Crystallographic evidence of anion?π interactions in the pyrazine bridged {[Pt(en)Cl]2(μ-pz)}Cl2 complex and a comparative study of the catalytic ability of mononuclear and binuclear platinum(II) complexes in the hydrolysis of N-acetylated l-methionylglycine

Article abstract of DOI:10.1016/j.poly.2012.12.037

This paper reports on the synthesis and the X-ray characteristics of the binuclear {[Pt(en)Cl]₂(μ-pz)}Cl₂ complex (en is ethylenediamine, acting as a bidentate ligand; pz is a bridging pyrazine ligand). This complex was converted into the corresponding aqua complex, {[Pt(en)(H₂O)]₂(μ-pz)}⁴⁺, and ¹H NMR spectroscopy was applied for a comparison of its catalytic activities in the hydrolysis of N-acetylated l-methionylglycine (Ac-l-Met-Gly) dipeptide with those for the mononuclear [Pt(en)(H₂O)₂]²⁺ complex. The peptide and the corresponding platinum(II) complex were reacted in different molar ratios and all reactions were performed at 2.0 < pH < 2.5 in D₂O solvent at 37 °C. The course of these hydrolytic reactions is discussed and the difference in the catalytic ability between the mononuclear and binuclear Pt(II) complexes was correlated with the presence of the different hydrolytically active platinum(II)-peptide complexes formed during their reactions with the Ac-l-Met-Gly dipeptide.

Full text of DOI:10.1016/j.poly.2012.12.037

Polyhedron 51 (2013) 255–262
Contents lists available at SciVerse ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Crystallographic evidence of anionꢀ ꢀ ꢀ
p
interactions in the pyrazine bridged
{[Pt(en)Cl]2(
l
-pz)}Cl2 complex and a comparative study of the catalytic ability
of mononuclear and binuclear platinum(II) complexes in the hydrolysis of
N-acetylated L-methionylglycine
a
a
a
b
b,
⇑
ˇ
_
´
ˇ
´
Darko P. Ašanin , Marija D. Zivkovic , Snezana Rajkovic , Beata Warzajtis , Urszula Rychlewska
,
Miloš I. Djuran a,
⇑
a Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovica 12, P. O. Box 60, 34000 Kragujevac, Serbia
b Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper reports on the synthesis and the X-ray characteristics of the binuclear {[Pt(en)Cl]2(
complex (en is ethylenediamine, acting as a bidentate ligand; pz is a bridging pyrazine ligand). This
complex was converted into the corresponding aqua complex, {[Pt(en)(H2O)]2(
-pz)}4+, and 1H NMR
spectroscopy was applied for a comparison of its catalytic activities in the hydrolysis of N-acetylated
-methionylglycine (Ac-
-Met-Gly) dipeptide with those for the mononuclear [Pt(en)(H2O)2]2+ complex.
The peptide and the corresponding platinum(II) complex were reacted in different molar ratios and all
reactions were performed at 2.0 < pH < 2.5 in D2O solvent at 37 °C. The course of these hydrolytic reac-
tions is discussed and the difference in the catalytic ability between the mononuclear and binuclear Pt(II)
complexes was correlated with the presence of the different hydrolytically active platinum(II)–peptide
l-pz)}Cl2
Received 31 August 2012
Accepted 21 December 2012
Available online 11 January 2013
l
L
L
Keywords:
Binuclear platinum(II) complex
L
-methionylglycine
Proton NMR spectroscopy
Hydrolysis
complexes formed during their reactions with the Ac-
L
-Met-Gly dipeptide.
Ó 2013 Elsevier Ltd. All rights reserved.
Anionꢀ ꢀ ꢀp interactions
1. Introduction
calculations, in which an anion is placed above the center of an
aromatic ring appeared in the literature ten years ago and initiated
a continuous discussion concerning its presence and structure
determining role [7,8]. On the basis of the results derived from
theoretical calculations and searches of the Cambridge Crystallo-
graphic Database (CSD), the authors have demonstrated the
Pyrazine, a weak base, acts as a monodentate or bridging
bidentate ligand in transition metal chemistry. As a bridging
bidentate ligand it commonly exhibits a simple and controllable
coordination mode and possesses small steric hindrance, there-
fore it has been recently utilized as a building unit for molecular
architectures with transition metals [1–3]. Another interesting
property of this ligand is modification of its basicity as
consequence of coordination to transition-metal fragments [4].
Combined together, the two properties make the pyrazine ligand
existence of anionꢀ ꢀ ꢀ
p interactions involving mainly electron
deficient aromatic systems, although the involvement of non-
electron-deficient aromatic rings was also considered as possible
whenever the aromatic ring was simultaneously interacting with
a
a cation [9]. The existence of anionꢀ ꢀ ꢀ
p interactions in metal com-
plexes stemming from encapsulation of a chloride anion by four
a good alternative to triazine in studies on anionꢀ ꢀ ꢀ
p
interactions
in metal complexes and their utilization for building new molec-
pyridine rings has been noted in 2004 [10]. Notably, the authors
ular architectures. The involvement of pyrazine and oxo anions in
pointed out that the observed chlorideꢀ ꢀ ꢀpyridine anionꢀ ꢀ ꢀ
p inter-
anionꢀ ꢀ ꢀ
p
interactions has already been reported [5,6]. In this pa-
actions were favored because the pyridine rings are coordinated
to copper ions, which enhances their electron-poor character. Fol-
lowing this report, other papers demonstrating the enhancing role
per we demonstrate the presence of such interactions between
chloride and pyrazine units.
