Addressing lead toxicity: Complexation of lead(II) with thiopyrone and hydroxypyridinethione O,S mixed chelators

Article abstract of DOI:10.1021/ic0493696

The lead(II) ion is regarded as a serious environmental contaminant. A considerable need exists to develop selective ligands for remediation of this metal ion. Herein, the coordination chemistry of lead(II) is investigated with three O,S donor ligands: thiomaltol, 3-hydroxy-1-methyl-2(1H)-pyridinethione (3,2-HOPTO), and 3-hydroxy-1,2-dimethyl-4(1H)-pyridinethione (3,4-HOPTO). The X-ray structures of [Pb(thiomaltolato)₂] and [Pb(3,4-HOPTO) ₂] have been solved, revealing the expected 4-coordinate geometries. Electronic spectra have been obtained for the lead(II) complexes with all three ligands. Preliminary solution studies show that the thiomaltol ligand binds lead(II) preferentially over magnesium(II) and calcium-(II); however, [Pb(thiomaltolato)₂] is not stable in the presence of 1 equiv of EDTA. Tetradentate ligands derived from these O,S chelators are expected to generate higher affinity ligands for lead-(II) sequestration.

Full text of DOI:10.1021/ic0493696

Inorg. Chem. 2004, 43, 6534−6536
Addressing Lead Toxicity: Complexation of Lead(II) with Thiopyrone
and Hydroxypyridinethione O,S Mixed Chelators
Jana A. Lewis and Seth M. Cohen*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
La Jolla, California 92093-0358
Received May 14, 2004
The lead(II) ion is regarded as a serious environmental contami-
nant. A considerable need exists to develop selective ligands for
remediation of this metal ion. Herein, the coordination chemistry
of lead(II) is investigated with three O,S donor ligands: thiomaltol,
3-hydroxy-1-methyl-2(1H)-pyridinethione (3,2-HOPTO), and 3-hy-
droxy-1,2-dimethyl-4(1H)-pyridinethione (3,4-HOPTO). The X-ray
structures of [Pb(thiomaltolato)2] and [Pb(3,4-HOPTO)2] have been
solved, revealing the expected 4-coordinate geometries. Electronic
spectra have been obtained for the lead(II) complexes with all
three ligands. Preliminary solution studies show that the thiomaltol
ligand binds lead(II) preferentially over magnesium(II) and calcium-
(II); however, [Pb(thiomaltolato)2] is not stable in the presence of
1 equiv of EDTA. Tetradentate ligands derived from these O,S
chelators are expected to generate higher affinity ligands for lead-
(II) sequestration.
continues to be a primary hypothesis underlying the detri-
mental effects of lead exposure.10,11
In light of the continued interest in understanding lead
toxicity and detecting this widespread contaminant, progress
toward designing and characterizing lead-selective ligands
remains an important topic.1,12 Compounds presently used
for lead chelation therapy, such as 2,3-dimercaptopropanol
(British Anti-Lewisite, BAL) and meso-2,3-dimercapto-
succinic acid (DMSA), were not specifically optimized for
“heavy” metal chelation and suffer from side effects associ-
ated with this lack of selectivity. The identification of high
affinity ligands for lead would prove useful not only for
treating lead poisoning, but also for developing molecular
probes for elucidating the biodistribution and biological
interactions of this ion in living systems. The work of
Raymond and co-workers on thiohydroxamic acids has often
been cited as a noteworthy effort toward the development
of lead(II) specific sequestering agents (Figure 1).13-16 These
mixed O,S donor ligands are proposed to have an optimal
hard/soft Lewis basicity to match the preferences of the lead-
(II) ion and as such have been reported to form extremely
stable lead(II) complexes (log â120 ) 20.7, for N-phenylth-
iobenzohydroxamic acid in 70% aqueous dioxane).17 Despite
these encouraging results, no significant advancements of
these systems have been reported for nearly a decade. Herein,
we report several O,S ligands, including thiopyrones and
hydroxypyridinethiones, which form stable, mononuclear
complexes with lead(II) and may be promising new selective
chelators for this biologically toxic metal ion.
