated for C24H31N6 [M+H]+ =
403.2532.
Synthesis of tris[2-(3-pyridylmethyl)aminoethyl]amine (tren3pyr, L4)
Tren3pyr was prepared by a slight modification of the previously reported method for the
synthesis of trenpyr.14,20 In brief, 349 mg (2,38 mmol) of trisꢀ(2ꢀaminoethyl)amine (tren) and
841 mg (7,85 mmol) of the corresponding aldehyde was mixed in 50 mL waterꢀfree methanol
with 3Å molecular sieves, and refluxed for 4 h. After cooling 1.0 g (26.6 mmol) NaBH4 was
added to the solution in small portions and stirred overnight. Than the methanol was
evaporated, the crude product dissolved in 50 mL chloroform, extracted with 3×20 mL
aqueous 10% Na2CO3 solution, and dried over Na2SO4. After filtering, the filtrate was treated
with dry HCl gas, which resulted in precipitation of the hydrochlorid salts (tren3pyr×6HCl).
1
Purity was checked by HꢀNMR in 10%/90% D2O/H2O at pH = 2.98: (8.74, s. 3H; 8.69, d,
3H; 8.28, d, 3H; 7.77, dd, 3H; 4.39, s, 6H; 3.24, t, 6H; 2.90, t, 6H, no other signals were
detected, see Fig. S2 in Electronic Supporting Information). (HR)ESIꢀMS m/z = 420.2715,
calculated for C24H34N7 [M+H]+ = 420..2876.
Potentiometric Measurements
The protonation and coordination equilibria were investigated by potentiometric titrations in
aqueous solution (I = 0.1 M NaCl, and T = 298.0 ± 0.1 K) under Ar using an automatic titration
set including a PC controlled Dosimat 665 (Metrohm) autoburette and an Orion 710A precision
digital pHꢀmeter. The Metrohm Micro pH glass electrode (125 mm) was calibrated35 via the
modified Nernst equation (1):
JOH ⋅ Kw
[H+ ]
E = E0 + K ⋅log[H+ ] + JH ⋅[H+ ] +
(1)
where JH and JOH are fitting parameters in acidic and alkaline media for the correction of
experimental errors, mainly due to the liquid junction and to the alkaline and acidic errors of
the glass electrode; Kw = 10–13.75 M2 is the autoꢀionization constant of water.36 The parameters
were calculated by the nonꢀlinear least squares method. In pure aqueous solutions the titrations
were performed between pH 1.7 and 11.0.
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In 60% (w/w) dimethylsulfoxide (dmso)ꢀwater mixture (I = 0.1 M NaCl, and T = 298.0 ± 0.1
K) the electrode system was calibrated to the pH = log [H+] scale by means of blank titrations
(HCl versus NaOH), which is similar to the method suggested by Irving et al.37 in pure aqueous
solutions. The obtained ionization constant of water under the conditions used pKw
=
15.586±0.05, which corresponds well to the literature data.38 The reproducibility of the titration
points included in the calculations was within 0.005 pH units. In 60% (w/w) DMSOꢀwater
mixture the copper(II)ꢀtach3pyr 1/1 and zinc(II)ꢀtach3pyr 1/1 systems were clear between pH
1.9ꢀ10 and pH 1.9ꢀ7.6, respectively.
The complex formation was described by a general equilibrium process as follows:
β
MpHqLr
pM + qH + rL←→Mp Hq Lr
(2)
[Mp Hq Lr ]
[M]p [H]q [L]r
βM H L
=
(3)
p
q
r
where M denotes the metal ion, L the nonꢀprotonated ligand molecule, and H stands for
protons. Charges are omitted for simplicity, but can be easily calculated taking into account
that the fully deprotonated ligands are neutral. The corresponding formation constants (βMpH L
q r
≡
β
pqr) were calculated using the PSEQUAD computer program.39
Using the above mentioned calibration protocol, the protonation and formation
constants obtained in 60% (w/w) dimethylsulfoxide (dmso)ꢀwater mixture are considered to be
β
mixed (or practical) constants40 and are valid only under the given conditions.
The protonation constants were determined from four independent titrations (90 data
points per titration), with ligand concentration 2–3×10–3 M. The complex formation constants
were evaluated from 5ꢀ7 independent titrations (~90 data points per titration). The metalꢀtoꢀ
ligand ratios were 3:2, 1:1, and 1:2. The metal ion concentrations varied between 1.0–2.9×10–3
M, depending on the metalꢀtoꢀligand ratio.
UV-Vis, EPR and NMR Measurements
UVꢀVis spectra were measured on Unicam Helios α or Thermo Scientific Evolution 200
spectrophotometers using a cell with 1 cm optical pathlength. Similar concentrations were used
as described above for the potentiometric titrations. The individual UVꢀVis spectra of the
complexes were calculated by PSEQUAD.39 The EPR spectra were recorded at room
temperature and at 77 K using a BRUKER EleXsys E500 spectrometer (microwave frequency
9.81 GHz, microwave power 13 mW, modulation amplitude 5 G, modulation frequency 100
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kHz). The EPR spectra were determined in aqueous solutions (or in 60% (w/w) dmsoꢀwater),
and were simulated by a spectral decomposition algorithm.41 Since the copper(II) salt used to
make the stock solution was a natural mixture of isotopes, the spectrum of each species was
calculated as the sum of spectra containing 63Cu and 65Cu weighted by their natural
abundances. The copper and ligand coupling constants are given in units of gauss (1 G = 10–4
T).
The 1H NMR measurements were performed on a Bruker Avance DRX 500 spectrometer. The
spectra were recorded at 25 °C in 10% D2O/H2O or 100% D2O solution, at ligand
concentrations of ~ 3.0×10–3 M with a tube diameter of 5 mm. The chemical shifts (δ) were
measured relative to dioxane as internal reference and converted to SiMe4 reference using
δdioxane = 3.70. Data were processed using the Topspin 2.0 software package (Bruker).
Hydrolysis of bis(p-nitrophenyl) phosphate (bnpp)
The reaction was followed in 60% (w/w) dmsoꢀwater (I =0.1 M NaCl, T = 298 K). The
increase in the absorbance maximum at 405 nm of the pꢀnitrophenolate anion (ε = 18900
M‒1cm‒1) was monitored in a buffered solution (20 mM CHES or HEPES). The pK of pꢀ
nitrophenol was determined independently for our conditions (pK = 7.50±0.05). The initial
concentration of bnpp varied from 0.5 mM to 6.5 mM. The initial slope method (~ 4%
conversion) was used to determine the pseudo first order rate constants. The reported data are
the average of triplicate measurements (reproducibility ~ 10%).
X-ray data collection, structure solution and refinement for compounds 1, 2, 3 and 4
Single crystals suitable for Xꢀray crystallography of compounds
1 and 2 were grown from
water solution containing Zn(ClO4)2 and tachpyr in molar ratio of 3/2 and 1/1, respectively.
