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Heteroleptic Titanium (IV) Catecholato/Piperazine Systems and their
Anti-cancer Properties
Stuart L. Hancock,a Rachael Gati,b Mary F. Mahon,a Edit Y. Tshuvab,* and Matthew D. Jonesa,*
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Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
In this paper we report the synthesis and full characterisation of a range of Ti(IV)-catecholato systems
complexed to piperazine or homopiperazine salan ligands. The steric/electronic environment of the
catecholate moiety has been varied and the effect this has on cytotoxicity discussed. It was observed that
the 7-membered homopiperazine complexes are more stable to hydrolysis than their piperazine cousins in
biological media. In general the homopiperazine complexes show higher cytotoxicity than the piperazine
complexes, with the most cytotoxic complex exhibiting IC50(µM) values of 3±0.5 µM (HT-29) and 4±1
µM (OVCAR).
catechol derivatives to generate a series of monomeric Ti(IV)
complexes. These have been tested for their anticancer properties
against HT-29 and OVCAR cell lines.
Introduction
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Cis-Platin is the classical example of a metal-centred anticancer
drug and has been used against cancer for many decades.1
However, certain cell lines are resistant to such treatments and
therefore new metal-based treatments are required to overcome
these drawbacks.2 As a consequence the applicability of various
Ti(IV) complexes e.g. TiCp2Cl2 or budotitane have been
investigated, however these suffer from poor stability and
solubility in biological media.3 Therefore, there is an exigent
desire to prepare new stable and potent Ti(IV) complexes as
potential anti-cancer drugs.3-4 For example, Ti(IV) complexes of
salans with an N,N’-dimethylethylenediamine backbone have
shown to be effective against HT-29 and OVCAR cell lines with
IC50 values greatly improved compared to cis-platin.4c, 4l, 4o
Studies have shown that it is important to tune the structural
parameters (sterics, electronics, chirality) of the ligand to achieve
potent anticancer properties.4j, 4k, 4p, 5
Salan ligands with a bridging piperazine or homopiperazine
backbone have been shown to react with a variety of metal
centres, forming, on the whole, dimeric systems.6 For example,
reaction with Ti(OiPr)4 generated complexes with the empirical
formula Ti2L1(OiPr)6.7 Furthermore, depending upon the steric
requirements of the ligand a Ti2L2(OiPr)4 species was also
observed in solution and in the solid-state.7 Titanium catecholato
systems have also been previously prepared and have shown
promise as initiators for the polymerisation of -caprolactone.8
There are examples of the preparation and structural
characterisation of mixed salan/catecholato systems.4p In such
cases C1-symmetric complexes have been isolated with the
phenoxides of the salan moiety being oriented cis to one
another.4p We have recently prepared a series of homopiperazine
and piperazine group 4 metal complexes which have found utility
in the ring opening polymerisation of rac-lactide.7, 9 In this paper
we have taken these piperazine complexes and reacted them with
This journal is © The Royal Society of Chemistry [year]
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Results and Discussion
Complex Preparation
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The salan ligands were prepared by a modified Mannich
reaction using literature procedures.7 The complexes were
prepared, Scheme 1, by reacting 1 equivalent of the piperazine
ligand L6H2 (piperazine based; 6-membered ring) or L7H2
(homopiperazine based; 7-membered ring) with Ti(OiPr)4
followed by the addition of the catechol moiety. Initial addition
of the salan to Ti(OiPr)4 resulted in a pale yellow solution which,
after addition of catechol, turned to deep red.
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Scheme 1 Preparation of the metal complexes under discussion.
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At room temperature the reaction of catechol, the
homo/piperazine salan ligand and Ti(O iPr)4 in a 1:1:1 ratio
yielded monometallic complexes, Scheme 1. The formation of
these monometallic complexes, as opposed to dimeric species
formed without the catechol, is presumably a consequence of the
reduced steric demands of catechol when compared to two
isopropoxide moieties. The investigation of this salan ligand
series was limited to ortho methyl substituents, as the presence of
bulky alkyl groups is normally detrimental to water solubility,
which is a consideration particularly in administration of a
potential drug.5, 10 Due to the limitations upon the piperazine
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salan phenoxy moieties a variety of readily available catechol
ligands with varying substituents were utilised for the preparation
of the complexes. Additionally homopiperazine and piperazine
complexes were investigated for a direct comparison of the
bridging moiety.
