Synthesis, spectroscopic and X-ray characterization of various pyrazine-bridged platinum(II) complexes:1H NMR comparative study of their catalytic abilities in the hydrolysis of methionine- and histidine-containing dipeptides

Article abstract of DOI:10.1016/j.poly.2016.06.011

Four pyrazine (pz)-bridged Pt(II) complexes, [{Pt(1,3-pd)Cl}₂(μ-pz)]Cl₂·LiCl (1) (1,3-pd = 1,3-propylenediamine), [{Pt(2,2-diMe-1,3-pd)Cl}₂(μ-pz)]Cl₂·2[Li(H₂O)₄]Cl·2H₂O (2) (2,2-diMe-1,3-pd = 2,2-dimethyl-1,3-propylenediamine), [{Pt(1,3-pnd)Cl}₂(μ-pz)](ClO₄)₂·H₂O (3) (1,3-pnd = (±)-1,3-pentanediamine) and [{Pt(1,3-pnd)Cl}₂(μ-pz)]Cl₂·2[Pt(1,3-pnd)Cl₂]·2H₂O (4) have been synthesized. NMR and UV-Vis spectroscopic characterization has been performed for compounds 1-3, while single-crystal X-ray analysis has been carried out for complexes 2 and 4. Atomic distribution in the crystals of 4 indicated a disorder which could be attributed to the presence at the same crystallographic site of four distinct stereoisomers of the [{Pt(1,3-pnd)Cl}₂(μ-pz)]²⁺complex cation. The presence of four stereoisomeric products was also observed in complex 3 by¹³C NMR spectroscopy. Complexes 1-3 were converted into the corresponding aqua complexes, [{Pt(X)(H₂O)}₂(μ-pz)]⁴⁺(X is 1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd, respectively), and¹H NMR spectroscopy was applied for comparison of their catalytic activities with those of the analogous mononuclear [Pt(X)(H₂O)₂]²⁺and pyrazine-bridged [{Pt(en)(H₂O)}₂(μ-pz)]⁴⁺complexes in the hydrolysis of the N-acetylated l-methionylglycine (Ac-l-Met-Gly) and l-histidylglycine (Ac-l-His-Gly). All reactions were performed in the pH range 2.0-2.5 at 37 °C. It was found that all investigated dinuclear Pt(II)-aqua complexes promote selective cleavage of the amide bond involving carboxylic group of the anchoring amino acid methionine in the Ac-l-Met-Gly or histidine in the Ac-l-His-Gly.¹H NMR data indicate that neither the size of the chelated diamine ring (five-membered in ethylenediamine and six-membered in 1,3-propylenediamine) nor the bulky substituents incorporated into the 1,3-propylenediamine ligand have significant influence on the rate of hydrolysis of Ac-l-Met-Gly dipeptide. Meanwhile, the rate of hydrolysis of Ac-l-His-Gly depends on both of these factors and decreases in order en > 1,3-pd > 1,3-pnd > 2,2-diMe-1,3-pd. Moreover, it has been shown that all investigated dinuclear Pt(II)-aqua complexes are better catalytic agents in the hydrolysis of the dipeptides than the analogous mononuclear Pt(II)-aqua complexes. The present findings are expected to play a crucial role in the development of new Pt(II) complexes, which can act as effective catalytic reagents for the selective hydrolysis of peptides containing either methionine or histidine residues.

Full text of DOI:10.1016/j.poly.2016.06.011

Polyhedron 117 (2016) 367–376
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, spectroscopic and X-ray characterization of various
1
pyrazine-bridged platinum(II) complexes: H NMR comparative study
of their catalytic abilities in the hydrolysis of methionine- and
histidine-containing dipeptides
a
a
b
b,
a,
⇑
⇑
ˇ
_
ˇ
´
´
Snezana Rajkovic , Marija D. Zivkovic , Beata Warzajtis , Urszula Rychlewska , Miloš I. Djuran
a Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovi´ca 12, 34000 Kragujevac, Serbia
b Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89B, 61-614 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Four pyrazine (pz)-bridged Pt(II) complexes, [{Pt(1,3-pd)Cl}2(
l
-pz)]Cl2ÁLiCl (1) (1,3-pd = 1,3-propylenedi-
Received 14 March 2016
Accepted 8 June 2016
Available online 15 June 2016
amine), [{Pt(2,2-diMe-1,3-pd)Cl}2(
propylenediamine), [{Pt(1,3-pnd)Cl}2(
(1,3-pnd)Cl}2(
l
-pz)]Cl2Á2[Li(H2O)4]ClÁ2H2O (2) (2,2-diMe-1,3-pd = 2,2-dimethyl-1,3-
l
-pz)](ClO4)2ÁH2O (3) (1,3-pnd = ( )-1,3-pentanediamine) and [{Pt
l
-pz)]Cl2Á2[Pt(1,3-pnd)Cl2]Á2H2O (4) have been synthesized. NMR and UV–Vis spectro-
scopic characterization has been performed for compounds 1–3, while single-crystal X-ray analysis has
been carried out for complexes 2 and 4. Atomic distribution in the crystals of 4 indicated a disorder which
could be attributed to the presence at the same crystallographic site of four distinct stereoisomers of the
Keywords:
Pyrazine-bridged platinum(II) complex
X-ray crystallography
Methionine- and histidine-containing
dipeptides
NMR spectroscopy
Hydrolysis
[{Pt(1,3-pnd)Cl}2(
observed in complex 3 by 13C NMR spectroscopy. Complexes 1–3 were converted into the corresponding
aqua complexes, [{Pt(X)(H2O)}2(
-pz)]4+ (X is 1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd, respectively), and 1
NMR spectroscopy was applied for comparison of their catalytic activities with those of the analogous
mononuclear [Pt(X)(H2O)2]2+ and pyrazine-bridged [{Pt(en)(H2O)}2( -pz)]4+ complexes in the hydrolysis
of the N-acetylated -methionylglycine (Ac- -Met-Gly) and -histidylglycine (Ac- -His-Gly). All reactions
l
-pz)]2+ complex cation. The presence of four stereoisomeric products was also
l
H
l
L
L
L
L
were performed in the pH range 2.0–2.5 at 37 °C. It was found that all investigated dinuclear Pt(II)-aqua
complexes promote selective cleavage of the amide bond involving carboxylic group of the anchoring
amino acid methionine in the Ac-L-Met-Gly or histidine in the Ac-L
-His-Gly. 1H NMR data indicate that
neither the size of the chelated diamine ring (five-membered in ethylenediamine and six-membered in
1,3-propylenediamine) nor the bulky substituents incorporated into the 1,3-propylenediamine ligand
have significant influence on the rate of hydrolysis of Ac-
L-Met-Gly dipeptide. Meanwhile, the rate of
hydrolysis of Ac- -His-Gly depends on both of these factors and decreases in order en > 1,3-pd > 1,3-
L
pnd > 2,2-diMe-1,3-pd. Moreover, it has been shown that all investigated dinuclear Pt(II)-aqua complexes
are better catalytic agents in the hydrolysis of the dipeptides than the analogous mononuclear Pt(II)-aqua
complexes. The present findings are expected to play a crucial role in the development of new Pt(II) com-
plexes, which can act as effective catalytic reagents for the selective hydrolysis of peptides containing
either methionine or histidine residues.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
findings that these complexes can be an effective catalytic reagents
for the regioselective amide bond hydrolysis in these peptides
Our recent interest in the study of the reactions between dinu-
clear platinum(II) complexes with bridging diazine ligands and
methionine- and histidine-containing peptides stems from the
[1–3]. In accordance to this, the 1H NMR study of the hydrolytic
reactions between two Pt(II) complexes, mononuclear [Pt(en)
(H2O)2]2+ (en is ethylenediamine) and dinuclear [{Pt(en)
(H2O)}2(
glycine (Ac-
mononuclear Pt(II) complex, the two Pt(II) ions bridged with one
aromatic pyrazine ligand in the [{Pt(en)(H2O)}2(
-pz)]4+ complex
are more efficient in the hydrolysis of the Ac- -Met-Gly dipeptide,
l
-pz)]4+ (pz is pyrazine), and N-acetylated
L
-methionyl-
L-Met-Gly) have shown that in comparison with the
⇑
Corresponding authors. Fax: +48 61 829 1555 (U. Rychlewska), +381 34 335040
(M.I. Djuran).
l
E-mail addresses: urszular@amu.edu.pl (U. Rychlewska), djuran@kg.ac.rs
(M.I. Djuran).
