Syntheses and characterization of Cu2+, Ni2+ and Zn2+ binding capability of histidinehydroxamic acid derivatives

Article abstract of DOI:10.1016/j.poly.2010.08.023

Two histidinehydroxamic acid derivatives (N-methyl-histidinehydroxamic acid, N-Me-Hisha and Z-histidinehydroxamic acid, Z-Hisha) have been synthesized and their complexation with Cu²⁺-, Ni²⁺- and Zn ²⁺-ions has been studie

Full text of DOI:10.1016/j.poly.2010.08.023

Polyhedron 29 (2010) 3137–3145
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Syntheses and characterization of Cu2+, Ni2+ and Zn2+ binding capability
of histidinehydroxamic acid derivatives
Edit Csapó a, Péter Buglyó a, Nóra Veronika Nagy b, M. Amélia Santos c, Alma Corona d, Etelka Farkas a,
⇑
a Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
b Institute of Structural Chemistry, Chemical Research Center of the Hungarian Academy of Sciences, H-1525 P.O. Box 17, Budapest, Hungary
c Centro de Química Estrutural, Instituto Superior Técnico, 1049-001 Lisboa, Portugal
d Universidad de Guanajuato, Facultad de Quimica, Guanajuato, GTO. 36050, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Two histidinehydroxamic acid derivatives (N-methyl-histidinehydroxamic acid, N-Me-Hisha and Z-his-
tidinehydroxamic acid, Z-Hisha) have been synthesized and their complexation with Cu2+-, Ni2+- and
Zn2+-ions has been studied by using pH-potentiometric, UV–Vis, CD, 1H NMR, EPR and ESI-MS methods.
Both of the two new derivatives contain one donor atom less compared to the histidinehydroxamic acid
(Hisha). In the case of N-Me-Hisha the hydroxamate-N as donor is eliminated, while the coordination of
the amino-N of Z-Hisha is not possible at all.
Received 13 July 2010
Accepted 19 August 2010
Available online 24 August 2010
Keywords:
Histidinehydroxamic acid derivatives
Cu2+-, Ni2+-, Zn2+-complexes
Solution equilibrium
With the ambidentate N-Me-Hisha, the histamine-type coordination mode is favoured if the metal ion
is Ni2+ and the bis-[NH2,Nimid] complex is the most stable in this system. The mixed type, [NH2,Nimid] +
[O,O], coordination mode dominates in the Cu2+- N-Me-Hisha complexes, while different low stability
Potential metalloenzyme inhibitors
mono-chelated linkage isomers are formed with Zn2+
.
With Z-Hisha (having poor water solubility) hydroxamate-type coordination mode predominates in
low stability complexes in the Ni2+ and Zn2+ containing systems. Interestingly, the interaction with
Cu2+ is very strong and results in the formation of a high stability 12-MC-4 type metallacrown with
involvement of 5-membered and 7-membered chelates.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
phores in the Fe3+ uptake, transfer and storage in the microorgan-
isms via complexation is commonly known [9].
Selective inhibition of metalloenzymes is an area of intense
interest because numerous serious diseases are correlated with
the dysfunction of such type of enzymes. For example, the zinc-
containing matrix metalloproteinases (MMPs) play a determinant
role in the evolvement of arthritis, periodontal diseases, multiple
sclerosis and also in the metastatic spread of various human can-
cers [1,2]. This is one reason why the selective inhibition of MMPs
has become one of the prominent drug design targets for medicinal
chemists. There is no doubt that the inhibitory effect is correlated
with the chelation of the catalytic metal center, thereby the linkage
of the substrate molecule is hindered [3,4]. Previous results related
to zinc-containing histone deacetylases and MMPs, or nickel-
containing ureases show that hydroxamic acids, which have good
metal binding capability, are effective inhibitors of these enzymes
[5–8]. Besides the metalloenzyme inhibitory effects with impor-
tant roles in several pathological processes, antibiotic effects as
well as metal ion sequestering ability of hydroxamic acids are also
well-known and the crucial role of hydroxamate-based sidero-
Since amino acid based and especially peptide based hydroxa-
mic derivatives are often among the possible candidates as inhibi-
tors for various metalloenzymes, it is interesting to know the main
factors affecting the metal binding ability/binding mode of such
molecules. In order to learn more about the stability, binding mode
and structure of those complexes, we have studied the interaction
between metal ions and various amino- and peptidehydroxamic
acids in solution during the past 20 years. Within this time, numer-
ous systems have been investigated in our lab and also in others by
using first of all potentiometric, spectroscopic, mass spectrometric,
EPR and NMR methods, and the results are discussed in reviews
and regular articles [10–18].
As it is well-known, an imidazole function in the side chain of
amino acids [16], small peptides [19] or protein molecules [20],
is one of the most effective metal binding sites. This is the reason,
why the role of the imidazole moiety at the RC substituent of var-
ious monohydroxamic acids (RCC(O)N(RN)OH) has been intensively
studied previously. First of all, metal complexation of his-
tidinehydroxamic acid (Hisha) has been investigated [16,21–24].
In addition to the imidazole-N and hydroxamic function, this mol-
ecule also contains an amino-N, what can play crucial role in the
⇑
Corresponding author.
E-mail addresses: efarkas@delfin.unideb.hu, efarkas@delfin.klte.hu (E. Farkas).
0277-5387/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2010.08.023

3138
E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
O
Cu2+
O
H2
C
H2N
CH
H2
C
C
C
CH
CH
HO
CH
N2H
Ni2+
N
N
NH
C
O
O
N
H2N
NH
O
H2N
N
N
Cu2+
Cu2+
H
Cu2+
NH2
CH
CH2
N
H2N
CH
H2N
CH
N
NH2
CH
O
N
HN
N
HN
N
OH
C
C
C
HN
H2
C
H2
O
O
Scheme 1.
coordination. According to the results, the coordination with Cu2+
starts at pH ca. 3–3.5 via hydroxamate-O donors, but as the pH is
increased, the binding via the nitrogen donors becomes more and
more dominant. Between pH 4.5–7 the amino-N and the imidaz-
ole-N donors coordinate in the complexes [CuH2L2]2+ and [CuHL2]+
(Scheme 1(I)). Further increase of the pH results in the formation of
[CuL2], in which the hydroxamate-N (instead of imidazole-N) to-
gether with the amino-N coordinates the metal ion. Above pH 9,
the deprotonation of one of the coordinated hydroxamates occurs
and a ‘‘hydroximato” chelate appears in the complex [CuHꢀ1L2]ꢀ
(II). Within the pH-range 4–7 oligonuclear species in low concen-
tration with mixed coordination mode (III) were also supported
[16]. The ‘‘histamine-type” coordination mode (I) was found to
dominate in the complexes [NiH2L2]2+ and [NiHL2]+, while amino-
N, imidazole-N and hydroxamate-N donors bind to the metal ion
in [NiL2] (IV). Above pH ca. 9, parallel with the formation of
[NiHꢀ1L2]ꢀ the geometry of the complex changes from octahedral
to square planar [16].
