Spectroscopic and potentiometric characterization of oxovanadium(IV) complexes formed by 3-hydroxy-4-pyridinones. Rationalization of the influence of basicity and electronic structure of the ligand on the properties of V IVO species in aqueous solution

Article abstract of DOI:10.1021/ic0605571

Aqueous solution studies regarding the identification and characterization of complexes formed by the V^IVO ion and 11 3-hydroxy-4-pyridinone derivatives have been performed using EPR and UV/vis spectroscopic techniques. For the three ligands (HL) adequately soluble in water (1-methyl-3-hydroxy-4- pyridinone, 1-methyl-2-ethyl-3-hydroxy-4-pyridinone, and 1,2-diethyl-3-hydroxy- 4-pyridinone), potentiometric titrations were performed; the results are consistent with the formation of [V^IVOL]⁺, [V ^IVOL₂], [V^IVOL₂H_-1] ^-, [(V^IVO)₂L₂H_-2], and [V^IVL₃]⁺ species. Bis chelated complexes are characterized by a cis-trans isomerism, the trans isomer being strongly favored with respect to the cis arrangement. Tris chelated non-oxo V^IV species were prepared in CH₃COOH; their spectroscopic features point to a d_z² ground state and a geometry intermediate between an octahedron and a trigonal prism, related to the steric requirements of the substituent on the carbon atom in position 2 of the pyridinone ring. Four new solid derivatives, [V^IVO(1,2-diethyl-3-hydroxy-4-pyridinonato) ₂], [V^IVO(1-(p-tolyl)-2-ethyl-3-hydroxy-4-pyridinonato) ₂], [V^IVO-(1-(p-(n-butyl)phenyl)-2-ethyl-3-hydroxy-4- pyridinonato)₂], and [V^IVO(1-(p-(n-hexyl)phenyl)-2-ethyl- 3-hydroxy-4-pyridinonato)₂], were isolated and characterized; they exhibited a five-coordinate geometry close to square-pyramid. A criterion for establishing the degree of distortion toward the trigonal-bipyramid on the basis of the electronic absorption spectra is provided. Relationships between the pK_a of the -OH group in position 3 of the ring and (i) log K of mono and bis chelated complexes, (ii) pK of the water molecule in cis-[V ^IVOL₂(H₂O)], (iii) log K of tris chelated species [V^IVL₃]⁺, and (iv) ⁵¹V hyperfine coupling constant (A_z) have been established and discussed for a number of pyrone, pyridinone, and catechol ligands. The results are rationalized by assuming for pyridinones an electronic structure intermediate between that of pyrones and catechols. The relationships are valuable to the understanding of the behavior of V^IVO species in aqueous solution.

Full text of DOI:10.1021/ic0605571

Inorg. Chem. 2006, 45, 8086−8097
Spectroscopic and Potentiometric Characterization of Oxovanadium(IV)
Complexes Formed by 3-Hydroxy-4-Pyridinones. Rationalization of the
Influence of Basicity and Electronic Structure of the Ligand on the
Properties of VIVO Species in Aqueous Solution
Maria Rangel, Andreia Leite, and M. Joa˜o Amorim
REQUIMTE, Instituto de Cieˆncias Biome´dicas de Abel Salazar, UniVersidade do Porto,
Largo Abel Salazar 2, 4099-003 Porto, Portugal
Eugenio Garribba* and Giovanni Micera*
Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via Vienna 2, I-07100 Sassari, Italy
Elzbieta Lodyga-Chruscinska
Institute of General Food Chemistry, Technical UniVersity of Lodz, ulice Stefanowskiego 4/10,
PL-90924 Lodz, Poland
Received April 3, 2006
Aqueous solution studies regarding the identification and characterization of complexes formed by the VIVO ion
and 11 3-hydroxy-4-pyridinone derivatives have been performed using EPR and UV/vis spectroscopic techniques.
For the three ligands (HL) adequately soluble in water (1-methyl-3-hydroxy-4-pyridinone, 1-methyl-2-ethyl-3-hydroxy-
4-pyridinone, and 1,2-diethyl-3-hydroxy-4-pyridinone), potentiometric titrations were performed; the results are
consistent with the formation of [VIVOL]+, [VIVOL2], [VIVOL2H-1]-, [(VIVO)2L2H-2], and [VIVL3]+ species. Bis chelated
complexes are characterized by a cis−trans isomerism, the trans isomer being strongly favored with respect to the
cis arrangement. Tris chelated non-oxo VIV species were prepared in CH3COOH; their spectroscopic features point
2
to a dz ground state and a geometry intermediate between an octahedron and a trigonal prism, related to the
steric requirements of the substituent on the carbon atom in position 2 of the pyridinone ring. Four new solid
derivatives, [VIVO(1,2-diethyl-3-hydroxy-4-pyridinonato)2], [VIVO(1-(p-tolyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], [VIVO-
(1-(p-(n-butyl)phenyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], and [VIVO(1-(p-(n-hexyl)phenyl)-2-ethyl-3-hydroxy-4-pyri-
dinonato)2], were isolated and characterized; they exhibited a five-coordinate geometry close to square-pyramid. A
criterion for establishing the degree of distortion toward the trigonal-bipyramid on the basis of the electronic absorption
spectra is provided. Relationships between the pKa of the −OH group in position 3 of the ring and (i) log K of mono
and bis chelated complexes, (ii) pK of the water molecule in cis-[VIVOL2(H2O)], (iii) log K of tris chelated species
[VIVL3]+, and (iv) 51V hyperfine coupling constant (Az) have been established and discussed for a number of pyrone,
pyridinone, and catechol ligands. The results are rationalized by assuming for pyridinones an electronic structure
intermediate between that of pyrones and catechols. The relationships are valuable to the understanding of the
behavior of VIVO species in aqueous solution.
Introduction
of the element became an intensive field of research in the
last decades of the 20th century, after being identified in
biological systems2 and related with potential therapeutic
properties.3
VIV complexes are most commonly observed in the form
of compounds of the vanadyl ion, VO2+.4 Many complexes
are formed by bidentate ligands with a variety of donor
Vanadium is an element with a very rich chemistry that
forms an enormous variety of compounds in which the most
important oxidation states are +3, +4, and +5.1 The study
* To whom correspondence should be addressed. E-mail: garribba@uniss.it
(E.G.).
8086 Inorganic Chemistry, Vol. 45, No. 20, 2006
10.1021/ic0605571 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/06/2006

VIVO Complexes Formed by 3-Hydroxy-4-Pyridinones
sets such as (O, O), (O, N), (O, S), (N, N), (N, S), and (S,
S), in which the coordinating atoms belong to different
functional groups.1,4,5 The most common geometry observed
for VIVOL2 complexes is the square-pyramidal, although
distortions toward a trigonal-bipyramidal structure have been
reported for some bidentate ligands.6,7 For VIVOL2 species,
there is the possibility of cis-trans isomerism, where cis is
the bis chelated complex in which the two ligand molecules
adopt an (equatorial-equatorial) and an (equatorial-axial)
arrangement with respect to the VdO bond and one solvent
molecule is coordinated in the fourth equatorial position;
trans is the complex in which both ligand molecules adopt
an (equatorial-equatorial) arrangement with respect to VdO
group.5 Non-oxo (so-called “bare”) VIV centers hold im-
portant biological functions and have been reported for
amavadin8 and for the cofactor in vanadium nitrogenase,9
but only a few such complexes have been fully characterized
in comparison with VIVO species.10
spectroscopic parameters and the degree of distortion toward
the two possible geometries for the complexes.6,7
Vanadium plays an important role in life and one of its
most relevant properties identified thus far is its capacity to
act as an insulin-enhancing agent, either in the form of its
inorganic salts or complexed with organic ligands.3 Among
the several complexes exhibiting the latter properties, [VIVO-
(maltolato)2] (BMOV) has been extensively analyzed from
a chemical and pharmacological point of view.14,15 Up to
this time, many ligands of the 3-hydroxy-4-pyrone type have
been studied, mostly by Orvig and his research group;16
particularly, [VIVO(ethylmaltolato)2] (BEOV) has completed
phase I clinical trials in humans.17
Replacement of the O atom in the pyrone ring of
3-hydroxy-4-pyrone by a N-R group yields 3-hydroxy-4-
pyridinone derivatives.18 Pyridinone ligands can be obtained
by the reaction of pyrones with the appropriate amines and,
like pyrones, can act as anionic bidentate ligands with the
set (O, O) forming stable complexes, mainly with many
trivalent metal ions,19 such as FeIII,20 AlIII,20a,21 GaIII,21b,21c,21e,22
and InIII,22a,23 but also with divalent ions.24 Pyridinones have
Several spectroscopic techniques are available for the
characterization of VIV species.11 EPR spectroscopy (mainly
in conjunction with UV/vis) has revealed itself to be the most
powerful tool not only for structurally characterizing VIV
complexes12,13 but also for identifying the presence of isomers
in certain solvents and establishing relationships between the
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Inorganic Chemistry, Vol. 45, No. 20, 2006 8087

