Organometallics
Article
on analogous mononuclear species. This arsenal of com-
pounds, which might be viewed as dinuclear analogues of
ferrocenes, holds an intriguing but unexplored potential in
terms of medicinal applications. In this light, the behavior of a
selection of complexes based on the [Fe2Cp2(CO)x] core and
containing a bridging hydrocarbyl ligand was evaluated for the
first time. The compounds displayed a variable stability in
water and in the presence of a cell culture medium and were
investigated for their antiproliferative activity toward a panel of
cell lines. Complexes containing a bridging aminocarbyne
ligand, featuring fair water stability and a good balance
between hydrophilicity and lipophilicity, exhibit the best
cytotoxicity patterns, including a significant selectivity against
cancer cells in comparison to normal cells. The action of these
compounds seems multimodal, including interaction with
proteins and, possibly, interference with redox processes
(moderate catalytic effect on NADH oxidation), but not
significant DNA binding. Also the observed, slow degradation
of the complexes in water, leading to extensive disruption of
the diiron frame, may be functional to the cytotoxicity; in
particular, although deeper studies would be needed to clarify
this latter point, carbon monoxide, dissociated from coordina-
tion, might exert some activity complementary to the
anticancer effect.48 The antiproliferative action of cationic
diiron compounds described in this work and containing a C1
bridging ligand appears somehow different from that of related
diiron complexes with a bridging C3 vinyliminium ligand, the
latter clearly triggering ROS production and being almost
unreactive toward model proteins.12
Chart 1. Structure of the Cation of cis-11a
with Me3NO·2H2O (30 mg, 0.27 mmol). After 1 h, the IR spectrum
recorded on an aliquot of the darkened solution indicated the clean
formation of 8a. The solvent was removed under vacuum. The dark
brown residue was dissolved in acetone (8 mL), and then PTA (1,3,5-
triaza-7-phosphatricyclo[3.3.1.1]decane; 43 mg, 0.27 mmol) was
added. The dark brown solution was stirred at reflux temperature
under N2 for 2 h, progressively turning to dark green. The conversion
was checked by 31P NMR, and then the volatiles were removed under
vacuum. The residue was dissolved in a small volume of MeCN and
charged on an alumina column (height 6 cm, diameter 2.3 cm).
Impurities were eluted with MeCN, and then a green band was eluted
using MeCN/MeOH 10/1 v/v. Volatiles were removed under
vacuum (40 °C), affording 11a as a dark green solid (cis/trans ratio
5/1; 1H/31P NMR in acetone-d6). Yield: 152 mg, 84%. Subsequently,
the mixture of isomers was suspended in CHCl3 (10 mL) and filtered.
The dark green solid that was obtained was thoroughly washed with
CHCl3 and then Et2O, affording pure cis-11a (1H/31P NMR in
acetone-d6). The solid was dried under vacuum (40 °C) and stored
under N2 (slightly hygroscopic). Yield: 69 mg, 38%. Compound cis-
11a is soluble in water, MeOH, and MeCN, less soluble in acetone,
poorly soluble in CH2Cl2 and CHCl3, and insoluble in toluene and
Et2O. Anal. Calcd for C22H28F3Fe2N4O5PS: C, 40.02; H, 4.27; N,
8.49. Found: C, 39.85; H, 4.37; N, 8.50. IR (solid state): ν
̃
/cm−1
EXPERIMENTAL SECTION
3566w, 3089w, 3067w-sh, 2933w, 2880w-sh 1976m-sh (CO), 1952s
(CO), 1815w-sh, 1787s (μ-CO), 1781s (μ-CO), 1665w, 1572m (μ-
CN), 1448w, 1422w, 1392w, 1261s, 1246s-sh, 1221m-sh, 1193w,
1160s, 1148s, 1105m, 1046w, 1028s, 1020s-sh, 973s, 950s, 897w,
■
Materials and Methods. Syntheses were carried out under a
nitrogen atmosphere using standard Schlenk techniques; all other
operations were conducted in air with common laboratory glassware.
When required, reaction vessels were oven-dried at 140 °C prior to
use, evacuated (10−2 mmHg), and then filled with nitrogen. Organic
reactants (TCI Europe or Merck) and Fe2Cp2(CO)4 (Strem; Cp = η5-
C5H5) were commercial products of the highest purity available.
Compounds 3,14a 4,15a 5a−e,16a 6,18 7,19 9a,b,20 and 1016a were
prepared according to published procedures. Solvents were distilled
before use under nitrogen from appropriate drying agents.
