Efficient route to highly water-soluble aromatic cyclic hydroxamic acid ligands

Article abstract of DOI:10.1002/ejoc.200800147

2-Hydroxyisoquinolin-1-one (1,2-HOIQO) is a new member of the important class of aromatic cyclic hydroxamic acid ligands which are widely used in metal sequestering applications and metal chelating therapy. The first general approach for the introduction

Full text of DOI:10.1002/ejoc.200800147

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800147
Efficient Route to Highly Water-Soluble Aromatic Cyclic Hydroxamic Acid
Ligands
Michael Seitz[a] and Kenneth N. Raymond*[a]
Keywords: O ligands / Ligand design / Aromatic substitution / Heterocycles
2-Hydroxyisoquinolin-1-one (1,2-HOIQO) is a new member
of the important class of aromatic cyclic hydroxamic acid li-
gands which are widely used in metal sequestering applica-
tions and metal chelating therapy. The first general approach
for the introduction of substituents at the aromatic ring of
the chelating moiety is presented. As a useful derivative, the
highly water-soluble sulfonic acid has been synthesized by
an efficient route that allows general access to 1,2-HOIQO
3-carboxylic acid amides, which are the most relevant for ap-
plications.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
HOPO.[11] Unlike hydroxypyridinones, a key precursor for
the synthesis of 1,2-HOIQO can be modified by electro-
philic aromatic substitution reactions, yielding, for example,
the chlorosulfonated isocoumarin 1 (Scheme 1). In this
Introduction
Hydroxypyridinones constitute a very important class of
ligands for the complexation of hard Lewis-acidic metal
ions.[1] This motif occurs in nature, e.g. in the amino acid
-minosine[2] or naturally occurring siderophores.[3] In ad-
dition, these species have been utilized for a number of me-
dicinal applications, such as chelation treatment of metal
ion imbalances (e.g. iron[4] or aluminum[1a,5]). One of the
three isomeric forms of hydroxypyridinone is 1-hydroxypyr-
idin-2-one (1,2-HOPO).
Figure 1. 1,2-HOIQO – a benzannulated analogue of 1,2-HOPO.
Ligands of this type have a number of very attractive
properties, such as facile synthetic access, high affinity/sta-
bility with a wide range of metal ions under physiological
conditions, and useful photophysical properties. As a conse-
quence, 1,2-HOPO has been widely used for the design of
multidentate ligands for a number of applications, such as
actinide sequestering,[6] magnetic resonance imaging,[7]
treatment of iron overload,[8] and lanthanide lumines-
cence.[9] Despite these advantageous characteristics, 1,2-
HOPO ligand architectures often suffer from low aqueous
solubility of the corresponding metal complexes. In other
ligand systems (e.g. catechols or 8-hydroxyquinolines) this
problem has been solved by sulfonation of aromatic scaf-
folds which usually increases the solubility greatly.[10] Un-
fortunately, the pyridinone scaffold is not easily amenable
to the facile introduction of substitutents, because most
aromatic substitution reactions cannot be used because of
the instability of 1,2-HOPO under the harsh reaction condi-
tions. To solve this problem, we recently introduced deriva-
tives of 2-hydroxyisoquinolin-1-one (1,2-HOIQO) 3-car-
boxylic acid (Figure 1), a benzanullated analogue of 1,2-
[a] Department of Chemistry, University of California,
Berkeley, CA 94720-1460, USA
Fax: +1-510-486-5283
E-mail: raymond@socrates.berkeley.edu
Scheme 1. Synthesis of the sulfonated hydroxamic acid ligand 6.
Eur. J. Org. Chem. 2008, 2697–2700
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Seitz, K. N. Raymond
SHORT COMMUNICATION
communication we report the synthesis and functionaliza-
Because 3 is the first molecule of this kind, characteriza-
tion of the corresponding sulfonated 1,2-HOIQO species, tion of the structure and regiochemistry of the 1,2-HOIQO
which has extremely high water solubility.
derivative was performed. The 7-position for the sulfonic
acid functionality, as well as the presence of the expected
1,2-HOIQO core, was confirmed through single-crystal X-
ray crystallography of the corresponding disodium salt
1
(Figure 2).[12] In addition, a 2D H NMR COSY experi-
Results and Discussion
ment confirmed the major isomer in solution to be the one
substituted in 7-position (Figure 3).
