C 1-symmetrical titanium(IV) complexes of salan ligands with differently substituted aromatic rings: Enhanced cytotoxic activity

Article abstract of DOI:10.1021/ic500001j

Diaminobis(phenolato) ( salan ) titanium(IV) complexes of differently substituted aromatic rings were synthesized, and their hydrolytic stability and cytotoxicity were analyzed and compared to those of the C ₂-symmertrical analogues and their equimolar mixtures. The hydrolytic stability of the asymmetrical complexes was in between those of the symmetrical analogues, implying an additive influence of the ligand structural parameters. Most mixed halogenated/nitrated complexes showed a marked improvement of cytotoxic activity relative to the symmetrical analogues and their mixtures, with IC₅₀ values as low as <1 μM corresponding to activity exceeding that of cisplatin by up to 30-fold. In contrast, asymmetrical complexes with substitutions of similar properties revealed an added influence of both, with cytotoxicity in between those of the symmetrical analogues. With the presumption that the active species is generally a polynuclear hydrolysis product kept in mind, it is overall evident that particular ligand design and fine-tuning of the parameters of influence including hydrophilicity and hydrophobicity are essential for maximizing biological efficiency.

Full text of DOI:10.1021/ic500001j

Article
pubs.acs.org/IC
C1‑Symmetrical Titanium(IV) Complexes of Salan Ligands with
Differently Substituted Aromatic Rings: Enhanced Cytotoxic Activity
Hagai Glasner and Edit Y. Tshuva*
Institute of Chemistry, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel
S
* Supporting Information
ABSTRACT: Diaminobis(phenolato) (“salan”) titanium(IV)
complexes of differently substituted aromatic rings were
synthesized, and their hydrolytic stability and cytotoxicity
were analyzed and compared to those of the C2-symmertrical
analogues and their equimolar mixtures. The hydrolytic
stability of the asymmetrical complexes was in between those
of the symmetrical analogues, implying an additive influence of
the ligand structural parameters. Most mixed halogenated/
nitrated complexes showed a marked improvement of
cytotoxic activity relative to the symmetrical analogues and
their mixtures, with IC50 values as low as <1 μM corresponding
to activity exceeding that of cisplatin by up to 30-fold. In
contrast, asymmetrical complexes with substitutions of similar
properties revealed an added influence of both, with cytotoxicity in between those of the symmetrical analogues. With the
presumption that the active species is generally a polynuclear hydrolysis product kept in mind, it is overall evident that particular
ligand design and fine-tuning of the parameters of influence including hydrophilicity and hydrophobicity are essential for
maximizing biological efficiency.
reactivity. Particularly, ortho halogenation increased the hydro-
lytic stability,17 and large steric bulk negatively influenced the
cytotoxic activity,18,23 presumably by reducing the solubility of
the complexes and potential for cellular penetration. Later
studies have evinced that the active species operating in the cell
is a rather bulky trinuclear hydrolysis product forming therein,
following labile ligands hydrolysis.24 Nevertheless, a correlation
between stability and activity was mostly detected for active
complexes.15−18
INTRODUCTION
■
Titanium(IV) complexes have been studied as antitumor
compounds for several decades.1 Budotitane ((bzac)2Ti(OEt2))
(Scheme 1a), titanocene dichloride (Cp2TiCl2) (Scheme 1b),
Scheme 1
To expand the structure−activity relationship established for
the salan-TiIV complexes, we investigated the anticancer
features of C1-symmetrical salan-TiIV complexes, bearing
different substitutions on the two aromatic rings.25,26 In our
recent communication we reported on the highly cytotoxic
asymmetrical salan TiIV complexes, which proved markedly
more efficient than the two C2-symmetrical analogues and their
equimolar mixtures.27 This paper reports the expanded study
on this family of complexes to include various combinations of
aromatic substitutions, their influence on the complex perform-
ance, and mechanistic implications.
and their derivatives demonstrated high anticancer activity
toward a range of cancer cells with reduced toxicity relative to
cisplatin; their main limitation was their relatively rapid
hydrolysis in water environments.2−13 We have introduced
the “salan” antitumor TiIV complexes, which are based on
tetradentate diaminobis(phenolato) ligands (Scheme 1c).14−22
Complexes of this family showed enhanced hydrolytic stability
relative to known compounds. These C2-symmetrical com-
plexes also demonstrated markedly higher anticancer activity
than those of (bzac)2Ti(OiPr)2, Cp2TiCl2, and cisplatin toward
various human and murine, drug-sensitive and -resistant, cancer
cell lines.14 Structural parameters of the ligands, including
various aromatic substitutions, markedly affected the complex
RESULTS AND DISCUSSION
■
Synthesis and Characterization. Ligands with different
aromatic substitutions (H2LX,Y, Scheme 2) were synthesized
stepwise based on known procedures by reacting a substituted
Received: January 1, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Article
Scheme 2
Table 1. Selected Bond Lengths (Å) and Angles (°) for
L1,3Ti(OiPr)2 and L2,3Ti(OiPr)2
L1,3Ti(OiPr)2
L2,3Ti(OiPr)2
Lengths
O(1)−Ti
O(2)−Ti
O(5)−Ti
O(6)−Ti
N(1)−Ti
N(1)−Ti
1.919(2)
1.939(2)
1.772(2)
1.798(2)
2.355(2)
2.328(2)
O(1)−Ti
O(2)−Ti
O(5)−Ti
O(6)−Ti
N(1)−Ti
N(1)−Ti
1.918(5)
1.894(5)
1.790(5)
1.780(5)
2.312(6)
2.311(6)
Angles
O(1)−Ti−O(2)
O(1)−Ti−O(5)
O(1)−Ti−O(6)
O(2)−Ti−O(5)
O(2)−Ti−O(6)
O(5)−Ti−O(6)
N(1)−Ti−N(2)
O(1)−Ti−N(1)
O(2)−Ti−N(1)
O(5)−Ti−N(1)
O(6)−Ti−N(1)
O(1)−Ti−N(2)
O(2)−Ti−N(2)
O(5)−Ti−N(2)
O(6)−Ti−N(2)
161.49(9)
96.2(1)
O(1)−Ti−O(2)
O(1)−Ti−O(5)
O(1)−Ti−O(6)
O(2)−Ti−O(5)
O(2)−Ti−O(6)
O(3)−Ti−O(4)
N(1)−Ti−N(2)
O(1)−Ti−N(1)
O(2)−Ti−N(1)
O(5)−Ti−N(1)
O(6)−Ti−N(1)
O(1)−Ti−N(2)
O(2)−Ti−N(2)
O(5)−Ti−N(2)
O(6)−Ti−N(2)
164.4 (2)
96.4(2)
91.6(2)
93.2 (2)
97.4(2)
106.5(2)
76.0(2)
81.1(2)
86.7(2)
89.6(2)
163.1(2)
87.3(2)
80.3(2)
164.4(2)
88.5(2)
97.28(9)
96.5(1)
92.08(9)
106.1(1)
76.16(8)
80.39(8)
83.95(9)
165.4(1)
88.5(1)
salicylaldehyde with N,N′-dimethylethylenediamine, followed
by reaction with the differently substituted benzylchloride.25,26
The H NMR features were consistent with the formation of
1
CS-symmetrical ligands, with several different signals for the
aromatic region as follows: four in H2L2,3; five in H2L1,2, H2L1,3,
H2L1,4, and H2L1,7; six in H2L1,5, and seven in H2L1,6. Synthesis
of C1-symmetrical TiIV complexes, LX,YTi(OiPr)2 (Scheme 2),
was performed analogously to that of known compounds under
an inert atmosphere by mixing the ligand with 1 equiv of
Ti(OiPr)4 in THF at room temperature and stirring for at least
2 h.27 Removing the solvent under reduced pressure produced
the product in quantitative yield. The complexes were analyzed
86.19(8)
80.52(8)
89.5(1)
163.5(1)
reported.17 These values represent hydrolytic stability similar to
that previously reported for related salan TiIV complexes and
greater than that of Cp- and diketonato-based com-
pounds.11,12,17,18 The rates of isopropoxo hydrolysis obtained
for the asymmetrical complexes were generally, as expected, in
the same order of magnitude as, or in between, those of their
C2-symmetrical analogues. This implies that the influence of the
aromatic substitutions on the hydrolytic stability is mostly
additive.
