Isomerization of platinum-coordinated iminoethers induced by spectator ligands: Stabilization of the Z anti configuration

Article abstract of DOI:10.1021/ic4017118

Iminoether derivatives of the formula trans-[PtCl₂{HN=C(R) OR′}₂] proved to be endowed with remarkable antitumor activity in vivo. Moreover, these trans compounds were more cytotoxic than their cis congeners, a trend opposite to that generally observed for corresponding platinum complexes with ammines. The imino ligands can have either E or Z configuration about the C=N double bond, and in the case of R = R′ = Me, the E configuration is by far thermodynamically preferred. However, substitution of chloride anions with neutral ligands (L) alters the relative stability of the E and Z isomers. Upon investigation of the derivatives with L = PPh ₃, AsPh₃, Me₂S=O, and (H₂N) ₂C=S, it has been concluded that an electrostatic interaction between the oxygen lone pair of the iminoether and the platinum center, fostered by the net positive charge of the complex and the low dielectric constant around the metal core provided by the hydrophobic L ligands, stabilizes the Z configuration. The same factors can favor iminoether isomerization. These conclusions are fully supported by X-ray crystal data. In the case of a reaction with thiourea, an aminic group of thiourea can substitute the methoxy group of a cis-iminoether, leading to the formation of a cyclic compound in a process reminiscent of the McLafferty rearrangement. Such a rearrangement could play a role in the interaction of the platinum-iminoether compounds with target DNA and proteins.

Full text of DOI:10.1021/ic4017118

Article
pubs.acs.org/IC
Isomerization of Platinum-Coordinated Iminoethers Induced by
Spectator Ligands: Stabilization of the Z anti Configuration
Daniela Giardina-Papa, Francesco P. Intini, Concetta Pacifico, and Giovanni Natile*
̀
Dipartimento di Chimica, Universita degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy
S
* Supporting Information
ABSTRACT: Iminoether derivatives of the formula trans-[PtCl2{HN
C(R)OR′}2] proved to be endowed with remarkable antitumor activity in
vivo. Moreover, these trans compounds were more cytotoxic than their cis
congeners, a trend opposite to that generally observed for corresponding
platinum complexes with ammines. The imino ligands can have either E or
Z configuration about the CN double bond, and in the case of R = R′ =
Me, the E configuration is by far thermodynamically preferred. However,
substitution of chloride anions with neutral ligands (L) alters the relative
stability of the E and Z isomers. Upon investigation of the derivatives with
L = PPh3, AsPh3, Me2SO, and (H2N)2CS, it has been concluded that
an electrostatic interaction between the oxygen lone pair of the iminoether and the platinum center, fostered by the net positive
charge of the complex and the low dielectric constant around the metal core provided by the hydrophobic L ligands, stabilizes the
Z configuration. The same factors can favor iminoether isomerization. These conclusions are fully supported by X-ray crystal
data. In the case of a reaction with thiourea, an aminic group of thiourea can substitute the methoxy group of a cis-iminoether,
leading to the formation of a cyclic compound in a process reminiscent of the McLafferty rearrangement. Such a rearrangement
could play a role in the interaction of the platinum−iminoether compounds with target DNA and proteins.
Scheme 1. Sketches of the E and Z Configurations of
Iminoether Ligand
INTRODUCTION
■
The antitumor activity of cis-diamminedichloridoplatinum(II)
(cis-DDP), a drug used worldwide, is limited by side effects and
acquired or intrinsic resistance of several types of tumors.1,2
Because the trans isomer of cis-DDP is clinically ineffective,
initially it was assumed that only compounds with cis geometry
could have a therapeutic effect. However, over the years, several
platinum compounds with trans geometry have been tested and
found to exhibit remarkable antitumor activities, sometimes
comparable to or even greater than that of cis-DDP.3,4
Of particular interest are the iminoether derivatives,
analogous to trans-DDP, having the formula trans-
[PtCl2{HNC(R)OR′}2], which have been shown to be
endowed with remarkable antitumor activitiy in vivo.4−6
Moreover, these trans compounds were more cytotoxic than
their cis congeners.4,7,8
Iminoether complexes are generally prepared from related
platinum nitrile complexes by reaction with an alcohol under
basic condition, the configuration of the azomethine double
bond can be E or Z, depending upon the relative position of the
alkoxy group and the N-bonded Pt residue with respect to the
CN double bond (trans and cis for E and Z isomers,
respectively, Scheme 1).9
thermodynamic stability of the planar iminoether ligand
depends upon the steric interaction between cis substituents
at the CN double bond, the more sterically demanding
substituent at the carbon atom (OR′ or R) being better
accommodated in position trans to the N-bound platinum
moiety. Therefore, with constant OR′ (OMe), when R = Me,
the E configuration is thermodynamically preferred, whereas
when R = t-Bu, the Z configuration is preferred.11
In this paper, we report an investigation showing how, in
complexes of the type trans-[PtCl2‑x{(E)-HNC(Me)-
OMe}2(L)x]Yx (L = PPh3, AsPh3, DMSO, thiourea; Y = Cl−,
−
−
ClO4 , BF4 ; x = 1, 2), the stability of the iminoether
configuration (E or Z) can be modulated by the cis ligands and
the rate of isomerization is influenced by the nature of the
counteranion. Moreover, in the case of reaction with thiourea,
an aminic group of thiourea substitutes the methoxy group of a
The configuration of the iminoether ligand(s) can modulate
the antitumor potential of the platinum complex and sometime
species with the Z configuration resulted to be more active than
those with the E configuration.8,10
The Z isomer is always kinetically favored (trans addition of
Received: July 8, 2013
the alcohol to the nitrile triple bond), whereas the
Published: November 4, 2013
© 2013 American Chemical Society
13058
dx.doi.org/10.1021/ic4017118 | Inorg. Chem. 2013, 52, 13058−13067

Inorganic Chemistry
Article
1H NMR (D2O, δ, 295 K, pH = 3): 2.23 (s, 6H, CCH3), 3.39 (s,
6H, OCH3), 7.58−7.77 (m, 15H, AsPh3 ortho + meta + para H).
195Pt{1H} NMR (D2O, δ, 295 K, 64 MHz): −3230 (s).
cis-iminoether, leading to formation of a cyclic compound in a
process reminiscent of the McLafferty rearrangement.12 The
latter reaction could play a role also in the interaction of the
drug with target DNA.
trans-[PtCl{(E)-HNC(Me)OMe}2(DMSO)](NO3), [PtCl((E)-
ime)2DMSO)](NO3). A solution of trans-[PtCl(NO3){(E)-HN
C(Me)OMe}2] (50 mg, 0.11 mmol) in water (5 mL) was treated
with an excess of DMSO (86 mg, 1.1 mmol) and stirred at room
temperature for 30 min. The colorless solution was evaporated to
dryness, and the obtained white solid was washed with Et2O (3 × 5
mL) and dried under vacuum. Yield: 57.1 mg (97%). Anal. Calcd for
C8H20Cl2N2O3PtS: C, 19.60; H, 4.11; N, 5.71%. Found: C, 19.66; H,
4.05; N, 5.58%. ESI-MS, exact mass for C8H20ClN2O3PtS: 454.9.
Measured m/z: 455.0 Da [M]+. 1H NMR (D2O, δ, 295 K, 300 MHz):
2.54 (s, 6H, CCH3), 3.46 (s, 6H, SCH3), 3.91 (s, 6H, OCH3).
