Syntheses and characterization of anti-inflammatory dinuclear and mononuclear zinc indomethacin complexes. Crystal structures of [Zn2(indomethacin)4(L)2] (L = N,N-dimethylacetamide, pyridine, 1-methyl-2-pyrrolidinone) and

Article abstract of DOI:10.1021/ic991477i

The syntheses and spectral and structural characterizations of Zn(II) indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid = IndoH] complexes, as different solvent adducts, have been studied. The complexes are unusual in that both

Full text of DOI:10.1021/ic991477i

3742
Inorg. Chem. 2000, 39, 3742-3748
Ar ticles
Syntheses and Characterization of Anti-inflammatory Dinuclear and Mononuclear Zinc
Indomethacin Complexes. Crystal Structures of [Zn2(Indomethacin)4(L)2] (L )
N,N-Dimethylacetamide, Pyridine, 1-Methyl-2-pyrrolidinone) and [Zn(Indomethacin)2(L1)2]
(L1 ) Ethanol, Methanol)
Qingdi Zhou,† Trevor W. Hambley,*,† Brendan J. Kennedy,*,† Peter A. Lay,*,† Peter Turner,†
Barry Warwick,‡ John R. Biffin,‡ and Hubertus L. Regtop‡
Centre for Heavy Metals Research, School of Chemistry, The University of Sydney, Sydney,
NSW 2006, Australia, and Biochemical Veterinary Research Pty Ltd., Braemar, NSW 2575 Australia
ReceiVed December 22, 1999
The syntheses and spectral and structural characterizations of Zn(II) indomethacin [1-(4-chlorobenzoyl)-5-methoxy-
2-methyl-1H-indole-3-acetic acid ) IndoH] complexes, as different solvent adducts, have been studied. The
complexes are unusual in that both monomeric and dimeric complexes are formed and that this is the first example
of the same carboxylato ligand binding via both carboxylate oxygen atoms in monomeric and dimeric Zn(II)
complexes. The crystal structures of Zn-Indo complexes with N,N-dimethylacetamide (DMA), pyridine (Py),
1-methyl-2-pyrrolidinone (NMP), EtOH, and MeOH as solvent ligands, [Zn2(Indo)4(DMA)2]‚2DMA, 1, [Zn2-
(Indo)4(Py)2]‚2H2O, 2b, [Zn2(Indo)4(NMP)2], 3, cis-[Zn(Indo)2(EtOH)2], 4, and cis-[Zn(Indo)2(MeOH)2], 5, were
determined. Complexes 1, 2b, and 3 crystallize in the triclinic space group P1h (No. 2): a ) 13.628(2) Å, b )
17.462(2) Å, c ) 11.078(1) Å, R ) 99.49(1)°, â ) 108.13(1)°, γ ) 110.10(1)° for 1; a ) 13.347(3) Å, b )
16.499(5) Å, c ) 10.857(1) Å, R ) 99.48(2)°, â ) 108.25(2)°, γ ) 106.24(2)° for 2; a ) 14.143(3) Å, b )
14.521(2) Å, c ) 11.558(2) Å, R ) 109.07(1)°, â ) 90.80(2)°, γ ) 116.40(1)° for 3. The three complexes
exhibit dinuclear paddle-wheel structures with a Zn‚‚‚Zn distance of 2.9686(6) Å, Zn-ORCOO distances of 2.035-
(2)-2.060(2) Å, and a Zn-ODMA distance of 1.989(2) Å in 1, a Zn‚‚‚Zn distance of 2.969(1) Å, Zn-ORCOO
distances of 2.020(3)-2.049(3) Å, and a Zn-NPy distance of 2.036(3) Å in 2, and a Zn‚‚‚Zn distance of 2.934(1)
Å, Zn-ORCOO distances of 2.009(3)-2.051(3) Å, and a Zn-ONMP distance of 1.986(3) Å in 3. In these cases, the
zinc ions are offset along the z direction such that the L-Zn‚‚‚Zn-L moiety is nonlinear, unlike the Cu analogues.
Each Zn has a square-pyramidal geometry bridged by four carboxylato ligands in the basal plane with the solvent
ligands containing an O- or N-donor atom at the apex. Complexes 4 and 5 are isostructural, with space group
C2/c (No. 15). For 4, a ) 30.080(2) Å, b ) 5.3638(6) Å, c ) 24.739(2) Å, â ) 90.342(7)°, and for 5, a )
29.419(2) Å, b ) 5.320(2) Å, c ) 24.461(2) Å, â ) 90.840(4)°. The Zn resides on a 2-fold axis and the complexes
have a distorted cis octahedral structure with Zn-ORCOO bond lengths of 2.183(3) and 2.169(3) Å, a Zn-OEtOH
bond length of 2.015(3) Å in 4, Zn-ORCOO bond lengths of 2.195(2) and 2.151(2) Å, and a Zn-OMeOH bond
length of 2.022(3) Å in 5.
Introduction
tory drug (NSAID) that exhibits favorable anti-inflammatory,
analgesic, and antipyretic properties, but it has the undesirable
side effects of inducing gastrointestinal ulceration and hemor-
rhages.1 Numerous studies have been undertaken in order to
reduce the side effects associated with the clinical use of IndoH
and related carboxylate-containing NSAIDs. One strategy that
has met with success has been the use of d-block metal
complexes of the NSAIDs as therapeutic agents. In part this
approach is based on the observation that some d-block metal
ions, especially Cu(II) and Zn(II), can act as anti-inflammatory
agents in their own right.2-4 It has been demonstrated that the
Indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-
(1) Singla, A. K.; Wadhwa, H. Int. J. Pharm. 1995, 120, 145-155.
(2) Fraser, P. M.; Doll, R.; Langman, M. J. S.; Misiewicz, J. J.; Shawdon,
H. H. Gut 1972, 13, 459-463.
(3) Frommer, D. J. Med. J. Aust. 1975, 2, 793-796.
(4) Simkin, P. A. Lancet 1976, 2, 539-542.
indole-3-acetic acid ) IndoH] is a nonsteroidal anti-inflamma-
† The University of Sydney.
‡ Biochemical Veterinary Research Pty Ltd.
