Platinum(II) complexes with the diethyl aminomethylphosphonate ligand (amp): Characterization, properties, and unusual solution behavior

Article abstract of DOI:10.1002/ejic.200701245

Cisplatin is one of the most widely prescribed drugs for the treatment of solid tumors, even though its pharmacological potential is often limited by side effects (nephrotoxicity, neurotoxicity, alopecia) and a limited spectrum of activity. Overcoming these limitations is one of the most chased goals by researchers in the field of medicinal chemistry. Since phosphonates have a great selectivity for bone tissues, we have extended a previous study on a platinum(II) complex with a diethyl [(methylsulfinyl)methyl]phosphonate (smp) ligand, [PtCl₂(S,O-smp)], to another phosphonate ester ligand, diethyl aminomethylphosphonate (amp). Further interest in this investigation was generated by the observation that [PtCl₂(S,O-smp)] was capable of inhibiting matrix metalloproteinases (MMPs), which also play a role in tumor growth. The interaction of the amp ligand with the tetrachloroplatinate(II) anion resulted in the production of the mono- and bis(amp) adducts in which the ligand acts as a monodentate N-coordinated species; however, no stable species with the chelating ligand could be isolated. A rationale for the different chelating abilities of amp and smp is offered. A solution of cis-[PtCl ₂(N-amp)₂] in organic solvents is very stable if kept in the dark; if it is exposed to light, it undergoes a ready and clean cis/trans isomerization, affording the trans-[PtCl₂(N-amp)₂] complex. The compounds have been characterized by means of spectroscopic techniques (¹H, ³¹P, and ¹⁹⁵Pt NMR), ESI-MS, and elemental analysis. In the case of trans-[PtCl₂(N-amp) ₂], the X-ray structure has revealed a peculiar in-plane orientation of the amp ligand. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejic.200701245

FULL PAPER
DOI: 10.1002/ejic.200701245
Platinum(II) Complexes with the Diethyl Aminomethylphosphonate Ligand
(amp): Characterization, Properties, and Unusual Solution Behavior
Daniele Cornacchia,[a] Leonardo Cerasino,[a] Concetta Pacifico,[a] and Giovanni Natile*[a]
Keywords: Platinum / Diethyl aminomethylphosphonate / Antitumor agents / MMP inhibitors / Crystal structure
Cisplatin is one of the most widely prescribed drugs for the
treatment of solid tumors, even though its pharmacological
potential is often limited by side effects (nephrotoxicity, neu-
rotoxicity, alopecia) and a limited spectrum of activity. Over-
coming these limitations is one of the most chased goals by
researchers in the field of medicinal chemistry. Since phos-
phonates have a great selectivity for bone tissues, we have
extended a previous study on a platinum(II) complex with
a diethyl [(methylsulfinyl)methyl]phosphonate (smp) ligand,
[PtCl2(S,O-smp)], to another phosphonate ester ligand, di-
ethyl aminomethylphosphonate (amp). Further interest in
this investigation was generated by the observation that
[PtCl2(S,O-smp)] was capable of inhibiting matrix metallo-
proteinases (MMPs), which also play a role in tumor growth.
The interaction of the amp ligand with the tetrachloroplati-
nate(II) anion resulted in the production of the mono- and
bis(amp) adducts in which the ligand acts as a monodentate
N-coordinated species; however, no stable species with the
chelating ligand could be isolated. A rationale for the dif-
ferent chelating abilities of amp and smp is offered. A solu-
tion of cis-[PtCl2(N-amp)2] in organic solvents is very stable
if kept in the dark; if it is exposed to light, it undergoes a
ready and clean cis/trans isomerization, affording the trans-
[PtCl2(N-amp)2] complex. The compounds have been charac-
terized by means of spectroscopic techniques (1H, 31P, and
195Pt NMR), ESI-MS, and elemental analysis. In the case of
trans-[PtCl2(N-amp)2], the X-ray structure has revealed a pe-
culiar in-plane orientation of the amp ligand.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Scheme 1). In comparison to the smp ligand, amp has an
amino group instead of a methylsulfinyl group. The amp
ligand is virtually a bidentate ligand bearing two donor
atoms: the nitrogen atom of the amine function and the
nonalkylated oxygen atom of the phosphonate group. We
succeeded in isolating monodentate N-coordinated amp
complexes but failed in isolating any N,O-chelated species.
