Highly cytotoxic vanadium(v) complexes of salan ligands; Insights on the role of hydrolysis

Article abstract of DOI:10.1039/c2dt11514j

Vanadium(v) oxo complexes with tetradentate diamine bis(phenolato) "salan" ligands of the type LVO(OiPr) (L is salan) with different steric and electronic substitutions at the ortho and para positions to the binding phenolato moiety were synthesized and t

Full text of DOI:10.1039/c2dt11514j

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PAPER
Highly cytotoxic vanadium(V) complexes of salan ligands; insights on the role
of hydrolysis†
Lilia Reytman,a Ori Braitbardb and Edit Y. Tshuva*a
Received 11th August 2011, Accepted 7th February 2012
DOI: 10.1039/c2dt11514j
Vanadium(V) oxo complexes with tetradentate diamine bis(phenolato) “salan” ligands of the type LVO
(OiPr) (L is salan) with different steric and electronic substitutions at the ortho and para positions to the
binding phenolato moiety were synthesized and their hydrolytic stability and cytotoxicity were analyzed.
With one exception bearing large steric groups, all complexes examined displayed marked cytotoxic
activity, comparable to, and often higher than, that of cisplatin. While the hydrolytic stability changed
significantly depending on the substituent at the ortho position relative the O-donor with little effect of
para substitutions, the cytotoxic activity largely was not affected, and high cytotoxicity was recorded also
for relatively unstable complexes. Additional measurements revealed that the cytotoxicity is largely
maintained following pre-incubation of up to 18 hours of the complexes in the biological medium prior to
cell addition, suggesting that hydrolysis products might serve as the active species. In addition,
appreciable cytotoxic activity was measured for an isolated hydrolysis product that was analyzed
crystallographically to exhibit a dimeric structure with bridging oxo ligand where both metal centers are
bound to the salan ligand, supporting the aforementioned conclusions.
Additionally, vanadium compounds possess therapeutic potential
Introduction
in several diseases including diabetes11,12 and cancer.13–15 In
Since the discovery of the anti-tumor activity of cisplatin, the
research of novel metal compounds for cancer treatment has
been rapidly evolving.1–7 Due to the limited activity range result-
ing from inherent or acquired resistance of some cell types, and
severe toxicity of platinum compounds, other transition metals
are being investigated, which may introduce different coordi-
nation features leading to different mechanisms of action, where
structure–activity relationship studies aim at elucidating the influ-
ences of different electronic and steric properties of the metal
center on its medicinal potential.
particular, recent studies of in vivo influence of an anticancer
oxo-vanadium complex of the type L2VO(X) (L is a methylated
phenanthroline ligand and X is a sulfato ligand) on mice
revealed favorable pharmacokinetics and toxicity profiles.16
These features, combined with evidence of significantly higher
vanadium concentration in cancerous compared to normal breast
tissue,17 contribute to the promise of vanadium compounds in
cancer therapy and encourage the search for new V-based cyto-
toxic compounds.
The chemistry of vanadium in aqueous solutions is compli-
cated due to rapid hydrolysis, polymerization and multiple oxi-
dation states.8,10 Therefore for biological applications it is of
interest to develop compounds with improved hydrolytic stability
and defined hydrolysis products.18 Salans are known diamine bis
(phenolato) tetradentate ligands, for which Ti(IV) complexes
showed remarkable stability towards hydrolysis, where struc-
ture–activity relationship studies revealed a significant influence
of the different substituents on the phenolato rings on the
complex properties.19–23 Therefore, in this study we present a
new family of cytotoxic agents based on vanadium(V) complexes
of salan ligands. We investigated the cytotoxic activity of com-
plexes with different substituents on the salan ligand, while ana-
lyzing their hydrolytic behavior and its effect on cytotoxicity.
Most related studies reported on salen vanadium(IV) and salicy-
laldehyde semicarbazone vanadium(V) complexes with fair
cytotoxicity24–26 and on practically inactive vanadium(V) species
with a carboxylated salan ligand of NH donors.27
One of the most promising metals studied is vanadium. It is a
physiologically essential element and was found to activate or
inhibit several enzymes and influence gene expression.8–11
aInstitute of Chemistry, The Hebrew University of Jerusalem, 91904
Jerusalem, Israel. E-mail: tshuva@chem.ch.huji.ac.il; Fax: +972 2
6584282
bDepartment of Cell and Developmental Biology, Alexander Silberman
Institute of Life Sciences, The Hebrew University of Jerusalem, 91904
Jerusalem, Israel
†Electronic supplementary information (ESI) available: Crystallographic
data for L1VO(OiPr) and (L1VO)2μ-O, plots of cytotoxicity measure-
ments towards OVCAR-1 cells for L1–7VO(OiPr) and (L1VO)2μ-O and
for L1VO(OiPr) following different periods of pre-incubation in biologi-
cal medium without cells, apoptosis vs. necrosis measurements plots for
L1VO(OiPr) and cyclic voltammetry measurements of L1VO(OiPr) and
(L1VO)2μ-O. CCDC reference numbers 838966 and 838967. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2dt11514j
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Table 1 Selected bond lengths (Å) and angles (°) for L1VO(OiPr)
Atoms
Value
Atoms
Value
Lengths
O(1)–V
O(2)–V
O(3)–V
1.880(3)
1.861(3)
1.595(3)
1.777(3)
N(1)–V
N(2)–V
—
2.276(4)
2.375(3)
—
O(4)–V
—
—
Angles
O(1)–V–O(2)
O(1)–V–O(3)
O(1)–V–O(4)
O(2)–V–O(3)
O(2)–V–O(4)
O(3)–V–O(4)
N(1)–V–N(2)
—
161.5(1)
97.9(2)
90.4(1)
96.9 (2)
96.0(2)
106.7(2)
76.7(1)
—
O(1)–V–N(1)
O(2)–V–N(1)
O(3)–V–N(1)
O(4)–V–N(1)
O(1)–V–N(2)
O(2)–V–N(2)
O(3)–V–N(2)
O(4)–V–N(2)
82.3(1)
86.7(2)
59.5(2)
163.1(1)
81.8(1)
81.2(1)
166.1(2)
87.2(1)
Scheme 1 Synthesis of vanadium(V)–salan complexes.
