Synthesis, structure and spectroscopy of new thiopyrone and hydroxypyridinethione transition-metal complexes

Article abstract of DOI:10.1039/b505034k

The coordination chemistry of several O,S mixed donor ligands, namely thiopyrone and hydroxypyridinethione chelators, with a variety of middle and late first-row transition-metal ions is described. Complexes of 3-hydroxy-2-methyl-4-thiopyrone (thiomaltol) with cobalt(II), copper(II) and zinc(II); 3-hydroxy-1,2-dimethyl-4(1H)-pyridinethione (3,4-HOPTO) with iron(III), nickel(II), copper(II) and zinc(II); and 3-hydroxy-1-methyl-2(1H)- pyridinethione (3,2-HOPTO) with iron(III), nickel(II), copper(II) and zinc(II) have been synthesized and characterized. The structures, absorbance spectroscopy, cyclic voltammetry and superconducting quantum interferometer device (SQUID) measurements of selected metal complexes, as well as ligand protonation constants, are reported. Most of the metal complexes show coordination geometries indicative of a strong trans influence by the O,S chelators. The data presented herein provide the most detailed study of the transition-metal coordination chemistry of both thiopyrone and hydroxypyridinethione O,S donor ligands to date, and provide the basis for the investigation of these ligands in realm of biological inorganic chemistry. The Rayal Society of Chemistry 2005.

Full text of DOI:10.1039/b505034k

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F U L L P A P E R
Synthesis, structure and spectroscopy of new thiopyrone and
hydroxypyridinethione transition-metal complexes†
Jana A. Lewis, Ba L. Tran, David T. Puerta, Evan M. Rumberger, David N. Hendrickson and
Seth M. Cohen*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla,
California, USA. E-mail: scohen@uscd.edu; Fax: 858-822-5598; Tel: 858-822-5596
Received 11th April 2005, Accepted 3rd June 2005
First published as an Advance Article on the web 23rd June 2005
The coordination chemistry of several O,S mixed donor ligands, namely thiopyrone and hydroxypyridinethione
chelators, with a variety of middle and late first-row transition-metal ions is described. Complexes of 3-hydroxy-
2-methyl-4-thiopyrone (thiomaltol) with cobalt(II), copper(II) and zinc(II); 3-hydroxy-1,2-dimethyl-4(1H)-
pyridinethione (3,4-HOPTO) with iron(III), nickel(II), copper(II) and zinc(II); and 3-hydroxy-1-methyl-2(1H)-
pyridinethione (3,2-HOPTO) with iron(III), nickel(II), copper(II) and zinc(II) have been synthesized and characterized.
The structures, absorbance spectroscopy, cyclic voltammetry and superconducting quantum interferometer device
(SQUID) measurements of selected metal complexes, as well as ligand protonation constants, are reported. Most of
the metal complexes show coordination geometries indicative of a strong trans influence by the O,S chelators. The
data presented herein provide the most detailed study of the transition-metal coordination chemistry of both
thiopyrone and hydroxypyridinethione O,S donor ligands to date, and provide the basis for the investigation of these
ligands in realm of biological inorganic chemistry.
Introduction
Pyrones and hydroxypyridinones have been widely investigated
in the bioinorganic community, particularly for use in medicinal
applications. For example, 3-hydroxy-2-methyl-4-pyrone (mal-
tol, Fig. 1) has been studied as a non-toxic, water-soluble iron(III)
delivery agent for the treatment of iron-deficiency anemia.1
The complex [Al(maltolato)3] has been used to investigate how
aluminum reaches the brain, which may be relevant to patholo-
gies such as Alzheimer’s disease.2,3 Vanadyl (V O) complexes
=
of maltol-derived compounds have been extensively studied as
promising leads for treating diabetes, because of their insulin-
mimetic activity. Indeed, bis(ethylmaltolato)oxovanadium(IV)
Fig. 1 List of pyrone, hydroxypyridinone (HOPO), thiopyrone and
(BEOV) has reached clinical trials for the treatment of adult
onset diabetes.4–6 For hydroxypyridinones, compounds such
as 1-methyl-3-hydroxy-2(1H)-pyridinone (3,2-HOPO) and 3-
hydroxy-1,2-dimethyl-4(1H)-pyridinone (3,4-HOPO) and re-
lated derivatives have been examined as therapeutic chelating
agents for iron overload7–13 and aluminum toxicity.14,15 Molyb-
denum complexes of both maltol and HOPO derivatives have
shown protective ability for diabetic hearts.16 Finally, complexes
with technetium(V), rhenium(V), gallium(III), indium(III) and
gadolinium(III) have been studied as radiopharmaceuticals and
magnetic contrast agents for medical imaging.17–20
Despite the potentially far-reaching applications of pyrone
and hydroxypyridinone chelators, few studies have been reported
on the sulfur-containing analogues of these important metal
chelators (Fig. 1). Extensive studies have been focused on the
commercially available 1-hydroxypyridine-2(1H)-thione (1,2-
HOPTO) and related compounds.21–31 Some HOPTO and thio-
hydroxamate ligands have been proposed as iron sequestering
agents based on siderophores, which are used by microbes
for iron transport.32–34 HOPOs and HOPTOs have been pro-
posed to be therapeutic antioxidants for treating Alzheimer’s
disease.35 Like their O,O donor analogues, thiopyrone and
hydroxypyridinethione (HOPTO) compounds.