10.1021/ic991477i CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/26/2000

Zinc Indomethacin Complexes
Inorganic Chemistry, Vol. 39, No. 17, 2000 3743
Experimental Section
Zn(II) complex of aspirin has a better therapeutic index (2.64
times) than aspirin itself and has improved physicochemical
characteristics.5 Furthermore, the Zn-aspirin complex displays
more favorable therapeutic properties, is more effective, and
less ulcerogenic than either aspirin alone or a physical mixture
of aspirin and ZnSO4.1,5-6
Syntheses. IndoH was pharmaceutical grade (Sigma Pharmaceutical).
All other chemicals were of high purity (Aldrich or Sigma) and were
used without further purification.
Bis(N,N-dimethylacetamide)tetrakis-µ-(O,O′-Indo)dizinc(II)-2-
N,N-dimethylacetamide, [Zn2(Indo)4(DMA)2]‚2DMA, 1. To a solu-
Recently, the Cu complex of IndoH was introduced for use
as a veterinary anti-inflammatory drug. This drug is superior
to uncomplexed IndoH for treatment of a range of conditions
and most importantly induces considerably lower incidences of
gastrointestinal damage.7,8 Detailed studies of [Cu2(Indo)4L2]
complexes have recently been reported,9,10 and it was demon-
strated that the complex adopts a dimeric structure similar to
that found in Cu acetate and in the Cu-aspirin complex.11,12
Weder and co-workers have shown that in the solid state the
Indo units form a hydrophobic package containing the Cu2O8
core, and they postulated that this might contribute to its
pharmaceutical efficacy.9 In both the Cu-aspirin and Cu-Indo
complexes, the sixth coordination site is occupied by a Lewis
base, which is usually a molecule of the solvent.
Three Cu-acetate-like dinuclear carboxylato Zn(II) complexes
have been described in the literature.13-15 By contrast, [Zn(O2-
CR)2(OH2)2] form six-coordinate monomeric species in the solid
state for the acetato, salicylato, and acetylsalicylato ligands.16-18
The Zn-Indo complexes have anti-inflammatory properties and
have been patented as veterinary pharmaceutics.19 A key step
in understanding the biological function of these complexes is
to establish their structures and to investigate the relative
stabilities of the monomeric or dimeric arrangements. A Zn-
aspirin structure has been described in the literature;18 however,
as far as we know, there have been no structural reports of Zn-
Indo complexes. Accordingly, a number of Zn-Indo complexes
have been prepared and characterized using a variety of
coordinating solvents including N,N-dimethylacetamide (DMA),
pyridine (Py), 1-methyl-2-pyrrolidinone (NMP), alcohols, dim-
ethyl sulfoxide (DMSO), water, methylamine, and imidazole.
(5) Singla, A. K.; Mediratta, D. K.; Pathak, K. Int. J. Pharm. 1990, 60,
27-33.
(6) Singla, A. K.; Wadhwa, H. Int. J. Pharm. 1994, 108, 173-185.
(7) Regtop, H. L.; Biffin, J. R. Preparation of Divalent Metal Salts of
Indomethacin. U.S. Patent 5310936, Biochemical Veterinary Research
Pty. Ltd., Australia, 1994.
tion of IndoH (3.66 g, 10.23 mmol) in DMA (10 mL), a solution of
Zn(OAc)2‚2H2O (1.24 g, 5.65 mmol) in DMA (10 mL) was added
dropwise. The mixture was stirred and heated (ca. 60 °C) overnight,
cooled to room temperature, and then set aside in a fume hood for 3
weeks, during which time small yellow crystals formed. These were
collected by filtration under reduced pressure and air-dried. Further
product was obtained on extended standing. Anal. Found: C, 57.67;
H, 4.68; N, 5.97; Zn, 6.69%. Calcd for Zn2C84H78Cl4N6O18‚2C4H9NO:
(8) IVS Annual; MIMS Publishing: Crows Nest, NSW, Sydney, 1997;
pp 145, 276.
(9) Weder, J. E.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; MacLachlan,
D.; Bramley, R.; Delfs, C. D.; Murray, K. S.; Moubaraki, B.; Warwick,
B.; Biffin, J. R.; Regtop, H. L. Inorg. Chem. 1999, 38, 1736-1744.
(10) Weser, U.; Sellinger, K. H.; Lengfelder, E.; Werner, W.; Strahle, J.
Biochim. Biophys. Acta 1980, 631, 232-245.
1
C, 57.96; H, 5.08; N, 5.88; Zn 6.86%. H NMR (in DMSO-d6): δ
(ppm) 7.76(H-13,14), 7.74(15,16), 7.13(H-3), 7.01(H-4), 6.78(H-6),
3.80(H-9), 3.42(H-18), 2.27(H-19).
(11) Van Niekerk, J. N.; Schoening, F. R. L.; Talbot, J. H. Acta Crystallogr.
1953, 6, 720-723.
Bis(pyridine)tetrakis-µ-(O,O′-Indo)dizinc(II)-2-acetonitrile, [Zn2-
(Indo)4(Py)2]‚2CH3CN, 2. To a warm solution of IndoH (3.58 g, 10.01
mmol) in acetonitrile (100 mL) a solution of Zn(OAc)2‚2H2O (1.04 g,
4.74 mmol) in water (3 mL) and acetonitrile (3 mL) was slowly added.
The mixture was briefly heated to 60 °C, then pyridine (2 mL) was
added. The resultant mixture was stirred for 3 h, cooled to room
temperature, and set aside in a fume hood overnight. The resulting
yellow crystalline solid was filtered and washed with a small amount
of dry diethyl ether and air-dried (1.74 g, 44.8%). Anal. Found: C,
59.91; H, 4.14; N, 6.34; Zn, 7.61%. Calcd for Zn2C86H70Cl4N6O16‚2CH3-
(12) Manojlovic´-Muir, L. Acta Crystallogr., Sect. B 1973, B29, 2033-
2037.
(13) Singh, B.; Long, J. R.; de Biani, F. F.; Gatteschi, D.; Stavropoulos, P.
J. Am. Chem. Soc. 1997, 119, 7030-7047.
(14) Clegg, W.; Little, I. R.; Straughan, B. P. J. Chem. Soc., Dalton Trans.