The coordination chemistry of the lead(II) ion has re-
mained a subject of continuing interest due to the persistence
of this metal ion as a high priority environmental toxin,1-3
and substantial effort has been invested in the design of
selective sensors of lead to detect this pollutant.4-7 Significant
advancements, by using both biochemical and model-based
studies,8 have been made in understanding the molecular
mechanisms that cause lead toxicity.9 The ability of lead(II)
to undergo metathesis reactions with zinc(II) and calcium-
(II) metalloproteins resulting in loss of metabolic function
* To whom correspondence should be addressed. E-mail: scohen@
ucsd.edu.
(1) Claudio, E. S.; Magyar, J. S.; Godwin, H. A. In Progress in Inorganic
Chemistry; Karlin, K. D., Ed.; John Wiley & Sons: Hoboken, NJ,
2003; Vol. 51, pp 1-144 and references therein.
(2) Tong, S.; von Schirnding, Y. E.; Prapamontol, T. Bull. World Health
Org. 2000, 78, 1068-1077.
(10) Payne, J. C.; ter Horst, M. A.; Godwin, H. A. J. Am. Chem. Soc. 1999,
121, 6850-6855.
(11) Bouton, C. M. L. S.; Frelin, L. P.; Forde, C. E.; Godwin, H. A.;
Pevsner, J. J. Neurochem. 2001, 76, 1724-1735.
(12) Claudio, E. S.; ter Horst, M. A.; Forde, C. E.; Stern, C. L.; Zart, M.
K.; Godwin, H. A. Inorg. Chem. 2000, 39, 1391-1397.
(13) Abu-Dari, K.; Hahn, F. E.; Raymond, K. N. J. Am. Chem. Soc. 1990,
112, 1519-1524.
(3) Jang, Y.-C.; Townsend, T. G. EnViron. Sci. Technol. 2003, 37, 4778-
4784.
(4) Deo, S.; Godwin, H. A. J. Am. Chem. Soc. 2000, 122, 174-175.
(5) Chae, M.-Y.; Yoon, J.; Czarnik, A. W. J. Mol. Recognit. 1996, 9,
297-303.
(6) Liu, J.; Lu, Y. J. Am. Chem. Soc. 2003, 125, 6642-6643.
(7) Li, J.; Lu, Y. J. Am. Chem. Soc. 2000, 122, 10466-10467.
(8) Bridgewater, B. M.; Parkin, G. J. Am. Chem. Soc. 2000, 122, 7140-
7141.
(14) Abu-Dari, K.; Karpishin, T. B.; Raymond, K. N. Inorg. Chem. 1993,
32, 3052-3055.
(15) Rupprecht, S.; Franklin, S. J.; Raymond, K. N. Inorg. Chim. Acta 1995,
235, 185-194.
(16) Rupprecht, S.; Langemann, K.; Lu¨gger, T.; McCormick, J. M.;
Raymond, K. N. Inorg. Chim. Acta 1996, 243, 79-90.
(17) Dietzel, R.; Thomas, P. Z. Anorg. Allg. Chem. 1971, 381, 214-218.
(9) Needleman, H. Annu. ReV. Med. 2004, 55, 209-222.
6534 Inorganic Chemistry, Vol. 43, No. 21, 2004
10.1021/ic0493696 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/21/2004

COMMUNICATION
Figure 1. Mixed O,S ligands studied for selective lead(II) complexation.
Thiohydroxamic acids and 1,2-HOPTO ligands (top, outside box) had been
previously synthesized and studied for lead(II) sequestration. New ligands
3,2-HOPTO, 3,4-HOPTO, and thiomaltol (left to right, in box) are presented
here. One-step synthesis of 3,4-HOPTO and 3,2-HOPTO (bottom).
Figure 2. Structural diagram of [Pb(thiomaltolato)2] (top) and [Pb(3,4-
HOPTO)2] (bottom) with partial atom numbering schemes (ORTEP, 50%
probability ellipsoids). Hydrogen atoms have been omitted for clarity.
An efficient synthesis of thiopyrones derived from 3-hy-
droxy-2-methyl-4-pyrone (maltol) and 3-hydroxy-4-pyrone
(pyromeconic acid) has been recently reported.18 On the basis
of these findings, we sought to prepare hydroxypyridine-
thiones (HOPTOs) derived from 3-hydroxy-1-methyl-2(1H)-
pyridinone and 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone.