The solutions also contained NaCl, and the pH was adjusted to pH=8 by NaOH solution.
Colourless single crystals were mounted on loops and transferred to the goniometer. Xꢀray
diffraction data were collected at room temperature (20 °C) on a Rigaku RAXISꢀRAPID II
diffractometer (using a CuꢀKα radiation for crystal
and with high volume a very careful Multiꢀscan absorption correction was carried out using
the program CrystalClear.42
was obtained from aqueous solution at pH 7 standing at room temperature for three months,
1 and MoꢀKα for crystal 2). For crystals 1
2
3
and single crystal Xꢀray diffraction data were measured using a BrukerꢀNonius MACH3
diffractometer at room temperature (20 °C). A ψ scan absorption correction was applied,43 the
number of ψ scan sets was 3. Theta correction and averaged transmission function was applied.
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For Fourier smoothing the window value was 5. Sir201444 and SHELXL45 under WinGX46
softwares were used for solution and refinement, respectively. The structures were solved by
direct methods. The models were refined by fullꢀmatrix least squares on F2. A summary of data
collection parameters is given in Table 1. In the structures
1 and 2 hydrogen atom positions
were located in difference electron density maps or placed into geometric positions. They were
included in structure factor calculations but they were not refined. The isotropic displacement
parameters of the hydrogen atoms were approximated from the U(eq) value of the atom they
were bonded to. Refinement of nonꢀhydrogen atoms was carried out with anisotropic
temperature factors except for the disordered oxygen of water in structure
occupancy was set to 0.5 and hydrogens were not defined) and ClO4 in structure
Suitable single crystals of were prepared by dissolving the precipitate formed in
1 (for which the
2.
4
aqueous 0.1 M NaCl solution (at [Cu(II)]/[tren3pyr] ratio 2/1 and at pH 4ꢀ5) in ethanol, and
allowed to slowly evaporate the solvent during several weeks at room temperature. Xꢀray
diffraction data were collected on a RigakuꢀOxford Diffraction SuperNova Dual source
diffractometer equipped with an Atlas detector using CuꢀKα radiation. For data collection and
absorption correction the CrysAlis software was used.47 The summary of data collection and
refinement parameters are also collected in Table 1.
Selected bond lengths and angles of compounds were calculated by PLATON
software.48 The graphical representation and the edition of CIF files were done by the
Mercury49 and PublCif50 softwares, respectively.
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Table 1. Crystal data and structure refinement for [Zn(tachpyr)]×(ClO4)2×(O) (1), [Zn(tachpyr)]×(ClO4)×(Cl) (2), [Cu(tachpyr)]×(ClO4)2×(H2O) (3) and
[Cu11(tren3pyr)6Cl11](Cl)11×6H2O×6EtOH (4)
1
2
3
4
Color/shape
Empirical formula
Moiety formula
Colourless/Platelet
C24H30N6O9Cl2Zn
Colourless/Chunk
C24H30N6O4Cl2Zn
Blue/Block
C24H32N6O9Cl2Cu
Blue/Block
C156H246N42O12Cl22Cu11
[Zn(C24H30N6)](ClO4)2(O) [Zn(C24H30N6)](Cl)(ClO4) [Cu(C24H30N6)](ClO4)2(H2O) [Cu11(C24H33N7)6(Cl)11](Cl)11
(C2H6O)6(H2O)6
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
682.81
293(2)
1.54178
monoclinic
P21/n
602.81
293(2)
0.71073
trigonal
Rꢀ3c
682.99
293(2)
0.71073Å
monoclinic
P21/n
4380.77
298(2)
1.54178
cubic
Space group
I23
Unit cell dimensions
a , b, c (Å)
8.5454(2), 14.1957(3),
24.2629(6)
13.9000(5), 13.9000(5),
45.0290(14)
8.5315(16), 14.200(6),
24.011(6)
26.8501(1)
90, 100.298(1), 90
2895.87(12)
4/1
90, 90, 120
7534.5(6)
12/1
90, 99.230(10), 90
2871.3(15)
4/1
90, 90, 90
19357.0(2)
4/0.1667
α, β, γ (°)
Volume (Å3)
Z/Z’
Density (calc.) (Mgmꢀ3)
Absorption coeff. (mmꢀ1)
F(000)
1.566
3.415
1408
1.594
1.236
3744
1.580
1.009
1412
1.503
4.60
9060
Crystal size (mm)
Diffractometer
Absorption correction
Min. and max. transmission
θ ange for data collection (°)
Index ranges
0.50 × 0.30 × 0.05
Rigaku RAXISꢀRAPID II Rigaku RAXISꢀRAPID II
0.25 × 0.25 × 0.20
0.55 × 0.45 × 0.15
Enraf Nonius MACH3
ψ scan
0.30 × 0.26 × 0.25
RigakuꢀOxford SuperNova
Multiꢀscan
Multiꢀscan
0.5159, 1.0000
6.506 ≤ θ ≤ 58.920
Multiꢀscan
0.8646, 1.0000
3.230 ≤ θ ≤ 27.472
0.736, 0.863
0.63, 1.0000
2.694 ≤ θ ≤ 25.975
3.29 ≤ θ ≤ 67.68
ꢀ9 ≤ h
ꢀ24 ≤ l
20821
≤
8, ꢀ15≤ k
≤15,
ꢀ18 ≤ h
≤
18, ꢀ18≤ k
58
≤
18,
0 ≤ h
ꢀ29 ≤ l
8665
≤
10;ꢀ7≤ k
≤
17;
ꢀ33 ≤ h
ꢀ32 ≤ l
73532
≤
33, ꢀ31≤ k
≤133
≤
26
ꢀ58 ≤ l
≤
≤
29
≤
24
No. reflections collected
72365
10

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Dalton Transactions
0.977
4076 (0.0455)
3202
0.997
1924 (0.0377)
1614
0.995
5615 (0.0325)
4436
0.995
6505 (0.03)
6034
Completeness to 2θ
No. independent reflections (Rint)
Reflections I>2σ(I)
Refinement method
fullꢀmatrix leastꢀsquares on F2
Data / restraints / parameters
Goodnessꢀofꢀfit on F2
4076 /7 /406
1.148
1924 /0 /107
1.148
5615 /5 /394
1.060
6505 /5 /381
1.09
0.0493, 0.1262
0.0635, 0.1537
0.006, 0.000
0.415 and ꢀ0.369
0.0531, 0.1697
0.0595, 0.1812
0.000, 0.000
0.711 and ꢀ1.145
0.0875, 0.2192
0.1049, 0.2353
0.001;0.000
0.0837
Final R indices [I>2σ(I)] R1, wR2
R indices (all data) R1, wR2
Max. and mean shift/esd
0.0866, 0.2415
2.593, 0.02
1.69 and ꢀ1.81
Largest diff. peak and hole (e.Åꢀ3)
1.187 and ꢀ0.852
11

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Results and Discussion
Crystal structures of tachpyr complexes
The crystal structure of [Zn(tachpyr)] (ClO4)2
DOSVAI) by Planalp and coꢀworkers18 and it crystallized in the cubic space group P213 with
unit cell dimensions a,b,c = 14.3088 . The ZnN6 coordination sphere was described as a
distorted octahedron. In this study, two new crystal forms of [Zn(tachpyr)] complex cation was
crystallized and their structure determined: [Zn(tachpyr)] (ClO4)2 O ( ) crystallized in a
monoclinic P21/n space group and [Zn(tachpyr)] (ClO4) Cl ( ) in trigonal crystal system, Rꢀ3c
space group. The copper(II) complex [Cu(tachpyr)] (ClO4)2 H2O ( ) crystallized in P21/n
space group (Table 1), which was found to be isostructural with the known crystal structure of
[Cu(tachpyr)] (ClO4)2 0.5(C2H3N) (unit cell a/b/c = 8.4921/14.3418/23.9735 and β =
99.874°) for which the CSD ref. code is CAFXEN.19 Figure 1 depicts the ORTEP
representation of the complex cations from and . In all cases, the coordination sphere of
metal ions is best described as a distorted octahedron.