The room temperature synthesis of piperazine salan titanium
catecholato complexes resulted in high yields of analytically pure
materials after recrystallisation. The complexes were
characterised by 1H NMR, 13C{1H} NMR spectroscopy and
elemental analysis. Recrystallisation from hot toluene or CH2Cl2
resulted in crystals suitable for X-ray crystallography for
L6Ti(O2Ar1), L6Ti(O2Ar2), L6Ti(O2Ar4) and L7Ti(O2Ar2).
A representative example of a solid-state structure for the 6
membered piperazine bridged salan titanium catecholato
complexes is given in figure 1 for L6Ti(O2Ar1). The solid-state
structure for L7Ti(O2Ar2) is displayed in figure 2. All structures
were found to be six coordinate with pseudo octahedral
geometries, specifically the β-cis geometric configuration is
adopted (Figure 1 and 2) in all cases. Both Λ and Δ forms are
present in the solid state.
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Fig. 1 Solid-state structure for L6Ti(O2Ar1). Hydrogen atoms have been
removed for clarity ellipsoids are shown at the 30 % probability level.
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Fig. 2 Solid-state structure for L7Ti(O2Ar2). Hydrogen atoms and disorder
have been removed for clarity ellipsoids are shown at the 30 %
probability level.
Selected bond lengths and angles for the homo/piperazine
titanium catecholato complexes are given in table 1. Typically,
the catecholato Ti–O bonds (Ti–O1, Ti–O2) are longer than
titanium phenoxy Ti–O bonds (Ti–O3, Ti–O4). There is little
effect upon the bond length from the trans ligand on the Ti–O
distances. The N1–Ti1–O4 angle deviates from the ideal value of
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180° affording angles between 146.30 – 153.41°, the N1–Ti1–O3
angle deviates from 90° giving angles between 78.84 – 80.57°,
highlighting the pseudo octahedral nature of the complexes. The
homopiperazine complex enables a larger bite angle between the
two nitrogen groups with the N1–Ti1–N2 angles being 66.03(8)°
and 69.91(6)° for L6Ti(O2Ar2) and L7Ti(O2Ar2) respectively.
Without the employment of forcing conditions the
monometallic titanium catecholato complexes were isolated and
the 1H/13C{1H} NMR spectroscopic analyses were consistent
with the structures identified by X-ray crystallography and
elemental analysis. However, despite extensive efforts, the purity
of L7Ti(O2Ar4) was not supported by elemental analysis. The 1H
NMR spectrum for L6Ti(O2Ar1) shows the ring –CH2 protons
present as discrete multiplets at 2.18, 2.63, 3.23, and 3.80 ppm.
Two distinct doublets at 3.38 and 4.51 ppm were assigned to the
two sets of N–CH2–Ar protons respectively. Although the
aromatic region of the spectrum is sharp the region was
complicated by overlapping of resonances that originated from
the catechol moiety.
For L7Ti(O2Ar1) the NMR spectra are consistent with the solid
state structure. The 1H NMR spectra for the homopiperazine salan
titanium catecholato complexes all show distinct broadening of
resonances when compared to their analogous piperazine
complexes. However, the N–CH2–Ar protons still result in
distinctive doublets. The homopiperazine ring-CH2 protons
displayed a significant degree of complexity including a
noteworthy broadening of the resonances. It was deduced that the
broadening of the spectra is related to the higher degree of
fluxionality typically observed for the homopiperazine
compounds in comparison to the piperazine compounds.
However, it is clear that, in all cases, the solid-state structures are
preserved in solution.