Cytotoxicity. The cytotoxic activity of the complexes was
studied on human colon HT-29 cancer cell line, employing the
methylthiazolyldiphenyltetrazolium bromide(MTT) assay.30
Relative IC50 and maximal cell growth inhibition values are
summarized in Table 3. Cytotoxicity plots are given in Figures
2 and 3.
1
by H NMR, which verified that the desired C1-symmetrical
complexes had been obtained based on, for instance, the two
different septet signals of the isopropoxo groups and AB
doublets for the methylene protons. C2-symmetrical analogues
(Scheme 2) were generally synthesized as previously
described.15,17,28,29
Single crystals of L1,2Ti(OiPr)2,27 L1,3Ti(OiPr)2, and L2,3Ti-
(OiPr)2 that were obtained from dichloromethane were
analyzed by X-ray crystallography. Selected bond lengths and
angles for L1,3Ti(OiPr)2 and L2,3Ti(OiPr)2 are given in Table 1
and ORTEP drawings of the structures are presented in Figure
1. The X-ray structures exhibit similar general geometry to
those of C2-symmetrical salan TiIV complexes previously
reported,17,18,27 where the symmetry was reduced to C1 due
to the different aromatic rings. The two labile isopropoxo
ligands bound to the octahedral metal center in cis
configuration and the LX,Y ligand bound with a trans geometry
of the phenolato units. The structures are all similar in bond
lengths and angles, and there is no apparent clear influence of
the different aromatic substitutions on the metal coordination
center. All Ti−O bonds and Ti−N bonds are in the typical
ranges of covalent and coordinative bonds, respectively, with
typically shorter bonds to the monoanionic ligands.
By examination of the activity of L1,2Ti(OiPr)2, L1,3Ti-
(OiPr)2, and L1,4Ti(OiPr)2 (Figure 2), the cytotoxic activity of
the asymmetrical complexes is especially high, with IC50 values
corresponding to activity exceeding that of cisplatin by up to
30-fold. Most importantly, the cytotoxicity is significantly
higher than that of each of the C2-symmetrical analogues. This
may be regarded as a “synergistic” rather than additive influence
of the aromatic substitutions on activity.27 It is particularly
interesting that for L1,3Ti(OiPr)2 and L1,4Ti(OiPr)2, a marked
enhancement of activity relative to the nitrated symmetrical
analogue L1,1Ti(OiPr)2 is observed, despite the complete
inactivity of the symmetrical brominated and iodinated
derivatives L3,3Ti(OiPr)2 and L4,4Ti(OiPr)2, respectively
(Figure 2b,c). The inactivity of L3,3Ti(OiPr)2 and L4,4Ti(OiPr)2
is presumably a result of steric effects, reducing the solubility,
membrane penetration ability, and thus general accessibility of
the complexes to the biological target;18,24 it thus appears that
the increased activity of the asymmetrical complexes results
from reducing the size below a particular threshold by
employing a single halogenated ring. On the other hand,
Hydrolysis. The hydrolytic stability of the complexes was
evaluated by 1H NMR, adding 10% D2O to a THF-d8 solution
of the complexes and monitoring changes in the signals
integration, as previously described.17,18 Although these
conditions do not mimic the biological environment, this
measurement provides a comparative tool to assess relative
stability. The t1/2 values for isopropoxo hydrolysis to give free
isopropanol are summarized in Table 2. The C1-symmetrical
complexes exhibit marked hydrolytic stability with t1/2 > 1 h, for
which ortho halogenation increased the stability as previously
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Table 3. Relative IC50 (μM) and Maximal Cell Growth
a
Inhibition (%) Values for HT-29 Cells of C1-Symmetrical
Complexes in Comparison to Analogous C2-Symmetrical
b
Complexes, Their Combinations, and Cisplatin
complex
1,2Ti(OiPr)2
R
R′
IC50 (μM)
L
p-NO2
p-NO2
o,p-Cl
o,p-Cl
p-NO2
o,p-Cl
0.7 0.4 (95%)27
3.3 0.3 (95%)27
2.8 0.7 (87%)27
2.4 0.9 (71%)27
0.8 0.3 (84%)27
inactive27
3.1 0.6 (85%)27
1.3 0.3 (84%)
inactive
L1,1Ti(OiPr)2
L2,2Ti(OiPr)2
L1,1/L2,2Ti(OiPr)2
L1,3Ti(OiPr)2
L3,3Ti(OiPr)2
L1,1/L3,3Ti(OiPr)2
L1,4Ti(OiPr)2
L4,4Ti(OiPr)2
L1,1T/L4,4Ti(OiPr)2
L1,5Ti(OiPr)2
L5,5Ti(OiPr)2
L1,1/L5,5Ti(OiPr)2
c
c
p-NO2
o,p-Br
o,p-Br
o,p-Br
p-NO2
o,p-I
o,p-I
o,p-I
c
6
3 (86%)
p-NO2
o-Br
o-Br
o-Br
1.8 0.4 (95%)
2.4 0.9 (87%)
3.4 0.7 (91%)
4.4 0.7 (95%)
16 8 (92%)
c
L1,6Ti(OiPr)2
L6,6Ti(OiPr)2
L1,1/L6,6Ti(OiPr)2
p-NO2
H
H
H
c
6
3
3 (92%)
1 (93%)
L1,7Ti(OiPr)2
L7,7Ti(OiPr)2
p-NO2
o,p-F
o,p-F
o,p-F
2.13 0.07 (90%)
c
L1,1/L7,7Ti(OiPr)2
3.1 0.8 (93%)
d
L2,3Ti(OiPr)2
o,p-Cl
o,p-Br
c
d
L2,2/L3,3Ti(OiPr)2
cisplatin32
20
2
a
Maximal cell growth inhibition refers to the % inhibition recorded at
the highest compound concentration tested, relative to untreated
b
c
control. Error values are based on standard deviations. 1:1 mixture of
d
the two; concentration determined per TiIV center. Negligible activity
(does not reach 50% inhibition).