works, the formation of the well-known tris-hydroxamato-type
complex is significantly hindered in the Fe3+-Hisha system even
at 1:10 metal to ligand ratio. On the other hand, the results indi-
cated metal-metal coupling in the pH range, where stepwise
deprotonation of the bis-complex, [Fe(H2L)2]5+ started (above pH
4). Based on the findings, the involvement of the nonprotonated
side chain donors (imidazole-N and, at higher pH the amino-N)
in the coordination was suggested and coordinative or noncovalent
interaction (e.g., H-bond between the already nonprotonated and
still protonated imidazoles, or between the imidazole-N and
+
ammonium-NH3 protons, and/or stacking interaction) was as-
sumed. At high pH ESI-MS supported the existence of bis-hydrox-
amato-monohydroxo species [16].
As a continuation of the previous study, new imidazole analo-
gous of
N-methyl-
investigated in our lab in a recent work [25]. In this study we have
found that, the presence of the strong imidazole-N donor in -or b
a-alaninehydroxamic acid, b-alaninehydroxamic acid and
a-alaninehydroxamic acid have been synthesized and
a
In the Zn2+-containing systems, although different coordination
isomers were found, but the preference of the hydroxamate oxy-
gens for metal binding was evidenced. Hydroxamate-type coordi-
nation is suggested in the [ZnHL]2+ and [ZnH2L2]2+ below pH 6.
Above this pH, where the ligands loose their dissociable proton,
NMR results support the binding via the amino-N, imidazole-N
and one of the hydroxamic-O donors [16].
position to the hydroxamic moiety can significantly affect the me-
tal binding capability of the molecule. The imidazole-N is the an-
chor donor not only in the case of Cu2+-, and Ni2+-, but even in
the Zn2+-containing systems. Water insoluble polynuclear com-
plexes were formed with the
a-derivative, but a pentanuclear
metallocrown, [Cu5Hꢀ4L4]2+ exclusively exists with the b-deriva-
tive over a wide pH-range in the Cu2+-containing system. Interest-
One of the most surprising results was obtained for the com-
ingly, this metallocrown was also confirmed with Ni2+ and Zn2+
although with lower stability than with Cu2+ [25].
,
plexation of this ligand with Fe3+. According to one of our previous
NH+
NH3
+
HN
H
N
CH
C
C
OH
H2
O
Histidinehydroxamic acid (H3L2+)
(Hisha)
Z
NH+
NH3
+
NH+
CH3
N
HN
CH
HN
HN
H
N
CH
C
C
OH
C
C
OH
H2
H2
O
O
N-methyl-histidinehydroxamic acid (H3L2+)
(N-Me-Hisha)
Z-histidinehydroxamic acid (H2L+)
(Z-Hisha)
Scheme 2.

E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
3139
In the present work two new histidinehydroxamic acid deriva-
tives (N-methyl-histidinehydroxamic acid and Z-histidinehydroxa-
mic acid) have been synthesized and their metal binding capability
with Cu2+, Ni2+ and Zn2+ has been studied by using pH-potentio-
metric, UV–Vis, CD, EPR, 1H NMR and ESI-MS measurements. In or-
der to have a better comparison of the results, some reproductive
measurements for the previously studied Hisha-containing sys-
tems [16,21–24] were also performed.
Both of the two new derivatives contain one donor atom less
than Hisha. Namely, in the case of N-Me-Hisha the hydroxamate-
N as donor is eliminated, while the coordination of the amino-N
of Z-Hisha is not possible at all. The formulae of the totally proton-
ated new ligands together with the parent Hisha are summarized
in Scheme 2. (The possible coordinating donor atoms are marked
with bold letters).
9.27 mmol). After 40 min of stirring at 0 °C the solid was filtered
and the solution was added dropwise to the previously prepared
solution of the free hydroxylamine. The reaction mixture was
stirred under N2 in ice bath for 2 h and for further 2 h at ambient
temperature. The solvent was evaporated and the oil obtained
was purified by column chromatography (Kieselgel 60, eluent:
CHCl3:MeOH = 95:5, Rf = 0.20) Yield: 550 mg, 20%. 1H NMR
(360 MHz, DMSO-d6) d: 8.01 (s, 1H, imH2), 7.73–7.32 (m, 11H, –
C6H5, –NH), 6.95 (s, 1H, imH5), 5.00–4.93 (m, 5H, C6H5CH2ꢀ and
–CH–), 3.15 (s, 3H, –CH3), 2.89–2.77 (m, 2H, –CH2–).
2.1.4. N-methyl-
L
-
a
-Histidinehydroxamic acidꢁ2HCl (N-Me-Hisha)(4)
-histidinehydroxamic acid (3) (150
Z-N-methyl-O-benzyl- -a
L
mg, 0.37 mmol) was subjected to hydrogenolysis in methanol
(20 mL), using palladium charcoal (35 mg, 10% Pd) and 4–5 drops
concentrated (36% (m/m)) HCl solution for four hours. After filtra-
tion and evaporation a pale yellow oil was remained. After drying
in high vacuum, and treatment with ether to remove vestigiary
amounts of water afforded 80 mg (90%) white crystals as the pure
compound (4). 1H NMR (360 MHz, D2O) d: 8.55 (s, 1H, imH2), 7.35
(s, 1H, imH5), 4.45 (q, 1H, –CH–), 3.45 (s, 3H, –CH3), 3.06–3.02 (m,
2H, –CH2ꢀ). ESI-TOF MS, m/z:: 185.102 [C7H13N4O2]+.
2. Experimental
2.1. Synthesis
All chemicals and solvents were analytical grade and were used
without further purification. L-a-histidine, N-a-carbobenzyloxy-L-
histidine, NH2OHꢁHCl, ethylchloroformiate and N-methylmorpho-
line were purchased from Aldrich, palladium/carbon (10%(m/m))
from Merck. Methanol was dried under N2 using magnesium turn-
ings and iodine, while dry tetrahydrofurane was also made under
N2 using sodium wire and benzophenone, according to the litera-
ture [26].
