Dinuclear oxidovanadium(IV) and dioxidovanadium(V) complexes of 5,5′-methylenebis(dibasic tridentate) ligands: Synthesis, spectral characterisation, reactivity, and catalytic and antiamoebic activities

Article abstract of DOI:10.1002/ejic.200900677

The synthesis of dinuclear oxidovanadium(IV) and dioxidovanadium(V) complexes of two hydrazones [CH₂(H₂Salnah)₂ (I) and CH₂(H₂sal-inh)₂ (II)] derived from 5,5′-methylenebis(salicylaldehyde)

Full text of DOI:10.1002/ejic.200900677

FULL PAPER
DOI: 10.1002/ejic.200900677
Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes of
5,5Ј-Methylenebis(dibasic tridentate) Ligands: Synthesis, Spectral
Characterisation, Reactivity, and Catalytic and Antiamoebic Activities
Mannar R. Maurya,*[a] Aftab Alam Khan,[a] Amir Azam,[b] Amit Kumar,[c] Samir Ranjan,[d]
Neelima Mondal,[d] and J. Costa Pessoa*[c]
Keywords: Vanadium / EPR spectroscopy / NMR spectroscopy / Catalytic activity / Antiamoebic activity
The synthesis of dinuclear oxidovanadium(IV) and dioxido-
vanadium(V) complexes of two hydrazones [CH2(H2sal-
nah)2 (I) and CH2(H2sal-inh)2 (II)] derived from 5,5Ј-methyl-
enebis(salicylaldehyde) [CH2(Hsal)2] and nicotinic acid hy-
drazide (nah) or isonicotinic acid hydrazide (inh) is de-
scribed. The compounds were characterised in the solid state
and in solution, namely by spectroscopic techniques (IR, UV/
Vis, EPR, 1H, 13C and 51V NMR). It has been demonstrated
that the dioxidovanadium(V) complexes K2[CH2{VVO2(sal-
nah)}2]·2H2O (3), Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4) and
Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5) of I and II are active in
the oxidative bromination of salicylaldehyde by H2O2, there-
fore acting as functional models of vanadium-dependent
haloperoxidases, and it has also been shown that the corre-
sponding oxidovanadium(IV) complexes [CH2{VIVO(sal-
nah)(H2O)}2] (1) and [CH2{VIVO(sal-inh)(H2O)}2] (2) are cata-
lyst precursors for the catalytic oxidation, by peroxide, of
methyl phenyl sulfide and diphenyl sulfide, yielding the cor-
responding sulfoxide and sulfone. Plausible intermediates in-
volved in these catalytic processes are established by UV/
Vis, EPR and 51V NMR studies. The dioxidovanadium(V)
complexes along with ligands I and II were also screened
against HM1:1MSS strains of Entamoeba histolytica. The re-
sults showed that the IC50 values of compounds 3 and 5 are
lower than the IC50 value of metronidazole. The toxicity stud-
ies against human cervical (HeLa) cell lines showed that
compounds 3 and 5 are not much toxic but are more toxic
than metronidazole.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The intestinal protozoan parasite Entamoeba histolytica
has the capacity to invade intestinal mucosa, resulting in
intestinal amoebiasis. Around 50 million people also suffer
from liver abscess caused by E. histolytica, resulting in
50000–100000 deaths yearly.[13] Amoebiasis is the second
leading cause of death among parasite diseases.[14] For the
treatment of amoebiasis, metronidazole has been the drug
of choice, but recent studies have shown that this drug has
several toxic effects such as genotoxicity, gastric mucus irri-
tation and spermatozoid damage.[15–17] Furthermore, fail-
ures in the treatment of several intestinal protozoan para-
sites may result from drug-resistant parasites.[18,19] There-
fore, there is therapeutic demand for research on new drugs
for treatment. Metal ions are known to often accelerate
drug action, and the efficacy of a therapeutic agent may be
enhanced upon coordination with a metal ion.[20] Vanadium
complexes show a variety of biological properties, and ox-
idovanadium(IV) complexes have been used to prevent and
improve dexamethasone-induced insulin resistance in 3T3-
L1 adipocytes.[21] These compounds have also been used in
receptor-mediated signals[22] and as anticancer agents.[23,24]
Recently, we have reported the antiamoebic activity of vari-
ous vanadium complexes, which gave encouraging results in
in vitro experiments.[25,26]
The discovery of vanadium-dependent haloperoxidase
enzymes and the catalytic potential of several model vana-
dium complexes in oxidation and oxygen-transfer reactions,
including the oxidative halogenation of organic sub-
strates[1–5] and oxidation of organic sulfides to sulfoxides,
has stimulated the study of coordination chemistry of vana-
dium with multidentate ligands.[6–10] Several vanadium
complexes have been shown to be active as insulin mimetics
in vitro and in vivo, and [VIVO(ethylmaltolato)2] has passed
phase I and II clinical tests,[11,12] demonstrating the usabil-
ity of coordinating compounds of vanadium for the treat-
ment of diabetes mellitus in humans.
[a] Department of Chemistry, Indian Institute of Technology
Roorkee,
Roorkee 247667, India
Fax: +91-1332-273560
E-mail: rkmanfcy@iitr.ernet.in
[b] Department of Chemistry, Jamia Milia Islamia, Jamia Nagar,
New Delhi 100025, India
[c] Centro de Química Estrutural, Instituto Superior Técnico, TU
Lisbon,
Av Rovisco Pais, 1049-001 Lisbon, Portugal
[d] School of Life Sciences, Jawaharlal Nehru University,
New Delhi 110062, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.200900677.
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M. R. Maurya, A. A. Khan, A. Azam, A. Kumar, S. Ranjan, N. Mondal, J. C. Pessoa
FULL PAPER
In this paper, we describe the synthesis and characterisa- similar reaction conditions the complex of ligand II always
tion of dinuclear oxidovanadium(IV) and dioxidovanadi- gave an emulsified mixture from which the desired complex
um(V) complexes of hydrazones I and II derived from 5,5Ј- could not be isolated.
methylenebis(salicylaldehyde) [CH2(Hsal)2] and nicotinic
acid hydrazide (nah) or isonicotinic acid hydrazide (inh)
2 K[VO3] + CH2(HKsal-nah)2 + 2 H2O Ǟ
K2[CH2{VVO2(sal-nah)}2]·2H2O + 2 KOH
(3)
(Scheme 1). The catalytic activity is demonstrated consider-
ing the oxidation, by peroxide, of methyl phenyl sulfide and
diphenyl sulfide using the oxidovanadium(IV) complexes as
catalyst precursors. In addition, the haloperoxidase activity
is confirmed as the dioxidovanadium(V) complexes are
active in the oxidative bromination of salicylaldehyde. The
dioxidovanadium(V) complexes have also been screened
against HM1:1MSS strains of Entamoeba histolytica.
All complexes are soluble in methanol, ethanol, dmso
and dmf. Scheme 2 presents the structures proposed for
these complexes, which are supported by the spectroscopic
characterisation (IR, electronic, 1H, 13C and 51V NMR, and
EPR), elemental analyses and thermogravimetric patterns.
The coordination of the dianionic ligands involves their
enolate tautomeric form (ONO2–) (cf. Scheme 1).
Scheme 1. Structures of ligands designated by I and II used in this
work.
Results and Discussion
Scheme 2. Schematic structure of the VIVO and VVO2 complexes
prepared.
The reaction between [VIVO(acac)2] and CH2(H2sal-
nah)2 or CH2(H2sal-inh)2 in a 2:1 ratio in refluxing meth-
anol leads to the formation of dinuclear oxidovanadi-
um(IV) complexes [CH2{VIVO(sal-nah)(H2O)}2] (1) and
[CH2{VIVO(sal-inh)(H2O)}2] (2), respectively. These com-
plexes exhibit normal magnetic moment values of 1.71 and
1.70 µB, respectively, indicating only very weak or possibly
no magnetic exchange interaction between the two vanadi-
um(IV) centres. Aerial oxidation of these complexes in the
presence of KOH or CsOH·H2O in methanol results in the
formation of the corresponding salt of dioxidovanadium(V)
species [CH2{VVO2(sal-nah)}2]2– and [CH2{VVO2(sal-
inh)}2]2–, respectively. Alternatively, these complexes can
also be isolated directly by the aerial oxidation of in situ
generated VIVO complexes in the presence of the corre-
sponding hydroxide. Equations (1) and (2) present the
whole synthetic procedure considering CH2(H2sal-nah)2 as
a representative ligand.