L
http://dx.doi.org/10.1016/j.poly.2016.06.011
0277-5387/Ó 2016 Elsevier Ltd. All rights reserved.

´
S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
368
even when the hydrolytic reaction was performed with an excess
of [Pt(en)(H2O)2]2+ complex [1]. Moreover, reactions of two dinu-
clear diazine-bridged Pt(II) aqua complexes, [{Pt(en)(H2O)}2
(pz) and K2[PtCl4] were purchased from the Sigma–Aldrich Chem-
ical Co. All common chemicals were of reagent grade. The dipep-
tides L-Met-Gly and L-His-Gly were obtained from Bachem A.G.
(l
-pz)]4+ and [{Pt(en)(H2O)}2(
Ac- -Met-Gly and Ac-
(H2O)}2(
-pydz)]4+ complex reacts only with methionine sulfur
l
-pydz)]4+ (pydz is pyridazine), with
The terminal amino group in these peptides was acetylated by a
standard method [4]. The mononuclear platinum(II) complexes of
the type [Pt(X)Cl2] (X is 1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd) were
synthesized according to a procedure published in the literature
[5–7]. K2[PtCl4] was dissolved in water and mixed with an equimo-
lar amount of diamine ligand. The pH of the solution was adjusted
to ca. 3 by addition of 1 M HCl and the mixture was stirred at 80 °C
for 2 h. All complexes were crystallized from water at room tem-
perature. The pure complexes were obtained by recrystallization
from a small amount of water. The yield was between 80–90%.
These complexes were used for further synthesis of the corre-
sponding pyrazine-bridged Pt(II) complexes.
L
L-His-Gly indicated that the [{Pt(en)
l
atom and promotes the sole cleavage of the amide bond involving
the carboxylic group of this anchoring amino acid, while the anal-
ogous pyrazine Pt(II) aqua dimer reacts with both residues, pro-
moting cleavage of the amide bonds involving the carboxylic
groups of both amino acids, methionine and histidine [2]. The cat-
alytic disparity of these two diazine-bridged Pt(II) aqua dimers was
explained by the X-ray analysis of their chlorido analogues, [{Pt
(en)Cl}2(
the two complexes confirmed the presence of a hidden position
of the Pt(II) centers in the [{Pt(en)Cl}2( -pydz)]Cl2 complex caused
l-pydz)]Cl2 and [{Pt(en)Cl}2(l-pz)]Cl2. The X-ray data for
l
by their close proximity due to the ortho-substitution (the two Pt
2.2. Synthesis of Pt(II) dinuclear complexes 1–4
(II) centers are only 3.2535(4) Å apart), compared to the separation
of 6.7890(3) Å in [{Pt(en)Cl}2(
hindrance from the amine ligand, which in [{Pt(en)Cl}2(
l
-pz)]Cl2), and an additional steric
-pydz)]
The complexes [{Pt(1,3-pd)Cl}2(
diMe-1,3-pd)Cl}2(
-pz)]Cl2Á2[Li(H2O)4]ClÁ2H2O (2), [{Pt(1,3-pnd)
Cl}2(
l
-pz)]Cl2ÁLiCl (1), [{Pt(2,2-
l
l
Cl2 is hydrogen bonded to the chlorido ligand belonging to the
other Pt(II) center. Also, it was proposed that displacement of this
chlorido ligand by a water molecule would make this hydrogen
bond shorter due to the shortening of the metal–ligand bond dis-
tance [2].
In the course of the above investigations, we have recently
studied the rate of hydrolysis of the amide bond in Ac-
dipeptide in the presence of various [{Pt(X)(H2O)}2(
type complexes (X stands for bidentate coordinated diamine
ligands ethylenediamine, en; ( )-1,2-propylenediamine, 1,2-pn;
isobutylenediamine, ibn; trans-( )-1,2-diaminocyclohexane, dach)
[3]. We have demonstrated that the hydrolytic cleavage of the
amide bond involving the carboxylic group of methionine in
l
-pz)](ClO4)2ÁH2O (3) and [{Pt(1,3-pnd)Cl}2( -pz)]Cl2Á2[Pt
l
(1,3-pnd)Cl2]Á2H2O (4) were synthesized by modification of the
procedure published in the literature [1,8,9].
The mononuclear [Pt(X)Cl2] complex was converted into the
corresponding monodimethylformamide (dmf) complex [Pt(X)Cl
(dmf)]NO3 by treatment with 0.98 equivalents of AgNO3. To a solu-
tion of 55.3 mg (0.325 mmol) of AgNO3 in 5 cm3 of dmf was added
a suspension of 0.332 mmol of [Pt(X)Cl2] in 10 cm3 of dmf. The
mixture was stirred overnight at room temperature in the dark.
The precipitated AgCl was removed by filtration and the resulting
pale yellow dmf solution of [Pt(X)Cl(dmf)]NO3 was used as a start-
ing material for the preparation of the required pyrazine-bridged
platinum(II) complexes.
L
-Met-Gly
l
-pz)]4+
Ac-
hence can be notably hindered by increasing steric crowding in the
diamine part of the [{Pt(X)(H2O)}2(
-pz)]4+ complex. Giving impor-
tance to the fact that dinuclear Pt(II) complexes with diazine-
bridged ligands were shown to be effective catalytic reagents for
the hydrolytic cleavage of the amide bonds in the methionine-
and histidine-containing peptides and that selectivity and effi-
ciency of this hydrolytic reaction could be controlled by structural
modification of these dinuclear Pt(II) complexes, we have
synthesized four pyrazine (pz)-bridged Pt(II) complexes,
L
-Met-Gly dipeptide decreases in order en > 1,2-pn > ibn > dach,
The dmf solution of the pyrazine ligand (13.29 mg, 0.166 mmol)
was added dropwise to the solution of [Pt(X)Cl(dmf)]NO3. The mix-
ture was stirred at room temperature in the dark for 12 h. The sol-
vent was then rotary evaporated and the residue washed with
ether. The crude product was dissolved in a minimal amount of
0.5 mol/dm3 LiCl aqueous solution for 1, 2 and 4 or 0.5 mol/dm3
LiClO4 for 3. The obtained solution was left overnight in the dark.
The pale-yellow precipitate of the corresponding dinuclear Pt(II)
complex was removed by filtration, washed with methanol and
then ether, and air-dried. Depending on the type of diamine ligand
(X) the yield of complexes 1–4 was between 35% and 40%. Anal.