×
×(CH3OH) has been reported (CSD ref. code
Å
×
×
1
×
×
2
×
×
3
×
×
Å
1,
2
3
Figure 1. Molecular structures of the metal complex cations of
1 (with the indication of rings
AꢀG),
2
and
3
(from left to right). Displacement parameters are drawn at 30% probability
level and hydrogens are omitted for clarity.
The different counter ions affected not only the arrangement of the crystal lattice but
the conformation of the tachpyr molecule around the metal ions, as well. In the crystals of 1, 3
and CAFXEN the three 2ꢀpyridylmethyl arms have different conformation. In contrary, in
2
and DOSVAI a C3 trigir goes through the Zn(II) ion and the asymmetric unit contains one
pyridine arm of the ligand. Though crystal
1
contains Zn(II) ion, its conformation is much
and CAFXEN, see Fig. S3) than to the other
more similar to the two copper(II) complexes (
3
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Figure 2. Conformational comparison for the metal complex cations [Zn(tachpyr)] in crystal
structure (colored by element), (blue), DOSVAI [18] (pink) and [Cu(tachpyr)] from
crystal
1
2
3
(yellow) and CAFXEN [19] (green). The twist angle defined for the coordination
sphere of [M(tachpyr)] complexes [18] are also shown.
two zinc(II) complexes (2 and DOSVAI). Figure 2 shows overlayed structures of the metal
complex cations of
1,
2, 3 together with DOSVAI18 and CAFXEN.19
For conformational comparison root mean square of the distances between pair of
atoms (RMSD) and maximum difference (max.D) have been calculated by Mercury program.49
The closest geometrical similarity is between
3
and CAFXEN (RMSD = 0.042 and max.D =
0.089), but high similarities are between
1
/3 (RMSD = 0.124 and max.D = 0.220) and
2/DOSVAI (RMSD=0.172 and max.D=0.267), too. Despite of the conformational and cell
similarities (cell similarity index51,52 = 0.00566), the relatively low isostructurality index51,52
(68.4%) suggests that the position of the complexes is slightly shifted in
CAFXEN. The cell similarity and isostructurality indices are somewhat higher for structures
(0.0072 and 82.1 %, respectively). The calculation of these indices can be found in the
legend of Fig. S3.
For comparison, some selected bond lengths and angles together with angles between
3 as compared to
1/3
different ring planes are collected in Table 2. The asymmetric pyridine arms resulted in three
significantly different ZnꢀNpyr bond distances and NpyrꢀZnꢀNpyr angles for [Zn(tachpyr)] in
13

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crystal 1. Similarly, different angles can be measured between the ring planes (Table 2) in this
complex. Twist angle (α) (Fig. 2) defined for the comparison of [M(tachpyr)] coordination
sphere15,18 also shows significant difference in the conformation of the three arms. Though in
crystal
distance is significantly longer and the twist angle is smaller for
and Fig. 1). The position of the counter ions around the metal complexes are accounted for the
conformational differences. In crystal the perchlorate anions positioned exactly on the C3
axis, above the pyridine rings of tachpyr, however in DOSVAI they localized aside of the
pyridine rings (Fig. S4 and S5). In crystal and CAFXEN the perchlorate anions are in
2
and DOSVAI the [Zn(tachpyr)] complex has the same C3 symmetry, the ZnꢀNpyr bond
2
than for DOSVAI (Table 2
2
1, 3
different hydrogen bond connection with the three pyridine arms (Fig. S5). Bond distances and
angles of the determining hydrogen bonds are collected in Table S1.
All compounds were racemates. Structures 1, 2, 3 and CAFXEN has centrosymmetric
space group and the relative configuration of N1, N2 and N3 are S,S,S. Structure DOSVAI is in
chiral space group and in the deposited structure the secondary amines have the chirality R,R,R.
For comparison, the structure of
4 (see later) was solved and refined well in nonꢀ
centrosymmetric space group as inversion twin, and the relative configuration of the secondary
nitrogen atoms were found to be S,S,R.
Table 2. Selected structural parameters of [M(tachpyr)] complexes in crystals
reference compounds DOSVAI18 and CAFXEN.19
1, 2, 3 and
[Zn(tachpyr)]
[Cu(tachpyr)]
(1)
2.164(3)
2.174(4)
2.158(4)
2.160(4)
2.137(3)
2.219(4)
78.7(1)
79.2(1)
78.5(1)
87.1(1)
90.1(1)
91.0(1)
97.1(1)
102.9(1)
89.9(1)
69.6(2)
58.5(2)
53.6(2)
13.8(2)
1.0(2)
(2)
DOSVAI[18]
2.160(3)
(3)
2.022(5)
2.223(5)
2.105(5)
2.061(5)
2.031(5)
2.438(5)
81.8(2)
76.9(2)
80.3(2)
89.2(2)
91.7(2)
92.5(2)
97.4(2)
99.9(2)
86.6(2)
72.7(3)
55.2(3)
51.2(3)
13.9(3)
1.1(3)
CAFXEN[19]
2.033(5)
2.245(5)
2.099(5)
2.053(5)
2.032(5)
MꢀNtach (Å)
MꢀNpyr (Å)
2.157(3)
2.228(3)
77.3(1)
2.165(4)
79.01(14)
90.21(14)
93.97(14)
63.44(14)
9.85(14)
2.458(5)
81.9(2)
77.4(2)
79.8(2)
89.1(2)
90.6(2)
93.0(2)
97.2(2)
100.5(2)
86.5(2)
73.1(2)
55.9(2)
50.7(2)
13.3(2)
2.5(2)
NtachꢀMꢀNpyr (°)
NtachꢀMꢀNtach (°)
NpyrꢀMꢀNpyr (°)
88.9(1)
92.95(9)
68.78(15)
10.83(18)
Cg(A)ꢀCg(B),
Cg(A)ꢀCg(C),
Cg(A)ꢀCg(D) (°)a
Cg(B)ꢀCg(E),
Cg(C)ꢀCg(F),
Cg(D)ꢀCg(G) (°)a
14.0(2)
20.1(3)
21.3(2)
14

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49.1(2)
43.6(2)
44.9(2)
49.3(3)
44.9(3)
47.3(3)
49.8(2)
44.1(2)
47.5(2)
36.8(2)
43.7(2)
twist angle α (°)
a Angles between planes calculated for the rings AꢀG drawn in Figure 1.