Fig. 1 ORTEP drawing of L1VO(OiPr) in 50% probability ellipsoids;
H atoms and disorder in the isopropoxo group were omitted for clarity.
Results and discussion
Synthesis and characterization
The complexes prepared and studied herein are of the type
LVVO(OiPr) (Scheme 1) where L is a dianionic tetradentate
salan ligand. The influence of steric and electronic effects on the
cytotoxic activity and hydrolytic stability of the complex was
examined by employing N-methylated ligands28 with different
substituents at the ortho and para positions of the aromatic
rings.
Fig. 2 Plots of the relative integration of the isopropoxo signal in the
1H-NMR spectra as a function of the time following the addition of 10%
D2O to THF-d8 solution of L1–7VO(OiPr).
The structure (Fig. 1) features an octahedral complex, with a
C1-symmetry that was reduced from C2 due to in equivalency of
the two monodentate ligands. The two phenolato oxygen donors
bind in a trans configuration, as observed for related group (IV)
metal complexes,29,33–40 and the two monodentate ligands are
cis to one another. Interestingly, the V–N(2) bond to the N-donor
trans to the oxo group (2.38 Å) is substantially longer that the
V–N(1) from the metal to the N-donor trans to the isopropoxo
ligand (2.28 Å).
The synthesis of the known salan ligands H2L1–7 (Scheme 1)
was conducted through one of two procedures previously
described;19–21,29–31 H2L1–3,5–7 were prepared from commer-
cially available substituted phenols, dimethylethylenediamine
and formaldehyde by a single step Mannich condensation and
H2L4 was prepared by a two-step procedure from the substituted
benzaldehyde and ethylene diamine with a following methyl-
ation step. The synthesis of vanadium(V)–salan complexes was
conducted under an inert atmosphere similarly to known pro-
cedures,32 by reacting the commercially available VO(OiPr)3
with equimolar amounts of the ligand precursor, and treating the
product with cold hexane (Scheme 1). The complexes L1–7VO
(OiPr) (Scheme 1) were obtained in quantitative yields, as
Hydrolysis
The relative stability of the complexes towards hydrolysis was
evaluated by adding of 10% (>1000 equivalents) D2O to a THF-
d8 solution of a complexes and measuring the rate of hydrolysis
by NMR based on pseudo first order reaction, monitoring the
integration of the isopropoxo group and isopropanol relative to
an internal standard, as previously described.19,20 Fig. 2 depicts
1
evident by H NMR, which is consistent with the low symmetry
of the complexes.
A representative complex L1VO(OiPr) was crystallized from
cold pentane, to give single crystals suitable for X-ray crystallo-
graphy. Its ORTEP drawing is presented in Fig. 1, and a list of
selected bond lengths and angles is provided in Table 1. The
structure displays disorder in the isopropoxo group.
the integration change with time for L1–7VO(OiPr), and t values
1
for isopropoxo hydrolysis are provided in Table 2. Ad2ditional
5242 | Dalton Trans., 2012, 41, 5241–5247
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1
Table 2
t values for the release of the isopropoxo group to give
2
isopropanol for complexes L1–7VO(OiPr)
1
Complex
Substituents
t (min)
2
L1VO(OiPr)
L2VO(OiPr)
L3VO(OiPr)
L4VO(OiPr)
L5VO(OiPr)
L6VO(OiPr)
L7VO(OiPr)
o-Me, p-Me
o-Br, p-Me
o-Cl, p-Me
o-H, p-Me
o-Cl, p-Cl
o-H, p-Cl
20
230
90
<5
70
<5
<5
o-tBu, p-tBu
changes in the spectrum included growing signals of the
hydrolysis products, while no signals belonging to free salan
ligands were detected.
The results imply that substituents at the ortho positions to the
binding O-donor induce significant steric and electronic effects
on the hydrolytic stability, while the para substitutions are of
lesser influence. Both o-H complexes L4,6VO(OiPr) hydrolyze
fairly quickly, where complete dissociation of isopropoxo
ligands to give isopropanol is observed within a few minutes,
despite the different electronic nature of the para-substituent.
