Late metal salicylaldimine complexes derived from 5-aminosalicylic acid - Molecular structure of a zwitterionic mono Schiff base zinc complex

Article abstract of DOI:10.1139/v05-091

Condensation of salicylaldehyde (2-HOC₆H₄C(O)H) with 5-aminosalicylic acid (5-H₂NC₆H₃-2-(OH)-CO ₂H) afforded the Schiff base 2-HOC₆H₄C(H)= NC₆H₃-

Full text of DOI:10.1139/v05-091

1063
Late metal salicylaldimine complexes derived from
5-aminosalicylic acid — Molecular structure of a
zwitterionic mono Schiff base zinc complex
Tara A. Bourque, Megan E. Nelles, Teri J. Gullon, Christian N. Garon,
Melissa K. Ringer, Lisa J. Leger, Jamie W. Mason, Susan L. Wheaton,
Felix J. Baerlocher, Christopher M. Vogels, Andreas Decken, and
Stephen A. Westcott
Abstract: Condensation of salicylaldehyde (2-HOC6H4C(O)H) with 5-aminosalicylic acid (5-H2NC6H3-2-(OH)-CO2H)
afforded the Schiff base 2-HOC6H4C(H)=NC6H3-2-(OH)-5-CO2H (a). Similar reactivity with 5-bromosalicylaldehyde
was also observed to give 5-Br-2-HOC6H3C(H)=NC6H3-2-(OH)-5-CO2H (b). Reaction of these salicylaldehydes with
Pd(II), Cu(II), and Zn(II) salts gave the corresponding bis(N-arylsalicylaldiminato)metal complexes (M = Pd (1), Cu
(2), Zn (3)). The molecular structure of the Schiff base compound a has been confirmed by an X-ray diffraction study.
Crystals of a were monoclinic, space group P2(1)/c, a = 7.0164(7) Å, b = 11.0088(11) Å, c = 14.8980(15) Å, β =
102.917(2)°, Z = 4. The molecular structure of a novel zwitterionic conformer of 3a was also characterized by an X-
ray diffraction study. Crystals of 4 were monoclinic, space group P2(1)/c, a = 9.5284(5) Å, b = 19.5335(11) Å, c =
8.6508(5) Å, β = 90.596(1)°, Z = 4. All new compounds have been tested for their antifungal activity against
Aspergillus niger and Aspergillus flavus.
Key words: 5-aminosalicylic acid (5-ASA), antifungal, copper, palladium, salicylaldimines, Schiff base, zinc.
Résumé : La condensation du salicylaldéhyde (2-HOC6H4C(O)H) avec l’acide 5-aminosalicylique (5-H2NC6H3-2-(OH)-
CO2H) conduit à la formation de la base de Schiff 2-HOC6H4C(H)=NC6H3-2-(OH)-5-CO2H (a). On a observé une réacti-
vité semblable avec le 5-bromosalicylaldéhyde qui conduit à la formation de la 5-Br-2-HOC6H3C(H)=NC6H3-2-(OH)-5-
CO2H (b). La réaction de ces salicylaldéhydes avec des sels de Pd(II), Cu(II) et Zn(II) conduit aux complexes corres-
pondants bis(N-arylsalicylaldiminato)métal (M = Pd (1), Cu (2), Zn (3)). La structure moléculaire de la base de Schiff
a a été confirmée par une étude de diffraction des électrons. Les cristaux de a sont monocliniques, groupe d’espace
P2(1)/c, avec a = 7,0164(7) Å, b = 11,0088(11) Å et c = 14,8980(15) Å, β = 102,917(2)° et Z = 4. Faisant appel à la
diffraction des rayons X, on a aussi caractérisé la structure moléculaire d’un nouveau conformère zwitterionique du com-
posé 3a. Les cristaux de 4 sont monocliniques, groupe d’espace P2(1)/c, avec a = 9,5284(5) Å, b = 19,5335(11) Å et c =
8,6508(5) Å, β = 90,596(1)° et Z = 4. L’activité fongicide des tous les nouveaux composés a été vérifiée contre Asper-
gillus niger et Aspergillus flavus.