13C NMR (D2O, δ, 295 K, 75 MHz, 2D-1H,13C HMQC, and HMBC):
EXPERIMENTAL SECTION
■
Starting Materials. The complex trans-[PtCl2{(E)-HNC(Me)-
OMe}2] was prepared by a published procedure.13 Commercial
reagent grade chemicals were used without further purification.
Physical Measurements. C, H, and N analyses were carried out
on a Carlo Erba Model 1106 CHN Elemental Analyzer. IR spectra
were recorded on a Perkin-Elmer 283 spectrophotometer. NMR
spectra were recorded with a Bruker Avance 300 UltraShield
spectrometer, frequencies being referenced to external Me4Si (1H
and 13C), 85% H3PO4 (31P), and H2PtCl6 (195Pt).
28.0 (CCH3), 43.3 (S−CH3), 55.9 (OCH3), 175.5 (CN).
195Pt{1H} NMR (D2O, δ, 295 K, 64 MHz): −3000 (s).
Because all compounds investigated have trans configurations, in
the abbreviation used to identify a complex we will omit the prefix
trans and indicate the configuration of the iminoether ligands (E or Z)
followed by the letter code ime. For example, trans-[PtCl2{(E)-HN
C(Me)OMe}2] will be abbreviated [PtCl2((E)-ime)2].
trans-[Pt{(E)-HNC(Me)OMe}2(thiourea)2]Cl2, [Pt((E)-
ime)2(thiourea)2]Cl2. A chloroform solution (5 mL) of [PtCl2((E)-
ime)2] (100 mg, 0.24 mmol) was treated with a small excess of
thiourea (38.0 mg, 0.50 mmol), and the mixture was stirred at room
temperature for 4 h; meanwhile, the yellow solution turned into a
white suspension. The white solid ([Pt((E)-ime)2(thiourea)2]Cl2) was
filtered off, washed with Et2O (3 × 5 mL) and with a small amount of
cold chloroform (1 mL), and dried under vacuum. Yield: 130.0 mg
(99%). Anal. Calcd for C8H22Cl2N6O2PtS2·H2O: C, 16.50; H, 4.15; N,
14.43%. Found: C, 15.93; H, 3.92; N, 14.69%. ESI-MS, exact mass for
C8H22N6O2PtS2: 493.1. Measured m/z: 460.0 Da corresponding to [M
− CH3OH2]+ formed via McLafferty’s type rearrangement. The NMR
characterization of this compound was carried out in CD2Cl2. 1H
NMR (CD2Cl2, δ, 295 K, 300 MHz): 2.61 (s, 6H, CCH3), 3.99 (s,
6H, OCH3), 7.08 (s, br, 2H, NH), 7.34 (s, br, 8H, S(NH2)2). 13C
NMR (CD2Cl2, δ, 295 K, 75 MHz, 2D-1H,13C-HMQC, and HMBC):
21.5 (CCH3), 54.7 (OCH3), 173.4 (CN). 195Pt{1H} NMR
(D2O, δ, 295 K, 64 MHz): −3111 (s).
Synthesis of trans-[PtCl{(E)-HNC(Me)OMe}2(PPh3)]Cl, [PtCl-
((E)-ime)2(PPh3)]Cl. [PtCl2((E)-ime)2] (100 mg, 0.24 mmol) was
suspended in Et2O (5 mL) and treated with PPh3 (73.4 mg, 0.29
mmol). The yellow suspension was stirred overnight at room
temperature, and meanwhile it turned white. The white solid
([PtCl((E)-ime)2(PPh3)]Cl) was filtered off, washed with Et2O (3 ×
5 mL), and dried under vacuum. Yield: 159.9 mg (98%). Anal. Calcd
for C24H29Cl2N2O2PPt·2H2O: C, 40.57; H, 4.68; N, 3.94%. Found: C,
40.42; H, 4.48; N, 3.89%. ESI-MS, exact mass for C24H29ClN2O2PPt:
1
638.1. Measured m/z: 638.1 Da [M]+. H NMR (D2O, δ, 295 K, 300
MHz): 2.25 (s, 6H, CCH3), 3.44 (s, 6H, OCH3), 7.57 (ddd, 6H,
3
PPh3 meta H, JH,H(ortho) = 7.8 Hz, 3JH,H(para) = 7.6 Hz, 4JH,P = 2.7 Hz),
3
4
7.66 (ddd, 3H, PPh3 para H, JH,H(meta) = 7.6 Hz, JH,H(ortho) = 1.3 Hz,
5JH,P = 6.4 Hz), 7.79 (ddd, 6H, PPh3 ortho H, JH,H(meta) = 7.8 Hz,
3
4JH,H(para) = 1.3 Hz, JH,P = 12.2 Hz). 13C NMR (D2O, δ, 295 K, 75
3
trans-[Pt{(E)-HNC(Me)OMe}2(PPh3 )2]Cl2 , [Pt((E)-
ime)2(PPh3)2]Cl2. A chloroform solution (5 mL) of [PtCl2((E)-
ime)2] (100 mg, 0.24 mmol) was treated with PPh3 (125.9 mg, 0.48
mmol) and stirred at room temperature for 10 min. The solution was
evaporated to dryness and the obtained white solid was washed with
Et2O (3 × 5 mL) and dried under vacuum. Yield: 213.6 mg (95%).
Anal. Calcd for C42H44Cl2N2O2P2Pt·H2O: C, 52.84; H, 4.86; N, 2.93%.
Found: C, 52.97; H, 4.71; N, 2.71%. ESI-MS, exact mass for
C42H44N2O2P2Pt: 865.8. Measured m/z: 864.9 Da [M − H]+. 1H
NMR (CDCl3, δ, 295 K, 300 MHz): 1.34 (s, 6H, CCH3), 3.31 (s,
6H, OCH3), 7.50 (m, 9H, PPh34meta + para H), 8.08 (ddd, 6H,
MHz) (associated via 2D-1H,13C HMQC, and HMBC NMR): 21.5
(CCH3), 55.5 (OCH3), 128.8 (PPh3 meta C), 132.1 (PPh3 para
C), 134.0 (PPh3 ortho C), 174.0 (CN). 31P{1H} NMR (D2O, δ, 295
K, 121.5 MHz): 2.47 (s with 195Pt satellites, JP−Pt = 3960 Hz).