However, increasing the steric bulk at the ortho position
increased the stability by ∼5 fold for the methylated complex
L1VO(OiPr), and by ∼20 fold and ∼40 fold for the halogenated
complexes, the chlorinated ones L3,5VO(OiPr) and the bromi-
nated one L2VO(OiPr), respectively, where the bigger increased
in stability is achieved for the complex of the bigger o-Br substi-
tuent, and little effect of the para position is again observed.
This is similar to the observation with salan Ti(IV) complexes,
where negligible effect of para substitutions on hydrolysis was
observed, and a stabilizing effect of ortho-halogenation was
detected, where steric hindrance at ortho positions was proposed
to inhibit formation of polynuclear hydrolysis products.19,20 An
exception is L7VO(OiPr), for which, despite the large o-tBu sub-
stitution, a poor stability is measured.
In order to elucidate the structure of the hydrolysis products of
the vanadium(V)–salan complexes, a representative complex
L1VO(OiPr) was reacted with 1000 equivalents of water for 3
days. The product was characterized by mass spectrometry and
elemental analysis. A dinuclear species of the type (L1VO)2μ-O
formed as the main product of the hydrolysis of L1VO(OiPr), in
which two vanadium centers are bridged by an oxo ligand, and
each center is still attached to the salan ligand.41,42 Further
support for the structure was obtained from X-ray crystallogra-
phy conducted on single crystals obtained from a cold
1 : 1 mixture of toluene and pentane (Fig. 3, Table 3). It is
evident that the C2-symmetrical dimeric structure includes two
octahedral metal centers bound to the oxo group and the salan
ligand, where the two phenolato O-donors of each ligand bind in
a trans configuration similar to the monomeric structure but
different to the related dimeric structures obtained with other
metals.28 Other structural features of each metal center are also
highly similar to that of the monomeric structure of L1VO(OiPr)
(Fig. 1), including the two unequivalent V–N bonds. The two
metal centers are bridged by a single oxo ligand, with a V⋯V
distance of 3.51 Å. Interestingly, the nearest distance between
two ortho-methyl substituents is 4.33 Å, whereas the corre-
sponding distance between two para-methyl groups is 3.66 Å.
Fig. 3 ORTEP drawing of (L1VO)2μ-O, the hydrolysis product of
L1VO(OiPr), in 50% probability ellipsoids; H atoms and disordered
solvent were omitted for clarity.
Table 3 Selected bond lengths (Å) and angles (°) for (L1VO)2μ-O, the
hydrolysis product of L1VO(OiPr)
Atoms
Value
Atoms
Value
Lengths
O(1)–V
O(2)–V
O(3)–V
1.866(3)
1.875(3)
1.785(1)
1.603(4)
N(1)–V
N(2)–V
V⋯V
—
2.164(4)
2.387(4)
3.514
O(4)–V
—
Angles
O(1)–V–O(2)
O(1)–V–O(3)
O(1)–V–O(4)
O(2)–V–O(3)
O(2)–V–O(4)
O(3)–V–O(4)
N(1)–V–N(2)
—
161.6(2)
91.5(2)
98.5(2)
94.8 (2)
95.9(2)
108.3(2)
76.9(2)
—
O(1)–V–N(1)
O(2)–V–N(1)
O(3)–V–N(1)
O(4)–V–N(1)
O(1)–V–N(2)
O(2)–V–N(2)
O(3)–V–N(2)
O(4)–V–N(2)
82.6(2)
86.3(2)
162.3(1)
89.1(2)
82.2(1)
81.1(2)
85.8(1)
165.8(2)
This finding supports the notion that steric hindrance near and
around the metal center increases kinetic stability by inhibiting
formation of this dimer. It is also plausible that the large ortho
and para tBu groups in L7VO(OiPr) prohibit formation of the
dimeric product altogether as observed for related Ti(IV) com-
plexes,20 thus resulting in a different, and apparently faster,
hydrolysis reaction.
Cytotoxicity
The cytotoxic activity of the vanadium(V) complexes was tested
on colon HT-29 and ovarian OVCAR-1 cells and analyzed by
the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay.19
Generally, similar results were obtained towards both cell lines.
A plot of the cell viability dependence on the complex concen-
tration (Fig. 4) enables calculating the IC50 and maximal cell
growth inhibition values, as summarized in Table 4.
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Fig. 4 Dependence of HT-29 cell viability on administered concen-
tration of L1–7VO(OiPr) following 3 day incubation obtained by the
MTT assay.
Fig. 5 Dependence of HT-29 cell viability on administered concen-
tration of L1VO(OiPr) following pre-incubation in aqueous medium for
varying periods (given in hours) prior to cell addition and 3 day incu-
bation with cells, obtained by MTT assay.