The term anionꢀ ꢀ ꢀ
p
interaction to describe an attractive and
of metal coordination in anionꢀ ꢀ ꢀ
p interactions have appeared
non-covalent contact geometry, derived from quantum chemistry
[6,11,12]. To date, there are many reports on this subject due to
the various possible applications of these interactions in supramo-
lecular chemistry, including design of anion receptors and trans-
porters across bilayer membranes [13,14]. The most recent
perspective on the subject has been published by Reedijk and co-
⇑
Corresponding authors. Tel.: +48 61 8291 268; fax: +48 61 865 8008 (U.
Rychlewska), tel.: +381 34 300 251; fax: +381 34 335040 (M.I. Djuran).
E-mail addresses: urszular@amu.edu.pl (U. Rychlewska), djuran@kg.ac.rs (M.I.
Djuran).
workers [15]. Notably, anionꢀ ꢀ ꢀ
p interactions have been reported
0277-5387/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.poly.2012.12.037

256
D.P. Ašanin et al. / Polyhedron 51 (2013) 255–262
as being persistent in solution and in the gas phase [16], and a re-
view on the studies of these interactions in solution has appeared
only very recently [17].
13.12; H, 2.75; N, 11.48. Found: C, 13.16; H, 2.98; N, 11.19%. NMR
(1H and 13C) characterization (D2O, 200 MHz). 1H NMR (d, ppm):
2.68–2.79 (m, 4CH2, en), 9.03 (s, 4CH, pz); 13C NMR (d, ppm): 52.34
(4CH2, en), 153.46 (C2, C3, C4 and C5, pz).
From the other side, recent studies showed that the thiolate-
bridged (Me4N)2[Pd2(
different methionine-containing peptides of the type Ac-
l
-SPh)2Cl4] complex in the reactions with
L
-Met–X
2.4. Preparation of [Pt(en)(H2O)2]2+ and {[Pt(en)(H2O)]2(
l
-pz)}4+
(X is Gly, Val, Phe or Ala) was a very effective hydrolytic reagent
in the cleavage of these dipeptides in non-aqueous solvents [18].
An important advantage of dimerization is the possibility of coop-
eration between the metals, as was shown for hydrolysis of DNA,
RNA and their models catalyzed by polynuclear metal complexes
and metalloenzymes [19–24]. The above mentioned findings sug-
gested that polynuclear platinum(II) complexes could also be good
reagents for amide bond hydrolysis in reactions with methionine-
containing peptides.
The [Pt(en)Cl2] and {[Pt(en)Cl]2( -pz)}Cl2 complexes were con-
l
verted into the corresponding aqua complexes by treatment with
1.98 and 3.98 equivalents of AgNO3, respectively, according to a
previously published method [28]. In each case, the formed solid
AgCl was removed by filtration in the dark, and the fresh solutions
of the aqua complexes were kept in a refrigerator and used in sub-
sequent experiments.
In the present study we have synthesized and structurally char-
2.5. Analyses
acterized the new pz-bridged binuclear {[Pt(en)Cl]2(
plex. This complex was converted into the corresponding aqua
complex, {[Pt(en)(H2O)]2(
-pz)}4+, and 1H NMR spectroscopy was
applied for comparison of its catalytic activity in the hydrolysis of
l-pz)}Cl2 com-
Elemental microanalyses for carbon, hydrogen and nitrogen
were performed by the Microanalytical Laboratory, Faculty of
Chemistry, University of Belgrade.
l
N-acetylated L-methionylglycine (Ac-L-Met-Gly) dipeptide with that
of the mononuclear [Pt(en)(H2O)2]2+ complex. All the reactions were
2.6. pH Measurements
investigated at 2.0 < pH < 2.5 and at 37 °C in D2O solution.
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. Experimental
2.1. Materials
2.7. 1H NMR measurements
Distilled water was demineralized and purified to a resistance
greater than 10 M
ylenediamine (en), pyrazine (or 1,4-diazine), pz and K2[PtCl4] were
obtained from Aldrich Chemical Co. All common chemicals were of
reagent grade. The dipeptide L-methionylglycine (L-Met-Gly) was
obtained from Sigma Chemical Co. The terminal amino group in
this peptide was acetylated by a standard method [25]. The
[Pt(en)Cl2] complex was synthesized according to a procedure pub-
lished in the literature [26]. The purity of the complex was checked
by elemental microanalyses and NMR (1H and 13C) spectroscopy.
X
cmꢁ1. The compounds D2O, DNO3, NaOD, eth-
The 1H NMR spectra of D2O solutions containing TSP (sodium
trimethylsilylpropane-3-sulfonate) as the internal reference were
recorded with a Varian Gemini 2000 spectrometer (200 MHz).
Fresh solutions of the [Pt(en)(H2O)2]2+ and {[Pt(en)(H2O)]2(
l-
pz)}4+ complexes and Ac-
L-Met-Gly were prepared separately
(the initial concentration of each reactant was 40 mM) and then
mixed in an 5 mm NMR tube, and spectra were recorded at appro-
priate time intervals. All reactions were performed at 2.0 < pH < 2.5
and at 37 °C. The reactions between the platinum(II) complexes
and Ac-
lar ratios: [Pt(en)(H2O)2]2+:Ac-
{[Pt(en)(H2O)]2(
-pz)}4+:Ac- -Met-Gly = 1:1 and 1:2. 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 relaxa-
tion delay, collection of 16–128 transients and final digital resolu-
tion of 0.18 Hz per point. All proton NMR spectra were processed
using the Varian V NMR software (version 6.1, revision C). The
chemical shifts are reported in ppm.