2.2. Equilibrium measurements
2.2.1. Metal ion and ligand stock solutions
The purity of the ligands and the concentrations of the ligand
stock solutions were determined by Gran’s method [27]. The Cu2+
and Ni2+ stock solutions were prepared from CuCl2ꢁ2H2O and
NiCl2ꢁ6H2O (Reanal) dissolved in bi-distilled water. ZnO (Reanal)
was dissolved in a known amount of HCl solution (0.10 M). The
concentration of the metal ion stock solutions was determined
gravimetrically via precipitation of quinolin-8-olates [28]. The
HCl concentration of the Zn2+ solution and the exact concentration
of the carbonate-free KOH titrant were determined by pH-
potentiometry.
2.1.1. Z-
L
-
a
-Histidine methyl estherꢁHCl (1)
-carbobenzyloxy-L-histidine (Z-histidine)
A
solution of N-
a
(2.00 g, 6.92 mmol) in freshly distilled dry methanol (30 mL) was
bubbled with dry hydrogen chloride gas for one hour under cooling
in water-ice-bath. Solvent was evaporated in vacuo affording the
pure product (1) as white crystals. Yield: 2.00 g, 85%. 1H NMR
(360 MHz, DMSO-d6) d: 7.96 (s, 1H, imH2), 7.37–7.26 (m, 6H,
imH5 and –C6H5), 4.99 (s, 2H, C6H5CH2ꢀ), 4.44 (q, 1H, –CH–),
3.63 (s, 3H, –CH3), 3.07–3.01 (m, 2H, –CH2–).
2.2.2. Potentiometric and spectroscopic studies
The pH-potentiometric and spectrophotometric measurements
were carried out at an ionic strength of 0.2 M (KCl). Temperature
was 25.0 0.1 °C. Carbonate-free KOH solution of known concen-
tration (0.2 M) was used as titrant. HCl stock solution was prepared
from conc. HCl. The concentration of the HCl solution was also
determined by pH-potentiometric titrations using the Gran’s
method [27]. For N-Me-Hisha both pH-potentiometric and spectro-
scopic measurements were made in aqueous solution. Radiometer
pHM 84 instrument equipped with Metrohm combined electrode
(type 6.0234.100) was used for pH-potentiometric measurements
with a Metrohm 715 Dosimat automatic burette. The electrode
system was calibrated according to Irving et al. [29] and the pH-
metric readings could, therefore be converted into hydrogen con-
centration. The water ionization constant (pKw) is 13.76 0.01 in
aqueous solution under the conditions employed. Due to solubility
problems of the complexes of Z-Hisha all the measurements were
performed in DMSO/water 50:50% (m/m) mixture. For comparison,
the previously already studied [25] Imidazole-4-carbohydroxamic
acid (im-4-Cha), because its complexes show similar solubility
problems, was also investigated in the present work in DMSO-
water 50:50% (m/m) solvent mixture. In these cases the solvent
mixture was also used for the preparation of KCl and HCl stock
solutions and for the KOH titrant. The electrode was conditioned
in DMSO/water 50:50% (m/m) for 3–4 days before the measure-
ments. For the calibration of the electrode system aqueous potas-
sium hydrogen ftalate solution was used as it is recommended
by IUPAC [30]. The water ionization constant (pKw) was found to
be 15.41 0.01 at these conditions.
2.1.2. Z-
L
-
a
-Histidinehydroxamic acidꢁHCl (Z-Hisha) (2)
-histidine methyl estherꢁHCl (1)
To a cooled solution of Z- -a
L
(2.00 g, 5.89 mmol) in dry MeOH (30 mL) was added a solution of
KOH in MeOH (0.33 g, 5.89 mmol) under stirring. In another flask
0.74 g (10.60 mmol) NH2OHꢁHCl and 0.86 g (15.32 mmol) KOH
pastilles were dissolved in 30 mL MeOH at 0 °C. The mixture was
stirred for 15 min in water-ice bath and KCl was filtered out. Solu-
tion of free ester was added dropwise to the solution of the free
hydroxylamine. The reaction mixture was stirred at 0 °C for one
hour and it was kept at 4 °C overnight. The white solid was filtered,
washed with ether and dried in vacuo. The crude product was
recrystallized from MeOH affording pure hydroxamic acid (2).
Yield: 350 mg, 18% 1H NMR (360 MHz, DMSO-d6) d: 7.61 (s, 1H,
imH2), 7.37–7.31 (m, 5H, C6H5), 6.83 (s, 1H, imH5), 5.00 (s, 2H,
C6H5CH2ꢀ), 4.22 (q, 1H, –CH–), 2.97–2.90 (m, 2H, –CH2–). ESI-
TOF MS (m/z): 305.125 [C14H17N4O4]+.
2.1.3. Z-N-methyl-O-benzyl-L-a-histidinehydroxamic acid (3)
To an ice-cooled solution of N-methyl-O-benzyl hydroxylamine
hydrochloride (1.85 g, 10.85 mmol) in dry, freshly distilled MeOH
(10 mL) was added a solution of KOH (0.60 g, 10.70 mmol) in MeOH
(5 mL) and the mixture was stirred for 25 min in ice-water bath
under N2. KCl was filtered and the solution was kept at 0 °C.
To a chilled solution of Z-histidine (2.06 g, 7.13 mmol) in dry,
freshly distilled tetrahydrofurane (50 mL) was added ethylchloro-
formiate (0.82 mL, 8.56 mmol) and N-methylmorpholine (1.02 mL,

3140
E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
All the pH-potentiometric titrations were performed over the
accumulated and recorded by a digitalizer at a sampling rate of
2 GHz. The spectrometer was operated at unit mass resolution
and was calibrated to sodium trifluoroacetate.
pH-range of 2–11 or until precipitation occurred. Initial volume
of the samples was 4.00 or 5.00 mL. Ligand concentration was 2–
3 ꢂ 10ꢀ3 M and the metal to ligand ratios were 1:1, 1:2 and 1:3,
1:4 or 1:5. During the titrations purified, strictly oxygen-free argon
was continuously bubbled through the samples. The pH-metric re-
sults were utilized to find the stoichiometry of species and to cal-
culate the stability constants. The calculations were made with the
aid of the computer program PSEQUAD [31].
3. Results and discussion
3.1. Acidity of the ligands
Similarly to Hisha, N-Me-Hisha involves three dissociable pro-
tons in its totally protonated form (H3L2+), one at the terminal ami-
no-N, another one at the hydroxamic function, while the third one
at the side chain imidazole-N. Due to the presence of the Z-protect-
ing group, Z-Hisha can liberate only two protons, one from the
hydroxamic moiety while the other from the imidazole-N. The
overall stability constants (log b) of the two new ligands and Hisha
have been determined by pH-potentiometry, and together with the
stepwise dissociation constants (pKa) calculated from the overall
values are summarized in Table 1.