Calc. for 1 = C10H24Cl5LiN6Pt2 (FW = 802.70): C, 14.96; H, 3.01;
N, 10.47. Found: C, 14.80; H, 3.03; N, 10.07%. Anal. Calc. for 2 =
l
[{Pt(1,3-pd)Cl}2(
[{Pt(2,2-diMe-1,3-pd)Cl}2(
diMe-1,3-pd = 2,2-dimethyl-1,3-propylenediamine), [{Pt(1,3-pnd)
Cl}2(
-pz)](ClO4)2ÁH2O (3) (1,3-pnd = ( )-1,3-pentanediamine)
and [{Pt(1,3-pnd)Cl}2(
l
-pz)]Cl2ÁLiCl (1) (1,3-pd = 1,3-propylenediamine),
l
-pz)]Cl2Á2[Li(H2O)4]ClÁ2H2O (2) (2,2-
l
C14H52Cl6Li2N6O10Pt2 (FW = 1081.35): C, 15.55; H, 4.85; N, 7.77.
l
-pz)]Cl2Á2[Pt(1,3-pnd)Cl2]Á2H2O (4). Com-
Found: C, 16.04; H, 4.72; N, 8.17%. Anal. Calc. for 3 = C14H34Cl4N6
O9Pt2 (FW = 962.43): C, 17.47; H, 3.56; N, 8.73. Found: C, 17.46;
H, 3.48; N, 8.58%. Anal. Calc. for 4 = C24H64Cl8N10O2Pt4
(FW = 1588.77): C, 18.14; H, 4.06; N, 8.82. Found: C, 18.16; H,
3.80; N, 8.84%.
pounds 1–3 were characterized by elemental microanalysis, NMR
and UV–Vis spectroscopy. The structures of dinuclear complexes
2 and 4 have been established by single-crystal X-ray diffraction
analysis. The catalytic activities of the aqua derivatives of 1–3, with
general formulae [{Pt(X)(H2O)}2(
1,3-pd and 1,3-pnd, respectively), in the reactions with Ac-
l
-pz)]4+ (X is 1,3-pd, 2,2-diMe-
-Met-
L
2.3. Preparation of aqua Pt(II) complexes
Gly and Ac-L-His-Gly dipeptides have been investigated by
applying 1H NMR spectroscopy.
The dinuclear chlorido complexes 1–3 were converted into the
corresponding aqua derivatives, with general formulae [{Pt(X)
(H2O)}2(l
-pz)]4+, according to a previously published method
2. Experimental
[10] by treatment with 4.98, 5.98 and 3.98 equivalents of AgNO3
for 1–3, respectively. The same method was used for the prepara-
tion of mononuclear [Pt(X)(H2O)2]2+ complexes starting from the
corresponding chlorido complexes by reacting with AgNO3 in
1:1.98 molar ratio, respectively. In each case, the precipitated
white solid product was removed by filtration in the dark, and
the fresh solutions of the aqua complexes were kept in a refriger-
ator and used in the further experiments.
2.1. Materials
Distilled water was demineralized and purified to a resistance
greater than 10 M
cmÀ1. The compounds D2O, DNO3, NaOD,
1,3-propylenediamine (1,3-pd), ( )-1,3-pentanediamine (1,3-pnd),
2,2-dimethyl-1,3-propylenediamine (2,2-diMe-1,3-pd), pyrazine
X

´
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S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
2.4. Measurements
Crystal data and experimental details are summarized in Table 1.
The structures were solved by direct methods using SHELXS-86
[13] and refined by full-matrix least-squares calculations on F2
with SHELXL-97 [13]. The intensity data were corrected for absorp-
tion effects [12]. Anisotropic displacement parameters were
refined for all non-hydrogen atomic positions. Hydrogen atoms
attached to the carbon and nitrogen atoms were placed in calcu-
lated positions (methyl C–H = 0.96, methylene C–H = 0.97, methine
C–H = 0.98, aromatic C–H = 0.93 and amine N–H = 0.90 Å). Water
hydrogens were located on difference Fourier maps and the O–H
distances have been standardized to 0.85 Å. During the refinement,
isotropic displacement parameters for H-atoms were assigned 20%
higher than the isotropic equivalent for the atom to which the
H-atom was bonded. All H-atoms were refined as riding. Owing
2.4.1. pH measurements
All pH measurements were realized at ambient temperature
using an Iskra MA 5704 pH meter calibrated with Fischer certified
buffer solutions of pH 4.00 and 7.00. The results were not corrected
for the deuterium isotope effect.
2.4.2. NMR spectroscopy
The 1H and 13C NMR spectra were recorded on a Varian Gemini
2000 spectrometer (1H at 200 MHz, 13C at 50 MHz) using 5 mm
NMR tubes. The NMR samples were prepared in D2O as solvent
and the total volume was 0.6 cm3. Sodium trimethylsilylpropane-
3-sulfonate (TSP) was used as an internal reference. The 1H NMR
spectra were acquired using the WATERGATE sequence for water
suppression. Typical acquisition conditions were as follows: 90°
pulses, 24000 data number points, 4 s acquisition time, 1 s relax-
ation delay, collection of 16–128 transients and final digital resolu-
tion of 0.18 Hz per point. The 13C NMR spectra were recorded with
Waltz 16 1H broadband decoupling, 159136 scans, 0.5 s relaxation
delay, 1 s acquisition time, line broadening 1.0 Hz and 12500 Hz
spectral width. All the NMR spectra were processed using the Var-
ian VNMR software (version 6.1, revision C). The chemical shifts
are reported in ppm.
to the disorder of the dinuclear [{Pt(1,3-pnd)Cl}2(l
-pz)]2+ complex
cation, which manifested in alternating positions of the ethyl sub-
stituent, the occupancy factors for the pairs of equivalent carbon
atoms of these ethyl group were first refined freely with their
sum constrained to unity, while the displacement parameters of
the corresponding components of disorder were kept equivalent.
The site occupation factor refined to 0.50(1) indicating 1:1 occu-
pancy ratio. This value was kept fixed at the final stages of the
refinement allowing the individual displacement parameters of
the disorder components to vary. Multicomponent constitution of
the investigated single crystals prompted us to evaluate whether
these single crystals represent the whole bulk of the samples. For
this purpose we have recorded the X-ray powder patterns for sam-
ples 2 and 4 and compared the obtained patterns with the corre-
sponding patterns calculated on the basis of the known crystal
structures, by utilizing a procedure included in the MERCURY [14]
program. The measured and calculated powder patterns confirm
the purity of the sample of 4, but the experimental powder pattern
of 2 contains an extra line at 2h = 9.276°, suggestive of the presence
of some impurity. The calculated and measured powder patterns
are displayed in Fig. S1 of the Supporting information. SIEMENS
[15] and MERCURY [14] computer graphics programs were used to
prepare drawings.
Fresh solutions of the aqua derivatives of dinuclear complexes
1–3 or their mononuclear [Pt(X)(H2O)2]2+ analogues (X is 1,3-pd,
2,2-diMe-1,3-pd and 1,3-pnd, respectively) and Ac-
L-Met-Gly and
Ac- -His-Gly dipeptides were prepared separately and then mixed
L
in 1:1 molar ratio. The initial concentrations of dipeptide and aqua
complex solutions were 40 mM. All reactions were performed in
the pH range 2.0–2.5 at 37 °C. The rate constants were obtained
from the 1H NMR measurements. The values of the rate constants
for the reactions between an equimolar amount of the given
[{Pt(X)(H2O)}2(l L-His-Gly dipeptide were
-pz)]4+ complex and Ac-
determined when the data from the early part of the reaction (up
to 2 h) were fitted to a second-order process [11] by plotting x/ao
(ao À x) against t (where ao is the initial concentration of the Ac-
L-His-Gly dipeptide and x is the concentration of the corresponding
hydrolytically active Pt(II)-dipeptide [{Pt(X)(Ac-
L-His-Gly-N3)}
Table 1
Crystal data for 2 and 4.
(l
-pz){Pt(X)(H2O)}]4+ complex at time t). The concentration of
the given Pt(II)-dipeptide complex was determined from the inte-
gral values of the resonances at 7.30 and 7.06 ppm, which corre-
spond to the C5H imidazole protons of, respectively, free and
monodentate coordinated through N3, the Ac-L-His-Gly dipeptide.
Data was collected and analyzed using OriginPro 8 and Microsoft
Office Excel 2007 programs.