The synthesis of the sulfonated 1,2-HOIQO ligand starts
with the chlorosulfonated isocoumarin derivative
1
(Scheme 1).[11]
Hydrolysis with methanolic KOH furnished the corre-
sponding potassium sulfonate in good yield after recrystalli-
zation. Transformation to the 2-hydroxyisoquinolin-1-one
3 with hydroxylamine hydrochloride in refluxing pyridine,
followed by a simple workup procedure (filtration and ion
exchange with a strongly acidic resin: Dowex 50Wx2, H+
form) gave the analytically pure hydroxamic acid derivative
3 as the dihydrate. The next step proved to be critical for
the success of this synthetic route due to a number of chal-
lenges: 3 is only soluble in water, the dianion in 4 after
benzyl protection cannot be purified by strongly acidic ion-
exchange chromatography due to the lability of the protect-
ing group under these conditions, and finally, the key inter-
mediate 4 has to be soluble in organic solvents in order
to enable further transformations such as amide coupling
reactions. After a number of unsuccessful approaches, the
best strategy for the protection reaction was found to be
the use of tetrabutylammonium hydroxide/benzyl chloride
in MeOH to yield the tetrabutylammonium salt 4, which
is highly soluble in apolar media (e.g. CHCl3, CH2Cl2,
CH3CN, EtOAc) and can be purified easily by column
chromatography on silica. The carboxylate 4 can directly be
coupled to methylamine under standard conditions using
HATU to give the corresponding N-methylamide 5, which
can again be purified by straightforward column
chromatography on silica. Acidic benzyl deprotection fol-
lowed by strongly acidic ion-exchange chromatography
(Dowex 50Wx2, H+ form) gives the final sulfonated ligand
6 in pure form.
Figure 2. Asymmetric unit of the disodium salt monohydrate of 3.
Thermal ellipsoid plot (ORTEP-3 for Windows,[13] 50% probability
level) with atom-numbering scheme. Hydrogen atoms are omitted
for clarity. Selected bond lengths [Å] and angles [°]: N1–O2
1.393(2), N1–C1 1.365(3), C1–O1 1.240(3), C1–C2 1.461(3), C2–
C7 1.410(3), C2–C3 1.401(3), C3–C4 1.379(3), C4–S1 1.776(2), S1–
O5 1.460(2), S1–O6 1.456(2), S1–O7 1.452(2), C4–C5 1.402(3), C5–
C6 1.372(3), C6–C7 1.415(3), C7–C8 1.424(3), C8–C9 1.356(3), C9–
C10 1.512(3), C10–O3 1.285(3), C10–O4 1.230(3), Na1–O1
2.304(2), Na1–O3 2.365(2), Na1–O4 2.599(2), Na1–O6 2.378(2),
Na1–O7 2.404(2), Na1–O8 2.246(2), Na2–O1 2.450(2), Na2–O2
2.471(2), Na2–O4 2.335(2), Na2–O5 2.420(2), Na2–O6 2.704(2),
Na2–O7 2.479(2); C9–N1–O2 119.5(2), C1–N1–O2 114.7(2), N1–
C1–O1 119.9(2), C2–C1–O1 125.3(2).
To test whether the carboxylate in the key intermediate
4 could also be activated in a different way, the correspond-
ing acyl chloride 7 was prepared under standard conditions
(oxalyl chloride, cat. DMF) (Scheme 2). The resulting crude
material is reasonably stable and shows high reactivity
towards amines in preliminary experiments, e.g. reaction
with MeNH2 yields an amide that is identical to 5 which
was obtained by HATU coupling. The activated carboxylic
acid 7 will be very useful in the future for less reactive
amines (e.g. aromatic amines, secondary amines, etc.).