1
195Pt{1H} NMR (D2O, δ, 295 K, 64 MHz): −3455 (d, JPt−P = 3960
1
Hz).
trans-[PtCl{(E)-HN=C(Me)OMe}2(PPh3)](ClO4), [PtCl((E)-
ime)2(PPh3)](ClO4). Addition of [PtCl((E)-ime)2(PPh3)]Cl (50 mg,
0.074 mmol) to a water solution of HClO4 (pH = 3) caused the
immediate precipitation of a white solid, which was collected by
filtration of the mother liquor, washed with H2O until pH = 7, and
dried under vacuum. Yield: 54.5 mg (98%). Anal. Calcd for
C24H29Cl2N2O6PPt: C, 39.04; H, 3.96; N, 3.79%. Found: C, 39.50;
H, 3.91; N, 3.32%. The complex, insoluble in water, dissolved in
CH2Cl2 and CHCl3 and was slightly soluble also in acetone. 1H NMR
(CDCl3, δ, 295 K, 300 MHz): 2.27 (s, 6H, CCH3), 3.38 (s, 6H,
OCH3), 6.55 (s, br, 2H, NH), 7.57 (m, 9H, PPh3 meta + para H),
7.77 (m, 6H, PPh3 ortho H). 13C NMR (CDCl3, δ, 295 K, 75 MHz)
(from 2D-1H,13C HMQC, and HMBC NMR): 22.1 (CCH3), 55.2
(OCH3), 130.9 (PPh3 meta + para C), 134.4 (PPh3 ortho C), 173.4
(CN). 31P{1H} NMR (CDCl3, δ, 295 K, 121.5 MHz): 3.9 (s with
3
3
PPh3 ortho H, JH,H(meta) = 5.9 Hz, J
= 1.5 Hz, J
= 11.6
H,P
H,H(para)
Hz), 9.18 (s, br, 2H, NH). 13C NMR (CDCl3, δ, 295 K, 75 MHz,
2D-1H,13C-HMQC, and HMBC): 22.5 (CCH3), 57.8 (OCH3),
129.0 (PPh3 meta C), 131.4 (PPh3 para C), 135.2 (PPh3 ortho C),
172.0 (CN). 31P{1H} NMR (CDCl3, δ, 295 K, 121.5 MHz): 12.8 (s
with 195Pt satellites, JP−Pt = 2598 Hz).
1
trans-[Pt{(Z)-HNC(Me)OMe}2(PPh3)2]Cl2, [Pt((Z)-
ime)2(PPh3)2]Cl2. Under the conditions of the previous preparation,
if the reaction is not stopped 10 min after mixing of the reactants by
evaporation of the solvent but left standing at room temperature, the
initially formed [Pt((E)-ime)2(PPh3)2]Cl2 isomerizes to the EZ and
ZZ forms. The latter form, [Pt((Z)-ime)2(PPh3)2]Cl2, is sparingly
soluble in chloroform and precipitates in a crystalline form.
1
195Pt satellites, JP−Pt = 3795 Hz).
trans-[PtCl{(E)-HNC(Me)OMe}2(AsPh3)]Cl, [PtCl((E)-
ime)2(AsPh3)]Cl. A chloroform solution (5 mL) of [PtCl2((E)-
ime)2] (120 mg, 0.29 mmol) was treated with an excess of AsPh3 (150
mg, 0.49 mmol) and stirred at room temperature for 20 min. The
solution was evaporated to dryness, and the obtained white solid was
washed with Et2O (3 × 5 mL) and dried under vacuum. Yield: 184.5
mg (89%). Anal. Calcd for C24H29AsCl2N2O2Pt: C, 40.12; H, 4.07; N,
3.90%. Found: C, 39.88; H, 4.06; N, 3.92%. ESI-MS, exact mass for
C24H29AsClN2O2Pt: 682.9. Measured m/z: 682.9 Da [M]+. The NMR
characterization was carried out in D2O because in CDCl3 this
complex is stable only in the presence of excess AsPh3, whereas in the
absence of free AsPh3 partial displacement of AsPh3 by Cl− takes place.
trans-[Pt{(E)-HNC(Me)OMe}2(PPh3)2](BF4)2, [Pt((E)-
ime)2(PPh3)2](BF4)2. Addition of [Pt((E)-ime)2(PPh3)2]Cl2 (50 mg,
0.053 mmol) to a water solution of HBF4 (pH = 3) caused the
immediate precipitation of a white solid. This was collected by
filtration of the mother liquor, washed with H2O until pH = 7, and
dried under vacuum. Yield: 54.9 mg (98%). Anal. Calcd for
C42H44B2F8N2O2P2Pt: C, 48.53; H, 4.27; N, 2.70%. Found: C,
48.07; H, 4.24; N, 2.66%. The complex, insoluble in chloroform and
1
water, dissolves in CH2Cl2. H NMR (CD2Cl2, δ, 295 K, 300 MHz):
1.27 (s, 6H, CCH3), 2.88 (s, 6H, OCH3), 6.95 (s, br, 2H, NH),
7.58−7.98 (m, 30H, PPh3 ortho + meta + para H). 13C NMR (CD2Cl2,
13059
dx.doi.org/10.1021/ic4017118 | Inorg. Chem. 2013, 52, 13058−13067

Inorganic Chemistry
Article
δ, 295 K, 75 MHz, 2D-1H,13C HMQC, and HMBC): 21.7 (CCH3),
55.6 (OCH3), 129.7 (PPh3 meta C), 132.1 (PPh3 para C), 134.4
(PPh3 ortho C), 174.0 (CN). 31P{1H} NMR (CD2Cl2, δ, 295 K,
Table 1. Crystal Data and Structure Refinement Parameters
for [Pt((Z)-ime)2(PPh3)2]Cl2·3CHCl3
1
121.5 MHz): 13.5 (s with 195Pt satellites, JP−Pt = 2488 Hz).
empirical formula
formula weight
wavelength (Å)
crystal system
space group
a (Å)
C45H47Cl11N2O2P2Pt
1294.81
X-ray Crystallography. A selected crystal of trans-[Pt{(Z)-HN
C(Me)OMe}2(PPh3)2]Cl2, [Pt((Z)-ime)2(PPh3)2]Cl2, was mounted
on a Bruker AXS X8 APEX CCD system equipped with a four-circle
Kappa goniometer and a 4K CCD detector (radiation Mo Kα). For
data reduction and unit cell refinement, the SAINT-IRIX package was
employed.14 A total of 13 286 reflections (Θmax = 36.35°) were
collected, indexed, integrated, and corrected for Lorentz, polarization,
and absorption effects using the program SADABS.15
The compound [Pt((Z)-ime)2(PPh3)2]Cl2, which crystallizes from
CHCl3, incorporates three disordered molecules of solvent per
molecule of compound ([Pt((Z)-ime)2(PPh3)2]Cl2·3CHCl3). The
unit cell dimensions were calculated from all reflections, and the
0.71073
triclinic
P1
̅
9.5619(1)
11.8213(2)
13.9609(2)
102.679(1)
113.885(1)
96.269(1)
1372.59(3)
1
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
volume (Å3)
structure was solved using direct methods technique in the P1 space
̅
Z
group. The model was refined by full-matrix least-squares methods. All
non-hydrogen atoms were refined anisotropically. Two bond lengths
in a phenyl ring were restrained to be equal (SADI in SHELXL). All
hydrogen atoms were placed at calculated positions and refined given
isotropic parameters equivalent to 1.5 (methyl groups) or 1.2 (other
groups) times those of the atom to which they were attached.
All atoms, except platinum and the coordinating nitrogens and
phosphorus, are arranged in two different sets of coordinates (the two
sets labeled “a” and “b”) each one having an occupancy factor of 0.5.
For the iminoether ligands, the disorder corresponds to 180° rotation
around the Pt−N bond. Adjacent molecules cannot be both “a” or
both “b” because this would lead to some very short intermolecular
distances such as (C23b···C23b(x + 1, −y + 1, −z + 2) = 2.46(1) Å,
C16b···C17b(−x − 1, −y, −z + 2) = 2.98(1) Å, and H16b···H17b(−x
− 1, −y, −z + 2) = 1.81 Å).
density (calculated)
(Mg/m3)
1.566
absorption coefficient
3.186
(mm−1
)
F(000)
crystal size (mm3)
642
0.45 × 0.36 × 0.135
1.67−36.35°
Θ range for data
collection
index ranges
−15 ≤ h ≤ 15, −19 ≤ k ≤ 19, −23 ≤ l ≤23
36675
reflections collected
independent reflections
13286 [R(int) = 0.0441]
13286/1/399
data/restraints/
parameters
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
1.073
R1 = 0.0399, wR2 = 0.0950
R1 = 0.0418, wR2 = 0.0962
+2.574 and −0.961
All calculations and molecular graphics were carried out using
SIR2004,16 SHELXL97,17 PARST97,18 WinGX,19 and ORTEP-3 for
Windows packages.20 Details of the crystal data are listed in Table 1.