2
4
Crystal data
Chemical formula
(C14H32Cl2N6Pt2)Á2
(H8LiO4)Á4(Cl)Á2
(H2O)
1081.38
monoclinic, P21/c
(C14H32Cl2N6Pt2)Á2
(C5H14Cl2N2Pt)Á2(Cl)Á
2(H2O)
1588.81
triclinic, P1
Mr
ꢀ
Crystal system, space group
a, b, c (Å)
8.8468 (2),
13.2566 (2),
16.6892 (2)
7.5635 (3), 10.7877
(4), 14.0360(5)
2.4.3. UV–Vis spectrophotometry
The UV–Vis spectra for 1–3 were recorded on a Perkin Elmer
Lambda 35 double-beam spectrophotometer equipped with ther-
mostated 1.00 cm quartz Suprasil cells. The concentrations of the
stock solutions of dinuclear Pt(II) complexes in water were
5 Â 10À5 mol/dm3. The spectra were recorded over the wavelength
range 200–500 nm.
a
, b,
c
(°)
90, 91.505 (1), 90
83.241 (3), 88.064
(3), 87.868 (3)
1135.99 (7)
1
12.78
0.15 Â 0.05 Â 0.04
V (Å3)
1956.61 (6)
2
7.60
0.40 Â 0.13 Â 0.08
Z
l
(mmÀ1
)
Crystal size (mm)
Data collection
2.4.4. Elemental microanalyses
Tmin, Tmax
No. of measured, independent
and observed [I > 2r(I)]
reflections
0.356, 1.000
41298, 3457, 3090 18859, 3996, 3011
0.645, 1.000
Elemental microanalyses for carbon, hydrogen and nitrogen
parameters were performed by the Microanalytical Laboratory,
Faculty of Chemistry, University of Belgrade.
Rint
0.033
0.595
0.058
0.595
(sin h/k)max (ÅÀ1
)
2.5. X-ray analysis of 2 and 4
Refinement
R[F2 > 2 (F2)], wR(F2), S
r
0.019, 0.041, 1.05
0.036, 0.065, 1.02
No. of reflections
No. of parameters
No. of restraints
3457
185
0
0.85, À0.37
3996
237
37
0.83, À0.64
Single crystals suitable for X-ray analysis were obtained only for
2 and 4. Diffraction data for these complexes were measured with
a Xcalibur kappa-geometry diffractometer using CrysAlisPro soft-
D
qmax
,
D
qmin (e ÅÀ3
)
ware [12] and monochromated Mo Ka radiation (k = 0.71073 Å).

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S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
370
3. Results and discussion
Four pyrazine (pz)-bridged Pt(II) complexes ([{Pt(1,3-pd)Cl}2
-pz)]Cl2ÁLiCl (1), [{Pt(2,2-diMe-1,3-pd)Cl}2( -pz)]Cl2Á2[Li(H2O)4]
ClÁ2H2O (2), [{Pt(1,3-pnd)Cl}2( -pz)](ClO4)2ÁH2O (3) and
[{Pt(1,3-pnd)Cl}2(
-pz)]Cl2Á2[Pt(1,3-pnd)Cl2]Á2H2O (4); 1,3-pd =
(l
l
l
l
1,3-propylenediamine, 2,2-diMe-1,3-pd = 2,2-dimethyl-1,3-propy-
lenediamine and 1,3-pnd = ( )-1,3-pentanediamine) have been
synthesized. Compounds 1–3 have been characterized by NMR
(1H and 13C) spectroscopy, UV–Vis spectrophotometry and elemen-
tal microanalysis, while X-ray analysis has been applied for struc-
ture determination of 2 and 4, for which suitable single crystals
could be obtained. The catalytic activities of the aqua derivatives
of 1–3, with the general formulae [{Pt(X)(H2O)}2(
l
-pz)]4+, in the
L-His-Gly dipeptides have
reactions with Ac- -Met-Gly and Ac-
L
been investigated by applying 1H NMR spectroscopy. The catalytic
activities of the dinuclear aqua complexes 1–3 have been com-
pared with those displayed by the corresponding mononuclear
[Pt(X)(H2O)2]2+ complexes (X is 1,3-pd, 2,2-diMe-1,3-pd and 1,3-
pnd for 1–3, respectively) with the same two dipeptides.
Fig. 2. Constituents of the multicomponent crystals of 4. The crystal is a solid
solution of stereoisomers of the [{Pt(1,3-pnd)Cl}2(
-pz)]2+ complex cation (shown
l
in Fig. 3) that occupy the same crystallographic site. This is manifested by
alternating positions of the ethyl substituent distinguished here by bonds drawn
with full and open lines. The full lines refer to the equatorial and the open lines to
3.1. Complex characterization
the axial orientation of the ethyl substituent. As the [{Pt(1,3-pnd)Cl}2(l
-pz)]2+
3.1.1. X-ray crystallography
Single crystals suitable for X-ray analysis have been obtained
only for 2 and 4. The content of the multicomponent crystals of 2
and 4 is displayed in Figs. 1 and 2, respectively. Selected geometri-
cal parameters for these complexes are compared in Table 2.
Crystals of 2 consist of four different units, i.e. dinuclear [{Pt(2,2-
cation occupies an inversion center, only the symmetry independent part of the
complex is marked by labeled atoms. Displacement ellipsoids are drawn at 40%
probability level and H-atoms are shown as spheres of arbitrary radii.
The chelate rings adopt a chair conformation, significantly flat-
tened at the coordination site. The N–Pt–N angles in the
six-membered chelate rings (91.8(3) and 90.8(1)°) present a major
difference from those forming the five-membered rings in which
this angle reduces to 82.8(2)° [2].
diMe-1,3-pd)Cl}2(l
-pz)]2+ complex cation and lithium tetraaqua
ion, chloride anions and water molecules as illustrated in Fig. 1.
Crystals of 4 contain two types of Pt(II) complexes, mono- and
dinuclear, of the formulae Pt(1,3-pnd)Cl2 and [{Pt(1,3-pnd)Cl}2
(l
-pz)]2+, respectively, chloride anions and water molecules. The
In the multicomponent crystal of 4 the site occupied by the [{Pt
(1,3-pnd)Cl}2(l
-pz)]2+ cation is disordered. The disorder can be
constituents of this crystal lattice are displayed in (Fig. 2). In both
crystal structures the pyrazine ligand displays a bidentate-bridging
function leading to the formation of dinuclear complex cations of
modelled in two different ways that, in principle, might mirror
the presence at one site of four distinct stereoisomers illustrated
in Fig. 3. The stereoisomerism arises from the presence of stere-
ogenic center at one of the carbon atoms forming 1,3-propylenedi-
amine ring and from distinction to which of the two ring nitrogens
this carbon atom is attached. We differentiate the two nitrogen
atoms by their positioning with respect to the coordinated
chloride, as either trans (N1) or cis (N2). In the six-membered
1,3-propylenediamine ring ethyl substituent attached to the carbon
atom proximal to N1 adopts an equatorial position, while the one
attached to the carbon atom proximal to N2 is axial. With regards
to the configuration at the two carbon stereogenic centers, all
stereoisomers that mirror the electron density distribution at this
site possess the R,S or S,R configuration. Of four stereoisomers that
fit to the atomic positions obtained from the X-ray analysis, two
display Ci symmetry, i.e. they are either trans,trans-(R,S) or cis,cis-
(R,S) (Fig. 3a and b). Another two belong to asymmetrical trans-
(S), cis-(R) and cis-(S), trans-(R), isomers (Fig. 3c and d), randomly
distributed around the inversion center at this site in crystal. Con-
tribution of each type of the four possible stereoisomers to the
superposition picture that comes out from the electron density
map could not be established on the grounds of X-ray analysis.