Stability and Cytotoxicity
Given that a significant drawback of Cp2TiCl2 and
(bzac)2Ti(OiPr)2 is their facile hydrolysis generating inactive
products, we first tested the hydrolytic stability of our complexes,
using 1H NMR spectroscopy as described previously.4p, 5 Stability
of complexes towards hydrolysis was investigated (in 90% dTHF and 10% D2O greater than 1000 times excess of D2O
compared to Ti(IV)) and the half lives (t½) are given in table 2.
These measurement, although not mimicing biological
conditions, provide a means of comparing systems. As expected,
the methoxy group generally increases the complex stability,
while the nitro substituent decreases it. Additionally, it is
apparent that the 7-membered ring systems are more stable to
hydrolysis than their 6-membered ring cousins; this could result
either from the reduced steric strain of the 7-membered
homopiperazine ring, offering stability towards hydrolysis, or
from higher flexibility of the larger ring enabling stronger
binding in solution. Upon hydrolysis it is evident from 1H NMR
spectra that free ligands and catechol are the primary products.†
Preliminary cytotoxicity data was investigated with colon HT29 and ovarian OVCAR human tumour cells lines, IC50 values
are outlined in Table 2. L6Ti(O2Ar1) and L7Ti(O2Ar1) were
evidently toxic towards the investigated cell lines with IC50
values offering enhanced toxicity compared to cisplatin.4s The
tBu substituted catecholato system was also investigated but this
was shown to be biologically inactive, as also observed with
This journal is © The Royal Society of Chemistry [year]
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other tBu-substituted salan derivatives presumably due to reduced
solubility and large steric bulk.4p Interestingly, the complex
L6Ti2(OiPr)6 was also inactive, indicating that for this ligand
system the formation of the discrete monometallic complexes by
the addition of catechol is essential for cytotoxicity. Thus,
indicating that the combination of Ti(IV), ligand and catechol are
essential for biological activity. Futhermore, when the free
ligands were tested they were also shown to be biologically
inactive.
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Table 1 Selected bond lengths (Å) and angles (°) for the complexes
L6Ti(O2Ar1), L6Ti(O2Ar2), L6Ti(O2Ar4) and L7Ti(O2Ar2) as determined by
X-ray crystallography
Ti1–O1
Ti1–O2
Ti1–O3
Ti1–O4
Ti1–N1
Ti1–N2
N1–Ti1–O1
N1–Ti1–O2
N1–Ti1–O3
N1–Ti1–O4
N1–Ti1–N2
L6Ti(O2Ar1) L6Ti(O2Ar2)
1.934(3)
1.939(2)
1.975(3)
1.999(2)
1.864(3)
1.8589(19)
1.855(3)
1.8395(19)
2.207(3)
2.206(2)
2.230(3)
2.211(2)
93.05(12)
95.86(9)
98.47(12)
97.49(9)
79.56(12)
79.35(8)
146.30(12)
146.54(9)
65.87(12)
66.03(8)
L6Ti(O2Ar4)
1.920(3)
1.944(3)
1.888(3)
1.861(3)
2.219(3)
2.232(3)
95.63(12)
94.40(12)
78.84(12)
147.81(13)
65.32(13)
L7Ti(O2Ar2)
1.9607(15)
1.9583(15)
1.8484(15)
1.8541(15)
2.2515(18)
2.2679(18)
93.99(7)
94.54(6)
80.57(6)
153.42(7)
69.91(6)
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complex
Half Life/mins
L6Ti(O2Ar1)
L7Ti(O2Ar1)
L6Ti(O2Ar2)
L7Ti(O2Ar2)
L6Ti(O2Ar3)
L7Ti(O2Ar3)
cisplatin4r
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2300
-
IC50 (μM)
(HT-29)
22±5
3±0.5
21±7
12±4
20±3
17±5
20± 2
IC50 (μM)
(OVCAR)
28±5
4±1
26±3
7±3
13±2
15±2
13± 1
Comparing the activity of L7Ti(O2Ar1-3), Figure 3 for HT-29, it
appears that an increase in the steric bulk has a negative effect on
cytotoxicity, as observed previously with related compounds.4f, 4p
The electronic effect is obviously negligible, as the nitrated
complex is slightly more active than its methoxylated analogue,
presumably due to its reduced steric demands.5 For the analogous
L6Ti(O2Ar1-3), however, the steric effect is negligible, which may
reflect the decreased size of these derivatives containing the 6membered ring. For L6,7Ti(O2Ar1), L6,7Ti(O2Ar2), the more stable
complexes of the 7-membered homopiperazine rings are
markedly more active, Figure 3. For L6,7Ti(O2Ar3), however,
similar activity is observed; it is possible that the steric bulk of
the methoxylated derivative is more influential for L7Ti(O2Ar3)
due to the increased steric bulk already present of the diamino
ring.