Mots clés : acide 5-aminosalicylique (5-AAS), fongicide, cuivre, palladium, salicylaldimines, base de Schiff, zinc.
[Traduit par la Rédaction] Bourque et al. 1070
Introduction
for treating these disorders include glucocorticoids and 5-
aminosalicylic acid (5-ASA, Fig. 1a) derivatives. Despite
the well-documented benefits of 5-ASA in the treatment of
IBD, its efficacy is limited due to side effects and allergic
reactions associated with its mode of delivery. For example,
sulfasalazine (Fig. 1b) was introduced over 60 years ago and
has become the most widely prescribed agent for IBD,
where the pharmacological action of this compound has
been attributed to 5-ASA (14). When ingested orally, 88%
Inflammatory bowel disease (IBD) is a serious disorder of
the lower gastrointestinal tract where tissue damage and in-
flammation can impair the use of the bowel (1–13). Ulcer-
ative colitis involves inflammation of the lining of the colon
while Crohn’s disease affects all layers of the intestinal wall.
Both disorders are chronic, progressive diseases whose
etiopathogenesis is not well understood. Current therapies
Received 31 January 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 14 September 2005.
T.A. Bourque, M.E. Nelles, T.J. Gullon, C.N. Garon, M.K. Ringer, L.J. Leger, J.W. Mason, S.L. Wheaton, C.M. Vogels, and
S.A. Westcott.1 Department of Chemistry, Mount Allison University, Sackville, NB E4L 1G8, Canada.
F.J. Baerlocher. Department of Biology and Biochemistry, Mount Allison University, Sackville, NB E4L 1G7, Canada.
A. Decken.2 Department of Chemistry, University of New Brunswick, Fredericton, NB E3B 5A3, Canada.
1Corresponding author (e-mail: swestcott@mta.ca).
2Corresponding author regarding X-ray crystallography (e-mail: adecken@unb.ca).
Can. J. Chem. 83: 1063–1070 (2005)
doi: 10.1139/V05-091
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Can. J. Chem. Vol. 83, 2005
Fig. 1. (a) 5-ASA and (b) sulfasalazine.
5-{[(1E)-(5-Bromo-2-hydroxyphenyl)methylene]amino}-
2-hydroxybenzoic acid (b)
HO
N
To an EtOH (10 mL) solution of 5-aminosalicylic acid
(0.50 g, 3.26 mmol) was added an EtOH (5 mL) solution of
5-bromosalicylaldehyde (0.72 g, 3.58 mmol). The mixture
was heated at reflux for 2 h to ensure completion, at which
point a yellow precipitate was collected by suction filtration
and washed with EtOH (3 × 5 mL) and Et2O (3 × 10 mL).
The pale yellow solid was then dried to afford b (0.93 g,
85%); mp 271 °C. IR (Nujol, cm–1) ν: 1604 (C=N). Spectro-
HO
NH
2
N
SO
N
2
HOOC
NH
HOOC
(b)
(a)
of the sulfasalazine reaches the colon where it is degraded
by azo reductases of the colonic microflora, into 5-ASA and
sulfapyridine (8). All toxic effects associated with sulfa-
salazine are believed to arise from the sulfapyridine and, as
a result, there has been a considerable amount of research
focussed on designing new prodrugs of 5-ASA with less
harmful side effects.
As part of our program designing metal complexes con-
taining biologically active ligands, we have made Schiff base
metal complexes derived from 5-ASA. As an initial screen
of potential biological properties, we have examined all new
complexes for their ability to act as antifungal agents.