Figure 1. ORTEP drawings of L1,2Ti(OiPr)2 (a),27 L1,3Ti(OiPr)2 (b),
and L2,3Ti(OiPr)2 (c) in 50% probability ellipsoids; H-atoms were
omitted for clarity.
concentration; in this equimolar mixture, participation of
both compounds in activity is apparent, with little to no
synergistic effect. The difference in activity may be attributed to
different active species forming in the cell;17,18 the asymmetrical
complexes should yield well-identified trinuclear hydrolysis
product/s,31 whereas a larger mixture of clusters may be
envisioned for the 1:1 combination, and particularly, the
homoligated clusters should be less active as evident from the
reduced activity of the symmetrical monomeric precursors.
Notably, the t1/2 for formation of the clusters from the two
symmetrical precursors is markedly different (Table 2; see for
example, L1,1Ti(OiPr)2 vs L2,2Ti(OiPr)2). Thus, it is logical that
for the 1:1 mixture, the homoligated clusters would form with
preference. This explains the additive behavior observed for the
mixture, emphasizing the advantage of the asymmetrical
derivatives that apparently yield new species with higher
activity. Nevertheless, as the stability of symmetrical ortho-
halogenated complexes is fairly high, their participation as
active species prior to hydrolysis is certainly reasonable. These
observations overall emphasize the importance of fine-tuning
the structural parameters of the ligands for maximizing the
cytotoxic activity.
Table 2. T1/2 (h) Values for Isopropoxo Hydrolysis from C1-
Symmetrical Complexes in 1:9 D2O/THF-d8 Solution at
Room Temperature Based on Pseudo-First-Order Fit and
Comparison to Analogous C2-Symmetrical Complexes
complex
R
R′
t1/2 (h)
L1,2Ti(OiPr)2
L1,1Ti(OiPr)2
L2,2Ti(OiPr)2
L1,3Ti(OiPr)2
L3,3Ti(OiPr)2
L1,4Ti(OiPr)2
L4,4Ti(OiPr)2
L1,5Ti(OiPr)2
L5,5Ti(OiPr)2
L1,6Ti(OiPr)2
L6,6Ti(OiPr)2
L1,7Ti(OiPr)2
L7,7Ti(OiPr)2
L2,3Ti(OiPr)2
p-NO2
p-NO2
o,p-Cl
p-NO2
o,p-Br
p-NO2
o,p-I
o,p-Cl
p-NO2
o,p-Cl
o,p-Br
o,p-Br
o,p-I
o,p-I
o-Br
10
117
10017
20
100
10
150
30
p-NO2
o-Br
o-Br
15015
3
p-NO2
H
H
H
215
4
p-NO2
o,p-F
o,p-F
o,p-F
o,p-Br
10
o,p-Cl
70
L1,5Ti(OiPr)2 does not exhibit significantly higher cytotox-
icity than the C2-symmetrical analogue L5,5Ti(OiPr)2 (Figure
3a); this probably results from the decreased size of only a
single halide, enabling the enhanced accessibility and
cytotoxicity also of the symmetrical derivative L5,5Ti(OiPr)2.15
L1,6Ti(OiPr)2 and L1,7Ti(OiPr)2 also show an additive effect of
the two ring substitutions with IC50 values similar to those of
greater hydrolytic stability relative to the nonhalogenated
derivative L1,1Ti(OiPr)2 is achieved (Table 2),17 while solubility
is increased with the nitro substitution on the second ring. Of
further interest is the reduced activity of the 1:1 mixtures of the
C2-symmetrical analogues to give an identical final TiIV
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Figure 2. Cytotoxicity against human colon cancer HT-29 cells, of L1,2Ti(OiPr)2,27 L1,3Ti(OiPr)2,27 and L1,4Ti(OiPr)2. The analysis was conducted
following a 3 day incubation period, based on the MTT assay. The C1-symmetrical complexes are compared to the C2-symmetrical analogues and
their combination (1:1 mixture; concentration determined per TiIV center).
CONCLUSION
■
This paper presents an extended structure−activity study on
C1-symmetrical TiIV complexes of salan ligands with differently
substituted aromatic rings, as anticancer compounds. The
cytotoxicity and hydrolytic stability of the complexes was
measured and compared to those of the symmetrically
substituted analogues. Very high cytotoxic activity toward
human colon cancer cells was recorded, with IC50 values as low
as <1 μM, corresponding to activity greater than that of
cisplatin by an order of magnitude. In fact, the highest activity
recorded is for asymmetrical compounds, for which fine-tuning
of the ligand structural parameters has proven crucial in
determining the biological activity.
When comparing the properties of the asymmetrical
complexes to those of the symmetrical analogues, it appears
that the influence of ligand substitution on the hydrolytic
stability is additive, whereas that on the cytotoxicity ranges
from additive to synergistic. Structural parameters that increase
hydrolytic stability, such as ortho-halogenation,17 may often
decrease cytotoxicity due to limited solubility of the sym-
Figure 3. Cytotoxicity against human colon cancer HT-29 cells, of
metrical complex and potentially hampered cellular penetration
due to increased size.24 Thus, the replacement of one ring
substitution with a hydrophilic moiety such as NO2, although it
somewhat decreases the stability, enables biological accessi-
bility. Consequently, better activity is obtained for the
asymmetrical derivative relative to both symmetrical analogues
and their equimolar mixture. In contrast, for asymmetrical
complexes with substituents of similar characters, an additive
influence is normally obtained, even in cases where a markedly
different activity was recorded for both symmetrical derivatives.