However, by solving this crystal structure we were able to demon-
strate that preparation of the monodimethylformamide (dmf)
complex [Pt(1,3-pnd)Cl(dmf)]NO3 and consequent formation of
the dimetallic pyrazine complex did not proceed regiospecifically,
as either of the two chloride ligands was predisposed to play a role
of a leaving group. As a consequence, we have obtained a mixture
of stereoisomeric products which showed the unexpected property
of preferentially crystallizing together in a form of substitutional
solid solution.
the general formulae [{Pt(X)Cl}2(l
-pz)]2+ (X is 2,2-diMe-1,3-pd
and 1,3-pnd), and in both crystal structures these complexes are
positioned on the inversion centers. Each of the two Pt(II) ions in
the complex is surrounded by three nitrogen atoms and a chloride
ion. Both mono- and dinuclear Pt(II) complexes display a square-
planar geometry. In the cationic binuclear complexes the average
values of the Pt–N bond lengths to the aliphatic and aromatic
nitrogen atoms amount, respectively, to 2.037(5) and 2.027(3) Å.
Fig. 1. Constituents of the multicomponent crystals of 2. As the [{Pt(2,2-diMe-1,3-
pd)Cl}2(l
-pz)]2+ cation occupies an inversion center, only the symmetry indepen-
dent part of the complex is marked by labeled atoms. Displacement ellipsoids are
drawn at 40% probability level and H-atoms are shown as spheres of arbitrary radii.

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S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
Table 2
Selected geometrical parameters (Å, °).
[{Pt(2,2-diMe-1,3-pd)Cl}2(
l
-pz)]2+
[{Pt(1,3-pnd)Cl}2(l
-pz)]2+
Pt1Á Á ÁPt1i
6.8250 (2)
58.5 (2)
Pt1Á Á ÁPt1i
6.8137 (6)
56.4 (2)
Angle between coordination plane and the pz plane
Angle between coordination plane and the pz plane
N1–Pt1
N2–Pt1
N3–Pt1
Cl1–Pt1
2.041 (2)
2.030 (2)
2.030 (2)
2.2991 (9)
N1–Pt1
N2–Pt1
N3–Pt1
Cl1–Pt1
2.041 (6)
2.035 (6)
2.024 (6)
2.298 (2)
N3–Pt1–N2
N3–Pt1–N1
N2–Pt1–N1
N3–Pt1–Cl1
N2–Pt1–Cl1
N1–Pt1–Cl1
178.27 (10)
90.81 (10)
90.84 (10)
90.21 (8)
88.15 (8)
178.77 (8)
N3–Pt1–N2
N3–Pt1–N1
N2–Pt1–N1
N3–Pt1–Cl1
N2–Pt1–Cl1
N1–Pt1–Cl1
176.9 (3)
89.0 (2)
91.8 (3)
91.04 (17)
88.1 (2)
179.9 (2)
N1–C1–C2–C3
C1–C2–C3–N2
C2–C3–N2–Pt1
C3–N2–Pt1–N1
N2–Pt1–N1–C1
Pt1–N1–C1–C2
À67.0(5)
65.4(5)
À58.9 (4)
42.2 (3)
À42.9 (2)
60.8 (4)
N1–C1–C2–C3
C1–C2–C3–N2
C2–C3–N2–Pt1
C3–N2–Pt1–N1
N2–Pt1–N1–C1
Pt1–N1–C1–C2
65.7(13)
À69.4(13)
56.7 (10)
À38.4 (7)
33.9 (7)
À50.0 (11)
[Pt(1,3-pnd)Cl2]
N4–Pt2
N5–Pt2
2.039 (7)
2.044 (6)
Cl2–Pt2
Cl3–Pt2
2.306 (2)
2.308 (2)
N4–Pt2–N5
N4–Pt2–Cl2
N5–Pt2–Cl2
92.4 (3)
86.51 (19)
177.9 (2)
N4–Pt2–Cl3
N5–Pt2–Cl3
Cl2–Pt2–Cl3
178.3 (2)
88.1 (2)
92.88 (9)
N4–C8–C9–C10
C8–C9–C10–N5
C9–C10–N5–Pt2
71.6(9)
C10–N5–Pt2–N4
N5–Pt2–N4–C8
Pt2–N4–C8–C9
À35.6(6)
38.2(6)
À58.1(9)
À71.7(10)
55.6(9)
Symmetry code(s): (i) Àx + 1, Ày, Àz + 1.
In both investigated crystal structures there are numerous
N–HÁ Á ÁCl, N–HÁ Á ÁO and O–HÁ Á ÁCl hydrogen bonds, which together
with electrostatic interactions take part in the cohesion of the
investigated crystals. Two types of hydrogen-bonding interactions
can be distinguished, namely direct N–HÁ Á ÁCl hydrogen bonds
between metal complexes or between ligand amine and ClÀ ion,
and water-bridged hydrogen bonding from amine group to a water
molecule and then to the ClÀ ion. Hydrogen bond parameters are
listed in Table S1 of SI.
coordination to the Pt(II) center was also observed for 2 (Table 3)
and the 1H NMR spectrum of 2,2-diMe-1,3-pd ligand became more
complex. The singlet at 0.84 ppm for two CH3 groups was shifted
downfield to 1.01 ppm while that at 2.41 ppm for C1 and C3 termi-
nal methylene protons of free 2,2-diMe-1,3-pd ligand was split into
two singlets (2.38 and 2.49 ppm). Also observed was the splitting
of the carbon-13 resonance at 51.69 ppm for C1 and C3 terminal
carbon atoms, again displaying stereochemical and environmental
non-equivalence of the two carbons (Table 3).
All 1H NMR resonances for complex 3 were shifted downfield in
respect to those for the uncoordinated 1,3-pnd ligand. The triplet
at 0.86 ppm for C5 methyl protons of the free ligand, after coordi-
nation to Pt(II) ion was split into two triplets at 0.93 and 1.00 ppm,
which overlap into doublet of triplets. Two remaining multiplets in
this spectrum at larger chemical shifts were assigned to C2 and C4
methylene protons (1.82 ppm), and to C1 methylene and C3
methine protons (2.82 ppm). In the 13C NMR spectrum of the free
1,3-pnd ligand five peaks were observed in the region of
12–53 ppm indicating the nonequivalence of all carbons. The peaks
at 12.08 and 31.94 ppm were assigned to the C5 methyl and C4
methylene carbon resonances of ethyl group, respectively. The
peak at 40.27 ppm was assigned to the middle C2 methylene
carbon atom, while the remaining two peaks at 41.49 and
52.02 ppm were assigned to the terminal C1 methylene and C3
methine carbon resonances of 1,3-propylenediamine chain, respec-
tively. After coordination of 1,3-pnd to the Pt(II) ion in complex 3
its 13C NMR spectrum becomes more complex. Thus, two reso-
nances for C5 methyl and C2 methylene carbon atoms were split
into two pairs of signals at 11.93 and 12.04 ppm for C5 and
42.84 and 42.94 ppm for C2 atoms. However, each of the reso-
nances for C1, C3 and C4 carbons in complex 3 was split into four
signals, almost all shifted downfield in respect to those for the free
1,3-pnd ligand. The appearance of four distinct resonances for C1,
C3 and C4 carbon atoms can be explained by assuming the
3.1.2. NMR spectroscopy
The 1H and 13C NMR chemical shifts of free diamine (1,3-pd,
1,3-pnd and 2,2-diMe-1,3-pd) and pyrazine ligands and those for
these ligands coordinated to Pt(II) in the corresponding [{Pt(X)
Cl}2(l
-pz)]2+ complexes 1–3 are listed in Table 3. The NMR chem-
ical shifts for complexes 1 and 2 have been previously reported [9]
and here these spectral data have been repeated and discussed in
comparison with those for the uncoordinated diamine ligands
and complex 3. All chemical shifts for the uncoordinated diamine
X and pz ligands generally agree with the literature values [16].