Electronic Spectral Studies
Electronic spectroscopic data of ligands and complexes
are presented in Table 1. Ligands I and II exhibit four ab-
sorption bands at about 216, 243, 294 and 341 nm that are
assigned to φ Ǟ φ*, π Ǟ π1*, π Ǟ π2* and n Ǟ π* transi-
tions, respectively. In complexes, these bands are generally
shifted towards lower wavelengths. In addition, a new band
of medium intensity appears at 407–414 nm, which is as-
signed to a ligand-to-metal charge transfer (LMCT) band.
The band at 565 nm, observed at higher concentration for
complexes 1 and 2, is assigned to a d–d transition. For com-
plexes 3–5 no such bands were detected.
Table 1. Electronic spectroscopic data of compounds.
Compounds
λ [nm]
2 [VIVO(acac)2] + CH2(H2sal-nah)2 + 2 H2O Ǟ
CH2(H2sal-nah) (I)
341, 294, 243, 216
342, 294, 244, 217
565, 408, 325, 242, 207
408, 323, 292, 242
408, 325, 288, 240, 206
565, 407, 328, 282, 239
414, 327, 283, 234
[CH2{VIVO(sal-nah)(H2O)}2] + 4 Hacac
(1)
CH2(H2sal-inh) (II)
[CH2{VIVO(sal-nah)(H2O)}2] (1)
K2[CH2{VVO2(sal-nah)}2]·2H2O (3)
Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4)
[CH2{VIVO(sal-inh)(H2O)}2] (2)
Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5)
[CH2{VIVO(sal-nah)(H2O)}2] + 2 KOH + 1/2 O2 Ǟ
K2[CH2{VVO2(sal-nah)}2]·2H2O + H2O
(2)
Complex K2[CH2{VVO2(sal-nah)}2]·2H2O was also iso-
lated by the reaction of potassium vanadate, generated in
situ by dissolving V2O5 in an aqueous KOH solution, with
the solution of the K+ salt of I and adjustment of the pH
IR Spectral Studies
The IR spectroscopic data of ligands and complexes are
of the reaction mixture to about 7.0 [Equation (3)]. Under presented in Table 2 (see also the Supporting Information).
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Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes
Table 2. IR spectra of compounds [cm–1].
Compounds
ν(C=O)
ν(C–O)
ν(C=N)
ν(V=O)
ν(N–N)
CH2(H2sal-nah) (I)
1655
1653
–
–
–
–
–
–
–
1278
1283
1278
1287
1286
1617
1617
1594
1597
1597
1593
1593
–
–
983
926, 950
921, 950
987
961
968
1056
1029
1033
1034
1066
CH2(H2sal-inh) (II)
[CH2{VIVO(sal-nah)(H2O)}2] (1)
K2[CH2{VVO2(sal-nah)}2]·2H2O (3)
Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4)
[CH2{VIVO(sal-inh)(H2O)}2] (2)
Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5)
927, 950
The IR spectra of the ligands show bands at 1655 and 3204 and their assignments are included in the Supporting Infor-
[CH2(H2sal-nah)2, I] and 1653 and 3250 cm–1 [CH2(H2sal- mation (Table S2), being compatible with the structures
inh)2, II] because of ν(C=O) and ν(N–H) stretches, respec- proposed.
tively. This is indicative of their ketone nature in the solid
state. Both bands disappear upon complex formation, indi-
cating the enolisation and dissociation of H+ induced by
the metal ion. Other changes observed upon complex for-
Solution Behaviour of K2[CH2{VVO2(sal-nah)}2]·2H2O (3)
mation are as expected, namely the ligand band appearing
The 51V NMR spectrum of K2[CH2{VVO2(sal-nah)}2]·
2H2O (3) dissolved in MeOH has a resonance at δ =
at 961 (in I) and 968 cm–1 (in II) because the ν(N–N) stretch
undergoes a blueshift of 95–98 cm–1. This high-frequency
–538 ppm and a minor one at δ = –545 ppm (Figure 1a). In
shift of the ν(N–N) band is expected because of the de-
dmso a single peak is obtained at δ = –533 ppm [Fig-
creased repulsion between the lone pairs of adjacent nitro-
ure 2A(a)]. The assignment of these and other resonances
was done by also considering the experiments described be-
gen atoms.[27]
All dioxidovanadium(V) complexes exhibit one sharp
low.
band in the 921–927 cm–1 region and one weak band at
about 950 cm–1 due to νsym(O=V=O) and νasym(O=V=O)
stretches. The O atoms of the VVO2 units are probably in-
volved in binding to K+/Cs+ in the crystal structure; such
oxygen coordination has been confirmed in anionic diox-
idovanadium(V) complexes.[28,29] Oxidovanadium(IV) com-
plexes display only one sharp band each at 983–987 cm–1
because of the ν(V=O) stretch.
1H and 13C NMR Studies
1H NMR spectra of the ligands and complexes were re-
corded to obtain further evidence for the coordinating
mode of ligands. The relevant data are presented in
Table S1. The 1H NMR spectra of ligands exhibit signals at
δ = 10.84 (I) and at δ = 10.85 (II) due to the –NH proton,
indicating their existence in the ketone form. The absence
of these signals in VV complexes is in agreement with enoli-
sation and the subsequent replacement of H by the metal
ion. Similarly, the absence of the signal for the phenol OH
group (δ ≈ 12.25 ppm in the ligands) indicates the coordina-
tion of the phenolate oxygen atom. A significant downfield
shift of the azomethine (–CH=N–) proton signal in VV
complexes, as compared with the corresponding free li-
gands, also indicates the coordination of the azomethine
1
nitrogen atom. This and the other H NMR spectroscopic
data are thus consistent with the ONO dibasic tridentate
binding mode of each unit of ligands and in agreement with
the conclusions drawn from IR data.
Figure 1. 51V NMR spectra for solutions (about 4 m) of
K2[CH2{VVO2(sal-nah)}2]·2H2O (3): (a) in MeOH and (b–h) after
stepwise additions of an aqueous solution of 30% H2O2; (b)
0.5 equiv. H2O2 added; (c) 2 equiv. H2O2 (total) added; (d)
4.0 equiv. H2O2 (total) added; (e) 6.0 equiv. H2O2 (total) added; (f)
8.0 equiv. H2O2 (total) added; (g) 10 equiv. H2O2 (total) added; (h)
solution of (g) after 2 h leaving tube open; (i) solution of (h) after
The 13C NMR spectra recorded for complexes 3–5 con-
tain 13 signals corresponding to the 27 carbon atoms of the
molecules owing to their symmetry. The peaks observed 36 h leaving tube open.
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M. R. Maurya, A. A. Khan, A. Azam, A. Kumar, S. Ranjan, N. Mondal, J. C. Pessoa
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new signals are detected at δ = –651 and –683 ppm, which
we assign to inorganic peroxidovanadates {tentatively
[VVO(O2)]+ (CIV)[32] and [VVO(O2)2(H2O)]– (CV)}[33–39]
(see Scheme 3). Leaving the NMR tube open for 36 h after
recording the spectrum of Figure 1h, spectrum (i) was ob-
tained, indicating the reversibility of the process.
The behaviour of 3 dissolved in dmso differs from what
was observed in methanol (Figure 2). Upon addition of
3 equiv. HClO4 the 51V NMR spectrum shows two new sig-
nals at δ = –470 (br.) (about 86%) and –559 (about 9%)
ppm, as well as the original resonance at δ = –533 (about
5%) ppm [Figure 2A(b), pH ≈ 3.1]. Similarly, addition of
3 equiv. of HCl to the solution of 3 in dmso yields two new
signals at δ = –439 (br.) (about 82%) and –559 (about 14%)
ppm, as well as the original resonance at δ = –533 (about
4%) ppm [Figure 2A(d)]. Similar results were obtained
upon addition of H2SO4 instead of HCl or HClO4.