It is thus obvious that any combination of substitutions should
be examined separately and particular ligand design is essential
for obtaining maximal biological efficiency.
Previous studies have revealed that the hydrolysis products of
salan TiIV complexes are oxo-bridged trinuclear salan-bound
clusters,17,18 and suggested that such clusters participate as
active species following their formation in the cell.24 It is thus
obvious that a single asymmetrical molecule is better than a
mixture of C2-symmetrical derivatives for obtaining combined
properties, which minimizes the number of different active
species forming in the biological environment, as supported by
the cytotoxicity results described herein. The clusters are
normally inactive when administered directly in a non-
formulated manner,33 presumably due to their reduced
solubility and hampered cellular penetration;24,34 this further
emphasizes the importance of not only the direct biological
L1,5Ti(OiPr)2, L1,6Ti(OiPr)2, L1,7Ti(OiPr)2, and L2,3Ti(OiPr)2. The
analysis was conducted following a 3 day incubation period, based on
the MTT assay. The C1-symmetrical complexes are compared to the
C2-symmetrical analogues and their combination (1:1 mixture;
concentration determined per TiIV center).
the C2-symmetrical analogues (Figure 3b,c, Table 3). This
implies that accessibility is not a significant limitation in the
symmetrical derivatives, which overall feature similar solubility,
stability, and cytotoxicity properties (Tables 2−3). This is also
supported by the similar cytotoxicity observed for the 1:1
mixtures of the symmetrical analogues. For L2,3Ti(OiPr)2
(Figure 3d, Table 3), another additive influence of the ligand
structural parameters is observed despite the markedly different
cytotoxicity of the symmetrical complexes, one being inactive;
the activity is between those of the two symmetrical analogues,
similarly to that of their 1:1 mixture. This may reflect the
similar properties of the halide substituents, both decreasing the
complex solubility and accessibility, and thus an intermediate
cytotoxicity is recorded. Interestingly, the t1/2 for cluster
formation is similar for both symmetrical derivatives L2,2Ti-
(OiPr)2 and L3,3Ti(OiPr)2; thus, whatever the ratio of clusters
that form (if any) from their 1:1 mixture is, an additive behavior
results because there is apparently no clear advantage in the
heteroligated cluster.
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using 1−5 mM of the complex solution in THF-d8 and adding D2O to
give a final solution of 1:9 D2O/THF-d8. The t1/2 values were
determined based on a pseudo first order fit for each compound. The
results were verified by including p-dinitrobenzene as an internal
standard. Structural information for hydrolysis products is provided in
SI.
activity of a potential drug in terms of its interaction with the
cellular target, but also its biological accessibility,35 as is also
evident from the exceptionally high cytotoxicity of the C1-
symmetrical complexes. A recent report on the cellular
biodistribution of related compounds and their accumulation
in the nuclei further emphasizes the need for compact
structures.36 Future studies should therefore take into
consideration, among other aspects, the balance between
hydrophobicity (for cellular permeability) and hydrophilicity
(for water solubility), in the fine design of future hydrolytically
stable and particularly active antitumor titanium(IV) com-
plexes. Nevertheless, it should be noted that other structural
parameters of the different derivatives may also be of influence
on the biological reactivity, the exact mechanism of which is yet
to be determined.
Cytotoxicity was measured on HT-29 colon cells obtained from
ATCC Inc. using the methylthiazolyldiphenyl-tetrazolium bromide
(MTT) assay as previously described.30 Cells (6 × 105) in medium
(contains: 1% penicillin/streptomycin antibiotics; 1% L-glutamine;
10% fetal bovine serum (FBS), all purchased from Biological
Industries Inc., and 88% medium RPMI-1640, purchased from
Sigma Inc.) were seeded into 66 wells in a 96-well plate and allowed
to attach for 24 h. The cells were consequently treated with the
reagent tested at different concentrations. Solution of reagent was
prepared by dissolving the reagent in THF to give final concentrations
of up to 200 mg/L. From the resulting solution, 10 μL was added to
each well already containing 200 μL of the aforementioned suspension
of cells in the medium. After a standard of 72 h of incubation at 37 °C
in 5% CO2 atmosphere, MTT (0.1 mg in 20 μL) was added and the
cells were incubated for additional 3 h. The MTT solution was then
removed, and the cells were dissolved in 200 μL isopropanol. The
absorbance at 550 nm was measured for 200 μL of the aforementioned
solution by a Bio-Tek EL-800 microplate reader spectrophotometer.
The control representing 100% viable cells was based on a reference
measurement with THF alone at identical concentration. Each analysis
was repeated at least 3 × 3 times, meaning three independent
measurements were conducted for three wells each. Relative IC50
values were determined by a nonlinear regression of a variable slope
(four parameters) model by Graph Pad Prism 5.0 program, where
error values are based on standard deviations.
Control measurements of free ligands confirmed that the ligands are
either inactive or of activities markedly lower than those of their
complex, with generally 20-fold activity decrease (see SI). Previous
studies have also confirmed that any activity of the salan titanium(IV)
complexes does not result from those of free ligands.18
2-Bromo-6-((methyl(2-(methylamino)ethyl)amino)methyl)-
phenol. To a stirred solution of 3-bromo-2-hydroxybenzaldehyde
(0.88 gr, 4.4 mmol) in methanol (40 mL) was added a solution of
N,N′-dimethylethylenediamine (0.47 mL, 4.4 mmol) in methanol (10
mL). The solution was stirred for 2 h and NaBH4 (0.33gr, 8.8 mmol)
was added in small portions. The solution was stirred overnight and
the white precipitate was collected by vacuum filtration (0.75 gr, 62%).
