Distinctive structural features of hydroxyamino-1,3,5-triazine ligands leading to enhanced hydrolytic stability of their titanium complexes

Article abstract of DOI:10.1039/b606072b

Three bis(homoleptic) titanium complexes of hydroxyamino-1,3,5-triazine ligands 3a-c were synthesized and characterized, and their kinetic behavior in THF-water solutions was studied at various pH conditions using UV-vis, based on the characteristic Ti-O band at 380 nm. One of these complexes, 3c, was analyzed by X-ray crystallography. Due to the characteristic electronic structure of the triazine rings, high electron density on the nitrogen atoms leads to strong N-Ti bonds, as indicative by the 2.0 coordinative bond lengths in the X-ray structure. Consequently, these complexes exhibit high hydrolytic stability over a wide pH range, where hydrolysis was observed to be promoted by basic conditions. At neutral pH, t_1/2 was estimated to be >200 h, whereas at pH = 5.5, no hydrolysis was observed for a period of at least three days. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606072b

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www.rsc.org/dalton | Dalton Transactions
Distinctive structural features of hydroxyamino-1,3,5-triazine ligands leading
to enhanced hydrolytic stability of their titanium complexes
Dani Peri,a Jacob S. Alexander,a Edit Y. Tshuva*a and Artem Melmanb
Received 28th April 2006, Accepted 21st June 2006
First published as an Advance Article on the web 4th July 2006
DOI: 10.1039/b606072b
Three bis(homoleptic) titanium complexes of hydroxyamino-1,3,5-triazine ligands 3a–c were
synthesized and characterized, and their kinetic behavior in THF–water solutions was studied at
various pH conditions using UV-vis, based on the characteristic Ti–O band at 380 nm. One of these
complexes, 3c, was analyzed by X-ray crystallography. Due to the characteristic electronic structure of
the triazine rings, high electron density on the nitrogen atoms leads to strong N–Ti bonds, as indicative
˚
by the 2.0 A coordinative bond lengths in the X-ray structure. Consequently, these complexes exhibit
high hydrolytic stability over a wide pH range, where hydrolysis was observed to be promoted by basic
conditions. At neutral pH, t1/2 was estimated to be >200 h, whereas at pH = 5.5, no hydrolysis was
observed for a period of at least three days.
base binding.7,16,20,21 More specifically, we chose the hydroxylamine
ligand family presented in Scheme 1.
Introduction
Complexes of titanium(IV) metal are widely studied for a variety
of purposes, mainly serving as catalysts in different organic
reactions.1–6 Known ligands for titanium(IV) include numerous
cyclopentadienyl systems, as well as nitrogen- and oxygen-based
compounds. One general feature common to most titanium com-
plexes is their hydrolytic instability, due to their d0 configuration
and thus highly oxophilic nature. Therefore, in the presence of
water, hydroxide groups replace other ligands, followed by the
formation of oxo-bridged polynuclear aggregates, with the final
thermodynamic product being titanium dioxide.7–11
Hydrolytically stable titanium complexes have the advantage
of easier handling, both for industrial applications12,13 as well
as for small-scale laboratory work. In addition, water-stable ti-
tanium complexes may have medicinal applications in anti-cancer
therapy.14 More specifically, titanocene dichloride and budotitane
complexes are active against certain types of tumor cells, however,
their decomposition in aqueous solutions impeded mechanistic
investigations, lowered their efficiency, and ultimately resulted in
failure in clinical trials. Thus, identifying parameters affecting
hydrolytic stability, and producing titanium(IV) complexes of inert
ligands exhibiting enhanced water resistance, is extremely valuable.
Following the discovery of their possible therapeutic value, only a
few most relevant titanium systems were studied thus far in actual
aqueous solutions at various pH conditions in order to evaluate
the hydrolysis rate of their inert ligands, which mostly hydrolyze
within several hours.14–19 We are interested in exploring additional
ligand families that may produce stable complexes, and investigate
their hydrolysis and the relevant factors affecting it.