1986, 1283-1288.
(15) Clegg, W.; Hunt, P. A.; Straughan, B. P. Acta Crystallogr., Sect. C
1995, C51, 613-617.
(16) Ishioka, T.; Murata, A.; Kitagawa, Y.; Nakamura, K. T. Acta
Crystallogr., Sect. C 1997, C53, 1029-1031.
1
(17) Klug, H. P.; Alexander, L. E.; Sumner, G. G. Acta Crystallogr. 1958,
11, 41-46.
CN: C, 60.11; H, 4.26; N, 6.23; Zn, 7.27%. H NMR (in DMSO-d6):
δ (ppm) 7.74(H-13,14), 7.72(15,16), 7.13(H-3), 7.01(H-4), 6.78(H-6),
3.81(H-9), 3.48(H-18), 2.27(H-19).
Bis(1-methyl-2-pyrrolidinone)tetrakis-µ-(O,O′-Indo)dizinc(II), [Zn2-
(Indo)4(NMP)2], 3. Zn(OAc)2‚2H2O (1.21 g, 5.51 mmol) in NMP (12
mL) was slowly added to IndoH (3.69 g, 10.31 mmol) in NMP (15
(18) Hartmann, U.; Vahrenkamp, H. Bull. Pol. Acad. Sci., Chem. 1994,
42, 155-161.
(19) Regtop, H. L.; Biffin, J. R. Divalent Metal Complexes of Indomethacin,
Compositions and Medical Methods of Use Thereof. U.S. Patent
5466824, Biochemical Veterinary Research Pty. Ltd., Australia, 1995.

3744 Inorganic Chemistry, Vol. 39, No. 17, 2000
Zhou et al.
mL). The mixture was heated overnight at 60 °C, then EtOH (60 mL)
was added. The mixture was placed in a fume hood for 12 h during
which time a crystalline solid formed (2.08 g, 45.9%). Anal. Found:
C, 58.48; H, 4.32; N, 4.71; Zn, 7.33%. Calcd for Zn2C86H78Cl4N6O18:
C, 58.82; H, 4.48; N, 4.79; Zn, 7.45%. H NMR (in DMSO-d6): δ
(ppm) 7.74(H-13,14), 7.72(15,16), 7.12(H-3), 7.01(H-4), 6.78(H-6),
H, 3.95; N, 3.04; Zn, 8.38%. Calcd for ZnC38H34Cl2N2O10: C, 56.00;
H, 4.20; N, 3.44; Zn, 8.02%. H NMR (in DMSO-d6): δ (ppm) 7.73-
(H-13,14), 7.71(15,16), 7.11(H-3), 6.99(H-4), 6.76(H-6), 3.81(H-9),
3.44(H-18), 2.25(H-19).
1
1
Aqua(methylamine)bis(η2-O,O′-Indo)zinc(II)‚1.25H2O, [Zn(Indo)2-
(NH2Me)(OH2)]‚1.25H2O, 11. [Zn(Indo)2(OH2)2] was slowly added
to a THF solution of methylamine (2.0 M, 15 mL) until a saturated
solution was formed. The mixture was stirred for 1.5 h at 45 °C, then
set aside in a fume hood overnight. The white precipitate was collected
by filtration, washed with a small amount of EtOH, and air-dried. Anal.
Found: C, 54.75; H, 4.19; N, 4.95; Zn, 7.73%. Calcd for ZnC39H37-
3.82(H-9), 3.51(H-18), 2.27(H-19).
cis-Bis(ethanol)bis(η2-O,O′-Indo)zinc(II), cis-[Zn(Indo)2(EtOH)2],
4. A solution of Zn(OAc)2‚2H2O (2.16 g, 9.84 mmol) in DMA (10
mL) was added slowly to a solution of IndoH (7.26 g, 20.29 mmol) in
DMA (10 mL). The mixture was stirred and heated at 50 °C overnight.
The resultant yellow solution was cooled to room temperature, at which
time ethanol (100 mL) was added. When the solution stood for a few
days, a pale-yellow crystalline solid formed, which was collected by
filtration under vacuum, washed with absolute ethanol (ca. 50 mL),
and air-dried (7.43 g, 87%). Anal. Found: C, 57.49; H, 4.34; N, 3.29;
Zn, 7.93%. Calcd for ZnC42H42Cl2N2O10: C, 57.91; H, 4.86; N, 3.22;
1
Cl2N3O9‚1.25H2O: C, 55.07; H, 4.68; N, 4.94; Zn, 7.69%. H NMR
(in DMSO-d6): δ (ppm) 7.7(H-13,14), 7.71(15,16), 7.12(H-3), 7.03-
(H-4), 6.75(H-6), 3.82(H-9), 3.43(H-18), 2.26(H-19).
Aquaimidazolebis(η2-O,O′-Indo)zinc(II)‚1.25H2O, [Zn(Indo)2-
(Im)(OH2)]‚1.25H2O, 12. [Zn(Indo)2(OH2)2] (0.40 g, 0.49 mmol) was
slowly added to a solution of imidazole (0.034 g, 0.50 mmol) in MeOH
(10 mL). The resultant mixture was stirred for 2 h, then filtered and
washed with a small amount of MeOH, and air-dried. Anal. Found:
C, 55.20; H, 4.30; N, 6.16; Zn, 6.89%. Calcd for ZnC41H36Cl2N4O9‚
1.25H2O: C, 55.48; H, 4.37; N, 6.31; Zn, 7.37%. 1H NMR (in DMSO-
d6): δ (ppm) 7.75(H-13,14), 7.73(15,16), 7.14(H-3), 7.04(H-4), 6.78(H-
6), 3.80(H-9), 3.41(H-18), 2.28(H-19).
1
Zn, 7.51%. H NMR (in DMSO-d6): δ (ppm) 7.74(H-13,14), 7.72-
(15,16), 7.13(H-3), 7.02(H-4), 6.78(H-6), 3.83(H-9), 3.43(H-18), 2.27-
(H-19).
cis-Bis(methanol)bis(η2-O,O′-Indo)zinc(II), cis-[Zn(Indo)2(MeOH)2],
5. To a solution of IndoH (3.61 g, 10.09 mmol) in DMF (10 mL), a
solution of Zn(OAc)2‚2H2O (1.24 g, 5.65 mmol) in DMF (10 mL) was
added slowly. The mixture was stirred and heated at ca. 50 °C for 6 h
and cooled to room temperature. Then methanol (50 mL) was added.