The dissociation constants obtained in the present work for the
Hisha are in good agreement with the previously published ones
[16]. As it is known from the literature, the three dissociation pro-
cesses of this ligand overlap significantly [16,33]. As a conse-
quence, the values in Table 1 are macroconstants and can not be
ascribed unambiguously to the individual groups. Although great
effort has been previously made by NMR for determination of the
dissociation microconstants of Hisha, but because of the significant
electronic effect of each group on the dissociation of the others, the
microconstants could not be obtained, therefore, only trends for
the acidity were suggested. Namely, the imidazolium moiety is
the most acidic, while the acidity of the other two groups is close
to each other [16,33]. In this latter issue the NH3+ group was found
UV–Vis measurements on systems containing Cu2+ and Ni2+ were
performed. In the case of Cu2+-containing systems ligand concen-
trations were varied within the range 2.2–2.8 ꢂ 10ꢀ3 M and the
Cu2+ to ligand ratios were 1:1 and 1:2 for both ligands. For Ni2+
-
containing systems the concentration of the N-Me-Hisha was
1.2 ꢂ 10ꢀ2 M and the metal to ligand ratios were 1:2 and 1:4. A
Perkin–Elmer Lambda 25 spectrophotometer was used to record
the spectra in the region of 290–900 nm. Path length was 1 cm in
all cases.
CD spectra for Cu2+-N-Me-Hisha samples at 1:1 and 1:2 metal to
ligand ratios were also obtained at 25 °C under a constant flow of
nitrogen on a Jasco J-810 spectropolarimeter, which was calibrated
with an aqueous solution of the ammonium salt of (1R)-(-)-10-
camphorsulfonate. The ligand concentration in the samples was
2.5 ꢂ 10ꢀ3 M. Measurements were carried out in aqueous solution
at different pH values, using 1 cm path length cuvettes in the 290–
800 nm wavelength regions.
1H NMR spectra were recorded for N-Me-Hisha and Z-Hisha and
for their Zn2+complexes on a Bruker Avance AM 360 by using D2O
or (CD3)2SO as solvent and DSS ((2,2-dimethyl-2-silapentane-5-
sulfonic acid, sodium salt) as standard under the following condi-
tions: metal to ligand ratio was 1:2 in all samples and the analyt-
ical concentration was 5 ꢂ 10ꢀ3 M for both ligands. 0.1 M NaOD
and DCl solutions were used to adjust the appropriate pD.
EPR spectra of frozen aqueous solutions of the Cu2+-N-Me-Hisha
systems were recorded at 77 K at different pH values, using a Bru-
ker EleXsys X-band spectrometer. (Parameters: microwave fre-
quency: 9.81 GHz, modulation amplitude: 5G, modulation
frequency: 100.0 kHz, microwave power: 12 mW) Methanol was
added to the samples to avoid the crystallization of the water.
The concentration of the Cu2+ was 2 ꢂ 10ꢀ3 M in all samples. The
spectra were recorded at five different pH values within the pH-
range 2–7 at ca. 1:1 metal to ligand ratio, while eleven spectra
were registered in the pH-range 2–9 at 1:5 ratio. For the calcula-
tion of the spectra, ‘‘EPR program” was used [32]. Decomposition
of the measured spectra were done by fitting the anisotropic EPR
a bit more acidic than the CONHOH function in simple
ohydroxamic acids [16,34].
a-amin-
If a comparison of the values of N-Me-Hisha with those of Hisha
is made, the following conclusion can be drawn: (i) The pKa1 val-
ues, which in high extent, belong to the deprotonation of the imi-
dazolium group, are similar in both molecules. (ii) The difference
between the second and third dissociation macroconstants of N-
Me-Hisha is less than that of Hisha. This might be attributed to
the lack of possibility for hydrogen bonding in N-Me-Hisha, which
can be expected between the hydroxamic-NH and amino-NH2 in
Hisha. Moreover, the methyl-substituent on the hydroxamic-N
slightly decreases the basicity of the hydroxamate group of N-
Me-Hisha as compared to the Hisha1 [16].
Due to the solubility problem of the metal complexes of Z-Hisha
the stability constants of these species could not be determined in
aqueous solution, therefore DMSO-water 50:50% (m/m) solvent
mixture was applied. As a consequence, to calculate the stability
constants of the metal complexes, determination of the dissociation
macroconstants of Z-Hisha not only in water but also in the solvent
mixture was necessary. If the corresponding pKa values determined
in the two solvents are compared with each other, one can see that
the pKa1 (which belongs to the deprotonation of the imidazolium-
NH+) is lower, but the pKa2 (belongs to the hydroxamic function)
is higher in DMSO-water mixture. This observation is in good agree-
ment with earlier findings in the literature [36]. Namely, the depro-
tonation of the positively charged imidazolium-NH+ yielding
neutral moiety is more favoured in the less polar DMSO-water mix-
ture than in aqueous solution, while the deprotonation of the neu-
tral hydroxamic function, resulting in negatively charged species, is
less favoured in the solvent mixture.
parameters (g||, g\, copper hyperfine couplings A , A\, and nitro-
k
gen superhyperfine couplings aN), the orientation dependent
linewidth parameters, and the concentration ratio of the compo-
nents. Since the copper(II) used in the solutions was a natural mix-
ture of the isotopes, the spectrum of each species was calculated as
the sum of spectra containing 63Cu and 65Cu in their natural
abundances.
To obtain additional support for the complexes formed in the
Cu2+-Z-Hisha and Cu2+-N-Me-Hisha systems electro-spray ioniza-
tion time-of-flight mass spectrometric (ESI-TOF MS) analysis was
carried out on a Bruker BIOTOF II ESI-TOF instrument. The metal
to ligand ratio was 1:1 in both cases. The pH of the Cu2+-Z-Hisha
sample was 4.50, the concentration of the ligand was 5 ꢂ 10ꢀ4 M.
For the other system the applied ligand concentration was
1 ꢂ 10ꢀ3 M and the spectrum was recorded at pH 5.30. The solu-
tions were introduced directly into the ESI source by a syringe
pump (Cole-Parmer Ins. Comp. type 74900) at a flow rate of
2 lL/min. The temperature of drying gas (N2) was 100 °C. The pres-
1
This is the case, because the electron density donating ability of the methyl group
sure of the nebulizating gas (N2) was 30 psi. Voltages applied at the
capillary entrance, capillary exit and the first and the second skim-
mers were ꢀ4500, 120, 40 and 30 V, respectively. The spectra were
increases the delocalization of the lone pair electrons of N via the C–N bond. This
effect allows positive charge density to build up on the N atom and thereby stabilizes
the conjugate base anion by induction [35].