Crystal structure of [Cu11(tren3pyr)6Cl11](Cl)11×6H2O×6EtOH (4)
In the solid state tren3pyr forms a 3D metalꢀorganic framework (MOF) with copper(II). This is
the first published crystal structure with the novel tren3pyr ligand. The cubic structure is based
on distinct copper(II) containing secondary building units (SBU) in the nodes and (3ꢀ
pyridylmethyl)amino groups at the edges forming a high symmetry MOF. The formation of
this MOF is explained by the strong metal binding ability of all nitrogens of tren3pyr, and by
the position of pyridine nitrogens which are not able to form chelate rings with the
secondary/tertiary amines. In this way, all tren3pyr molecules are bound to four different
copper(II) ions (Figure 3.a). This structural feature results in the formation of an infinite
(Cu11L6)n polymer, in which each copper(II) has a coordinated chloride, and the counter ions
are also chlorides. Two of these polymers create an interpenetrated network in the crystal
structure. Beside the rigid framework, more than 20% of the unit cell volume consists of
separated voids (Figure S6). In these cavities the remaining electron density could be well
modelled by chloride ions, solvent ethanol and water molecules hence the void volume of the
unit cell is 1.7%, 326 Å3 in the refined complete structure.
Within this metalꢀorganic framework three distinctly different copper centres or SBUs can be
identified. The first one has slightly distorted trigonal bypiramidal geometry (τ = 0.885), and
this type of copper is bound to all trenꢀlike moieties (Figure 3.a). The second has nearly perfect
square pyramidal geometry (τ = 0.053) with four pyridine nitrogens in its basal plain (Figure
3.b). The distance of the metal ion from the mean plane of the four nitrogens is 0.3
Å. All
pyridine rings originated from different ligand molecules, i.e. this copper(II) centre connects
four type 1 SBUs, and is therefore responsible for the formation of the hexanuclear subunits
with a large inside cavity (Figures 4 and S6). The third type of copper centre has distorted
tetrahedral geometry (Figure 3.c) constituted by three pyridine nitrogens and a chloride ion.
Distances of the metal ion and the centroid of the tetragon to the N3 plane are 0.4 and 0.7 Å,
respectively. The three coordinated pyridine rings belong to three different hexanuclear
subunits, consequently these copper centres create the 3D MOF. Two of these 3D polymers are
interlaced and form an interpenetrated network with special topology in the crystal structure
(Figure 6S).
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Altogether the unit cell (Figure S6) contains 24 tren3pyr ligands with 168 nitrogen
donors, all of them are coordinated, and 44 copper(II) ions (24, 12 and 8 of type 1, 2 and 3,
respectively). Selected data for the coordination are shown in Table 3, some of the values are
equal because of the lattice symmetry. The shortest Cu··Cu distances are 6.796 Å. Several
mononuclear structures related to type 1 and 2 copper(II) centres can be found in the
literature,53,54 but only copper(I) complexes55 are reported to have similar coordination sphere
to type 3 SBU. The structures of individual SBUs are close to their mononuclear
counterparts,53ꢀ55 i.e. despite the extensive coordination connectivity within this MOF (Figure
4) the whole structure is surprisingly unstrained.
Table 3. Coordination modes and relevant bond lengths and bond angles for structure 4.
type 1 (tbp)
2.021(4)
type 2 (sp)
‒
type 3 (Td)
‒
CuꢀNtertiary (Å)
2.132(6), 2.125(8)
2.131(8)
CuꢀNsecondary (Å)
‒
‒
2.051(8), 2.037(8)
2.051(8), 2.037(8)
2.479(2)
CuꢀNpyridine (Å)
CuꢀCl (Å)
2.109(13)
2.443(11)
‒
2.2159(15)
85.0(2), 83.7(3)
84.8(3), 109.6(5)
122.1(5), 125.5(3)
178.6(2), 94.9(2),
95.0(2), 96.3(2)
88.0(2), 89.6(2)
161.5(4), 164.7(6)
NꢀCuꢀN (°)
ClꢀCuꢀN (°)
116.1(2)
101.6(3)
97.6(2), 99.3(2)
a
b
c
Figure 3. Structure of the three types of Cu(II) centres in
4 and their immediate environments
(type 1 (a), type 2 (b) and type 3 (c)). Displacement parameters are drawn at 30% probability,
and hydrogen atoms are omitted for clarity.
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a
b
Figure 4. Top (a) and side view (b) of the Cu6(tren3pyr)4 subunit in
4 with a large inside
cavity. For clarity, the third 3ꢀpyridylmethyl leg is shown only for one of the ligand molecules,
together with a type 3 copper which connects the hexanuclear subunits. Displacement
parameters are drawn at 30% probability, hydrogen atoms, solvent water and ethanol
molecules as well as chloride counter ions are also omitted for clarity.
The solid state structure is further stabilized by weak CꢀH··Cl and strong NꢀH··Cl or Oꢀ
H··Cl hydrogen bonds involving solvent molecules and chloride counter ions, too. The large
cavity in the structure resulted uncertainty in the coordinates of the solvent water molecules
and one of the chloride ions leading to errors in the CIF but the overall structure is considered
to be correct. Data collection was performed both at room temperature and 100 K, but no
improvement in the refinement could be reached using the low temperature dataset, because of
considerable disorder of the solvent molecules in the voids.
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Solution chemical studies
Protonation of the ligands
Since unusual sequence of protonation has been reported for the amine and pyridine nitrogens
1
of trenpyr,20 we supplemented our pHꢀpotentiometric data by pHꢀdependent H NMR studies.
As the pHꢀdependence of the proton NMR signals of tachpyr, tach3pyr and tren3pyr clearly
indicate (Figures S1 and S2 in ESI), the secondary amino groups (pKNH ≥ 5) are in all cases
more basic than the pyridine nitrogens. In fact, only one pyridine pK can be determined by pHꢀ
potentiometry for tachpyr and trenpyr (Table 4), the others are deprotonated already at the
beginning of potentiometric titrations (pH ~ 1.8). Consequently, the average pKs of pyridine
nitrogens are considerably higher for tach3pyr and tren3pyr, than for the 2ꢀpyridylmethylꢀ
derivatives (ꢀpK > 1.5), which is probably related to the strong intramolecular Hꢀbonds formed
1
within tachpyr and trenpyr. As reflected by our H NMR study (Figure S2), the tertiary
nitrogen of tren3pyr is not protonated between pH 2ꢀ11, due to the strong electronꢀwithdrawing
effect of the three protonated legs.