We were aware of the fact that, contrary to (aminoalkyl)-
phosphonates, which easily form N,O-chelates,[10] the corre-
sponding diester species have only the P=O oxygen, a weak
nucleophile, available for coordination to platinum. Never-
theless, we expected that amp would behave like smp,
Introduction
Although Cisplatin (cis-ddp) is widely prescribed for the
treatment of several solid tumors, such as testicular and
ovarian carcinomas,[1] its pharmacological potential is lim-
ited by its side effects (in particular its toxicity to the kid-
neys) and the acquired or intrinsic resistance of many can-
cer types.[1,2] With the aim of overcoming these limitations,
research has focused on the synthesis of new platinum com-
plexes that could have better effectiveness and lower toxic-
ity. In this context, platinum complexes with aminophos-
phonate ligands have been exploited as chemotherapeutic
agents specific for the treatment of bone tumors.[3–7] Re-
cently, it has also been found that platinum(II) complexes
containing phosphonic acid ester ligands can act as inhibi-
tors of matrix metalloproteinases (MMPs), a group of en-
zymes which plays a key role in the progress of metastasiz-
ing tumors. In particular, the complex [PtCl2(S,O-smp)], in
which smp stands for diethyl [(methylsulfinyl)methyl]phos-
phonate, was demonstrated to be an MMP inhibitor that is
more effective than some inhibitors in clinical use.[8,9] This
prompted us to extend the investigation to complexes
with the diethyl aminomethylphosphonate ligand (amp,
[a] Università degli Studi di Bari, Dipartimento Farmaco-Chimico,
via E. Orabona 4, 70125 Bari, Italy
Scheme 1. Schematic view of the amp and smp ligands and of the
complexes described in this paper.
Fax: +39-080-5442230
E-mail: natile@farmchim.uniba.it
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Eur. J. Inorg. Chem. 2008, 1822–1829

Platinum(II) Complexes with the Diethyl Aminomethylphosphonate Ligand
which, although carrying a diethyl phosphonate moiety, is
able to produce S,O-chelated species.
In this paper we describe the synthesis and characteriza-
tion of three compounds, namely X[PtCl3(N-amp)] [X =
+
PPh4 (1a) or K+ (1b)], cis-[PtCl2(N-amp)2] (2), and trans-
[PtCl2(N-amp)2] (3) (Scheme 1). Some peculiar features,
3
such as a strong dependence of the JPt,P upon the nature
of the cation, the easy cis/trans isomerization of 2 to 3 if
the sample is exposed to light, and the in-plane orientation
of the amp ligand in the crystal structure of 3, will be dis-
cussed. Moreover, a rationale for the different chelating
abilities of amp and smp will be provided.
Results
Compound 1
Direct reaction between (PPh4)2[PtCl4] and amp 1:1 mo-
lar ratio in methanol/dichloromethane solution affords the
monoadduct (PPh4)[PtCl3(N-amp)] (1a). The 1H NMR
spectrum of 1a taken in CDCl3 is shown in Figure 1a. The
formation of the complex was confirmed by the shift of all
ligand signals with respect to free amp (Table 1). The shift
is particularly large for the central methylene proton signals
(δ = 3.33 ppm; 0.24 ppm downfield), which, however, do
not show resolved satellite peaks stemming from scalar
coupling with platinum. The coupling with platinum is in-
stead very well-resolved for the amino protons (δ =
2
3.66 ppm, JH,Pt = 52 Hz).
The amp phosphorus nucleus resonates at δ = 22.5 ppm
(4.3 ppm upfield with respect to the free ligand) and has
1
Figure 1. H (a), 31P (b), and 195Pt NMR (c) spectra of compound
broad satellite peaks due to coupling with the metal center.
The 3JP,Pt coupling constant is 220 Hz and falls in the range
of values found for analogous compounds.[10] The phospho-
rus nucleus of the PPh4+ ion resonates at δ = 24.9 ppm (Fig-
ure 1b). In the 195Pt NMR spectrum (Figure 1c), the plati-
1a in CDCl3.
The ESI-MS spectrum of 1a confirmed the given formula
num nucleus gives rise to a doublet (coupling with 31P) cen- with a molecular peak at m/z = 467.6 corresponding to
tered at –1890 ppm. This chemical shift is consistent with a [PtCl3(amp)]–. The MS/MS spectrum of the parent ion
set of NCl3 donor atoms, and falls in the range of values shows only a major peak at m/z = 302.5 corresponding to
reported for a series of [PtCl3(NH2–R)]– compounds.[11]
[M – amp]–.
Table 1. NMR spectroscopic data for the free amp ligand and related platinum complexes 1–3. Chemical shifts are expressed in ppm: 1H
values are referenced to TSP in the case of D2O and to residual solvent peaks in the case of other solvents; 31P values are referenced to
2–
85% H3PO4 (δ = 0 ppm); 195Pt values are referenced to PtCl6 (δ = 0 ppm). Coupling constants are expressed in Hz.