1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 7.9, 1.1 Hz, 1H, Ar−H),
EXPERIMENTAL SECTION
■
All symmetrically substituted ligands H2L1,1−H2L7,7 and the sym-
metrical bis(isopropoxo) TiIV complexes L1,1Ti(OiPr)2−L3,3Ti(OiPr)2
and L5,5Ti(OiPr)2−L7,7Ti(OiPr)2 were synthesized according to
published procedures.15,17,25,28,29,37 H2L1,2, H2L1,3, L1,2Ti(OiPr)2, and
L1,3Ti(OiPr)2 were prepared as described in our previous communi-
cation.27 The syntheses of differently substituted ligands and
complexes were based on those previously reported for related
compounds (see details below).25,26 All complexes were obtained in
quantitative yields with >95% purity. All reagents were purchased from
Aldrich Chemical Co. Inc., Acros Organics, Fluka Riedel-deHaen, or
̈
TCI. All solvents were purchased dry from Aldrich Chemical Co. Inc.,
purified on alumina column on M. Braun Drying Solvent System SPS-
800, or distilled from potassium or potassium/benzophenone under
nitrogen. All experiments requiring dry atmosphere were performed in
a M. Braun drybox under nitrogen atmosphere. NMR data were
recorded using AMX-400 MHz or AMX-500 MHz Bruker
spectrometer. X-ray diffraction data were obtained with Bruker
Smart Apex diffractometer, running the SMART software package.
After collection, the raw data frames were integrated by the SAINT
software package. The structures were solved and refined using
SHELXTL software package. Crystal data for L1,3Ti(OiPr)2 and
L2,3Ti(OiPr)2 are summarized in Table 4. HRMS analyses were
preformed in the microanalytical laboratory in our institute on 6520
Accurate-Mass Q-TOF LC/MS.
Comparative hydrolysis studies by 1H NMR to monitor dissociation
of isopropoxo groups were performed as previously described,17,18
6.89 (dd, J = 6.9, 1.5 Hz, 1H, Ar−H), 6.53 (t, J = 7.8 Hz, 1H, Ar−H),
3.38 (s, 2H, CH2), 2.86 (t, J = 6.4 Hz, 2H, CH2), 2.62 (t, J = 6.4 Hz,
2H, CH2), 2.44 (s, 3H, CH3), 2.24 (s, 3H, CH3). 13C NMR (500
MHz, CDCl3) δ 156.61, 132.11, 128.46, 124.47, 118.20, 111.32, 59.38,
54.85, 47.90, 41.93, 35.14. HRMS (C11H16Br2N2O +H) Calc:
273.0597. Found: 273.0621.
Table 4. Crystal Data for L1,3Ti(OiPr)2 and L2,3Ti(OiPr)2
parameter/compound
L1,3Ti(OiPr)2
L2,3Ti(OiPr)2
formula
MW
C24H33Br2N3O6Ti
667.25
P21/c
C24H32Br2Cl2N2O4Ti
691.14
P21/c
2,4-Difluoro-6-((methyl(2-(methylamino)ethyl)amino)-
methyl)phenol. This was synthesized similarly by reacting 3,5-fluoro-
2-hydroxybenzaldehyde (1.15 gr, 7.3 mmol) with N,N′-dimethylethy-
lenediamine (0.78 mL, 7.3 mmol) to give the product (0.79 gr, 47%).
1H NMR (400 MHz, CDCl3) δ 6.70 (m, 1H, Ar−H), 6.50 (m, 1H,
Ar−H), 7.85 (d, J = 2.0 Hz, 1H, Ar−H), 3.51 (s, 2H, CH2), 2.88 (t, J =
6.4 Hz, 2H, CH2), 2.63 (t, J = 6.4 Hz, 2H, CH2), 2.45 (s, 3H, CH3),
2.25 (s, 3H, CH3). 13C NMR (400 MHz, CDCl3) δ 152.18 (dd, J = 68,
36 Hz), 125.93 (dd, J = 32, 16 Hz), 110.85 (dd, J = 88, 13 Hz), 110.16
(dd, J = 90, 12 Hz), 103.95 (dd, J = 194, 88 Hz), 103.41 (dd, J = 104,
91 Hz), 54.59, 54.22, 47.63, 42.33, 34.74. HRMS (C11H16F2N2O +H)
Calc: 231.1318. Found: 231.1312.
space group
a (Å)
b (Å)
c (Å)
α (°)
β (°)
8.673(1)
24.148(3)
13.457(2)
90
8.395(2)
12.710(3)
23.572(6)
90
100.741(2)
90
95.155(4)
90
γ (°)
V (Å3)
T (K)
Z
2769.1(6)
173(1)
4
2803(1)
173(1)
4
H2L1,4. 2,4-Diiodo-6-((methyl(2-(methylamino)ethyl)amino)-
methyl)phenol25 (1.00 gr, 2.2 mmol) in THF(50 mL) was added to
a stirred solution of 2-chloromethyl-4-nitrophenol (0.42 gr, 2.2 mmol)
in THF (30 mL). Triethylamine (0.4 mL) was then added and the
solution was stirred for 2 h. The solution was filtrated and the volatiles
were removed under vacuum. The solid was dissolved in dichloro-
methane and washed twice with water. The solvent was removed
under vacuum and the red crude was purified on silica column and
μ (Mo−Kα) (mm−1
reflns measd
reflns unique
Rint
)
3.237
3.379
31787
29165
6607
6097
0.0298
0.0415
0.1145
0.1104
0.0919
0.2301
2
R(f0 ) [I > 2σ(I)]
Rw [I > 2σ(I)]
3174
dx.doi.org/10.1021/ic500001j | Inorg. Chem. 2014, 53, 3170−3176

Inorganic Chemistry
Article
washed with methanol to give the yellow product H2L1,4 (0.97
gr,73%). H NMR (400 MHz, C6D6) δ 8.11 (d, J = 3.2 Hz, 1H, Ar−
(500 MHz, CDCl3) δ 169.46, 161.75, 146.60, 139.44, 127.66, 126.92,
126.44, 125.33, 118.49, 90.77, 80.17, 79.85, 79.78, 79.08, 64.42, 64.39,
52.89, 52.73, 48.45, 47.72, 30.91, 26.84, 26.58, 26.55. HRMS
(C24H33I2N3O6Ti +Na) Calc: 783.9842. Found: 783.9833.
1
H), 8.02 (dd, J = 9.0, 3.2 Hz, 1H, Ar−H), 7.85 (d, J = 2.0 Hz, 1H, Ar−
H), 7.39 (d, J = 2.0 Hz, 1H, Ar−H), 6.87 (d, J = 9.2 Hz, 1H, Ar−H),
3.73 (s, 2H, CH2), 3.69 (s, 2H, CH2), 2.70 (m, 4H, CH2CH2), 2.23 (s,
3H, CH3), 2.22 (s, 3H, CH3). 13C NMR (500 MHz, C6D6) δ 164.78,
158.15, 146.26, 146.00, 141.05, 137.58, 126.19, 126.01, 125.18, 124.47,
121.96, 116.97, 60.90, 60.78, 53.57, 53.44, 41.16, 41.14. HRMS
(C18H21I2N3O4Ti +H) Calc: 597.9686. Found: 597.9694.