Table 4. Protonation constants of the studied ligands and some related compounds (T = 298
K, I=0.1M (NaCl), with estimated errors in parentheses (last digit)).
tach3pyr
trenpyr
[in 1M KNO3]c
a
tachpyr
tachb
tren3pyr
trend
log βpqr
[in 60 w/w %
dmsoꢀH2O]
8.36(1)
[8.05(1)]
15.01(1)
[14.47(2)]
20.20(3)
[19.44(4)]
23.84(5)
[22.15(10)]
8.92(1)
[9.12]
16.70(1)
[8.14]
23.04(1)
[6.91]
25.21(3)
[2.50]
‒
8.63(1)
16.20(1)
22.60(2)
26.34(3)
29.55(4)
32.24(5)
8,48(1)
15.27(1)
20.54(1)
22.40(6)
10.21
18.88
25.93
10.12
19.53
27.95
log β011
log β021
log β031
log β041
log β051
log β061
26.89(5)
[23.95(20)]
29.40(7)
[1.1]
[25.85(25)]
a p, q and r are the stoichiometric numbers of metal ion, proton and ligand, respectively, in the
given species; b in 0.1 M NaClO4 [29]; c [21]; d in 0.1 M NaClO4 [56]
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Metal complexes of the 2-pyridylmethyl-derivatives (tachpyr and trenpyr)
The formation constants of of Mn(II), Cu(II) and Zn(II) complexes are listed in Table 5.
According to the presence of 6/7 nitrogen donors in tachpyr/trenpyr, the stability of their metal
complexes are very high. In the copper(II) containing systems the concentration of free
(uncomplexed) metal ion is low even at the beginning of titrations (pH ~ 1.7), therefore the
acquisition of independent spectrophotometric data were necessary to determine the correct
formation constants. The equilibrium study was further complicated by the slow kinetics in the
copper(II)ꢀ and zinc(II)ꢀtachpyr systems, which was found to be strongly pH dependent. In the
zinc(II)ꢀtachpyr system the equilibrium was attained within 10ꢀ20 minutes at any pH, but the
formation and especially the dissociation of copper(II) complexes (see e.g. Figure 7) needed
considerably more time above pH ~ 1.5.
Table 5. Formation constants of copper(II), zinc(II) and manganese(II) complexes of the
studied ligands and some related compounds (T = 298 K, I=0.1M (NaCl), with estimated
errors in parentheses (last digit)).
tachpyr
tach3pyr
tach
pqr
Cu(II)
Zn(II)
Cu(II)
Zn(II)
Mn(II)
Mn(II) Cu(II)b Zn(II)c
[in 60 w/w % [in 60 w/w %
dmsoꢀH2O] dmsoꢀH2O]
11.75(1)
[12.01(9)]
5.26(1)
[7.49(4)]
[ꢀ0.43(6)]
[ꢀ10.11(7)]
10.30(6)
[10.54(2)]
3.15(5)
111 21.8(2)a 18.02(5) 11.97(6)
101 20.0(2)a 15.18(3) 6.47(5)
10.26(7) 15.95
2.34(5) 10.86
2.36
6.95
[3.87(1)]
1ꢀ11
1ꢀ20
2ꢀ22
8.48
trenpyr
tren3pyr
tren
pqr
Cu(II)
Zn(II)
[in 1M
Mn(II)
Cu(II)
Zn(II)
Mn(II) Cu(II)g Zn(II)
[in 1M
KNO3]d KNO3]f
131
121
27.35(3)
23.56(3)
23.10(6)
[23.92]
111 26.75(15)e 20.81(3)
[27.7]
101 21.2(1)e
[21.4]
15.56(3)
10.48(2)
19.39(3)
14.07(3)
[21.38]
15.52(3)
[15.62]
18.50 14.50g
9.33
4.10h
14.63(3)
6.22(3)
8.96(1)
1ꢀ11
ꢀ0.38(2)
a determined from spectrophotometric data; b in 0.1 M NaClO4 [29]; c in 0.1 M NaClO4 [57];
d [20]; e determined from both spectrophotometric (log
β111 = 26.7±0.1, log β101 = 21.2±0.1) as
f
well as ligand displacement and pHꢀmetric study (log β111 = 26.8±0.1, log β101 = 21.2±0.1);
[21]; in 0.1 M NaClO4 [56]; h in 1 M NaClO4 [58]
g
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The formation constants of the Cu(Htachpyr) and Cu(tachpyr) complexes (Table 5)
were determined by pHꢀdependent spectrophotometric titration (Figure 5), allowing 6 days for
equilibration. The estimated errors of the formation constants was increased ± 0.2 due to the
uncertainties induced by I > 0.1 M at the acidic end of the titration. The speciation of the
Cu(Htachpyr) complex shows a maximum around pH 1.7, while Cu(tachpyr) is the solely
species in the solution above pH 4 (Figure 6). The pHꢀdependent Vis/NIR and EPR spectra of
the copper(II)ꢀtachpyr system are depicted in Figures 6 and 7. In Cu(Htachpyz) one of the
secondary amino group is still protonated, i.e. the metal ion is either 4N or 5N coordinated.
The Vis/NIR spectrum detected around pH 1.7 (Figure 5) shows a transition at 620 nm with a
relatively strong lowꢀenergy shoulder at 840 nm, indicating square pyramidal geometry with
0.3
0.3
0.2
0.1
0.2
0
0
2
4
6
pH
0.1
0
400
600
800
Wavelength (nm)
1000
Figure 5. Effect of pH on the Vis/NIR spectra of the copper(II)ꢀtachpyr systems (T = 298 K, I =
0.1 M NaCl, [Cu2+] = [tachpyr] = 0.00226 M, the blue spectrum corresponds to CuL, the red and
green ones mostly to CuHL and Cu2+(aq)). The insert show the changes of absorbance at 620 nm.
100
MnL
CuL
ZnL
80
60
40
20
0
CuHL
ZnHL
MnHL
0
2
4
6
8
10
pH
Figure 6. Speciation diagram of the M(II)ꢀtachpyr complexes (T = 298 K, I = 0.1 M NaCl,
[M2+] = [tachpyr] = 0.002 M, the curves of the uncomplexed metal ions have been deleted for
clarity).