Selected bond lengths and angles are listed in Table 2.
largest diff peak and hole
(e·Å−3
)
Because there are disordered solvent molecules of crystallization,
the PLATON software21 was used to assess the solvent-accessible
volume (25.2%), then the “SQUEEZE” method, as implemented in
PLATON,22 was used to subtract from the observed data the
contribution to the diffraction pattern of the solvent molecules
(located in the voids of the lattice channels), and the modified Fo2 was
written to a new HKL file. The PLATON SQUEEZE procedure
evaluated that the contribution of the solvent molecules to the unit cell
was equivalent to 183 e−, these were assigned to three molecules of
chloroform. Therefore, three chloroform molecules are included in the
formula, formula weight, calculated density, μ, and F(000).
Table 2. Selected Bond Lengths (Å) and Angles (deg) for
[Pt((Z)-ime)2(PPh3)2]Cl2
a
Pt1−P1
Pt1−N1
P1−C13
P1−C1
2.3265(6)
2.021(2)
1.802(3)
1.803(3)
1.811(3)
1.297(6)
1.288(6)
1.316(8)
1.434(10)
1.497(9)
1.333(7)
1.433(8)
1.490(9)
N1#−Pt1−N1
N1#−Pt1−P1
N1−Pt1−P1
180.00(1)
87.93(7)
92.07(7)
180.00(1)
123.0(3)
121.9(3)
121.9(7)
117.4(5)
121.6(6)
121.0(6)
121.2(6)
117.9(5)
122.0(5)
120.0(6)
a
a
P1−Pt1−P1#
P1−C7
C21a−N1−Pt1
C21b−N1−Pt1
C21a−O1a−C23a
N1−C21a−O1a
N1−C21a−C22a
O1a−C21a−C22a
C21b−O1b−C23b
N1−C21b−O1b
N1−C21b-C22b
O1b−C21b−C22b
N1−C21a
N1−C21b
O1a−C21a
O1a−C23a
C21a−C22a
O1b−C21b
O1b−C23b
C21b−C22b
RESULTS
■
While investigating the reaction of trans-[PtCl2{(E)-HN
C(Me)OMe}2] with guanine bases, we observed that, although
starting from the pure E isomer ([PtCl2((E)-ime)2]), with time,
partial E → Z isomerization of the iminoether ligands took
place. Such an isomerization does not take place as long as the
chlorides are retained in the platinum-coordination shell. To
unravel the effect of ancillary ligands upon the thermodynamic
stability of the iminoether configuration, we have undertaken a
systematic investigation in which the chlorido ligands have been
replaced by neutral ligands chosen among those most
frequently used in coordination chemistry such as PPh3,
AsPh3, DMSO, and thiourea.
a
Symmetry transformations used to generate equivalent atoms: # −x,
−y + 1, −z + 2.
displacement of a chlorido ligand is in accord with the greater
lability of trans-chlorides, as compared to trans-N-donor
iminoethers.11 The 1H NMR signals (Table 3) indicate a
downfield shift of the NH and an upfield shift of the CMe
and OMe protons, with respect to the corresponding signals
in the starting [PtCl2((E)-ime)2] substrate. The 31P{1H} NMR
spectrum (D2O solution) shows a singlet flanked by 195Pt
Reaction of trans-[PtCl2{(E)-HNC(Me)OMe}2]
([PtCl2((E)-ime)2]) with PPh3. Performing the reaction of
[PtCl2((E)-ime)2] with excess PPh3 in Et2O, only the
monosubstituted complex trans-[PtCl{(E)-HNC(Me)-
OMe}2(PPh3)]Cl, [PtCl((E)-ime)2(PPh3)]Cl, which precip-
itates from solution, is formed in quantitative yield. The
1
satellites (2.47 ppm, JP−Pt = 3960 Hz), whereas the 195Pt{1H}
NMR spectrum (D2O solution), shows a doublet (−3455 ppm,
1JP−Pt = 3960 Hz).
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a
Table 3. Proton Chemical Shifts (δ, Downfield from Me4Si) of the Complexes in CDCl3
compound
NH
O−CH3
C−CH3
trans-[PtCl2{(E)-HNC(Me)OMe}2]
[PtCl2((E)-ime)2]
7.72
7.94
6.55
9.18
6.95
3.76
3.46
3.36
3.31
3.13
2.64
2.20
2.30
1.34
1.27
trans-[PtCl{(E)-HNC(Me)OMe}2(PPh3)]Cl
trans-[PtCl{(E)-HNC(Me)OMe}2(PPh3)](ClO4)
trans-[Pt{(E)-HNC(Me)OMe}2(PPh3)2]Cl2
trans-[Pt{(E)-HNC(Me)OMe}2(PPh3)2](BF4)2*
trans-[PtCl2{(Z)-HNC(Me)OMe}2]
[PtCl((E)-ime)2(PPh3)]Cl
[PtCl((E)-ime)2(PPh3)](ClO4)
[Pt((E)-ime)2(PPh3)2]Cl2
[Pt((E)-ime)2(PPh3)2](BF4)2*
[PtCl2((Z)-ime)2]
trans-[PtCl{(Z)-HNC(Me)OMe}2(PPh3)]Cl
trans-[PtCl{(Z)-HNC(Me)OMe}2(PPh3)](ClO4)
trans-[Pt{(Z)-HNC(Me)OMe}2(PPh3)2]Cl2
trans-[Pt{(Z)-HNC(Me)OMe}2(PPh3)2](BF4)2**
[PtCl((Z)-ime)2(PPh3)]Cl
[PtCl((Z)-ime)2(PPh3)](ClO4)
[Pt((Z)-ime)2(PPh3)2]Cl2
[Pt((Z)-ime)2(PPh3)2](BF4)2**
8.98
7.70
3.54
3.62
2.88
3.44
2.10
2.15
1.51
1.45
10.90
8.53
a
(* solvent CD2Cl2, ** solvent acetone-d6).
1
Figure 1. H NMR spectra taken at various times for [PtCl((E)-ime)2(PPh3)]Cl dissolved in D2O at 295 K and pH 6.5. Isomers: [PtCl((E)-
ime)2(PPh3)]Cl (A), [PtCl((E)-ime)((Z)-ime)(PPh3)]Cl (B), [PtCl((Z)-ime)2(PPh3)]Cl (C).
Although the [PtCl2((E)-ime)2] complex is very stable in
solution, the phosphine-substituted complex [PtCl((E)-im-
e)2(PPh3)]Cl undergoes isomerization.5
shift of the 195Pt resonance. Less important are the changes in
31P chemical shifts (Figure S2, Supporting Information). A
small downfield shift is observed only on passing from the EE
(2.5 ppm) to the EZ isomer (2.8 ppm) whereas the ZZ isomer
is isochronous with the EZ form.