Table 4 Relative IC50 values (μM) and maximum cell growth
inhibition (%) values for L1–7TiO(OiPr), the vanadium precursor VO
(OiPr)3 and cisplatin towards colon HT-29 and ovarian OVCAR-1 cell
lines
Table 5 Relative IC50 values (μM) and maximum cell growth
inhibition (%) values for L1VO(OiPr) following pre-incubation in
aqueous medium for varying periods prior to cell addition
Complex
OVCAR-1
HT-29
L1VO(OiPr)
L2VO(OiPr)
L3VO(OiPr)
L4VO(OiPr)
L5VO(OiPr)
L6VO(OiPr)
L7VO(OiPr)
VO(OiPr)3
Cisplatin
12.0 2.4 (81%)
7.5 1.3 (89%)
8.3 2.2 (92%)
9.5 1.9 (96%)
5.9 1.1 (93%)
8.0 0.7 (97%)
Inactive
13 2 (81%)
10.9 1.3 (84%)
10.5 2.8 (92%)
10.3 1.6 (97%)
6.8 0.9 (92%)
8.4 0.8 (96%)
Inactive
Pre-incubation time (hours)
OVCAR-1
HT-29
0
0.5
1
12.0 2.4 (81%)
6.8 1.4 (89%)
13 2 (81%)
9.6 2.9 (87%)
9.8 3.8 (91%)
30.4 18.4 (87%)
7
2 (88%)
18
27 13 (82%)
21.0 6.9 (89%)
8.8 2.1 (91%)
25 9 (87%)
12.2 2.3 (90%)
The vanadium(V)–salan complexes L1–6VO(OiPr) exhibit
marked cytotoxic activity with IC50 values that represent activity
that is comparable to, and often lower than, that of cisplatin for
the examined cells, with clear activity enhancement relative to
the vanadium(V) precursor VO(OiPr)3. Moreover, additional
measurements have revealed that apoptosis is probably the main
pathway of cell death, rather than necrosis (see ESI†). When
comparing the cytotoxicity of the different vanadium(V)–salan
complexes L1–6VO(OiPr), no significant difference is detected.
An exception, again, is the tert-butylated complex L7VO(OiPr)
which did not display significant cytotoxic activity. The lack of
activity may be attributed to the large steric bulk inhibiting cell
penetration and/or interaction with cellular target, or to indirect
parameters such as reduced solubility.
It is thus obvious that for this family of cytotoxic agents,
hydrolytic stability is not a pre-requisite for activity. Thus, to
assess the period through which the complexes may be exposed
to biological environment and still retain cytotoxic activity,
L1VO(OiPr), a complex of relatively minor stability (Table 2)
was pre-incubated in an aqueous biological medium for different
periods without cells, followed by administration to the cancer
cells for additional incubation of 3 days and measuring cell via-
bility (Fig. 5). A summary of the IC50 values obtained is dis-
played in Table 5. A slight improvement in the cytotoxic activity
was observed after short periods of pre-incubation (0.5 and
1 hours), probably as a result of enhanced solubility of the active
species. Surprisingly, despite the relatively rapid hydrolysis of
the complex, even following pre-incubation of 18 hours, the
Fig. 6 Dependence of HT-29 cell viability on administered concen-
tration of L1VO(OiPr) and its hydrolysis product (L1VO)2μ-O following
3 day incubation obtained by the MTT assay.
cytotoxic activity of the complex was not completely abolished,
but only slightly diminished, seemingly accompanied by partial
precipitation of the dimeric product of hydrolysis. This implies
that the dimeric hydrolysis product, or related polynuclear com-
plexes formed in the biological environment, might play a role
in the cytotoxicity mechanism, as also suggested for Ti(IV) com-
plexes of diketonato ligands.43–46
Consequent to these results, and following the hypothesis that
the product of hydrolysis may penetrate into the cell, the cyto-
toxic activity of (L1VO)2μ-O, the isolated hydrolysis product of
L1VO(OiPr) (Fig. 3), was studied (Fig. 6). Indeed, (L1VO)2μ-O
5244 | Dalton Trans., 2012, 41, 5241–5247
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exhibits cytotoxic activity, although lower than that of the pre-
cursor L1VO(OiPr), which may be attributed to decreased solubi-
lity in aqueous medium. This supports the notion that this dimer
or related clusters may indeed manifest activity in the cellular
environment.
apoptotic cell death pathway. A marked improvement in cytotox-
icity is observed relative to the vanadium(V) precursor, pointing
to an important effect of the salan ligand both in enhancing cyto-
toxicity and in enabling formation of more defined hydrolysis
products that are themselves stable for days in biological
environment, which may be the active species as discussed
above. These results encourage further development of this
family of complexes, and full analysis of their mechanism of
action.
Conclusions
In this paper we presented a new family of cytotoxic vanadium
(V)–salan complexes and evaluated the effect of different elec-
tronic and steric properties on the cytotoxic activity and hydro-
lytic stability of the complexes. We observed significant
electronic and steric effects of groups located at the ortho pos-
itions on the hydrolytic stability of the complexes. However,
when these groups are situated at the para position, no signifi-
cant effect on the hydrolytic stability is observed, presumably as
they are more distant from the metal center. Hence it can be
deduced that the hydrolytic stability of the complexes can be
controlled by structural changes at the ortho position. In contrast
to these observations, the cytotoxic activity did not display vari-
ation between the studied complexes, with one exception with
particularly large steric bulk. In previous studies a correlation
was found between hydrolytic stability of related Ti(IV)-salan
complexes and their cytotoxic activity, where cytotoxicity gener-
ally increased with hydrolytic stability.19,20 This behavior was
considered to arise from formation of polynuclear hydrolysis
products that were either inactive or unable to penetrate through
the cellular membrane. In the current study we showed that a
dimeric hydrolysis products of a precursor vanadium(V) complex
demonstrates cytotoxic activity, and therefore it is presumably
able to enter into the cell and interact with the cellular target.