After chelation of 1,3-pd ligand to Pt(II) in complex 1 its two 1H
NMR multiplets centered at 1.60 and 2.65 ppm for middle C2 and
terminal C1 and C3 methylene protons, respectively, are shifted
downfield (Dd = 0.29 for C2 and 0.14 ppm for C1 and C3 methylene
protons). Downfield shifting of two signals for middle and terminal
carbon atoms of 1,3-pd was also observed in the 13C NMR spectrum
of the corresponding Pt(II) complex. Moreover, a signal for C1 and
C3 terminal carbon atoms of 1,3-pd at 39.40 ppm was split into
two (44.55 and 45.66 ppm), which demonstrates that upon coordi-
nation to Pt(II) the two carbon nuclei are found in different chem-
ical environments, similarly as the nitrogen nuclei to which they
are attached, i.e. upon coordination, one of these nitrogen atoms
becomes cis and the other trans oriented with respect to the coor-
dinated chloride. Not surprisingly the downfield shifting upon

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S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
Fig. 3. trans,cis-(S,R) Stereoisomers of the [{Pt(1,3-pnd)Cl}2(
l
-pz)]2+ complex cation, whose possible presence in the crystal lattice is consistent with the observed electron
density distribution: trans,trans-(S,R) (a), cis,cis-(S,R) (b), trans,cis-(S,R) (c) and cis,trans-(S,R) (d).
Table 3
1H and 13C NMR chemical shifts (d, ppm) for the free 1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd ligands and the corresponding pyrazine-bridged Pt(II) complexes 1–3, respectively, in
D2O as solvent with TSP as the internal standard.
Diamine (X)/Pt(II) complexa
1H NMR
13C NMR
4
1
5
2
2
4
H N
2
NH
2
H N
H N
2
NH
2
2
3
NH
2
1
3
1
5
3
2
2,2-diMe-1,3-pd
1,3-pd
1,3-pnd
1,3-pd
[{Pt(1,3-pd)Cl}2(
2,2-diMe-1,3-pd
1.60 (m, C2), 2.65 (m, C1 and C3)
1.89 (m, C2), 2.79 (m, C1 and C3), 9.02 (s, pz)
0.84 (s, C4 and C5), 2.41 (s, C1 and C3)
1.01 (s, C4 and C5), 2.38 and 2.49 (2s, C1 and C3),
9.05 (s, pz)
28.52 (C2), 39.40 (C1 and C3)
l
-pz)]2+b (1)
29.82 (C2), 44.55, 45.66 (C1 and C3) 153.56 (pz)
24.72 (C4 and C5), 35.81 (C2), 51.69 (C1 and C3)
25.57 (C4 and C5), 36.14 (C2), 53.97, 54.99
(C1 and C3), 153.58 (pz)
[{Pt(2,2-diMe-1,3-pd)Cl}2(
l
-pz)]2+b (2)
1,3-pnd
[{Pt(1,3-pnd)Cl}2(l-pz)] (3)
0.86 (t, C5), 1.45 (m, C2 and C4), 2.66 (m, C1 and C3)
0.93, 1.00 (dt, C5), 1.82 (m, C2 and C4), 2.82
(m, C1 and C3), 9.06 (s, pz)
12.08 (C5), 31.94 (C4), 40.27 (C2), 41.49 (C1), 52.02 (C3)
11.93,12.04 (C5), 30.12, 30.28,33.21, 33.54 (C4), 42.84,
42.94 (C2), 43.26, 43.36, 43.73, 43.78 (C1), 56.18,
56.25, 57.14, 57.27 (C3), 153.62 (pz)
2+
a
1H and 13C NMR chemical shifts of free pz are at 8.66 (s) and 143.86 ppm, respectively.
Ref [9].
b
presence of four distinct stereoisomeric products of 3. The exis-
tence of such mixture of stereoisomers in a crystal has been indi-
cated by the X-ray analysis of complex 4, see Fig. 3.
pyrazine ligand was detected in the range 9.02–9.06 ppm (Table 3).
This is in accordance with data previously reported for similar din-
uclear Pt(II) complexes [1,8,16]. Four protons of uncoordinated
pyrazine appear as a singlet at 8.66 ppm and this singlet is being
shifted downfield after bidentate coordination of pyrazine to two
In the aromatic region of the 1H NMR spectra of investigated
dinuclear Pt(II) complexes a singlet corresponding to the bridging

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S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
equivalent mononuclear Pt(II) units. Free pyrazine shows carbon-
13 signal at 143.86 ppm, which after bidentate coordination to Pt
(II) shifts downfield to 153.56–153.71 ppm.
(H2O)}2(l
-pz)]4+ complex (chemical shifts of this singlet is depen-
dent from the type of Pt(II) complex) decreased while two sym-
metric multiplets in the range 8.75–9.00 ppm increased. The
appearance of these two new multiplets indicates that one Pt(II)–
N(pyrazine) bond of Pt(II) complex was broken and that the four
pyrazine protons of this ligand coordinated in a monotopic fashion
to Pt(II) ion were split into two multiplets because of vicinal and
long-range coupling [1,8,16].
3.1.3. UV–Vis spectrophotometry
A typical plot of the UV–Vis spectra of 1–3 is given in Fig. 4. All
complexes have absorption maxima within a wavelength range of
280–290 and shoulders in the range of 340–360 nm. These spectra
have been compared with those for the analogous [{Pt(en)Cl}2(l-
pz)]Cl2 complex. The crystal structure of this complex has been
previously reported [1] and herein its UV–Vis spectrum is pre-
sented as a reference. As it can be seen in Fig. 4, the spectra of
all presently investigated Pt(II) complexes are almost identical
with that of [{Pt(en)Cl}2(l-pz)]Cl2 of the known crystal structure
indicating that they have bidentate coordinated diamine ligand
3.2.1. Ac-
When an equimolar amount of [{Pt(X)(H2O)}2(
incubated with Ac- -Met-Gly, under the above mentioned experi-
mental conditions, all reactions ended up with the formation of
L-Met-Gly
l
-pz)]4+ was
L
the platinum(II)-dipeptide [{Pt(X)(Ac-L-Met-Gly-S)}(l-pz){Pt(X)
(H2O)}]4+ complex (Fig. 5a) in a yield of more than 95% achieved
in less than 30 min. Formation of this intermediate product was
detected by the simultaneous decline of the proton NMR resonance
and pyrazine ligand bridging two equivalent Pt(II) units.