complexes with gallium(III) and indium(III) have been studied as
radiopharmaceuticals for medical imaging.22,39–42
Recently, we and others have communicated some initial
studies on the transition-metal chemistry of thiopyrones. Farmer
and co-workers have suggested that metal complexes with sulfur-
containing ligands, such as disulfiram and thiomaltol, may
find application as melanoma-specific apoptosis inducers.43,44
Orvig and co-workers have recently described the coordination
chemistry of four thiopyrone and hydroxypyridinethione ligands
with vanadyl, group 13 and lanthanide ions.38,42 We have been
primarily concerned with the use of these ligands as novel chela-
tors for metalloprotein inhibition45,46 and as potential heavy-
metal sequestering agents.47–50 Despite the growing interest in
this class of ligands, very few elementary studies of their
coordination chemistry or the characteristics of the resulting
transition-metal complexes have been described.51,52 Therefore,
based on the potential medical and environmental applica-
tions of thiopyrones and hydroxypyridinethiones, we report
herein on the basic coordination chemistry of these ligands
with iron(III), cobalt(II), nickel(II), copper(II) and zinc(II). The
protonation constants for thiomaltol, thiopyromeconic acid,
3,2-HOPTO and 3,4-HOPTO (Fig. 1) have been determined by
spectrophotometric titrations. Spectroscopic, electrochemical,
and magnetic properties of select complexes are discussed, which
will contribute to expanding our fundamental knowledge about
these important ligand systems.
=
HOPTO complexes of vanadyl (V O) and zinc(II) have been
studied as insulin mimetics for treatment of diabetes,36–38 and
† Electronic supplementary information (ESI) available: Additional
characterization data. See http://dx.doi.org/10.1039/b505034k
2 5 8 8
D a l t o n T r a n s . , 2 0 0 5 , 2 5 8 8 – 2 5 9 6
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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(5600). EI-HRMS: Calc. for C12H10O4S2Co: 340.9347. Found, D:
340.9343, −1.3 ppm.
Experimental
General
[Cu(thiomaltolato)2]. [Cu(thiomaltolato)2] was synthesized
by the same procedure used for [Co(thiomaltolato)2] starting
from thiomaltol (100 mg, 0.70 mmol) and [CuCl2]·2H2O (60 mg,
0.35 mmol). The product was a red–brown powder. Yield: 76%.
Unless otherwise noted, starting materials were obtained from
commercial suppliers and used without further purification.
The ligands 3-hydroxy-2-methyl-4-thiopyrone (thiomaltol), 3-
hydroxy-4-thiopyrone (thiopyromeconic acid), 3-hydroxy-1,2-
dimethyl-4(1H)-pyridinethione (3,4-HOPTO) and 3-hydroxy-1-
methyl-2(1H)-pyridinethione (3,2-HOPTO) were synthesized as
described.50,51 Elemental analysis data were obtained through
NuMega Resonance Labs, Inc. (San Diego, CA) or Robertson
Microlit Laboratories (Madison, NJ). 1H/13C NMR spectra
were recorded on a Varian FT-NMR spectrometer running
at 300 or 400 MHz located in the Department of Chemistry
and Biochemistry, University of California, San Diego. Infrared
spectra were collected on either a Nicolet AVATAR 320 FT-
IR, Nicolet AVATAR 360 FT-IR, or a Perkin Elmer Spectrum
One FT-IR instrument under PC control at the Department
of Chemistry and Biochemistry, University of California, San
Diego. UV-visible spectra were recorded in methanol or dimethyl
sulfoxide (DMSO) using either a Hewlett-Packard 8452A
spectrophotometer with the ChemStation software suite or a
Perkin Elmer Lambda 25 spectrometer with the UVWinLab
4.2.0.0230 software package. Absorbance maxima are given as
kmax/nm (e/M−1 cm−1). Mass spectra were acquired at the Small
Molecule Mass Spectrometry Facility located in the Department
of Chemistry and Biochemistry, University of California, San
Diego. A ThermoFinnigan LCQ-DECA mass spectrometer was
used for the APCI analysis, and the data were analyzed using
the Xcalibur software suite. A ThermoFinnigan MAT 900XL
mass spectrometer was used to acquire the data for the high-
resolution mass spectra (HRMS). The value D is the error in
the measurement (in ppm), given by the equation D = [(ME −
MT)/MT] × 106, where ME is the experimental mass and MT is
the theoretical mass. The HRMS result for [Zn(3,2-HOPTO)2]
was obtained with fast atom bombardment (FAB) as the ion
source with 3-nitrobenzyl alcohol as the matrix and polyethylene
glycol as a reference. The HRMS results for all other complexes
were obtained with electron impact (EI) as the ion source and
perfluorokerosene as the reference.
Mp 224–227 ◦C (decomp.). IR (neat, ATR): m 821, 902, 1182
−1
=
(C S), 1215, 1273, 1410, 1490, 1575 cm . UV-Vis in MeOH:
269 (29000), 313 (27000), 389 (26700). APCI-MS: m/z 345.84
[M + H]+. EI-HRMS: Calc. for C12H10O4S2Cu: 344.9311. Found,
D: 344.9316, 1.5 ppm.
[Zn(thiomaltolato)2]. [Zn(thiomaltolato)2] was synthesized
by the same procedure used for [Co(thiomaltolato)2] starting
from thiomaltol (100 mg, 0.70 mmol) and [Zn(OAc)2]·2H2O
(77.0 mg, 0.35 mmol). The product was a yellow powder. Yield:
91%. Mp 265–268 ◦C (decomp.). 1H NMR (CDCl3, 300 MHz,
25 ◦C): d 2.60 (s, 6H, CH3), 7.56 (d, J = 4.5 Hz, 2H, Ar–H), 7.69
(d, J = 4.5 Hz, 2H, Ar–H). IR (neat, ATR): m 801, 897, 1178
−1
=
(C S), 1226, 1293, 1409, 1479, 1572 cm . UV-Vis in MeOH:
264 (15000), 303 (10400), 380 (23600). APCI-MS: m/z 346.88
[M + H]+. Anal. Calc. for C12H10O4S2Zn·H2O: C, 39.41; H, 3.31.
Found: C, 39.51; H, 2.96%.