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This journal is © The Royal Society of Chemistry [year]
We wish to thank the University of Bath and the EPSRC (DTA)
for funding a PhD studentship to SLH. EYT thanks the European
Research Council under the European Community's Seventh
Framework Programme (FP7/2007-2013) / ERC Grant agreement
n° [239603].
Experimental
For the preparation and characterisation of metal complexes, all
reactions and manipulations were performed under an inert
atmosphere of argon using standard Schlenk or glovebox
techniques. All chemicals were purchased from Aldrich. All
solvents used in the preparation of metal complexes were dry and
obtained via SPS (solvent purification system). 1H and 13C{1H}
NMR spectra were recorded on Bruker 250, 300 or 400 MHz
instruments and referenced from residual solvent peaks. Coupling
constants are given in Hertz. Elemental analyses were performed
by Mr Stephen Boyer, London Metropolitan University. The
ligands were prepared according to standard literature procedures
and their purities confirmed via 1H/13C{1H} NMR spectroscopy
and HR-MS prior to use.
Single Crystal Diffraction
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Conclusions
A series of homo/piperazine complexes based on Ti(IV)
catecholato complexes have been prepared and characterised. The
complexes are discrete monomers in the solution and in the solidstate, which proved to be of importance for their appreciable
anticancer activity. The homopiperazine complexes are generally
more stable than the piperazine complexes to hydrolysis which
we believe to be responsible for their enhanced cytotoxicity,
rendering them promising for further exploration. Complexes
Fig. 3: HT-29 cell viability dependence on concentration of L6,7Ti(O2Ar13
) following a 3d incubation period. Left: L6Ti(O2Ar1-3); Right:
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L Ti(O2Ar1-3). Key: Red L6,7Ti(O2Ar1): Blue L6,7Ti(O2Ar2): Green
L6,7Ti(O2Ar3).
Acknowledgements
Table 2 Summary of IC50 values (μM) for complexes L6-7Ti(O2Ar1-3)
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based on the unsubstituted catechol ligand and the
homopiperazine ligand offer the greater degree of cytotoxicity,
confirming that a combination of small size and high stability is
essential for complex efficiency.
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All data were collected on a Nonius kappa CCD diffractometer
with MoK radiation,  = 0.71073 Å, see Table 3. T = 150(2) K
throughout and all structures were solved by direct methods and
refined on F2 data using the SHELXL-97 suite of programs.11
Hydrogen atoms, were included in idealised positions and refined
using the riding model. Refinements were generally
straightforward with the following exceptions and points of note:
For L6Ti(O2Ar1) one molecule of CH2Cl2 was present in the
asymmetric unit, while for L6(TiO2Ar2) half a molecule of
CH2Cl2 was present in the asymmetric unit. L6Ti(O2Ar4) one tBu
group (C49-C51) was disordered over two positions in a 50:50
ratio, ADPs for disordered carbons are slightly less isotropic than
desirable, but efforts to further model disorder in this region of
the electron density map afforded no improvement in
convergence. Additionally, one molecule of CH2Cl2 per Ti(IV)
centre was present in the asymmetric unit. 4 molecules of toluene
were present in the asymmetric unit for L7Ti(O2Ar2) and the –
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NO2 group was disordered over two positions in a 50:50 ratio.