For further investigation both solutions of (b) and (d) in
Figure 2A were divided into three parts. On addition of
MeOH to one of these only the peak at δ = –538 ppm [Fig-
ure 2A(e)] was detected, and this can be assigned to species
CII (S = MeOH). Addition of 4 equiv. of KOH to the sec-
ond portion yielded a resonance at δ = –533 ppm, indicat-
ing the reversibility of the reaction. The third portion of
this solution was kept at room temperature for 48 h and
then showed a major resonance at δ = –539 ppm corre-
sponding to CII.
We assign the δ = –559 ppm lower-field resonances of
Figure 2A(b) and (d) to the oxido/hydroxido species (CVI).
The partial protonation of the ligand is also a plausible
possibility (see below).
Figure 2. 51V NMR spectra for K2[CH2{VVO2(sal-nah)}2]·2H2O
(3). (A): (a) in dmso (about 4 m), (b) solution of (a) after addition
of 3.0 equiv. of an aqueous solution of HClO4 (15.8 ), the pH
being about 3.1; (c) solution of (b) after addition of MeOH, the
solution now containing equal volumes of dmso and MeOH; (d)
solution of (a) after addition of 3.0 equiv. of an aqueous solution
of HCl (11.6 ), the pH being about 3.3; (e) solution of (d) after
addition of MeOH, the solution now containing equal volumes of
dmso and of MeOH. (B): 51V NMR spectra of 3 (a) in MeOH,
about 4 m; (b) after addition of 2.0 equiv. of an aqueous solution
of HCl (11.6 ); (c) solution of spectrum (b) after standing for
about 15 h.
Additionally, the spectra of Figure 2A(b) and (d) show a
global decrease and broadening of the 51V NMR signals,
indicating the presence of an oxidovanadium(IV) species in
Addition of methanol to a 4 m solution of 3 in dmso the solution, and this was confirmed by recording the EPR
shifts the δ = –533 ppm resonances to δ = –538 ppm, iden- spectra for both solutions. The spectra are reasonably in-
tical to the spectrum of 3 in MeOH only. The signal at δ tense, and the spin Hamiltonian parameters obtained are
= –538 ppm is assigned to [CH2{VO2(sal-nah)(MeOH)}2]2– both similar to those of solutions of 1 in dmso (see below)
(CII, S = MeOH) in Scheme 3.[30,31]
indicating an O3N binding mode around the vanadium cen-
Addition of acid (HCl/HClO4), viz. 1, 2, 3, 4 equiv., to a tre, that is, a binding mode identical to that of 1.
methanolic solution of 3 leads to a decrease in intensity of
To explain the peaks at δ ≈ –440/–475 ppm, because of a
the δ = –538 ppm peak and an increase at the δ = –545 ppm VV species, we now consider three possibilities: (i) the for-
peak (see Figure 2B); the colour of the solution turns to mation of a mixed-valence VIVO–O–VVO complex (see
red and the pH is about 2.5–3.3. The addition of acid may structure CVII in Scheme 3), (ii) a complex formulated as
protonate the ligand so the δ = –545 ppm band may either [CH2{VVO2(sal-nah)}{VIVO(sal-nah)}]
(see
structure
be due to CII (S = H2O) or to free vanadate (V1). As ad- CVIII) or (iii) the formation of a VVO–O–VVO complex
dition of H2O to the 4 m solution of 3 in dmso shows an (see structure CIX), along with a VIV complex, which corre-
upfield shift to δ = –539 ppm, this indicates the involvement sponds to 1. The 51V NMR peaks in assignments (i) or (ii)
of the solvent molecule; we assign the δ = –539 ppm signal correspond to the VV-“half-part” of the molecule.
of Figure 2B to [CH2{VVO(sal-nah)(H2O)}2]2– (CII, S =
H2O).
If a VIVO–O–VVO complex such as that represented in
structure CVII is formed, the V–O–V angle should not be
Upon the stepwise addition of an aqueous 30% solution close to 180°, so that the unpaired electron is localised on
of H2O2 to the methanolic solution of 3 (about 4 m) the one of the V atoms of the V–O–V dinuclear unit. To the
resonance at δ = –538 ppm progressively disappears, and best of our knowledge there is no previous example of 51V
resonances at δ = –607 ppm are observed (Figure 1), which NMR signals being obtained for VIVO–O–VVO complexes
we tentatively assign to [CH2{VVO(O2)(sal-nah)}2]2– (CIII). (or reports of attempts to measure them). In order that the
Upon further stepwise additions of H2O2 (8 equiv. or more) δ = –440/–475 ppm resonances may be assigned to the
the resonance at δ = –538 ppm totally disappears, and two VVO2-“half-part” of a species such as structure CVIII,
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Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes
Scheme 3. Summary of speciation of vanadium species in solution.
which correspond to significantly deshielded VV species, at δ = –606 and –649 ppm are recorded, which we assign to
some electron density should have also been delocalised CIII and CIV, respectively (Scheme 3). Leaving the solution
from the VIV to the VV centre, and it is not clear if this is of Figure 3(f) in contact with air, spectrum (g) of Figure 3
feasible in CVIII. Globally, we consider structure CIX as a was obtained after about 36 h, indicating that the reactions
reasonable hypothesis of assignment for the
δ
=
are reversible. Addition of acid (HCl or HClO4, e.g.,
–440/–475 ppm resonances; the different values recorded 2 equiv.) to a methanolic solution of 4 (see Figure S1) leads
possibly result from some electrostatic influence of the to a decrease in intensity of the δ = –538 ppm peak and
–
counterions present (Cl–, ClO4 or SO42–) nearby.
an increase at δ = –545 ppm. This may be due either to
The formation of [CH2{VVOL}2] complexes, containing protonation of the ligand, or to generation of CII (S =
the VVO3+ moiety, upon addition of acid, as reported for a H2O) or to free vanadate (V1).
few vanadium systems {e.g., salen and EHGS, ethyl-
In dmso, complex 4 gives a resonance at δ ≈ –532 ppm
enebis[(o-hydroxyphenyl)glycine]},[40,41] could also be a pos- [Figure 4(a) or (d)]. Addition of methanol and water yielded
sible explanation of the 51V NMR signal appearing at δ ≈ the upfield resonances at δ = –537 and –538 ppm, respec-
–444 to –466 ppm. However, no strong CT band was ob- tively, confirming the involvement of solvent molecules in
served in the 500–600 nm range for complexes with our li- these CII species. Upon addition of 2 equiv. of concentrated
gands I and II (see below) as was found in the salen and HCl solution, two new resonances at δ = –444 (about 35%)
EHGS systems, so we assume these high-field resonances and –559 (about 25%) ppm appear along with the original
are not due to the formation of VVOL-type complexes.
resonance at δ = –532 (about 30%) ppm. A similar behav-
iour was observed upon addition of 2 equiv. of HClO4 (or
H2SO4). A broadening of the bands also occurs, and rather
intense EPR spectra could be recorded with the solutions
Solution Behaviour of Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4)
Similar to 3, complex 4 dissolved in MeOH shows two of Figure 4(b) and (d) confirming the formation of VIVO
resonances at δ = –537 and –544 ppm [Figure 3(a)], but the complexes. The upfield resonance is assigned to the forma-
latter signal is more intense than the corresponding one in tion of an hydroxidooxidovanadium(V) species at δ =
3. The major signal at δ = –537 ppm is assigned to –559 ppm. Addition of 4 equiv. of KOH to the solutions of
[CH2{VO2(sal-nah)(MeOH)}2]2– (CII, S = MeOH), and the Figure 4(b) and (d) yielded only the resonance at δ =
minor one is probably vanadate (V1) or a complex resulting –532 ppm, corresponding to 4 in dmso, confirming the re-
from protonation of the coordinated N atom.[42,43] Upon versibility of the reaction. Addition of methanol to the
stepwise addition of 30% H2O2 (up to 8 equiv.) resonances solutions of Figure 4(b) and (d) yielded resonances at δ =
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M. R. Maurya, A. A. Khan, A. Azam, A. Kumar, S. Ranjan, N. Mondal, J. C. Pessoa
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resonance is assigned as in the case of complex 3 (see
Scheme 3 and the above discussion regarding structures
CVII–CIX).