[Fe(3,4-HOPTO)3]. 3,4-HOPTO (50 mg, 0.32 mmol) was
suspended in 3 mL of methanol and was dissolved by the
addition of 32 lL of 10 M NaOH (∼1 equiv.) and 5 mL of water
producing a yellow solution. [FeCl3]·6H2O (29 mg, 0.11 mmol)
was dissolved in 10 mL of water and was added dropwise to
the reaction mixture resulting in the formation of a dark navy-
blue precipitate. The reaction flask was covered in aluminum
foil, fitted with a condenser and heated to reflux (∼95 ◦C) under
a dinitrogen atmosphere for 30 min. The solution was filtered
through a fine glass frit and washed with ∼40 mL of water
to obtain a dark navy-blue powder. The product was dried in
a vacuum oven with heat for ∼12 h. Yield: 89%. Mp 312 ◦C
(decomp.). IR (solid pellet with KBr): m 818, 893, 943, 1194
−1
=
(C S), 1294, 1456, 1581 cm . UV-Vis in DMSO: 352 (36800),
550 (4900). APCI-MS: m/z 365.49 [M − L + H]+. Anal. Calc.
for C21H24N3O3S3Fe·H2O: C, 47.01; H, 4.88; N, 7.83. Found: C,
46.85; H, 4.75; N, 7.77%.
[Ni(3,4-HOPTO)2]. [Ni(3,4-HOPTO)2] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,4-HOPTO (50 mg, 0.32 mmol) and [Ni(OAc)2]·4H2O (40 mg,
0.16 mmol). The product◦obtained was a bright orange powder.
[Ni(maltolato)2(H2O)2]. Maltol (100 mg, 0.79 mmol) was
suspended in 3 mL of MeOH. The addition of 79 lL 10 M
NaOH to the reaction flask produced a colorless solution.
[Ni(OAc)2]·4H2O (99 mg, 0.39 mmol) was dissolved in 4 mL
water, and added dropwise to the reaction flask to yield a
transparent lime green solution. The flask was fitted with a
reflux condenser under a dinitrogen atmosphere and heated to
∼65 ◦C. Within 0.5 h, a green precipitate formed, which was
collected by vacuum filtration with a fine glass frit, and washed
with water. The product was dried in a vacuum oven with heat
for ∼12 h. Yield: 88%. Mp 227–232 ◦C. IR (neat, ATR): m 833,
917, 1206, 1280, 1465, 1498, 1567 cm−1. APCI-MS: m/z 308.94
[M + H]+. EI-HRMS Calc. for C12H10O6Ni: 307.9825. Found,
D: 307.9828, 0.9 ppm. Anal. Calc. for C12H14O8Ni·0.25H2O: C,
41.25; H, 4.18. Found: C, 41.20; H, 3.84%.
1
Yie◦ld: 95%. Mp > 315 C. H NMR (DMSO-d6, 400 MHz,
25 C): d 2.33 (s, 6H, CH3), 3.80 (s, 6H, NCH3), 6.92 (d, J =
6.0 Hz, 2H, Ar–H), 7.29 (d, J = 6.4 Hz, 2H, Ar–H). IR (solid
−1
=
pellet with KBr): m899, 1203 (C S), 1294, 1462, 1587 cm . UV-
Vis in DMSO: 280 (44500), 314 (17000), 380 (6300), 426 (7500),
458 (6600). APCI-MS: m/z 367.53 [M + H]+. Anal. Calc. for
C14H16N2O2S2Ni: C, 45.80; H, 4.39; N, 7.63. Found: C, 45.44;
H, 4.57; N, 7.43%.
[Cu(3,4-HOPTO)2]. [Cu(3,4-HOPTO)2] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,4-HOPTO (76 mg, 0.49 mmol) and [CuCl2]·2H2O (42 mg,
0.25 mmol). The product obtained was a brown powder. Yield:
[Co(thiomaltolato)2]. Thiomaltol (100 mg, 0.70 mmol) was
suspended in 4 mL of methanol and was dissolved by the
addition of 70.0 lL of 10 M NaOH (∼1 equiv.) producing a
bright yellow solution. [CoCl2]·6H2O (84 mg, 0.35 mmol) was
dissolved in 2 mL of water, and added dropwise to the reaction
mixture resulting in the formation of a brown precipitate. The
reaction flask was fitted with a condenser and was heated to
reflux (∼95 ◦C) under a dinitrogen atmosphere for 30 min. The
solution was filtered utilizing a fine glass frit and washed with
∼25 mL of water to obtain a brown powder. The powder was
86%. Mp 254–258 ◦C (decomp.). IR (neat, ATR): m 787, 893, 949,
−1
=
1165, 1200 (C S), 1295, 1445, 1583 cm . UV-Vis in DMSO: 292
(13900), 332 (21800), 372 (20800). APCI-MS: m/z 371.95 [M +
H]+. EI-HRMS: Calc. for C14H16N2O2S2Cu: 370.9944. Found,
D: 370.9945, 0.4 ppm.
[Zn(3,4-HOPTO)2]. [Zn(3,4-HOPTO)2] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,4-HOPTO (76 mg, 0.49 mmol) and [Zn(OAc)2]·2H2O (54 mg,
0.25 mmol). The product◦ obtained was an off-white powder.
1
dried in a vacuum oven with heat for ∼12 h. Yield: 80%. Mp 233–
Yield: 90%. Mp 239–244 C (decomp.). H NMR (DMSO-d6,
◦
=
235 C. IR (neat, ATR): m 898, 1176 (C S), 1217, 1279, 1408,
300 MHz, 25 ◦C): d 2.46 (s, 6H, CH3), 3.90 (s, 6H, NCH3), 7.39
1480, 1567 cm−1. UV-Vis in MeOH: 288 (22300), 395 (9000), 454
(d, J = 6.3 Hz, 2H, Ar–H), 7.50 (d, J = 6.6 Hz, 2H, Ar–H).