When the solution stood overnight, colorless crystals were formed that
were collected through filtration and air-dried (3.04 g, 71.5%). Anal.
Found: C, 57.18; H, 4.26; N, 3.45; Zn 7.74%. Calcd for ZnC40H38-
Cl2N2O10: C, 56.99; H, 4.54; N, 3.32; Zn, 7.76%. 1H NMR (in DMSO-
d6): δ (ppm) 7.75(H-13,14), 7.73(15,16), 7.13(H-3), 7.02(H-4), 6.78(H-
6), 3.83(H-9), 3.44(H-18), 2.27(H-19).
Physical Methods. Infrared spectra were recorded using a KBr
matrix on a BIO-Rad Win-IR FTS-40 infrared spectrometer. Elemental
microanalyses were performed by the Department of Chemical
Engineering, University of Sydney. A Varian AA-800 air-acetylene
flame atomic absorption spectrophotometer was used for the Zn
analyses. 1H and 13C NMR spectra were recorded at room temperature
in DMF-d7, DMSO-d6, or pyridine-d5 on a Bruker AM400 spectrometer
using the solvents as internal standards but with shifts cited versus
tetramethylsilane (TMS).
X-ray Crystallographic Analyses. Crystal data and processing
parameters of complexes 1-5 are listed in Table 1. Diffraction data
were collected at 21 ( 1 °C on a Rigaku AFC7R diffractometer
employing graphite monochromated Cu KR radiation (λ ) 1.541 78
Å) from a rotating anode generator. There were no significant changes
in the intensities of three representative reflections measured every 150
reflections during the data collections for complexes 1, 2, and 4. A
generator anomaly during the data collection for complex 3 resulted in
a 30.0% increase in the reference reflections intensities, whereas the
intensities of the complex 5 standards decreased by 23.0% during the
data collection. A polynomial correction factor was accordingly applied
to the data for complexes 3 and 5. An empirical absorption correction
based on azimuthal scans of three reflections was applied to the data
for complexes 1, 3, and 5, and an analytical correction was applied to
the complex 2 and 4 data. The diffraction data were also corrected for
Lorentz and polarization effects.
Bis(1-butanol)bis(η2-O,O′-Indo)zinc(II)‚2.25H2O, [Zn(Indo)2(1-
butanol)2]‚2.25H2O, 6; Bis(2-butanol)bis(η2-O,O′-Indo)zinc(II)‚
3.25H2O, [Zn(Indo)2(2-butanol)2]‚3.25H2O, 7; and Bis(2-methyl-2-
propanol)bis(η2-O,O′-Indo)zinc(II)‚2.5H2O, [Zn(Indo)2(t-butanol)2]‚
2.5H2O, 8. Zn(OAc)2‚2H2O (0.58 g, 2.64 mmol) in the appropriate
warm butanol (20 mL) was slowly added to a warm solution of IndoH
(1.85 g, 5.17 mmol) in butanol (20 mL). The mixture was heated at
ca. 60 °C for 3 h, during which time a precipitate rapidly formed. Upon
cooling to room temperature, the mixture was then filtered and the
isolated solid was washed with a small amount of EtOH and finally
air-dried. For 6, yield 88.4%. Anal. Found: C, 56.71; H, 4.99; N, 2.85;
Zn 7.11%. Calcd for ZnC46H50Cl2N2O10‚2.25H2O: C, 57.09; H, 5.68;
N, 2.89; Zn, 7.05%. 1H NMR (in DMSO-d6): δ (ppm) 7.76(H-13,14),
7.73(15,16), 7.13(H-3), 7.02(H-4), 6.78(H-6), 3.83(H-9), 3.46(H-18),
2.27(H-19). For 7, yield 80.0%. Anal. Found: C, 55.57; H, 5.43; N,
2.71; Zn 7.52%. Calcd for ZnC46H50Cl2N2O10‚3.25H2O: C, 56.05; H,
1
5.78; N, 2.84; Zn, 7.05%. H NMR (in DMSO-d6): δ (ppm) 7.75(H-
All calculations were undertaken with the teXsan20 crystallographic
software package. Neutral atom scattering factors were taken from
Cromer and Waber.21 Anomalous dispersion effects were included in
Fc,22 and the values for ∆f ′ and ∆f ′′ were those of Creagh and
McAuley.23 The values for the mass attenuation coefficients were those
of Creagh and Hubbell.24 The structures were solved by direct methods25
and expanded using Fourier techniques.26 The least-squares planes were
13,14), 7.74(15,16), 7.13(H-3), 7.01(H-4), 6.78(H-6), 3.83(H-9), 3.49-
(H-18), 2.27(H-19). For 8, yield 68.6%. Anal. Found: C, 56.49; H,
5.05; N, 2.81; Zn 7.12%. Calcd for ZnC46H50Cl2N2O10‚2.5H2O: C,
56.83; H, 5.70; N, 2.88; Zn, 7.05%. 1H NMR (in DMSO-d6): δ (ppm)
7.75(H-13,14), 7.73(15,16), 7.13(H-3), 7.01(H-4), 6.78(H-6), 3.82(H-
9), 3.46(H-18), 2.27(H-19).
Bis(dimethyl sulfoxide)bis(η2-O,O′-Indo)zinc(II), [Zn(Indo)2-
(DMSO)2], 9. This complex was prepared in a manner similar to that
of 1 except that dimethyl sulfoxide was used as the solvent. The mixture
was heated with stirring for 7 h, then cooled to room temperature. The
precipitate that formed after a few weeks was collected by filtration
and washed with ethanol, then air-dried (0.95 g, 21.1%). Anal. Found:
C, 53.48; H, 4.49; N, 3.09; Zn, 6.84%. Calcd for ZnC42H42-
Cl2N2O10S2: C, 53.94; H, 4.53; N, 3.00; Zn, 6.99%. 1H NMR (in
DMSO-d6): δ (ppm) 7.71(H-13,14), 7.69(15,16), 7.09(H-3), 6.97(H-
4), 6.74(H-6), 3.79(H-9), 3.45(H-18), 2.23(H-19).