In D2O solution (pH = 6.5; Figure 1), the initial EE isomer
(A) (peaks at 2.25 (C−Me) and 3.44 (O−Me) ppm), gradually
converts to the EZ isomer (B) (peaks at 1.82 and 2.11 (C−Me)
ppm and at 3.49 and 3.59 (O−Me) ppm), which, in turn,
converts to the ZZ isomer (C) (peaks at 1.85 (C−Me) and
3.55 (O−Me) ppm). The equilibrium composition is reached
in ca. 6 days and contains the three isomers (EE, EZ, and ZZ)
in 0.2:1:1 ratios.
The E/Z isomerization of the iminoether ligands, which was
quite slow in D2O (pH 6.5), became much faster in acetone.
Therefore, [PtCl((E)-ime)2(PPh3)]Cl, dissolved in acetone-d6,
undergoes fast isomerization (5 min) with formation of a white
precipitate of pure ZZ. The ZZ isomer was filtered off and fully
1
characterized by H and 31P{1H} NMR spectra.
Because a downfield shift is expected for protons that come
closer to platinum,23,24 upon conversion from the E to the Z
configuration, the C−Me signal shifts upfield whereas the O−
Me signal shifts downfield. The shift is greater (twice as much)
for the C−Me protons, which are stereochemically more rigid
than the O−Me protons.
It can be observed how the E to Z conversion of each
iminoether ligand causes an upfield shift (shielding) of the
platinum resonance of about 16 ppm (Figure S1, Supporting
Information). Also, the Pt−P coupling constant increases upon
moving from the EE to the EZ isomer (ΔJ = 100 Hz) and from
the EZ to the ZZ form (ΔJ = 135 Hz), paralleling the upfield
Having at our disposal the pure ZZ isomer, we wanted to
check if in D2O it would undergo reverse isomerization with
formation of the EZ and EE forms. After 6 days, the EE/EZ/ZZ
ratios were 0.2:1:1 (Figure S3, Supporting Information),
coincident with those obtained at equilibrium starting from
pure EE isomer.
The much faster rate of isomerization observed in acetone
with respect to water (the two solvents characterized by a very
different dielectric constant) led us to investigate the possible
role of the counterion. Therefore, we substituted ClO4− for Cl−
by precipitation of [PtCl((E)-ime)2(PPh3)](ClO4) from a
water solution of [PtCl((E)-ime)2(PPh3)]Cl and HClO4.
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Figure 2. 1H NMR spectra taken at various times for [Pt((E)-ime)2(thiourea)2]Cl2 dissolved in D2O at 295 K and pH 6.5. Isomer EE (A), isomer
EZ (B), cyclic product (G).
[PtCl((E)-ime)2(PPh3)](ClO4), dissolved in acetone-d6 or
CDCl3, does not show signs of isomerization (1H and
31P{1H} NMR) even after several days. Moreover, the chemical
shift of the iminic protons (6.55 ppm in CDCl3, Table 3 and
Figure S4, Supporting Information) was considerably upfield
with respect to the corresponding signal in [PtCl((E)-
ime)2(PPh3)]Cl (7.94 ppm in CDCl3, Table 3) and in the
usual range for iminic protons of neutral iminoether complexes,
which do not have counterions. The downfield shift (Δδ =
1.39) of the iminic proton in the case of the chloride
counterion points to a specific interaction between the chloride
anion and the iminic proton. We will come back to this point
later on in the discussion. When Cl− was added to the acetone-
d6 solution of the perchlorate complex, the isomerization of the
iminoether ligands became fast.
Reaction of [PtCl2((E)-ime)2] with AsPh3. The reaction
between [PtCl2((E)-ime)2] and AsPh3, carried out in CHCl3,
yielded the trans-[PtCl{(E)-HNC(Me)OMe}2(AsPh3)]Cl
complex, [PtCl((E)-ime)2(AsPh3)]Cl. This compound is stable
in CDCl3 solution only in the presence of excess AsPh3. In the
absence of free arsine, partial displacement of AsPh3 by Cl−
takes place, affording [PtCl2((E)-ime)2] and free AsPh3. Such a
reverse reaction does not take place in D2O solution.
compounds in which a neutral ligand (PPh3 or AsPh3) has
substituted a chlorido ligand.
Reaction of [PtCl2((E)-ime)2] with DMSO. [PtCl2((E)-
ime)2] reacts with DMSO in water affording trans-[PtCl{(E)-
HNC(Me)OMe}2(DMSO)]Cl, [PtCl((E)-ime)2(DMSO)]-
Cl. Unlike PPh3 and AsPh3, DMSO can be used in large excess
(even pure DMSO) without formation of the bis adduct. The
reaction is quite slow and can be accelerated by using trans-
[PtCl(NO3){(E)-HNC(Me)OMe}2], [PtCl(NO3)((E)-
ime)2], instead of [PtCl2((E)-ime)2], as the starting substrate.
The nitrato ligand is known to be a much better leaving group
than chloride.
1
The H NMR spectrum of [PtCl((E)-ime)2(DMSO)]Cl in
D2O (signals at 2.54 (CMe), 3.46 (SMe), and 3.91 (O
Me) ppm) shows a set of minor peaks belonging to the
hydrolyzed mono adduct trans-[Pt{(E)-HNC(Me)-
OMe}2(H2O)(DMSO)]Cl2, [Pt((E)-ime)2(H2O)(DMSO)]Cl2
(Figure S6, Supporting Information). This assignment is
supported by the observation that addition of NaCl converts
[Pt((E)-ime)2(H2O)(DMSO)]Cl2 into [PtCl((E)-
ime)2(DMSO)]Cl.25 The 195Pt{1H} NMR spectrum gives a
singlet at −3000 ppm.
Unlike compounds [PtCl((E)-ime)2(PPh3)]Cl and [PtCl-
((E)-ime)2(AsPh3)]Cl, compound [PtCl((E)-ime)2(DMSO)]
Cl was stable in D2O solution at neutral pH and room
temperature and did not show signs of isomerization to EZ and
ZZ isomers during a period of 1 week (Figure S6, Supporting
Information). In a recent paper Arnesano, Liu, et al. found a
similar behavior in the reaction of [PtCl2((E)-ime)2] with
AcMet or Met.26 However, by changing the solvent (DMSO-d6
instead of water) the initially former [PtCl((E)-ime)2(DMSO)]
Cl complex undergoes isomerization with formation of the EZ
and ZZ forms. After 6 days, the equilibrium ratios of the three
isomers, EE, EZ, and ZZ, were 1:2:0.7 (Figure S7, Supporting
Information).
Similarly to complex [PtCl((E)-ime)2(PPh3)]Cl, complex
[PtCl((E)-ime)2(AsPh3)]Cl undergoes an isomerization equi-
librium to EZ and ZZ forms in D2O at pH 6.5 (Figure S5,
Supporting Information). Therefore, the signals of the EE
isomer (A) (peaks at 2.23 (C−Me) and 3.39 (O−Me) ppm)
decrease with time with a simultaneous increase of the signals
of the EZ isomer (B) (peaks at 1.77 and 2.08 (C−Me) and at
3.38 and 3.45 (O−Me) ppm) and of the ZZ form (C) (peaks at
1.81 (C−Me) and 3.39 (O−Me) ppm). After 6 days, a
composition equilibrium was reached with the three isomers
EE, EZ, and ZZ, present in 0.15:1:1 ratios, respectively. The
greater stability of the Z form, with respect to the E form,
appears to be a common feature of the iminoether ligand in
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Scheme 2. Formation of the Cyclic Species G
Figure 3. 1H NMR spectra taken at various times for [Pt((E)-ime)2(PPh3)2]Cl2 dissolved in CDCl3 at 295 K. Isomer EE (A), isomer EZ (B) (peaks
at 1.38 and 1.45 ppm (CMe) and at 2.83 and 3.16 ppm (OMe)), isomer ZZ (C) (peaks at 1.50 (CMe) and 2.89 (OMe) ppm), trans-
[PtCl{(Z)-HNC(Me)OMe}(PPh3)2]Cl (D) (peaks at 1.23 (CMe) and 3.16 ppm (OMe), free iminoether (L) (peaks at 2.02 (CMe) and
3.70 ppm (OMe)).