E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
3141
Table 1
Table 2
Overall stability constants (log b) and the stepwise dissociation constants (pKa) of
Overall stability constants (log bpqr) for the Cu2+-, Ni2+- and Zn2+-complexes formed
with N-Me-Hisha, t = 25.0 °C, I = 0.20 M (KCl).b
Hisha, N-Me-Hisha and Z-Hisha, t = 25.0 °C, I = 0.20 M (KCl).a
+
Ligand
Hisha
Solvent
water
[H3L]2+
[H2L
]
[HL]
Complex
p
q
r
log bpqr
log b
pKa
log b
21.47(1)
5.35
21.70(1)
5.39
16.12(1)
7.09
16.31(1)
7.37
15.22(1)
6.42
15.43(1)
5.62
9.03(1)
9.03
8.94(1)
8.94
8.80(1)
8.80
9.81(1)
9.81
Cu2+
Ni2+
Zn2+
N-Me-Hisha [MH2L]3+
[MHL]2+
1
1
1
1
2
1
1
1
1
1
2
1
0
1
1
1
1
2
2
2
2
3
3
20.2(1)
17.46(2)
N-Me-Hisha
Z-Hisha
water
water
15.45(2) 13.52(3)
[ML]+
[MH-1L]
9.09(3)
6.97(3)
log b
pKa
log b
pKa
ꢀ1
ꢀ1.37(4)
[M2L2]
0
2
1
0
1
0
29.52(3)
32.61(9)
25.5(1)
DMSO-water
50:50% (m/m)
[MH2L2]2+
[MHL2]+
29.69(4) 26.86(4)
22.69(7) 19.70(6)
14.53(9) 11.51(7)
26.9(2)
a
[ML2]
17.45(7)
Numbers in parentheses indicate standard deviations.
[MHL3]
[ML3]ꢀ
18.4(2)
Number of experimental
points
220
150
90
0.0021
3.2. Metal complexes
3.2.1. Cu2+-, Ni2+- and Zn2+-complexes of N-Me-Hisha
Fitting parameter (cm3)
0.0038
0.0028
b
Numbers in parentheses indicate standard deviations.
As a result of the methylation of the hydroxamate-N in the N-
Me-Hisha this ligand contains two separated chelating groups,
which are not able to coordinate to the same metal ion at the same
time. One chelate can be formed via the hydroxamate oxygens
([O,O]- coordination) and another one via the amino-N and imidaz-
ole-N donors ([NH2,Nimid]-chelate). To determine the stoichiometry
and stability constants of the metal complexes, pH-potentiometric
titrations were performed. Representative titration curves re-
corded for the N-Me-Hisha and for the Cu2+-, Ni2+- and Zn2+-con-
taining systems at 1:1 metal to ligand ratio are shown in Fig. 1.
As it is well demonstrated in Fig. 1 the ligand starts to interact
with Cu2+ below pH = 3, with Ni2+ at only pH ꢃ4, while the com-
plexation with Zn2+ starts above pH ꢃ5. Precipitation occurs in
the Cu2+-containing system (1) above pH ꢃ5, while it occurs at
pH ca. 10 or pH ꢃ8 if the metal ion is Ni2+ (2) and Zn2+ (3), respec-
tively. Under conditions of 1:2 metal to ligand ratio (curves not
shown here) precipitation does not occur in the Cu2+ and Ni2+ -con-
taining systems, which indicate some interactions with ligand
excess.
([Cu2L2]2+ = 247 m/z, [Cu2L2]Cl+ = 529 m/z), therefore the equilib-
rium model involving the dimeric complex was finally accepted.
In order to determine the most probable binding modes of the
complexes, UV–Vis, CD and EPR measurements have been
performed.
Out of the results, representative concentration distribution
curves calculated at 1:2 metal to ligand ratio, together with the
kmax values of the visible spectra as a function of pH are presented
in Fig. 2.
By the decomposition of the registered EPR spectra, individual
spectra (Fig. 3) could be calculated for the mononuclear complexes
formed in this system. As it is demonstrated in Fig. 2, at pH ca. 2.5
the free Cu2+ dominates, which was also supported by the EPR re-
sults (S1 shows the measured EPR spectra together with simulated
curves). The first measurable (but not dominant) complex is
[CuH2L]3+. Out of the two possible coordination modes in this spe-
cies (monodentate coordination of imidazole-N or hydroxamate-
[O,O]-chelation) the former seems more probable by the EPR
parameters (A|| = 139.6 ꢂ 10ꢀ4 cmꢀ1 and g|| = 2.373) [37]. This is
Stoichiometry of the complexes and the overall stability con-
stants yielding the best fit of the pH-metric titration curves are
shown in Table 2.
further supported by lack of the charge-transfer band at kmax
=
Table 2 shows the formation of numerous protonated mono-
and bis-complexes and the formation of tris-complexes is also de-
tected in the Ni2+-containing system. With Cu2+, similar fitting was
obtained with two models. The first included a monomeric [CuL]+
instead of the dimeric [Cu2L2]2+ which was involved in the second
one. (Fitting parameters were: 3.9 and 3.8 ꢂ 10ꢀ3 cm3, respec-
tively). Because pH-potentiometry could not differentiate between
these two species, ESI-MS measurement was used to solve this
problem. The result obtained for aqueous solution at pH 5.3 unam-
biguously showed the existence of [Cu2L2]2+ in this system
380 nm, which would be characteristic for the involvement of
the hydroxamate-O in the coordination below pH ꢃ3 [14,38].
Upon increasing the pH, [CuHL]2+ is formed and the EPR results
clearly indicate the existence of two different isomers of this com-
plex. The hydroxamate-O donors coordinate to the metal ion in one
of the isomers (the A|| = 166.8 ꢂ 10ꢀ4 cmꢀ1 and g|| = 2.305 parame-
ters are similar to those previously published for [O,O] coordina-
tion [39] and also the characteristic charge-transfer band in the
1.0
Cu2+
12
800
0.8
10
[Cu2L2]2+
2
[CuHL]2+
750
L
0.6
[CuL2]
8
700
3
[CuH2L2]2+
[CuHL2]+
0.4
6
2
1
650
600
0.2
0.0
4
2
[CuH2L]3+
2.5
3.5
4.5
5.5
6.5
7.5
8.5
9.5
-2.0
-1.0
0.0
1.0
2.0
3.0
4.0
5.0
base equivalent
pH
Fig. 1. Representative pH-potentiometric titration curves registered for N-Me-
Hisha (L) and for Cu2+-(1), Ni2+-(2), Zn2+-(3) N-Me-Hisha systems at 1:1 metal to
ligand ratio, cL = 2.6 ꢂ 10ꢀ3 M.