Compd. Solvent
NH2
2JH,Pt
C–CH2–O
3JH,P
N–CH2–P 2JH,P/3JH,Pt CH3–C
31P
3JP,Pt
195Pt
amp
D2O
4.16
4.18
4.09
4.10
4.11
4.29
4.17
4.30
4.31
4.24
4.19
7.3
7.3
7.9
8.3
8.5
8.1
8.4
7.9
7.7
8.1
8.4
3.08
3.09
3.23
3.33
3.19
3.32
3.26
3.38
3.34
3.24
3.25
10.9
11.0
17.2
1.32
1.33
1.26
1.31
1.29
1.40
1.31
1.42
1.43
1.36
1.38
30.9
26.9
CDCl3
[D6]acetone
CDCl3
[D6]acetone
D2O
[D6]acetone
D2O
CDCl3
D2O
CDCl3
2.15
N.A.
3.66
3.92
23.8
1a
1b
2
52
10.1/[a]
10.9/[a]
12.4/27
11.4/[a]
11.9/26
13.2/34
12.4/20
11.0/[a]
22.7[b]
22.5[d]
24.5
220
216
161
194
166
76
–1890
[c]
[e]
–1925
[c]
[e]
4.23
5.12
3.88
22.8
25.1
24.8
24.9
–2220
[e]
57
54
3
140
200
–2198
[e]
21.3
+
[a] Not determined because satellites overlap with the main peak. [b] The PPh4 phosphorus nucleus resonates at δ = 25.2 ppm. [c] Not
+
determined because the signal is very broad. [d] The PPh4 phosphorus nucleus resonates at δ = 24.7 ppm. [e] Data not available.
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D. Cornacchia, L. Cerasino, C. Pacifico, G. Natile
1
FULL PAPER
Performing an analogous reaction between K2[PtCl4] and plicity disappears in the 31P-decoupled H NMR spectrum,
amp in water solution, the same monoadduct can be iso- where a broad singlet with satellite peaks due to coupling
lated as potassium salt 1b. The NMR spectra of 1b were with the platinum nucleus (2JH,Pt = 57 Hz) is observed. The
substantially identical to those of 1a and will not be com- central methylene protons give a doublet of triplets (δ =
2
mented on in detail. It is, however, worth mentioning a sig- 3.34 ppm) as a result of J coupling with the phosphorus
nificantly smaller coupling constant between platinum and nucleus (13.17 Hz) and 3J coupling with the two amino pro-
phosphorus (161 instead of 220 Hz) and a broad peak for tons (ca. 6.6 Hz). The 31P NMR spectrum (Figure 2b)
platinum with unresolved coupling with the phosphorus nu- shows a singlet at δ = 24.8 ppm (1.07 ppm upfield with re-
cleus.
spect to the free ligand) with broad satellite peaks due to
coupling with platinum (3JP,Pt = 76 Hz). This value of 3JP,Pt
is considerably smaller than the values found for com-
pounds 1 and 3 in CDCl3 (220 and 200 Hz, respectively).
However, the JP,Pt value is larger in D2O (166 Hz) and
comparable to those found for 1 and 3 in the same solvent
(161 and 140 Hz, respectively).
Compound 2
3
The bis adduct cis-[PtCl2(N-amp)2] can be obtained in
good yield by the reaction of K2[PtCl4] and amp (1:2 molar
ratio) in water solution. The H NMR spectrum of 2 in
1
In the 195Pt spectrum (Figure 2c), a broad signal is visible
at –2220 ppm. Such a broadening with respect to the corre-
sponding signal in compound 1 is due to the increased
number of N-donor ligands and the unresolved coupling
with 31P. The value of the chemical shift is compatible with
a set of N2Cl2 donor atoms.
The formula of the compound was confirmed by the
ESI-MS spectrum (parent peak at m/z = 622.7 correspond-
ing to [{PtCl2(amp)2} + Na]+) and the MS/MS spectrum of
the parent ion (major fragments at m/z = 455.8 [M – amp
+ Na]+ and 419.8 [M – amp – HCl + Na]+).
CDCl3 is shown in Figure 2a. Complex formation was con-
firmed by the change in the chemical shift of all ligand sig-
nals with respect to free amp. The central methylene pro-
tons give a multiplet (δ = 3.34 ppm), which is shifted
0.25 ppm downfield with respect to the free ligand. The
downfield shift is 0.13 and 0.09 ppm for the ethoxy methyl-
ene and methyl protons, respectively. The amino protons
give a broad doublet due to coupling with the phosphorus
nucleus (with a coupling constant of 17.4 Hz). This multi-
Compound 3
Compound 2 dissolved in dichloromethane and layered
under diethyl ether, if not kept in the dark, undergoes
cis/trans isomerization to afford yellow crystals of trans-
[PtCl2(N-amp)2] (3). The 1H NMR spectrum of 3 in CDCl3
is shown in Figure 3a. As in the previous cases, complex
formation has been confirmed by the downfield shift of all
proton signals with respect to the free ligand. The changes
in chemical shifts are 0.16, 0.01, and 0.05 ppm downfield
for the central methylene, the ethoxy methylene and methyl
protons, respectively. Moreover, the amino protons have
satellite peaks due to coupling with the platinum atom
(2JH,Pt = 54 Hz). In the 31P NMR spectrum (Figure 3b), a
unique signal is visible at δ = 21.3 ppm (5.6 ppm upfield
with respect to the free ligand). The signal has broad satel-
lites due to coupling with the platinum nucleus, with a 3JP,Pt
coupling constant of 200 Hz.