Diaquabis(η2-O,O′-Indo)zinc(II), [Zn(Indo)2(OH2)2], 10. To a
solution of IndoH (3.00 g, 8.38 mmol) in NaOH (0.1 M, 50 mL) a
solution of Zn(OAc)2‚2H2O (0.90 g, 4.10 mmol) in water (10 mL) was
slowly added. The mixture was stirred and heated at 60 °C for 3 h,
during which time a pale-yellow precipitate formed. After the mixture
was cooled, the precipitate was collected by filtration, washed with
water and EtOH, and air-dried (2.91 g, 89.3%). Anal. Found: C, 55.64;
(20) TEXSAN: Crystal Structure Analysis Package, Molecular Structure
Corporation; The Woodlands, TX, 1985-1992.
(21) Cromer, D. T.; Waber, J. T. International Tables for X-ray Crystal-
lography; The Kynoch Press: Birmingham, England, 1974; Vol. 4.
(22) Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17, 781-782.
(23) Creagh, D. C.; McAuley, W. J. International Tables for Crystal-
lography; Wilson, A. J. C., Ed.; Kluwer Academic Publishers: Boston,
1992; Vol. C, Table 4.2.6.8, pp 219-222.
(24) Creagh, D. C.; Hubbell, J. H. International Tables for Crystallography;
Wilson, A. J. C., Ed.; Kluwer Academic Publishers: Boston, 1992;
Vol. C, Table 4.2.4.3, pp 200-206.
(25) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl.
Crystallogr. 1993, 26, 343-350.
(26) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de
Gelder, R.; Israel, R.; Smits, J. M. M. The DIRDIF-94 program system;
Technical Report; Crystallography Laboratory, University of
Nijmegen: The Netherlands, 1994.

Zinc Indomethacin Complexes
Inorganic Chemistry, Vol. 39, No. 17, 2000 3745
Table 1. Crystal Data and Processing Parameters for Complexes 1-5
complexes
1
2
3
4
5
empirical formula
fw
C92H96Cl4N8O20Zn2
1906.38
yellow, prism
triclinic
C86H70Cl4N6O18Zn2
1748.10
yellow, prism
triclinic
C86H78Cl4N6O18Zn2
1756.18
colorless, blade
triclinic
C42H42Cl2N2O10Zn
871.09
C40H38Cl2N2O10Zn
843.05
colorless, columnar
monoclinic
0.25 × 0.05 × 0.03
C-centered
C2/c(#15)
cryst color, habit
cryst syst
cryst size (mm)
lattice type
space group
Z value
yellow, blade
monoclinic
0.50 × 0.15 × 0.05
C-centered
C2/c(#15)
4
0.38 × 0.17 × 0.15
primitive
P1h (#2)
0.25 × 0.09 × 0.06
primitive
P1h (#2)
0.35 × 0.12 × 0.08
primitive
P1h (#2)
1
1
1
4
a (Å)
b (Å)
c (Å)
13.628(2)
17.462(2)
11.078(1)
99.49(1)
108.13(1)
110.10(1)
2241.0(7)
1.412
13.347(3)
16.499(5)
10.857(1)
99.48(2)
108.25(2)
106.24(2)
2094(1)
14.143(3)
14.521(2)
11.558(2)
109.07(1)
90.80(2)
116.40(1)
1973.6(8)
1.472
30.086(2)
5.3638(6)
24.739(2)
29.419(2)
5.320(2)
24.461(2)
R (deg)
â (deg)
90.342(7)
90.840(4)
γ (deg)
V (Å3)
3992.2(5)
1.429
3827(1)
1.463
D
calc (g cm-3
)
1.386
F000
992.0
23.81
7981
900.0
24.75
7418
902.0
26.27
6124
1808.0
26.01
4079
1744.0
26.95
3508
µ(Cu KR) (cm-1
)
total data
total unique data
no. variables
7622
568
7077
532
5834
524
3799
257
3437
249
no. observations
6531 [I > 2.50σ(I)]
5667 [I > 3.00σ(I)]
4697 [I > 2.50σ(I)]
2400 [I > 3.00σ(I)]
2393 [I > 3.00σ(I)]
final diff mapmaxi (e-/Å3)
final diff mapmini (e-/Å3)
residuals:a R; Rw
0.71
0.63
0.50
0.43
0.67
-0.70
0.043; 0.044
-0.58
0.053; 0.056
-0.65
0.050; 0.058
-0.59
0.050; 0.055
-0.63
0.042; 0.046
2
a R ) ∑(|Fo| - |Fc|)/∑ |Fo|. Rw ) (∑w(|Fo| - |Fc|)2/∑w|Fo| )1/2, w ) 1/σ2(Fo).
calculated with the XTAL software package.27 In general non-hydrogen
atoms were modeled with anisotropic atomic displacement parameters
and hydrogen atoms were included in the model at calculated positions
with group thermal parameters. The crystals of complexes 1 and 2 are
isomorphous, and the complexes are isostructural and centered about
inversion sites in P1h (No. 2), as is the isostructural complex 3. The
asymmetric unit of the complex 1 structure contains two solvent
molecules, and the asymmetric unit for complex 2 includes two sites
treated as the oxygen atoms of two water molecules, with 50%
occupancies. There are no additional molecules in the asymmetric unit
for complex 3. The crystals of complexes 4 and 5 are isomorphous,
and the complexes are isostructural with the metal ion residing on a
2-fold axis in C2/c (No. 15). The ethanol ligand of complex 4 is
disordered, with the occupancies of the isotropically modeled C(20a)
and C(20b) sites initially refined and then fixed at 0.5. There were no
hydrogen atoms included in the model for the ethanol ligand of complex
4. The methanol oxygen hydrogen site of complex 5 could not be
located; however, the inclusion in the complex 5 model of a hydrogen
at a calculated position corresponding to an sp2-hybridized oxygen
lowered the refinement residuals by 0.1%. Placement of the hydrogen
at an sp3 position resulted in no change in the residuals in one position
and an increase of 0.2% in the second position. Projections of the
Figure 1. IR spectra in KBr of (a) IndoH, (b) [Zn2(Indo)4(DMA)2],
(c) [Zn2(Indo)4(Py)2], (d) [Zn2(Indo)4(NMP)2], (e) [Zn(Indo)2(EtOH)2],
and (f) [Zn(Indo)2(MeOH)2].
complex molecules were generated with ORTEP.28
Results
Synthesis and Spectroscopic Characterization. Highly
crystalline samples of all the complexes were prepared in good
yields, with diffraction-quality single crystals for 1-5 being
obtained on prolonged standing of the reaction solutions.