Solution Behaviour of Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5)
Similarly to the previous observations with 3 and 4, the
51V NMR spectrum of Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5)
dissolved in MeOH (Figures S2a and S3a) shows signals at
δ = –539 and –545 ppm, assigned to CII (S = MeOH and
H2O) and free vanadate. Upon addition of aqueous solu-
tions of either HCl or HClO4 (2 equiv. of acid) a peak at δ
= –545 ppm was detected, which may at least partly corre-
spond to vanadate (Figure S3). Formation of the peroxido
complexes CIII and CIV (δ = –606 and –649 ppm, respec-
tively) was confirmed upon addition of an aqueous solution
of 30% H2O2 (1, 2 and 10 equiv.) (Figure S2). In dmso (Fig-
ure S4) the behaviour is similar to what was recorded for
complexes 3 and 4.
Figure 3. 51V NMR spectra for Cs2[CH2{VVO2(sal-nah)}2]·2H2O
(4): (a) in MeOH (about 4 m of 4) and upon stepwise addition of
aqueous 30% solution H2O2; (b) 1.0 equiv. H2O2; (c) 4.0 equiv.
H2O2; (d) 6.0 equiv. H2O2; (e) 8.0 equiv. H2O2; (f) solution of (e)
after 24 h leaving the tube open; (g) solution of (e) after 36 h of
leaving the tube open.
EPR and UV/Vis Study
The EPR spectra of “frozen” solutions (77 K) in dmso
of complexes 1 and 2 are depicted in Figure 5. Two sets of
eight-line spectra showing hyperfine splitting due to the 51
V
–539 ppm corresponding to the dioxido species (CII, S =
MeOH). The EPR spectra of the solutions of Figure 4(b)
and (d) were simulated,[44] and the data indicate that the
binding mode of the VIVO species present is identical to
that of complex 1 in dmso (see below). The broad downfield
nucleus are obtained, characteristic of square-pyramidal
complexes with an axially compressed d1 configuration.
xy
The spectra were simulated, and the spin Hamiltonian pa-
rameters obtained[44] are included in Table 3.
The value of Aʈ can be calculated by using the additivity
relationship [Aʈest
= ΣAʈ,i (i = 1–4)] proposed by
Wurthrich[45] and Chasteen,[46] with estimated accuracy of
Ϯ3ϫ10–4 cm–1. The Aʈ values obtained for 1 and 2
(Table 3) agree with the values calculated from the partial
contributions of the equatorial donor groups: H2O
(45.7ϫ10–4 cm–1), Ophenolate (38.9ϫ10–4 cm–1), Nimine
,
(38.1ϫ10–4 to 43.7ϫ10–4 cm–1), O-enolate(1–) (37.6ϫ
10–4 cm–1), Odmso (41.9ϫ10–4 cm–1) and OMeOH (45.7ϫ
10–4 cm–1).[47,48]
The EPR spectra of both complexes in dmso are in good
agreement with an O3N binding mode, one of the equato-
rial donor atoms being Odmso. The effect of solvent on EPR
parameters was examined by also measuring the spectra in
MeOH (e.g., Figure 6). As indicated in Table 3 for 1, the gʈ
value decreases from 1.951 to 1.948, and Aʈ increases from
163.3 to 166.4, this being compatible with the substitution
of one coordinated Odmso by an OMeOH atom.[48] Similar
data were obtained for 2 (Table 3).
Addition of H2O2 portions to solutions of 1 or 2 in
MeOH acidifies the solutions, and different VIVO species
form with EPR parameters gʈ = 1.936, Aʈ = 177.8ϫ10–4
cm–1 for 1 and gʈ = 1.935, Aʈ = 178.0ϫ10–4 cm–1 for 2; the
VIVO is also progressively oxidised to VV (Figures S5 and
S6). According to the gʈ and Aʈ values obtained for these
partially oxidised solutions, in these VIVO species the bind-
ing mode is probably O4, the VIVO complexes being exten-
sively hydrolysed.
Figure 4. 51V NMR spectra for Cs2[CH2{VVO2(sal-nah)}2]·2H2O
(4): (a) in dmso and after additions of aqueous acids: (b) 2.0 equiv.
HCl and (d) 2.0 equiv. HClO4. Upon addition of MeOH to the
solutions of spectra (b) and (d) so that the mixtures contain equal
volumes of MeOH and dmso, spectra (c) and (e), respectively, were
recorded.
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Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes
Figure 5. EPR spectra of frozen solution (4 m) samples of [CH2{VIVO(sal-nah)(H2O)}2] (1) (a) and [CH2{VIVO(sal-inh)(H2O)}2] (2) (b)
in dmso.
Table 3. Spin Hamiltonian parameters obtained by simulation[44] of the experimental EPR spectra recorded for dmso solutions of com-
plexes 1 and 2 at 77 K.
Complex
Solvent
gʈ
Aʈ ϫ104 [cm–1]
gЌ
AЌ ϫ104 [cm–1]
[CH2{VIVO(sal-nah)(H2O)}2] (1)
dmso
MeOH
MeOH
dmso
MeOH
MeOH
1.951
1.948
1.936
1.951
1.949
1.935
163.3
166.4
177.8
162.3
165.9
178.0
1.980
1.979
1.977
1.981
1.979
1.977
56.7
57.5
66.0
56.8
57.4
66.2
0.5 equiv. H2O2
[CH2{VIVO(sal-inh)(H2O)}2] (2)
0.5 equiv. H2O2
Figure 6. First-derivative EPR spectra (at 77 K) of a solution of [CH2{VO(sal-nah)(H2O)}]2 (1): (a) in dmso (about 4 m); (b) after
addition of an equal volume of MeOH; and (c) after addition of 0.5 equiv. of an aqueous 30% H2O2 solution.
Upon leaving solutions of 1 or 2 in dmso in contact
The formation of peroxido complexes in methanol by
with air, after about 3–4 d 51V NMR resonances were re- treatment of the respective dioxido complexes with H2O2
corded at δ ≈ –532 ppm (Figure S6). VVO2 complexes could also be established by electronic absorption. Thus,
therefore form with signals similar to those recorded for the addition of 30% aqueous H2O2 (30 drops, 18.04 mmol)
dmso solutions of 3–5. With the stepwise addition of aque- to 20 mL of an approximately 4.135ϫ10–5  solution of
ous H2O2 solution (1, 2, 3, 4, 5 equiv.) peaks at δ ≈ –597 Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5) and recording of the
and –648 ppm were obtained, corresponding to the perox- spectral changes after every 25 min resulted in the spectra
ido complexes CIII and CIV, respectively. Subsequent ad- presented in Figure 7. The band at 412 nm slowly shifted to
dition of 10 equiv. of methyl phenyl sulfide produced, after 415 nm along with a decrease in intensity. The two UV
about 12 h, the resonance at δ = –539 ppm, corresponding bands appearing at 232 and 282 nm (not within the scale of
to a dioxido species (CII, S = MeOH), supporting the re- the figure) increase in intensity, whereas the 328 nm band
versibility of the processes.
becomes a shoulder. A band at about 470 nm slightly in-
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M. R. Maurya, A. A. Khan, A. Azam, A. Kumar, S. Ranjan, N. Mondal, J. C. Pessoa
FULL PAPER
creases its intensity. This change in spectra is interpreted [VO(salim)(acac)] (salim = a Schiff base ligand also con-
as the formation of a peroxido compound. Similar spectral taining imidazole), where the EPR and ESEEM spectra re-
changes were recorded with solutions of 3 and 4 upon sim- corded upon addition of acid were explained by the proton-
ilar treatment (Figures S7 and S8).
ation of the imine N atom.[43]
Catalytic Activity Studies
Oxidation of Methyl Phenyl Sulfide and Diphenyl Sulfide
It is known that several vanadium-dependent haloperox-
idases also catalyse sulfoxidations.[47,52,53] We tested com-
plexes [CH2{VIVO(sal-nah)(H2O)}2] (1) and [CH2{VIVO-
(sal-inh)(H2O)}2] (2) as catalyst precursors, taking methyl
phenyl sulfide and diphenyl sulfide to model these reactions
using aqueous 30% H2O2 as oxidant. Between the two com-
plexes studied, 1 was chosen as a representative one, and
the amounts of catalyst precursor and oxidant were varied
to obtain maximum conversion (based on substrate con-
sumption). The effect of H2O2 was studied (Figure S11) by
considering substrate/oxidant ratios of 1:1, 1:2 and 1:3 for
the fixed amount of catalyst (0.015 g) and substrate (1.24 g,
10 mmol) in petroleum ether (10 mL), and the reaction was
monitored at room temperature. Thus, in 7 h of contact
time, on increasing the substrate/oxidant ratios from 1:1 to
1:2 the conversion increased from 11.4% to 99.6%. Increas-
ing this ratio to 1:3 did not improve conversion except for
the completion of the reaction within 6 h and a slight
change in the selectivity of products.