In the 195Pt spectrum (Figure 3c), the species exhibits a
broad signal at –2198 ppm with unresolved coupling with
the phosphorus nucleus. The value of the chemical shift is
compatible with a set of N2Cl2 donor atoms and is compar-
able to that found for 2.
In the ESI-MS spectrum, the parent ion is at m/z = 622.9
{[PtCl2(amp)2] + Na}+, and the MS/MS spectrum of the
parent ion has major fragments at m/z = 455.9 [M – amp
+ Na]+ and m/z = 419.9 [M – amp – HCl + Na]+.
1
Figure 2. H (a), 31P (b), and 195Pt NMR (c) spectra of compound
2 in CDCl3.
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Eur. J. Inorg. Chem. 2008, 1822–1829

Platinum(II) Complexes with the Diethyl Aminomethylphosphonate Ligand
Table 2. Selected bond lengths [Å] and angles [°] for 3.
Bond lenghts
Angles
Pt1–N2
Pt1–N1
Pt1–Cl2
Pt1–Cl1
N1–C1
N2–C6
C1–P1
P1–O1
P1–O2
P1–O3
P2–O4
P2–O6
P2–O5
2.064(5)
2.064(5)
2.304(2)
2.309(2)
1.457(8)
1.474(8)
1.801(7)
1.460(5)
1.560(7)
1.562(6)
1.466(5)
1.561(5)
1.567(6)
N2–Pt1–N1
N2–Pt1–Cl2
N1–Pt1–Cl2
N2–Pt1–Cl1
N1–Pt1–Cl1
Cl2–Pt1–Cl1
C1–N1–Pt1
C6–N2–Pt1
N1–C1–P1
N2–C6–P2
172.7(2)
93.5(2)
93.8(2)
86.3 (2)
86.4(2)
179.5(1)
123.2(4)
122.6(4)
112.7(5)
111.6(4)
ligands, in accord with a transoid disposition which brings
the bulky platinum and phosphorus-centered moieties far-
ther away. Moreover, the phospohonate group is rotated in
such a way as to direct the P=O oxygen atom (electron-rich)
towards the amine protons (electron-deficient), forming an
intraligand hydrogen bond [N1···O1 3.00(1) Å, (N1)H11···
O1 2.60(1) Å, N1–H11···O1 108(1)°; N2···O4 3.00(1) Å,
(N2)H21···O4 2.56(1) Å, N2–H21···O4 110(1)°]. The N–C–
P=O torsion angles for the two amp ligands are 25.2(6)°
and 24.4(6)°. It is surprising that the dihedral angles be-
tween the platinum coordination plane and the ligand pla-
nes (through the atoms N–C–P) are very small (3° and 11°).
In square-planar complexes the ligand planes usually tend
to be orthogonal to the coordination plane in order to mini-
mize steric interactions between cis ligands. A possible ex-
planation for this unusual conformation is that the in-plane
orientation of each amp ligand is fostered by favorable elec-
trostatic interactions between the amine protons and the cis
chlorido ligand [average N···Cl and (N)H···Cl distances of
3.00 and 2.93 Å, respectively], and between the protons of
the methylene group bridging the N and P atoms of the
amp ligands and the second chlorido ligand [average C···Cl
and (C)H···Cl distances of 3.20 and 2.95 Å, respectively]. In
several occasions, theoretical investigations[12] have sug-
gested the existence of positive electrostatic interactions be-
tween amino and cis chlorido ligands. The occurrence of
such an interaction also in the present case is fully sup-
ported by the narrowing of the two Cl–Pt–N angles
(average 86.3°) where the amine protons reside. In the com-
plex, one ethyl group (C9/C9a) is disordered.
1
Figure 3. H (a), 31P (b), and 195Pt NMR (c) spectra of compound
3 in CDCl3.
X-ray Diffraction Analysis of 3
Yellow crystals of trans-[PtCl2(N-amp)2] were obtained
by crystallization of the cis isomer 2 from a mixture of
dichloromethane and diethyl ether (1:1, v/v). The asymmet-
ric unit comprises one independent molecule of the sub-
strate. An ORTEP drawing of 3 is shown in Figure 4. A
selection of bond lengths and angles is listed in Table 2.