The disordered H-atom associated with the catecholato moiety
was not present in the final model. The Rint values for
L6(TiO2Ar1) and L6Ti(O2Ar4) are higher than desirable, but,
despite excessive attempts, only poorly diffracting crystals could
be obtained. Nonetheless, the structures have been
unambiguously determined. Before biological testing all
complexes were dried, elemental analysis confirms the removal
of solvent.
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Biological Testing
The cytotoxicity was measured on HT-29 colon cells and on
OVCAR ovarian cells obtained from ATCC using the methylthiazolildiphenyltetrazolium bromide (MTT) assay as previously
described.4l Cells (1.2 × 106) in medium (containing: 1%
penicillin/streptomycin antibiotics, 1% L-glutamine, 10% fetal
bovine serum (FBS) –Biological Industries Inc, and 88% medium
RPMI-1640, Sigma) were seeded into a 96-well plate and allowed
to attach for 24 h at 37 ºC in a 5% CO2 atmosphere. The cells
were treated with the reagents at different concentrations.
Solution of reagents were prepared by dissolving the reagent
tested in 10 μL THF and diluting with 90 μL of medium to give
final concentration, up to 200 mg/L. From the resulting solution,
10 μL was added to each well already containing 200 μL of the
abovementioned solution of cells in medium. After a standard of
3 days incubation, 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 using a
Bio-Tek EL-800 microplate reader spectrophotometer. Each
measurement was repeated at least 3 times. Absolute IC50 values
were determined by a non-linear regression of a variable slope (4
parameters) model. The hydrolytic stability was determined by
previously detailed methodology.4p, 5 The t½ value is based on a
pseudo first-order fit for each compound.
Preparation and Characterisation
Catecholato Complexes
of
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Titanium(IV)
L6Ti(O2Ar1): L6H2 (0.60 g, 1.69 mmol) and Ti(O iPr)4 (0.50 ml,
1.69 mmol) were dissolved in CH2Cl2 (30 ml) and stirred (1 h).
Catechol (0.185 g, 1.68 mmol) was added to the yellow solution
and the resulting dark red solution was stirred (16 h) before the
solvent was removed in-vacuo and recrystallised from hot toluene
(30 ml) to yield a orange crystals (0.71 g, 1.39 mmol, 83%). 1H
NMR (CDCl3): δ 2.18 (2H, d, J = 6.5 Hz, CH2), 2.25 (6H, s,
CH3), 2.26 (6H, s, CH3), 2.63 (2H, d, J = 5.5 Hz, CH2), 3.23 (2H,
d, J = 6.5 Hz, CH2), 3.38 (2H, d, J = 14.0 Hz, CH2), 3.80 (2H, d, J
= 5.5 Hz, CH2), 4.51 (2H, d, J = 13.5 Hz, CH2), 6.40 (1H, d, J =
3.5 Hz, ArH), 6.42 (1H, d, J = 3.5 Hz, ArH), 6.62 (1H, d, J = 3.5
Hz, ArH), 6.64 (1H, d, J = 3.5 Hz, ArH), 6.65 (2H, s, ArH), 6.96
(2H, s, ArH). 13C{1H} NMR (CDCl3): δ 16.7 (CH3), 20.7 (CH3),
49.7 (CH2), 50.1 (CH2), 58.5 (CH2), 111.2 (ArH), 119.1 (ArH),
121.9 (Ar), 126.1 (Ar), 126.8 (ArH), 129.0, (Ar), 131.4, (ArH),
157.3, (ArO), 158.7, (ArO). Calc. (%) for C28H32N2O4Ti: C
66.14, H 6.34, N 5.51. Found (%), C 66.28, H 6.20, N 5.55.