Figure 3. 2D 1H NMR spectrum (500 MHz, D2O, 20 °C) of 3;
COSY: aromatic region.
Conclusions
With the development of this synthetic route, access to
sulfonated, highly water-soluble aromatic cyclic hydroxamic
acid derivatives has been achieved for the first time. The
key intermediates 4 and 7, which can readily be coupled to
Scheme 2. Synthesis of the acid chloride 7.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2697–2700

Highly Water-Soluble Aromatic Cyclic Hydroxamic Acid Ligands
MeOH, 6.67 mL solution, 6.67 mmol, 3.0 equiv.) was added drop-
wise, followed by BnCl (309 mg, 2.44 mmol, 1.1 equiv.). The yellow
mixture was heated to reflux for 24 h. After concentration of the
solution in vacuo, the viscous yellow oil was subjected to column
chromatography (SiO2; gradient: CH2Cl2/MeOH, 9:1 to CH2Cl2/
MeOH, 7:1). The fractions with Rf = 0.9 (TLC: SiO2; CH2Cl2/
MeOH, 1:1;, UV detection) were collected, concentrated, and dried
under reduced pressure at 50 °C (bath temperature) for 12 h. The
pale yellow, oily product was obtained as the dihydrate (890 mg,
45%). 1H NMR (400 MHz, CDCl3): δ = 8.86 (d, J = 1.7 Hz, 1 H),
8.14 (dd, J = 8.3, 1.7 Hz, 1 H), 7.80–7.74 (m, 2 H), 7.46 (d, J =
8.3 Hz, 1 H), 7.39–7.30 (m, 3 H), 6.57 (s, 1 H), 5.56 (s, 2 H), 3.23–
3.09 (m, 16 H), 1.60–1.46 (m, 16 H), 1.40–1.23 (m, 16 H), 0.92 (t,
J = 7.3 Hz, 24 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.0,
158.8, 145.4, 144.5, 137.6, 135.4, 130.4, 130.1, 128.4, 128.1, 126.0,
125.0, 124.8, 100.8, 78.2, 58.4, 23.7, 19.5, 13.6 ppm. MS (ES–): m/z
(%) = 615.3 (25) [M + NBu4]–, 374.0 (22) [M + H]–, 283.3 (33) [M
+ H – Bn]–, 246.0 (51) [M – OBn – CO2 + Na]–, 223 (100) [M –
OBn – CO2]. C49H83N3O7S·2H2O (894.30): calcd. C 65.81, H 9.81,
N 4.70; found C 65.41, H 10.24, N 4.64.
amines under standard conditions, will especially be very
useful for the preparation of new hydroxamate ligands, with
potential applications in aqueous chelation. Investigations
into the coordination chemistry of this ligand class are cur-
rently under way.
Experimental Section
General: Chemicals were purchased from commercial suppliers and
used as received unless stated otherwise. Solvents and Et3N were
dried by standard procedures (MeOH: Mg/I2; CH2Cl2 and NEt3:
CaH2). Pyridine was distilled before use. “Millipore water” used
for ion-exchange chromatography refers to water obtained from a
Millipore Milli-Q water purification system (resistivity: 18.2
MΩϫcm–1 at 25 °C). Elemental analyses and mass spectrometry
were performed by the microanalytical and mass spectrometry fa-
cilities of the University of California, Berkeley. NMR spectra were
measured at 20 °C with Bruker AVQ-400 (1H: 400 MHz; 13C:
101 MHz) and AV-500 (1H: 500 MHz) spectrometers.
Protected Methyl Amide 5: The protected carboxylate 4 (610 mg,
682 µmol, 1.0 equiv.) was dissolved in dry CH2Cl2 (20 mL), and
HATU (285 mg, 750 µmol, 1.1 equiv.) was added. The mixture was
stirred for 1 h before MeNH2 (40% in H2O, 2 mL) was added drop-
wise. Stirring was continued for 12 h, the yellow solution was con-
centrated, and the residue was subjected to column chromatog-
raphy (SiO2, column length: 28 cm, inner diameter: 1.3 cm; gradi-
ent: CH2Cl2/MeOH, 9:1 to CH2Cl2/MeOH, 7:1). The fractions with
Rf = 0.64 (TLC: SiO2; CH2Cl2/MeOH, 7:1; UV detection) were
collected, concentrated, and dried under reduced pressure at 50 °C
(bath temperature) for 8 h to yield a colorless glassy solid (292 mg)
that contained Bu4NPF6 (0.34 equiv.). This material was used in
the next step without further purification. 1H NMR (400 MHz,
CD3OD): δ = 8.72 (s, 1 H), 8.03 (dd, J = 8.3, 1.8 Hz, 1 H), 7.67
(d, J = 8.3 Hz, 1 H), 7.45–7.38 (m, 2 H), 7.31–7.23 (m, 3 H), 6.72
(s, 1 H), 5.25 (s, 2 H), 3.15–3.06 (m, 8 H), 2.78 (s, 3 H), 1.61–1.46
(m, 8 H), 1.36–1.22 (m, 8 H), 0.89 (t, J = 7.4 Hz, 12 H) ppm. 13C
NMR (101 MHz, CD3OD): δ = 160.9, 157.0, 143.3, 137.2, 134.7,
132.3, 128.5, 128.2, 127.3, 126.6, 125.8, 124.7, 122.9, 103.6, 77.2,
56.5, 23.8, 21.8, 17.7, 10.9 ppm. MS (ES–): m/z (%) = 387.1 (100)
[M]–, 281.0 (87) [M – OBn + H]–.
Potassium 3-Carboxyisocoumarin-7-sulfonate Hemihydrate (2): 3-
Carboxy-7-(chlorosulfonyl)isocoumarin (1)[11] (313 mg, 1.08 mmol,
1.0 equiv.) was suspended in MeOH (5 mL). A solution of KOH
(128 mg, 2.28 mmol, 2.1 equiv.) in MeOH (5 mL) was added, and
the reaction mixture was heated to reflux for 9 h. After cooling to
ambient temperature, the solid was collected on a filter, washed
with MeOH, and air-dried. The crude product was dissolved in a
minimum of water (pH = 2, HCl), KCl (30 mg) was added, and the
solution was stored at 0 °C for 2 d. The precipitate was collected,
washed with MeOH and dried in vacuo at 50 °C overnight to yield
an off-white solid (309 mg, 90%). M.p. Ͼ200 °C. 1H NMR
(400 MHz, D2O): δ = 8.47 (d, J = 1.8 Hz, 1 H), 8.11 (dd, J = 8.2,
1.8 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.46 (s, 1 H) ppm. 13C
NMR (101 MHz, D2O): δ = 164.5, 162.9, 146.0, 144.3, 137.8, 132.2,
129.0, 126.3, 121.8, 111.0 ppm. MS (ES–, MeOH): m/z (%) = 283
(50) [M
– K + MeOH – –
H2O]–, 269, (100) [M K]–.
C10H5KO7S·0.5H2O (317.32): calcd. C 37.85 H 1.91; found C 37.46,
H 1.79.
3-Carboxy-2-hydroxy-1-oxoisoquinolin-7-sulfonic Acid Dihydrate
(3): Potassium 3-carboxy-isocoumarin-7-sulfonate hemihydrate (2)
(300 mg, 973 µmol, 1.0 equiv.) was suspended in pyridine (10 mL).
Hydroxylamine hydrochloride (81.1 mg, 1.17 mmol, 1.2 equiv.) was
added, and the mixture was heated to 100 °C (bath temperature)
for 5.5 h. After cooling, the yellow solid was collected, washed with
MeOH, and air-dried to yield a light-yellow solid (324 mg). This
crude product was dissolved in Millipore water (5 mL) and sub-
jected to ion-exchange chromatography (Dowex 50Wx2-200, H+
form, activated with 8 wt.-% H2SO4). The fractions showing UV
activity on a Merck silica TLC plate F254 (λex = 254 nm) were com-
bined, concentrated, and dried under reduced pressure (p ≈
0.2 mbar, Tbath = 35 °C). The product was obtained as the dihy-
drate in the form of a colorless solid (222 mg, 71%). M.p. Ͼ200 °C.