Similarly, four different amounts of catalyst precursor,
viz 0.005, 0.015, 0.025, 0.035 g, were taken at fixed reaction
conditions optimised as above [i.e., substrate (1.24 g,
10 mmol), H2O2 (2.27 g, 20 mmol) and petroleum ether
(10 mL)] to see the effect of amount of catalyst on the reac-
tion, and the results are presented in Figure S12. It is clear
from the figure that 0.015 g of catalyst was sufficient to give
99.6% conversion with a turnover frequency of 57.1 h–1. A
higher amount of catalyst only reduced the time taken to
achieve the steady state of the reaction.
Figure 7. UV/Vis spectrum of 20 mL of an approximately
4.135ϫ10–5  methanolic solution of Cs2[CH2{VVO2(sal-inh)}2]·
2H2O (5) and spectral changes observed with time after addition
of 30% aqueous H2O2 (30 drops, 18.04 mmol). Each spectrum was
recorded at 25-min intervals.
The reactivity of methanolic solutions of dioxidovanadi-
um(V) complexes with HCl was also monitored by elec-
tronic absorption spectroscopy. Thus, the dropwise addition
of HCl gas saturated in methanol to 20 mL of a
6.535ϫ10–5  solution of Cs2[CH2{VVO2(sal-inh)}2]·2H2O
(5) caused the darkening of the solution along with an in-
crease in intensity of the 279 nm band and its transforma-
tion into a shoulder (Figure 8). The other UV bands at 274
and 298 nm only gained intensity. The band appearing at
412 nm apparently progressively broadened with decrease
in its intensity, whereas the band at about 470 nm increased
in intensity. Very similar features have been observed with
3 and 4 upon similar treatment (Figures S9 and S10).
Therefore, from these experiments, the best reaction con-
ditions for the maximum oxidation of methyl phenyl sulfide
are considered to be: substrate (1.24 g, 10 mmol), catalyst
(0.015 g), H2O2 (2.27 g, 20 mmol) and petroleum ether
(10 mL). The other substrate (diphenyl sulfide) with 1 as
catalyst precursor under the above reaction conditions, as
well as the other catalyst precursor 2 for both substrates,
was also tested, and the corresponding results are summa-
rised in Table 4.
Figure 8. Spectral changes obtained during titration of 20 mL of a
6.535ϫ10–5  methanolic solution of Cs2[CH2{VVO2(sal-inh)}2]·
2H2O (5) with HCl gas saturated in methanol; the spectra were
recorded after the successive additions of one-drop portions.
From Table 4, it is clear that more than 99% of methyl
As done by other authors for other systems,[34,49–51] we phenyl sulfide was converted into products using both cata-
interpret these results in terms of the formation of an oxido/ lysts, whereas diphenyl sulfide was only converted by 62.8–
hydroxido species [CH2{VO(OH)(L)}2]. It is also possible 68.4% under the conditions used. Normally, two major
that the ligand might become protonated, complexes products, sulfoxide and sulfone, were obtained in major
[CH2{VO2(HL)(S)}2] being formed. Protonation of the hy- yield along with only small amounts (Ͻ0.4%) of an un-
drazone nitrogen atom has been reported, for example, for identified product. The selectivity of the major product
the structurally characterised complex [VO(Hsal-bhz)] (sulfone) is about 85%, whereas that of sulfoxide is about
(H2sal-bhz derives from salicylaldehyde and benzoyl hydra- 15% in all cases. In the absence of the catalyst, the reaction
zide), which forms on treatment of the corresponding an- mixture gave 35.3% conversion of methyl phenyl sulfide
ionic dioxido complex with HCl,[42] as well as for complex with 65.5% selectivity towards sulfoxide, 34.2% towards
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Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes
Table 4. Percent conversion[a] of methyl phenyl sulfide and diphenyl sulfide along with the turnover frequency and selectivity of the
reaction products after 7 h of reaction time.
Entry
Catalyst
Substrate[b]
Conversion [%]
TOF [h–1]
Selectivity [%]
Sulfone
Sulfoxide
Others
1
2
3
4
1
1
2
2
mps
dps
mps
dps
99.6
68.4
99.2
62.8
62.6
45.0
62.4
39.4
16.8
15.4
13.3
14.3
82.5
84.5
86.3
85.4
0.2
0.2
0.4
0.4
[a] Reaction conditions: substrate (10 mmol), catalyst (0.015 g), H2O2 (2.27 g, 20 mmol) and petroleum ether (10 mL), room temperature.
[b] mps = methyl phenyl sulfide, dps = diphenyl sulfide.
sulfone and about 0.3% of an unidentified product. Blank
reaction with diphenyl sulfide under the above reaction con-
ditions gave about 5% conversion with a sulfoxide/sulfone
selectivity of 57:43. Thus, catalysts not only improve the
conversion of substrates, they alter the selectivity of the
products as well.
The conversion of methyl phenyl sulfide and the selectiv-
ity of different reaction products with 1 as catalyst under
the optimised reaction conditions have been analysed as a
function of time and are presented in Figure 9. It is clear
from the plot that the formation of methyl phenyl sulfoxide
Figure 9. Conversion of methyl phenyl sulfide and variation in the
is good (75.6%) at the beginning but decreases considerably
selectivity of different reaction products as a function of time with
1 as catalyst: (a) conversion of methyl phenyl sulfide, (b) selectivity
of methyl phenyl sulfoxide, (c) selectivity of methyl phenyl sulfone
and (d) other unidentified product.
with time, being 16.8% after 7 h of reaction. The selectivity
of methyl phenyl sulfone is 24.2% after 1 h of reaction time
and reaches 83.0% after 7 h. The unidentified product,
which is only in a minor amount, remains nearly constant
throughout.
oxidative bromination of salicylaldehyde to give 5-bromo-
salicylaldehyde, 3,5-dibromosalicylaldehyde and 2,4,6-trib-
romophenol by using H2O2/KBr in the presence of HClO4
in aqueous solution at room temp. (cf. Scheme 4).
Oxidative Bromination of Salicylaldehyde
It is known that vanadium(V) complexes can also act as
functional models of vanadium-dependent haloperoxidases,
catalysing the oxidative bromination of organic substrates
in the presence of H2O2 and bromide ion.[46,47,49,54] During
oxidation, the vanadium complex reacts with 1 or 2 equiv.
of
H2O2,
forming
oxidomono(peroxido)
{[CH2-
{VVO(O2)(L)}2]2–, CIII} or oxido(peroxido) {[VVO(O2)]+,
CIV} or oxidobis(peroxido) (CV) species (vide supra). Spe-
Scheme 4. Oxidation products of salicylaldehyde.
cies CIII (Scheme 3) or its protonated form ultimately oxi-
After several trials, the best suited reaction conditions
–
dises bromide species (to Br2, Br3 and/or HOBr), the bro- obtained for the maximum conversion of salicylaldehyde in
mination of the substrate then proceeding with the libera- 7 h of reaction time were: salicylaldehyde (2.44 g, 20 mmol),
tion of a proton.[50] We have found that the dioxidovanadi- KBr (5.95 g, 50 mmol), aqueous 30% H2O2 (13.62 g,
um(V) complexes reported here satisfactorily catalyse the 120 mmol), catalyst (0.020 g for 4 and 5 or 0.016 g for 3),
Table 5. Conversion of salicylaldehyde and selectivity of oxidative brominated product data after 7 h of contact time.[a]
Entry
Catalyst
Substrate/H2O2 ratio
TOF [h–1]
Selectivity of products
Conversion [%]
Monobromo
Dibromo
Tribromo
1
2
3
4
5
6
7
8
9
5
5
5
5
5
3
3
4
4
1:2
1:3
1:4
1:5
1:6
1:2
1:4
1:2
1:4
89.4
88.7
91.0
92.7
94.5
87.2
93.1
86.8
91.8
122
121
125
127
129
120
128
119
126
71.5
69.3
51.7
28.8
12.9
78.1
50.4
76.3
57.3
26.3
27.9
42.8
59.4
64.9
19.8
41.3
19.1
39.2
2.1
2.8
5.5
11.8
22.2
2.1
8.3
4.6
3.5
[a] Other reaction conditions: salicylaldehyde (2.44 g, 20 mmol), KBr (5.95 g, 50 mmol), catalyst (0.020 g for 4 and 5 or 0.016 g for 3),
aqueous 70% HClO4 (11.44 g, 80 mmol) and water (40 mL).