Scheme 1
Simple hydroxylamine based ligands have been reported to
form complexes with titanium as well as aluminium and gallium
cations22–26 but to the best of our knowledge did not find
substantial use. The presence of alkyl and aryl hydroxyamino
groups as metal ligands is deterred by their low stability toward
oxidizing reagents and relatively weak binding. In this paper
we describe a new family of chelating hydroxylamine based
ligands for Ti(IV) cations, possessing two hydroxy(alkyl)amino
groups attached to a 1,3,5-triazine scaffold. The strong electron-
withdrawing properties of the 1,3,5-triazine cycle results in a
substantial increase of acidity of OH groups and prevents ox-
idation of hydroxy(alkyl)amino units. In addition, the nitrogen
atom at position 1 of the 1,3,5-triazine cycle, which is at a
suitable location for coordination to the metal center, should be
relatively electron-rich due to the resonative structure presented in
Scheme 2. Stable octahedral titanium complexes of two tridentate
bis(hydroxyamino)triazine ligands could thus be envisioned.
Resistance towards hydrolysis should increase with the complex
thermodynamic stability. Therefore, we searched for electron-rich
oxygen-based ligands that may lead to strong hard acid–hard
Results and discussion
aDepartment of Inorganic Chemistry, The Hebrew University of Jerusalem,
91904, Jerusalem, Israel. E-mail: tshuva@chem.ch.huji.ac.il; Fax: +972 2
6585319; Tel: +972 2 6586084
Synthesis of the bis(hydroxyamino)triazine ligands was based
on facile nucleophilic substitution at the 1,3,5-triazine rings
(Scheme 1). Sequential substitution of three chlorine atoms in
bDepartment of Organic Chemistry, The Hebrew University of Jerusalem,
91904, Jerusalem, Israel
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Scheme 2
2,4,6-trichloro-1,3,5-triazine proceeded with high selectivity in all
stages thus providing ligands with general formula 2a–c.27,28 This
method allows an easy adjustment of the structural properties
of the ligands by introducing different substituents at position
4. More complex structures can be introduced using tethered
carboxylic groups in compounds of type 2b.
The reaction of Ti(OiPr)4 with two equivalents of 2a (Scheme 1)
in THF at room temperature gave a dark-yellow product which
precipitated out of solution. The 1H NMR spectrum of the
crystalline product indicated the formation of a single isomer of the
homoleptic TiL2 type complex 3a (Scheme 3) in quantitative yield.
A single singlet representing all four N–CH3 groups and a single
morpholine system are observed, indicative of a D2d symmetry. The
ESI-MS spectrum of 3a supported formation of a TiL2 species of
molecular weight of 556 with a typical isotope pattern of titanium.
Fig. 1 ORTEP drawing of 3c at 50% probability ellipsoids, presented
from two angles (H atoms and solvent molecules in the un◦it cell were
˚
omitted for clarity). Selected bond lengths (A) and angles ( ): Ti–N(5)
2.018(3), Ti–N(10) 2.025(3), Ti–O(1) 1.953(3), Ti–O(2) 1.959(3), Ti–O(3)
1.965(3), Ti–O(4) 1.956(3), O(2)–N(4) 1.385(4); N(5)–Ti–N(10) 165.7(2),
O(1)–Ti–O(2) 143.7(1), O(1)–Ti–O(3) 96.7(1).
115.8◦ and a N(2)–C(1)–N(5) angle of 125.0◦ (Fig. 1);30 and (c)
highly planar arrays of the bodies of each ligand including all six N
atoms, the inner ring as well as out-of-ring nitrogen atoms; this may
be observed by the sum of bond angles of nearly 360◦ surrounding
the out-of-ring nitrogen atoms, two such examples are summarized
in Table 1. These facts are all in agreement with a large contribution
of the resonative structure presented in Scheme 2, according to
which all out-of-ring nitrogen atoms are of approximately sp2
configuration, while the inner ring nitrogen atoms, including the
one coordinating to the titanium, possess high electron densities.
Therefore, a strong electron donation to the titanium center is
observed in the form of a short bond. This complex also exhibits a
single singlet in the 1H NMR spectrum for the four N–CH3 groups
as observed with 3a and 3b (Scheme 3).
Scheme 3
The UV-vis spectrum of 3c in THF shows a characteristic
In a similar manner, the reactions of Ti(OiPr)4 with two
equivalents of 2b or 2c (Scheme 1) in THF or diethyl ether at room
temperature gave clear yellow or orange solutions. The NMR
spectra of the products were consistent with formation of single
isomers of 3b and 3c, respectively (Scheme 3). Cooling a solution
of 3c in diethyl ether afforded single crystals suitable for X-ray
crystallography. The crystal structure is presented in Fig. 1.