1H NMR (400 MHz, D2O): δ = 8.48 (d, J = 1.5 Hz, 1 H), 7.97 (dd,
J = 8.6, 1.5 Hz, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.22 (s, 1 H) ppm.
13C NMR (101 MHz, D2O): δ = 164.3, 159.2, 142.7, 135.6, 133.0,
129.3, 129.1, 125.7, 123.9, 110.7 ppm. MS (ES–): m/z (%) = 239 (9)
2-Hydroxy-3-methylcarbamoyl-1-oxoisoquinolin-7-sulfonic Acid Di-
hydrate (6): The protected methyl amide 5 (292 mg) was dissolved
in a mixture of concd. HCl (3 mL) and glacial HOAc (3 mL) and
stirred at ambient temperature for 48 h and at 45 °C for 12 h. The
solvents were removed under reduced pressure, the colorless oil was
redissolved in a minimum of water and applied onto a strongly
acidic ion-exchange column (Dowex 50Wx2-400, H+ form, acti-
vated with 8 wt.-% H2SO4, elution with water). The fractions show-
ing blue fluorescence on a Merck silica TLC plate F254 (λex
=
365 nm) were combined, concentrated, and dried under reduced
pressure (p ≈ 0.2 mbar, Tbath = 35 °C). The product was obtained
1
as the dihydrate as a colorless solid (69 mg, 30% over 2 steps). H
NMR (400 MHz, CD3OD): δ = 8.78 (s, 1 H), 8.11 (d, J = 8.3 Hz,
1 H), 7.78 (d, J = 8.3 Hz, 1 H), 6.93 (s, 1 H), 2.94 (s, 3 H) ppm.
13C NMR (101 MHz, CD3OD): δ = 160.9, 159.2, 142.8, 136.0,
134.4, 127.9, 125.7, 122.6, 103.5, 23.7 ppm. MS (ES–): m/z (%) =
[M
–
COOH]–, 226.9 (9), 141.4 (100) [M
–
2
H]2–.
297.0 (83) [M
–
H+]–, 281.0 (100) [M
– –
H+ O]–.
C10H7NO7S·2H2O (321.26): calcd. C 37.39 H 3.45, N 4.36; found
C 37.39, H 3.39, N 4.19.
C11H10N2O6S·2H2O (334.30): calcd. C 39.52, H 4.22, N 8.38; found
C 39.22, H 4.37, N 7.93.
Protected Carboxylate 4: 3-Carboxy-2-hydroxy-1-oxoisoquinolin-7-
sulfonic acid dihydrate (3) (714 mg, 2.12 mmol, 1.0 equiv.) was dis-
solved in dry MeOH (30 mL), and a solution of Bu4NOH (1  in
Tetrabutylammonium 2-Benzyloxy-3-(chlorocarbonyl)-1-oxoisoquin-
olin-7-sulfonate (7): Under argon, the protected carboxylate 4
Eur. J. Org. Chem. 2008, 2697–2700
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2699

M. Seitz, K. N. Raymond
SHORT COMMUNICATION
[2]
[3]
a) J. Rudinger, K. Poduska, M. Zaoral, Collect. Czech. Chem.
Commun. 1960, 25, 2022–2028; b) R. L. N. Harris, Aust. J.
Chem. 1976, 29, 1329–1334.
a) J. R. Telford, K. N. Raymond, Siderophores in Comprehen-
sive Supramolecular Chemistry (Eds.: J. L. Atwood, J. E. D.
Davies, D. D. MacNicol, F. Vögtle), Elsevier, Oxford, 1996, vol.
1, p. 245.
a) R. C. Hider, T. Zhou, Ann. N. Y. Acad. Sci. 2005, 1054, 141–
154; b) Z. D. Liu, R. C. Hider, Med. Res. Rev. 2002, 22, 26–64;
c) M. Blanusa, V. M. Varnai, M. Piasek, K. Kostial, Curr. Med.