This makes the dimer a good candidate for the active species
formed in the biological environment when starting from the pre-
cursor complex, although other related polynuclear products may
also be participating in the fruitful biological interactions. Conse-
quently, the hydrolytic stability does not play a significant role in
the cytotoxic ability of these precursor complexes, which is of
significance for their potential medicinal utility allowing for
longer shelf lives. Additionally, the indication that different
structural changes at both the ortho and the para positions do
not affect much the cytotoxic activity of the complexes enables
the design of complexes with other desired qualities, such as
improved water solubility, without diminishing the cytotoxic
activity. This may enable isolating dimeric hydrolysis products
that would be of sufficient solubility to serve themselves as
potential drugs. The only property found in this study to demol-
ish the cytotoxicity of this family of complexes is particularly
large steric bulk at the ortho and the para positions, which is
also in accordance with the argument that the active species is
the dimeric hydrolysis product, formation of which may be
inhibited where large steric hindrance occurs near and around
the metal center. Nevertheless, the effect of other parameters
relating to solubility, cell penetration ability and more cannot be
ruled out.
Experimental
Data on H2L1–7 can be found elsewhere.19,29–31 VO(OiPr)3
(98%) was purchased from Strem and used without further
purification. Solvents used in the complex synthesis were dis-
tilled from K–benzophenone under nitrogen or dried over
alumina columns on M. Braun SPS-800 solvent purification
system. All experiments requiring a dry atmosphere were per-
formed in a M. Braun glove box under nitrogen atmosphere.
NMR data were recorded using an AMX-500 MHz Bruker spec-
trometer. X-ray diffraction data were obtained with a Bruker
Smart Apex diffractometer, running the SMART software
package. Hydrolysis studies by NMR were performed as pre-
viously described,19,20 using a solution of the complex in THF-
d8 and adding >1000 equiv of D2O to give a final solution of
1
2
1 : 9 D2O–THF-d8. The t value is based on a pseudo first order
fit for each compound. The results were verified by including p-
dinitrobenzene as an internal standard.
Cytotoxicity was measured on a HT-29 colon and OVCAR-1
ovarian cells obtained from ATCC Inc. using the methylthiazo-
lyldiphenyl-tetrazolium bromide (MTT) assay.19 Cells (0.6 ×
106) in medium (contains: 1% penicillin/streptomycin anti-
biotics; 1% L-glutamine; 10% fetal bovine serum (FBS) and
88% medium RPMI-1640, all purchased from Biological Indus-
tries Inc.) were seeded into a 96-well plate and allowed to attach
for a day. The cells were consequently treated with the reagent
tested at 10 different concentrations. A solution of reagent was
prepared by dissolving 8 mg of the reagent in 100 μL of THF,
with further diluting with THF to obtain the different concen-
trations, and diluting 20 μL of resulting solution with 180 μL of
medium. From the resulting solution, 10 μL was added to each
well already containing 200 μL of the above solution of cells in
the medium to give a final concentration of up to 100 mg L−1
.
Control wells were treated with similar amounts of THF only.
After a standard of 3 days incubation at 37 °C in 5% CO2 atmos-
phere, MTT (0.1 mg in 20 μL) was added and the cells were
incubated for additional 3 hours. The MTT solution was then
removed, and the cells were dissolved in 200 μL isopropanol.
The absorbance at 550 nm was measured by a Bio-Tek
EL-800 microplate reader spectrophotometer. Each measurement
was repeated at least 3 × 3 times, namely, three repeats per plate,
all repeated at least 3 times on different days (9 repeats
altogether). Relative IC50 values were determined by a non-
linear regression of a variable slope (four parameters) model.
Synthesis of L1–7VO(OiPr), general procedure: A solution of
H2L1–7 (0.42 mmol) in THF (1 ml) was added to a stirred sol-
ution of VO(OiPr)3 (0.42 mmol) in THF (3 ml). The reaction
mixture was stirred at room temperature for 15 minutes, and the
The vanadium(V)–salan complexes presented herein exhibit
high promise as cytotoxic agents, as their activity towards the
examined HT-29 and OVCAR-1 cell lines may even reach levels
higher than those achieved by cisplatin, while involving an
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volatiles were removed under vacuum. A dark purple powder
was obtained after adding cold hexane and removing it under
vacuum. The products were obtained in quantitative yields (>
95%).
20.4 ppm. Anal. calcd for C23H31Cl2N2O4V: C, 52.99; H, 5.99;
N, 5.37. Found: C, 52.77; H, 5.70; N, 5.42%.