1
scopic NMR data (in DMSO-d6): H NMR δ: 13.05 (br s,
1H, -OH), 8.94 (s, 1H, C(H)=N), 7.84–7.81 (ov m, 2H, Ar),
7.62 (d of d, J = 8, 3 Hz, 1H, Ar), 7.50 (d of d, J = 8, 3 Hz,
1H, Ar), 7.03 (d, J = 8 Hz, 1H, Ar), 6.90 (d, J = 8 Hz, 1H,
Ar). 13C{1H} NMR δ: 172.2, 161.0, 160.9, 159.8, 139.8,
135.8, 134.6, 129.7, 123.3, 121.9, 119.6, 118.9, 114.2,
110.5.
Compound 1a
To an EtOH (50 mL) solution of palladium(II) acetate
(0.20 g, 0.89 mmol) was added an EtOH (15 mL) solution of
a (0.48 g, 1.87 mmol). The mixture was heated at reflux for
3 h at which point a yellow-green precipitate was collected
by suction filtration and washed with cold EtOH (3 × 5 mL)
and Et2O (3 × 10 mL). The pale yellow solid was then dried
to afford complex 1a (0.47 g, 85%); mp 305 to 306 °C (de-
composition). IR (Nujol, cm–1) ν: 1608 (C=N). Spectro-
Experimental
General
Reagents and solvents used were purchased from Aldrich
Chemicals. Pd(OAc)2 was purchased from Precious Metals
Online Ltd. (Melbourne, Australia). NMR spectra were re-
corded on a JEOL JNM-GSX270 FT spectrometer or a
Varian Mercury Plus 200 NMR spectrometer. 1H NMR
chemical shifts are reported in ppm and referenced to resid-
ual solvent protons in deuterated solvent at 270 and
200 MHz, respectively. 13C NMR chemical shifts are refer-
enced to solvent carbon resonances as internal standards at
68 and 50 MHz, respectively, and are reported in ppm. Mul-
tiplicities are reported as singlet (s), doublet (d), triplet (t),
multiplet (m), broad (br), and overlapping (ov). IR spectra
were obtained using a Mattson Genesis II FT-IR spectrome-
ter. Melting points were determined using a Mel-Temp appa-
ratus and are uncorrected. Microanalyses for C, H, and N
were carried out at Guelph Chemical Laboratories, Guelph,
Ontario.
1
scopic NMR data (in DMSO-d6): H NMR δ: 8.11 (s, 2H,
C(H)=N), 7.71 (d, J = 3 Hz, 2H, Ar), 7.47–7.43 (ov m, 4H,
Ar), 7.17 (d of d, J = 8, 3 Hz, 2H, Ar), 6.99 (d, J = 8 Hz,
2H, Ar), 6.51 (t, J = 8 Hz, 2H, Ar), 6.03 (d, J = 8 Hz, 2H,
Ar). 13C{1H} NMR δ: 172.1, 164.5, 164.4, 160.2, 140.8,
135.9, 135.7, 132.9, 126.2, 120.6, 120.1, 116.7, 115.4,
112.8. Anal. calcd. for C28H20N2O8Pd (%): C 54.34, H 3.26,
N 4.53; found: C 53.95, H 2.89, N 4.09.
Compound 1b
To an EtOH (40 mL) solution of palladium(II) acetate
(0.15 g, 0.67 mmol) was added an EtOH (10 mL) solution of
b (0.47 g, 1.40 mmol). The mixture was heated at reflux for
2 h at which point a yellow-green precipitate was collected
by suction filtration and washed with cold EtOH (3 × 5 mL)
and Et2O (3 × 10 mL). The pale yellow solid was then dried
to afford complex 1b (0.47 g, 90%); mp 294 to 295 °C (de-
composition). IR (Nujol, cm-1) ν: 1603 (C=N). Spectro-
1
5-{[(1E)-(2-Hydroxyphenyl)methylene]amino}-2-
hydroxybenzoic acid (a)
scopic NMR data (in DMSO-d6): H NMR δ: 8.09 (s, 2H,
C(H)=N), 7.67 (d of d, J = 8, 3 Hz, 4H, Ar), 7.48 (d of d,
J = 8, 3 Hz, 2H, Ar), 7.25 (d of d, J = 8, 3 Hz, 2H, Ar), 6.97
(d, J = 8 Hz, 2H, Ar), 5.93 (d, J = 8 Hz, 2H, Ar). 13C{1H}
NMR δ: 172.2, 164.1, 163.4, 160.3, 140.6, 138.1, 137.2,
133.1, 126.2, 122.5, 122.4, 117.0, 112.7, 105.6. Anal. calcd.
for C28H18N2Br2O8Pd (%): C 43.30, H 2.34, N 3.61; found:
C 43.62, H 2.32, N 3.27.