L6Ti(O2Ar2): An analogous procedure was employed but 4Nitrocatechol was employed. Yield (0.44 g, 0.80 mmol, 78%). 1H
NMR (CDCl3): δ 2.25 (6H, s, CH3), 2.27 (6H, s, CH3), 2.31 (2H,
d, J = 7.0 Hz, CH2), 2.75 (2H, d, J = 5.5 Hz, CH2), 3.32 (2H, d, J
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= 6.0 Hz, CH2), 3.47 (2H, d, J = 14.0 Hz, CH2), 3.79 (2H, d, J =
6.0 Hz, CH2), 4.48 (2H, d, J = 14.0 Hz, CH2), 6.38 (1H, d, J = 8.5
Hz, ArH), 6.70 (2H, s, ArH), 6.98 (2H, s, ArH), 7.25 (1H, s,
ArH), 7.70 (1H, dd, J = 8.5 Hz, J = 2.5 Hz, ArH). 13C{1H} NMR
(CDCl3): δ 16.5 (CH3), 20.8 (CH3), 49.8 (CH2), 55.2 (CH2), 58.5
(CH2), 106.2 (ArH), 110.0 (ArH), 117.5 (ArH), 121.7 (Ar), 125.9
(Ar), 126.8 (ArH), 130.1 (Ar), 131.7 (ArH), 144.5 (Ar), 157.1
(ArO), 158.2 (ArO), 166.3 (ArO). Calc. (%) for C28H31N3O6Ti: C
60.77, H 5.65, N 7.59. Found (%), C 60.81, H 5.79, N 7.49.
L6Ti(O2Ar3): An analogous procedure was employed but 3Methoxycatechol was employed. Yield (0.25 g, 0.46 mmol,
46%). 1H NMR (CDCl3): δ 2.19 (2H, d, J = 6.5 Hz, CH2), 2.23
(6H, s, CH3), 2.25 (6H, s, CH3), 2.63 (2H, d, J = 5.5 Hz, CH2),
3.22 (2H, d, J = 6.0 Hz, CH2), 3.38 (2H, d, J = 13.5 Hz, CH2),
3.69 (3H, s, CH3), 3.83 (2H, d, J = 5.5 Hz, CH2), 4.53 (2H, d, J =
13.5 Hz, CH2), 6.12 (1H, dd, J = 8.0 Hz, J = 1.0 Hz, ArH), 6.33
(1H, dd, J = 8.5 Hz, J = 1.5 Hz, ArH), 6.54 (1H, t, J = 8.0 Hz,
ArH), 6.64 (2H, s, ArH), 6.94 (2H, s, ArH).13C{1H} NMR
(CDCl3): δ 16.6 (CH3), 20.7 (CH3), 49.7 (CH2), 55.2 (CH2), 56.9
(CH3), 58.6 (CH2), 115.7 (ArH), 115.9 (ArH), 118.3 (ArH), 122.0
(Ar), 126.1 (Ar), 126.7 (ArH), 128.9 (Ar), 131.3 (ArH), 144.1
(Ar), 146.7 (ArO), 157.4 (ArO), 160.0 (ArO). Calc. (%) for
C29H34N2O5Ti: C 64.69, H 6.36, N 5.20. Found (%), C 64.74, H
6.29, N 5.39.
L6Ti(O2Ar4): An analogous procedure was employed but 3,5-Ditert-butylcatechol was employed. Yield (0.42 g, 0.68 mmol,
67%). 1H NMR (CDCl3) δ 1.12 (9H, s, tBu), 1.26 (9H, s, tBu),
2.19 (2H, d, J = 6.0 Hz, CH2), 2.24 (6H, s, CH3), 2.27 (6H, s,
CH3), 2.65 (2H, d, J = 5.5 Hz, CH2), 3.24 (2H, d, J = 6.0 Hz,
CH2), 3.40 (2H, d, J = 13.5 Hz, CH2), 3.91 (2H, d, J = 5.5 Hz,
CH2), 4.51 (2H, d, J = 13.5 Hz, CH2), 6.34 (1H, d, J = 2.5 Hz,
ArH), 6.62 (1H, d, J = 4.5 Hz, ArH), 6.61 (2H, s, ArH), 6.96 (2H,
s, ArH). 13C{1H} NMR (CDCl3): δ 16.5 (CH3), 20.7 (CH3), 29.6
(CH3), 32.1 (CH3), 34.3 (C), 34.5 (C), 49.8 (CH2), 55.1 (CH2),
58.6 (CH2), 106.9 (ArH), 112.9 (ArH), 121.7 (Ar), 126.2 (Ar),
126.6 (ArH), 128.5 (Ar), 131.1 (ArH), 131.3 (Ar), 141.1 (Ar),
154.8, (ArO), 157.6, (ArO), 158.8, (ArO). Calc. (%) for
C36H48N2O4Ti: C 69.67, H 7.80, N 4.51. Found (%), C 64.47, H
7.25, N 4.23.