Rangel et al.
Scheme 1. Ligands
recently been tested and proposed as promising orally
effective chelators for FeIII and AlIII removal,25 and the
compound 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdmpp or
DHP), commercially known as Deferiprone, is currently used
in the treatment of â-thalassaemia, a genetic disorder to
which an iron-overload is associated.25a-25d,25f From the
synthetic point of view, 3-hydroxy-4-pyridinones are much
more versatile than 3-hydroxy-4-pyrones, as the modification
of the side-chain on the nitrogen atom and of the substituents
on the six-membered ring allows for a fine-tuning of the
hydrophilic/lipophilic balance, a factor that is crucial for in
vivo transport properties.21d
Complexation of VIVO26-28 and VVO2 ions29,30 with 1,2-
dimethyl-3-hydroxy-4-pyridinone (Hdmpp) was studied in
aqueous solution by potentiometric and spectroscopic meth-
ods. VIVO readily forms various mono and bis complexes,
[VIVOL]+, [VIVOL2], and [VIVOL2H-1]-, with the bis che-
lated [VIVOL2] species being predominant in the pH range
4-9.26-28 The species of composition [VIVOLH-1], first
proposed,26,27 was better explained in a later study in terms
of an EPR-silent dinuclear species [(VIVO)2L2H-2].28 By
means of simultaneous potentiometric and spectrophotomet-
ric titrations, Taylor also detected and characterized a minor
non-oxo species [VIVL3]+,26 confirmed by the recent data of
Buglyo´ et al.28 Under aerobic conditions, [VIVO(dmpp)2] is
slowly oxidized to [VVO2(dmpp)2]-.26,30 Some bis chelated
VIVO pyridinonate complexes were characterized in the solid
state by spectroscopic techniques (UV/vis, EPR, and EX-
AFS),31 and the geometry of the [VIVOL2] species was
described as being slightly distorted square-pyramidal.
The insulin-enhancing properties of [VIVOL2] compounds
formed by 3-hydroxy-4-pyridinones were recently tested in
vitro by Rangel et al., who found that they are effective in
terms of free fatty acid release from isolated rat adipocytes
and have a significantly better insulin-mimetic activity than
VOSO4.32 A study on the interaction of [VIVO(dmpp)2] with
low-molecular-mass binders present in extra- or intracellular
biofluids revealed that, unlike the systems with [VIVO-
(maltolato)2], [VIVO(picolinato)2(H2O)], and [VIVO(6-methyl-
picolinato)2],33 the transformation of binary into ternary
complexes is almost negligible, also in the presence of a
strong ligand as citrate.28 Only serum transferrin can ef-
ficiently compete with Hdmpp for VIVO binding.
In the present work, we investigated, through the combined
application of spectroscopic (EPR and UV/vis) and poten-
tiometric techniques, the formation of VIVO complexes with
11 pyridinone derivatives (Scheme 1). For the ligands
adequately soluble in water (Hmpp, Hempp, Hdepp), po-
tentiometric titrations were performed and the speciation
diagrams as a function of pH were established. To the best
of our knowledge, no data have been reported in the literature
on these systems in aqueous solution. Four new solid
derivatives, [VIVO(depp)2], [VIVO(eptp)2], [VIVO(epbp)2], and
[VIVO(ephp)2], were isolated and characterized. The VIVO
3-hydroxy-4-pyridinonate complexes previously described by
one of us31 have been reexamined in a more exhaustive
spectroscopic study and the results obtained are compared
with those described for Hdmpp.26-28
(24) Clarke, E. T.; Martell, A. E. Inorg. Chim. Acta 1992, 191, 57-63.
(25) (a) Kontoghiorghes, G. J. Lancet 1985, 1, 817-818. (b) Kon-
toghiorghes, G. J.; Aldouri, M. A.; Hoffbrand, A. V.; Barr, J.; Wonke,
B.; Kourouclaris, T.; Sheppard, L. Br. Med. J. 1987, 295, 1509-1512.
(c) Kontoghiorghes, G. J. Br. Med. J. 1988, 296, 1672-1673. (d)
Olivieri, N. F.; Koren, G.; Hermann, C.; Bentur, Y.; Chung, D.; Klein,
J.; St Louis, P.; Freedman, M. H.; McClelland, R. A.; Templeton, D.
M. Lancet 1990, 336, 1275-1279. (e) Orvig, C. In Coordination
Chemistry of Aluminium; Robinson, G., Ed.; VCH Publishers: New
York, 1993; pp 85-120. (f) Liu, Z. D.; Hider, R. C. Coord. Chem.
ReV. 2002, 232, 151-171.
(26) Taylor, P. D. J. Chem. Soc., Chem. Commun. 1996, 405-406.
(27) Rangel, M. Transition Met. Chem. 2001, 26, 219-223.
(28) Buglyo´, P.; Kiss, E.; Kiss, T.; Sanna, D.; Garribba, E.; Micera, G. J.
Chem. Soc., Dalton Trans. 2002, 2275-2282.
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J. Inorg. Biochem. 2000, 80, 177-179.
(30) Castro, M. M. C. A.; Avecilla, F.; Geraldes, C. F. G. C.; de Castro,
B.; Rangel, M. Inorg. Chim. Acta 2003, 356, 142-154.
(31) Burgess, J.; De Castro, B.; Oliveira, C.; Rangel, M.; Schlindwein, W.
Polyhedron 1997, 16, 789-794.
(32) Rangel, M.; Tamura, A.; Fukushima, C.; Sakurai, H. J. Biol. Inorg.
Chem. 2001, 6, 128-132.
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80, 65-73.
8088 Inorganic Chemistry, Vol. 45, No. 20, 2006