Elemental analyses and IR spectroscopy showed that the
complexes contained varying amounts of solvent molecules, and
structural studies demonstrated that these act as ligands to the
Zn(II), as well as occupy noncoordinated solvent sites. The
presence of noncoordinated solvent molecules was confirmed
during the crystallographic study of 1. In the case of the
imidazole complex a mixed aquaimidazole complex of the type
[Zn(Indo)2(Im)(OH2)] was obtained, even when an excess of
imidazole was used in the reaction.
The IR spectra of all the complexes show strong absorptions
near 1680 and 1700 cm-1 (Supporting Information and Figure
1) corresponding to the amide and carbonyl CdO stretches in
the Indo ligand. Whereas the amide CdO frequency is es-
sentially constant in all the complexes, the carbonyl stretching
frequency shows two distinct patterns. The IR spectra of
complexes 1-3 are similar, as are those of 4-12, but the spectra
of these two groups of complexes are clearly different. This is
most evident in the region around 1400 cm-1, where in the
spectra of complexes 4-12, there is a strong band near 1440
cm-1 that is absent in complexes 1-3. This moderately strong
(27) Hall, S. R.; Stewart, J. M. Reference Manual; Universities of Western
Australia and Maryland, 1995.
(28) Johnson, C. K. ORTEP; Report ORNL-5138; Oak Ridge National
Laboratory: Oak Ridge, TN, 1976.

3746 Inorganic Chemistry, Vol. 39, No. 17, 2000
Zhou et al.
Table 2. Selected Bond Lengths (Å) and Angles (deg) for
Complexes 1-3
consist of centrosymmetric dinuclear Zn units and are typical
of dinuclear [M2(carboxylate)4L2] complexes, with the Indo
ligands providing the four metal-bridging bidentate carboxylate
residues. The Indo ligands display a paddle wheel like arrange-
ment about the Zn‚‚‚Zn axis. Each Zn(II) cation has a square-
pyramidal coordination geometry, with the apex provided by
axial coordination of a solvent ligand (DMA, Py, or NMP). The
metal to apical atom distances are 1.989(2), 2.036(3), and 1.986-
(3) Å for DMA, Py, and NMP, respectively, and the mean Zn-
O(carboxylate) bond length is 2.042 Å in 1, 2.039 Å in 2, and
2.034 Å in 3. These distances are typical and unremarkable.13-15
The metal displacement from the square-pyramid-base least-
squares plane is 0.0373(1), 0.0382(1), and 0.0355(1) Å for 1,
2, and 3, respectively, and this pattern follows the donor capacity
of the axial ligands. Charge donation from the axial ligand would
cause a nephelauxetic swelling of the metal-based orbitals that
would tend to electrostatically displace the metal from the basal
plane. Additionally, the charge donation would lift the metal-
based orbital energies and so slightly weaken the basal bonding.
The tetracarboxylate bridging framework can accommodate
metal-metal separations of up to 3.452 Å.31 The Zn‚‚‚Zn
separations of 2.9686(6), 2.969(1), and 2.934(1) Å for 1, 2, and
3, respectively, are shorter than this maximum but much longer
than the corresponding Cu‚‚‚Cu distance observed in [Cu2-
(Indo)4(DMF)2] (2.630 Å). This may reflect attractive metal-
metal interactions in the copper complex. The average Zn-O
distance is also somewhat longer than that determined for the
analogous Cu complex (1.965 Å).9 Interestingly, the L-Zn‚‚‚
Zn-L units are not collinear as they are in the Cu dimers.9,10
There is a small lateral shift of the two zincs, with respect to
the principal dimer axis, of 0.13 Å for complex 1, 0.34 Å for
complex 2, and 0.20 Å for complex 3. Additionally, the metal
to apex atom bond forms an angle of 3.43(5), 6.85(8), and 3.38-
(9)° with the base least-squares plane normal of 1, 2, and 3,
respectively. The Zn‚‚‚Zn‚‚‚apex atom angle is 175.21(6)°,
166.93(9)°, and 172.6(1)° for complexes 1, 2, and 3, respec-
tively. Dinuclear [Zn2(carboxylate)4L2] complexes have previ-
ously been observed to be either collinear13,14 or similarly
offset.15
The methanol and ethanol complexes are isostructural with
the metal residing on a 2-fold axis in C2/c (No. 15). As shown
in the ORTEP diagram for the methanol complex (Figure 3),
the complexes are pseudo-octahedral, with the equatorial plane
defined by the carboxylate atoms O(1), O(2), and O(2*) (where
O(2*) is generated from O(2) with 1 - x, y, 0.5 -z) and O(5)
of the methanol ligand. The methanol O(5*) is then axial with
the angle between the equatorial atoms least-squares plane
normal and the Zn(1)-O(5*) line being 5.53(5)°. The angle
between the Zn to carboxylate O(1*) bond line and the
equatorial atoms least-squares plane normal is 21.56(5)°. The
analogous angles for 5 are 5.23(5)° and 21.71(5)°, respectively.
Apparently the bidentate carboxylate geometry hinders metal-
ligand orbital overlap. The Zn-ORCOO bond distances of 2.183-
(3) and 2.169(3) Å in 4 and 2.196(2) and 2.152(2) Å in 5 are
similar to those observed in zinc acetate dihydrate.26 Other
selected bond angles and distances are listed in Table 3.
