Hydrolysis of vanadocene dichloride: A revisit

Article abstract of DOI:10.1016/j.ica.2016.07.054

A key hydrolysis product of vanadocene dichloride was isolated and structurally characterized. The oligomeric character of the species precludes its detection by classical EPR spectroscopic tools. A detailed study of the with high purity reagents disproves appearance of Cp₂V(OH)₂, which was postulated previously based on mechanistic approach.

Full text of DOI:10.1016/j.ica.2016.07.054

Inorganica Chimica Acta 453 (2016) 39–41
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journal homepage: www.elsevier.com/locate/ica
Research paper
Hydrolysis of vanadocene dichloride: A revisit
a
b
b,
⇑
Jan Honzí cˇ ek , Zde nˇ ka R u˚ zˇ i cˇ ková , Jaromír Vinklárek
a
Institute of Chemistry and Technology of Macromolecular Materials, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A key hydrolysis product of vanadocene dichloride was isolated and structurally characterized. The oli-
gomeric character of the species precludes its detection by classical EPR spectroscopic tools. A detailed
Received 22 February 2016
Received in revised form 6 June 2016
Accepted 29 July 2016
study of the with high purity reagents disproves appearance of Cp
2
V(OH)
2
, which was postulated previ-
ously based on mechanistic approach.
Available online 30 July 2016
Ó 2016 Elsevier B.V. All rights reserved.
Keywords:
Metallocene
Vanadocene dichloride
Hydrolysis
Cytostatic drug
EPR spectroscopy
X-ray crystal structure
1
. Introduction
hydroxide, but the formation of dihydroxo complex Cp
was not unambiguously disproved [7]. We note that the molecular
structure of Cp V(O,O-CO has been established based on
experiments with C-labeled carbonates and quantum-chemical
calculations [7]. Very recently, Garribba et al. assumed, based on
theoretical approach and mass spectrometric measurements,
2 2
V(OH)
5
Hydrolysis of bis(
g
-cyclopentadienyl)dichlorovanadium(IV)
2
3
)
5
13
aka vanadocene dichloride (1, Cp
2
VCl
2
; Cp =
g
-C
5 5
H ) has emerged
shortly after discovery of its antitumor activity by Köpf and Köpf-
Maier [1]. In 1985, Toney and Marks reported fast hydrolysis of
chloride ligands in aqueous solution, see Scheme 1 [2]. The
virtually the same magnetic parameters for both Cp
2 2
V(OH) and
2+
appeared diaqua complex [Cp
2
V(H O)
2 2
]
(2), stable only in highly
Cp V(O,O-CO ) implying important role of the early complex in
2
3
acidic solutions, was isolated afterwards and characterized by
common analytical methods including structure determination
by single X-ray diffraction [3–5]. We note that the paramagnetic
the biological systems [8]. In order to see if the dihydroxide species
could be detected, we performed a set of experiments with strictly
carbonate free sodium hydroxide; the results are presented here.
1
nature of vanadium(IV) compounds (electronic configuration 3d )
precludes the use of classical NMR tools making difficult the full
characterization. Nevertheless, the EPR spectroscopic measure-
2
. Results and discussion
2
ments enabled to recognize the aqua-chloro intermediate [Cp V
Dissolution of dichloride complex 1 in distilled water gives
+
(
H
2
O)Cl] in saline solution [3] and in mixtures water/DMSO [6].