VIVO Complexes Formed by 3-Hydroxy-4-Pyridinones
Table 1. pKa of the Ligands and Stability Constants of the VIV
Complexes (log â) at 25.0 ( 0.1 °C and I ) 0.1 M (KNO3)a
O
Experimental Section
Chemicals. The ligands were prepared according to procedures
described for 3-hydroxy-4-pyridinones.21e,34,35 All the other chemi-
cals were Aldrich products of puriss. quality. Their purity and their
concentration in solution were determined by the Gran method.36
VIVO solutions were prepared with VOSO4‚5H2O by following the
procedure described in the literature.37 All operations were per-
formed under a purified argon atmosphere in order to avoid
oxidation of the VIVO ion.
pKa/log â
ligand/complex
Hmpp
Hempp
Hdepp
-OH/-NpyrH+ (pKa1)
-OH (pKa2)
VOL
VOL2
VOL2H-1
3.50(2)
9.70(1)
3.69(2)
9.85(1)
3.78(1)
9.92(1)
12.05(1)
22.42(2)
11.95(2)
17.91(12)
37.95(1)
12.20(1)
22.90(1)
12.25(2)
19.51(16)
38.70(3)
12.30(1)
23.10(2)
12.35(1)
20.00(15)
39.10(1)
(VO)2L2H-2
VL3+‚H2O
Potentiometric Measurements. The deprotonation constants of
the ligands (pKa) and the stability constants of VIVO complexes
(log â) were determined by pH-potentiometric titrations of 2.0
mL samples. The ligand:metal molar ratio was in the range 1:1-
10:1, and the concentration of VIVO was 0.001 M. Measurements
were carried out at 25 ( 0.1 °C and at a constant ionic strength of
0.1 M KNO3 with a MOLSPIN pH meter equipped with a digitally
operated syringe (the Molspin DSI 0.250 mL) controlled by
computer. The titrations were performed with a carbonate-free
NaOH solution of known concentration (ca. 0.1 M) using a Russel
CMAWL/S7 semi-micro combined electrode, calibrated for hy-
drogen ion concentration by the method of Irving et al.38 The
number of experimental points was 100-150 for each titration
curve. The reproducibility of the titration points included in the
evaluation was within 0.005 pH units in the whole pH range
examined (2-12). The stability constants of the complexes, reported
a The uncertainties (σ values) of the stability constants are given in
parentheses.
V2O5, 17.4. Found: C, 64.36; H, 5.35; N, 5.21; H2O, 0.0; V2O5,
17.5. [VIVO(epbp)2]. Anal. Calcd for C34H40N2O5V (607.64): C,
67.21; H, 6.63; N, 4.61; H2O, 0.0; V2O5, 15.0. Found: C, 67.03;
H, 6.78; N, 4.44; H2O, 0.0; V2O5, 14.6. [VIVO(ephp)2]. Anal. Calcd
for C38H48N2O5V (663.75): C, 68.76; H, 7.29; N, 4.22; H2O, 0.0;
V2O5, 13.7. Found: C, 68.87; H, 7.10; N, 4.06; H2O, 0.0; V2O5,
14.0.
Preparation of [VIVL3]+ Complexes. [VIVOL2] complex (10
µM) was dissolved in 1 mL of concentrated CH3COOH. To the
solution was added 50 µM of ligand HL. The formation of the
[VIVL3]+ complex can be detected through UV/vis and EPR
spectroscopies. EPR spectra were recorded on a 0.01 M solution
of [VIVL3]+ and electronic absorption spectra by diluting the sample
to 0.25 mM. In particular, the absence of EPR signals in the ranges
2700-2800 and 3900-4000 G, which are assigned to VIVO species.
must be verified.
Spectroscopic and Analytical Measurements. Anisotropic EPR
spectra were recorded on aqueous solutions with an X-band (9.15
GHz) Varian E-9 spectrometer in the temperature range 120-140
K. The spectra were simulated with the computer suite program
Bruker WinEPR/SimFonia. Electronic spectra were obtained with
a Perkin-Elmer Lambda 9 spectrometer and deconvoluted with
Origin. Elemental analyses (C, H, N) were performed with a
Perkin-Elmer 240 B analyzer. The thermogravimetric studies,
which allowed the determination of the V2O5 and H2O contents,
were carried out with a Perkin-Elmer TGS-2 instrument under a
nitrogen atmosphere.
as the logarithm of the overall formation constants âpqr
)
[VOpLqHr]/[VO]p[L]q[H]r, where VO is the vanadyl ion, L is the
deprotonated form of the ligand, and H is the proton, were calculated
with the aid of the SUPERQUAD program.39 The conventional
notation has been used, and negative indices for H in the formulas
indicate the presence of hydroxo ligands. The following hydroxo
species of VIVO were taken into account in the calculations: [VIVO-
(OH)]+ (log â10-1 ) -5.94) and [(VIVO)2(OH)2]2+ (log â20-2
)
-6.95), with stability constants calculated from the data of Henry
et al.40 and corrected for the different ionic strengths by use of the
Davies equation,41 [VIVO(OH)3]- (log â10-3 ) -18.0) and
[(VIVO)2(OH)5]- (log â20-5 ) -22.0).42 The uncertainties (σ values)
of the stability constants are given in parentheses in Table 1.
Preparation of [VIVOL2] Complexes. [VIVOL2] complexes were
prepared by dissolving stoichiometric amounts of VOSO4‚5H2O
and the ligand in water, adjusting the pH to 9 with a diluted solution
of NaOH, and refluxing for about 1 h. The solids formed were
filtered when the solution was still warm and dried in vacuo over
P2O5. [VIVO(depp)2]. Anal. Calcd for C18H24N2O5V (399.34): C,
54.14; H, 6.06; N, 7.01; H2O, 0.0; V2O5, 22.8. Found: C, 54.35;
H, 5.97; N, 7.27; H2O, 0.0; V2O5, 23.2. [VIVO(eptp)2]. Anal. Calcd
for C28H28N2O5V (523.48): C, 64.24; H, 5.39; N, 5.35; H2O, 0.0;
Results
Determination of Acid-Base Properties of Ligands.
Potentiometric titrations were performed on the alkyl ligands
Hmpp, Hempp, and Hdepp, the only three ligands adequately
soluble in water. From the fully protonated ligands, two
stepwise deprotonation processes are observed in the pH
range that we are able to titrate. The values obtained for the
two acidity constants, designated as pKa1(H2L+) and pKa2-
(HL), are presented in Table 1, and the protonation equilibria
considered are shown in Scheme 2. When the differences in
the experimental conditions are taken into consideration, the
two pKa values determined for Hmpp, Hempp, and Hdepp
are in good agreement with published data.20d,21d,22a,22b,24,28
The values of the first pKa lie in the range 3.5-3.8 and
are in accord with the results previously reported.20d,21d,22a,22b,24,28
There is a common agreement in the literature that the
protonation of HL species takes place mainly on the
carbonyl-O rather than on the nitrogen-N of the ring. This
(34) Fa¨rber, M.; Osiander, H.; Severin, T. J. Heterocycl. Chem. 1994, 31,
947-956.
(35) Finnegan, M. M.; Rettig, S. J.; Orvig, C. J. Am. Chem. Soc. 1986,
108, 5033-5035.
(36) Gran, G. Acta Chem. Scand. 1950, 4, 559-577.
(37) Nagypa´l, I.; Fa´bia´n, I. Inorg. Chim. Acta 1982, 61, 109-113.
(38) Irving, H.; Miles, M. G.; Pettit, L. D. Anal. Chim. Acta 1967, 38,
475-481.
(39) Gans, P.; Vacca, A.; Sabatini, A. J. Chem. Soc., Dalton Trans. 1985,
1195-1200.
(40) Henry, R. P.; Mitchell, P. C. H.; Prue, J. E. J. Chem. Soc., Dalton
Trans. 1973, 1156-1159.
(41) Davies, C. W. J. Chem. Soc. 1938, 2093-2098.
(42) (a) Komura, A.; Hayashi, M.; Imanaga, H. Bull. Chem. Soc. Jpn. 1977,
50, 2927-2931. (b) Vilas Boas, L. F.; Costa Pessoa, J. In Compre-
hensiVe Coordination Chemistry; Wilkinson, G., Gillard, R. D.,
McCleverty, J. A., Eds.; Pergamon Press: Oxford, U.K., 1987; Vol.
3, pp 453-583.
Inorganic Chemistry, Vol. 45, No. 20, 2006 8089

Rangel et al.
Scheme 2. Protonation Steps of the Ligands
Figure 1. Species distribution for the VIVO/Hmpp system with a 1:3 metal:
ligand molar ratio and a VIVO concentration of 1 mM.
Table 2. EPR Parameters and Donor Sets for the VIVO Complexes in
Aqueous Solution
a
ligand
Hmpp
complex
VOL
cis-VOL2
trans-VOL2
gz
Az
donor set
was recently confirmed by a very slight change in the
chemical shifts of the methyl protons on the nitrogen atom
of Hdmpp.28 The pKa1 values obtained for the 3-hydroxy-
4-pyridinones are about 5 orders of magnitude higher than
those reported for 3-hydroxy-4-pyrones,43 and can be ex-
plained taking into account that in pyridinones the oxygen
in the heterocyclic ring is replaced by a nitrogen atom, which
is more efficient in delocalizing the positive charge in the
ring and favors the stabilization of the 3,4-dihydroxypyri-
dinium cation H2L+, a highly delocalized pseudo-aromatic
π electronic system (Scheme 2).
The values of pKa2 are in the range 9.7-9.9 (Table 1); a
comparison with those reported for two 3-hydroxy-4-pyrones
such as kojic acid (7.67) and maltol (8.44)44 shows that
pyridinones are stronger bases. The values for pyridinones
are related to the partially negatively charged oxygen in
position 4 of the ring, which confirms the contribution of
the zwitterionic form in the neutral form HL; this is due to
the transfer of the nitrogen lone pair to the carbonyl oxygen
in position 4 of the ring, which is promoted by the
re-establishment of the pseudo-aromatic character (Scheme
2).
The presence of different substituents in positions 1 and
2 of the pyridinone ring is reflected by the values of pKa
listed in Table 1, which indicate that the basicity of the
ligands increases in the order hydrogen < methyl < ethyl.
This is due to the electron-releasing properties of the alkyl
groups. However, the effect is smaller than 0.3 pKa units
and so does not affect the predominance of the neutral species
in a wide pH range, including physiological pH.
Characterization of Metal-Ligand Species in Aqueous
Solution. The potentiometric titrations performed in aqueous
solution suggest that a 1:2 metal:ligand molar ratio is
enough to prevent hydrolytic processes. The equilibrium
constants are shown in Table 1 and are consistent with a
model that assumes the [VIVOL]+, [VIVOL2], [VIVOL2H-1]-,
[(VIVO)2L2H-2], and [VIVL3]+ species. The order of stability
of all the complexes is Hdepp > Hempp > Hmpp and
1.939 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 166 [(O-, O-); (O-, O-ax); H2O]
1.950 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
Hempp VOL
cis-VOL2
trans-VOL2
1.939 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 166 [(O-, O-); (O-, O-ax); H2O]
1.950 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
Hdepp
Hppp
Hepp
Hptp
VOL
cis-VOL2
trans-VOL2
1.939 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 166 [(O-, O-); (O-, O-ax); H2O]
1.951 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.944 161 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.938 171 [(O-, O-); H2O; H2O; H2Oax]
1.940 167 [(O-, O-); (O-, O-ax); H2O]
1.950 159 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.939 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 166 [(O-, O-); (O-, O-ax); H2O]
1.950 159 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.939 171 [(O-, O-); H2O; H2O; H2Oax]
1.940 166 [(O-, O-); (O-, O-ax); H2O]
1.950 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
Heptp
Hpbp
Hepbp
Hphp
Hephp
VOL
cis-VOL2
trans-VOL2
1.938 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 167 [(O-, O-); (O-, O-ax); H2O]
1.951 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.944 161 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.938 171 [(O-, O-); H2O; H2O; H2Oax]
1.941 166 [(O-, O-); (O-, O-ax); H2O]
1.950 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.939 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 167 [(O-, O-); (O-, O-ax); H2O]
1.950 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.938 171 [(O-, O-); H2O; H2O; H2Oax]
1.940 167 [(O-, O-); (O-, O-ax); H2O]
1.950 159 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.943 162 [(O-, O-); (O-, O-ax); OH-]
VOL
cis-VOL2
trans-VOL2
1.939 170 [(O-, O-); H2O; H2O; H2Oax]
1.941 166 [(O-, O-); (O-, O-ax); H2O]
1.950 158 [(O-, O-); (O-, O-)]
cis-VOL2H-1 1.944 161 [(O-, O-); (O-, O-ax); OH-]
a Az measured in units of 1 × 10-4 cm-1
.
reflects the basicity of the ligands. The distribution diagram
for the binary system formed by VIVO and Hmpp is shown
in Figure 1.
The EPR data presented in Table 2 corroborate the
proposed set of equilibria and, as an example, the spectra
(43) Choux, G.; Benoit, R. L. J. Org. Chem. 1967, 32, 3974-3977.
(44) Buglyo´, P.; Kiss, E.; Fa´bia´n, I.; Kiss, T.; Sanna, D.; Garribba, E.;
Micera, G. Inorg. Chim. Acta 2000, 306, 174-183.
8090 Inorganic Chemistry, Vol. 45, No. 20, 2006