Crystal Packing
Molecules are piled along the a direction (Figure 5). Ad-
jacent molecules are displaced in such a way as to align the
chlorido ligand of one molecule with the platinum atoms of
the two sandwiching molecules, the Pt···Cl distance being
Figure 4. A view of the asymmetric unit of trans-[PtCl2(N-amp)2],
showing the atomic numbering scheme. Displacement ellipsoids are
drawn at the 30% probability level.
The platinum center has a square-planar coordination. 4.02 Å. Each molecule of the pile donates hydrogen bonds
The deviations [Å] from the least-squares plane defined by (N–H···O=P) to the two adjacent molecules [N1···O4-
the four donor atoms are: Pt –0.0075(3), Cl1 0.002(2), Cl2 (2 – x, –y, 1 – z) 2.98(1) Å, (N1)H12···O4(2 – x, –y, 1 – z)
0.003(2), N1 –0.016(5), and N2 –0.014(5). The Pt–N–C–P 2.08(1) Å, N1–H12···O4(2 – x, –y, 1 – z) 177(1)°, N2···
torsion angles are 174.8(3)° and 171.0(3)° for the two amp O1(1 – x, –y, 1 – z) 2.95(1) Å, (N2)H22···O1(1 – x, –y,
Eur. J. Inorg. Chem. 2008, 1822–1829
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D. Cornacchia, L. Cerasino, C. Pacifico, G. Natile
FULL PAPER
1 – z) 2.05(1) Å, N2–H22···O1(1 – x, –y, 1 – z) 172(1)°]
In general, the cis/trans isomerization of square-planar
while accepting symmetrically related hydrogen bonds from complexes can occur by two major mechanisms: the
them.
dissociative mechanism and the associative mechanism
(Scheme 2).[13a–13g] In the dissociative path,[13a–13e] the ini-
tial square-planar complex (let us assume it has cis configu-
ration) loses one ligand to form a T-shaped intermediate/
transition state (often stabilized by loose association of a
solvent molecule), which can easily isomerize to a second
T-shaped intermediate/transition state in which the two for-
merly cis ligands are now trans. Reassociation of the ligand
dissociated in the first step would afford the trans complex.
The dissociative mechanism generally requires the presence
of a strong trans-labilizing ligand or of particularly bulky
ligands that can relieve the strain in the coordination shell
by the dissociation of one donor group.[14] In the associative
mechanism,[13f–13g] the presence of a catalytic amount of a
free ligand and the occurrence of two consecutive ligand
substitution processes are necessary. Starting with a cis-
[MX2A2] complex and a catalytic amount of A, the first
ligand substitution (replacement of X by A) leads to
[MXA3], and the second substitution process (reentering of
the displaced X into the complex and loss of one A) leads
to trans-[MX2A2]. Generally, the rate of isomerization is
subject to variation with temperature regardless of whether
the mechanism is associative or dissociative.
Figure 5. View of the crystal packing along the a axis of trans-
[PtCl2(N-amp)2].
Within the pile of molecules running along the a direc-
tion the Pt–Cl bonds are nearly orthogonal to the a direc-
tion (92.7°) while the Pt–N bonds are slanted to the a direc-
tion (57.2°). The result is that the distances between the
planes defined by the four donor atoms of two adjacent
molecules [alternatively 3.409(1) and 3.413(1) Å] are shorter
than the distance between Pt···Cl atoms aligned in the a
direction (4.02 Å).
Complex chains extending along the a direction are held
together by weak hydrogen bonds between ethyl protons of
the phosphonate groups and the chlorido ligands.
Discussion and Conclusions
There are some features of the compounds just described
which deserve further discussion. In particular: (i) the spon-
taneous isomerization of cis-[PtCl2(N-amp)2] (2) to trans-
3
[PtCl2(N-amp)2] (3), (ii) the great variation of JP,Pt as a
function of the solvent as observed for compound 2, and
(iii) the instability of the N,O-chelate form of the amp li-
gand.
Study of the cis/trans Isomerization of cis-[PtCl2(N-amp)2]
(2)
Scheme 2. Schematic view of the three possible cis/trans isomeriza-
tion mechanisms.