D a l t o n T r a n s . , 2 0 0 5 , 2 5 8 8 – 2 5 9 6
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=
IR (solid pellet with KBr): m 889, 945, 1109, 1199 (C S), 1307,
Cyclic voltammetry
1455, 1585 cm−1. UV-Vis in DMSO: 290 (8400), 356 (35600).
EI-HRMS: Calc. for C14H16N2O2S2Zn: 371.9939. Found, D:
371.9951, 3.2 ppm.
Cyclic voltammetry experiments were performed by using a
Bioanalytical Systems (BAS) CV-50W voltammetric analyzer
under PC control. Solutions were prepared by dissolving ∼10 mg
of metal complex in ∼10 mL CH2Cl2 containing 0.1 M n-
Bu4N(PF6). A platinum wire and a silver electrode (Ag/AgClaq)
were used as the auxiliary and reference electrodes, respec-
tively. A platinum electrode (BAS) was used for the working
electrode. Samples were purged with N2(g) for ∼2 min before
experiments were performed. Sweep rates were varied from
0.050 to 1.500 V s−1 in order to check the reversibility of the
couple. The data are reported at a sweep rate of 0.050 V s−1
at ambient temperature (∼25 ◦C). The ferrocenium–ferrocene
couple (Fc+/Fc0) was measured under identical conditions for
use as a reference measurement (E1/2 = +0.473 V, DEp = 0.232 V,
0.500 V s−1); potentials are reported relative to Fc+/Fc0.
[Fe(3,2-HOPTO)3]. [Fe(3,2-HOPTO)3] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,2-HOPTO (100 mg, 0.70 mmol) and [FeCl3]·6H2O (63 mg,
0.23 mmol). The product obtained was a dark navy-blue powder.
Yield: 80%. Mp > 300 ◦C. IR (solid pellet with KBr): m 732,
−1
=
1044, 1131 (C S), 1300, 1393, 1456, 1593 cm . UV-Vis in
DMSO: 376 (40400), 482 (6200), 584 (6300). EI-HRMS: Calc.
for C12H12N2O2S2Fe [ML2]−: 335.9684. Found, D: 335.9688,
1.0 ppm.
[Ni(3,2-HOPTO)2]. [Ni(3,2-HOPTO)2] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,2-HOPTO (30 mg, 0.21 mmol) and [Ni(OAc)2]·4H2O (26 mg,
0.11 mmol). The product◦obtained was a bright orange powder.
1
Yield: 65%. Mp > 300 C. H NMR (DMSO-d6, 400 MHz,
Magnetic measurements
25 ◦C): d 4.00 (s, 6H, CH3), 6.78 (d, J = 8.0 Hz, 2H, Ar–H),
Magnetic susceptibility measurements were performed on
a Quantum Design model MPMS-5 SQUID magnetometer
equipped with a 5.5 T superconducting magnet. The instru-
ment operates in the 1.8–400 K temperature range. Variable-
temperature dc susceptibility measurements were performed
with an applied field of 1 T. The sample was immobilized in
an eicosane matrix prior to measurement. The diamagnetic
contributions from the sample container and eicosane were
subtracted from the experimental data. Pascal’s constants were
also used to subtract the diamagnetic contributions, yielding
paramagnetic susceptibilities.54
7.02 (t, J = 7.2 Hz, 2H, Ar–H), 7.55 (d, J = 6.4 Hz, 2H, Ar–
=
H). IR (neat, ATR): m 786, 1041, 1123 (C S), 1306, 1401, 1458,
1589 cm−1. UV-Vis in DMSO: 312 (37000), 454 (26000). APCI-
MS: m/z 338.97 [M + H]+. Anal. Calc. for C12H12N2O2S2Ni: C,
42.51; H, 3.57; N, 8.26. Found: C, 42.51; H, 3.34; N, 8.08%.
[Cu(3,2-HOPTO)2]. [Cu(3,2-HOPTO)2] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,2-HOPTO (100 mg, 0.70 mmol) and [CuCl2]·2H2O (60 mg,
0.35 mmol). The product obtained was an olive green powder.
Yield: 97%. Mp 265–270 ◦C (decomp.). IR (neat, ATR): m 765,
−1
=
1045, 1127 (C S), 1298, 1397, 1416, 1458, 1590 cm . UV-Vis in
DMSO: 326 (11200), 386 (34400). APCI-MS: m/z 343.88 [M +
H]+. Anal. Calc. for C12H12N2O2S2Cu: C, 41.91; H, 3.52; N, 8.15.
Found: C, 41.77; H, 3.53; N, 8.27%.
Spectrophotometric titrations
Measurements were performed with an Orion microcombina-
tion glass electrode. The electrode was calibrated for −log[H3O+]
by titration of a standardized HCl solution (Aldrich, 0.1 M
volumetric standard) with KOH (Aldrich, 0.1 M volumetric
standard) at 25 ◦C and 0.1 M ionic strength (KCl) using a
motorized burette (Dosimat, Metrohm, Switzerland) by adding
a total of 50 aliquots of KOH under a N2 atmosphere (solvent-
vapor-saturated gas). The endpoint, electrode potential, and
slope were determined by using Gran’s method as implemented
in the software GLEE.55,56 The calibration procedure was
repeated three times prior to each pKa value determination.
The electrode potential was measured with the Corning pH/Ion
Analyzer 355, and the emf measurements were reproducible with
0.1 mV accuracy.
[Zn(3,2-HOPTO)2]. [Zn(3,2-HOPTO)3] was synthesized by
the same procedure used for [Fe(3,4-HOPTO)3] starting from
3,2-HOPTO (84 mg, 0.59 mmol) and [Zn(OAc)2]·2H2O (66 mg,
0.30 mmol). The product◦ obtained was an off-white powder.