VIVO Complexes Formed by 3-Hydroxy-4-Pyridinones
from 80:20 to 90:10. These results are in agreement with
those previously reported28 and can be explained in terms
of a cis-trans equilibrium observed for several VIVO
systems, like those with malonate and oxalate,44 6-methylpi-
colinate,47 and 8-hydroxyquinolinate.48 A comparison be-
tween the experimental and calculated EPR parameters
suggests that the major species is the trans isomer, with the
four oxygen donors of the two ligand molecules occupying
the equatorial sites of VIVO ion. The spectral parameters are
comparable with those of the bis chelated species of catechol
and 3,4-dihydroxybenzoic acid,49 meaning that pyridinones
coordinate the VIVO ion with a donor set similar to that (O-,
O-) observed for catechols, rather than that (CO, O-) of
maltol.14a,14c,44 The weaker resonances in the pH range 4-10
are assigned to the cis isomer of the [VIVOL2] complex, in
which a water molecule in cis position with respect to the
VdO bond is coordinated in the equatorial plane and one
of the two ligand molecules adopts an (equatorial-axial)
coordination mode.
The deprotonation of the equatorial water in [VIVOL2]
yields a [VIVOL2H-1]- species (IV in Figure 2), with a
hydroxo ion in cis to the VdO group. The conversion from
cis-[VIVOL2(H2O)] to cis-[VIVOL2(OH)]- species is indicated
in the EPR spectra by the change of the gz and Az values.
Particularly, the parameters for cis-[VIVOL2H-1]- (gz )
1.943-1.944 and Az ) 161-162 × 10-4 cm-1, Table 2) are
those expected for a species with three deprotonated oxygen
donors and a OH- on the equatorial plane of the VIVO ion.
On the basis of the additivity rule, the replacement of a H2O
by a OH- donor should decrease Az by ∼(5-6) × 10-4
cm-1.45 As for Hdmpp,28 the pK values for the deprotonation
of the equatorially coordinated water molecule are rather
high, in the range 10.47-10.75, confirming that pyridinones
are stronger donors than kojate or maltolate.44
Figure 2. High-field region of the X-band anisotropic EPR spectra
recorded at 140 K as a function of pH on an aqueous solution of VIVO and
Hempp with a 1:2 metal:ligand molar ratio and a VIVO concentration of 4
mM. I, II, III, and IV denote the [VIVOL]+, cis-[VIVOL2], trans-[VIVOL2],
-
and cis-[VIVOL2H-1
]
complexes, respectively.
recorded for Hempp are displayed in Figure 2. At L:M ) 2,
the complexation starts at pH < 2 with the formation of the
[VIVOL]+ complex (I in Figure 2), characterized by gz in
the range 1.938-1.939 and Az in the range 170-171 × 10-4
cm-1 (Table 2). Az values, calculated with the additivity rule,
support an equatorial (O-, O-) coordination of the ligands.45
A significant improvement in the analysis of the data is
achieved by considering a dinuclear species with a
[(VIVO)2L2H-2] stoichiometry, mainly observed in equimolar
solution. The formation of such a species can be rationalized
in terms of the deprotonation of an equatorially coordinated
water molecule in [VIVOL]+ and the dimerization of the
resulting [VIVOL(OH)] unit according to the rule proposed
by Felcman and Frau´sto da Silva for the hydrolysis of VIVO
species.46 Its presence is confirmed by a significant loss in
intensity of the EPR signal in equimolar solution around pH
5.0, followed by the formation of a precipitate.
At L:M ) 2 or at higher ligand excess, the bis complexes
[VIVOL2] are the predominant species between pH 4 and 10.
In this pH range, the EPR spectra indicate a major (gz )
1.950-1.951 and Az ) 158-159 × 10-4 cm-1, III in Figure
2) and a minor species (gz ) 1.940-1.941 and Az ) 166-
167 × 10-4 cm-1, II in Figure 2). For each system, the ratio
between the intensities of the two signals remains unchanged
as a function of pH and, depending on the ligand, ranges
For all the systems, we observed an intense deep violet
color in the acidic pH range 2-4, suggesting the formation
of a tris chelated non-oxo VIV complex with 3 × (O-, O-)
donor set, as previously reported for catechol and its
derivatives,50 as well as for Hdmpp.26,28 The formation of
these non-oxo species, not observed with pyrone ligands,
reflects the stronger basic properties of pyridinones.
Synthesis and Characterization of Non-Oxo [VIVL3]+
Complexes. In aqueous solutions containing VIVO and
ligands at molar ratios as high as 1:100, EPR spectroscopy
indicates the formation of [VIVL3]+ species, which always
coexist with [VIVOL]+ and [VIVOL2]. Synthesis of the tris
chelated species may be achieved by dissolving the solid
[VIVOL2] in concentrated acetic acid containing an excess
of ligand. The acidic media induces the cleavage of the VdO
(47) Kiss, E.; Garribba, E.; Micera, G.; Kiss, T.; Sakurai, H. J. Inorg.
Biochem. 2000, 78, 97-108.
(48) Garribba, E.; Micera, G.; Sanna, D.; Chruscinska, E. Inorg. Chim.
Acta 2003, 348, 97-106.
(49) Jezowska-Bojczuk, M.; Koslowski, H.; Zubor, A.; Kiss, T.; Branca,
M.; Micera, G.; Dess`ı, A. J. Chem. Soc., Dalton Trans. 1990, 2903-
2907.
(45) Chasteen N. D. In Biological Magnetic Resonance; Berliner, L. J.; J.
Reuben, J. Eds.; Plenum Pess: New York, 1981; Vol. 3, pp 53-
119.
(50) Buglyo´, P.; Dess`ı, A.; Kiss, T.; Micera, G.; Sanna, D. J. Chem. Soc.,
Dalton Trans. 1993, 2057-2063.
(46) Felcman, J.; Frau´sto da Silva, J. J. R. Talanta 1983, 30, 565-570.
Inorganic Chemistry, Vol. 45, No. 20, 2006 8091