As described in detail in the Experimental Section, when
cis-[PtCl2(N-amp)2] (2) is dissolved in a mixture of CH2Cl2
A third mechanism can be hypothesized in which the
and diethyl ether (1:1, v/v) and kept in a vial, it undergoes isomerization takes place without bond-breaking and bond-
isomerization, and nice crystals of the corresponding trans making; however, this mechanism requires passing from a
isomer 3 form in two days. It took us some time to realize square-planar to a tetrahedral structure and vice-versa. Al-
that the isomerization was purely photochemical and can though this mechanism results to be symmetry-forbidden,
be completely prevented if the sample is kept in the dark.
photochemical isomerization of square-planar metal com-
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Eur. J. Inorg. Chem. 2008, 1822–1829

Platinum(II) Complexes with the Diethyl Aminomethylphosphonate Ligand
plexes by such a mechanism has already been reported.[15] pure [PtCl2(amp)] compound was unsuccessful. The N,O-
The photochemical isomerization mechanism is also repre- chelated species was clearly unstable and formed several by-
sented in Scheme 2.
products, thus indicating that amp does not stabilize chela-
The observation of isomerization only in the presence of tion as much as smp. We can provide a rationale for this
light led us to conclude that in the present case the isomer- difference in behavior. We have to consider specific proper-
ization process occurs by photoactivation and involves a ties that could favor smp chelation and disfavor amp chela-
tetrahedral transition state without bond dissociation.
tion. Chelation of smp could be promoted by two factors.
One factor is the presence of two bulky substituents on the
sulfur atom (the –CH3 and the O atom as compared to the
two protons present on the nitrogen atom of amp). Steric
repulsion between the substituents on sulfur and those on
phosphorus (the two ethoxy groups) can favor a gauche dis-
position of the S- and (P)O-donor atoms and favor the che-
lation of smp to platinum. The gauche conformation of the
smp ligand found in the X-ray structure of K[PtCl3(smp)]
with monodentate S-bound smp (Pt–S–C–P torsion angle
of 58°) lends support to this conclusion.[17] This effect is
similar to that first described by Thorpe and Ingold in rela-
tion to the cyclization of organic moieties[18a–18c] and dis-
cussed in greater detail in later work.[19] An additional fac-
tor that could favor chelation of smp is the cis-labilizing
effect of the coordinated sulfoxide group,[20a–20d] which
could favor the release of a cis-chlorido ligand in the adduct
with monocoordinated smp. Once the chelate ring has been
formed, the sulfur-bound oxygen points outward from the
chelate ring and does not labilize the cis-coordinated phos-
phonic group. We can also consider features of the amp
ligand which could prevent the coordination of the P=O
oxygen to platinum. The X-ray structure of compound 3
has shown that monodentate amp has a transoid conforma-
tion with a Pt–N–C–P torsion angle of 172°. Such a confor-
mation, while favoring intraligand N–H···O=P hydrogen
bond formation, certainly disfavors the coordination of the
P=O oxygen atom to platinum.
3
Variability of JP,Pt in Compound 2
Another observation which deserves an explanation is
3
why the JP,Pt coupling, usually in the range 160–210 Hz
(compounds 1 and 3), was as small as 70 Hz for compound
2 in CDCl3 solution. In general, the 3J coupling constant is
deeply affected by the value of the three-bond (Pt–N–C–P)
torsion angle according to the Karplus rule:[16] a greater
coupling constant is expected for a torsion angle close to
zero (this would be the case for a N,O-chelated amp ligand)
or to 180° (as in the case of the monodentate amp ligand
observed in the crystal structure of 3). For some reason, for
compound 2 in CDCl3 solution, the Pt–N–C–P torsion an-
gle is intermediate between 0 and 180°, so as to justify a
3JP,Pt that is about one third the usual value. This could be
a consequence of specific interactions between mono-
dentate cis-coordinated amp ligands. We wanted to check if
this interligand interaction between cis amp ligands could
be disrupted by changing the ionic strength of the medium.
As matter of fact, addition of an equimolar amount of
(PPh4)Cl brings the 3JP,Pt coupling constant in CDCl3 solu-
tion to the usual value of ca. 200 Hz.
A Rationale for the Instability of the Chelated Form of the
amp Ligand
As a final comment, we want to recall that the aim of
Another feature of the amp ligand is the instability of this study was the preparation of compounds that could
the N,O-chelated form. We were aware of the fact that, rela- possibly have an inhibitory effect on MMP. We believe that
tive to aminomethylphosphates, dialkyl aminomethylphos- the best candidate for this investigation is compound 1,
phonates are less susceptible to undergo chelation, since the which will shortly undergo a complete series of biological
only phosphorus-bound oxygen still available for coordina- tests.
tion to platinum has sp2 hybridization and does not carry
negative charge. However, the preparation of the S,O-che-
lated form of the closely related diethyl [(methylsulfinyl)-
methyl]phosphonate species was rather promising. The
most straightforward procedure for obtaining the N,O-che-
lated form that we could think of was treatment of trichlor-
ido species 1 with silver nitrate. The reaction, performed in
water, leads to the formation of a new species characterized
by a slight upfield shift of the signals due to central methyl-
ene protons (δ = 3.18 ppm; 0.14 ppm upfield with respect
to 1) and to the phosphorus nucleus (δ = 23.8 ppm; 0.7 ppm
upfield with respect to 1). The ESI-MS spectrum of the
final solution showed a molecular peak at m/z = 494.6, cor-
responding to {[PtCl2(amp)] + NO3}– in the negative cur-
rent and two peaks at m/z = 455.8 and 471.8, corresponding
to {[PtCl2(amp)] + Na}+ and {[PtCl2(amp)2] + K}+, respec-
tively, in the positive current. However, other species were
Experimental Section
Starting Compounds: (PPh4)2[PtCl4] was prepared from K2[PtCl4]
by using the procedure reported in the literature for the preparation
of (AsPh4)2[PtCl4],[21] and ampH hydrogen oxalate was purchased
from Acros Organics, Belgium.