Chromatography separations were carried out on columns of
deactivated alumina (Merck, 4% w/w water). Infrared spectra of
solid samples were recorded on a PerkinElmer Spectrum One FT-IR
spectrometer, equipped with a UATR sampling accessory. Infrared
spectra of solutions were recorded on a PerkinElmer Spectrum 100
FT-IR spectrometer with a CaF2 liquid transmission cell (2300−1500
cm−1 range). NMR spectra were recorded at 298 K on a Bruker
Avance II DRX400 instrument equipped with a BBFO broad-band
probe. Chemical shifts (expressed in parts per million) are referenced
to the residual solvent peaks49 (1H, 13C) or to external standard (19F
to CCl3F, 31P to 85% H3PO4). NMR spectra were assigned with the
877m, 853m, 842m-sh, 831w, 807m, 763s, 764s. IR (MeCN): ν/
̃
cm−1
1966s (CO), 1799s (μ-CO), 1572m (μ-CN). 1H NMR (acetone-d6):
δ/ppm 5.27 (s, 5H, Cp), 5.14 (d, 3JHP = 1.5 Hz, 5H, Cp′), 4.38−4.33
(m, 6H, NMe + NCH2), 4.31−4.26 (m, 6H, NMe′ + NCH2), 3.94−
3.82 (m, 6H, PCH2). 13C{1H} NMR (acetone-d6): δ/ppm 324.4 (d,
2
2JCP = 17 Hz, μ-CN), 263.1 (d, JCP = 17 Hz, μ-CO), 216.3 (CO),
3
89.9 (Cp), 87.9 (Cp′), 72.9 (d, JCP = 7 Hz, NCH2), 54.5 (PCH2),
54.4, 54.2 (NMe2). 19F{1H} NMR (acetone-d6): δ/ppm 78.8.
1
31P{1H} NMR (acetone-d6): δ/ppm −22.0. H NMR (CD3OD): δ/
ppm 5.18 (s, 5H, Cp), 5.03 (d, 3JHP = 1.2 Hz, 5H, Cp′), 4.40 (d, 2JHH
= 13.2 Hz, 3H, NCH2), 4.30 (d, 2JHH = 13.1 Hz, 3H, NCH2), 4.22 (s,
3H, NMe2), 4.18 (s, 3H, NMe2), 3.84−3.75 (m, 6H, PCH2). 31P{1H}
NMR (CD3OD): δ/ppm −20.2.
trans-11a (in Admixture with cis-11a). IR (CH2Cl2): ν/
̃
̃
cm−1
cm−1
1965vs (CO), 1799s (μ-CO), 1575m (CN). IR (THF): ν/
1
1960vs (CO), 1779s (μ-CO), 1579m (μ-CN). H NMR (acetone-
d6): δ/ppm 5.21 (s, 5H, Cp), 5.05 (d, 3JHP = 1.4 Hz, 5H, Cp′), 4.47−
4.39 (m, 9H, NCH2/NMe). 31P{1H} NMR (acetone-d6): δ/ppm
−18.1. 1H NMR (D2O): δ/ppm 5.12 (s, 5H, Cp), 4.96 (d, 3JHP = 1.3
Hz, 5H, Cp). 31P{1H} NMR (D2O): δ/ppm −13.1.
1
assistance of H−13C (gs-HSQC and gs-HMBC) correlation experi-
ments.50 Raman analysis was conducted with a Renishaw Invia micro-
Raman instrument equipped with a Nd:YAG laser working at 532 nm
and 0.1 mW, with an integration time of 10 s. Carbon, hydrogen, and
nitrogen analyses were performed on a Vario MICRO cube
instrument (Elementar). GC analyses were performed on a Clarus
500 instrument (PerkinElmer) equipped with a 5 Å MS packed
column (Supelco) and a TCD detector. Samples were analyzed by
isothermal runs (120 °C, 4 min) using He as a carrier gas. Synthesis
and characterization of compounds (Charts 1−3).
A few X-ray-quality crystals of [Fe2Cp2(CO)(μ-CO){μ-CNMe2}-
(PTA)]Cl (11aCl) were collected by slow diffusion of diethyl ether
into a methanol solution of 11a and NaCl at room temperature.
[Fe2Cp2(CO)(μ-CO){μ-η1:η1-CNMe2}{κP-Ph2P(2-C6H4OH)}]-
CF3SO3 (11b). The title product was prepared by using a procedure
analogous to that described for 11a, from 5a (200 mg, 0.377 mmol)
and Ph2P(2-C6H4OH) (157 mg, 0.564 mmol). The acetone solution
was refluxed for 5 h. Green solid, yield 85%. Anal. Calcd for
C34H31F3Fe2NO6PS: C, 52.26; H, 4.00; N, 1.79. Found: C, 52.12; H,
cis-/trans-[Fe2Cp2(CO)(μ-CO){μ-η1:η1-CNMe2}(κP-PTA)]-
CF3SO3 (11a). Compound 8a was preliminarily prepared by a slight
modification of the literature procedure:20 a solution of 5a (174 mg,
0.277 mmol) in deareated acetonitrile (15 mL) was allowed to react
4.05; N, 1.88. IR (CH2Cl2): ν
̃
/cm−1 1992vs (CO), 1788s (μ-CO),
1586m (μ-CN). IR (THF): ν/
̃
cm−1 1978vs (CO), 1785s (μ-CO),
1590m (μ-CN). 1H NMR (acetone-d6): δ/ppm 9.44 (br-s, 1H, OH);
G
Organometallics XXXX, XXX, XXX−XXX