Rangel et al.
Table 3. EPR and Electronic Absorption Parameters for Tris Chelated Non-Oxo VIV Complexes in CH3COOH
complex
gx
gy
gz
Ax
Ay
Aza
|Ax - Ay|
λ (ꢀ)b
a
a
a
[V(mpp)3]+
[V(empp)3]+
[V(depp)3]+
[V(ppp)3]+
[V(epp)3]+
[V(ptp)3]+
1.916
1.918
1.918
1.916
1.918
1.915
1.918
1.916
1.919
1.916
1.918
1.914
1.916
1.916
1.913
1.916
1.914
1.916
1.914
1.916
1.914
1.916
1.988
1.989
1.988
1.987
1.988
1.988
1.988
1.988
1.988
1.988
1.988
118.2
122.1
122.0
118.6
122.4
117.9
122.7
118.1
122.6
118.5
121.9
101.9
97.8
97.9
101.7
98.1
102.0
98.2
102.3
98.5
102.2
98.4
10.2
10.2
10.2
10.0
10.2
10.1
10.0
10.1
9.9
16.3
24.3
24.1
16.9
24.3
15.9
24.5
15.8
24.1
16.3
23.5
348(7600), 445(6700), 528(7900), 596(7300)
338(7600), 440(6500), 524(8100), 608(7200)
337(7600), 438(6500), 522(8100), 609(7100)
350(7500), 446(6700), 530(7900), 594(7300)
338(7500), 441(6400), 524(8000), 610 (7200)
351(7500), 443(6700), 528(8000), 594(7300)
339(7600), 439(6500), 523(8100), 611(7200)
352(7600), 444(6600), 527(7900), 595(7300)
336(7600), 442(6400), 526(8100), 609(7200)
349(7600), 444(6700), 529(7900), 592(7300)
340(7600), 440(6500), 525(8100), 612(7200)
[V(eptp)3]+
[V(pbp)3]+
[V(epbp)3]+
[V(php)3]+
[V(ephp)3]+
9.8
10.3
a Ax, Ay, Az, and |Ax - Ay| measured in units of 1 × 10-4 cm-1
.
b λ measured in nanometers and ꢀ in M-1 cm-1
.
bond with the consequent formation of a water molecule51
+
VOL2 + HL + CH3COOH f VL3
+
H2O + CH3COO- (1)
The formation of [VIVL3]+ species can be demonstrated by
EPR spectroscopy. All the experimental EPR spectra were
simulated, and the parameters are reported in Table 3. The
g and A values (gz ≈ 2 > gx ≈ gy and Az , Ax ≈ Ay), with
Az close to 10 × 10-4 cm-1, are consistent with an unpaired
electron residing in a nondegenerate molecular orbital that
is largely dz in character.52 This electronic configuration
2
Figure 3. X-band anisotropic EPR spectra recorded at 140 K in CH3-
COOH on tris chelated non-oxo VIV species with a VIV concentration of
0.01 M: (a) [VIV(empp)3]+ and (b) [VIV(mpp)3]+. Diphenylpicrylhydrazyl
(dpph) is the standard field marker (g ) 2.0036).
suggests for the non-oxo species a distorted geometry
intermediate between the octahedron and the trigonal prism,53
as a consequence of the steric requirements of the ligand
molecules.54 On the basis of the spectral parameters, the non-
oxo VIV complexes can be grouped in two sets of com-
pounds: one with ligands with R1 ) methyl (Hmpp, Hppp,
Hptp, Hpbp, Hphp) and the other with ligands with R2 )
ethyl (Hempp, Hdepp, Hepp, Heptp, Hepbp, Hephp). The
spectra of [VIV(empp)3]+ and [VIV(mpp)3]+ are shown in
Figure 3, with the second being very similar to that of
Hdmpp.28 The anisotropy between the x and y axes, expressed
as |Ax - Ay|, can be related to the degree of rhombic
distortion of the species and depends mainly on the steric
hindrance of the substituents on the carbon in the R-position
with respect to 3-hydroxy group. Table 3 suggests that the
bulkier ethyl (|Ax - Ay| ≈ 24-25 × 10-4 cm-1) produces a
bigger distortion than the methyl group (|Ax - Ay| ≈ 16-17
× 10-4 cm-1).
Figure 4. Electronic absorption spectrum recorded in CH3COOH of the
[VIV(empp)3]+ complex with a VIV concentration of 0.25 mM.
bands have been interpreted in terms of charge-transfer
transitions, which cover the d-d absorptions.55,56 First, the
transitions above 500 nm have been assigned to L(π) f V(d)
and those below 400 nm to V(d) f L(π) charge trans-
fers.55a,55b,56 Subsequently, Raymond and co-workers pro-
posed that, for non-oxo VIV species formed by catecholates,
all the transitions must be considered ligand-to-metal charge
The electronic absorption spectra of the non-oxo species
were recorded in CH3COOH, and that of [VIV(empp)3]+ is
presented in Figure 4. All the complexes show an intense
deep violet color. The detection of four bands between 350
and 750 nm with ꢀ in the range 2000-12000 M-1 cm-1 is
a distinctive feature of the non-oxo VIV complexes.55 Such
(55) (a) Cooper, S. R.; Koh, Y. B.; Raymond, K. N. J. Am. Chem. Soc.
1982, 104, 5092-5102. (b) Hawkins, C. J.; Kabanos, T. A. Inorg.
Chem. 1989, 28, 1084-1087. (c) Karpishin, T. B.; Dewey, T. M.;
Raymond, K. N. J. Am. Chem. Soc. 1993, 115, 1842-1851. (d) Klich,
P. R.; Daniher, A. T.; Challen, P. R.; McConville, D. B.; Youngs, W.
J. Inorg. Chem. 1996, 35, 347-356.
(56) (a) VonDeele, R. B.; Fay, R. C. J. Am. Chem. Soc. 1972, 94, 7935-
7936. (b) Hambley, T. W.; Hawkins, C. J.; Kabanos, T. A. Inorg.
Chem. 1987, 26, 3740-3745.
(51) Dess`ı, A.; Micera, G.; Sanna, D.; Strinna Erre, L. J. Inorg. Biochem.
1992, 48, 279-287.
(52) Desideri, A.; Raynor, J. B.; Diamantis, A. A. J. Chem. Soc., Dalton
Trans. 1978, 423-426.
(53) Olk, R.-M.; Dietzsch, W.; Kirmse, R.; Stach, J.; Hoyer, E.; Golic, L.
Inorg. Chim. Acta 1987, 128, 251-259.
(54) Branca, M.; Micera, G.; Dess`ı, A.; Sanna, D.; Raymond, K. N. Inorg.
Chem. 1990, 29, 1586-1589.
8092 Inorganic Chemistry, Vol. 45, No. 20, 2006