L
1,5Ti(OiPr)2. This was synthesized similarly from Ti(OiPr)4 (134
mg, 0.47 mmol) and H2L1,5 (200 mg, 0.47 mmol) to give the product
1
in a quantitative yield. H NMR (400 MHz, CDCl3) δ 8.10 (dd, J =
8.8, 3.2 Hz, 1H, Ar−H), 7.96 (d, J = 3.2 Hz, 1H, Ar−H), 7.48 (m, 1H,
Ar−H), 6.92 (m, 1H, Ar−H), 6.67 (d, J = 8.8 Hz, 1H, Ar−H), 6.58 (t,
J = 8.0 Hz, 1H, Ar−H), 5.21 (sept, J = 6.0 Hz, 1H, CHCH3), 4.96
(sept, J = 6.0 Hz, 1H, CHCH3), 4.66 (d, J = 13.2 Hz, 1H, CH2), 4.61
(d, J = 14.0 Hz, 1H, CH2), 3.28 (d, J = 14.0 Hz, 1H, CH2), 3.21 (d, J =
14.0 Hz, 1H, CH2), 2.93 (m, 2H, CH2), 2.50 (s, 3H, CH3), 2.46 (s,
3H, CH3), 1.91 (m, 2H, CH2), 1.30 (d, J = 6.0 Hz, 3H, CHCH3), 1.25
(d, J = 6.0 Hz, 6H, CHCH3), 1.24 (d, J = 6.0 Hz, 3H, CHCH3). 13C
NMR (500 MHz, THF-d8) δ 169.90, 159.31, 139.36, 133.49, 129.88,
126.90, 126.45, 125.46, 119.38, 118.88, 118.51, 112.96, 79.93, 79.55,
65.09, 64.35, 52.91, 52.56, 47.88, 47.78, 26.44, 26.36, 26.06, 25.98.
HRMS (C24H34BrN3O6Ti +Na) Calc: 610.1014. Found: 610.1007.
H2L1,5. This was synthesized similarly by reacting 2-bromo-6-
((methyl (2-(methylamino)ethyl)amino)methyl)phenol (0.71 gr, 2.02
mmol) with 2 chloromethyl-4-nitrophenol (0.38 gr, 2.02 mmol) to
1
give yellow product (0.56 gr, 65%). H NMR (500 MHz, THF-d8) δ
8.05 (dd, J = 8.9, 2.7 Hz, 1H, Ar−H), 8.00 (d, J = 2.7 Hz, 1H, Ar−H),
7.36 (dd, J = 7.9, 2.9 Hz, 1H, Ar−H), 6.95 (d, J = 6.6 Hz, 1H, Ar−H),
6.83 (d, J = 8.9 Hz, 1H, Ar−H), 6.62 (t, J = 7.7 Hz, 1H, Ar−H), 3.84
(s, 2H, CH2), 3.75 (s, 2H, CH2), 2.74 (m, 4H, CH2CH2), 2.32 (s, 3H,
CH3), 2.29 (s, 3H, CH3). 13C NMR (500 MHz, THF-d8) δ 156.08,
141.23, 133.10, 133.10, 128.87, 125.83, 125.80, 124.70, 123.87, 120.59,
117.05, 111.14, 61.96, 61.79, 54.77, 54.68, 41.81, 41.72. HRMS
(C18H22BrN3O4 +H) Calc: 426.0844. Found: 426.0848.
L
1,6Ti (OiPr)2. This was synthesized similarly from Ti(OiPr)4 (113
mg, 0.40 mmol) and H2L1,6 (137 mg, 0.40 mmol) to give the product
in a quantitative yield. 1H NMR (500 MHz, THF-d8) δ 8.04 (ddd, J =
8.9, 2.9, 0.5 Hz, 1H, Ar−H), 7.97 (d, J = 2.8 Hz, 1H, Ar−H), 7.11 (m,
1H, Ar−H), 6.98 (dd, J = 7.4, 0.4 Hz, 1H, Ar−H), 6.66 (dt, J = 7.3, 1.2
Hz, 1H, Ar−H), 6.63 (d, J = 9.0 Hz, 1H, Ar−H), 6.57 (dd, J = 8.1, 1.2
Hz, 1H, Ar−H), 4.97 (sept, J = 6.1 Hz, 1H, CHCH3), 4.95 (sept, J =
6.1 Hz, 1H, CHCH3), 4.61 (d, J = 13.4 Hz, 1H, CH2), 4.57 (d, J = 13.6
Hz, 1H, CH2), 3.38 (d, J = 13.8 Hz, 1H, CH2), 3.26 (d, J = 13.5 Hz,
1H, CH2), 2.93 (m, 2H, CH2), 2.47 (s, 3H, CH3), 2.46 (s, 3H, CH3),
1.95 (m, 2H, CH2), 1.28 (d, J = 6.0 Hz, 3H, CHCH3), 1.25 (d, J = 6.4
Hz, 6H, CHCH3), 1.24 (d, J = 6.0 Hz, 3H, CHCH3). 13C NMR (500
MHz, THF-d8) δ 166.80, 159.96, 127.43, 126.99, 126.81, 123.91,
123.48, 122.69, 122.41, 116.10, 115.65, 114.68, 76.35, 76.02, 75.29,
62.28, 62.12, 61.42, 49.88, 49.57, 49.51, 44.77, 44.73, 44.68. HRMS
(C24H35N3O6Ti +Na) Calc: 532.1893. Found: 532.1900.
H2L1,6. This was synthesized similarly by reacting 2-((methyl(2-
(methylamino)ethyl)amino)methyl)phenol38 (1.00 gr, 5.15 mmol)
with 2 chloromethyl-4-nitrophenol (0.97 gr, 5.15 mmol) to give yellow
product (0.72 gr, 40%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J =
3.2 Hz, 1H, Ar−H), 7.98 (dd, J = 9.2, 2.8 Hz, 1H, Ar−H), 7.18 (dd, J
= 7.2, 1.6 Hz, 1H, Ar−H), 7.12 (dt, J = 8.0, 1.6 Hz, 1H, Ar−H), 7.10
(m, 1H, Ar−H), 6.74 (m, 1H, Ar−H), 6.67 (d, J = 8.8 Hz, 1H, Ar−H),
3.75 (s, 2H, CH2), 3.63 (s, 2H, CH2), 2.78 (m, 2H, CH2CH2), 2.72
(m, 2H, CH2CH2), 2.27 (s, 3H, CH3), 2.23 (s, 3H, CH3). 13C NMR
(500 MHz, DMSO-d6) δ 162.42, 154.82, 152.50, 136.07, 137.34,
126.32, 125.80, 124.15, 123.90, 117.49, 111.19, 110.45, 59.69, 59.48,
52.47, 52.40, 42.39, 42.36. HRMS (C18H23N3O4 +H) Calc: 346.1770.