Chem. 2005, 12, 2771–2794.
a) R. A. Yokel, Coord. Chem. Rev. 2002, 228, 97–113; b) R. A.
Yokel, P. Ackrill, E. Burgess, J. P. Day, J. L. Domingo, T. P.
Flaten, J. Savory, J. Tox. Environ. Health 1996, 48, 667–683; c)
P. Nayak, Environ. Res. Sect. A 2002, 89, 101–115.
A. E. V. Gorden, J. Xu, K. N. Raymond, P. W. Durbin, Chem.
Rev. 2003, 103, 4207–4282 and refs cited therein.
a) E. J. Werner, S. Avedano, M. Botta, B. P. Hay, E. G. Moore,
S. Aime, K. N. Raymond, J. Am. Chem. Soc. 2007, 129, 1870–
1871; b) J. Xu, D. G. Churchill, M. Botta, K. N. Raymond,
Inorg. Chem. 2004, 43, 5492–5494.
a) K. N. Raymond, R. C. Scarrow, D. L. White, patent US
796815, 1987; b) I. Turcot, A. Stintzi, J. Xu, K. N. Raymond,
J. Biol. Inorg. Chem. 2000, 5, 634–641.
a) E. G. Moore, J. Xu, C. J. Jocher, E. J. Werner, K. N. Ray-
mond, J. Am. Chem. Soc. 2006, 128, 10648–10649; b) F. Gutier-
rez, C. Tedeschi, L. Maron, J.-P. Daudey, R. Poteau, J. Azema,
P. Tisnès, C. Picard, Dalton Trans. 2004, 1334–1347.
A. Du Moulinet d’Hardemare, S. Torelli, G. Serratrice, J.-L.
Pierre, Biometals 2006, 19, 349–366 and refs. cited therein.
a) M. Seitz, M. D. Pluth, K. N. Raymond, Inorg. Chem. 2007,
46, 351–353; b) M. Seitz, A. G. Oliver, K. N. Raymond, J. Am.
Chem. Soc. 2007, 129, 11153–11160.
Crystal data for the disodium salt of 3: colorless plate,
C10H5NNa2O7S·H2O (347.21 g/mol), monoclinic, space group
P21/n, a = 7.0552(6) Å, b = 17.0307(15) Å, c = 10.7581(10) Å,
β = 107.422(1)°, V = 1233.34(19) Å3, Z = 4, T = 142(2) K, λ
= 0.71073 Å, ρdiff. = 1.87 g/cm3, µ = 0.377 mm–1, θmax = 26.42°,
measd. refls.: 6939, independent refls.: 2514, refls. in refinement
[IϾ2σ(I)]: 1941, parameters: 208, R(Fo) = 0.039, wR(Fo2) =
0.095, GOF = 1.039. CCDC-664339 contains the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Ortep-3 for Windows: L. J. Farrugia, J. Appl. Crystallogr. 1997,
30, 565.