VIVO Complexes Formed by 3-Hydroxy-4-Pyridinones
Table 4. EPR Parameters for Bis Chelated Solid VIVO Complexes in
DMF
Table 5. Electronic Absorption Parameters for Bis Chelated Solid
VIVO Complexes in DMF
a
a
a
a
complex
gx
gy
gz
Ax
Ay
Aza
|Ax - Ay|
complex
λ
IV (ꢀIV
)
λ λ
III (ꢀIII)a II (ꢀII)a λI (ꢀI)a ∆λ ) (λIII - λII)a
[VO(mpp)2]
1.985 1.978 1.951 45.4 53.1 158.1
[VO(empp)2] 1.985 1.978 1.951 45.3 53.1 157.8
[VO(depp)2] 1.985 1.978 1.951 45.2 53.2 157.7
7.7
7.8
8.0
7.9
8.1
7.8
8.1
7.7
8.2
7.8
7.9
[VO(mpp)2] 399(130) 540(60) 623(56) 695(25)
[VO(empp)2] 403(156) 547(57) 620(56) 699(15)
[VO(depp)2] 405(153) 546(62) 620(56) 700(21)
83
73
74
85
75
83
75
81
78
87
76
[VO(ppp)2]
[VO(epp)2]
[VO(ptp)2]
[VO(eptp)2]
[VO(pbp)2]
1.984 1.977 1.950 45.3 53.2 158.1
1.985 1.978 1.950 45.4 53.5 158.0
1.985 1.978 1.950 45.4 53.2 158.2
1.985 1.978 1.951 45.1 53.2 158.1
1.984 1.978 1.951 45.5 53.2 158.2
[VO(ppp)2]
[VO(epp)2]
[VO(ptp)2]
402(188) 539(59) 624(48) 698(26)
402(145) 544(67) 619(60) 700(32)
400(190) 541(69) 624(62) 699(30)
[VO(eptp)2] 401(165) 543(68) 618(63) 698(28)
[VO(pbp)2] 399(168) 538(73) 619(63) 697(25)
[VO(epbp)2] 404(170) 542(72) 620(64) 699(27)
[VO(php)2] 398(173) 538(65) 625(59) 698(26)
[VO(ephp)2] 403(178) 545(68) 621(61) 700(28)
[VO(epbp)2] 1.986 1.978 1.951 45.2 53.4 157.9
[VO(php)2] 1.985 1.977 1.950 45.5 53.3 158.3
[VO(ephp)2] 1.985 1.978 1.951 45.3 53.2 157.8
a Ax, Ay, Az, and |Ax - Ay| measured in units of 1 × 10-4 cm-1
.
a λ measured in nanometers and ꢀ in M-1 cm-1
.
transfers between the a2 and eπ orbitals of catechol and ea(dxy,
2
2
d
x -y ) and eb(dxz, dyz) orbitals of vanadium in the D3
symmetry of the complexes;55d particularly, they attributed
the four absorptions to the L(a2) f V(ea), L(eπ) f V(ea),
L(a2) f V(eb) and L(eπ) f V(eb) transitions, in order of
increasing energy.55d An analysis of our data (Table 3)
supports, however, two different types of electronic spectra
related to the two types of distortion of the species, according
to the presence of a methyl or an ethyl on the C atom in the
R-position to 3-hydroxy group (Table 3). This suggests, of
2
2
course, that the energy of the ea(dxy, dx -y ) and eb(dxz, dyz)
vanadium orbitals depends on the degree of distortion of the
complexes, as confirmed by EPR spectra, even if a more
detailed analysis is necessary to clarify this point.
Synthesis and Characterization of [VIVOL2] Solid
Complexes. The reaction of the ligands Hdepp, Heptp,
Hepbp, and Hephp (see Scheme 1) with VOSO4‚5H2O gives
rise to the formation of [VIVOL2] solid complexes. The
composition has been determined through the combined
application of elemental (C, H, N) and thermogravimetric
analyses. The thermogravimetry allows us to determine the
V2O5 and H2O content of the samples and rule out the
presence of water in their stoichiometry (the decomposition
of all the complexes starts above 300 °C). These complexes
are isostructural with the bis chelated complexes formed by
Hmpp, Hempp, Hppp, Hepp, Hptp, Hpbp, and Hphp, which
were prepared and characterized elsewhere.31 [VIVO(dmpp)2]
was first studied by Burgess et al.31 and later by Buglyo´ et
al.28 Because it has not been possible to isolate single crystals
suitable for an X-ray diffraction study, the characterization
has been performed through spectroscopic (EPR and UV/
vis) techniques. EPR and electronic absorption spectra were
measured on the powders dissolved in several organic
solvents (DMF, DMSO, and CH3CN); the spectral data
obtained in DMF are reported in Tables 4 and 5. To compare
the data, we have re-examined the compounds studied
previously31 in the present work, and all the spectra have
been recorded and simulated in the same conditions.
Figure 5. (a) Experimental and (b) simulated X-band anisotropic EPR
spectrum recorded at 140 K on [VIVO(depp)2] dissolved in DMF. (c) Low-
and high-field regions, amplified 20-fold, of the X-band anisotropic EPR
spectrum recorded at 140 K on [VIVO(depp)2] dissolved in DMSO; I
indicates the resonances of the cis-[VIVO(depp)2(dmso)] complex. Diphe-
nylpicrylhydrazyl (dpph) is the standard field marker (g ) 2.0036).
3,4-dihydroxybenzoic acid (Az ) 154-155 × 10-4 cm-1)49
rather than by maltol (Az ) 163 × 10-4 cm-1),14c thus
suggesting for pyridinones a (O-, O-) rather than a (CO,
O-) donor set. An x,y anisotropy (gx ) 1.984-1.986, gy )
1.977-1.978, and Ax ) 45-46 × 10-4 cm-1, Ay ) 53-54
× 10-4 cm-1) is observed, comparable with that of [VIVO-
(maltolato)2], for which a rhombic spectrum is detected in
CH2Cl2 with a |Ax - Ay| value of 9.3 × 10-4 cm-1.14c
The electronic absorption spectra, measured in DMF, are
similar for all the compounds and are characterized by four
absorption bands in the visible region (Table 5 and Figure
6), with the low-energy transition (band I or λI) strongly
shifted toward lower wavelengths with respect to aqua ion
[VIVO(H2O)5]2+ and with λI and λII values very close to each
other. The deconvolution of the spectra is necessary to
resolve band I, which otherwise appears as only a weak
shoulder.
For
a pentacoordinated complex of stoichiometry
In DMF, only the trans isomer is detected by EPR,
supporting the weak coordinating properties of such a
solvent. This is in agreement with the previous results
obtained on [VIVO(dmpp)2].28 The experimental spectrum of
[VIVO(depp)2] in DMF is presented in Figure 5a. All the
complexes exhibit Az values (Table 4) closer to those
displayed by bis chelated species formed by catechol and
[VIVOL2], two geometries are conceivable: one close to the
square-pyramid and another distorted toward the trigonal-
bipyramid. The degree of distortion can be described by a
structural index of trigonality, τ ) (â-R)/60, where â is
the angle subtended by vanadium between the two pseudo-
apical donors and R the angle between the two pseudo-
Inorganic Chemistry, Vol. 45, No. 20, 2006 8093

Rangel et al.
For moderate distortions (a and b in Scheme 3), like those
observed for VIVO pyridinonate complexes, intermediate
values of λI and λII are expected, with λI in the range 695-
700 nm and λII in the range 618-625 nm (Table 5). Finally,
for square-pyramidal structures, λI and λII collapse into a
single band observed between 650 and 700 nm; for [VIVO-
(acetylacetonato)2], for example, this band is detected at 675
nm in the solid, at 665 nm in CHCl3, and at 655 nm in
benzene and toluene.60 Thus, the detection of the low-energy
band below 640-650 nm could suggest the presence of a
unresolved band at higher wavelength and the probable
distortion toward a trigonal-bipyramidal geometry.
Only a slight distortion is expected for bis chelated VIVO
complexes formed by pyridinones in the light of the solid-
state structures reported for [VIVO(maltolato)2]14a and
[VIVO(catecholato)2]2-,55a close to the square-pyramid and
characterized by very small values of τ (0.103 and 0.007,
respectively). Therefore, the structure of [VIVOL2] complexes
is square-pyramidal with a very slight distortion toward the
trigonal-bipyramid. The degree of such a distortion can be
described by the splitting ∆λ between the two central bands
(λIII and λII) in the electronic spectra,7 related to the steric
hindrance of the substituents on carbon atom in R-position
to 3-hydroxy group, which favors the shift toward a trigonal-
bipyramid arrangement.6,7 As can be seen in Scheme 3, the
greater the distortion, the lower the ∆λ value. Analogously
to what was observed for non-oxo complexes, the presence
of the ethyl group (∆λ ) 73-78 nm, Scheme 3b) results in
a bigger distortion with respect to that of methyl (∆λ ) 81-
87 nm, Scheme 3a).
Figure 6. Electronic absorption spectrum recorded in DMF of [VIVO-
(empp)2] with a VIVO concentration of 0.25 mM. The colored curves,
attributable to the four electronic transitions, have been obtained from the
deconvolution of the spectrum.
Scheme 3. Orbital Correlation Diagram for the Transformation of a
Square-Pyramid (C4V) into a Trigonal-Bipyramid (D3h)a
As a final comment, we would like to refer to the behavior
of [VIVOL2] complexes in DMSO (or CH3CN). Both solvents
have stronger coordinating ability than DMF and favor the
partial isomerization of the [VIVOL2] species with the
formation of the cis isomer, in agreement with the results
obtained for other ligands.48 For example, in DMSO, both
the trans-[VIVOL2] and cis-[VIVOL2(dmso)] isomers are
observed (Figure 5c), and the relative amount of the cis
species varies between 10 and 20%, depending on the ligand.
a Arrows indicate the arbitrary distortion of VIVO complexes formed by
(a) 2-methyl-3-hydroxy-4-pyridinones, (b) 2-ethyl-3-hydroxy-4-pyridinones
and (c) R-hydroxycarboxylates.
equatorial donors (â > R).57 It was recently demonstrated
that only the concurrent detection of rhombicity in the EPR
and four transitions in the electronic absorption spectra is a
criterion for proving a distortion of the VIVO complexes from
a square-pyramidal toward a trigonal-bipyramidal geom-
etry.6,7 This is due to the loss of degeneracy of the dxz and
dyz atomic orbitals. In Scheme 3, the orbital correlation
diagram calculated by Rossi and Hoffmann for the trans-
formation of a square-pyramid into a trigonal-bipyramid is
displayed.58 In particular, the dxz orbital (b1 in C2v symmetry)
undergoes the greater stabilization. In the diagram, it can be
noticed that, with increasing extent of the distortion, the λI
band shifts to higher and λII to lower wavelengths. The λIII
and λIV bands undergo smaller changes. For severe distortions
(Scheme 3c), λI > 800 nm and λII < 600 nm, as reported
for the bis chelated species formed by R-hydroxycarbox-
ylates;7 for example, for [VIVO(benzilato)2]2-, characterized
by τ ) 0.31,59 the λI and λII bands fall at 859 and 586 nm.7
Discussion
The comparison of the present results with those reported
for progressively stronger ligands, like kojic acid,44 maltol,44
L-mimosine,61 Hdmpp,28 catechol,49 and 3,4-dihydroxy-
benzoic acid (3,4-DHB),49 allows us to infer some general
features about the effect of the basicity and electronic
structure on the thermodynamic (stability constants of the
complexes) and spectroscopic (51V hyperfine coupling
constant) properties of VIVO species. Given the insulin-
mimetic properties displayed by many of such systems, this
could be useful for analyzing their biological behavior.
Even if, at first sight, it could seem that all these ligands
are able to coordinate the VIVO ion in a similar way, a more
careful analysis reveals that their complexing ability is very
(57) Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.; Verschoor, G.
C. J. Chem. Soc., Dalton Trans. 1984, 1349-1356.
(58) Rossi, R.; Hoffmann, R. Inorg. Chem. 1975, 14, 365-374.
(59) Chasteen, N. D.; Belford, R. L.; Paul, I. C. Inorg. Chem. 1969, 8,
408-418.
(60) Selbin, J. Chem. ReV. 1965, 65, 153-175.
(61) Lodyga-Chruscinska, E.; Garribba, E.; Micera, G.; Panzanelli, A. J.
Inorg. Biochem. 1999, 75, 225-232.
8094 Inorganic Chemistry, Vol. 45, No. 20, 2006