Fig. 2. Representative concentration distribution curves calculated for Cu2+-N-Me-
Hisha system at 1:2 metal to ligand ratio, together with the kmax values of the d–d
band, cL = 2.5 ꢂ 10ꢀ3 M.

3142
E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
Vis and EPR results, but the EPR spectra registered at 1:5 metal
oligomer species
2 x (N,N)
to ligand ratio also indicate the formation of bis-complex(es) with
4N donors (two [NH2, Nimid]-chelates in low concentration. The
well resolved superhyperfine structure of the EPR spectra could
be well described by taking into account two pairs of equivalent
nitrogens and the rhombic symmetry of g- and A-tensors for this
complex (gxx = 2.043, gyy = 2.055, gzz = 2.259, Axx = 13.7 ꢂ 10ꢀ4
(N,N)-[CuHL]2+
cmꢀ1
,
Ayy = 8.6 ꢂ 10ꢀ4 cmꢀ1
,
Azz = 186.1 ꢂ 10ꢀ4 cmꢀ1
aNxx = 8 ꢂ
,
10ꢀ4 cmꢀ1 (13 ꢂ 10ꢀ4 cmꢀ1), aNyy = 14 ꢂ 10ꢀ4 cmꢀ1 (9 ꢂ 10ꢀ4
cmꢀ1
)
aNzz = 10 ꢂ 10ꢀ4 cmꢀ1 (6 ꢂ 10ꢀ4 cmꢀ1)). Although cis or
(O,O)-[CuHL]2+
trans arrangement of the two [NH2, Nimid] chelates in this bis-com-
plex cannot be determined from the EPR parameters, the sharp
perpendicular lines (well resolved nitrogen splitting) and the steric
hindrance of the two imidazole ring in the cis arrangement make
the predominance of the trans isomer more probable (structure
(I) in Scheme 1).
[CuH2L]3+
Cu2+
In the case of Ni2+ the first buffer region in Fig. 1 shows that two
protons of the ligand are liberated by this metal ion in one step
(below pH ꢃ4.5), while the third dissociable proton is released in
a separated process in the pH-range 6.0–8.0, where the deprotona-
tion of a non-coordinated hydroxamic function can occur. Taking
these findings into account, one can conclude that the first buffer
region most probably belongs to the deprotonation and coordina-
tion of the amino-N and imidazole-N, while the hydroxamate moi-
ety is still protonated. The separated second base-consuming
region most probably belongs to the deprotonation of the non-
coordinated hydroxamic function. Due to the formation of bis-
and tris-complexes, ligand excess is able to hinder the hydrolysis
of the metal ion. Representative concentration distribution curves
calculated at 1:4 metal to ligand ratio, demonstrate the high pref-
erence of the bis- and tris-complexes in this system (Fig. 4). This
figure also shows the kmax values belonging to the 3A2 ? 3T1 (F)
transition in the visible spectra.
2500
2750
3000
3250
3500
Magnetic field (G)
Fig. 3. Simulated component EPR spectra of some of the complexes formed in the
Cu2+-N-Me-Hisha system.
UV–Vis spectrum appears), while the greater linewidth of the par-
allel lines and the stronger ligand field (A|| = 165.5 ꢂ 10ꢀ4 cmꢀ1 and
g|| = 2.272) support the formation of the [NH2,Nimid]-chelate in the
other isomer. Based on the EPR results at 1:1 metal to ligand ratio,
it was possible to make an estimation for the ratio of these isomers
and 60:40% was calculated for the ratio of the (O,O)-[CuHL]2+ to the
There is no indication for the formation of square planar com-
plexes in the Ni2+-N-Me-Hisha system, only octahedral complexes
exist in the pH-range 3–10. The coordination of the amino-N and
imidazole-N is unambiguously supported by the UV–Vis results
histamine-type (N,N)-[CuHL]2+
.
Regardless of the metal to ligand ratio the minimum kmax of the
registered d–d band is at 625 nm in this system. This is demon-
strated e.g. in Fig. 2, where the kmax does not show any change
above pH 4.5, but remains at the above mentioned 625 nm. Taking
into account that the kmax is 650 nm for the bis(acetohydroxamato-
O,O)copper complex [38], while 600 nm for the bis(histamine-
N,N)copper [40] and by using the Sigel–Martin’s equation [41],
the kmax = 625 nm strongly supports the presence of two hydroxa-
mate oxygens, plus one amino-nitrogen and one imidazole-nitro-
gen per Cu2+ in the coordination sphere of all the complexes
([Cu2L2]2+, [CuH2L2]2+, [CuHL2]+, [CuL2]) formed above pH 4.5 in
the Cu2+-N-Me-Hisha system. Similarly, the CD parameters also
indicate the presence of these types of chelates by the two bands
at kmax = 380 nm(+) and 680 nm(+)) at pH ca. 4. (The band at
kmax = 380 nm indicates the involvement of the hydroxamate-O
in the coordination [15], while the positive Cotton-effect at
674 nm can be assigned to the histamine-type coordination [42].)
As the pH is further increased, any change in the CD spectrum, ex-
cept some increase in the intensity of the bands does not occur. The
spectroscopic results detailed above support the parallel coordina-
tion of the hydroxamate-type [O,O] and histamine-type [NH2,Ni-
mid] chelates of N-Me-Hisha. However, in a 1:1 metal to ligand
complex this is not possible in monomeric species. This assump-
tion is supported by the existence of species with a broad singlet
EPR line in the system above pH 3.5 and fits to the formation of
the dimeric complex [Cu2L2]2+, in which the line broadening can
be explained by the dipole–dipole coupling between the two para-
magnetic centers. The amount of this complex is dominant even at
ligand excess (see Fig. 2). The predominance of this mixed coordi-
nation mode ([O,O]- and [NH2,Nimid]-chelates) is also supported in
the bis-complexes ([CuH2L2]2+, [CuHL2]+, [CuL2]) both by the UV–
(see Fig. 4, where the kmax (3A2 ? 3T1 (F)) is at 550 nm,
e
ꢃ50 molꢀ1 dm3 cmꢀ1 at pH ꢃ7.0 and parallel with the formation
of tris-complexes above pH ꢃ7.5, it decreases to 542 nm,
e
ꢃ48 molꢀ1 dm3 cmꢀ1). Hydroxamate-[O,O] coordination would re-
sult in significantly higher kmax values. (The corresponding kmax for
the bis-[NH2,Nimid]-chelated complex of Ni2+-histamine is at
570 nm [40], while it is at 649 nm for the bis(acetohydroxamato-
O,O)nickel complex [38]). As a conclusion, it can be suggested that
histamine-like coordination mode predominates in the Ni2+-N-Me-
Hisha complexes and there is no indication for the coordination of
the hydroxamate-oxygens. The proposed structure of the [NiL3]ꢀ is
presented in Scheme 3.