L
-Met-Gly dipeptide were investigated in the following mo-
2.2. Preparation of [Pt(en)(dmf)Cl]NO3
L-Met-Gly = 1:1, 2:1 and 1:2 and
l
L
The [Pt(en)Cl2] complex was converted into the corresponding
monodimethylformamide (dmf) complex [Pt(en)(dmf)Cl]NO3 by
treatment with 0.98 equivalents of AgNO3, according to
previously published method [27]. To a solution of 55.3 mg
(0.325 mmol) of AgNO3 in 5 cm3 of dmf was added a suspension
of 108.3 mg (0.332 mmol) of [Pt(en)Cl2] in 10 cm3 of dmf. The mix-
ture 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(en)(dmf)Cl]NO3 was used as the starting
material for the preparation of the required pyrazine-bridged binu-
a
2.8. X-ray analysis of the {[Pt(en)Cl]2(l-pz)}Cl2 complex
clear platinum(II) complex, {[Pt(en)Cl]2(
2.3. Preparation of the {[Pt(en)Cl]2( -pz)}Cl2 complex
dmf solution of the pyrazine ligand (pz) (13.29 mg,
0.166 mmol) was added dropwise to a solution of [Pt(en)(dmf)-
Cl]NO3. The mixture was stirred at room temperature in the dark
for 3 h. The solvent was then rotary evaporated and the residue
was washed with ether. The crude product was dissolved in a mini-
mal amount of 0.5 mol/dm3 LiCl aqueous solution. The obtained
solution was left overnight in the dark. The pale-yellow precipitate
l-pz)}Cl2.
Diffraction data for the {[Pt(en)Cl]2(
measured with a Xcalibur kappa-geometry diffractometer using
CrysAlisPro software [29] and monochromated Mo K radiation
l-pz)}Cl2 complex were
l
a
(k = 0.7173 Å). Crystal data and experimental details are summa-
rized in Table 1. The structure was solved by direct methods using
SHELXS-86 [30] and refined by full-matrix least-squares calculations
on F2 with SHELXL-97 [30]. The intensity data were corrected for
absorption effects [29]. Anisotropic displacement parameters were
refined for all non-hydrogen atomic positions. Hydrogen atoms at-
tached to the carbon and nitrogen atoms were placed in calculated
positions (methylene C–H = 0.97, aromatic C–H = 0.93 and amine
N–H = 0.90 Å). During the refinement isotropic displacement
parameters for H-atoms were assigned 20% higher than the isotro-
pic equivalent for the atom to which the H-atom was bonded. All
A
of {[Pt(en)Cl]2(
methanol and then ether, and air-dried. Yield 48.61 mg (40%). Anal.
Calc. for {[Pt(en)Cl]2( -pz)}Cl2 = C8H20N6Cl4Pt2 (FW = 732.25): C,
l-pz)}Cl2 was removed by filtration, washed with
l

D.P. Ašanin et al. / Polyhedron 51 (2013) 255–262
257
Table 1
Table 3
Crystal data for {[Pt(en)Cl]2(l-pz)}Cl2.
Hydrogen bond parameters for {[Pt(en)Cl]2(l-pz)}Cl2.
Crystal data
Chemical formula
Mr
Crystal system, space group
T (K)
a (Å)
b (Å)
c (Å)
D–Hꢀ ꢀ ꢀ
D–H (Å)
Hꢀ ꢀ ꢀA (Å)
Dꢀ ꢀ ꢀA (Å)
D–Hꢀ ꢀ ꢀA (°)
C8H20Cl2N6Pt2ꢀ2(Cl)
732.28
monoclinic, P21/n
295
5.07703(9)
12.6594(2)
14.1839(2)
97.7545(16)
903.29(2)
2
N1–H1Bꢀ ꢀ ꢀCl2
N1–H1Aꢀ ꢀ ꢀCl2i
N2–H2Aꢀ ꢀ ꢀCl2ii
N2–H2Bꢀ ꢀ ꢀCl2iii
0.90
0.90
0.90
0.90
2.44
2.41
2.46
2.34
3.291 (3)
3.230 (3)
3.313 (3)
3.211 (3)
156.9
150.9
157.4
161.9
b (°)
V (Å3)
Z
Radiation type
Mo Ka
16.06
l
(mmꢁ1
)
Crystal size (mm)
0.20 ꢂ 0.20 ꢂ 0.10
Data collection
Diffractometer
Xcalibur
Absorption correction
Tmin, Tmax
No. of measured, independent and observed
Multi-scan
0.405, 1.000
20103, 1588, 1545
[I > 2r(I)] reflections
Rint
0.026
0.595
Fig. 1. Perspective view of the dinuclear complex cation {[Pt(en)Cl]2(l .
-pz)}2+
(sin h/k)max (Åꢁ1
)
Atomic displacement ellipsoids are drawn at the 40% probability level. The
molecule possesses a center of symmetry, so only the asymmetric part of it has
been labeled. The other half of the molecule is generated from the original
coordinates by symmetry transformation 1 ꢁ x, 1ꢁy, ꢁz.