VIVO Complexes Formed by 3-Hydroxy-4-Pyridinones
Scheme 4. Resonance Forms of Pyrone, Pyridinones, and Catechol
Ligands
different and that pyrones, like kojic acid and maltol, are
much weaker ligands than pyridinones and catechols, whereas
L-mimosine shows an intermediate behavior. The combina-
tion of the inductive and resonance effects determines the
following order of basicity: kojic acid < maltol < L-
mimosine < pyridinones < catechol ≈ 3,4-DHB. As
suggested previously,21d,21e,22a the contribution of the pseudo-
aromatic form of the fully deprotonated ligands with both
of the oxygen atoms of each ligand molecule negatively
charged increases with increasing basicity (Scheme 4). When
the characteristics of the donor set are compared, it is
noticeable that this changes from that (CO, O-) typical of
maltol and kojic acid (I in Scheme 4) to that (O-, O-) of
catechol and 3,4-DHB (III in Scheme 4), with the intermedi-
ate form (Oδ-, O-) displayed by pyridinones lying between
(II in Scheme 4). Therefore, it can be suggested that kojic
acid and maltol exist almost exclusively in form I in Scheme
4, whereas catechol and 3,4-DHB exist in form III. L-
mimosine and pyridinone derivatives should show an inter-
mediate electronic structure with a partial negative charge
on the oxygen atom in position 4 and a pseudo-aromatic
configuration of the six-membered ring.
These findings are confirmed by the analysis of the X-ray
solid structures of [VIVO(maltolato)2]2a and [VIVO-
(catecholato)2]2-.55a To establish the predominance of the
resonance forms I or III, we could introduce two structural
parameters, ∆d(V-O) ) [d(V-O(keto)) - d(V-O(hy-
droxy))] and ∆d(C-O) ) [d(C-O(hydroxy)) - d(C-
O(keto))], related to the asymmetry of the V-O(keto) and
V-O(hydroxy) on one hand, and C-O(keto) and C-O(hy-
droxy) distances on the other hand. The larger the values of
∆d(V-O) and ∆d(C-O), the greater the contribution of form
I. ∆d(V-O) and ∆d(C-O) are 0.046 and 0.080 Å for [VIVO-
(maltolato)2]14a and 0.013 and 0.007 Å for [VIVO-
(catecholato)2]2-,55a in good agreement with the hypothesis
illustrated in Scheme 4.
Figure 7. Stepwise stability constants (log K1 and log K2) of the mono
and bis chelated complexes formed by the discussed ligands as a function
of the pKa values of the -OH group. Values are taken from refs 28, 44,
49, 61, and from this work.
K2 ) 14.63 for catechol, and log K1 ) 17.13 and log K2 )
14.29 for 3,4-DHB).49 The above results show that pyridi-
nones have an intermediate coordinating strength with respect
to maltol and catechol. In Figure 7, the stepwise stability
constants for mono and bis chelated complexes (log K1 and
log K2, respectively) formed by a number of pyrones,
pyridinones, and catechols are represented as a function of
the pKa values of -OH group in position 3 of the six-
membered ring.
In Figure 7, a linear relationship between the basicity of
the ligands and the stepwise stability constants of the VIVO
complexes is observed. Greater values of stability constants
are expected for complexes of more basic ligands, as has
already often been reported in the literature, for example,
for substituted pyridine derivatives.62
With increasing basicity of the ligands, an increased
tendency to stabilize the trans arrangement of the four donors
with respect the VdO bond is observed. Indeed, bis
complexes formed by kojic acid and maltol are present in
aqueous solution only as cis isomers with one of the two
ligand molecules in an (equatorial-axial) arrange-
ment;14a,14c,16a,44 L-mimosine forms mainly the cis isomer, but
a small amount of the trans isomer is detected.61 With
pyridinones, the trans complex prevails over the cis,28
whereas with catechol and 3,4-DHB only the trans species
exist in water.49 The experimental EPR spectra for the latter
four cases are displayed in Figure 8.
These results are confirmed by EPR spectroscopy and
potentiometry, which suggest a cis-VIVOL2H-1 species,
formed upon deprotonation of the equatorially coordinated
water molecule, in all the systems except in those with
catechol and 3,4-DHB. By proceeding from the weakest
ligand (kojic acid) to the strongest (Hdepp), the pK of the
water in the equatorial plane of VIVO ion increases progres-
sively: values of 8.46 (kojate),44 8.78 (maltolate),44 9.22 (L-
mimosinate),61 and 10.59 (Hdmpp)28 are reported in the
literature. The pK values measured in this work lie in the
range 10.47-10.75 (Table 1). The bis chelated VIVOL2
complexes are stabilized by stronger ligands and the forma-
tion of cis-VIVOL2H-1 species is shifted to higher pH values.
The stepwise stability constants (log K1 and log K2) for
the formation of mono and bis chelated complexes of
pyridinones through the reactions VO + L f VOL and VOL
+ L f VOL2 (log K1 ) 12.05-12.30 and log K2 ) 10.37-
10.80, Table 1) are about 3 and 4 orders of magnitude bigger
than for maltol (log K1 ) 8.69 and log K2 ) 7.60)44 and
kojic acid (log K1 ) 7.63 and log K2 ) 6.74)44 and about
two orders of magnitude bigger than for L-mimosine (log
K1 ) 10.21 and log K2 ) 9.31).61 Catechol and 3,4-DHB
can be considered the final terms of the series, and their
stepwise stability constants are about 4 orders of magnitude
greater than those of pyridinones (log K1 ) 16.75 and log
(62) Kapinos, L. E.; Sigel, H. Inorg. Chim. Acta 2002, 337, 131-142.
Inorganic Chemistry, Vol. 45, No. 20, 2006 8095