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Table 6. Calculated EPR parameters for the different copper(II) complexes studied, with
estimated errors in parentheses (last digit).
complex
g// or gz
A// or Az (G)
go
Ao (G)
g⊥ or gx, gy
A⊥ or Ax,Ay (G)
Cu(II)-tachpyr
2.0439(3)
2.0662(2)
2.0745(1)
25.0(4)
52.8(3)
35.2(2)
CuHL
CuL
2.1065(4) 66.1(5)
2.1141(8) 58(1)
2.2082(1)
2.2455(2)
167.2(1)
146.4(2)
Cu(II)-tach3pyr
2.0442(5)
37.7(9)
38.7(6)
35.7(1)
20.8(1)
CuL
2.1144(4) 51.5(3)
2.2555(3)
147.2(3)
2.0824(8)
2.0593(1)
2.0527(1)
CuL(OH) 2.1207(2) 58.2(2)
CuL(OH)2 2.1222(4) 60.2(4)
2.2546(1)
2.2532(1)
148.8(1)
157.7(1)
Cu(II)-tren3pyr
CuH4L
CuH3L
CuH2L
CuHL
CuL
ꢀ
ꢀ
2.060(2)
2.182(2)
2.144(2)
2.188(2)
2.145(2)
2.187(2)
2.424(1)
15(2)
101(2)
71(2)
103(2)
77(2)
90(2)
130(1)
80(2)
2.1272(5) 59.1(3)
2.029(1)
2.1272(5) 59.1(3)
2.020(1)
1.998(1)
72(1)
78(1)
CuL(OH) 2.1329(4) 40.3(3)
isotrop
ꢀ
ꢀ
2.113(2)
20(2)
componenta
a see text
strong apical coordination, similarly to the copper(II) complexes of several related tach
derivatives.12,17,59
The EPR spectrum recorded in acidic solution (Figure 7, Table 6) is also consistent with
a distorted square pyramidal structure. The basicity corrected formation constants of the
Cu(Htachpyr) and Cu(Htach) complexes allow an approximate comparison of their stability
(log β∗ = logβ111 – (logβ01(4/3) ꢀ logβ011) = 8.08 and 0.23 for tachpyr and tach, respectively,
Table 5). Considering the nearly eight orders of magnitude differences, the Cu(Htachpyz)
complex is very likely 5N coordinated.
The formation of Cu(tachpyr) results in a red shift of dꢀd bands (620 nm → 650 nm,
840 nm → 940 nm), indicating even stronger coordination along the zꢀaxis.60 This is also
confirmed by the nearly 13 orders of magnitude difference in the basicity corrected formation
constants of Cu(tachpyr) and Cu(tach) (log β∗ = logβ101 – logβ01(4/3) = ꢀ2.3 and ꢀ15.07 for
tachpyr and tach, respectively, Table 5). The complex Cu(tachpyr) has higher g and smaller A
values as compared to its protonated form (Table 6), which also suggests stronger axial
binding, i.e. 6N coordination in a distorted octahedral environment, as was observed in the
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crystal structure of complex 3. The broad room temperature spectra of this complex (Figure
7.A) is probably due to the dynamic JahnꢀTeller effect, which is known to operate in 6Nꢀ
coordinated copper(II) complexes.61
A
B
Cu(tachpyr)
Cu(tachpyr)
Cu(Htachpyr)
Cu(Htachpyr)
2+
2+
Cu (aq)
Cu (aq)
pH = 6.05
pH ~ 1.6
pH = 6.05
pH ~ 1.60
3000
3200
3400
3600
2400 2600 2800 3000 3200 3400 3600
Magnetic field (G)
Magnetic field (G)
Figure 7. Experimental (black) and simulated (red) EPR spectra of the copper(II)ꢀtachpyr
system at room temperature (A) and at 77 K (B) ([Cu2+] = [tachpyr] = 0.003 M). The
calculated component spectra of the main species are also shown on the top. At pH = 6.05 the
solution was not fully equilibrated and contained ~ 20 % Cu(Htachpyr) complex, too.
In the zinc(II)ꢀtachpyr system two complexes can be identified, too (Figure 6). The
species Zn(Htachpyr) is only a minor complex around pH 3, and Zn(tachpyr) is a dominant one
above pH 5, which indicates high thermodynamic stability. Indeed, its basicity corrected
stability constant is 12 orders of magnitude higher than that of the corresponding Zn(tach)
complex (Table 4 and 5). The ligand exchange process of Zn(tachpyr) is slow on the NMR
timeꢀscale (Figure 8). The important differences in the spin coupling pattern between the free
and bound ligand (considerably decreased coupling constants between the CH and CH2 protons
of the cyclohexane ring, which results in a broad singlet and two doublets, respectively),
clearly show the switch between the two chair conformations (triequatorial NH → triaxial
NH).62 Although the triaxial conformer is energetically unfavoured in the free ligand, it is the
preferred one in metal complexes of all tach derivatives.15ꢀ19,63 In accordance with earlier
reports,15 the single set of signals observed for this slow exchanging species indicate C3
symmetry, the chemical inequivalence of benzylic protons (~ 4.16 ppm) shows conformational
rigidity even within the 2ꢀpyridylmethyl arms. All these facts, together with the significant
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ꢁ
ꢀ
ꢂ
ꢃ
■
□
ꢂ
ꢁ
ꢀ
ꢃ
1
Figure 8. The pHꢀdependence of HꢀNMR spectra of tachpyr in the presence of zinc(II)
([Zn2+] = 0.002 M, [tachpyr] = 0.003 M; squares: aromatic protons next to Npyr, circles:
benzylic protons, rhombus: CH of cyclohexane ring, triangles: inequivalent CH2 of
cyclohexane ring of the free (open) and bound (filled) ligand).
chemical shift difference of protons close to the nitrogen atoms in the bound and unbound
ligand (Figure 9) suggest tight 6Nꢀcoordination around zinc(II), as seen in the crystal structures
of
1 and 2.
Earlier RPꢀHPLC study on the aqueous Mn(II)ꢀtachpyr system indicated nearly complete
dissociation at pH 5.5.15 In agreement with this finding, our potentiometric data indicated the
formation of Mn(Htachpyr) and Mn(tachpyr) started at pH 4.6 (at metal ion and ligand
concentrations of 2 mM), and the latter species are the solely complex only above pH 8 (Figure
6). Consequently, the Mn(tachpyr) complex is considerably less stable than the corresponding
copper(II) or zinc(II) species (ꢀlog β101 = 13.21 and 8.66, respectively). This is in accordance
with the IrwingꢀWilliams series, although the complete transformation of Mn(II)(aq) into
Mn(tachpyr) at pH 8 in equimolar solution confirms the high metal ion sequestering ability of
tachpyr.
The formation constants of copper(II)ꢀ and zinc(II)ꢀtrenpyr complexes have been
already published for 1 M KNO3 background electrolyte.20,21 In order the have comparable data
with other formation constants reported in this work, we repeated the solution equilibrium
study of these systems in 0.1 M NaCl solutions, and complemented by pHꢀdependent Vis/NIR
and 1H NMR studies. The formation constants of the Cu(Htrenpyr) and Cu(trenpyr) complexes
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(Table 5) were determined by pHꢀdependent spectrophotometric titration (Figure 9). Since
slow kinetics, comparable with the Cu(II)ꢀtachpyr system, was not observed, the stability of
Cu(trenpyr) complex was also determined by ligand displacement method at pH 10 using
diethylenetriamine pentaacetic acid (dtpa) (Figure S7). The formations constants determined by
the two methods agree with each other within ± 0.1 log units (Table 5).