Refinement
R[F2 > 2
r
(F2)], wR(F2), S
0.014, 0.035, 1.20
1588
91
0
H-atom parameters
constrained
0.65, ꢁ0.35
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
containing a discrete pyrazine-bridged Pt(II) dimer, deposited in
the CSD [33]. The Ci molecular symmetry ensures the mutually
trans orientation of the two Cl and (en) ligands. The atoms involved
in the Pt(II) square coordination deviate less than 0.045 Å from the
mean plane through the three nitrogens and Cl1. The Pt atom devi-
ates from this plane by only 0.010(1) Å and from the pyrazine best
plane by 0.084(6) Å. The Pt–N distances are in the expected range,
with the Pt–N(diamine) distances only slightly longer (2.032(3)
and 2.040(3) Å) than the Pt–N(pyrazine) distance of 2.018(3) Å,
probably a consequence of the more negative charge on the pyra-
zine nitrogen as compared with the diamine nitrogens, and the Pt–
Cl bond measures 2.298(3) Å. The N1–Pt–Cl(1), Cl1–Pt–N3 and N3–
Pt–N2 angles are 92.8(1)°, 90.5(1)° and 93.5(1)°, respectively, while
the N1–Pt–N2 angle in the five-membered chelate ring is only
83.2(1)°, a value similar to the mean N–Pt–N angle in other plati-
num complexes with ethylene diamine (mean value of 83.33(6)°
for 207 observations in structures with R < 5% [33]). The coordi-
nated pyrazine ring is oriented out of the Pt(II) square plane. The
dihedral angle between the pyrazine-ring plane and the square
plane around Pt(II) amounts to 58.4(1)°, and the Cl1–Pt–N3–C3
and Cl1–Pt–N3–C4 torsion angles are ꢁ60.6(3)° and 122.9(3)°,
respectively. The diamine rings adopt the usual twist conformation
(one k and the other d), with an approximate twofold axis passing
throuch the C1–C2 bond (Cremer and Pople parameters calculated
with PARST included in the WinGX package [34] are 0.439(4) Å and
ꢁ92.0(4)°).
D
qmax, D )
qmin (e Åꢁ3
Table 2
Selected geometrical parameters [Å] for {[Pt(en)Cl]2(
l
-pz)}Cl2.
Pt1–N1
Pt1–N2
2.032(3)
2.040(3)
Pt1–N3
Pt1–Cl1
2.018(3)
2.2980(10)
N1–Pt1–N2
N1–Pt1–N3
N2–Pt1–N3
83.24(12)
175.61(12)
93.51(11)
N1–Pt1–Cl1
N2–Pt1–Cl1
N3–Pt1–Cl1
92.82(10)
175.67(9)
90.52(8)
Pt1–N1–C1–C2
N1–C1–C2–N2
C1–C2–N2–Pt1
ꢁ41.0(4)
52.1(4)
ꢁ38.5(4)
C2–N2–Pt1–N1
N2–Pt1–N1–C1
13.2(2)
15.7(3)
H-atoms were refined as riding. SIEMENS [31] and MERCURY [32] com-
puter graphics programs were used to prepare the drawings. Se-
lected bond distances and angles are reported in Table 2.
Hydrogen-bond parameters are listed in Table 3. Atomic coordi-
nates, anisotropic displacement parameters and tables of all bond
distances and angles have been deposited at the Cambridge Crys-
tallographic Data Centre (Deposition No. CCDC 895153).
3. Results and discussion
3.1. X-ray structure of the {[Pt(en)Cl]2(l-pz)}Cl2 complex
3.2. Crystal packing of the {[Pt(en)Cl]2(l-pz)}Cl2 complex
The molecular structure and labeling scheme are shown in Fig. 1
and selected bond distances and angles are listed in Table 2. X-ray
analysis has unequivocally confirmed that the {[Pt(en)Cl]2(l-
The complex cations form columns extending along the a-direc-
tion, with distances of 5.077(1) Å between Pt(II) ions and the pz
rings (Fig. 2). The uncoordinated chloride anions (Cl2) are located
pz)}Cl2 complex is a binuclear complex of Pt(II) bridged by the pyr-
azine ligand. In the crystal the complex is positioned on an inver-
sion center and thus possesses Ci symmetry. Each platinum(II)
atom exhibits an approximately square planar coordination, with
one Pt–Cl bond, one Pt–N bond of pyrazine (pz), and two Pt–N
bonds of the same chelating diamine (en) ligand. The Ptꢀ ꢀ ꢀPt dis-
tance is 6.7890(3) Å, comparable with the mean value of
6.815(8) Å obtained from 17 observations for crystal structures
above and below the pyrazine rings and are involved in anion–
interactions with these aromatic rings. Pyrazine rings are typically
less electron poor than triazines, where the majority of anion–
interactions have been observed, but it has been demonstrated,
both experimentally and theoretically, that coordination to the
metal dramatically enhances the disposition of aromatic rings to-
p
p
ward anionꢀ ꢀ ꢀ
p binding [6,11,12,35]. Accordingly, in the investi-
gated complex the pyrazine ring is activated by coordination to

258
D.P. Ašanin et al. / Polyhedron 51 (2013) 255–262
formation of hydroxo-bridged oligomeric Pt(II) complexes, which
are catalytically inactive.