Found: 346.1761.
H2L1,7. This was synthesized similarly by reacting 2,4-difluoro-6-
((methyl(2-(methylamino)ethyl)amino)methyl)phenol (0.54 gr, 2.35
mmol) with 2 chloromethyl-4-nitrophenol (0.44 gr, 2.35 mmol) to
L
1,7Ti (OiPr)2. This was synthesized similarly from Ti(OiPr)4 (153
mg, 0.54 mmol) and H2L1,7 (201 mg, 0.54 mmol) to give the product
1
1
give yellow product (0.29 gr, 32%). H NMR (400 MHz, CDCl3) δ
in a quantitative yield. H NMR (500 MHz, THF-d8) δ 8.06 (dd, J =
8.08 (dd, J = 9.2, 2.8 Hz, 1H, Ar−H), 7.91 (d, J = 2.8 Hz, 1H, Ar−H),
6.85 (d, J = 8.8 Hz, 1H, Ar−H), 7.76 (m, 1H, Ar−H), 6.51 (m, 1H,
Ar−H), 3.79 (s, 2H, CH2), 3.71 (s, 2H, CH2), 2.71 (m, 4H, CH2CH2),
2.34 (s, 3H, CH3), 2.31 (s, 3H, CH3). 13C NMR (500 MHz, CDCl3) δ
166.52, 153.76 (dd, J = 940, 46 Hz), 150.53 (dd, J = 966, 50 Hz),
141.07 (dd, J = 51, 12 Hz), 137.34, 126.57 (dd, J = 33, 15 Hz), 125.80,
125.15, 123.68, 116.29, 111.30 (dd, J = 90, 12 Hz), 103.15 (dd, J =
107, 91 Hz), 56.59, 56.48, 52.87, 52.80, 40.89, 40.76. HRMS
(C18H21F2N3O4 +H) Calc: 382.1573. Found: 382.1579.
8.9, 2.5 Hz, 1H, Ar−H), 8.00 (d, J = 2.9 Hz, 1H, Ar−H), 6.85 (m, 1H,
Ar−H), 6.64 (d, J = 8.9 Hz, 1H, Ar−H), 6.62 (m, 1H, Ar−H), 5.00
(sept, J = 6.0 Hz, 1H, CHCH3), 4.96 (sept, J = 6.4 Hz, 1H, CHCH3),
4.56 (t, J = 13.8 Hz, 2H, CH2), 3.44 (d, J = 13.5 Hz, 1H, CH2), 3.32
(d, J = 14 Hz, 1H, CH2), 2.95 (m, 2H, CH2), 2.50 (s, 3H, CH3), 2.45
(s, 3H, CH3), 2.01 (m, 2H, CH2), 1.25 (d, J = 3.0 Hz, 3H, CHCH3),
1.24 (d, J = 5.8 Hz, 3H, CHCH3), 1.24 (d, J = 3.1 Hz, 3H, CHCH3),
1.23 (d, J = 5.9 Hz, 3H, CHCH3). 13C NMR (500 MHz, THF-d8) δ
169.53, 154.65 (dd, J = 940, 45 Hz), 151.57 (dd, J = 1027, 49 Hz),
147.69 (m), 139.36, 127.69 (dd, J = 35, 16 Hz), 126.96, 126.52,
125.50, 118.57, 111.44 (dd, J = 90, 13 Hz), 104.31 (dd, J = 105, 92
Hz), 80.01, 79.43, 64.32, 64.28, 52.79, 52.77, 47.66, 47.65, 26.46,
26.40, 26.01, 25.98. HRMS (C24H33F2N3O6Ti +Na) Calc: 568.1723.
Found: 568.1712.
H2L2,3. This was synthesized similarly by reacting 2,4-dichloro-6-
((methyl(2-(methylamino)ethyl)amino)methyl)phenol25 (2.28 gr,
9.89 mmol) with 2,4-dibromo-6- (bromomethyl)phenol (3.41 gr,
1
9.89 mmol) to give white product (3.91 gr, 75%). H NMR (400
MHz, DMSO-d6) δ 7.60 (d, J = 2.0 Hz, 1H, Ar−H), 7.38 (d, J = 2.8
Hz, 1H, Ar−H), 7.31 (m, 1H, Ar−H), 7.18 (m, 1H, Ar−H), 3.76 (s,
2H, CH2), 3.75 (s, 2H, CH2), 2.69 (s, 4H, CH2CH2), 2.22 (s, 3H,
CH3), 2.18 (s, 3H, CH3). 13C NMR (500 MHz, CDCl3) δ 155.08,
153.61, 135.59, 131.41, 130.14, 127.89, 125.05, 124.85, 124.64, 122.87,
112.27, 112.00, 62.28, 62.24, 55.20, 55.15, 42.97, 42.92. HRMS
(C18H20Br2Cl2N3O4 +H) Calc: 526.9312. Found: 526.9319.
L
2,3Ti (OiPr)2. This was synthesized similarly from Ti(OiPr)4 (124
mg, 0.44 mmol) and H2L2,3 (231 mg, 0.44 mmol) to give the product
in a quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 2.4
Hz, 1H, Ar−H), 7.28 (d, J = 2.4 Hz, 1H, Ar−H), 7.03 (d, J = 2.4 Hz,
1H, Ar−H), 6.86 (d, J = 2.4 Hz, 1H, Ar−H), 5.22 (sept, J = 6.0 Hz,
1H, CHCH3), 5.21 (sept, J = 6.4 Hz, 1H, CHCH3), 4.63 (m, 2H,
CH2), 3.15 (d, J = 4.8 Hz, 1H, CH2), 3.12 (d, J = 4.4 Hz, 1H, CH2),
2.91 (m, 2H, CH2), 2.46 (s, 3H, CH3), 2.45 (s, 3H, CH3), 1.88 (m,
2H, CH2), 1.29 (d, J = 6.0 Hz, 3H, CHCH3), 1.29 (d, J = 6.0 Hz, 6H,
CHCH3), 1.22 (d, J = 6.0 Hz, 3H, CHCH3). 13C NMR (500 MHz,
THF-d8) δ 158.90, 135.17, 132.46, 129.60, 128.83, 128.34, 128.30,
127.92, 123.37, 121.76, 113.85, 108.79, 79.75, 79.70, 64.51, 64.47,
52.78, 52.02, 47.87, 47.66, 26.74, 26.66, 26.29, 26.17. HRMS
(C24H32Br2Cl2N2O4Ti +K) Calc: 728.9207. Found: 728.9200.