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FULL PAPER
aqueous 70% HClO4 (11.44 g, 80 mmol) and water by EPR and 51V NMR spectroscopy. Upon titration with
(40 mL); the addition of HClO4, however, in four equal H2O2, complexes are oxidised and generate signals at δ =
portions during the first 2 h of reaction time was necessary –538, –597 and –649 ppm [dioxido complex CII, peroxido
to improve the conversion of the substrate and to avoid de- complex CIII, peroxido CIV and bis(peroxido) CV]. The
composition of catalyst. Under the above conditions, a addition of sulfide consumes the intermediates formed and
maximum of 89.4% conversion was achieved with yields only one 51V NMR signal, at δ = –539 ppm, corre-
Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5), and at least three sponding to the dioxidovanadium(V) complex CII. This
products were identified (see Table 5). Increasing the supports the involvement of these intermediate species dur-
amount of oxidant improves the conversion of salicylalde- ing the catalytic process, namely the hydroperoxido form of
hyde. However, the selectivity of 5-bromosalicylaldehyde CIII. The catalytic cycle for oxidation of methyl phenyl sul-
decreases considerably, whereas those of 3,5-dibromosali- fide (as a model reaction), proposed previously by several
cylaldehyde and 2,4,6-tribromophenol increase. The pres- authors,[55–57] is also given in Scheme 5.
ence of excess H2O2 facilitates the formation of more and
more HOBr, which ultimately helps in the further oxidative
bromination of salicylaldehyde in other position(s). Cata- Antiamoebic Activity
lysts 3 and 4 gave very similar results. The counterions (Cs+
Dioxidovanadium (V) complexes along with ligands I
and II were screened for antiamoebic activity in vitro
against the HM1:IMSS strain of E. histolytica. The IC50
values are in the micromolar range and are shown in
or K+) did not much affect the conversion. In the absence
of the catalyst, the reaction mixture gave about 4% conver-
sion of salicylaldehyde.
Table 6. The data are presented in terms of percentage
growth inhibition related to untreated controls and plotted
Mechanism of Bromination and Sulfide Oxidation
Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4), Cs2[CH2{VVO2- as percentage inhibition versus logarithm of the dose con-
(sal-inh)}2]·2H2O (5) and K2[CH2{VVO2(sal-nah)}2]·2H2O centration. The IC50 values were obtained by interpolation
(3) were used as catalysts to carry out oxidative bromina- in the corresponding dose response curves. Complexes
tions, and a global outline of the reaction is presented in K2[CH2{VVO2(sal-nah)}2]·2H2O (3) (IC50 = 0.47 µ) and
Scheme 5. The formation of intermediates proposed in the Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5) (IC50 = 0.32 µ) cause
catalytic cycles, that is, hydroxidooxido complexes such as a marked inhibition, whereas ligands I (IC50 = 8.97 µ) and
[CH2{VVO(OH)(L)}2] (CVI), oxidoperoxido complexes II (IC50 = 7.61 µ) are less active than metronidazole. This
[CH2{VVO(O2)(L)}2]2– (CIII) and peroxido complex shows that complexation of the organic ligands to vana-
[VVO(O2)]+ (CIV), were confirmed on the basis of 51V dium substantially enhances the activity. It is plausible that
NMR spectroscopy and characteristics in the UV/Vis spec- complexation directly or indirectly favours permeation of
tra of the anionic dioxidovanadium precursor compounds the complexes through the lipid layer of the cell mem-
[CH2{VVO2(L)}2]2– (CI or CII), treated with acid and hy- brane.[58] The significance of the statistical difference be-
drogen peroxide, which ultimately oxidise bromide, possibly tween the IC50 values of metronidazole and the most active
through a hydroperoxido intermediate. The oxidised bro- complexes 3 and 5 was evaluated by a t test. The values of
–
mine species (Br2, Br3 and/or HOBr) then brominate the the calculated t were found to be higher than the table value
substrate.[47,54,55]
of t at the 4% level,[59] thus clearly demonstrating that the
Complexes [CH2{VIVO(sal-nah)(H2O)}2] (1) and vanadium complexes are potent inhibitors of the develop-
[CH2{VIVO(sal-nah)(H2O)}2] (2) were used for sulfoxida- ment of E. histolytica in vitro and that they are more active
tions, and we tried to investigate the intermediate species than the standard drug metronidazole.
Scheme 5. Outline of the catalytic processes.
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Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes
Table 6. Vanadium complexes, antiamoebic activity against HM1:IMSS strain of E. histolytica and toxicity profile of compounds 3 and
5.
Entry
Compound
Antiamoebic
IC50 [µM][a]
Toxicity profile
IC50 [µM][a]
S.D.[b]
S.D.[b]
1
2
3
4
5
6
CH2(H2sal-nah)2 (I)
CH2(H2sal-inh)2 (II)
8.97
7.61
0.47
4.34
0.32
1.89
0.01
0.02
0.01
0.05
0.03
0.03
N.D.
N.D.
150
N.D.
50
N.C.
N.C.
0.045
N.C.
0.015
0.050
K2[CH2{VVO2(sal-nah)}2]·2H2O (3)
Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4)
Cs2[CH2{VVO2(sal-inh)}2]·2H2O (5)
Metronidazole
Ͼ750
[a] The values were obtained from at least three separate assays done in duplicate. [b] Standard deviation; N.D., not done; N.C., not
calculated.
Toxicity of Compounds Assessed by the MTT Assay
3 was 0.47–250 µ/L and for compound 5 0.32–250 µ/L.
The viable cells were measured after 24, 48 and 72 h by
MTT assay. At 72 h, the IC50 of compounds 3 and 5 are
150 and 50 µ/L, respectively. The cell survival assay was
also performed in the presence of metronidazole and the
IC50 value was found to be more than 750 µ, as given in
Table 6. This shows that compounds 3 and 5 are more toxic
than metronidazole.
The cells were treated with various concentrations of
compounds 3 and 5 or vehicle (dmso) alone for 24, 48 and
72 h (as indicated in Figures 10 and 11). Cell survival was
determined by an MTT assay. Cell viability was calculated
as described in the Materials and Methods section, as the
mean from three independent experiments in which each
treatment was done in triplicate. To assess the survival ef-
fects of the compounds, human cervical (HeLa) cells were
used; 6000 cells per well in 200 µL of complete DMEM
medium were plated. Different concentrations of the dif-
ferent compounds were added to the wells as indicated in
Figures 10 and 11. The concentration range for compound
Conclusions
The hydrazones CH2(H2sal-nah)2 (I) and CH2(H2sal-
inh)2 (II) derived from 5,5Ј-methylenebis(salicylaldehyde)
[CH2(Hsal)2] and nicotinic acid hydrazide (nah) or isonicot-
inic acid hydrazide (inh) and their VIVO and VVO2 com-
plexes were synthesised and characterised. The complexes
are dinuclear in the solid state and in solution, but no sig-
nificant interactions are detected between the vanadium
centres.
Compounds [CH2{VVO2(sal-nah)}2]2– and [CH2{VVO2-
(sal-inh)}2]2– were shown to be functional models of vana-
dium-dependent haloperoxidases, satisfactorily catalysing
the oxidative bromination of salicylaldehyde to give 5-bro-
mosalicylaldehyde, 3,5-dibromosalicylaldehyde and 2,4,6-
tribromophenol by using H2O2/KBr in the presence of
HClO4 in aqueous solution at room temperature. The com-
plexes [CH2{VIVO(sal-nah)(H2O)}2] and [CH2{VIVO(sal-
inh)(H2O)}2] were shown to be catalyst precursors for the
catalytic oxidation, by peroxide, of methyl phenyl sulfide
and diphenyl sulfide, yielding the corresponding sulfoxide
and sulfone at room temperature.