1
2
3
Zn(1)-Zn(1)
Zn(1)-O(1)
Zn(1)-O(2)
Zn(1)-O(5)
Zn(1)-O(6)
Zn(1)-O(9)
O(1)-C(1)
O(2)-C(1)
O(5)-C(20)
O(6)-C(20)
2.9686(6)
2.036(2)
2.035(2)
2.038(2)
2.060(2)
1.989(2)
1.245(3)
1.244(3)
1.249(3)
1.253(3)
2.969(1)
2.040(3)
2.048(3)
2.020(3)
2.049(3)
2.036(3)a
1.237(4)
1.242(4)
1.262(5)
1.235(5)
2.934(1)
2.048(3)
2.051(3)
2.009(3)
2.028(3)
1.986(3)
1.240(5)
1.260(5)
1.252(6)
1.249(6)
O(1)-Zn(1)-O(2)
O(1)-Zn(1)-O(5)
O(1)-Zn(1)-O(6)
O(1)-Zn(1)-O(9)
O(2)-Zn(1)-O(5)
O(2)-Zn(1)-O(6)
O(2)-Zn(1)-O(9)
O(5)-Zn(1)-O(6)
O(5)-Zn(1)-O(9)
O(6)-Zn(1)-O(9)
Zn(1)-O(1)-C(1)
Zn(1)-O(2)-C(1)
Zn(1)-O(5)-C(20)
Zn(1)-O(6)-C(20)
O(1)-C(1)-O(2)
O(1)-C(1)-C(2)
O(2)-C(1)-C(2)
158.70(8)
88.24(9)
89.36(9)
102.83(8)
87.50(9)
87.26(9)
98.47(8)
159.18(8)
103.06(8)
97.64(8)
129.4(2)
125.6(2)
125.0(2)
129.1(2)
126.1(2)
117.4(2)
116.5(2)
158.4(1)
89.2(1)
160.0(1)
88.0(1)
89.2(1)
103.2(1)
88.1(1)
87.7(1)
88.5(1)
98.3(1)a
87.9(1)
86.3(1)
103.1(1)a
158.4(1)
107.3(1)a
94.3(1)a
134.9(3)
120.6(3)
122.4(3)
132.4(3)
125.8(4)
117.5(3)
116.7(3)
96.8(1)
159.8(1)
101.1(1)
99.0(1)
122.2(3)
131.8(3)
126.0(3)
128.3(3)
125.9(4)
118.3(4)
115.8(4)
a In complex 2, atom O(9) is replaced by N(3).
band near 1440 cm-1 is assigned to the symmetric carboxyl
stretching frequency Vs(COO-). The analogous asymmetric
stretching frequency Vas(COO-) for complexes 1-3 is near 1600
cm-1, and the positions and separations, ca. 200 cm-1, of these
bands are indicative of a bridging bidentate coordination mode
of the carboxylate groups, as occurs in copper acetate like
dimers29 and in the [Cu2(Indo)4L2]9 complexes. In the spectra
of 4-12, the intensity of the band near 1400 cm-1 is consider-
ably lower than those in the spectra of 1-3, and it is probable
that this band also contains the symmetric carboxylate stretch
Vs (COO-). The smaller separations between Vas and Vs in the
spectra of complexes 4-12 are indicative of a chelating
geometry, as occurs in monomeric species.30
The 1H NMR spectra do not differ significantly for the
complexes. The 13C NMR spectra in the various complexes were
collected in three different solvents. The spectra reveal a
downfield chemical shift of the carboxylate carbon atom in all
the complexes relative to that of IndoH, and there is no
significant difference between spectra of the monomeric and
dimeric complexes. This suggests that either the species rapidly
equilibrate or the 13C NMR resonance is not sensitive to the
type of carboxylate coordination. We note that the 13C NMR
and IR spectral properties previously reported for a Zn-Indo
complex prepared in aqueous solutions are similar to those found
here for the monomeric complexes, and this indicates that the
complex formed in the previous study is most likely the
monomer [Zn(Indo)2(H2O)2].1
X-ray Crystallography. The single-crystal structures of
complexes 1-3 are isostructural, space group P1h (No. 2), and
they are also isostructural with the related Cu complexes [Cu2-
(Indo)4(L)2], L ) DMF, DMSO.9,10 Selected bond angles and
distances for complexes 1-3 are given in Table 2. The structures
Discussion
The structures of several monomeric, dimeric, trimeric, and
polymeric zinc carboxylates have been described and attempts
have been made to relate the physical properties of these with
(29) Mathey, Y.; Greig, D. R.; Shriver, D. F. Inorg. Chem. 1982, 21, 3409-
3413.
(30) Deacon, G. B.; Phillips, R. J. Coord. Chem. ReV. 1980, 33, 227-250.
(31) Allman, T.; Goel, R. C.; Jha, N. K.; Beauchamp, A. L. Inorg. Chem.
1984, 23, 914-918.

Zinc Indomethacin Complexes
Inorganic Chemistry, Vol. 39, No. 17, 2000 3747
Table 3. Selected Bond Length (Å) and Bond Angles (deg) for 4
and 5
4
5
Zn(1)-O(1)
Zn(1)-O(2)
Zn(1)-O(5)
O(1)-C(1)
O(2)-C(1)
2.183(3)
2.169(3)
2.015(3)
1.275(4)
1.244(5)
2.195(2)
2.151(2)
2.022(3)
1.274(4)
1.245(4)
O(1)-Zn(1)-O(1)
O(1)-Zn(1)-O(2)
O(1)-Zn(1)-O(2)
O(1)-Zn(1)-O(5)
O(1)-Zn(1)-O(5)
O(2)-Zn(1)-O(2)
O(2)-Zn(1)-O(5)
O(2)-Zn(1)-O(5)
O(5)-Zn(1)-O(5)
Zn(1)-O(1)-C(1)
Zn(1)-O(2)-C(1)
O(1)-C(1)-O(2)
O(1)-C(1)-C(2)
85.9(1)
60.1(1)
99.6(1)
152.8(1)
96.2(1)
153.8(2)
105.0(1)
92.9(1)
94.2(2)
89.2(2)
90.7(2)
119.7(4)
118.3(4)
85.8(1)
60.03(8)
98.66(9)
152.90(9)
94.7(1)
152.4(1)
93.2(1)
105.0(1)
96.9(2)
88.6(2)
91.4(2)
119.4(3)
118.3(3)
Hence, the present series of compounds provides the first
opportunity to compare the bonding contacts in monomeric and
dimeric zinc complexes. In general the Zn-ORCOO bond lengths
in the monomers are longer (average 2.175 Å) than those in
the dimeric complexes (average Zn-O 2.038 Å). This is a
consequence of the higher coordination number and hindered
orbital overlap in the bidentate carboxylate groups. The O-C-O
bond angle is reduced to ∼119° in the monomers compared to
∼126° in the dimers. These angles are similar to those observed
in other monomeric and dimeric carboxylate groups, including
zinc acetate dihydrate16 and [Cu2(Indo)4(DMF)2].9 These dif-
ferences account for the observed shifts in carboxylate stretching
frequencies observed in the IR spectra.