Preparation of the Complexes: The free amp ligand was obtained
from the commercial hydrogen oxalate salt by treatment with a
base. Briefly, a water solution of the ampH hydrogen oxalate was
treated with a stoichiometric amount of calcium oxide, and the
insoluble calcium oxalate was removed by filtration of the water
solution. The aminomethylphosphonate could be recovered from
the aqueous solution by evaporation of the solvent under reduced
pressure.
(PPh4)[PtCl3(N-amp)] (1a): (PPh4)2[PtCl4] (264.0 mg, 0.26 mmol),
dissolved in a mixture of methanol (5 mL) and dichloromethane
also present in the solution, and any attempt to isolate the (7 mL), was treated with amp (0.26 mmol dissolved in 2 mL meth-
Eur. J. Inorg. Chem. 2008, 1822–1829
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
1827

D. Cornacchia, L. Cerasino, C. Pacifico, G. Natile
FULL PAPER
anol). The mixture was stirred at room temperature for 2 h. The
resulting brown solution was concentrated to dryness by evapora-
tion of the solvents under reduced pressure. The resulting brown
solid was treated with methanol (10 mL), the yellow solution was
filtered (to remove a dark-gray residue of PPh4Cl mixed with met-
allic platinum) and concentrated to dryness by evaporation of the
solvent under reduced pressure. The yellow residue was demon-
strated to be a mixture of compound 1a, PPh4Cl, unreacted
(PPh4)2[PtCl4], and other byproducts. Chromatographic purifica-
tion on a silica gel column, by using dichloromethane/acetone (1:1)
as eluant, afforded pure compound 1a (48.0 mg, 23% yield). The
trum One System. Elemental analysis were carried out with a CHN
Eurovector EA 3011 instrument. ESI-MS analysis was performed
with an Agilent 1100 series LC-MSD Trap system VL.
X-ray Diffraction Analysis: X-ray data were collected with a Bruker
AXS X8 APEX CCD system equipped with a four-circle Kappa
goniometer and a 4 K CCD detector (radiation Mo-Kα). A total of
50687 reflections (Θmax = 30, 45°) were indexed, integrated, and
corrected for Lorentz, polarization, and absorption effects by using
multi-scan. 6610 were independent reflections. The unit cell dimen-
sions were calculated from all reflections. The structure was solved
by direct methods in the P21/c space group. The model was refined
by full-matrix least-squares methods. Anisotropic thermal param-
eters were applied for all non-hydrogen atoms. The hydrogen atoms
were located and refined isotropically. The weighting scheme em-
1
compound was characterized by IR, H, 31P and 195Pt NMR spec-
troscopy, ESI-MS, and elemental analysis. C29H34Cl3NO3P2Pt
(807.75): calcd. C 43.12, H 4.21, N 1.73; found C 42.90, H 4.35, N
1.65. ESI-MS: m/z = 467.6 [Pt(amp)Cl3]– (in the negative current),
339 [PPh4]+ (in the positive current).
2
ployed was w = 1/[σ2(Fo2) + (0.0286P)2 + 6.6000P] where P = (Fo
2
+ 2Fc )/3. The refinement converged to R1 = 0.0410, wR2 = 0.0773,
and S = 1.066 for 4157 reflections with IϾ2σ(I), and R1 = 0.0896,
wR2 = 0.0972, and S = 1.066 for 6610 unique reflections and 222
parameters. The final difference Fourier map showed electron den-
sity peaks (up to 1.0 eÅ–3) lying near the Pt atoms. All calculations
were performed and molecular graphics were drawn by using the
SIR2002,[22] SHELXL-97,[23] PARST97,[24,25] WinGX,[26] and
ORTEP-3 for Windows packages.[27] The crystallographic data are
listed in Table 3.
K[PtCl3(N-amp)] (1b): A solution of amp (0.72 mmol) in water
(2.5 mL) was added dropwise, at room temperature, to a solution
of K2[PtCl4] (300.0 mg, 0.72 mmol) in the same solvent (1.0 mL).