Figure 10. Percentage of viable cells after 24, 48 and 72 h on human
cervical (HeLa) cells on incubation with various concentrations of
compound 3 or vehicle (dmso). Cell survival was determined by
the MTT assay.
The reactivity in methanol and dmso of the VIVO and
VVO2 complexes of CH2(H2sal-nah)2 (I) and CH2(H2sal-
inh)2 (II) was studied by UV/Vis, EPR and 51V NMR spec-
troscopy, by adding H2O2 or acid (HCl or HClO4) or both.
The formation of several species was established, some of
them probably being intermediates in the catalytic processes
studied, namely [CH2{VVO(O2)(L)}2]2– and [CH2{VVO-
(OH)(L)}2]. On addition of acid (HCl or HClO4) the VV
species present are partly reduced, yielding VIVO species
containing the {VIVO(sal-nah)(S)} and {VIVO(sal-inh)(S)}
moieties (S = solvent), the hydroxidooxido complex and a
51V-NMR-active species whose nature is suggested.
Figure 11. Percentage of viable cells after 24, 48 and 72 h on human
cervical (HeLa) cells on incubation with various concentrations of
compound 5 or vehicle (dmso). Cell survival was determined by
the MTT assay.
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FULL PAPER
medium (170 µL). Each test included metronidazole as the stan-
dard amoebicidal drug; control wells (culture medium plus amoe-
bae) were prepared from a confluent culture by pouring off the
medium, adding medium (2 mL) and chilling the culture on ice to
detach the organisms from the side of the flask. The number of the
amoeba per millilitre was estimated with a heamocytometer, and
trypan blue exclusion was used to confirm viability. The cell sus-
pension used was diluted to 105 organism/mL by adding fresh me-
dium, and 170 µL of this suspension was added to the test and
control well in the plate so that the wells were completely filled
(total volume, 340 µL). An inoculum of 1.7ϫ104 organisms/well
was chosen so that confluent, but not excessive, growth took place
in control wells. The plate was sealed with expanded polystyrene
(0.5 mm), secured with tape, placed in a modular incubating cham-
ber (flow laboratories, High Wycombe, UK) and gassed for 10 min
with nitrogen before incubation at 37 °C for 72 h.
Amoebiasis is caused by Entamoeba histolytica, the sec-
ond leading cause of death among parasite diseases. For the
treatment of amoebiasis metronidazole has been, until now,
the drug of choice. The VV complexes of CH2(H2sal-
nah)2 (I) and CH2(H2sal-inh)2 (II) were also screened
against HM1:1MSS strains of Entamoeba histolytica, the
results showing that they are significantly more active than
metronidazole. The MTT assay results showed that com-
pounds 3 and 5 are not much toxic against human cervical
(HeLa) cell lines.
Experimental Section
Materials: V2O5, isonicotinic acid hydrazide (Loba Chemie, India),
nicotinic acid hydrazide (Fluka Chemie, GmbH, Switzerland),
acetylacetone (Aldrich, USA), salicylaldehyde (Hsal), 30% aque-
ous H2O2 and 70% HClO4 (Qualigens, India) were used as ob-
tained. Other chemicals and solvents were of analytical reagent
grade. [VIVO(acac)2] was prepared according to the method re-
ported in the literature.[60]
Assessment of Antiamoebic Activity: After incubation, the growth
of amoebae in the plate was checked with a low-power microscope.
The culture medium was removed by inverting the plate and shak-
ing gently. The plate was then immediately washed once in 0.9%
NaCl at 37 °C. This procedure was completed quickly, and the plate
was not allowed to cool in order to prevent the detachment of
amoebae. The plate was allowed to dry at room temperature and
the amoebae were fixed with methanol, when dry, and stained with
0.5% aqueous eosin for 15 min. The stained plate was washed once
with tap water and then twice with distilled water and allowed to
dry. A 200-µL portion of 0.1  NaOH solutions was added in each
well to dissolve the protein and release the dye. The optical density
of the resulting solution in each well was determined at 490 nm
with a microplate reader. The percentage of inhibition of amoebal
growth was calculated from the optical densities of the control and
test wells and plotted against the logarithm of the dose of the drug
tested. Linear regression analysis was used to determine the best-
fit straight line from which the IC50 value was found.
Characterisation Procedures: Elemental analyses of the compounds
were carried out with an Elementar model Vario-El-III. IR spectra
were recorded as KBr pellets with a Nicolet NEXUS Aligent 1100
series FTIR spectrometer. Electronic spectra were measured in
methanol or dmf with a UV-1601 PC UV/Vis spectrophotometer.
1H NMR spectra were obtained with a Bruker 200, and 13C and
51V NMR spectra with a Bruker Avance III 400 MHz spectrometer
by using the common parameter settings. NMR spectra were usu-
ally recorded in [D4]MeOD or [D6]dmso, and δ(51V) values are ref-
erenced relative to neat VOCl3 as external standard. Thermogravi-
metric analyses of the complexes were carried out under oxygen by
using a TG Stanton Redcroft STA 780 instrument. The magnetic
susceptibilities were measured with a Vibrating Sample Magnetom-
eter model 155 by using nickel as standard. Diamagnetic correc-
tions were carried out by using Pascal’s constants.[61] EPR spectra
were recorded with a Bruker ESP 300E X-band spectrometer. The
spin Hamiltonian parameters were obtained by simulation of the
spectra with the computer program of Rockenbauer and Korecz.[44]
A Thermax Nicolet gas chromatograph fitted with a HP-1 capillary
column (30 mϫ0.25 mmϫ0.25 µm) and FID detector was used to
analyse the reaction products, and their quantifications were made
on the basis of the relative peak area of the respective product. The
identity of the products was confirmed by using a GC–MS model
Perkin–Elmer Clarus 500 and comparing the fragments of each
product with the library available.
MTT Toxicity: The human cervical (HeLa) cells were obtained
from NCCS (Pune, India). The cells were cultured in DMEM (Invi-
trogen) with 10% foetal bovine serum and 1% penicillin/streptomy-
cin. The effect of active compounds 3 and 5, and the standard drug
(metronidazole) on cell proliferation was measured by using an
MTT-based assay.[66] Briefly, the cells (6000/well) were incubated in
triplicate in a 96-well plate in the presence of various concentra-
tions of compounds 3 and 5 as well as metronidazole or vehicle
(dmso) alone in a final volume of 200 µL at 37 °C in a humidified
chamber for different time lengths (24, 48 and 72 h). At the end of
each time point, 20 µL of MTT solution (5 mg/mL in PBS) was
added to each well, and the cells were incubated at 37 °C in a hu-
midified chamber for 4 h. After 4 h, the supernatant was removed
from each well. The coloured formazan crystal produced from
MTT was dissolved in 200 µL of dmso, and then the absorbance
(A) value was measured at 570 nm by a multiscanner autoreader.
The following formula was used for the calculation of the percen-
tage of cell viability (CV): CV (%) = (A of the experimental sam-
ples/A of the control)ϫ100.
In Vitro Testing against E. histolytica: The ligands and their diox-
idovanadium(V) complexes 3–5 were screened in vitro for anti-
amoebic activity against the HM1:1MSS strain of E. histolytica
by using a microplate method.[62] E. histolytica trophozoites were
cultured in TYIS-33 growth medium in a 96-well microtitre
plate;[63] dmso (40 µL) was added to all the samples (1 mg) followed
by enough culture medium to obtain a concentration of 1 mg/mL.