L7Ti(O2Ar1): Yield (0.33 g, 0.63 mmol, 62%). 1H NMR (CDCl3):
δ 2.00 (2H, m, CH2), 2.12 (6H, s, CH3), 2.23 (6H, s, CH3), 2.41
(2H, d, J = 7.5 Hz, CH2), 2.54 (1H, d, J = 7.0 Hz, CH2), 2.58 (1H,
d, J = 6.5 Hz, CH2), 3.16 (2H, d, J = 7.0 Hz, CH2), 3.22 (2H, d, J
= 13.5 Hz, CH2), 4.14 (2H, br, CH2), 4.39 (2H, d, J = 13.0 Hz,
CH2), 6.40 (1H, d, J = 3.5 Hz, ArH), 6.42 (1H, d, J = 3.5 Hz,
ArH), 6.62 (1H, d, J = 3.5 Hz, ArH), 6.64 (1H, d, J = 3.5 Hz,
ArH), 6.65 (2H, s, ArH), 6.96 (2H, s, ArH). 13C{1H} NMR
(CDCl3): δ 16.5 (CH3), 20.8 (CH3), 23.2 (CH2), 49.3 (CH2), 58.7
(CH2), 63.1 (CH2), 111.6 (ArH), 119.5 (ArH), 123.1 (ArH), 125.5
(Ar), 127.0 (ArH), 129.1 (Ar), 131.5 (ArH), 158.2 (br, ArO),
158.8 (br, ArO). Calc. (%) for C29H34N2O4Ti: C 66.67, H 6.56, N
5.36. Found (%), C 66.28, H 6.20, N 5.55.
L7Ti(O2Ar2): Yield (0.34 g, 0.60 mmol, 44%). 1H NMR (CDCl3):
δ 2.06 (2H, m, CH2), 2.15 (6H, s, CH3), 2.27 (6H, s, CH3), 2.32
(2H, m, CH2), 2.37 (Toluene-CH3), 2.53 (2H, d, J = 7.5 Hz, CH2),
2.63 (2H, m, CH2), 3.26 (2H, d, J = 7.0 Hz, CH2), 3.37 (2H, d, J =
14.0 Hz, CH2), 4.30 (2H, d, J = 13.5 Hz, CH2), 6.41 (1H, d, J =
9.0 Hz, ArH), 6.72 (2H, s, ArH), 6.98 (2H, s, ArH), 7.15-7.30 (m,
This journal is © The Royal Society of Chemistry [year]
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Toluene-ArH) 7.27 (1H, s, ArH), 7.74 (1H, dd, J = 8.5 Hz, J = 2.5
Hz, ArH). 13C{1H} NMR (CDCl3): δ 16.4 (CH3), 20.8 (CH3), 23.1
(CH2), 58.6 (CH2), 58.9 (CH2), 63.3 (CH2), 106.6 (ArH), 110.4
(ArH), 117.7 (ArH), 122.5 (Ar), 125.1 (Ar), 127.1 (ArH), 130.2
(Ar), 131.8 (ArH) 140.8, (ArO), 157.5 (ArO), 166.8 (ArO). Calc.
(%) for C29H33N3O6Ti: C 61.38, H 5.86, N 7.40. Found (%), C
61.47, H 6.00, N 7.11.