Neutralization of the aqueous solution of 2 was subject of sev-
eral studies. Mechanistically, the existence of Cp V(OH) was
highly acidic solution (pH = 3.5) of the aqua complex 2 as evidenced
by EPR spectroscopy (Fig. 1, Spectrum A; Scheme 1). In contrast to
previous studies, no other EPR active species appears during the
slow titration with aqueous sodium hydroxide. To our surprise,
the titration is accompanied with evolution of cyclopentadiene, as
evidenced by gas chromatography, and lowering of the EPR signal
intensity. At pH = 6.4, the EPR signal completely disappears reveal-
ing full conversion of aqua complex 2 to some EPR silent species
2
2
assumed already by Toney and Marks based on unusually high sta-
bility of Cp–V bonds observed at physiological conditions [2]. In
1
991, Pavlík and Vinklárek reported an EPR active species with
–4
magnetic parameters |Aiso| = 62.85 ꢀ 10 mT and giso = 1.9907,
for which they suggested aforementioned dihydroxide structure
[
3]. In 2004, Vinklárek and Honzí cˇ ek revised the experiments and
reassigned the signal to carbonate complex Cp V(O,O-CO ),
appearing from residual sodium carbonate in commercial sodium
(
Fig. 1, Spectrum B). The experiments were performed in several
runs, at different vanadium concentration (0.1 mmol L–1 to
2
3
–
1
0
.1 mol L ) and different rate of hydroxide addition giving always
the same outcome. We note that even small traces of carbonate give
observable spectrum of Cp V(O,O-CO ) that misdirected our origi-
nal assignment [3]. It is due to high sensitivity of EPR experiment
⇑
Corresponding author.
E-mail address: jaromir.vinklarek@upce.cz (J. Vinklárek).
2
3
http://dx.doi.org/10.1016/j.ica.2016.07.054
020-1693/Ó 2016 Elsevier B.V. All rights reserved.
0

4
0
J. Honzí cˇ ek et al. / Inorganica Chimica Acta 453 (2016) 39–41
Scheme 1. Hydrolysis of vanadocene dichloride.
2 2 2
V(l-OH) }
VO]2+ present in
Fig. 2. ORTEP drawing of the dicationic complex [{Cp
the crystal structure of 3-PF O (ellipsoids: 30% probability). Numbering of all
6
ꢁ4H
2
non-hydrogen atoms is shown.
Table 1
Selected geometric parameters of the compound 3-PF
6 2
ꢁ4H O.
Bond length (Å)
Bond angle (deg)
V1–O1
V1–O2
V1–O3
V1–O4
1.610(10)
1.960(10)
1.944(8)
1.937(8)
1.933(10)
1.953(7)
1.976(6)
2.007(8)
2.003(10)
1.975(7)
2.002(9)
1.983(9)
O2–V1–O3
O4–V1–O5
O2–V1–O4
O3–V1–O5
O2–V2–O3
O4–V3–O5
76.0(4)
76.2(4)
93.8(4)
89.2(4)
73.6(4)
73.7(4)
V1–O5
V2–Cg(C1-C5)
V2–Cg(C6-C10)
V2–O2
V2–O3
V3–Cg(C11-C15)
V3–O4
Fig. 1. A) EPR spectrum measured immediately after dissolution of
50 mg; 198 mol) in 10 mL of water (pH = 3.5; = 9.4153 GHz). B) EPR spec-
trum measured after slow dropwise addition of sodium hydroxide
pH = 6.4; = 9.4154 GHz). C) EPR spectrum measured after reverse acidification
of neutralized aqueous solution of 1 (pH = 3.5; = 9.4151 GHz).
1
(
l
m
(
m
m
V3–O5
that enables to observe the EPR active product in trace concentra-
tion when the major product is EPR silent.
Reverse acidification of the neutralized solution with strong
4
non-coordinating acid, e.g. HClO , (from pH = 6.4–7.6 to pH = 3.5
around vanadium atom. The bond distances between centroid of
the cyclopentadienyl ring and vanadium atom vary between
1
.952(7) and 1.976(6) Å. Due to contribution of the electrostatic
forces, the bonds V–O were found to be considerably shorter
1.983(9)–2.007(8)Å] than those previously reported for aqua com-
or lower) gives 2:1 mixtures of aqua complexes 2 and [VO
2
+
–4
(
H O)
2 5
]
(4: |Aiso| = 116.28 ꢀ 10 mT; giso = 1.963) as evidenced
[
by EPR spectroscopy (Fig. 1, Spectrum C). This observation suggests
only partial protonolysis of cyclopentadienyl ligands upon neutral-
ization that is accompanied with appearance of oligomeric species
plex 2 [2.058(1)–2.072(2) Å] [5].