To an EtOH (10 mL) solution of 5-aminosalicylic acid
(0.50 g, 3.26 mmol) was added an EtOH (5 mL) solution of
salicylaldehyde (0.44 g, 3.60 mmol). The mixture was
heated at reflux for 2 h to ensure completion, at which point
a yellow precipitate was collected by suction filtration and
washed with EtOH (3 × 5 mL) and Et2O (3 × 10 mL). The
yellow solid was then dried to afford a (0.63 g, 75%); mp
258–260 °C. IR (Nujol, cm–1) ν: 1610 (C=N). Spectroscopic
NMR data (in DMSO-d6): 1H NMR δ: 13.07 (br s, 1H, -OH),
8.98 (s, 1H, C(H)=N), 7.84 (d, J = 3 Hz, 1H, Ar), 7.67–7.64
(ov m, 2H, Ar), 7.39 (d of d, J = 8, 3 Hz, 1H, Ar), 7.06–6.94
(ov m, 3H, Ar). 13C{1H} NMR δ: 172.2, 162.2, 160.8, 160.7,
139.7, 133.4, 133.0, 129.1, 123.1, 119.8, 119.5, 118.6,
117.0, 114.1.
Compound 2a
To an EtOH (50 mL) solution of copper(II) acetate
(0.20 g, 1.10 mmol) was added an EtOH (15 mL) solution of
a (0.59 g, 2.29 mmol). The mixture was heated at reflux for
3 h at which point a yellow-green precipitate was collected
by suction filtration and washed with cold EtOH (3 × 5 mL)
and Et2O (3 × 10 mL). The pale yellow solid was then dried
© 2005 NRC Canada

Bourque et al.
1065
Scheme 1. Synthesis of Schiff base compounds derived from 5-ASA.
HO
HO
HO
N
H
O
H
HO
NH2
EtOH / ∆
+
C
C
-H2O
HOOC
HOOC
R
R
a: R = H
b: R = Br
to afford complex 2a (0.60 g, 95%); mp 291 to 292 °C (de-
composition). IR (Nujol, cm–1) ν: 1608 (C=N). Anal. calcd.
for C28H20N2CuO8 (%): C 58.38, H 3.51, N 4.86; found: C
57.74, H 3.32, N 4.75.
X-ray crystallography
Crystals of a and 4 were grown from saturated EtOH and
DMSO solutions, respectively, at 20 °C. Single crystals were
coated with Paratone-N oil, mounted using a glass fibre, and
frozen in the cold stream of the goniometer. A hemisphere
of data was collected on a Bruker AXS P4/SMART 1000
diffractometer using ω and θ scans with a scan width of 0.3°
and exposure times of 40 (a) and 30 s (4). The detector dis-
tances were 5 cm. The data were reduced (15) and corrected
for absorption (16). The structures were solved by direct
methods and refined by full-matrix least-squares on F2 (17).
All non-hydrogen atoms were refined anisotropically. Hy-
drogen atoms were placed in calculated positions and refined
using a riding model (a) or located in Fourier difference
maps and refined isotropically (4).
Compound 2b
To an EtOH (50 mL) solution of copper(II) acetate
(0.20 g, 1.10 mmol) was added an EtOH (15 mL) solution of
b (0.78 g, 2.32 mmol). The mixture was heated at reflux for
3 h at which point a yellow-green precipitate was collected
by suction filtration and washed with cold EtOH (3 × 5 mL)
and CHCl3 (3 × 10 mL). The pale yellow solid was then
dried to afford complex 2b (0.52 g, 64%); mp 318–320 °C
(decomposition). IR (Nujol, cm–1) ν: 1610 (C=N). Anal.
calcd. for C28H18N2Br2CuO8·1.5CHCl3 (%): C 38.80, H
2.16, N 3.07; found: C 38.90, H 2.03, N 2.79.