The complex 3c has a highly distorted octahedral geometry.
The cyclohexyl units appear to be different both in the solid
state and in solution due to restricted rotation, which reduces
the symmetry from D2d to C2.29 The two planes of the [ONO]
binding atoms of the two ligands are approximately perpendicular
to one another possessing a mer geometry. Additional interesting
LMCT signal of the O–Ti binding at 380 nm (e = 7000 M−1 cm−1),16
Table 1 Bond angles (◦) indicating planarity of out-of-ring nitrogen
atoms
structural features are the following: (a) an extremely short Ti–N
20
˚
coordinative bond is observed, of 2.0 A; this value nearly falls
in the range of covalent bonds, rather than coordinative bonds;
(b) highly twisted hexagons of the aromatic ring of the triazine
moieties, where all C–N–C angles are around 115◦ and all N–C–N
angles are around 125◦; for example, a C(1)–N(5)–C(3) angle of
C(19)–N(12)–C(23)
C(19)–N(12)–C(29)
C(23)–N(12)–C(29)
Sum
122.4
120.7
116.8
359.9
C(20)–N(9)–O(4)
C(20)–N(9)–C(22)
O(4)–N(9)–C(22)
Sum
114.2
129.1
116.6
359.9
4170 | Dalton Trans., 2006, 4169–4172
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Table 2 Kinetic behavior of ligand hydrolysis in 3c in 1 : 1 THF–water
which is the main hydrolysis route based on the pH dependence
observed. We are currently studying the structure and reactivity
of systems featuring different ligands and properties, such as
complexes exhibiting enhanced water solubility due to hydrophilic
substituents.
solutions at RT
pH
Buffer
Reaction time/h
t1/2/h
1
2
3
5.0 CH3COOH/CH3COONa 80
Not detected
>200a
34
7.1 H2KPO4/HK2PO4
11.5 HK2PO4/K3PO4
80
40
Experimental
a Estimated based on trend-line.
Synthesis of ligands was achieved as previously described.28
Titanium tetra(isopropoxide) (97%) was purchased from Aldrich
Chemical Company, Inc. All solvents were distilled from K or
K/benzophenone under nitrogen. All experiments requiring dry
atmosphere were performed in a M. Braun dry-box or under
nitrogen atmosphere using Schlenk-line techniques. NMR data
were recorded using an AMX-300 MHz Bruker spectrometer.
X-Ray diffraction data were obtained with Bruker Smart Apex
diffractometer. UV/Vis at different pH values were recorded on
a Jasco V-530 UV/Vis spectrophotometer at room temperature
using 1 cm path length cells. Elemental analyses were performed
in the microanalytical laboratory in our institute.
which does not appear in the free ligand spectrum. This signal was
used as the basis for kinetic studies upon addition of water at
different pH conditions to give a solution of 50% THF and 50%
H2O.† The signal was monitored for 40–80 h at room temperature.
The results are summarized in Table 2. No change in absorbance
was observed at pH = 5.0 for a period of at least 3 days, indicating
that 3c is very stable under these conditions (Fig. 2). Under higher
pH conditions, however, ligand dissociation is observed within a
few hours. The t1/2 at pH = 11.5 was found to be 34 h, while
at neutral pH the t1/2 was calculated to be significantly higher
(Table 2). This indicates that hydroxide ion attack is the favored
hydrolysis mechanism, rather than protonation followed by ligand
dissociation, similarly to the findings previously obtained with
other titanium systems, including titanocene dichloride and Ti–O
based compounds.15,16 It is also noteworthy that in comparison to
the previously reported systems studied under similar conditions,
including metallocenes and budotitane complexes,14–18 our system
indeed exhibits very high water stability.
Bis[2,6-bis(N-hydroxo-N-methylamino)-4-morpholino-1,3,5-
triazine]titanium, 3a
A solution of Ti(OiPr)4 (0.039 mmol) in tetrahydrofuran (5 mL)
was added to a solution of 2a (0.078 mmol) in tetrahydrofuran
(5 mL) at room temperature under nitrogen atmosphere. The
colour changed instantly from colourless to yellow. The reaction
mixture was stirred for additional 2 h and the tetrahydrofuran
was removed under reduced pressure to give crude 3a as a single
isomer in a quantitative yield (Found: C, 39.22; H, 5.16; N, 29.44.