It was proved that the methanolic solution of
[
{Cp
2
2
V(l-OH) }
2
VO][PF
6
2 2 6
] ꢁ4H O (3-PF ꢁ4H
2
O) behaves similarly
2
consisting of vanadocene (Cp V) and oxovanadium (VO) fragments,
as the aforementioned neutralized solution of aqua complex (at
pH = 6.4). Hence, it is EPR silent but the acidification with strong
non-coordinating acid gives 2:1 mixture of 2 and 4, see Scheme 2.
Our ongoing experimental study is focused on variable
temperature magnetic measurements of 3 those are necessary for
determination of its spin state and will help to understand the
magnetic behavior of EPR silent mixed hydroxo-cyclopentadienyl
vanadium complexes.
see Schemes 1 and 2. This interpretation well correlates with struc-
ture of three-nuclear species isolated from solution. Hence, treat-
ment of the neutralized solution (pH = 6.4) with aqueous KPF
solution gives a fine precipitate of [{Cp V( -OH) VO][PF
O) that was fully characterized.
X-ray structure analysis revealed that the dication of
-PF O is a linear trinuclear complex with two vanadocene
ꢁ4H
6
2
l
2
}
2
6
]
2 2
ꢁ4H O
6
(3-PF ꢁ4H
2
3
6
2
fragments connected with oxovanadium fragment via hydroxy
bridges, see Fig. 2 and Table 1. All three vanadium atoms are in a
formal oxidation state IV. The central oxovanadium unit forms a
square pyramid with terminal oxygen atom in the apical position
and bridging hydroxy groups in basal plane. The bond length V=O
is 1.610(10) Å and the bond lengths V–O vary between 1.933(10)
and 1.960(10) Å. The bond angles O–V–O in the basal plane facing
the vanadocene fragments were found to be considerably smaller
3. Conclusion
This study has clearly demonstrated that hydrolysis of vanado-
cene dichloride (1), does NOT give, after neutralization, expected
hydroxo complex Cp V(OH) . The bis(cyclopentadienyl)vanadium
2
2
moiety is unstable in absence of chelating ligands (e.g. carbonate,
phosphate, oxalate, -amino acid) [7,9–11]. It undergoes rapid
[
76.0(4) and 76.2(4)°] than those facing out [89.2(4)and93.8(4)°].
a
Both vanadocene units have typical distorted tetrahedral
structure with two cyclopentadienyl rings and two hydroxy groups
a
protonolysis of cyclopentadienyl ligands giving EPR silent mixed
hydroxo-cyclopentadienyl vanadium complexes. At pH = 6.4, an
unprecedented trinuclear complex 3 was observed and isolated.
This species is stable in the pH range 6.4–7.5. Decrease of the pH
value led to splitting of the oligomeric species according
Scheme 2 while the increase of pH leads to full decomposition of
the metal-organic bonds leading to trivial polyoxovanadates. On
the other hand, the role of complex 3 and related EPR-silent
hydroxycyclopentadienyl vanadium species in mechanism of anti-
tumor action of vanadocene dichloride (1) should not be overesti-
Scheme 2. Protonolysis of trinuclear complex 3.

J. Honzí cˇ ek et al. / Inorganica Chimica Acta 453 (2016) 39–41
41
mated. Hence, the role of the carbonate complex Cp
2
V(O,O-CO
3
) [7]
Table 2
Crystallographic data of the compound 3-PF
6 2
ꢁ4H O.
and oxalate complex Cp V(O,O-C ) [10] in transport of 1 in the
2
2 4
O
human organism remains valid due to previously described inter-
action of aqua complex 2 with carbonates and oxalate present in
biological systems [8,11]. Furthermore, the importance of polynu-
clear species, such as 3, usually decreases with decreasing vana-
dium concentration and so their amount in biological conditions
should be negligible [20].