The red solution was stirred for 24 h. During this time, a drift to
lower pH was observed, which required additions of small aliquots
of KOH (3.5 ) in order to keep the pH close to 7. The aqueous
solution was treated with dichloromethane in order to remove
traces of the neutral bis adduct cis-[PtCl2(N-amp)2] (compound 2),
which is soluble in the chlorinated solvent. The organic phase was
removed, and the aqueous phase was concentrated to dryness by
evaporation of the solvent under reduced pressure. The solid resi-
due was treated with absolute ethanol, the solution was filtered to
remove insoluble KCl and K2[PtCl4] and then treated with diethyl
ether, which induced the formation of an orange precipitate (very
hygroscopic) of compound 1b (179.2 mg, 49% yield). The com-
pound was characterized by IR, 1H, 31P and 195Pt NMR spec-
troscopy, ESI-MS, and elemental analysis. C5H14Cl3KNO3PPt
(507.61): calcd. C 11.83, H 2.76, N 2.76; found C 12.03, H 2.80, N
2.73. ESI-MS: m/z = 467.6 [Pt(amp)Cl3]– (in the negative current).
Table 3. Experimental details for the crystallographic analysis of 3.
Empirical formula
Formula weight
Temperature
C10H28Cl2N2O6P2Pt
600.27
293(2) K
Wavelength
0.71073 Å
Crystal system, space group monoclinic, P21/c
Unit cell dimensions
a = 8.0966(2) Å
b = 15.3135(5) Å
c = 17.7484(6) Å
α = 90°
β = 98.788(2)°
γ = 90°
2174.74(12) Å3
4
cis-[PtCl2(N-amp)2] (2): A solution of amp (0.96 mmol) in water
(2 mL) was added dropwise, at room temperature, to a solution of
K2[PtCl4] (200.0 mg, 0.48 mmol) in water (1 mL). The red solution
was stirred for 48 h under argon. During this time, a drift to lower
pH was observed, which required additions of small aliquots of
KOH (3.5 ) in order to keep the solution neutral. Extraction with
dichloromethane (3 ϫ 50 mL) afforded an organic fraction, which
was concentrated to dryness under reduced pressure. After tritura-
tion of the oily residue with diethyl ether, compound 2 was ob-
tained as a yellow solid (141.6 mg, 49% yield). The compound was
characterized by IR, 1H, 31P and 195Pt NMR spectroscopy, ESI-
MS, and elemental analysis. C10H28Cl2N2O6P2Pt (600.12): calcd. C
20.01, H 4.70, N 4.67; found C 20.13, H 4.68, N 4.62. ESI-MS:
m/z = 623 [M + Na]+.
Volume
Z
Calculated density
Absorption coefficient
F(000)
1.833 Mgm–3
6.868 mm–1
1168
Crystal size
0.1ϫ0.11ϫ2.51 mm
Θ range for data collection 1.77–30.45°
Limiting indices –11ՅhՅ11, –21ՅkՅ21,
–25ՅlՅ25
Reflections collected/unique 50687/6610 [R(int) = 0.0709]
Completeness to Θ = 30.45 100.0%
Refinement method
Full-matrix least-squares on F2
6610/6/222
1.066
R1 = 0.0410, wR2 = 0.0773
R1 = 0.0896, wR2 = 0.0972
0.00064(9)
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [IϾ2σ(I)]
R indices (all data)
trans-[PtCl2(N-amp)2] (3): A solution of 2 (80.0 mg, 0.13 mmol) in
a 1:1 (v/v) mixture (3 mL) of dichloromethane and diethyl ether
was kept under unfiltered light at room temperature. Pale yellow
needles of 3 separated out in 48 h. They were collected, washed
with cold dichloromethane, and dried in vacuo. The compound was
characterized by IR, 1H, 31P and 195Pt NMR spectroscopy, ESI-
MS, and elemental analysis. C10H28Cl2N2O6P2Pt (600.12): calcd. C
20.01, H 4.70, N 4.67; found C 20.66, H 4.75, N 4.77. ESI-MS:
m/z = 623 [M + Na]+.
Extinction coefficient
Largest diff. peak and hole 1.294 and –0.846 eÅ–3
CCDC-673719 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Acknowledgments
Physical Measurements: NMR spectra were collected at 298 K with
a Bruker DPX 300 MHz spectrometer. Monodimensional 31P and
195Pt spectra were acquired by using 1H-decoupling sequences.
FTIR spectra were recorded with a Perkin–Elmer mod. 283 Spec-
This research was supported by the University of Bari, the Italian
“Ministero dell’Universitá e della Ricerca (MUR)” (PRIN 2004
no. 20040590-78) and the EC (COST D39).
1828
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2008, 1822–1829

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Received: November 20, 2007
Published Online: February 22, 2008
Eur. J. Inorg. Chem. 2008, 1822–1829
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
1829