590
580
570
560
550
540
1.0
0.8
0.6
0.4
0.2
0.0
[NiH2L2]2+
[NiHL]2+
Ni2+
[NiL3]-
[NiHL2]+
[NiHL3]
[NiL2]
[NiL]+
3.5
4.5
5.5
6.5
7.5
8.5
9.5
pH
Fig. 4. Concentration distribution curves calculated for Ni2+-N-Me-Hisha system at
1:4 metal to ligand ratio together with the kmax values of the d–d band,
cL = 2.6 ꢂ 10ꢀ3 M.

E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
3143
and Zn2+. The equilibrium models yielding the best fit of the pH-
metric experimental data and the calculated stability constants
are summarized in Table 3.
H2
C
HN
CH
NH2
N
H2
N
Representative concentration distribution curves calculated for
the Cu2+-Z-Hisha system at 1:1 metal to ligand ratio together with
the kmax values of the d–d band are presented in Fig. 6. As Fig. 6
shows, the complexation starts above pH ꢃ2.5 and the stoichiom-
etry of the first complex formed is [CuHL]2+ (see also Table 3). In
this species, the hydroxamic function is still protonated and mono-
dentate-Nimid coordination mode is suggested. The charge-transfer
band at 380 nm, which is characteristic for the Cu2+-hydroxamate
interaction, appears only above pH 3.3 parallel with the formation
CH
Ni2+
H2C
NH
N
N
H2N
CH
C
N
H
H2
Scheme 3.
of the species [CuL]+ and the polynuclear complex, [Cu5H-4L4]2+
.
[CuL]+ is a minor complex in this system, existing in a narrow
pH-range and in a maximum of ca. 17% at 1:1 metal to ligand ratio
(Fig. 6). Because the stability constant associated with this species
is really high (even if the solvent effect is taken into account), most
probably both the hydroxamate moiety and the imidazole-N are
involved in the coordination. However, the simultaneous coordina-
tion of these donors (what would be resulted in formation of a se-
ven-membered chelate joined to a five-membered one) can not be
As Fig. 1 also indicates, this ligand starts to interact with Zn2+
above pH ꢃ5.0 and precipitation occurs above pH ꢃ8. Therefore
the pH-metric titration curves could be fitted in a relatively narrow
pH range. In contrast to the Ni2+-containing system, the three
equivalents base consumption does not occur in separated steps
in the case of Zn2+. The deprotonation of the ligand and the hydro-
lysis of the metal ion take place in overlapping processes. In addi-
tion to the pH-potentiometric measurements 1H NMR technique
has also been applied to investigate the interaction between the li-
gand and the diamagnetic Zn2+ ion.
The chemical shifts of the C(2)H and C(5)H protons of the imid-
azole are assumed to be sensitive to the metal ion coordination via
imidazole-N(3), while the N-methyl protons are expected to feel
the coordination of the hydroxamate function. In good agreement
with the pH-potentiometric titration, measurable interaction be-
tween the ligand and the metal ion was indicated by the NMR re-
sults above pH ꢃ5. It was also found that both the imidazole- and
methyl-protons showed similar changes (ꢃ0.05–0.06 ppm) in the
chemical shifts in the Zn2+-containing system compared to the free
ligand. This may suggest that neither the hydroxamate-[O,O], nor
the histamine-type [NH2,Nimid]-chelates play a major role in the
Zn2+ binding, therefore the formation of different linkage isomers
occurs in the Zn2+-N-Me-Hisha system.
favoured in monomeric species, therefore the formulae of [CuL]+
x+
might be given as [CuL]x
.
As the pH is increased above pH 3.5 the formation of a very sta-
ble pentanuclear complex starts. Both the ESI-MS result (Fig. 7) ob-
tained at pH 4.3 and fitting of the pH-potentiometric data (Fig. 5)
support predominance of the species [Cu5H-4L4]2+ (m/z = 763).
The structure of the suggested 12-metallacrown-4 (12-MC-4)-
type complex is shown in Scheme 4. Interestingly, as it can be seen
in this Scheme, 7-membered [Nimid, Nhydr]-and 5-membered [O,O]-
chelates are involved in this polynuclear species.
As it is well-known from previous results, extremely stable 12-
MC-4 type copper(II) complexes involving 6-membered [Namino
,
Nhydr]- and 5-membered [O,O]-chelates are predominant over a
wide pH-range with b-aminohydroxamates. If the ligand is
Table 3
Overall stability constants (log bpqr) for the Cu2+-, Ni2+- and Zn2+-complexes formed
with Z-Hisha in DMSO-water 50:50 % (m/m), t = 25.0 °C, I = 0.20 M (KCl).c
3.2.2. Cu2+-, Ni2+- and Zn2+-complexes of Z-Hisha
Due to the very poor water solubility of the complexes formed
with this ligand all the measurements were carried out in DMSO-
water 50:50% (m/m) solvent mixture. Representative pH-metric
titration curves of Cu2+-, Ni2+- and Zn2+ -Z-Hisha systems at 1:1
metal to ligand ratio are shown in Fig 5.
As Fig. 5 clearly shows, there are significant differences in the
pH effects, which obviously indicate great differences in binding
ability of this ligand towards Cu2+ compared to those with Ni2+
or Zn2+. While very strong interaction is suggested in the case of
Cu2+, the titration curves show only weak interaction with Ni2+
Ligand
Complex
Zn
p
q
r
log bpqr
Cu2+
Ni2+
Zn2+
Z-Hisha [MHL]2+
1
1
5
1
0
1
1
4
14.31(8) 13.02(7) 13.00(3)
[ML]+
10.40(6)
38.5(2)
90
6.81(3)
6.61(3)
[M5H-4L4]2+
ꢀ4
Number of experimental points
70
0.003
80
0.0022
Fitting parameter (cm3)
0.0034
c
Numbers in parentheses indicate standard deviations.
1.0
850
14
[Cu5H-4L4]2+
0.8
Cu2+
12
800
750
700
650
600
L
0.6
10
3
8
[CuHL]2+
0.4
[CuL]+
1
6
4
2
2
0.2
0.0
2.5
3.5
4.5
5.5
pH
6.5
7.5
-2.0
-1.0
0.0
1.0
2.0
3.0
4.0
base equivalent
Fig. 5. Representative pH-potentiometric titration curves registered for Z-Hisha (L)
and for Cu2+-(1), Ni2+-(2), and Zn2+-(3) Z-Hisha systems at 1:1 metal to ligand ratio
in DMSO-water 50:50% (m/m) solvent mixture, cL = 2.3 ꢂ 10ꢀ3 M.