The maximum concentration of dmso in the tests did not exceed
0.1%, at which level no inhibition of amoebal growth oc-
curred.[64,65] 1H NMR spectra of all complexes in [D6]dmso were
recorded to test whether the solvent induced any ligand solvolysis,
but all were found to be stable at room temperature for several
days. Samples were dissolved or suspended by mild sonication in a
Sonicleaner bath for a few minutes and then further dilution with
medium to a concentration of 0.1 mg/mL. Twofold serial dilutions
were made in the wells of a 96-well microtitre plate (Costar) in the
Preparations
CH2(H2sal-nah)2 (I) and CH2(H2sal-inh)2 (II): Ligands CH2(H2sal-
nah)2 (I) and CH2(H2sal-inh)2 (II) were prepared according to the
literature procedure with slight modifications.[67] A solution of 5,5Ј-
methylenebis(salicylaldehyde) (2.65 g, 10 mmol) was prepared in
hot methanol (40 mL) and was added to a solution of appropriate
hydrazide (2.743 g, 20 mmol) dissolved in methanol (20 mL) with
stirring. The obtained reaction mixture was refluxed on a water
bath for 2 h. After reducing the solvent volume to about 30 mL
5388
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2009, 5377–5390

Dinuclear Oxidovanadium(IV) and Dioxidovanadium(V) Complexes
and cooling to about 10 °C, the solid obtained was filtered, washed
with methanol and dried in a desiccator over silica gel.
nah)2}]·2H2O. Yield 0.682 g (74.0%). C27H22Cs2N6O10V2 (958.20):
calcd. C 33.84, H 2.31, N 8.77; found C 33.87, H 2.34, N 8.71. 51
V
NMR [300 MHz, (CD3)2SO, 25 °C]: δ = –532 ppm.
Data for CH2(H2sal-nah)2 (I): Yield 5.67 g (91%). C27H22N6O4
(494): calcd. C 65.56, H 4.49, N 17.00; found C 65.36, H 4.41, N
17.22.
Catalytic Reactions
Oxidation of Methyl Phenyl Sulfide and Diphenyl Sulfide: Methyl
phenyl sulfide (1.24 g, 10 mmol) or diphenyl sulfide (1.86 g,
10 mmol) and aqueous 30% H2O2 (2.27 g, 20 mmol) were added
to petroleum ether (10 mL). After addition of catalyst precursors
[oxidovanadium(IV) complexes 1 or 2, 0.020 g] to the above mix-
ture, the reaction mixture was stirred at room temperature for 7 h.
During this period, the products formed were analysed by gas
chromatography withdrawing small aliquots at fixed time intervals
and the identity of the products confirmed using GC–MS.
Data for CH2(H2sal-inh)2 (II): Yield 5.76 g (92%). C27H22N6O4
(494): calcd. C 65.56, H 4.49, N 17.00; found C 65.42, H 4.44, N
17.13.
[CH2{VIVO(sal-nah)(H2O)}2] (1): A solution of CH2(H2sal-nah)2
(0.494 g, 1 mmol) was prepared by refluxing in dry methanol
(80 mL) and filtered. A filtered solution of [VIVO(acac)2] (0.530 g,
2 mmol) in dry methanol (15 mL) was added to the above solution
while stirring and the reaction mixture was refluxed by means of a
water bath for 3 h. After reducing the volume to about 20 mL and
keeping at room temperature for 10 h, the separated brown solid
was filtered, washed with methanol and dried in a desiccator over
Oxidative Bromination of Salicylaldehyde: Complexes K2[CH2-
{VVO2(sal-nah)}2]·2H2O, Cs2[CH2{VVO2(sal-nah)}2]·2H2O and
Cs2[CH2{VVO2(sal-inh)}2]·2H2O were used as catalysts to carry out
silica gel. Yield: 0.451 g (72.3%). µeff(293 K)
= 1.71 µΒ.
oxidative bromination. In
a typical reaction, salicylaldehyde
C27H22N6O8V2 (660.39): calcd. C 49.11, H 3.36, N 12.73; found C
49.0, H 3.41, N 12.52.
(2.44 g, 20 mmol) was added to an aqueous solution (40 mL) of
KBr (5.95 g, 50 mmol), followed by addition of aqueous 30% H2O2
(13.62 g, 120 mmol) in a 100-mL reaction flask. The catalyst (0.02 g
for 4 and 5, and 0.016 g for 3) and 70% HClO4 (2.86 g, 20 mmol)
were added, and the reaction mixture was stirred at room tempera-
ture. Three additional 20-mmol portions of 70% HClO4 were fur-
ther added to the reaction mixture in three equal portions at half-
hour intervals under continuous stirring. After 7 h, the white prod-
uct that had separated was filtered off, washed with water and
dried. The crude mass was dissolved in CH2Cl2; insoluble material,
if any, was removed by filtration, and the solvent evaporated. A
CH2Cl2 solution of this material was subjected to gas chromatog-
raphy and the identity of the products confirmed by GC–MS.
[CH2{VIVO(sal-inh)(H2O)}2] (2): Complex 2 was prepared from
[VIVO(acac)2] (0.530 g, 2 mmol) and CH2(H2sal-inh)2 (0.494 g,
1 mmol) according to the method outlined for 1. Yield: 0.505 g
(80.9%). µeff(293 K) = 1.70 µΒ. C27H22N6O8V2 (660.39): calcd. C
49.11, H 3.36, N 12.73; found C 48.92, H 3.46, N 12.63.
K2[CH2{VVO2(sal-nah)}2]·2H2O (3). Method A: A mixture of
[CH2{VIVO(sal-nah)(H2O)}2] (0.312 g, 0.5 mmol) and KOH
(0.068 g, 1.2 mmol) in methanol (25 mL) was refluxed for 2 h and
then left for aerial oxidation as well as slow evaporation of the
solvent at room temperature. Complex 3 slowly precipitated in
about 3 d. This was filtered off, washed with cold methanol and
dried in a desiccator over silica gel. Yield: 0.265 g (72.0%). Method
B: A solution of CH2(H2sal-nah)2 (0.494 g, 1 mmol) dissolved in
aqueous KOH (0.224 g, 4 mmol) was added with stirring to a fil-
tered aqueous solution of KVO3 prepared in situ by dissolving va-
nadium(V) oxide (0.20 g, 2 mmol) in KOH (0.112 g, 2 mmol). The
pH of the reaction mixture was adjusted to about 7.5 by adding
Supporting Information (see footnote on the first page of this arti-
cle): IR, 1H and 13C NMR spectra of complexes, details of solution
studies of complexes 3 and 4, figures dealing with the details of the
optimisation of the reactions conditions for the catalytic reactions.
HCl (4 ). The yellow solid of 3 started to separate and was filtered Acknowledgments
after 2 h of stirring, washed with water and dried. Yield 0.512 g
(69.7%). C27H22K2N6O10V2 (770.59): calcd. C 42.08, H 2.88, N M. R. M. and A. A. K. are thankful to the Council of Scientific
10.91; found C 41.82, H 2.73, N 10.83. 51V NMR [300 MHz, (CD3)2-
SO, 25 °C]: δ = –533 ppm.
and Industrial Research for financial support. J. C. P. and A. K.
thank the Portuguese NMR Network (IST-UTL Center) and the
POCI 2010, FEDER, Fundação para a Ciência e Tecnologia
(SFRH/BPD/34835/2007) for financial support.
Cs2[CH2{VVO2(sal-nah)}2]·2H2O (4). Method A: A filtered solution
of [VIVO(acac)2] (0.463 g, 1.75 mmol) in methanol (15 mL) was
added while stirring to a solution of CH2(H2sal-nah)2 (0.321 g,
0.65 mmol) prepared as reported for 1 in methanol (80 mL). After
adding CsOH·H2O (0.300 g, 1.78 mmol), the reaction mixture was
refluxed for 2 h. The dark red solution obtained was allowed to
stand for aerial oxidation and became yellow within 24 h. After
reducing the volume to about 10 mL and keeping at room tempera-
ture, complex 4 separated within 24 h. This was filtered off, washed
with cold methanol and dried in a desiccator over silica gel. Yield
0.653 g (70.8%). C27H22Cs2N6O10V2 (958.20): calcd. C 33.84, H
2.31, N 8.77; found C 33.66, H 2.37, N 8.81. 51V NMR [300 MHz,
(CD3)2SO, 25 °C]: δ = –532 ppm. Method B: A mixture of
[CH2{VIVO(sal-nah)(H2O)}2] (0.312 g, 0.5 mmol) and CsOH·H2O
(0.202 g, 1.2 mmol) in methanol (25 mL) was refluxed for 2 h and
then left for aerial oxidation as well as slow evaporation of the
solvent at room temperature. Complex 4 slowly precipitated in
about 3 d. The rest of the procedure was the same as for method
A. Yield 0.39 g (84.6)%.
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Received: July 20, 2009
Published Online: October 29, 2009
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Eur. J. Inorg. Chem. 2009, 5377–5390