L4VO(OiPr)
1H NMR (CDCl3): δ = 6.99 (d, J = 8.2 Hz 2H; Ar), 6.83 (s, 1H;
Ar), 6.80 (s, 1H; Ar), 6.71 (d, J = 8.2 Hz 1H; Ar), 6.64 (d, J =
8.2 Hz 1H; Ar), 5.68 (sept, J = 6.1 Hz, 1H; CH(CH3)2), 4.82 (d,
J = 14.6 Hz, 1H; CH2), 4.63 (d, J = 13.6 Hz, 1H; CH2), 3.59 (d,
J = 14.7 Hz, 1H; CH2), 3.12 (d, J = 13.6 Hz, 1H; CH2), 3.03 (dt,
J = 12.9, 3.1 Hz, 1H; CH2), 2.90 (dt, J = 13.0, 2.9 Hz, 1H;
CH2), 2.61 (s, 3H; CH3), 2.44 (s, 3H; CH3), 2.28 (s, 3H; CH3),
2.27 (s, 3H; CH3), 1.95 (m, 2H; CH2), 1.43 (d, J = 6.1 Hz, 3H;
CH(CH3)2), 1.41 (d, J = 6.1 Hz, 3H; CH(CH3)2). 13C NMR
(CDCl3): δ 130.6, 129.3, 129.2, 129.1, 129.0, 127.9, 125.0,
121.1, 85.7, 66.5, 63.5, 54.1, 51.0, 48.8, 47.5, 24.6, 24.5, 20.7,
20.6 ppm. Anal. calcd for C23H33N2O4V: C, 61.05; H, 7.35; N,
6.19. Found: C, 61.52; H, 7.41; N, 6.15%.
L1VO(OiPr)
1H NMR (CDCl3): δ = 6.92 (s, 1H; Ar), 6.91 (s, 1H; Ar), 6.68
(s, 1H; Ar), 6.63 (s, 1H; Ar), 5.68 (sept, J = 6.1 Hz, 1H; CH
(CH3)2), 4.89 (d, J = 14.4 Hz, 1H; CH2), 4.61 (d, J = 13.3 Hz,
1H; CH2), 3.55 (d, J = 14.6 Hz, 1H; CH2), 3.11 (d, J = 13.7 Hz,
1H; CH2), 3.05 (dt, J = 13.1, 3.4 Hz, 1H; CH2), 2.93 (dt, J =
13.4, 3.3 Hz, 1H; CH2), 2.59 (s, 3H; CH3), 2.41 (s, 3H; CH3),
2.29 (s, 3H; CH3), 2.25 (s, 6H; CH3), 2.22 (s, 3H; CH3), 1.89
(m, 2H; CH2), 1.40 (d, J = 6.1 Hz, 3H; CH(CH3)2), 1.36 (d, J =
6.1 Hz, 3H; CH(CH3)2). 13C NMR (CDCl3): δ 130.5, 130.3,
128.5, 128.1, 127.1, 126.9, 124.4, 120.3, 84.9, 66.8, 63.5, 53.7,
50.9, 48.5, 47.1, 25.3, 24.5, 20.7, 20.6, 17.2, 17.0 ppm. Anal.
calcd for C25H37N2O4V: C, 62.49; H, 7.76; N, 5.83. Found: C,
62.43; H, 7.68; N, 5.74.
L5VO(OiPr)
1H NMR (CDCl3): δ = 7.30 (m, 2H; Ar), 6.93 (d, J = 2.5 Hz,
1H; Ar), 6.89 (d, J = 2.6 Hz, 1H; Ar), 6.02 (sept, J = 6.1 Hz,
1H; CH(CH3)2), 4.84 (d, J = 14.7 Hz, 1H; CH2), 4.55 (d, J =
13.9 Hz, 1H; CH2), 3.61 (d, J = 14.9 Hz, 1H; CH2), 3.18 (d, J =
14.1 Hz, 1H; CH2), 2.94 (dt, J = 13.1, 3.4 Hz, 1H; CH2), 2.84
(dt, J = 13.5, 3.4 Hz, 1H; CH2), 2.67 (s, 3H; CH3), 2.43 (s, 3H;
CH3), 2.05 (m, 2H; CH2), 1.44 (d, J = 6.1 Hz, 3H; CH(CH3)2),
1.43 (d, J = 6.1 Hz, 3H; CH(CH3)2). 13C NMR (CDCl3): δ
129.0, 128.7, 128.1, 127.1, 126.7, 123.6, 123.2, 122.5, 89.0,
65.8, 62.8, 53.8, 51.2, 48.8, 47.3, 24.9, 24.5 ppm. Anal. calcd
for C21H25Cl4N2O4V: C, 44.86; H, 4.48; N, 4.98. Found: C,
44.95; H, 4.38; N, 5.07.
Crystal data for L1VO(OiPr)
Crystallized from cold pentane (dark purple crystals);
C25H37N2O4V, M = 480.51, trigonal, a, b = 19.8537(8), c =
3
ˉ
67.448(5) Å, V = 23024(2) Å , T = 173(1) K, space group R3c,
Z = 36, μ(Mo Kα) = 0.419 mm−1, 82 154 reflections measured,
2
5590 unique (Rint = 0.1254). R(Fo ) for [I > 2σ(I)] = 0.1157, Rw
for [I > 2σ(I)] = 0.1853.