Reaction of [PtCl2((E)-ime)2] with Thiourea. [PtCl2((E)-
ime)2] reacts with thiourea in water, as well as in organic
solvents, forming always the bis-substituted species trans-
[Pt{(E)-HNC(Me)OMe}2(thiourea)2]Cl2, [Pt((E)-
ime)2(thiourea)2]Cl2, even when a defect of entering ligand
(0.5 or 1 equiv) is used. This compound is very soluble in water
but insoluble in chloroform or acetone, from which it
precipitates as a white solid.
(Figure S8, Supporting Information) and ESI-MS analysis. The
latter one showing a molecular peak at m/z: 460.0 Da
corresponding to [G − H]+ (exact mass for G: C7H18N6OPtS2,
461.0).
Formation of the Bis(phosphine) Adduct trans-[Pt{(E)-
HNC(Me)OMe}2(PPh3)2]Cl2, [Pt((E)-ime)2(PPh3)2]Cl2. The
reaction between [PtCl2((E)-ime)2] and excess PPh3, per-
formed in Et2O, affords only the 1:1 adduct [PtCl((E)-
ime)2(PPh3)]Cl, which separates out of solution soon after
formation. However, if the reaction is carried out in CHCl3, the
[Pt((E)-ime)2(PPh3)2]Cl2 complex is formed in quantitative
yield (95%). Upon passing from the monophosphine ([PtCl-
((E)-ime)2(PPh3)]Cl) to the bisphosphine derivative ([Pt((E)-
ime)2(PPh3)2]Cl2), the iminic nitrogen undergoes a remarkable
downfield shift (Δδ = 1.24 ppm), whereas the methyl protons
undergo an upfield shift, which is much greater for CMe (Δδ
= 0.86 ppm) that for OMe (Δδ = 0.15 ppm) (Table 3). The
upfield shift of the CMe and OMe protons could be due
to a shielding effect exerted by the phenyl groups of the
phosphine ligands, whereas the downfield shift of the iminic
proton could be due to H bond interaction with the
In D2O solution, [Pt((E)-ime)2(thiourea)2]Cl2 (A, 1H
signals at 2.49 (CMe) and 3.80 (OMe) ppm, Figure 2)
undergoes isomerization to the EZ form. However, concurrent
to the isomerization of the iminoether ligand, another
unexpected rearrangement takes place: methanol is released
and a new species (G), with two signals in the CMe region
(2.17 and 2.37 ppm), and only one signal in the OMe region
(3.79 ppm) is formed (Figure 2).
The release of a methoxy group from one iminoether ligand,
not observed in the previous experiments, could be fostered by
an aminic group of thiourea displacing the methoxyl group of a
cis-iminoether and forming a cyclic product (G, Scheme 2).
This hypothesis was fully confirmed by multinuclear NMR
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Figure 4. 31P{1H} NMR spectra taken at various times for [Pt((E)-ime)2(PPh3)2]Cl2 dissolved in CDCl3 at 295 K. Isomers: EE (A) (peak at 12.8
ppm with platinum satellites, 1JP−Pt = 2598 Hz), EZ (B) (peak at 14.0 ppm, 1JP−Pt = 2600 Hz), ZZ (C) (peak at 14.8 ppm, 1JP−Pt = 2630 Hz), trans-
[PtCl{(Z)-HNC(Me)OMe}(PPh3)2]Cl (D) (peak at 17.4 ppm, 1JP−Pt = 2641 Hz), cis-[PtCl2(PPh3)2] (E) (peak at 14.2 ppm, 1JP−Pt = 3668 Hz).
Figure 5. ORTEP drawing at 20% probability of [Pt((Z)-ime)2(PPh3)2]Cl2. The ligands ((Z)-ime and PPh3) can assume two different
conformations (labeled “a” and “b”), both conformations are shown. The chloride counterions are located near the iminoether ligands and form
strong H bonds with N−H.
counterions, see following X-ray Structure section and the
Discussion.
spectra in Figures S9, S10, and S11 (Supporting Information),
respectively).
In CDCl3, the isomerization of the EE form (A) to the EZ
form (B) and to the ZZ form (C) is also accompanied by
displacement of the iminoether ligand by chloride and
formation of trans-[PtCl{(Z)-HNC(Me)OMe}(PPh3)2]Cl
(D) and free iminoether (L) (Figure 3).
[Pt((E)-ime)2(PPh3)2]Cl2 undergoes fast isomerization to
the EZ and ZZ forms not only in chlorinated solvent (CDCl3)
but also in water. Therefore, unlike the monophosphine
derivative [PtCl((E)-ime)2(PPh3)]Cl, for which the isomer-
ization in D2O was very slow, the bisphosphine derivative
[Pt((E)-ime)2(PPh3)2]Cl2 undergoes fast isomerization into
the EZ and the ZZ forms, with the equilibrium being almost
completely shifted toward the ZZ form (1H, 31P, and 195Pt
The 31P NMR (Figure 4) also showed that, in addition to
species A, B, C, and D, there is also formation of a species in
which both iminoethers have been displaced by chloride, cis-
[PtCl2(PPh3)2], E. That in the case of the bisphosphine
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a
Scheme 3. Mechanism of Isomerization about the CN Double Bond
a
For the two limiting formulas, the formal charge on the ligand atoms is also indicated.
compound the equilibrium is completely shifted toward the ZZ
form could be checked by monitoring (1H NMR) a solution of
[Pt((Z)-ime)2(PPh3)2]Cl2 in D2O or CDCl3. No sign of
isomerization to the EZ and EE forms was observed (Figure
S9−S11, Supporting Information).
Interestingly, the chloride counterion is located near the
iminoether ligand and forms a strong hydrogen bond with NH
(N1···Cl1b 3.180(2) Å, N1H1b···Cl1b 2.347 Å, N1−H1b···
Cl1b 163.2(2)°; N1···Cl1a 3.247(4) Å, N1H1a···Cl1a 2.417 Å,
N1−H1a···Cl1a 162.3(2)°).
To investigate the effect of the counterion upon the rate of
isomerization of the iminoether ligand also in the case of the
bisphosphine derivative, we prepared the tetrafluoroborate
complex [Pt((E)-ime)2(PPh3)2](BF4)2, which is insoluble in
H2O and in CHCl3, but sufficiently soluble in CD2Cl2 and in
acetone-d6.
In CD2Cl2, a fast isomerization took place affording, after few
minutes, a white precipitate of the pure ZZ isomer. The same
fast isomerization was observed in acetone-d6 where the
[Pt((Z)-ime)2(PPh3)2](BF4)2 compounds is also soluble
(Figure S12, Supporting Information).