0.6
0.5
0.8
0.4
0.3
0.6
0.2
0
3
6
9
pH
0.4
0.2
0
400
600
800
Wavelength (nm)
1000
Figure 9. Effect of pH on the Vis/NIR spectra of the copper(II)ꢀtrenpyr systems (T = 298 K, I =
0.1 M NaCl, [Cu2+] = [tachpyr] = 0.00184, the blue and red spectra correspond to CuL and
CuHL, respectively) The insert show the changes of absorbance at 640 nm.
In our background electrolyte, too, Cu(Htrenpyr) and Cu(trenpyr) are the unique species
between pH 2ꢀ4 and 7ꢀ11, respectively (Figure 10). Taking into account the ionic strength
difference, our formation constants (Table 5) agree well with those reported earlier.21 The
Vis/NIR spectrum of Cu(Htrenpyr) is close to that of Cu(Htachpyr), including the low energy
transitions around 850 nm, indicating square pyramidal geometry in both species. On the other
hand, the spectrum of Cu(trenpyr) (λdꢀd
= 650 and 720 nm with nearly equal intensities,
max
Figure 9) is completely different from that of the 6N coordinated Cu(tachpyr), and indicates an
intermediate geometry between square pyramidal and trigonal bipyramidal.64,65
In the presence of zinc(II), the formation of Zn(H2trenpyr), Zn(Htrenpyr) and
Zn(trenpyr) was detected, similarly to the earlier report [20]. Zn(Htrenpyr) is a dominant
species at pH 4, its deprotonation is complete at pH 7. The 1H NMR data revealed slow ligand
exchange on the NMR timeꢀscale for both Zn(Htrenpyr) and Zn(trenpyr) complexes (Figure
11). The proton signals, especially the methylene protons of Zn(Htrenpyr) are considerably
broadened. Since the signals of the free ligand are sharp in the Zn(II)ꢀtrenpyr system at any pH,
the observed broadening for Zn(Htrenpyr) is due to the conformational changes, likely
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CuHL
ZnHL
100
80
60
40
20
0
MnL
CuL
ZnL
ZnH2L
MnHL
0
2
4
6
8
pH
Figure 10. Speciation diagram of the M(II)ꢀtrenpyr complexes (T = 298 K, I = 0.1 M NaCl,
[M2+] = [trenpyr] = 0.002 M, the curves of the uncomplexed metal ions have been deleted for
clarity).
Zn(II)-trenpyr, pH = 7.61
trenpyr, pH = 7.60
Zn(II)-trenpyr, pH = 4.01
trenpyr, pH = 4.03
Zn(II)-trenpyr, pH = 2.53
trenpyr, pH = 2.54
Figure 11. The pHꢀdependence of 1HꢀNMR spectra of trenpyr in absence and presence of
zinc(II) ([Zn2+] = 0.002 mM, [tachpyr] = 0.0024 M, 298 K)
induced by intramolecular protonꢀtransfer processes, i.e. the proton ‘hops’ between the
secondary nitrogens.
The signals belonging to Zn(trenpyr) complex are rather sharp (Figure 11). Since in the
crystal structure of [Zn(trenpyr)](ClO4)2 one of the pyridine rings is not coordinated, and
therefore the ligand is asymmetrically bound,20 it is surprising that only one set of signals is
present for the three ‘legs’ on the NMR spectrum of the slow exchanging Zn(trenpyr). This
indicates C3 symmetry of the complex, and either sevenꢀcoordinated {Ntert,3NH,3Npyr} or sixꢀ
coordinated {3NH,3Npyr} type binding mode of trenpyr. In the case of zinc(II) the latter is
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more likely, and this binding mode is present in the Zn(II) complex of the closely related
Schiffꢀbase derivative of trenpyr.66 Furthermore, the aromatic protons beside the pyridine N
(C6H), despite the expectations, are considerably more upfield shifted (7.48 ppm) in
Zn(Htrenpyr) than in Zn(trenpyr) (8.07 ppm), which indicates notable changes in the
coordination environment of zinc(II) during the deprotonation. All these facts may support the
{3NH,3Npyr} type coordination in Zn(trenpyr).
In presence of manganese(II) only two species were detected (Figure 9). The complex
Mn(Htrenpyr) is a minor complex around pH 5, its deprotonation results in Mn(trenpyr), which
is the solely species above pH 7 (at metal ion and ligand concentrations of 2 mM).
The significant differences between the deprotonation of CuHL/ZnHL complexes of
tachpyr and trenpyr are noteworthy (compare Figures 6 and 10), which is, however, does not
apply for the MnHL species. This is due to the different denticity of tachpyr and trenpyr, as
well as the different coordination geometry of their metal complexes. In the cases of tachpyr
complexes, the deprotonation of the 5N coordinated MHL complexes results in the increase of
coordinated nitrogen donors, i.e. the metal promoted deprotonation is favoured. In contrast, in
the copper(II)ꢀ and zinc(II)ꢀtrenpyr complexes, the coordination number is unchanged during
the MHL → ML deprotonation, therefore it is less favoured since the incoming secondary NH
should displace an already bound nitrogen from the coordination sphere. On the other hand,
our equilibrium data indicate that the process M(Htrenpyr) = M(trenpyr) + H+ is more favoured
for Mn(II) than for Zn(II) or Cu(II) (pK = 5.08, 5.23 and 5.56, respectively), despite the
striking differences in the stability of the corresponding M(trenpyr) complexes (Table 5). Since
manganese(II) is the weakest Lewisꢀacid among these metal ions, the above order of pKs is
unusual, and suggests that the coordination of secondary NHꢀgroup induces some additional
stabilization in the case of Mn(II). In this respect, it is worth noting that in the crystal structure
of [Mn(trenpyr)](PF6)2 the metal ion is seven coordinated.14 The above mentioned additional
stabilization is most likely provided by the chelate coordination of the third NHꢀgroup and
pyridine nitrogen on the same ‘leg’, i.e. the complex Mn(trenpyr) is probably sevenꢀ
coordinated ({Ntert,3NH,3Npyr}) in solution, too.