3.2. Hydrolytic reactions of pyrazine-bridged Pt(II) complexes with
at 2.11 ppm, arising from the S-methyl protons of free Ac-L-Met-
Ac-
L
-Met-Gly and Ac-
L
-His-Gly dipeptides
Gly, and the growth of the resonance at 2.45–2.55 ppm, corre-
sponding to the protons of the dipeptide coordinated to Pt(II)
through the sulfur atom. These chemical shifts are in accordance
with those previously reported for the reactions of Pt(II) complexes
with different methionine-containing molecules [20–22]. In all
The pyrazine (pz)-bridged Pt(II) complexes 1–3 were converted
into the corresponding aqua species, [{Pt(X)(H2O)}2(
-pz)]4+ (X is
1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd, respectively), and their cat-
alytic activities in the hydrolytic cleavage of Ac- -Met-Gly and
Ac-
-His-Gly dipeptides were investigated by 1H NMR spec-
troscopy. The rate of hydrolysis of these two dipeptides in the pres-
ence of [{Pt(X)(H2O)}2(
-pz)]4+ complexes with six-membered
diamine ring (X) were compared with those for [{Pt(en)
(H2O)}2(
-pz)]4+ complex having five-membered diamine ring
[1,2]. All these reactions were carried out with an equimolar
amounts of the Pt(II) complex and corresponding dipeptide in
the pH range 2.0–2.5 at 37 °C. As it was shown in our previous
studies [17–20], acidic solutions are needed to suppress the forma-
tion of hydroxo-bridged oligomeric Pt(II) complexes, which are
l
L
investigated reactions the [{Pt(X)(Ac-
(H2O)}]4+ complex is hydrolytically active and promotes the selec-
tive cleavage of the Met-Gly amide bond in the Ac- -Met-Gly
dipeptide. The 1H NMR resonance at 4.02 ppm corresponding to
the glycine protons of the Ac- -Met-Gly dipeptide attached to the
L-Met-Gly-S)}(l-pz){Pt(X)
L
L
l
L
l
Pt(II) decreased, while that at 3.76 ppm for the free glycine
increased (Fig. S2 of SI). Upon addition of glycine to the reaction
mixture the resonance at 3.76 ppm was enhanced confirming the
presence of uncoordinated glycine molecules. The amount of the
hydrolytic product was determined from the known initial concen-
tration of Ac-
tion of [{Pt(X)(Ac-
L
-Met-Gly (which was almost equal to the concentra-
catalytically inactive. All [{Pt(X)(H2O)}2(
l
-pz)]4+ complexes were
L-Met-Gly-S)}(
l
-pz){Pt(X)(H2O)}]4+ complex)
stable under the above mentioned experimental conditions. Thus,
no elimination of the bridging-pyrazine ligand or opening of
diamine ring X was observed during 24 h of the reaction time.
and from the integrated resonance for the methylene protons of
the free glycine. We have found that during the first 6 h the pyra-
zine-bridged Pt(II) complex with the five-membered ethylenedi-
amine ring was better promoter of the hydrolytic cleavage of the
Met-Gly amide bond than any of the presently investigated [{Pt
However, when the reactions of [{Pt(X)(H2O)}2(l
-pz)]4+ with
Ac-L-Met-Gly and Ac-L-His-Gly dipeptides were followed for more
than 24 h, some changes in the aromatic region of the 1H NMR
spectrum were observed. The singlet appeared in the region at
9.02–9.06 ppm for the bridging pyrazine ligand of [{Pt(X)
(X)(H2O)}2(l
-pz)]4+ complexes, all having the six-membered dia-
mine ring X. No significant difference in the catalytic activities
between 1,3-pd, 1,3-pnd and 2,2-diMe-1,3-pd dinuclear Pt(II)
Fig. 4. UV–Vis spectra of investigated complexes 1–3. These spectra were compared with that for [{Pt(en)Cl}2(l-pz)]Cl2 complex of the known crystal structure [1].

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S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
O
O
NH
NH
OH
OH
N
H
N
H
O
X
O
O
O
3
HN1
N
S
OH2
OH2
Pt
N
Pt
N
N
N
Pt
N
N
N
N
N
Pt
N
N
X
X
X
N
(a)
(b)
[{Pt(X)(Ac-L-Met-Gly-S)}(µ−pz){Pt(X)(H2O)}]4+
[{Pt(X)(Ac-L-His-Gly-N3)}(µ−pz){Pt(X)(H2O)}]4+
Fig. 5. Schematic presentation of the hydrolytically active platinum(II)-peptide complexes observed in the reaction of aqua derivatives of 1–3 with Ac-
Ac- -His-Gly (b) at pH 2.0–2.5 and 37 °C.
L-Met-Gly (a) and
L
complexes was observed during the 6 h time. However, when
these reactions were prolonged for up to 24 h the amount of
hydrolyzed Met-Gly amide bond achieved 85–90% for all Pt(II)
complexes, indicating that hydrolysis of the dipeptide has been
almost completed (Fig. 6a). Our recently published results obtained
3.2.2. Ac-
When an equimolar amount of [{Pt(X)(H2O)}2(
incubated with Ac- -His-Gly dipeptide for 24 h and in the pH range
2.0–2.5 at 37 °C, only one NMR detectable [{Pt(X)(Ac- -His-Gly-
N3)}(
-pz){Pt(X)(H2O)}]4+ complex was observed in the reaction
mixture (see Fig. 5b). As it is shown in this figure, the [{Pt(X)
(Ac- -His-Gly-N3)}(
-pz){Pt(X)(H2O)}]4+ complex contains the
Ac- -His-Gly dipeptide monodentate coordinated via the imidazole
L-His-Gly
l
-pz)]4+ was
L
L
l
for a series of dinuclear [{Pt(X)(H2O)}2(
l
-pz)]4+ complexes (X is
1,2-pn;
ethylenediamine, en; ( )-1,2-propylenediamine,
isobutylenediamine, ibn; and trans-( )-1,2-diaminocyclohexane,
L
l
L
dach) pointed to a steady decrease of the amount of the hydrolyzed
Ac-L-Met-Gly dipeptide with an increase of the steric hindrance
within the five-membered chelate ring (X) (en > 1,2-pn > ibn > -
dach) [3]. Conversely, our present results indicate that steric mod-
N3 atom. No coordination to N1 imidazole nitrogen was observed.
The formation of this Pt(II)-dipeptide complex was evidenced by
the appearance of new resonances in the 1H NMR spectrum at
8.08 and 7.06 ppm corresponding to the C2H and C5H imidazole
protons, respectively, and by the simultaneous decrease of the res-
onances at 8.58 and 7.30 ppm, which correspond to the resonances
of these two protons in a free dipeptide. The chemical shifts of the
ification of the six-membered diamine ring in [{Pt(X)(H2O)}2(l-
pz)]4+ complexes (X is 1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd) has
no significant influence on the rate of the hydrolysis of Ac-L-Met-
Gly dipeptide, see Fig. 6a.
C2H and C5H imidazole protons of the [{Pt(X)(Ac-
-pz){Pt(X)(H2O)}]4+ are in accordance to those for the reaction
of Ac-L-His-Gly dipeptide with mononuclear [Pt(en)(H2O)2]2+
[17,20,23,24] and dinuclear [{Pt(en)(H2O)}2(
-pz)]4+ [2] com-
plexes, all displaying a monodentate coordination of the dipeptide
through the N3 imidazole nitrogen atom. The given [{Pt(X)(Ac-
His-Gly-N3)}(
-pz){Pt(X)(H2O)}]4+ complex is an intermediate
product which promotes cleavage of the His-Gly amide bond in
L-His-Gly-N3)}
(l
100
l
(a)
80
60
40
20
0
L-
l
Ac-L-His-Gly dipeptide attached to the Pt(II). This hydrolytic reac-
tion can be successfully followed by observing changes in the 1H
NMR spectrum in time (Fig. S2 of SI). As the time passes, the reso-
nance at 3.92 ppm, which belongs to the methylene glycine pro-
tons of the uncoordinated Ac-
L
-His-Gly as well as to the same
protons in the [{Pt(X)(Ac- -His-Gly-N3)}(
L
l
-pz){Pt(X)(H2O)}]4+ type
of complex, decreases while a new resonance at 3.62 ppm from the
free glycine increases. Upon addition of glycine to the reaction
mixture, the resonance at 3.62 ppm has been markedly enhanced.
The concentration of free glycine resulting from this hydrolytic
process was determined from the known initial concentration of
1
0.5
2
2
3
4
4
6
5
24
50
40
30
20
10
0
en
(b)
1,3-pd
1,3-pnd
Ac-
concentrations of [{Pt(X)(Ac-
complex and uncoordinated Ac-
resonance of the free glycine. We have compared the catalytic
activities in the cleavage of the Ac- -His-Gly dipeptide for [{Pt(X)
(H2O)}2(
-pz)]4+ type complexes with those displayed by the pre-
viously investigated [{Pt(en)(H2O)}2(
-pz)]4+ complex [2] (Table 4).