3.3.1. Reactions of platinum(II) complexes with an equimolar amount
of Ac-
The mixing of [Pt(en)(H2O)2]2+ and {[Pt(en)(H2O)]2(
complexes with an equimolar amount of Ac- -Met-Gly dipeptide
L-Met-Gly
l
-pz)}4+
L
under the above-mentioned conditions resulted in the spontane-
ous coordination of these two platinum(II) complexes to the
methionine sulfur atom of the dipeptide. Different reaction path-
ways for the hydrolytic cleavage of this dipeptide in the reactions
with the two Pt(II) complexes are presented in Fig. 3. The coordina-
tion of Ac-L-Met-Gly through the sulfur atom of methionine shifted
the resonance for the methyl protons of free methionine at
2.11 ppm downfield to 2.54 ppm after its coordination to Pt(II)
and this reaction was almost completed after 10 min (Table 4).
These chemical shifts are in accordance with those previously re-
ported for the reaction of platinum(II) complexes with different
methionine-containing molecules [40–43]. The monodentate
coordination of Ac-
{[Pt(en)(H2O)]2(
-pz)}4+ complexes resulted in the formation of
two platinum(II)–peptide complexes [Pt(en)(Ac- -Met-Gly-S)
(H2O)]2+ (1) and {[Pt(en)(Ac- -pz)[Pt(en)(H2O)]}4+
-Met-Gly-S)](
L
-Met-Gly to the [Pt(en)(H2O)2]2+ and
l
L
L
l
(2) (Fig. 3). Complexes 1 and 2 are intermediate products and they
promote the regioselective cleavage of the Met-Gly amide bond in
the Ac-L-Met-Gly dipeptide. This hydrolytic reaction can be fol-
lowed successfully using 1H NMR spectroscopy by observing the
glycine protons in complexes 1 and 2 and these protons for free
glycine. The resonance at 3.99 ppm, corresponding to the glycine
protons of the dipeptide attached to platinum(II) in complexes 1
and 2, decreased while that at 3.77 ppm for free glycine increased.
Upon addition of glycine to the reaction mixture, the resonance at
3.77 ppm was enhanced. Due to the fact that after 10 min all the
Fig. 2. Specific intermolecular interactions in the crystal structure of {[Pt(en)Cl]2(l-
pz)}Cl2 involving complex cations and uncoordinated chloride anions. NHꢀ ꢀ ꢀCl
hydrogen bonds are marked by dotted lines while anionꢀ ꢀ ꢀ
p
interactions are shown
by broken lines joining the chloride anion (green ball) with the centre of gravity of
the pyrazine ring (gray ball). For clarity, only H-atoms involved in hydrogen bonds
are displayed. (For interpretation of the references to color in this figure legend, the
reader is referred to the web version of this article.)
Ac-L-Met-Gly was bound to platinum(II) (no resonance at
2.11 ppm was observed in the 1H NMR spectrum), it can be as-
sumed that the concentrations of complexes 1 and 2 were equal
to the initial concentration of the dipeptide. According to this,
the hydrolytic cleavage of the Met-Gly amide bond in complexes
1 and 2 was determined by integration of the resonances for the
glycine protons of the dipeptide attached to the platinum(II)
(3.99 ppm) and for the protons of the free glycine (3.77 ppm) (Ta-
ble 4). The changes in concentrations of free glycine and non-
hydrolyzed complexes 1 and 2 were followed over time and the
sum of their concentrations was always equal to the initial concen-
two Pt(II) metal centers. The Cl2ꢀ ꢀ ꢀCg distance (Cg stands for the
center of gravity of the pyrazine ring) amounts to 3.410 Å, while
the angle between the normal to the pz ring and the Cl2ꢀ ꢀ ꢀCgꢀ ꢀ ꢀCl2
line is 12.9°. For comparison, Mascal et al. have calculated an equi-
librium distance of 3.2 Å between chloride and the aryl centroid in
the Clꢁꢀ ꢀ ꢀ1,3,5-triazine complex, with the anion positioned on the
C3-axis above the triazine ring [8]. Moreover, the Cl2 anion acts as
a hydrogen bond acceptor from N–H groups belonging to four dif-
ferent complex cations situated in its neighborhood. The hydrogen
bond parameters are listed in Table 3. Notably, the coordinated
chloride anion (Cl1) is not involved in hydrogen bonding or any
other specific intermolecular interactions.
tration of Ac-L-Met-Gly. The hydrolysis of the Met-Gly amide bond
was followed over 24 h and no change in the chemical shifts of the
resonances at 2.54 and 2.64 ppm for the methyl protons of the
methionine and methylene protons of ethylenediamine, respec-
tively, were observed, indicating that the ligands were bound to
platinum(II) all the time (complexes 3 and 4; Fig. 3 and Table 4).
3.3. 1H NMR investigation of the hydrolytic reactions of the N-
However, when the reaction between {[Pt(en)(H2O)]2(
and the Ac- -Met-Gly dipeptide was followed for more than 24 h,
l
-pz)}4+
acetylated dipeptide Ac-
L
-Met-Gly in the presence of
L
{[Pt(en)(H2O)]2(
l
-pz)}4+ and [Pt(en)(H2O)2]2+ complexes
some changes in the aromatic region of the 1H NMR spectrum oc-
curred. These changes were manifested through the fact that the
singlet at 9.03 ppm for the bridging pyrazine ligand decreased
while two symmetric multiplets in the range 8.75–9.00 ppm
slowly increased (Table 4). The appearance of these two new mul-
tiplets indicates that one Pt(II)–N(pyrazine) bond in complex 2 was
broken and that the four pyrazine protons of this ligand coordi-
nated in a monotopic fashion to Pt(II) (complex 4, Fig. 3) were split
into two multiplets because of vicinal and long-range coupling.