1
Yield: 88%. Mp 187–190 C (decomp.). H NMR (DMSO-d6,
400 MHz, 25 ◦C): d 4.06 (s, 6H, CH3), 6.90 (d, J = 8.1 Hz, 2H,
Ar–H), 6.97 (t, J = 7.0 Hz, 2H, Ar–H), 7.70 (d, J = 5.9 Hz, 2H,
=
Ar–H). IR (neat, ATR): m 761, 1049, 1122 (C S), 1290, 1336,
1416, 1458, 1593 cm−1. UV-Vis in DMSO: 278 (12000), 362
(25500), 370 (26100). FAB-HRMS: Calc. for C12H13N2O2S2Zn
[M + H]+: 344.9704. Found, D: 344.9707, 0.8 ppm.
X-Ray crystallography
All protonation constants reported in this study were deter-
mined using spectrophotometric measurements. The titrations
were automated under PC control with programs written
in Varian ADL language by Prof. Christoph J. Fahrni at
the Georgia Institute of Technology. The UV/Vis absorption
spectra of the ligands were monitored with a Varian Cary 50 Bio
Spectrophotometer for a 3.0 mL solution of the corresponding
ligand (∼15 lM) in 0.1 M KCl under a dinitrogen atmosphere
(solvent-vapor-saturated gas) titrated with 30–60 aliquots of
KOH (0.66 mM) using a J-KEM Scientific syringe pump (Model
1250) and J-KEM Scientific Infinity Controller. Throughout
Single crystals of each compound suitable for X-ray diffrac-
tion structural determination (see ESI†) were mounted on
quartz capillaries by using Paratone oil and were cooled
in a nitrogen stream on the diffractometer. Data were col-
lected on a Bruker AXS area detector diffractometer. Peak
integrations were performed with the Siemens SAINT soft-
ware package. Absorption corrections were applied using the
program SADABS. Space group determinations were per-
formed by the program XPREP. The structures were solved
by direct methods and refined with the SHELXTL software
package.53 All hydrogen atoms were fixed at calculated po-
sitions with isotropic thermal parameters unless otherwise
noted; all non-hydrogen atoms were refined anisotropically.
The complexes [Cu(thiomaltolato)2], [Ni(maltolato)2(H2O)2],
[Fe(3,4-HOPTO)3] and [Zn(3,2-HOPTO)2] all possess crystal-
lographically imposed symmetry (see ESI† for details).
the titration, the temperature was maintained at 25
0.1 ◦C
by circulating constant-temperature water through a jacketed
titration cell. The emf of each solution was directly measured in
the UV quartz cell (electrode diameter 3 mm) and converted
to −log[H3O+] using the E◦ and slope, as obtained from
the electrode calibration procedure described above. The raw
spectral and emf data were processed with nonlinear least-
squares fit analysis using the SPECFIT (version 3.0.36) software
package.57
CCDC reference numbers 246105–246113.
See http://dx.doi.org/10.1039/b505034k for crystallographic
data in CIF or other electronic format.
2 5 9 0
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Results and discussion
Synthesis
We recently reported the synthesis of several new O,S mixed
ligands including thiopyrone and HOPTO chelators.50,51 Pyrones
were converted to thiopyrones using P4S10 in combination with
hexamethyldisiloxane in organic solvents.51,58 The use of P4S10
under solvent free conditions was found to smoothly convert
hydroxypyridinones to the corresponding hydropyridinethiones
in modest yields.50 The general constitution of these compounds
can be readily identified by their IR spectra. The sulfur
substitution results in the expected mC= stretching mode, which
S
is found at lower wavenumbers (∼1130–1200 cm−1) relative to a
normal mC= band.59 Reaction of these chelators with metal ion
O
salts in mixed methanol–water solvent systems in the presence of
stoichiometric base yielded the corresponding metal complexes
in high yields. The complexes typically precipitate from solution
and are isolated and purified by simple vacuum filtration
followed by washing with copious amounts of deionized water.
Metal complexes with thiomaltol, 3,4-HOPTO and 3,2-HOPTO
are described below; complexes with thiopyromeconic acid
were not investigated in detail, as they were anticipated to be
essentially identical to those obtained with thiomaltol.
Structural characterization
Although the solubility of the metal complexes varied signif-
icantly, several complexes were sufficiently soluble to generate
crystals for structural determination. The iron(III) and nickel(II)
complexes of thiomaltol have been previously described.51 The
iron(III) complex demonstrated a pronounced trans influence
with a fac arrangement of the ligands about the metal center. The
trans influence is a thermodynamic effect where the strongest
donor ligands arrange themselves trans to the weakest donor
ligands (which consequently lengthens the weaker metal–ligand
bond).60,61 For a tris(chelate) complex with a nonsymmetric
bidentate chelator, the mer geometry is statistically favored while
the fac geometry is enthalpically favored.61 The nickel(II) thioma-
ltol complex also showed a trans influence as demonstrated by
the cis coordination geometry of the ligands in this square-
planar complex.51 This is in contrast to [Ni(maltolato)2(H2O)2]
which possesses a distorted octahedral geometry (Fig. 2) with
the two maltol ligands forming a square plane and two water
molecules occupying the axial positions (Table 1). In this com-
plex the maltolato ligands have a trans geometry relative to each
other and thus do not display a trans influence; the same stere-
ochemistry is found in the complex [Zn(maltolato)2(H2O)2].62
The Ni–O bond lengths in [Ni(maltolato)2(H2O)2] are nearly
˚
˚
identical at 2.04 A (Ni–O1) and 2.05 A (Ni–O3) (Table 2).