The basicity corrected formation constants allow an approximate comparison of
M(tachpyr)/M(tach) or M(trenpyr)/M(tren) complexes, but it would provide erroneous results
in the case of M(tachpyr)/M(trenpyr) pairs. It is more appropriate to calculate the conditional
stability constants at a given pH (Kcond(pH) = (Σ[MHxL]/([M2+]free×(Σ[HxL]free)) in order to
compare their metal ion binding abilities. In the case of tachpyr log Kcond(pH 7.4) = 18.9, 14.0
and 5.3 for copper(II), zinc(II) and manganese(II), respectively. The analogous values for
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trenpyr are log Kcond(pH 7.4) = 19.1, 13.4 and 8.4, respectively. These data indicate that
tachpyr is more efficient zinc(II), nearly similar copper(II), and less efficient manganese(II)
chelator than trenpyr. Considering the energy demanding switch between the (triequatorial NH
→ triaxial NH) conformations of tachpyr and the conformational flexibility of trenpyr, these
data are somewhat surprising, and is very likely due to the encapsulating effect of the more
rigid tachpyr skeleton. On the other hand, the observed relative binding preference of tachpyr
for zinc(II) is probably related to the observation that zinc(II) is one of the principal metals
targeted by tachpyr in cells.27
Metal complexes of the 3-pyridylmethyl-derivatives (tach3pyr and tren3pyr)
The formation constants determined for the manganese(II), copper(II) and zinc(II)
complexes are listed in Table 4. In aqueous solution precipitate formation was observed for the
M(II)ꢀtach3pyr systems at pH 6.5 (Cu(II)), 7.5 (Zn(II)) and 8.5 (Mn(II)). Up to these pH values
only the M(Htach3pyr) and M(tach3pyr) complexes were detected, but none of them were
dominant species before the precipitation occurred.
Since one of our aims was to use tach3pyr as catalyst for phosphodiester hydrolysis, we
applied dmsoꢀwater mixture in order to increase the solubility of complexes. In 60% (w/w)
dmsoꢀwater mixed solvent the copper(II)ꢀtach3pyr systems were clear up to pH 10. Although,
in presence of zinc(II) precipitate was observed, too, further investigations were performed in
this medium. The formation constants of the copper(II) complexes in 60% (w/w) dmsoꢀwater
are also listed in Table 5, their speciation diagrams are depicted in Figure 12.
100
80
60
40
20
0
CuL
Cu(II)
8
6
4
2
0
CuL(OH)2
CuL(OH)
N
N
H
O
OH
2
2
M
N
NH
HN
NH
CuHL
3
5
7
9
pH
Figure 12. Speciation diagram of the copper(II)ꢀtach3pyr complexes ([Cu2+] = [tach3pyr] =
0.001 M, T = 298 K, I = 0.1 M NaCl in 60% (w/w) dmsoꢀwater) and the pH ꢀ kobs profile (■)
of the bnpp hydrolysis ([bnpp]ini = 0.002 M).
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In this medium the Cu(tach3pyr) complex has considerably higher stability than in pure
water, especially considering the somewhat lower basicity of the ligand. The Vis/NIR and EPR
parameters of the Cu(tach3pyr) complex (dꢀd transitions at 692 and ~ 1050 nm (Figure S8,
Table 6 and Figure S9), are very similar to those of some Nꢀalkylated tach derivatives,59 and
indicate square pyramidal geometry, which is enforced by the facial coordination of the ligand.
As expected, the presence of 3ꢀpyridylmethyl legs prevent the formation of the dihydroxoꢀ
bridged dicopper complex formed with tach,29 and above pH 7 two mononuclear mixed
hydroxoꢀcomplexes (Cu(tach3pyr)(OH) and Cu(tach3pyr)(OH)2) are formed (Figure 12). The
deprotonations of the coordinated water molecules (pK = 7.94 and 9.77) resulted in slight blueꢀ
shift of the Vis/NIR (Cu(tach3pyr)(OH): 650 and ~ 900 nm; Cu(tach3pyr)(OH)2: 640 and ~
900 nm) and EPR spectra (Table 6 and Figure S9), suggesting that the square pyramidal
geometry is retained in these species, too.
The relatively open coordination sphere of Cu(tach3pyr)(OH) species is favourable from
the point of view of hydrolytic catalysis. Indeed, we observed notable hydrolytic activity for
the monoꢀhydroxo species against bis(pꢀnitrophenyl) phosphate (bnpp), an activated
phosphodiester (Figure 12). The water molecule in the fifth position of copper(II) can be easily
replaced by the substrate, and the copperꢀbound hydroxide ion may act as an intramolecular
nucleophile (Figure S10). The initial rate of the hydrolysis as a function of bnpp concentration
(Figure S11) shows saturation kinetics. The treatment of these data, using the Michaelisꢀ
Menten model, yielded the following parameters: kcat = (3.0±0.4)×10‒5 s–1 and KM = (4.2±0.8)
mM (Figure S11). It is rather difficult to compare these values with those of the related
copper(II) complex of N,N’,N’’ꢀtrimethylꢀcis,cisꢀ1,3,5ꢀtriaminocyclohexane,33 due to the
different temperature and solvent used, as well as the unlike mechanism. Although it seems
that the Cu(tach3pyr)(OH) species is somewhat more active, the above KM value does not
indicate notable increase of substrate binding due to the expected πꢀπ interaction between
pyridyl and nitrophenyl rings. Therefore, further kinetic studies were not performed.
Tren3pyr forms more stable complexes with copper(II) and zinc(II) than tach3pyr
(Table 5), due to the four available nitrogens for metal ion binding of the tripodal platform. In
the solution of copper(II) and tren3pyr only mononuclear complexes (Cu(Hxtren3pyr), x = 3, 2,
1, 0, ꢀ1) have been observed (Figure 13). At twofold metal ion excess over tren3pyr precipitate
detected at pH 4ꢀ5, which prevented the equilibrium study. The precipitate was than
recrystallized from ethanol to obtain complex 4. In equimolar solutions precipitation and the
formation of polymeric species was not observed at 298 K, only mononuclear complexes were
detected (see the MS spectrum in Figure S12).
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100
80
60
40
20
0
CuL
N
Cu(II)
CuL(OH)
CuH2L
CuH3L
N
N
CuHL
H O
2
N
Cu
N
2
ꢀ
N
N
2
4
6
8
10
pH
Figure 13. Speciation diagram of the copper(II)ꢀtren3pyr complexes ([Cu2+] = [tren3pyr] =
0.002 M, T = 298 K, I = 0.1 M NaCl).
According to the relatively high stability of tren3pyr complexes, their formation start at
pH 2 and after three overlapped deprotonations the Cu(tren3pyr) species formed, a dominant
complex around pH 7 (Figure 13). During these processes the Vis/NIR spectra show gradually
increasing dꢀd bands at 870 nm with a shoulder at 700 nm (Figure 14). The calculated
individual spectra of these complexes (Figure S13) indicate invariable band positions.
The room temperature EPR spectra are also identical between pH 2ꢀ7 (Table 6, Figure
S14). Although, the parameters of EPR spectra measured at 77 K (Figure 15) show some subtle
variations with pH (Table 6), they are essentially similar. Both the typical dꢀd bands and the
‘reversed’ order of gꢀvalues (gz < gx ~ gy (Table 6), i.e. the complexes have a ground state with
1.2
1
0.8
0.6
0.4
0.2
0
500
600
700
800
900
1000
Wavelength (nm)
Figure 14. Effect of pH on the Vis/NIR spectra of the copper(II)ꢀtren3pyr systems (T = 298 K,
I = 0.1 M NaCl, [Cu2+] = [tren3pyr] = 0.003 M).
29