Symmetric multiplets for monodentate coordinated pyrazine were
also observed for cis- and trans-[Pt(NH3)2(pz)2](NO3)2 and for the
[Pt(tmda)(pz)2](NO3)2 (tmda is N,N,N0,N0-tetramethylenediamine)
complex [1]. The platinum(II) complex 4 (Fig. 3), with a monoden-
tate bound pyrazine ligand, was very stable and no resonance at
The hydrolytic cleavage of the Met-Gly amide bond in the Ac-
Met-Gly dipeptide in the presence of two platinum(II) complexes,
binuclear {[Pt(en)(H2O)]2(
-pz)}4+ (en = bidentate coordinated eth-
L-
l
ylenediamine and pz = bridging pyrazine (or 1,4-diazine) ligand)
and the mononuclear [Pt(en)(H2O)2]2+ was investigated by 1H
NMR spectroscopy. The corresponding peptide and platinum(II)
complexes were reacted in 1:1 and 2:1 M ratios and all reactions
were performed at 2.0 < pH < 2.5 in D2O as the solvent and at
37 °C. Additionally, the reaction between [Pt(en)(H2O)2]2+ and the
Ac-L-Met-Gly dipeptide was realized with an excess of the plati-
num(II) complex (2:1 M ratio, respectively). As was shown in pre-
vious studies [36–39], acidic solutions are needed to suppress the

D.P. Ašanin et al. / Polyhedron 51 (2013) 255–262
259
O
Ac-L-Met-Gly
C
(Ac =
)
CH3
2.0 < pH < 2.5
t = 37 o
C
{[Pt(en)(H2O)]2(μ-pz)}4+
[Pt(en)(H2O)2]2+
Ac
NH
Ac
Ac
O
H2O
NH
O
NH
O
OH
O
NH
N
O
OH
O
NH
NH
OH
S
OH2
H3C
S
S
H3C
H2N
H3C
H2N
Pt
NH2
H2N
Pt
N
Pt
OH2
Pt
OH2
H2N
NH2
NH2
internal delivery
NH2
external attack
2
{[Pt(en)(Ac-L-Met-Gly-S)](μ-pz)[Pt(en)(H2O)]}4+
1
[Pt(en)(Ac-L-Met-Gly-S)(H2O)]2+
Ac
NH
Ac
NH
OH
O
OH
[Pt(en)(H2O)2]2+ + Gly
Gly
+
+
O
S
S
H3C
H2N
H3C
H2N
Pt
N
N
Pt
OH2
NH2
NH2
4
3
[Pt(en)(Ac-L-Met-S)(pz)]2+
[Pt(en)(Ac-L-Met-S)(H2O)]2+
Fig. 3. Schematic presentation of the hydrolytic reactions of the Ac-
L-Met-Gly dipeptide with an equimolar amount of the platinum(II) complex.
Table 4
Characteristic 1H NMR chemical shifts observed in the reactions of the [Pt(en)(H2O)2]2+ and {[Pt(en)(H2O)]2(-pz)}4+ complexes with Ac-L-Met-Gly at 2.0 < pH < 2.5 in D2O and at
37 °C. All spectra were recorded in D2O solutions containing TSP (sodium trimethylsilylpropane-3-sulfonate) as the internal reference.
Dipeptide/Pt(II) complex/reaction product
Ac- -Met-Gly
{[Pt(en)(H2O)]2(
[Pt(en)(H2O)2]2+
[Pt(en)(Ac-
-Met-Gly-S)(H2O)]2+ (1 and 7)
{[Pt(en)(Ac-
Characteristic 1H NMR resonances (d, ppm)
L
2.11 (s, MetCH3)
2.64 (s, enCH2)
2.64 (s, enCH2)
2.54 (s, MetCH3)
2.54 (s, MetCH3)
2.54 (s, MetCH3)
2.53 (s, MetCH3)
2.54 (s, MetCH3)
2.53 (s, MetCH3)
3.77 (s, GlyCH2)
8.66 (s, pzCH)
3.99 (s, GlyCH2)
9.03 (s, pzCH)
l
-pz)}4+
L
2.84 (s, enCH2)
2.70, 2.84 (2s, enCH2)
2.84 (s, enCH2)
2.89 (s, enCH2)
2.89 (s, enCH2)
2.89 (s, enCH2)
L
-Met-Gly-S)](
l
-pz)[Pt(en)(H2O)]}4+ (2)
9.03 (s, pzCH)
[Pt(en)(Ac-
[Pt(en)(Ac-
[Pt(en)(Ac-
L
L
L
-Met-S)(H2O)]2+ (3)
-Met-S)(pz)]2+ (4)
-Met-Gly-S)2]2+ (5)
8.75–9.00 (m, pzCH)
9.03 (s, pzCH)
{[Pt(en)(Ac-L-Met-Gly-S)]2(l
-pz)}4+ (6)
Free glycine (Gly)
Free pyrazine (pz)
8.66 ppm for free pyrazine [1] was detected in the 1H NMR spec-
trum, even after this reaction was prolonged to 10 days. The time
dependences of the hydrolytic cleavage of the Met-Gly amide bond
in the reactions between different molar ratios of the platinum(II)
formed under the above-mentioned experimental conditions in
an excess of the Pt(II) complex (2:1 M ratio), the cleavage of the
peptide was faster than with equimolar amounts of these reac-
tants. The hydrolysis of the dipeptide in the presence of two equiv-
alents of the mononuclear [Pt(en)(H2O)2]2+ complex was still
slower than that with an equimolar amount of the binuclear
complex and Ac-L-Met-Gly dipeptide are given in Fig. 4. When an
equimolar amount of [Pt(en)(H2O)2]2+ was mixed with this dipep-
tide, only 35% of the Met-Gly amide bond was cleaved after 2 h.