However, combination of these starting materials with P4S10
with or without HMDO under a variety of solution conditions
failed to generate the desired compounds.18-20 Ultimately, a
solventless reaction where the hydroxypyridinone starting
material was pulverized with P4S10 and heated to 175 °C
under a nitrogen atmosphere allowed for isolation of the
desired 3,2-HOPTO and 3,4-HOPTO products, respectively
(Figure 1).21 Reaction of thiomaltol or HOPTO ligands with
lead(II) acetate proceeded smoothly in mixed aqueous/
methanolic solution resulting in the precipitation of the lead
complexes as yellow powders. A recent study reports the
preparation of [VdO(3,4-HOPTO)2] and its use as an insulin
mimetic, but experimental details on the synthesis of 3,4-
HOPTO or the vanadyl complex were not provided.22
Standard characterization of the lead(II) complexes with
thiomaltol, 3,2-HOPTO, and 3,4-HOPTO was consistent with
each of these ligands forming a 1:2 metal/ligand complex
(see Supporting Information). The composition of these
compounds was unambiguously confirmed by structural
characterization of [Pb(thiomaltolato)2] and [Pb(3,4-HOP-
TO)2] by using single crystal X-ray diffraction.23 The
structures of these complexes are shown in Figure 2. Both
complexes show a four-coordinate geometry around the lead-
(II) ion, quite similar to that observed in other O,S chelating
complexes.13-15 The bond lengths in each complex are
similar, with Pb-S and Pb-O distances of 2.81 and 2.36 Å
in [Pb(thiomaltolato)2] and 2.67 and 2.39 Å in [Pb(3,4-
HOPTO)2]. These bond distances are comparable to those
found in earlier thiohydroxamic acid complexes.13-15 The
coordination geometry around the lead(II) ion is distorted
due to the stereoactive lone pair of the metal center. This
irregular coordination geometry has been found in related
compounds.13-15 The crystal structures provide no evidence
for bridging interactions between neighboring complexes, as
has often been found in lead(II) complexes with thiohydrox-
amic acids and hydroxypyridinethiones (typically distant
Pb‚‚‚O interactions). The closest contact between neighboring
complexes in both structures is a Pb‚‚‚S contact of 3.50 and
4.37 Å for [Pb(thiomaltolato)2] and [Pb(3,4-HOPTO)2],
respectively (Figures S1-S3). In the structure of [Pb-
(thiomaltolato)2], the 3.50 Å contact is potentially within a
weak bonding distance, but it appears to be more a result of
the “nested” packing of the complexes than a specific
interaction.
The electronic spectra of these complexes show several
intense transitions. In DMF solution, [Pb(thiomaltolato)2]
shows two broad bands centered at 306 and 402 nm, while
both [Pb(3,2-HOPTO)2] and [Pb(3,4-HOPTO)2] show a
single broad transition at 376 and 378 nm, respectively but
lack a well-defined, higher energy feature at ∼300 nm
(Figure 3). The major transitions in all of the metal
complexes are shifted to lower energy relative to the
corresponding free ligands.10
The intense electronic transitions of these complexes
provided a spectroscopic handle for a preliminary evaluation
(18) Lewis, J. A.; Puerta, D. T.; Cohen, S. M. Inorg. Chem. 2003, 42,
7455-7459.
(19) Katoh, A.; Tsukahara, T.; Saito, R.; Ghosh, K. K.; Yoshikawa, Y.;
Kojima, Y.; Tamura, A.; Sakurai, H. Chem. Lett. 2002, 114-115.
(20) Curphey, T. J. J. Org. Chem. 2002, 67, 6461-6473.
(21) Davies, J. S.; Smith, K.; Turner, J. Tetrahedron Lett. 1980, 21, 2191-
2194.
(22) Thompson, K. H.; Orvig, C. In Metal Ions in Biological Systems; Sigel,
A., Sigel, H., Eds.; Marcel Dekker: New York, 2004; Vol. 41, pp
221-253.