Figure 2. ORTEP28 depiction of [Zn2(Indo)4(Py)2], with atomic
displacement ellipsoids shown at the 25% level.
It is believed that the biological activity of Cu(II) complexes
of Indo such as [Cu2(Indomethacin)4(DMF)2] is related to their
dimeric structure.7,9 The Cu(II) complex has a lower level of
gastric toxicity than IndoH itself, and this may be because the
dimeric complex presents a more effective “lipophilic pack-
age”.7,9,13 Partial decomposition of the dimeric Cu(II) complex
to monomeric species is observed under certain conditions
appropriate to their pharmaceutical preparation, and this may
increase the side effects and limit the efficacy of the drug. Thus,
the pharmaceutical effectiveness of Zn(II) Indo complexes of
Indo may critically depend on the relative stability of the dimeric
and monomeric forms.
The Py, DMA, or NMP adducts are dinuclear with pentaco-
ordination about the metal, whereas the alcohol adducts are
mononuclear with hexacoordination of the metal. Singh et al.13
have shown that the Zn-acetate-py system can yield mono-
meric, dimeric, or polymeric products depending on the solvents
used. Interestingly and significantly, the monomeric [Zn(Py)2-
(O2CCH3)2] complex is four-coordinate with unidentate car-
boxylate coordination.13 The polymeric {[Zn(O2CCH3)(Py)]n}
complex is five-coordinate,13 and the 4-vinylpyridinezinc
carboxylate trimer reported by Clegg et al.15 is also five-
coordinate. By contrast, the eight literature [Zn(OH2)2(O2CR)2]
Figure 3. ORTEP28 depiction of [Zn(Indo)2(MeOH)2], with atomic
displacement ellipsoids shown at the 25% level.
the structural changes.13-18,32-37 In the case of the zinc
carboxylates only three dimeric complexes have been structur-
ally characterized,13-15 whereas monomeric complexes are more
common,16-18,32-37 although these invariably have aqua donor
groups. No examples of monomeric and dimeric zinc complexes
with the same bidentate carboxylate group have been reported
previously, although examples are known where the ligand acts
as a bidentate in a dimer and a monodentate in a monomer.13
(33) Smith, G.; Lynch, D. E.; Mak, T. C. W.; Yip, W. H.; Kennard, C. H.
L. Polyhedron 1993, 12, 203-208.
(34) Smith, G.; O’Reilly, E. J.; Kennard, C. H. L.; Stadnicka, K.; Oleksyn,
B. Inorg. Chim. Acta 1981, 47, 111-120.
(35) O’Reilly, E. J.; Smith, G.; Kennard, C. H. L.; Mak, T. C. W. Aust. J.
Chem. 1987, 40, 1147-1159.
(36) Baumgartner, M. R.; Schmalle, H.; Dubler, E. Inorg. Chim. Acta 1996,
252, 319-331.
(32) Chan, W. H.; Mak, T. C. W.; Yip, W. H.; Smith, G.; O’Reilly, E. J.;
(37) Mak, T. C. W.; Yip, W. H.; Smith, G.; O’Reilly, E. J.; Kennard, C.
H. L. Inorg. Chim. Acta 1984, 84, 57-64.
Kennard, C. H. L. Polyhedron 1987, 6, 881-889.

3748 Inorganic Chemistry, Vol. 39, No. 17, 2000
Zhou et al.
complexes16-18,32-37 and 4 and 5 are six-coordinate when the
additional neutral ligand is a relatively weak Lewis base such
as water, methanol, or ethanol. This circumstantially suggests
that the water and the alcohols are unable to support a less than
six-coordinate metal center. Stronger Lewis bases such as Py,
DMA, or NMP apparently reduce or remove the need for
hexacoordination. Presumably the stronger Lewis bases elevate
the metal-based target orbitals beyond the reach of a sixth ligand
([Zn(Py)2(O2CCH3)2] uses only two of the four available
carboxylate oxygen atoms). The determining factor in Zn(II)
carboxylate dimer formation may simply be the ability of
theavailable ligand set to support a less than six-coordinate metal
ion center.
ion anti-inflammatory drugs may depend on the relative stability
of the dinuclear Indo complexes. This aspect will be the subject
of further research.
Acknowledgment. Support from an Australian Research
Council (ARC) SPIRT grant and Biochemical Veterinary
Research Pty Ltd., Australia (BVR) and an ARC RIEFP grant
for the crystallography is gratefully acknowledged. Q.Z. ac-
knowledges the award of an Australian Postgraduate Research
Award (Industry).
Supporting Information Available: Tables of crystal data, bond
distances, bond angles, hydrogen atom coordinates and parameters,
anisotropic thermal parameters for 1-5, IR stretching frequencies and
13C NMR spectra for 1-12, and figures of ORTEP projections for 1,
3, and 4. This material is available free of charge via the Internet at
http://pubs.acs.org. Structure factors may be obtained directly from the
authors.
What is clear is that dimeric carboxylate complexes are
preferred for Cu(II) relative to Zn(II). This may be a contribution
to the observation in preliminary animal studies that [Cu2(Indo)4-
(DMF)2]9 has low toxicity to both the stomach and the small
intestine, whereas [Zn2(Indo)4(DMA)2] has low toxicity in the
small intestine but is toxic to the stomach.38 This prompts the
hypothesis that the pharmacokinetics and efficacy of Indo-metal
IC991477I
(38) Davies, N. Department of Pharmacy, University of Sydney. Personal
communication, 1999.