{[Pt(en)(H2O)]2(l
-pz)}4+ complex (see Fig. 4). The better catalytic
However, in the reaction with the binuclear {[Pt(en)(H2O)]2(
l
-
ability of the binuclear {[Pt(en)(H2O)]2(l
-pz)}4+ complex in com-
pz)}4+ complex, this cleavage was two times faster and about 70%
of the Met-Gly amide bonds were cleaved in the same time. Finally,
after 24 h in the presence of the binuclear Pt(II) complex, more
than 83% of the Met-Gly amide bond hydrolyzed, while with the
mononuclear [Pt(en)(H2O)2]2+ complex, about 56% of this bond
had cleaved. However, when the reaction of the mononuclear
parison with the mononuclear [Pt(en)(H2O)2]2+ complex can be
attributed to the structural differences of their hydrolytically ac-
tive platinum(II)–dipeptide complexes (complexes
1 and 2;
Fig. 3). Hydrolysis of the Met-Gly amide bond in the presence of
the mononuclear [Pt(en)(H2O)2]2+ complex can occur by two possi-
ble limiting mechanisms, both represented in complex 1 (Fig. 3)
[44–46]. The first possibility is that the platinum(II) ion interacts
[Pt(en)(H2O)2]2+ complex with Ac-
L-Met-Gly dipeptide was per-

260
D.P. Ašanin et al. / Polyhedron 51 (2013) 255–262
{[Pt(en)(H2O)]2(μ-pz)}4+ : Ac-L-Met-Gly = 1 : 1
bond to occur by this mechanism, the aqua ligand on platinum(II)
should be proximate to the carbonyl carbon of the scissile amide
bond. Additionally, it was found that a coordinated aqua ligand
in Pd(II) and Pt(II) complexes plays an important role in promoting
the regioselective cleavage of the amide bond in histidine- and
methionine-containing peptides [36,44–50]. Two platinum(II) cen-
ters bridged with one aromatic pyrazine ligand in the hydrolyti-
cally active complex 2 are more efficient in the hydrolysis of the
scissile amide bond than even two equivalents of the mononuclear
[Pt(en)(H2O)2]2+ complex (Fig. 4). The two platinum(II) centers in
complex 2 can simultaneously participate in the cleavage of the
scissile amide bond, one by polarizing the carbonyl oxygen atom
and another by delivering a water molecule. Meanwhile the single
Pt(II) ion in the mononuclear [Pt(en)(H2O)2]2+ complex is incapable
in promoting these two interactions simultaneously. Our latest re-
sults for the good catalytic ability of the binuclear platinum(II)
[Pt(en)(H2O)2]2+ : Ac-L-Met-Gly = 2 : 1
[Pt(en)(H2O)2]2+ : Ac-L-Met-Gly = 1 : 1
∗
{[Pt(en)(H2O)]2(μ-pz)}4+ : Ac-L-Met-Gly = 1 : 2
80
60
40
20
2
24 h
6
complex in the cleavage of the Ac-L-Met-Gly dipeptide are also in
accordance with those previously reported for the reaction of a
binuclear palladium(II) complex having thiolate bridging ligands
with different methionine-containing peptides [19] and for differ-
ent polynuclear complexes with nucleic acids and phosphate esters
[20,51].
Fig. 4. Time dependence of the hydrolytic cleavage of the Met-Gly amide bond in
the Ac-L-Met-Gly dipeptide with platinum(II) complexes at 2.0 < pH < 2.5 and at
37 °C. ⁄No hydrolysis of the amide bond was observed in the reaction of
[Pt(en)(H2O)2]2+ with an excess of dipeptide.
with the oxygen atom of the scissile amide bond. This interaction
polarizes the carbonyl group and activates its carbon atom toward
attack by a water molecule from the solvent (external attack). For
the reaction to occur by this mechanism, the platinum(II) and car-
bonyl oxygen atoms should be proximate. The other possibility is
that an aqua ligand on platinum(II) is delivered to the carbon atom
in the amide bond (internal attack). For the cleavage of the amide
3.3.2. Reactions of platinum(II) complexes with an excess of Ac-
Gly
L-Met-
The hydrolytic cleavage of the Met-Gly amide bond in the
presence of the [Pt(en)(H2O)2]2+ and {[Pt(en)(H2O)]2( -pz)}4+ com-
plexes was studied with an excess of the Ac- -Met-Gly dipeptide.