In contrast to other O,S donor complexes, the structure
of [Cu(thiomaltolato)2] is rather surprising, showing a trans
geometry (Fig. 2), and hence is inconsistent with the prominent
trans influence observed with earlier reported complexes of this
ligand51 and related complexes reported here (vide infra). The
˚
copper(II) bond lengths are ∼2.26 and ∼1.93 A for the Cu–
S and Cu–O bonds, respectively. The structure is planar with
O1–Cu–S1 (interligand) angles of 91.6◦, close to the idealized
value of 90◦ for a square-planar complex. The reasons why this
complex does not show a geometry biased by the trans influence
have not been resolved.
The structure of [Co(thiomaltolato)2] reveals the expected
tetrahedral geometry (Fig. 2). The geometry at the metal center
is slightly distorted due to the substantially different Co–S
˚
vs. Co–O bond lengths at ∼2.32 and ∼1.95 A, respectively.
The O1–Co–O3 angle of 124.2◦ and the S1–Co–S2 angle
of 123.5◦ are both greater than the expected 109.5◦ for an
idealized tetrahedral geometry. As with [Co(thiomaltolato)2],
the structure of [Zn(thiomaltolato)2] also shows a distorted
tetrahedral coordination sphere (Fig. 2) due to the differing
Zn–S and Zn–O bond lengths (Table 2), resulting in the
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Table 2 Summary of M–X bond lengths and observed stereochemical trans influence for chelate metal complexes presented
˚
˚
Compound
M–S/A
M–O/A
Coord. geometry, trans influence?
[Ni(maltolato)2(H2O)2]a
[Fe(thiomaltolato)3]b
[Co(thiomaltolato)2]
[Ni(thiomaltolato)2]b
[Cu(thiomaltolato)2]
[Zn(thiomaltolato)2]
[Fe(3,4-HOPTO)3]
[Ni(3,4-HOPTO)2]
[Cu(3,2-HOPTO)2]
[Zn(3,2-HOPTO)2]
2.05 (M–O)
2.50
2.32
2.16
2.26
2.32
2.47
2.15
2.25
2.04
1.97
1.95
1.88
1.93
1.96
2.01
1.88
1.94
1.96
Octahedral, n/a
fac-Octahedral, yes
Tetrahedral, n/a
cis-Square-planar, yes
trans-Square-planar, no
Tetrahedral, n/a
fac-Octahedral, yes
cis-Square-planar, yes
cis-Square-planar, yes
Tetrahedral, n/a
2.31
a
Ni–OH2 2.08 A. b From ref. 50.
˚
and five-coordinate complexes.62 Presumably the stronger donor
ability of thiomaltol precludes the acquisition of additional
solvent ligands in the solid state.
The structure of [Fe(3,4-HOPTO)3] shows a distorted oc-
tahedral geometry (Fig. 3), similar to [Fe(thiomaltolato)3],
with a fac arrangement of the ligands, which reflects the
strong trans influence of the 3,4-HOPTO ligand (Table 1).51
˚
The Fe–S bond length is ∼2.47 A while the Fe–O bond
˚
length is ∼2.01 A (Table 2). In addition, there are several
similarities between the structures of [Fe(3,4-HOPTO)3] and
[Fe(3,4-HOPO)3], including the similar twist angles of the metal
centers (43.6 and 44.9◦, respectively). Furthermore, [Fe(3,4-
HOPO)3] also crystallizes as the fac isomer.63,64 Indeed, several
[M(3,4-HOPO)3] complexes have been found to crystallize as the
fac isomer rather than the statistically favored mer isomer,63–69
the latter of which is the commonly observed geometry of
tris(maltolato) complexes.1,2 The preference for the fac geometry
in [M(3,4-HOPO)3] complexes, which were co-crystallized with
12 water molecules, may be due to the extensive hydrogen
Fig. 2 Structural diagrams of (from top to bottom): [Ni(maltolato)2-
(H2O)2], [Cu(thiomaltolato)2], [Co(thiomaltolato)2] and
[Zn(thiomaltolato)2] with partial atom numbering schemes (ORTEP,
50% probability ellipsoids). Hydrogen atoms and solvent molecules
have been omitted for clarity.
Fig. 3 Structural diagrams of [Fe(3,4-HOPTO)3] (top) and [Ni(3,4-
HOPTO)2] (bottom) with partial atom numbering schemes (ORTEP,
50% probability ellipsoids). Hydrogen atoms have been omitted for
clarity.
O1–Zn–O3 angle of 119.9◦ and the S1–Zn–S2 angle of 125.4◦.
The [Zn(thiomaltolato)2] is distinct from the structurally charac-
terized [Zn(maltolato)2(H2O)2], which is comprised of both six-
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bonding reported in the crystal lattice of these compounds
(M = Al3+, Ga3+ and In3+).66,67 These [M(3,4-HOPO)3] structures
have been described as ‘exoclathrates’ where the metal complex is
rigidly positioned outside the aquo hydrogen-bonded network.70
Therefore, although [Fe(3,4-HOPTO)3] and [Fe(3,4-HOPO)3]
have fac coordination spheres in the solid state, the 3,4-HOPO
geometry is likely enforced by the extensive hydrogen bonding
network, while the 3,4-HOPTO geometry originates from the
trans influence of the O,S ligand (no solvent was co-crystallized
with [Fe(3,4-HOPTO)3]).
The [Ni(3,4-HOPTO)2] complex shows the expected square-
planar geometry (Fig. 3) with a cis coordination as predicted
from a strong trans influencing ligand. The average Ni–S bond
˚
length is ∼2.15 A while the average Ni–O bond length is
˚
∼1.88 A; these bond lengths are comparable to the corre-
sponding [Ni(thiomaltolato)2] complex (Table 2).51 As with
the analogous thiomaltol complex, the cis geometry causes
a slight distortion in the square-planar conformation with
the O,S chelators, making the O1–Ni–O2 slightly more acute
at 88.4◦ while opening the S1–Ni–S2 angle to 91.1◦. The
complex exhibits little out-of-plane distortion with a mean
Fig.