(23) X-ray data follow. Crystal data for [Pb(thiomaltolato)2] (PbC12H10O4S2,
Mr ) 489.51 g mol-1): monoclinic, space group C2/c, a ) 19.397-
(14) Å, b ) 4.131(3) Å, c ) 16.584(12) Å, â ) 91.865(10)°, V )
1328.2(16) Å3, Z ) 4, T ) 100(2) K, wR2 ) 0.0827, R1 ) 0.0338
(1509 unique reflections). Crystal data for [Pb(3,4-HOPTO)2]
(PbC14H16N2O2S2, Mr ) 515.60 g mol-1): orthorhombic, space group
Fdd2, a ) 8.7501(6) Å, b ) 31.678(2) Å, c ) 10.7750(7) Å, V )
2986.7(4) Å3, Z ) 4, T ) 100(2) K, wR2 ) 0.0673, R1 ) 0.0261
(1694 unique reflections).
Inorganic Chemistry, Vol. 43, No. 21, 2004 6535

COMMUNICATION
[Pb(EDTA)]2- complex (log â110 ) 18.10).1 Although we
have not yet determined the formation constants for these
complexes, the results are generally consistent with that
found for simple thiohydroxamic acids. The stability constant
of [Pb(acetothiohydroxamato)2] is log â120 ) 12.40 (in 1:1
MeOH/water), which is also substantially lower than that
found for EDTA.16 Tethering of two O,S chelators together
to prepare a tetradentate ligand may improve the stability of
the complexes reported here.
In summary, we have described a one-step synthesis for
two hydroxypyridinethiones for which essentially no coor-
dination chemistry has been described22 and reported novel
lead(II) complexes formed with O,S ligands. Spectrophoto-
metric studies suggest that these O,S chelators have some
selectivity for lead(II) over other biological relevant cations
such as magnesium(II) and calcium(II). Ongoing studies are
focused on a more detailed examination of the solution
thermodynamics of these ligands with various metal ions as
well as the synthesis of bis(bidentate) ligands with potentially
greater affinity and selectivity for the toxic lead(II) ion.
Figure 3. Electronic spectra of 3,2-HOPTO (0), 3,4-HOPTO (]), and
thiomaltol (O) ligands in DMF. Electronic spectra of [Pb(3,2-HOPTO)2]
(9), [Pb(3,4-HOPTO)2] ([), and [Pb(thiomaltolato)2] (b) complexes in
DMF. The complete spectra of the ligands are shown as dotted lines (‚‚‚),
and lead(II) complexes are shown as solid lines (s).
Acknowledgment. We thank Prof. Arnold L. Rheingold,
Dr. Lev N. Zakharov, and David T. Puerta (U.C. San Diego)
for help with the X-ray structure determinations, Ms. Alexis
Kaushansky for synthetic assistance, and Mr. Ba L. Tran
for obtaining some of the IR spectra. This work was
supported by the University of California, San Diego, and a
Chris and Warren Hellman Faculty Scholar award. S.M.C.
is a Cottrell Scholar of the Research Corporation. J.A.L. was
supported in part by a GAANN fellowship (GM-602020-
03), an ARCS award, and a fellowship from the U.C. Toxic
Substances Research & Teaching Program.
of the stability of these metal complexes in the presence of
biologically relevant metal ions. [Pb(thiomaltolato)2] was
dissolved in an aqueous solution containing 1.0 M DMF
(∼12:1 v/v water/DMF) to a concentration of ∼50 µM and
titrated with increasing amounts of CaCl2 or MgCl2. The
spectrum of the [Pb(thiomaltolato)2] complex is essentially
unchanged in the presence of ∼50-fold excess of Mg2+ or
Ca2+, indicating the thiopyrone has some selectivity for lead-
(II) (Figure S4). The [Pb(thiomaltolato)2] complex was also
examined in the presence of EDTA in aqueous buffer.
Incubation with 0.1 equiv of EDTA caused only small
changes in the [Pb(thiomaltolato)2] spectra; however, com-
petition with either 1 or 10 equiv of EDTA showed a
complete loss of the [Pb(thiomaltolato)2] complex within ∼24
h (Figure S5). This suggests that the stability of [Pb-
(thiomaltolato)2] is significantly lower that that of the
Supporting Information Available: Synthetic details for all
new ligands and metal complexes, Table S1, Figures S1-S5. X-ray
crystallographic files in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org. CIF data are also
available free of charge via the Internet at http://www.ccdc.
cam.ac.uk. Refer to CCDC reference numbers 235985 and 235986.
IC0493696
6536 Inorganic Chemistry, Vol. 43, No. 21, 2004