(51.0 mg, 57.0 µmol, 1.0 equiv.) was dissolved in dry CH2Cl2
(2 mL), and dry DMF (2 mg) was added. Oxalyl chloride (36.2 mg,
285 µmol, 5.0 equiv.) was added dropwise, and the yellow solution
was heated under reflux for 3 h. After cooling to ambient tempera-
ture, the volatiles were removed under reduced pressure, and the
remaining yellow solid (53 mg, quant.), consisting of a 1:1 mixture
of the title compound and tetrabutylammonium chloride, was dried
in vacuo overnight (ca. 20 h). This material can be used without
further purification. 1H NMR (400 MHz, [D6]DMSO): δ = 8.50 (s,
1 H), 7.94 (dd, J = 8.3, 1.2 Hz, 1 H), 7.79 (d, J = 8.3 Hz, 1 H),
7.54–7.46 (m, 2 H), 7.43–7.33 (m, 3 H), 7.12 (s, 1 H), 5.32 (s, 2 H),
3.23–3.00 (m, 16 H), 1.60–1.43 (m, 16 H), 1.25 (sext., J = 7.2 Hz,
16 H), 0.87 (t, J = 7.2 Hz, 24 H) ppm.
[4]
[5]
X-ray Crystallography of the Disodium Monohydrate Salt of 3:
Crystals were grown by slow concentration of a solution of the title
compound (prepared by addition of 2 equiv. of NaOH to 3) in
MeOH. A fragment of a colorless plate-like crystal of the title com-
pound having approximate dimensions of 0.35ϫ0.11ϫ0.07 mm
was mounted on a Kapton loop using Paratone N hydrocarbon oil.
All measurements were carried out with a Siemens SMART
CCD[14] area detector with graphite-monochromated Mo-Kα radia-
tion. Cell constants and an orientation matrix, obtained from a
least-squares refinement using the measured positions of 2082 cen-
tered reflections with IϾ10σ(I) in the range 2.32° Ͻ θ Ͻ 26.36°,
corresponded to a primitive monoclinic cell. The data were col-
lected at a temperature of 142(2) K. Frames corresponding to an
arbitrary hemisphere of data were collected using ω scans of 0.3°
counted for a total of 10 s per frame. Data were integrated by the
program SAINT[15] to a maximum θ value of 26.42°. The data were
corrected for Lorentz and polarization effects. Data were analyzed
for agreement and possible absorption using XPREP.[16] An empiri-
cal absorption correction based on comparison of redundant and
equivalent reflections was applied using SADABS.[17] (Tmax = 0.95,
Tmin = 0.75). Of the 6939 reflections collected, 2514 were unique;
equivalent reflections were merged. No decay correction was ap-
plied. The structure was solved within the Wingx[18] package by
direct methods (SIR92[19]) and expanded using Fourier techniques
(SHELXL-97[20]). The aromatic hydrogen atoms were included but
not refined. They were positioned geometrically, with C–H 0.93 Å,
and constrained to ride on their parent atoms. Uiso(H) values were
set at 1.2 times Ueq(C). The hydrogen atoms of the water molecule
and the hydrogen atom between the carboxylate and hydroxamate
groups were located in the difference Fourier map and refined.
Uiso(H) values were set at 1.2 times Ueq(O).
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
SMART (V5.059), Area-Detector Software Package, Bruker
Analytical X-ray Systems, Inc., Madison, WI, 1995–1999.
SAINT (V7.07B), SAX Area-Detector Integration Program, Si-
emens Industrial Automation, Inc., Madison, WI, 2005.
XPREP (V6.12), Part of the SHELXTL Crystal Structure De-
termination Package, Bruker AXS Inc., Madison, WI, 1995.
George Sheldrick, SADABS (V2.10), Siemens Area Detector
ABSorption Correction Program, 2005.
Acknowledgments
The authors thank Michael D. Pluth for help with NMR spectra.
M. S. thanks the German Research Foundation (DFG) for a re-
search fellowship. This work was supported in part by NIH grant
R01-HL69832 and by the Director, Office of Science, Office of Ba-
sic Energy Sciences, and the Division of Chemical Sciences, Geosci-
ences, and Biosciences of the U. S. Department of Energy at LBNL
under Contract No. DE-AC02-05CH11231.
Wingx (1.70.01): L. J. Farrugia, J. Appl. Crystallogr. 1999, 32,
837–838.
SIR92: A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagli-
ardi, J. Appl. Crystallogr. 1993, 26, 343–350.
G. M. Sheldrick, SHELX97 – Programs for Crystal Structure
Analysis (Release 97-2), Institut für Anorganische Chemie der
Universität Göttingen, Tammanstrasse 4, Göttingen, Ger-
many, 1998.
[1] a) M. A. Santos, Coord. Chem. Rev. 2002, 228, 187–203; b)
K. H. Thompson, C. A. Barta, C. Orvig, Chem. Soc. Rev. 2006,
35, 545–556 and refs cited therein.
Received: February 6, 2008
Published Online: April 16, 2008
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