L
1,4Ti(OiPr)2. Ti(OiPr)4 (48 mg, 0.17 mmol) in dry THF was
added to H2L1,4 (100 mg, 0.17 mmol) in dry THF under an inert
atmosphere. The two solutions were allowed to stir at room
temperature for 24 h to give the product following solvent removal
(>95%). 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.8, 3.2 Hz, 1H,
Ar−H), 7.96 (m, 2H, Ar−H), 7.23 (d, J = 1.6 Hz, 1H, Ar−H), 6.67 (d,
J = 9.2 Hz, 1H, Ar−H), 5.16 (sept, J = 6.0 Hz, 1H, CHCH3), 4.91
(sept, J = 6.4 Hz, 1H, CHCH3), 4.58 (m, 2H, CH2), 3.29 (d, J = 14.0
Hz, 1H, CH2), 3.12 (d, J = 14.0 Hz, 1H, CH2), 2.91 (m, 2H, CH2),
2.51 (s, 3H, CH3), 2.44 (s, 3H, CH3), 1.92 (m, 2H, CH2), 1.28 (d, J =
6.4 Hz, 3H, CHCH3), 1.24 (d, J = 6.0 Hz, 6H, CHCH3), 1.24 (d, J =
6.0 Hz, 3H, CHCH3), 1.23 (d, J = 5.6 Hz, 6H, CHCH3). 13C NMR
L
4,4Ti (OiPr)2. This was synthesized similarly from Ti(OiPr)4 (34
mg, 0.12 mmol) and H2L4,4 (91 mg, 0.11 mmol) to give the product in
1
a quantitative yield. H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.4
Hz, 2H, Ar−H), 7.21 (d, J = 2.0 Hz, 2H, Ar−H), 5.18 (sept, J = 6.0
3175
dx.doi.org/10.1021/ic500001j | Inorg. Chem. 2014, 53, 3170−3176

Inorganic Chemistry
Article
Hz, 2H, CHCH3), 4.59 (d, J = 13.6 Hz, 2H, CH2), 3.10 (d, J = 14.0
Hz, 2H, CH2), 2.88 (d, J = 10.0 Hz, 2H, CH2), 2.47 (s, 6H, CH3), 1.39
(d, J = 6.0 Hz, 2H, CH2), 1.27 (d, J = 6.0 Hz, 6H, CHCH3), 1.21 (d, J
= 6.0 Hz, 6H, CHCH3). 13C NMR (500 MHz, CDCl3) δ 160.66,
145.65, 138.10, 125.75, 90.45, 79.33, 77.89, 63.87, 51.77, 47.86, 26.27,
26.02. HRMS (C24H32I4N2O4Ti +Na) Calc: 990.7919. Found:
990.7915.
(20) Tshuva, E. Y.; Ashenhurst, J. A. Eur. J. Inorg. Chem. 2009, 2203−
2218.
(21) Manna, C. M.; Armony, G.; Tshuva, E. Y. Inorg. Chem. 2011, 50,
10284−10291.
(22) Manna, C. M.; Armony, G.; Tshuva, E. Y. Chem.Eur. J. 2011,
17, 14094−14103.
(23) Immel, T. A.; Groth, U.; Huhn, T. Chem.Eur. J. 2010, 16,
2775−2789.
(24) Meker, S.; Margulis-Goshen, K.; Weiss, E.; Magdassi, S.; Tshuva,
E. Y. Angew. Chem., Int. Ed. 2012, 51, 10515−10517.
(25) Cohen, A.; Kopilov, J.; Goldberg, I.; Kol, M. Organometallics
2009, 28, 1391−1405.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Integration decay plots of H NMR-based hydrolysis measure-
ments, cytotoxicity plots of representative free ligands vs their
titanium(IV) complexes, structural information on representa-
tive trinuclear hydrolysis products, and X-ray structures of
L1,3Ti(OiPr)2 and L2,3Ti(OiPr)2. This material is available free
of charge via the Internet at http://pubs.acs.org.
(26) Cohen, A.; Yeori, A.; Kopilov, J.; Goldberg, I.; Kol, M. Chem.
Commun. 2008, 2149−2151.
(27) Glasner, H.; Tshuva, E. Y. J. Am. Chem. Soc. 2011, 133, 16812−
16814.
(28) Chmura, A. J.; Davidson, M. G.; Jones, M. D.; Lunn, M. D.;
Mahon, M. F.; Johnson, A. F.; Khunkamchoo, P.; Roberts, S. L.;
Wong, S. S. F. Macromolecules 2006, 39, 7250−7257.
(29) Immel, T. A.; Debiak, M.; Groth, U.; Buerkle, A.; Huhn, T.
ChemMedChem 2009, 4, 738−741.
AUTHOR INFORMATION
■
Corresponding Author
*Fax:(+) 972-2-6584282. E-mail: edit.tshuva@mail.huji.ac.il.
Notes
(30) Ganot, N.; Meker, S.; Reytman, L.; Tzubery, A.; Tshuva, E. Y. J.
Vis. Exp. 2013, DOI: 10.3791/50767.
(31) Single crystals of poor quality were obtaine for the hydrolysis
product of L1,2Ti(OiPr)2. The X-ray structure, although unpublishable
due to major disorder, pointed to the formation of a salan-bound oxo-
bridged trinuclear complex as expected.17,18 HRMS also supported
formation of trinuclear hydrolysis prtoducts for additional representa-
tive complexes. See more information in SI.
(32) Tzubery, A.; Tshuva, E. Y. Inorg. Chem. 2011, 50, 7946−7948.
(33) Preliminary cytotoxicity studies of the hydrolysis products of
L1,2Ti(OiPr)2 and L1,3Ti(OiPr)2 showed no activity, as did clusters
previously studied.18
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Shmuel Cohen and Benny Bogoslavsky for
solution of X-ray structures. Funding was received from the
European Council under the European Community’s Seventh
Framework Programme (FP7/2007-2013)/ERC Grant agree-
ment (No. 239603), and from the Israel Science Foundation
(grant No. 124/09).
(34) Previous studies have suggested that even compounds exhibiting
t1/2 values of only several hours for labile ligand hydrolysis in 10% D2O
solutions undergo rapid cellular penetration, prior to formation of the
bulky polynuclear hydrolysis products.17,18
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