Fig. 6. Representative concentration distribution curves registered for Cu2+-Z-Hisha
system at 1:1 metal to ligand ratio together with the kmax values of the d–d band,
cL = 2.3 ꢂ 10ꢀ3 M.

3144
E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
250000
200000
150000
100000
50000
0
lacrown with Z-Hisha is the lowest in this series (triad), it is still high
enough to hinder the hydrolysis of the Cu2+ below pH 9.
In contrast to Cu2+, the other two investigated metal ions show
only weak interaction with Z-Hisha (Fig. 6). The titration curves
could be fitted only in a narrow pH range, because the complexa-
tion starts at ca. pH 4 and above pH 6 precipitate occurred. Only
the formation of [MHL]2+ and [ML]+ was found. With Ni2+ the titra-
tion curve indicates weak imidazole-N coordination, while in the
case of Zn2+, based on the previous results with Hisha, the complex
formation with the hydroxamate-O is likely. Weak interaction can
also be seen with the presence of the imidazole-N (Fig. 6), but the
chemical shifts of the C(2)H and C(5)H protons of the ligand show
negligible interaction of the metal ion with the imidazole moiety in
the NMR measurements.
760
762
764
766
768
770
m/z
Fig. 7. ESI-MS spectrum registered for Cu2+-Z-Hisha system at pH 4.3 at 1:1 ratio,
cL = 1 ꢂ 10ꢀ4 M.
4. Conclusion
H
N
Elimination of hydroxamate-N as a donor atom by its methyla-
tion provides a typical ambidentate character for the N-Me-Hisha.
The role of the two (practically independent) chelating functions,
histamine-type [NH2,Nimid]-chelate and hydroxamate-type [O,O]-
chelate, in the coordination highly depends on the metal ion.
N-Me-Hisha behaves towards Ni2+ ion as a histamine derivative,
the interaction starts at pH ꢃ4 and histamine-type chelates pre-
dominate in the nickel-complexes.
There is no significant difference between the conditional sta-
bility of a histamine-type and a hydroxamate-type chelate if the
metal ion is Cu2+, and also the pH-range of their formation overlaps
significantly. Both types of chelates have high stability, start to
form with Cu2+ at pH ꢃ3 and the mixed-type bis-chelated coordi-
nation mode is the most favoured in this system. This is resulted in
favoured formation of [Cu2L2]2+, in which the two chelates of each
ligand are coordinated to different metal ions, and also the coordi-
nation mode is mixed-type in the bis-complexes formed in pres-
ence of excess of the ligand.
H2
C
CH
O
C
N
HN
N
Cu2+
CH2
CH
N
O
Cu2+
O
C
N
C
O
Cu2+
O
O
N
CH
Cu2+
O
Cu2+
H2C
N
N
NH
N
C
O
CH2
CH
N
H
Scheme 4.
Because neither the hydroxamate-[O,O]-, nor the histamine-
type [NH2,Nimid]-chelates play a major role in the Zn2+ binding,
the formation of different low stability mono-chelated linkage iso-
mers occurs in the Zn2+-N-Me-Hisha system above pH 5.
In spite of the well-known very high affinity of a hydroxamate
chelate towards the Fe3+ ion, surprisingly, histamine-type chelate
was found to have some role in the complexes formed in the
Fe3+-N-Me-Hisha in a recent work in our laboratory [43].
The protecting of the terminal amino moiety of the his-
tidinehydroxamic acid (Hisha) results in the elimination of the
amino-N as a donor atom and also a significantly decreased solu-
bility of all the ligand and especially the metal complexes.
The arrangement of the donor atoms in Z-Hisha allow the for-
mation of a 5-membered hydroxamate [O,O]-chelate and a 7-
membered [Nimid,Nhydr]-chelate. Since, with Ni2+ and Zn2+ the sta-
bility of the latter chelate and also the monodentate coordination
of the imidazole-N is negligible compared to the stability of the for-
mer chelate, hydroxamate-type coordination mode predominates
in low stability complexes in these two systems. However, the
interaction between Cu2+ and Z-Hisha is very strong and results
in the formation of a high stability metallacrown. This complex
provides a good example for the existence of 12-MC-4 type metal-
lacrown with involvement of 5-membered and 7-membered
chelates.
an
restricted to an intermediate pH-range, ca. 4-6, because the con-
ditional stability of the 4N-coordinated species, bis( -aminohydr-
oxamate-Namino,Nhydr)copper, becomes higher compared to that of
the metallacrown above pH 6 [10–12,16]. The formation of a 12-
a-aminohydroxamate, the formation of the 12-MC-4 is
a
MC-4 type complex with two
(S)-glutamic- -hydroxamic acid and
acid, was found only recently and the stability of these metallacr-
c-aminohydroxamic derivatives,
c
c-aminobutanehydroxamic
owns are lower than the corresponding ones with
atives [10].
a-, or b-deriv-
Recently, we were able to confirm the formation of a 12-MC-4
type complex also with - and b-imidazole analoges [25] and
now, the results presented here in this paper clearly support the
existence of metallacrown with the -imidazole-hydroxamic acid
derivative, Z-Hisha. If the stability constants (log b) obtained for
the [Cu5H-4L4]2+ formed with
-, b- and -derivatives (Imidazole-
a
c
a
c
4-carbohydroxamic acid, Imidazole-4-acetohydroxamic acid and
Z-Hisha) are compared, the values of 44.112, 46.32 [25] and 38.5
(see Table 3), respectively, can be obtained. Especially, if it is taken
into account that the constant for the b-derivative was determined
in pure water, while the two others in DMSO-water mixture, the
same stability order (b > >a > c) can be seen as it was published with
aminohydroxamic acids [10]. Even if the value related to the metal-
2
In the case of im-4-Cha, which contains the imidazole-N in
a-position to the
Acknowledgements
hydroxamate function, the stability constant was determined and ESI-MS support of
[Cu5H-4L4]2+ was obtained in DMSO-water 50:50% (m/m) mixture at t = 25.0 °C and
I = 0.20 M (KCl) in the present work. The obtained log b[Cu5H-4L4]2+ = 44.11, m/z
= 408.
This work was supported by the Hungarian Scientific Research
Fund (OTKA-NKTH CK77586).

E. Csapó et al. / Polyhedron 29 (2010) 3137–3145
3145
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Appendix A. Supplementary data
}
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.poly.2010.08.023.
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