4
Structural diagrams of [Cu(3,2-HOPTO)2] (top) and
[Zn(3,2-HOPTO)2] (bottom) with partial atom numbering schemes
(ORTEP, 50% probability ellipsoids). Hydrogen atoms have been
omitted for clarity.
˚
deviation from the square plane (five atoms) of 0.01 A. No
structure of [Ni(3,4-HOPO)2] is available for comparison in the
Cambridge Crystallographic Data Center (CCDC); however,
[Cu(3,4-HOPO)2] and [Zn(3,4-HOPO)2]·7H2O both have two
hydroxypyridinone ligands that make up the square plane of
either a square-planar (Cu2+) or distorted square-pyramidal
coordination geometry (Zn2+). In both cases the 3,4-HOPO
chelators display a trans orientation relative to one another.7,62
In contrast, the related nickel(II) complex with 1-hydroxy-6-
methylpyridine-2(1H)-thione (a methyl-substituted derivative
of 1,2-HOPTO, Fig. 1) and [Ni(thiomaltolato)2] show square-
planar geometries with a cis orientation of the ligands, as
expected from a strong trans influencing O,S ligand.24
planar complexes with the O,S ligands examined in this study.
This suggests that the energy difference between the cis and trans
conformation in the copper(II) complexes is small, and only a
weak trans influence is present.
The [Zn(3,2-HOPTO)2] complex (Fig. 4), due to the sub-
stantially different M–S and M–O bond lengths (Table 2),
possesses a distorted tetrahedral coordination sphere as in the
other tetrahedral complexes described here. The structure of
the corresponding 3,2-HOPO metal complex is not available
in the CCDC for comparison; however, the related 1-hydroxy-6-
methylpyridine-2(1H)-thione complex with zinc(II) has a similar
distorted tetrahedral geometry.24 As described with other O,S
ligands and as expected based on ionic radii, the order of metal–
donor atom distances in the ML2 structures presented here is
Ni2+ < Cu2+ < Co2+ ≈ Zn2+.71
Fig. 4 shows the structure of [Cu(3,2-HOPTO)2], which has
a distorted square-planar geometry (Table 1). There was no
structure of the corresponding 3,2-HOPO metal complex in the
CCDC for comparison. The related copper(II) complex with 1-
hydroxy-6-methylpyridine-2(1H)-thione has a distorted square-
pyramidal geometry with the O,S ligands in a cis configuration
and the copper centers weakly bridged by N-oxide oxygen
atoms.24 The bond lengths in [Cu(3,2-HOPTO)2] are comparable
to the corresponding thiomaltol complexes (Table 2); however,
unlike [Cu(thiomaltolato)2], the 3,2-HOPTO complex shows
a trans influence with the corresponding cis coordination
geometry. Similar to other square-planar structures with O,S
ligands, [Cu(3,2-HOPTO)2] shows a distortion of the square-
planar structure due to the cis geometry with an opening of the
S1–Cu–S2 angle to 94.2◦ and a O1–Cu–O2 angle of 92.4◦. The
ligands are twisted from an idealized square plane with an RMS
UV-visible spectroscopy
With the exception of the closed shell zinc(II) complexes, the
metal complexes described here possessed a range of deep
colors from the reddish-brown [Cu(thiomaltolato)2] to the dark
navy blue [Fe(3,2-HOPTO)3]. Due to the varied solubility of
the metal complexes, the electronic spectra of the compounds
were recorded in either methanol (thiomaltol) or DMSO (3,2-
HOPTO, 3,4-HOPTO). The results of these measurements
are summarized in Table 3 and illustrated in Fig. 5. Typical
ligand centered transitions are observed in the high energy
region of these absorption spectra. In addition, the iron(III)
and cobalt(II) complexes show broad charge transfer transitions
˚
deviation from the plane (five atoms) of 0.17 A. The structure
of [Cu(3,2-HOPTO)2] further highlights the anomalous trans
conformation of [Cu(thiomaltolato)2] relative to other square-
Table 3 Summary of UV-visible absorption features for the coordination complexes described in this report
Compound
kmax/nm (e/M−1 cm−1
)
[Co(thiomaltolato)2]a
[Cu(thiomaltolato)2]a
[Zn(thiomaltolato)2]a
[Fe(3,4-HOPTO)3]b
[Ni(3,4-HOPTO)2]b
[Cu(3,4-HOPTO)2]b
[Zn(3,4-HOPTO)2]b
[Fe(3,2-HOPTO)3]b
[Ni(3,2-HOPTO)2]b
[Cu(3,2-HOPTO)2]b
[Zn(3,2-HOPTO)2]b
288 (22300), 395 (9000), 454 (5600)
269 (29000), 313 (27000), 389 (26700)
264 (15000), 303 (10400), 380 (23600)
352 (36800), 550 (4900)
280 (44500), 314 (17000), 380 (6300), 426 (7500), 458 (6600)
292 (13900), 332 (21800), 372 (20800)
290 (8400), 356 (35600)
376 (40400), 482 (6200), 584 (6300)
312 (37000), 454 (26000)
326 (11200), 386 (34400)
278 (12000), 362 (25500), 370 (26100)
a Obtained in MeOH. b Obtained in DMSO.
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Electrochemistry
The cyclic voltammetry of [Fe(thiomaltolato)3] has been
reported.51 Relative to ferrocene under the same conditions,
[Cu(thiomaltolato)2] and [Cu(3,2-HOPTO)2] (Fig. S1, ESI†)
showed quasireversible redox couples centered at −1.16 V
(DEp = 0.18 V) and at −1.28 V (DEp = 0.18 V), respectively. Both
[Cu(thiomaltolato)2] and [Cu(3,2-HOPTO)2] showed reduced
reversibility with increasing sweep rate. The electrochemistry
of the analogous O,O copper(II) complexes has not been
reported.