Calc. for C18H28N12O6Ti: C, 38.86, H, 5.07, N, 30.21%). 1H NMR
dH (300 MHz; CDCl3; Me4Si) 3.9 (8 H, t, J 4.7, CH2), 3.7 (8 H, t,
J 4.7, CH2), 3.4 (12 H, s, NMe). 13C NMR dC (300 MHz; CDCl3)
164.5 (Ar), 159.0 (Ar), 66.9 (CH2), 44.5 (CH2), 36.1 (NCH3).
kmax(CH2Cl2)/nm 376 (e/M−1 cm−1 7000) and 252 (52000).
Bis[2,6-bis(N-hydroxo-N-methylamino)-4-bis(ethoxycarbonylme-
thyl)amino-1,3,5-triazine]titanium, 3b
Similarly to the procedure described for 3a, 3b was obtained
quantitatively as a single isomer by reacting Ti(OiPr)4 (0.58 mmol)
with 2b (0.116 mmol) in tetrahydrofuran at room temperature
(Found: C, 40.64; H, 5.29; N, 22.50. Calc. for C26H40N12O12Ti:
Fig. 2 Dependence of the absorbance at 380 nm with time of 3c in 1 : 1
THF–water solution at RT under different pH conditions.
1
C, 41.06, H, 5.30, N, 22.10%). H NMR dH (300 MHz; CDCl3;
Me4Si) 4.4 (8 H, s, NCH2CO), 4.2 (8 H, q, J 7.2, CH2CH3), 3.4
(12 H, s, NMe), 1.3 (12 H, t, J 7.1, CH2CH3). 13C NMR dC
(300 MHz; CDCl3) 169.8 (CO), 165.2 (Ar), 158.3 (Ar), 61.1
(CH2), 50.2 (CH2), 35.9 (NCH3), 14.2 (CH3). kmax(THF)/nm 376
(e/M−1 cm−1 7000) and 244 (56000).
Conclusion
It is thus apparent that our titanium complexes are not only
“air stable” but are also highly resistant towards hydrolysis in
THF–water solutions at a relatively wide pH range compared
to previously reported compounds due to the unique electronic
structure introduced by the triazine ligands, leading to the
interesting structural features that contribute to the complex
thermodynamic stability. In addition, the steric crowding of two
such ligands probably adds a kinetic barrier to hydroxide attack,
Bis[2,6-bis(N-hydroxo-N-methylamino)-4-dicyclohexyl-
amino-1,3,5-triazine]titanium, 3c
Similarly to the previous procedures, 3c was obtained quantita-
tively as a single isomer by reacting Ti(OiPr)4 (0.21 mmol) with
of 2c (0.42 mmol) in diethyl ether at room temperature (Found:
C, 54.73; H, 7.58; N, 22.41. Calc. for C34H56N12O4Ti: C, 54.83,
H, 7.58, N, 22.57%). 1H NMR dH (300 MHz; CDCl3; Me4Si) 3.4
(12 H, s, NMe), 1.1–1.8 (44 H, m, Cy). 13C NMR dC (300 MHz;
† THF was employed both to provide a reference and allow accurate
monitoring of absorbance change as well as to enhance solubility (3a–
c are all poorly soluble in pure aqueous solutions).
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CDCl3) 164.2 (Ar), 159.1 (Ar), 56.0 (Cy), 50.2 (CH2), 36.1 (NCH3),
30.6 (Cy), 26.5 (Cy), 25.8 (Cy). kmax(THF)/nm 376 (e/M−1 cm−1
7000) and 254 (48000).
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3c was crystallized from diethyl ether at −30 ◦C. The unit cell
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¯
M = 893.05, triclinic, space group P1, a = 11.9542(12), b =
˚
12.6502(12), c = 17.5705(17) A, a = 79.126(2), b = 80.599(2),
◦
3
˚
14 E. Mel
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=
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0.1827.
CCDC reference number 604238.
For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b606072b
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Acknowledgements
We thank the Allon Foundation as well as the friends of the HU
USA for financial support. We also thank Dr Shmuel Cohen for
solution of the X-ray structure.
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