Antifungal testing
Compounds were tested for antifungal activity against
pure cultures of Aspergillus niger and Aspergillus flavus
supplied by Ward’s Natural Science Ltd. (St. Catharines,
Ontario). Cultures were maintained on Sabouraud dextrose
agar. Six agar plugs (10 mm diameter) were cut from a 5–
8 day old colony and homogenized in distilled, sterilized
water (3 mL). From this suspension, 0.5 mL was transferred
aseptically to a petri plate with Sabouraud dextrose agar
(15 mL) and spread evenly over the entire surface. Each
plate was provided with four evenly spaced paper disks
(6 mm Fisherbrand P8 filter paper) containing the compound
(100 µg). Each compound was applied to the disks as a solu-
tion (5 mg of compound per 1 mL of THF), where control
disks were treated with neat THF (20 µL). Amphotericin B
acted as a standard (100 µg) prepared in THF. Test plates
with fungal homogenates were incubated at 20 °C for 48 h.
Four replicate plates were used for each test. Antifungal ac-
tivity was taken by the diameter of the clear zone surround-
ing the disk.
Compound 3a
To an EtOH (50 mL) solution of zinc(II) acetate (0.20 g,
1.09 mmol) was added an EtOH (15 mL) solution of a
(0.59 g, 2.29 mmol). The mixture was heated at reflux for
3 h at which point a yellow-green precipitate was collected
by suction filtration and washed with cold EtOH (3 × 5 mL)
and Et2O (3 × 10 mL). The pale yellow solid was then dried
to afford complex 3a (0.60 g, 95%); mp 332–334 °C (de-
composition). IR (Nujol, cm–1) ν: 1608 (C=N). Spectro-
1
scopic NMR data (in DMSO-d6): H NMR δ: 13.36 (br s,
2H, -OH), 8.91 (s, 2H, C(H)=N), 7.79 (d, J = 3 Hz, 2H, Ar),
7.59 (d, J = 8 Hz, 2H, Ar), 7.44 (d of d, J = 8, 3 Hz, 2H,
Ar), 7.33 (t, J = 8 Hz, 2H, Ar), 6.95–6.80 (ov m, 6H, Ar).
13C{1H} NMR δ: 173.6, 161.5, 161.1, 160.8, 139.1, 133.3,
133.0, 127.6, 123.7, 120.0, 119.6, 118.1, 117.6, 117.1. Anal.
calcd. for C28H20N2O8Zn (%): C 58.19, H 3.50, N 4.85;
found: C 58.14, H 3.62, N 4.87.
Compound 3b
To an EtOH (50 mL) solution of zinc(II) acetate (0.20 g,
1.09 mmol) was added an EtOH (15 mL) solution of b
(0.77 g, 2.29 mmol). The mixture was heated at reflux for
3 h at which point a yellow-green precipitate was collected
by suction filtration and washed with cold EtOH (3 × 5 mL)
and Et2O (3 × 10 mL). The pale yellow solid was then dried
to afford complex 3b (0.64 g, 80%); mp 298–300 °C (de-
composition). IR (Nujol, cm–1) ν: 1601 (C=N). Spectro-
Results and discussion
Salicylaldimines
Schiff bases are remarkable compounds that have been
utilized extensively in organic syntheses (18–24). For in-
stance, a recent report describes a highly diastereo- and enantio-
selective asymmetric aldol reaction of glycinate Schiff bases
with aldehydes (24). In this study, we have found that
salicylaldehyde derivatives add to 5-aminosalicylic acid to
give compounds having spectroscopic data consistent with
the Schiff bases a and b (Scheme 1). As expected, a shift for
1
scopic NMR data (in DMSO-d6): H NMR δ: 13.33 (br s,
2H, -OH), 8.92 (s, 2H, C(H)=N), 7.81 (br m, 4H, Ar), 7.51–
7.44 (ov m, 4H, Ar), 6.91–6.84 (ov m, 4H, Ar). 13C{1H}
NMR δ: 173.1, 162.0, 159.9, 159.7, 138.4, 135.5, 134.5,
127.8, 123.6, 122.0, 119.6, 118.1, 118.0, 110.4. Anal. calcd.