Magnetic measurements
Both the [Fe(3,4-HOPTO)3] and the [Fe(3,2-HOPTO)3] com-
plexes have magnetic properties typical of a mononuclear high-
spin (S = 5/2, g = 2) iron(III) ion. The theoretical spin only value
of 5.92 lB is in good agreement with the experimental room
temperature moment of 5.9 lB from the SQUID experiments
(Fig. S2, ESI†). The high-spin ground state of these complexes is
consistent with early findings that [Fe(thiohydroxamato)3] com-
plexes are high-spin; these [Fe(thiohydroxamato)3] tris(chelate)
complexes were found to be surprisingly stable toward D-/K-
interconversion for a high-spin iron(III) complex.32,33
Ligand protonation constants
The protonation equilibria of the O,S donor ligands were
investigated by spectrophotometric titrations. The pKa values
were determined by titrating a solution of each ligand in water
(∼15 lM) with KOH at a constant ionic strength (Fig. S3, ESI†).
The experimentally measured potential data were converted
to −log[H3O+] values based on the electrode potential (E◦)
and slope, which were obtained from the electrode calibration
data using Gran’s method.56,74 The corresponding pKa values
were determined using a nonlinear least-squares fit analysis
(Table 4).55,75 The ligands show one protonation event, which can
be assigned to the hydroxyl group of each compound. The data
show that, in general, the O,S donor ligands are more acidic than
their O,O counterparts. This is the expected trend because sulfur
is less electronegative and more polarizable than oxygen, which
should increase delocalization into the aromatic heterocycle and
thereby stabilize the negative charge after deprotonation of the
hydroxyl oxygen. This effect appears to be attenuated in the 3,2-
HOPTO isomer, which has a pKa1 value that is slightly higher
than that of 3,2-HOPO. The thiopyrones are found to be more
acidic than 3,4-HOPTO or 3,2-HOPTO; this is because the more
electronegative ring oxygen atoms stabilize the deprotonated
form of the thiopyrones more effectively than does the ring
nitrogen atom of the HOPTOs. While this manuscript was in
preparation, Orvig and co-workers reported the protonation
constants for thiomaltol and 3,4-HOPTO as determined by
potentiometry;42 their findings are wholly consistent with the
values reported in Table 4.
In summary, the coordination chemistry of thiomaltol, 3,4-
HOPTO and 3,2-HOPTO ligands with iron(III), cobalt(II),
nickel(II), copper(II) and zinc(II) ions has been studied by
Fig. 5 Absorbance spectra of O,S ligands and coordination com-
plexes: (A) thiomaltol (solid line), [Co(thiomaltolato)2] (dotted line),
[Cu(thiomaltolato)2] (narrow dashed line) and [Zn(thiomaltolato)2]
(wide dashed line) in methanol; (B) 3,4-HOPTO (solid line),
[Fe(3,4-HOPTO)3] (dotted line), [Ni(3,4-HOPTO)2] (dashed-dotted
line), [Cu(3,4-HOPTO)2] (narrow dashed line) and [Zn(3,4-HOPTO)2]
(wide dashed line) in DMSO; (C) 3,2-HOPTO (solid line),
[Fe(3,2-HOPTO)3] (dotted line), [Ni(3,2-HOPTO)2] (dashed-dotted
line), [Cu(3,2-HOPTO)2] (narrow dashed line) and [Zn(3,2-HOPTO)2]
(wide dashed line) in DMSO.
Table 4 Protonation constants for thiomaltol, thiopyromeconic acid,
3,4-HOPTO and 3,2-HOPTO and for their corresponding O,O analogs
in aqueous solution
Ligand (O,S)
pKa Valuea Ligand (O,O)
pKa Value
Thiomaltol
Thiopyromeconic acid
3,4-HOPTO
8.16(2)
7.29(5)
9.47(2)
8.97(5)
Maltol
8.513(2)a,c
Pyromeconic acid 7.69(3)b
3,4-HOPO
3,2-HOPO
9.77(1)a,d
8.89(1)a,e
3,2-HOPTO
in the visible part of the spectrum, which is characteristic
of related complexes formed with catecholates, pyrones and
hydroxypyridinonates.51,72,73
a I = 0.10 M KCl, T = 25 ◦C. b I = 0.5 M, T = 25 ◦C, ref. 75. c Ref. 76.
d Ref. 77. e Ref. 78.
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crystallographic, spectroscopic, electrochemical and SQUID
experiments. Structural characterization of the homoleptic
complexes shows the presence of a strong trans influence,
with few exceptions. Spectrophotometric titrations have been
performed on thiopyrone and HOPTO ligands, showing that
they are generally more acidic than their O,O analogues. These
findings are the first extensive characterization of transition-
metal complexes of these ligands, which is a fundamental
step for considering their use in medicinal and environmental
bioinorganic chemistry. We are continuing our investigations
into the use of these sulfur-containing ligands for a variety of
applications from sequestering heavy metals to use as chelators
in metalloenzyme inhibitors.46,50
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Acknowledgements
We thank Prof. Arnold L. Rheingold and Dr Lev N. Zakharov
(U.C.S.D.) for help with the X-ray structure determinations
and Prof. Clifford P. Kubiak (U.C.S.D.) for use of his FT-
IR. We also thank Prof. Christoph J. Fahrni (Georgia Institute of
Technology) for his generous contribution of time, knowledge,
and facilities for solution thermodynamics studies. This work
was supported by the University of California, San Diego, a
Chris and Warren Hellman Faculty Scholar award, and an award
from the American Heart Association. J. A. L. was supported
in part by a GAANN fellowship (GM-602020-03), an ARCS
award, and a U.C. TSR & TP Fellowship. S. M. C. is a Cottrell
Scholar of the Research Corporation.
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