l
L
Ac-L-Met-Gly
(in excess)
2.0 < pH < 2.5
t = 37 oC
[Pt(en)(H2O)2]2+
{[Pt(en)(H2O)]2(
μ
-pz)}4+
Ac
OH
NH
OH
Ac
S
NH
O
O
OH
Ac
O
O
NH
NH
NH
NH
S
CH3
S
H3C
H2N
O
O
S
H3C
Pt
H3C
Ac
N
H
N
H2N
Pt
N
Pt
NH2
O
NH2
O
H2N
NH2
HN
OH
5
6
hydrolytically inactive complex
hydrolytically inactive complex
[Pt(en)(Ac-L-Met-Gly-S)2]2+
{[Pt(en)(Ac-L-Met-Gly-S)]2(μ-pz)}4+
after 4 h
Ac
NH
O
O
NH
OH
S
N
H3C
H2N
N
+
Pt
OH2
pyrazine
NH2
7
hydrolytically active complex
2 [Pt(en)(Ac-L-Met-Gly-S)(H2O)]2+
Fig. 5. Reaction pathways of the [Pt(en)(H2O)2]2+ and {[Pt(en)(H2O)]2(
2.0 < pH < 2.5 and at 37 °C.
l
-pz)}4+ complexes with an excess of the Ac-
L-Met-Gly dipeptide (1:2 M ratio, respectively) at

D.P. Ašanin et al. / Polyhedron 51 (2013) 255–262
261
The two platinum(II) complexes, [Pt(en)(H2O)2]2+ and {[Pt(en)
(H2O)]2(
-pz)}4+, and the corresponding dipeptide were mixed in
a 1:2 M ratio, respectively, and all reactions were performed at
2.0 < pH < 2.5 and at 37 °C. The formation of the [Pt(en)(Ac-
Met-Gly-S)2]2+ (5) and {[Pt(en)(Ac- -pz)}4+ (6)
-Met-Gly-S)]2(
with an excess of the dipeptide, only the binuclear {[Pt(en)(H2-
O)]2(
-pz)}4+ complex was shown to be a capable catalytic agent
in the hydrolysis of the dipeptide. The better catalytic ability of
the binuclear {[Pt(en)(H2O)]2(
-pz)}4+ complex than the corre-
l
l
L
-
l
L
l
sponding mononuclear Pt(II) complex can be attributed to the
complexes was evidenced by the simultaneous decline of the res-
presence of different hydrolytically active Pt(II)–peptide com-
onance at 2.11 ppm, arising from the S-methyl protons of free
plexes formed during the reaction with the Ac-L-Met-Gly dipep-
Ac-
L
-Met-Gly, and the growth of the resonance at 2.54 ppm, corre-
tide. These results together with those previously reported for
the reaction of a binuclear palladium(II) complex having thiolate
bridging ligands [18] should be taken into consideration when
designing new polynuclear platinum(II) and palladium(II) com-
plexes as effective agents in the hydrolysis of methionine-contain-
ing peptides. Studies aimed at investigating these new possible
synthetic metallopeptidases are in progress.
sponding to the S-methyl protons of the peptide coordinated to
Pt(II) through the sulfur atom (complexes 5 and 6; Fig. 5 and Table 4).
These reactions were followed over time and no resonance at
2.11 ppm for the free peptide was observed in the 1H NMR spectra
after 2 h. In addition, during this time, no cleavage of any amide
bond in Ac-L-Met-Gly was observed, indicating that the plati-
num(II)–peptide complexes 5 and 6 are hydrolytically inactive.
Moreover, in the reaction between [Pt(en)(H2O)2]2+ and Ac-v-
Met-Gly, the hydrolytic reaction was not observed, even when
the reaction was prolonged to 4 days. Additionally, no changes in
the 1H NMR spectrum for this reaction were observed during this
time, confirming that complex 5 is very stable under the employed
experimental conditions. However, the hydrolytically inactive
complex 6, formed in the reaction between the {[Pt(en)(H2O)]2
Acknowledgement
This work was funded in part by the Ministry of Education and
Science of the Republic of Serbia (Project No. 172036).
Appendix A. Supplementary material
(l
-pz)}4+ complex and the Ac-
under these experimental conditions and after 4 h of reaction, it
L-Met-Gly dipeptide, was unstable
CCDC 895153 contains the supplementary crystallographic
data for {[Pt(en)Cl]2(l-pz)}Cl2. 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.
was converted into the hydrolytically active [Pt(en)(Ac-L-Met-
Gly-S)(H2O)]2+ complex 7. This complex is structurally identical
with complex 1, obtained in the reaction between equimolar
amounts of the mononuclear [Pt(en)(H2O)2]2+ and Ac-
L-Met-Gly
dipeptide (see Fig. 3). The conversion of 6 into 7 was evident in
the 1H NMR spectrum by the simultaneous decline of the singlet
at 9.03 ppm, due to protons of the bridging pyrazine ligand, and
the growth at 8.66 ppm, due to the free pyrazine ligand (Table 4).
This conversion was very slow and only 30% of free pyrazine was
detected in the solution after 48 h. Along with the resonance for
the free pyrazine ligand, a new resonance at 3.77 ppm was also de-
tected in the 1H NMR spectrum. This resonance was assigned to
free glycine protons and its intensity increased upon addition of
glycine to the reaction mixture. This undoubtedly confirmed that
inactive complex 6 was converted into the hydrolytically active
species 7, which further promotes the cleavage of the Met-Gly
amide bond. The amounts of the hydrolysis products in this reac-
tion were determined from the known initial concentration of
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