for C28H18Br2N2O8Zn (%): C 45.71, H 2.47, N 3.81; found:
C 46.16, H 2.47, N 3.57.
1
the aldehyde proton from 10 to 9 ppm is observed in the H
NMR spectra and a resonance at ca. 160 ppm in the 13C
NMR spectra corresponds to the N=CH methine carbon.
Likewise, formation of these compounds can be monitored
© 2005 NRC Canada

1066
Can. J. Chem. Vol. 83, 2005
Table 1. Crystallographic data collection parameters for a and 4.
Complex
a
4
Chemical formula
C14H11NO4
C16H15NO5SZn
Formula weight
257.26
398.72
Crystal dimensions (mm3)
0.20 × 0.125 × 0.10
Monoclinic
P2(1)/c
0.30 × 0.15 × 0.125
Monoclinic
P2(1)/c
Crystal system
Space group
Z
4
4
a (Å)
b (Å)
c (Å)
7.016 4(7)
11.008 8(11)
14.898 0(15)
102.917(2)
1121.63(19)
1.517
9.528 4(5)
19.533 5(11)
8.650 8(5)
90.596(1)
1 610.03(15)
1.645
β (°)
V (Å3)
ρcalcd. (Mg m–3)
Temperature (K)
198(1)
173(1)
Radiation
Mo Kα (λ = 0.710 73 Å)
Mo Kα (λ = 0.710 73 Å)
µ (mm–1)
0.113
7445
2484
2482
1.681
10 977
3 617
3 617
Total reflections
Total unique reflections
Observed reflections (Fo > 4σ(Fo))
No. of variables
212
220
Rint
0.021 4
0.024 9
θ range (°)
2.32–27.48
1.106
0.047 9
2.09–27.48
1.036
0.031 2
S (GoF) on F2
R1 (I > 2σ(I))a
wR2 (all data)b
Largest diff. peak and hole (e Å–3)
0.140 4
0.087 0
0.779 and –0.220
0.905 and –0.273
aR1 = Σ2Fo* – *Fc2/Σ*Fo*.
2
4
2
2
bwR2 = (Σ[w(Fo – Fc2)2]/Σw[Fo ])1/2, where w = 1/[σ2(Fo ) + (0.0575·P)2 + (0.2611·P)] (a) and w = 1/[σ2(Fo ) +
(0.0513·P)2 + (0.7014·P)] (4), where P = (max (Fo , 0) + 2·Fc2)/3.
2
for the hydroxy imide tautomer of sulfasalazine, 5-[4-[(2-
pyridylideneamino)sulfonyl]phenyldiazenyl]salicylic acid (25).
For instance, both molecules are almost planar as a result of
extensive delocalization arising from an additional intra-
molecular interaction between the phenolic OH group on the
5-ASA fragment and the carboxylic acid C=O moiety (in a,
O(8)-H(8)···O(1) = 1.622(2) Å). The imine C(10)—N(9) bond
distance of 1.307(2) Å in a is comparable to bond lengths
observed in other salicylaldimine derivatives (26). Although
N-salicylaldimines are well-known to exist in tautomeric
forms because of the intramolecular proton shift between the
phenolic oxygen and the imine nitrogen (O-H···N ↔ O···H-
N), no evidence for the other keto amine tautomer is present
in the case of a (27).
Fig. 2. Molecular structure of a with ellipsoids drawn at the
30% probability level. Hydrogen atoms omitted for clarity.