X-ray Structure of [Pt((Z)-ime)2(PPh3)2]Cl2. [Pt((Z)-
ime)2(PPh3)2]Cl2 crystallizes, incorporating three molecules
of CHCl3 per molecule of complex. The asymmetric unit
comprises half a molecule of the complex, and the structure is
generated by inversion at the Pt1 center (Figure 5).
DISCUSSION
■
For the series of trans-[PtCl2{HNC(R)OMe}2] complexes
(R = Me, Et, Ph, t-Bu), it was found that the stability of the E
isomer decreases in the order Me > Et > Ph > t-Bu, indicating
that an increase of steric bulk of the R group destabilizes the E
isomer in which the R group is cis to the metal core with
respect to the CN double bond. Moreover, because the
addition of the alcohol to the coordinated nitrile to form the
iminoether takes place in trans positions, the Z isomer is always
kinetically favored and isomerization to the thermodynamically
preferred form takes place in a second step. In the case of R = t-
Bu, the Z isomer is both kinetically and thermodynamically
preferred.11
Unexpectedly, some evidence indicated that the relative
stability of the E and Z isomer could also be influenced by the
nature of the ancillary ligands. Therefore, although in the
dichlorido species trans-[PtCl2{HNC(Me)OMe}2] the
iminoether ligands have stable EE configuration (thermody-
namically preferred configuration), in the complex [PtCl-
{HNC(Me)OMe}2(PPh3)]Cl, both in protic as well as in
aprotic solvents, the E configuration of the iminoether is no
longer the most stable and an equilibrium composition
containing the three isomers (EE, EZ, and ZZ) is established.
For the isomerization about the CN double-bound, we can
postulate a mechanism similar to that suggested for isomer-
ization in basic conditions,24 that is attack of an external
nucleophile (Nu) upon the carbon atom of the imino residue
leading to formation of an amido species which afterward
eliminates the nucleophile restoring the iminoether ligand, but
in an isomerized form (upper row of Scheme 3). The positive
charge on the imino nitrogen should increase in the substituted
products, relative to the dichlorido species, facilitating the
nucleophilic attack at the imino carbon. In the latter mechanism
we have also to contemplate the possibility of exchange
between the alkoxy group and the attacking nucleophile. Such a
substitution has not been observed in the present investigation.
For the latter reason, we cannot exclude the possibility that
in the present case the isomerization could take place without
the intervention of an external nucleophile. Previous and
present X-ray investigations support the view that an oxygen
lone pair of the iminoether gets involved in conjugation with
the CN π system. In other words, the iminoether moiety can
The platinum ion has a square−planar coordination
geometry. As expected, also the iminoether ligands are planar
(maximum deviation from the plane passing through N1, C21,
C22, O1, and C23 0.03(1) Å). The dihedral angle between the
coordination plane and the iminoether plane is ca. 81°. The two
iminoether ligands have similar geometrical parameters. The
NC, C(sp2)O, and OC(sp3) bond distances (average
values 1.29(1), 1.32(1), and 1.43(1) Å, respectively) and the
PtNC and NCC angles (average values 123.5(6) and
121.8(6)°, respectively) are similar to those previously
observed in platinum−iminoether complexes (such as trans-
[PtCl2{(Z)-HNC(t-Bu)OMe}2],11 trans-[PtCl{(Z)-HNC-
(Me)OMe}2(PPh3)]Cl,27 and cis- and trans-[PtCl2{(E)-HN
24
C(Me)OMe}2] ) and indicate the presence of an extensive
electron charge delocalization over the NCO moiety.
The iminoether ligands have the oxygen-bound Me group
directed toward the CMe (Z anti configuration), whereas in
the other complexes with Z configuration of the iminoethers
previously investigated, trans-[PtCl2{(Z)-HNC(t-Bu)-
OMe}2], the oxygen-bound Me group was directed toward
the metal core (Z syn configuration).11 An electrostatic
interaction between the lone pair of electrons on the oxygen
of the iminoether ligand and the positively charged metal ion
(Pt···O distance of ca. 3.04[1] Å, shorter than the sum of the
van der Waals radii, which amounts to ca. 3.22 Å) could be
responsible for the observed Z anti configuration.
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be described in terms of two limiting formulas as shown in the
lower row of Scheme 3. The positive charge accumulated on
the metal core by the effect of substitution of Cl− by neutral
ligands could stabilize the limiting formula on the right that,
having a single NC bond, could undergo rotation finally
leading to E−Z isomerization of the iminoether.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic Data in CIF format. Additional H, 31P{1H},
and 195Pt{1H} NMR spectra and portion of 2D 1H−13C
HMBC spectrum. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
The X-ray investigation, performed on the bis(phosphine)
derivative (present work) as well as on the monophosphine
derivative [PtCl((Z)-ime)2(PPh3)]Cl,27 has revealed, for the
first time, a Z configuration for an iminoether with small C-
alkyl substituents (Me). Moreover, this Z configuration differs
from that previously observed for the t-Bu derivative for which
the Z configuration was stabilized by the bulky t-Bu preferring
to be trans to the bulky platinum residue with respect to the
azomethine double bond. For the latter complex, the oxygen-
bound Me group was directed toward platinum (approaching
the metal from an apical position) so to avoid steric clash with
the t-Bu group (Z syn configuration). In contrast, the
phosphine substituted compounds, trans-[Pt{(Z)-HNC-
(Me)OMe}2(PPh3)2]Cl2 and trans-[PtCl{(Z)-HNC(Me)-
OMe}2(PPh3)]Cl, also having the Z configuration, have the
oxygen-bound Me group directed not toward platinum but
toward the CMe group (Z anti configuration). The latter
configuration could be favored by the smaller steric hindrance
of the C−Me with respect to C(t-Bu); however, we
hypothesize that additional stability of the Z anti configuration
comes from the electrostatic interaction between the oxygen
lone pair and the platinum cation as witnessed by the rather
short Pt···O distance. Such an interaction could be fostered by
the net positive charge of the phosphine complexes, as opposed
to the neutral dichlorido species, and possibly by the lower
dielectric constant around the metal core provided by the
hydrophobic phosphine environment. The same factors, net
positive charge of the complex and reduced dielectric constant
around the metal core, could favor formation of a strong H
bond between the iminic proton and the chloride counterion.
Such an interaction, observed in the solid state, is also present
in solution of organic solvent as witnessed by the downfield
shift of the iminic proton in the case of Cl− counterion(s).
A particular case is that of the thiourea derivative in which an
aminic group of thiourea displaces the methoxyl group of a cis-
iminoether forming a cyclic product. Such a rearrangement,
reminiscent of the McLafferty rearrangement, could play a role
also in the interaction of iminoether compounds, such as trans-
[PtCl2{(Z)-HNC(Me)OMe}2], with target DNA. The latter
drug gives prevalently monofunctional adducts with DNA
(substitution of one chloride by a purinic base) which,
contrarily to monofunctional adducts formed by other platinum
complexes, are able to inhibit DNA and RNA polymerases. It is
conceivable that, in addition to platinum coordination to a
nucleobase, a McLafferty type rearrangement occurring
between an iminoether ligand and an amminic residue could
lead to cross-linking.