Rangel et al.
Figure 10. Stability constants (log K) of the non-oxo tris chelated
complexes VIVL3 formed by the discussed ligands as a function of the pKa
values of the -OH group. Values taken from refs 28, 50, 63, and from this
work.
Figure 8. Low-field region of the X-band anisotropic EPR spectra of the
bis chelated complexes formed by maltol, L-mimosine, Hdepp, and catechol
recorded in aqueous solutions at 140 K with VIVO concentration of 4 mM.
(a) Maltol: L:M ) 4, pH 5.50. (b) L-Mimosine: L:M ) 5, pH 5.25. (c)
Hdepp: L:M ) 3, pH 6.00. (d) Catechol: L:M ) 2, pH 5.00. I and II
denote the cis-VIVOL2 and trans-VIVOL2 complexes, respectively.
relationship proposed first by Wu¨trich64 and subsequently
developed by Chasteen45
4
A ) A (i) ) A (donor 1) + A (donor 2) +
∑
z
z
z
z
i)1
Az(donor 3) + Az(donor 4) (2)
Recently, the list of the donor atoms was completed by Tolis
et al. for Cl- and SCN- ions,65 by Hamstra et al. for a neutral
oxygen atom belonging to an amide CO group,66 by Cavaco
et al.67 and Garribba et al.68 for the imino nitrogen atom,
and by Tasiopoulos et al.69 and Garribba et al.68 for the
deprotonated amide nitrogen. Corrections to the contribution
of the carboxylate group and the imidazole nitrogen that is
dependent on the orientation of the aromatic ring with respect
to the VdO bond were proposed by Jakusch et al.70 and
Smith II et al., respectively.71
Usually, the contribution to Az is considered constant for
each donor function (for example, that for the Ph-O- group
is always 38.9 × 10-4 cm-1),45 without considering the
possible change in its basicity due to different subsituents
in the ligand molecule. With the values reported for the Az-
(Ph-O-)45 and Az(CdO) groups,66 the expected hyperfine
coupling constants for [VIVO(maltolato)2] (∼165 × 10-4
cm-1) and [VIVO(catecholato)2]2- (∼156 × 10-4 cm-1) are
easily calculated; the experimental values are 163 × 10-4
cm-1 14c and 154 × 10-4 cm-1.49,54 The results obtained in
this work allow us to establish how the hyperfine coupling
Figure 9. pK of the equatorial water molecule in the bis chelated cis-
VIVOL2 complexes formed by the discussed ligands as a function of the
pKa values of the -OH group. Values are taken from refs 28, 44, 61, and
from this work.
In Figure 9, the relationship observed between the pKa of
the -OH group in the free ligand and the pK of the equatorial
water molecule coordinated in cis position with respect to
the VdO bond is presented.
An analogous trend is found for the formation of the VIVL3
non-oxo species through reaction 1. The value of log K can
be calculated by the equation log K(VL3‚H2O) ) log â(VL3‚
H2O) - log â(VOL2) - log â(HL). In this case, the
comparison concerns a number of catechol derivatives, like
tiron,63 dopamine, D,L-epinephrine, D,L-norepinephrine, and
L-dopa.50 Pyridinones, the weakest ligands of the series, show
a decreased ability to form non-oxo tris chelated complexes,
as is demonstrated by the distribution diagram shown in
Figure 1. In Figure 10, log K(VL3‚H2O) is plotted as a
function of the pKa of the -OH group.
(64) Wu¨trich, K. HelV. Chim. Acta 1965, 48, 1012-1017.
(65) Tolis, E. J.; Teberekidis, V. I.; Raptopoulou, C. P.; Terzis, A.; Sigalas,
M.; Deligiannakis, Y.; Kabanos, T. A. Chem.sEur. J. 2001, 7, 2698-
2710.
(66) Hamstra, B. J.; Houseman, A. P. L.; Colpas, G. J.; Kampf, J. W.;
LoBrutto, R.; Frasch, W. D.; Pecoraro, V. L. Inorg. Chem. 1997, 36,
4866-4874.
(67) Cavaco, I.; Costa Pessoa, J.; Costa, D.; Duarte, M. T.; Gillard, R. D.;
Matias, P. J. Chem. Soc., Dalton Trans. 1994, 149-157.
(68) Garribba, E.; Lodyga-Chruscinska, E.; Micera, G.; Panzanelli, A.;
Sanna, D. Eur. J. Inorg. Chem. 2005, 1369-1382.
(69) Tasiopoulos, A. J.; Troganis, A. N.; Evangelou, A.; Raptopoulou, C.
P.; Terzis, A.; Deligiannakis, Y.; Kabanos, T. A. Chem.sEur. J. 1999,
5, 910-921.
The value of the hyperfine coupling constant along the z
axis of the unpaired electron with the 51V nucleus (Az) can
be calculated from the sum of the contribution of each donor
function in the equatorial plane, according to the additivity
(70) Jakusch, T.; Buglyo´, P.; Tomaz, A. I.; Costa Pessoa, J.; Kiss, T. Inorg.
Chim. Acta 2002, 339, 119-128.
(71) Smith, T. S., II; Roof, C. A.; Kampf, J. W.; Rasmussen, P. G.;
Pecoraro, V. L. J. Am. Chem. Soc. 2000, 122, 767-775.
(63) Buglyo`, P.; Kiss, T. J. Coord. Chem. 1991, 22, 259-268.
8096 Inorganic Chemistry, Vol. 45, No. 20, 2006

VIVO Complexes Formed by 3-Hydroxy-4-Pyridinones
2
by a dz ground state and by a geometry that can be described
as being intermediate between the octahedron and the trigonal
prism.
The donor set is intermediate between that of maltol (CO,
O-) and catechol (O-, O-) and shows a partial negative
charge on the oxygen atom in position 4 and a pseudo-
aromatic electronic configuration of the six-membered py-
ridinone ring. These features seem to explain the increased
coordinating strength of pyridinones in comparison with
those exhibited by simple pyrone derivatives.
The characterization of the solid derivatives, [VIVO-
(depp)2], [VIVO(eptp)2], [VIVO(epbp)2], and [VIVO(ephp)2],
was performed through EPR and UV/vis spectroscopies and
the structure is close to the square-pyramid, according to
the previous results.31 The detection of four bands in the
electronic spectra and rhombicity in the EPR spectra in DMF
suggest a slight distortion toward the trigonal-bipyramid.6,7
A structural index of trigonality τ between those of [VIVO-
(maltolato)2] (0.103)14a and [VIVO(catecholato)2]2- (0.007)55a
could be expected. A criterion for establishing the degree of
distortion is the position of bands I (λI) and II (λII) in the
electronic absorption spectrum: if λI > 800 nm and λII <
600 nm, the distortion is severe, as for bis chelated species
formed by R-hydroxycarboxylates;7 if λI ≈ 700 nm and λII
≈ 600-620 nm, the distortion is moderate, as happens with
pyridinones. It must be noticed that for moderate distortions,
band I could be unresolved; in such cases, the position of
the low-energy observable band (band II) below 640-650
nm should suggest a trigonal-bypiramidal distortion and a
deconvolution of the experimental spectrum is advisable to
resolve band I.
Figure 11. Hyperfine coupling constant value, Az, for the bis chelated
trans-VIVOL2 complexes formed by the discussed ligands as a function of
the pKa values of the -OH group. Values are taken from refs 14c, 28, 49,
54, and from this work.
constant change for the trans bis chelated complexes in the
transformation of the donor set from maltol to catechol. For
L-mimosine and pyridinone derivatives, it would be incorrect
to calculate the Az value from the data reported in the
literature,45,66 because the oxygen donor in position 4 of the
pseudo-aromatic ring exhibits a chemical behavior intermedi-
ate with respect to the two limiting cases I and III in Scheme
4. Interestingly, trans-VIVOL2 complexes formed by L-
mimosine and pyridinones are characterized by Az values of
161 × 10-4 cm-1 and 158-159 × 10-4 cm-1, respectively,
intermediate between those of pyrones and catechols. The
decrease in the Az value is evident in Figure 8. A similar
trend is observed for cis-VIVOL2(H2O) species (Figure 8):
from maltol to pyridinones, Az changes from 171 × 10-4
cm-1 14c,44 to 166-167 × 10-4 cm-1.28 Analogously, Az is
167 × 10-4 cm-1 for the hydrolytic cis-VIVOL2(OH) species
formed by maltol,44 and 161-162 × 10-4 cm-1 for those
formed by pyridinones. In Figure 11, the experimental values
of the hyperfine coupling constant, Az, are represented as a
function of the pKa of the -OH group.
A comparison with other pyrone, pyridinone, and catechol
ligands14a,14c,28,44,49,50,61,63 shows that, with an increase in the
pKa value of the -OH group in position 3 of the ring, there
is an increase in (i) stepwise stability constants (log K1 and
log K2) of the mono and bis chelated complexes, (ii) the pK
of the equatorial water molecule in cis-VIVOL2(H2O), and
(iii) log K of the non-oxo tris chelated complexes VIVL3,
whereas there is a decrease in (iv) 51V hyperfine coupling
constant Az. From these data, we can predict the relative
stability of the trans and cis isomers in terms of the basicity
and electronic structure of the ligands. In particular, in
aqueous solution, kojic acid and maltol form only cis
complexes,14a,14c,16a,44 L-mimosine almost exclusively the cis
species,61 pyridinones mainly the trans isomer,28 and cat-
echols only the trans complexes.49,55a
Conclusions
Eleven derivatives of 3-hydroxy-4-pyridinones coordinate
a VIVO ion at 1:2 metal:ligand molar ratios in the pH range
2-12 with the formation of complexes with [VIVOL]+, [VIV-
OL2], [VIVOL2H-1]-, [(VIVO)2L2H-2], and [VIVL3]+ stoichi-
ometries. The additivity rule allows us to identify the donors
coordinated in the equatorial plane of the VIVO ion.45 Bis
chelated species are characterized by a cis-trans isomerism,
with the trans arrangement strongly favored with respect to
the cis one. The presence of the cis isomer is displayed by
potentiometric titrations, which show a deprotonation process
in the pH range 10-11, and by EPR spectroscopy. Cis-
trans equilibrium now appears to be a general behavior of
VIVO complexes.5,44,47,48
Supporting Information Available: Tables S1 and S2 giving
the protonation constants of the ligands (pKa) and stability constants
of VIVO complexes (log â) formed by pyrone, pyridinone, and
catechol ligands reported in the literature. Figures S1 and S2
showing the electronic absorption spectra of [VIV(empp)3]+ and
[VIV(mpp)3]+ in CH3COOH and [VIVO(mpp)2] and [VIVO(depp)2]
in DMF. This material is available free of charge via the Internet
at http://pubs.acs.org.
Tris chelated species are not very stable in aqueous
solution, but can be synthesized in concentrated CH3COOH,
which allows for the cleavage of the VdO bond with
formation of a water molecule. As observed for VIV
complexes of catechol derivatives,49,54 they are characterized
IC0605571
Inorganic Chemistry, Vol. 45, No. 20, 2006 8097