L7Ti(O2Ar3): Yield (0.50 g, 0.91 mmol, 89%). 1H NMR (CDCl3):
δ 2.01 (2H, d, J = 6.5 Hz, CH2), 2.12 (6H, br, CH 3), 2.36 (6H, s,
CH3), 2.40 (2H, d, J = 7.5 Hz, CH2), 2.56 (2H, m, CH2), 3.15
(2H, d, J = 7.0 Hz, CH2), 3.22 (2H, d, J = 13.5 Hz, CH2), 3.75
15
20
(3H, s, CH3), 3.80 – 4.40 (2H, br, CH2) 4.41 (2H, d, J = 13.5 Hz,
CH2), 6.14 (1H, dd, J = 8.0 Hz, J = 1.5 Hz, ArH), 6.37 (1H, dd, J
= 8.0 Hz, J = 1.5 Hz, ArH), 6.58 (1H, t, J = 8.0 Hz, ArH), 6.65
(2H, br, ArH), 6.92 (2H, br, ArH). 13C{1H} NMR (CDCl3) (328
K): δ 16.4 (CH3), 20.7 (CH3), 23.5 (CH2), 49.6 (CH2), 57.2
(CH3), 58.9 (CH2), 63.3 (CH2), 106.3 (ArH), 106.7 (ArH), 118.9
(ArH), 123.2 (Ar), 125.6 (Ar), 126.9 (ArH), 129.1 (Ar), 131.6
(ArH), 144.5 (Ar), 158.4, (ArO), 160.4, (ArO), 177.6, (ArO).
Calc. (%) for C30H36N2O5Ti: C 65.22, H 6.57, N 5.07. Found (%),
C 65.18, H 6.65, N 5.16.
Table 3 Selected crystallographic parameters for L6Ti(O2Ar1), L6(TiO2Ar2), L6Ti(O2Ar4), L7Ti(O2Ar2).
Compound reference
Chemical formula
Formula Mass
Crystal system
a/Å
b/Å
c/Å
α/°
β/°
γ/°
Unit cell volume/Å3
Space group
No. of formula units per unit cell, Z
No. of reflections measured
No. of independent reflections
Rint
Final R1 values (I > 2σ(I))
2
Final wR(F ) values (I > 2σ(I))
Final R1 values (all data)
Final wR(F2) values (all data)
Goodness of fit on F2
L6Ti(O2Ar1)
C116H136O16N8Ti4Cl8
2373.53
Monoclinic
12.2350(4)
17.2330(8)
13.4000(5)
90
96.642(2)
90
2806.37(19)
P21/a
1
482977
5929
0.1302
0.0684
0.1672
0.1199
0.2017
1.069
L6(TiO2Ar2)
C28.50H32ClN3O6Ti
595.92
Monoclinic
12.7780(2)
13.3090(2)
16.4640(3)
90
101.097(1)
90
2747.56(8)
P21/n
4
40787
6270
0.0700
0.0638
0.1533
0.0785
0.1664
1.030
L6Ti(O2Ar4)
C37H50Cl2N2O4Ti
705.59
Monoclinic
19.8000(2)
12.5740(2)
30.7360(5)
90
103.808(1)
90
7431.05(18)
P21/c
8
98628
16983
0.1423
0.0867
0.2228
0.1194
0.2455
1.050
L7Ti(O2Ar2)
C43H49N3O6Ti
751.75
Monoclinic
20.0540(5)
18.6670(5)
22.6240(6)
90
113.361(2)
90
7775.0(4)
P21/c
8
153642
17723
0.0657
0.0508
0.1209
0.0830
0.1378
1.055
.
25
Notes and references
a
30
Department of Chemistry, University of Bath, Claverton Down, Bath
BA2 7AY, UK. Fax: +44 (0) 1225 386231 Tel: +44 (0) 1225 384908; Email: mj205@bath.ac.uk
b
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem
91904, Israel. Tel: +972 26586084; E-Mail: edit.tshuva@mail.ac.il
† Electronic Supplementary Information (ESI) available: [cell viabilty vs
concentration plots, selected NMR spectra and the crystallographic data].
See DOI: 10.1039/b000000x/
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