AUTHOR INFORMATION
■
Corresponding Author
*G. Natile. E-mail: giovanni.natile@uniba.it. Fax: +39-080-
5442230.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Ferdinando Scordari and Dr Ernesto
Mesto (University of Bari, Italy) for the X-ray diffraction data
collection. This work was supported by the University of Bari,
MIUR (RINAME Project RBAP114AMK), EU (COST
ACTION CM1105), and CIRCMSB (Consorzio Interuniversi-
tario di Ricerca in Chimica dei Metalli nei Sistemi Biologici).
REFERENCES
■
(1) (a) Lippert, B. Cisplatin: Chemistry and Biochemistry of a Leading
Anticancer Drug; Wiley-VCH, Zurich, 1999. (b) Go, R. S.; Adjei, A. A.
J. Clin. Oncol. 1999, 17, 409−422. (c) Jamienson, E. R.; Lippard, S. J.
Chem. Rev. 1999, 99, 2467−2498.
(2) (a) Fuertes, M. A.; Alonso, C.; Perez, J. M. Chem. Rev. 2003, 103,
645−662. (b) Akiyama, S.; Chen, Z. S.; Sumizawa, T. Anti-Cancer Drug
Des. 1999, 14, 143−151.
(3) (a) Kalinowska-Lis, U.; Ochocki, J.; Matlawska-Wasowska, K.
Coord. Chem. Rev. 2008, 252, 1328−1345. (b) Farrell, N. In Metal Ions
in Biological Systems; Sigel, A., Sigel, S., Eds.; Marcel Dekker, Inc.: New
York, Basel, Hong Kong, 1996; Vol. 32, p 603. (c) Dekker, M.; Farrell,
N.; Kelland, L. R.; Roberts, J. D.; Van Beusichem, M. Cancer Res. 1992,
52, 5065−5072. (d) Kelland, L. R.; Barnard, C. F. J.; Evans, I. G.;
Murrer, B. A.; Theobald, B. R. C.; Wyer, S. B.; Goddard, P. M; Jones,
M.; Valenti, M.; Bryant, A.; Rogers, P. M.; Harrap, K. R. J. Med. Chem.
1995, 38, 3016−3024.
(4) Coluccia, M.; Natile, G. Anti-Cancer Agents Med. Chem. 2007, 7,
111−123.
̀
(5) Coluccia, M.; Nassi, A.; Loseto, F.; Boccarelli, A.; Mariggio, M.
A.; Giordano, D.; Intini, F. P.; Caputo, P.; Natile, G. J. Med. Chem.
1993, 36, 510−512.
̀
(6) Coluccia, M.; Boccarelli, A.; Mariggio, M. A.; Cardellicchio, N.;
Caputo, P.; Intini, F. P.; Natile, G. Chem-Biol. Interact. 1995, 98, 251−
266.
(7) Natile, G.; Coluccia, M. In Topics in Biological Inorganic
Chemistry, Metallopharmaceuticals I, DNA Interactions; Clarke, M. J.,
Sadler, P. J., Eds.; Springer-Verlag: Berlin, 1999; p 73.
(8) Leng, M.; Locker, D.; Giraud-Panis, M. J.; Schwartz, A.; Intini, F.
P.; Natile, G.; Pisano, C.; Boccarelli, A.; Giordano, D.; Coluccia, M.
Mol. Pharmacol. 2000, 58, 1525−1535.
(9) (a) Fanizzi, F. P.; Intini, F. P.; Natile, G. J. Chem. Soc., Dalton
Trans. 1989, 947−951. (b) Lopez, G.; Ruiz, J.; Garcia, G.; Vicente, C.;
́
Martí, J. M.; Hermoso, J. A.; Vegas, A.; Martinez-Ripoll, M. J. Chem.
Soc., Dalton Trans. 1992, 53−58. (c) Casas, J. M.; Chisholm, M. H.;
Sicilia, M. V.; Streib, W. E. Polyhedron 1991, 10, 1573−1578.
(10) (a) Boccarelli, A.; Coluccia, M.; Intini, F. P.; Natile, G.; Locker,
D.; Leng, M. Anti-Cancer Drug Des. 1999, 14, 253−264. (b) Coluccia,
M.; Nassi, A.; Boccarelli, A.; Giordano, D.; Cardellicchio, N.; Locker,
D.; Leng, M.; Sivo, M.; Intini, F. P.; Natile, G. J. Inorg. Biochem. 1999,
77, 31−35.
CONCLUSION
■
The present investigation has highlighted the role that ancillary
ligands, formally not participating in a reaction, can play in
determining the stereochemistry and the reactivity of a metal-
coordination compound. We believe that the rearrangements/
interactions taking place within the coordination shell of a
platinum complex, as highlighted in the present work, have a
general significance and can apply to several other cases.
(11) Gonzalez, A. M.; Cini, R.; Intini, F. P.; Pacifico, C.; Natile, G.
Inorg. Chem. 2002, 41, 470−478.
13066
dx.doi.org/10.1021/ic4017118 | Inorg. Chem. 2013, 52, 13058−13067

Inorganic Chemistry
Article
(12) Nibbering, N. M. M. J. Am. Soc. Mass Spectrom. 2004, 15, 956−
958.
(13) Bandoli, G.; Caputo, P. A.; Intini, F. P.; Sivo, M. F.; Natile, G. J.
Am. Chem. Soc. 1997, 119, 10370−10376.
(14) Bruker: SAINT-IRIX. Bruker AXS, Inc.: Madison, WI, 2003.
(15) Sheldrick, G.M. SADABS, Program for Empirical Absorption
Correction of Area Detector Data; University of Gottingen: Germany,
̈
1996.
(16) Burla, M. C.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.;
Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 2003, 36,
1103.
(17) Sheldrick, G. M. Programs for Crystal Structure Analysis (release
97-2); Institut fur Anorganische Chemie der Universitat: Gottingen,
̈
̈
̈
Germany, 1998.
(18) (a) Nardelli, M. Comput. Chem. 1983, 7, 95−97. (b) J. Appl.
Crystallogr. 1995, 28, 659.
(19) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838.
(20) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(21) Spek, A. L. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009,
D65, 148−155.
(22) Van der Sluis, P.; Spek, A. L. Acta Crystallogr., Sect. A: Found.
Crystallogr. 1990, A46, 194−201.
(23) (a) Miller, R. G.; Stauffer, R. D.; Fahey, D. R. J. Am. Chem. Soc.
1970, 92, 1511−1521. (b) Fahey, D. R. J. Organomet. Chem. 1973, 57,
385−388.
(24) Cini, R.; Caputo, P. A.; Intini, F. P.; Natile, G. Inorg. Chem.
1995, 34, 1130−1137.
(25) Liu, Y. Z.; Vinje, J.; Pacifico, C.; Natile, G.; Sletten, E. J. Am.
Chem. Soc. 2002, 124, 12854−12862.
(26) (a) Li, C.; Huang, R.; Ding, Y.; Sletten, E.; Arnesano, F.;
Losacco, M.; Natile, G.; Liu, Y. Inorg. Chem. 2011, 50, 8168−8176.
(b) Li, C.; Li, Z.; Sletten, E.; Arnesano, F.; Losacco, M.; Natile, G.; Liu,
Y. Angew. Chem., Int. Ed. 2009, 48, 8497−8500.
(27) Giardina-Papa, D.; Intini, F. P.; Natile, G.; Pacifico, C. Acta
Crystallogr., Sect. C: Cryst. Struct. Commun. 2012, C68, m300−m302.
13067
dx.doi.org/10.1021/ic4017118 | Inorg. Chem. 2013, 52, 13058−13067