L
-His-Gly dipeptide (this concentration is equal to the sum of
-His-Gly-N3)}(
-pz){Pt(X)(H2O)}]4+
-His-Gly) and from the integrated
2,2-diMe-1,3-pd
L
l
L
L
l
l
The time dependence of the hydrolytic cleavage of the His-Gly pep-
tide bond in reactions between different dinuclear [{Pt(X)
0.5
2
4
6
24
5
(H2O)}2(
in Fig. 6b. From this figure it can be concluded that the amount
of the hydrolyzed Ac- -His-Gly dipeptide decreased in the follow-
l L-His-Gly dipeptide is given
-pz)]4+ complexes and Ac-
1
2
3
4
time (h)
Fig. 6. Time dependence of the hydrolytic cleavage of Ac-
Ac- -His-Gly (b) in the presence of an equimolar amount of aqua derivatives of 1–3
at pH 2.0–2.5 and 37 °C. The catalytic activities of investigated complexes are
L-Met-Gly (a) and
L
L
ing order: en > 1,3-pd > 1,3-pnd > 2,2-diMe-1,3-pd. This difference
in the hydrolytic ability of the investigated dinuclear [{Pt(X)
compared with that for [{Pt(en)(H2O)}2(
l
-pz)]4+ complex reported in literature
(H2O)}2(l
-pz)]4+ type complexes can be correlated with their
[1,2].

´
375
S. Rajkovic et al. / Polyhedron 117 (2016) 367–376
Table 4
participate in the cleavage of the scissile amide bond, one by polar-
izing the carbonyl oxygen atom and another by delivering a water
molecule (see Fig. 5a and b). However, the single Pt(II) ion in the
mononuclear [Pt(X)(H2O)2]2+ complexes is incapable in promoting
these two interactions simultaneously.
Second-order rate constants for formation of the hydrolytically active platinum(II)-
peptide [{Pt(X)(Ac-L-His-Gly-N3)}(
[{Pt(X)(H2O)}2(
with Ac-L-His-Gly dipeptide. The rate constants were correlated with the amount of
hydrolyzed His-Gly amide bond observed after 24 h, [%]. All reactions were performed
in the pH range 2.0–2.5 at 37 °C.
l
-pz){Pt(X)(H2O)}]4+ complex in the reactions of
l
-pz)]4+ complexes (X is en, 1,3-pd, 2,2-diMe-1,3-pd and 1,3-pnd)
Complex
k2, 103k2/MÀ1 sÀ1
Hydrolyzed
His-Gly, [%]
4. Conclusions
[{Pt(en)(H2O)}2(
[{Pt(1,3-pd)(H2O)}2(
[{Pt(1,3-pnd)(H2O)}2(
l
-pz)]4+
-pz)]4+
-pz)]4+
[{Pt(2,2-diMe-1,3-pd)(H2O)}2(
2.08 0.06
1.58 0.05
1.09 0.09
0.87 0.01
45
36
25
17
Our investigations of the reactions of pyrazine (pz)-bridged [{Pt
l
l
(X)(H2O)}2(l
-pz)]4+ complexes (X is chelated diamine ligand
l
-pz)]4+
1,3-propylenediamine, 1,3-pd; ( )-1,3-pentanediamine, 1,3-pnd;
and 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd) with
Ac-L-Met-Gly and Ac-L-His-Gly showed that all these complexes
promote selective cleavage of the amide bond involving carboxylic
group of the anchoring amino acid methionine and histidine in the
investigated N-acetylated dipeptides. Furthermore, it was demon-
strated that the investigated complexes are more reactive with
methionine- than histidine-containing dipeptides and that struc-
tural modification of the diamine ligand X has no measurable effect
reactivity with Ac-
reactions leading to the formation of the hydrolytically active
[{Pt(X)(Ac- -His-Gly-N3)}(
-pz){Pt(X)(H2O)}]4+ complex are pre-
sented in Table 4. It can be seen from this table that the values
of the rate constants for these reactions decreased in the same
order as the amount of the hydrolyzed His-Gly amide bond. This
L-His-Gly. Second-order rate constants for the
L
l
on the catalytic activity of the [{Pt(X)(H2O)}2(
the 24 h lasting process of hydrolysis of the Met-Gly amide bond of
Ac- -Met-Gly dipeptide. This contrasts with the observed differen-
tiation of the catalytic activity of these complexes in the process of
hydrolysis of Ac- -His-Gly dipeptide. More specifically, the amount
of the hydrolyzed Ac- -His-Gly dipeptide decreased with an
l
-pz)]4+ complexes in
is in accord with the observation that reactivity of Ac-
L-His-Gly
with [{Pt(X)(H2O)}2(
l
-pz)]4+ complexes can be correlated with
L
structural modification of the diamine X ligand. This type of ligand
contributes to the steric bulk of the dinuclear Pt(II) complex hin-
dering the approach of the N3 imidazole atom of the histidine resi-
due to the metal center and consequent formation of hydrolytically
L
L
active [{Pt(X)(Ac-L-His-Gly-N3)}(l
-pz){Pt(X)(H2O)}]4+ complex.
increasing steric hindrance in the chelated diamine ligand X in
the following order en > 1,3-pd > 1,3-pnd > 2,2-diMe-1,3-pd. All
investigated dinuclear Pt(II)-aqua complexes are better catalytic
agents in the hydrolysis of the dipeptides than the analogous
mononuclear Pt(II)-aqua complexes.
Kinetic data presented in Table 4 confirmed that presently investi-
gated hydrolytic reaction can be inhibited by increasing the size of
the X ring from five- in ethylenediamine to six-membered in
1,3-propylenediamine and/or by incorporation of ethyl (1,3-pnd)
or two methyl groups (2,2-diMe-1,3-pd) to the 1,3-propylenedi-
amine chain.
Acknowledgements
Furthermore, we compared hydrolytic activity between dinu-
clear aqua derivatives of 1–3 and the corresponding mononuclear
[Pt(X)(H2O)2]2+ complexes (X is 1,3-pd, 2,2-diMe-1,3-pd and
This work was funded in part by the Ministry of Education,
Science and Technological Development of the Republic of Serbia
(Project No. 172036).
1,3-pnd, respectively), in their reactions with Ac-
L-Met-Gly and
Ac- -His-Gly dipeptides. All reactions were performed under the
L
above mentioned experimental conditions. Differences in the
amount of the hydrolyzed amide bond [%] in these dipeptides are
given in Table 5. From this table it can be seen that each dinuclear
Pt(II)-aqua complex in comparison with the analogue mononuclear
complex showed better catalytic activity in the hydrolysis of Met-
Appendix A. Supplementary data
CCDC 1035721–1035722 contains the supplementary crystallo-
graphic data for [cis,trans-{Pt(1,3-pnd)Cl}2(
l
-pz)]Cl2Á2[Pt(1,3-pnd)
Cl2]Á2H2O and [{Pt(2,2-diMe-1,3-pd)Cl}2(
l
-pz)]Cl2Á2[Li(H2O)4]
Gly and His-Gly amide bonds of Ac-L-Met-Gly and Ac-L-His-Gly
ClÁ2H2O. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.poly.2016.06.011.
dipeptides, respectively. These results are in accordance with those
reported recently for the reaction of dinuclear [{Pt(en)(H2O)}2
(l
-pz)]4+ and mononuclear [Pt(en)(H2O)2]2+ complexes with
Ac-
L
-Met-Gly dipeptide [1]. The better catalytic activity of dinu-
clear [{Pt(X)(H2O)}2(
l
-pz)]4+ complexes in comparison to their
analogue mononuclear units can be explained by the facts that two
Pt(II) centers in these dinuclear complexes could simultaneously
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