L2VO(OiPr)
1H NMR (CDCl3): δ = 7.31 (s, 2H; Ar), 6.78 (s, 1H; Ar), 6.74
(s, 1H; Ar), 5.97 (sept, J = 6.1 Hz, 1H; CH(CH3)2), 4.90 (d, J =
14.6 Hz, 1H; CH2), 4.60 (d, J = 13.7 Hz, 1H; CH2), 3.58 (d, J =
14.7 Hz, 1H; CH2), 3.16 (d, J = 13.9 Hz, 1H; CH2), 2.96 (dt, J =
13.0, 3.3 Hz, 1H; CH2), 2.86 (dt, J = 13.3, 3.3 Hz, 1H; CH2),
2.67 (s, 3H; CH3), 2.44 (s, 3H; CH3), 2.25 (s, 6H; CH3), 1.96
(m, 2H; CH2), 1.45 (d, J = 6.1 Hz, 3H; CH(CH3)2), 1.43 (d, J =
6.1 Hz, 3H; CH(CH3)2). 13C NMR (CDCl3): δ 132.6, 132.4,
129.8, 129.6, 128.7, 128.5, 125.6, 122.2, 87.5, 66.5, 63.4, 53.7,
51.0, 48.9, 47.4, 25.3, 24.5, 20.3, 20.3 ppm. Anal. calcd for
C23H31Br2N2O4V: C, 45.27; H, 5.12; N, 4.59. Found: C, 45.38;
H, 4.70; N, 4.62%.
L6VO(OiPr)
1H NMR (CDCl3): δ = 7.13 (m, 2H; Ar), 7.00 (d, J = 2.7 Hz,
1H; Ar), 6.97 (d, J = 2.6 Hz, 1H; Ar), 6.73 (d, J = 8.6 Hz, 1H;
Ar), 6.66 (d, J = 8.7 Hz, 1H; Ar), 5.79 (sept, J = 6.1 Hz, 1H;
CH(CH3)2), 4.78 (d, J = 14.7 Hz, 1H; CH2), 4.57 (d, J = 13.7
Hz, 1H; CH2), 3.60 (d, J = 14.8 Hz, 1H; CH2), 3.13 (d, J = 13.8
Hz, 1H; CH2), 2.98 (dt, J = 13.6, 3.4 Hz, 1H; CH2), 2.84 (dt, J
= 13.9, 3.5 Hz, 1H; CH2), 2.61 (s, 3H; CH3), 2.42 (s, 3H; CH3),
2.02 (m, 2H; CH2), 1.43 (d, J = 6.1 Hz, 3H; CH(CH3)2), 1.40
(d, J = 6.1 Hz, 3H; CH(CH3)2). 13C NMR (CDCl3): δ 129.7,
128.8, 128.5, 128.4, 126.2, 124.0, 123.2, 122.8, 87.3, 65.8,
63.0, 54.1, 51.2, 48.9, 47.5, 24.7, 24.5 ppm. Anal. calcd for
C21H27Cl2N2O4V: C, 51.13; H, 5.52; N, 5.68. Found: C, 51.06;
H, 5.29; N, 5.48.
L3VO(OiPr)
1H NMR (CDCl3): δ = 7.12 (s, 2H; Ar), 6.73 (s, 1H; Ar), 6.70
(s, 1H; Ar), 5.94 (sept, J = 6.1 Hz, 1H; CH(CH3)2), 4.87 (d, J =
14.7 Hz, 1H; CH2), 4.61 (d, J = 13.6 Hz, 1H; CH2), 3.59 (d, J =
14.7 Hz, 1H; CH2), 3.16 (d, J = 13.8 Hz, 1H; CH2), 2.97 (dt, J =
13.1, 3.4 Hz, 1H; CH2), 2.86 (dt, J = 13.3, 3.4 Hz, 1H; CH2),
2.66 (s, 3H; CH3), 2.44 (s, 3H; CH3), 2.25 (s, 3H; CH3), 2.24 (s,
3H; CH3), 1.97 (m, 2H; CH2), 1.45 (d, J = 6.1 Hz, 3H; CH
(CH3)2), 1.43 (d, J = 6.1 Hz, 3H; CH(CH3)2). 13C NMR
(CDCl3): δ 129.7, 129.4, 129.2, 129.1, 128.0, 127.8, 126.0,
122.4, 87.4, 66.4, 63.2, 53.8, 51.0, 48.6, 47.3, 25.0, 24.4, 20.5,
L7VO(OiPr)
1H NMR (CDCl3): δ = 7.29 (d, J = 2.6 Hz, 1H; Ar), 7.26 (d, J =
2.4 Hz, 1H; Ar), 6.89 (d, J = 2.5 Hz, 1H; Ar), 6.79 (d, J = 2.6
Hz, 1H; Ar), 5.49 (sept, J = 6.1 Hz, 1H; CH(CH3)2), 4.84 (d, J =
14.4 Hz, 1H; CH2), 4.44 (d, J = 13.4 Hz, 1H; CH2), 3.68 (d, J =
14.6 Hz, 1H; CH2), 3.22 (dt, J = 13.0, 3.5 Hz, 1H; CH2), 3.14
(d, J = 13.5 Hz, 1H; CH2), 3.05 (dt, J = 13.3, 3.5 Hz, 1H; CH2),
5246 | Dalton Trans., 2012, 41, 5241–5247
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11 C. Slebodnick, B. J. Hamstra and V. L. Pecoraro, in Structure and
Bonding, Springer-Verlag, Berlin, Heidelberg, 1997, vol. 89, pp. 51–108.