Formula
C20H24O V ꢁ 2 F P ꢁ 4 H O
859.21
150(1)
5
3
6
2
Formula weight
Temp. (K)
Cryst. system
Space group
a (Å)
Monoclinic
P2 /c (No.14)
1
12.3780(12)
16.0861(16)
17.710(3)
90
117.479(8)
90
3128.5(7)
4
1.824
b (Å)
c (Å)
a
(deg)
b (deg)
(deg)
4
. Experimental section
c
3
V (Å )
4.1. Methods and materials
Z
D
l
(g cm–3
(mm
)
c
All operations were performed under nitrogen using conven-
–1
)
1.097
tional Schlenk-line techniques. The solvents were purified and
dried by standard methods [12]. Starting materials were available
F(0 0 0)
Cryst. size (mm)
h range
1724
0.59 ꢀ 0.42 ꢀ 0.29
1.81–27.12
commercially or prepared according to literature procedures: Cp
2
-
Index ranges
–16 6 h 6 15; –19 6 k 6 20; –22 6 l 6 20
25649
5746 (Rint = 0.1443)
112
VCl (1) [13]. Carbonate-free sodium hydroxide was prepared by
2
Reflections collected
Independent reflections
Parameters
dissolution of sodium metal in distilled water under inert atmo-
sphere of nitrogen; Caution! The reaction is highly exothermic and
accompanied with rapid evolution of hydrogen. The EPR spectra were
recorded on Miniscope MS 300 spectrometers at X-band at ambi-
ent temperature.
a,b
Final R indices [I > 2
r
(I)]
R
R
1
= 0.1625; wR
= 0.1793; wR
2
= 0.3755
= 0.3883
a,b
Final R indices (all data)
1
2
Largest diff. peak and hole (eÅ–3) 1.907, –1.425
P
P
a
R1 ¼ jjF
o
j ꢂ jF
c
jj= jF
o
j.
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
P
2
P
2
2
b
2
o
2
wR2 ¼
½wðF ꢂ F Þ ꢃ= ½wðF Þ ꢃ.
c
o
4
.2. Synthesis of [{Cp
2
V(l
2
-OH) }
2
VO][PF
6
]
2
ꢁ4H
2
O (3-PF
6
2
ꢁ4H O)
Compound 1 (0.5 g; 1.98 mmol) was dissolved in deoxygenated
distilled water (20 mL) and treated with aqueous solution of car-
–1
bonate-free sodium hydroxide (c = 1 molꢁL ) dropwise and moni-
tored with EPR spectroscopy. At pH = 6.4, the EPR signal
completely disappeared (3.96 mL of hydroxide was added). The
solution was treated with saturated solution of potassium hexaflu-
orophosphate (10 mL) and stirred for 2 h. The precipitate was fil-
tered, washed with distilled water (5 ꢀ 20 mL) and vacuum
dried. (Yield: 0.42 g; 0.49 mmol; 74 %). Green precipitate.
Mp = 220 °C (dec.). The methanolic solution is EPR silent
Appendix A. Supplementary data
Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, CCDC nos. CCDC 1448532. Copies of
this information may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge CB2 1EY, UK (fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www.
ccdc.cam.ac.uk). Supplementary data associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
ica.2016.07.054.
3
-PF
6
ꢁ4H
2
O. The treatment of the solution with HClO
4
gives
–4
spectrum of
4
2
(|Aiso
|
=
80.04 ꢀ 10
mT; giso = 1.979) and
–
4
(|Aiso| = 116.28 ꢀ 10 mT; giso = 1.963) in the molar ratio 2:1.
References
4
.3. Crystallography
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[
[
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6
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2
matrix least squares based on F (SHELXL97) [17]. Hydrogen atoms
were mostly localized on a difference Fourier map. However, to
ensure uniformity of the treatment of the crystal, all hydrogen
atoms were recalculated into idealized positions (riding model).
[
[
[
[
The non-transparent weakly diffracting crystals of 3-PF
6
ꢁ4H
2
O
revealed higher structural parameters. The structure contains posi-
tionally disordered cyclopentadienyl cycle (C16–C20) which was
split into two positions with occupancy of about 52:48. The disor-
der has been treated by Shelxl software instructions [18]. In the
second cyclopentadienyl cycle (C11–C15), the CAC distances were
optimized to 1.4 Å. Ideal positions of H atoms of water molecule
were assigned, according to ideal H bond geometry found by PARST
program [19].
[
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(
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[
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[