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2.58 (s, 3H; N CH3), 2.53 (s, 3H; CH3), 2.04 (m, 2H; CH2),
1.54 (s, 9H; tBu), 1.48 (d, J = 6.1 Hz, 3H; CH(CH3)2), 1.47 (s,
9H; tBu), 1.31 (s, 9H; tBu), 1.30 (s, 9H; tBu), 1.19 (d, J = 6.1
Hz, 3H; CH(CH3)2). 13C NMR (CDCl3): δ 141.0, 140.4, 124.8,
124.1, 123.4, 123.4, 122.9, 120.7, 83.7, 67.4, 64.8, 55.3, 51.8,
50.0, 48.8, 35.5, 35.3, 34.4, 34.3, 31.9, 31.8, 31.1, 30.8, 25.9,
24.4 ppm. Anal. calcd for C37H61N2O4V: C, 68.49; H, 9.48; N,
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(L1VO)2μ-O, product of the hydrolysis of L1VO(OiPr)
To a stirred solution of L1VO(OiPr) (0.52 mmol, 0.25 gr) in
THF (4 ml) were added 1000 equivalents (0.52 mol) of distilled
water. More THF was added as required. The reaction was
stirred at room temperature for 3 days; afterwards the volatiles
were removed by evaporation. The product can be recrystallized
from a cold pentane–toluene mixture (60%). HRMS (ESI): m/z
calcd for C44H60N4O7V2+H+: 859.3414 [M + H+]; found:
859.3424. Anal. calcd for C44H60N4O7V2: C, 61.46; H, 7.15; N,
6.52. Found: C, 61.69; H, 6.83; N, 6.50%.
19 D. Peri, S. Meker, C. M. Manna and E. Y. Tshuva, Inorg. Chem., 2011,
50, 1030–1038.
20 D. Peri, S. Meker, M. Shavit and E. Y. Tshuva, Chem.–Eur. J., 2009, 15,
2403–2415.
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Am. Chem. Soc., 2007, 129, 12098–12099.
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2218.
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26 J. D. A. Rivadeneira, D. A. Barrio, G. Arrambide, D. Gambino,
L. Bruzzone and S. B. Etcheverry, J. Inorg. Biochem., 2009, 103, 633–
642.
Crystal data for (L1VO)2μ-O
Crystallized from cold pentane–toluene mixture (dark blue crys-
tals); C44H60N4O7V2·2(C7H8), M = 1035.04, monoclinic, a =
11.704(1), b = 24.115(3), c = 19.876(2) Å, V = 5496(1) Å3, T =
27 H. Faneca, V. A. Figueiredo, I. Tomaz, G. Gonחalves, F. Avecilla, M.
C. Pedroso de Lima, C. F. G. C. Geraldes, J. C. Pessoa and
M. C. A. Castro, J. Inorg. Biochem., 2009, 103, 601–608.
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40, 9802.
29 S. Gendler, S. Segal, I. Goldberg, Z. Goldschmidt and M. Kol, Inorg.
Chem., 2006, 45, 4783–4790.
30 E. Y. Tshuva, N. Gendeziuk and M. Kol, Tetrahedron Lett., 2001, 42,
6405–6407.
173(1) K, space group C2/c, Z = 4, μ(Mo Kα) = 0.394 mm−1
,
2
29 432 reflections measured, 6544 unique (Rint = 0.0576). R(Fo )
for [I > 2σ(I)] = 0.1199, Rw for [I > 2σ(I)] = 0.2448.
31 C. J. Whiteoak, G. J. P. Britovsek, V. C. Gibson and A. J. P. White,
Dalton Trans., 2009, 2337–2344.
Acknowledgements
32 F. Wolff, C. Lorber, R. Choukroun and B. Donnadieu, Inorg. Chem.,
2003, 42, 7839–7845.
33 A. Cohen, J. Kopilov, I. Goldberg and M. Kol, Organometallics, 2009,
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34 S. Gendler, A. L. Zelikoff, J. Kopilov, I. Goldberg and M. Kol, J. Am.
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40 E. Y. Tshuva, I. Goldberg and M. Kol, J. Am. Chem. Soc., 2000, 122,
10706–10707.
We thank Dr Shmuel Cohen for solution of the X-ray structures.
This research received funding from the European Research
Council under the European Community’s Seventh Framework
Programme (FP7/2007-2013)/ERC Grant agreement no.
[239603]. Partial funding was also received by the Lower
Saxony Ministry of Science.
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