Interestingly, lavendustin A, a structural derivative of
compound a, has been reported to inhibit tyrosine kinase, an
enzyme whose activity is often overexpressed in proliferative
diseases (28). Compound a has also shown some inhibitory
activity against tyrosine kinase (29). Likewise, the anti-
inflammatory and antipyretic activities of Schiff bases
derived from mesalazine and arylaldehydes have also been
reported (30). These promising biological properties prompted
by the diagnostic C=N stretching band in the IR spectra at
ca. 1620 cm–1 (20).
Compound a has also been characterized by a single crys-
tal X-ray diffraction study, the molecular structure of which
is shown in Fig. 2. Crystallographic data are provided in Ta-
ble 13 and bond distances and angles are shown in Table 2.
Structural features of a are similar to those reported recently
3 Supplementary data for this article are available on the Web site or may be purchased from the Depository of Unpublished Data, Document
Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada. DUD 4009. For more information on obtaining mate-
rial refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 261731 and 261732 contain the crystallographic data for this manu-
script. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2005 NRC Canada

Bourque et al.
1067
Scheme 2. Synthesis of metal Schiff base complexes 1–3.
CO H
2
HO
HO
H
C
R
M(OAc)
HO
N
H
2
N
C
O
M
N
HOOC
O
R
CO H
2
R
C
H
a: R = H
b: R = Br
OH
1: M = Pd
2: M = Cu
3: M = Zn
Fig. 3. The molecular structure of 4 with ellipsoids drawn at the
30% probability level. Hydrogen atoms omitted for clarity.
us to investigate the antifungal properties of late metal com-
plexes containing these bioactive ligands.
Metal complexes
Schiff bases are ubiquitous in coordination chemistry and
several reviews have recently been published outlining the
practical aspects and challenges associated with these com-
plexes (31–33). As part of our investigation into designing
new chelating agents from biologically active compounds,
we decided to examine the synthesis, reactivity, and anti-
fungal properties of Schiff base Pd(II), Cu(II), and Zn(II)
complexes derived from 5-ASA. Related Schiff base Pd(II)
complexes derived from S-alkyldithiocarbazates have re-
cently shown considerable antimicrobial activity against a
number of pathogenic bacteria including methicillin-resistant
Staphylococcus aureus (MRSA) and Bacillus subtilis (34).
Copper and zinc Schiff base complexes have also shown
considerable antibacterial and antifungal activity (35, 36).
We have found that addition of a and b to M(OAc)2 (M =
Pd, Cu, Zn) afforded bis(salicylaldiminato)metal(II) com-
plexes (Scheme 2, 1–3) in high to excellent yields (64%–
95%). Complexes 1–3 have been characterized by a number
of physical methods. For instance, elemental analyses for
paramagnetic copper complexes 2 are consistent with bis-
Schiff base formulation (37). The diagnostic C=N stretching
band in the FT-IR spectra has shifted from ca. 1620 cm–1 to
ca. 1595 cm–1 upon coordination to the metal centre (38).
Multinuclear NMR spectroscopy was also used to character-
ize diamagnetic palladium and zinc complexes. For instance,
base ligand must be behaving as a divalent anion to balance
the Zn2+ cation. Indeed, the carboxylic carbon–oxygen bond
lengths are roughly equivalent with C(7)—O(1) (1.254(3) Å)
and C(7)—O(2) (1.261(3) Å), which is consistent with a
deprotonated resonance structure (39). In comparison, the
analogous distances in a are C(7)—O(1) (1.238(2) Å) and
C(7)—O(2) (1.308(2) Å), where the single C(7)—O(2) bond
is clearly defined as the benzylic oxygen. In related zinc 5-
ASA complexes, coordination is believed to occur through
the deprotonated carboxylate group (40).
Complex 4 exists as a self-assembled polymer consisting
of dimeric units where two zinc atoms are connected asym-
metrically by bridging Schiff base ligands via the phenolic
oxygens (Fig. 4) (Zn—O(17) = 1.980(2) Å, Zn—O(17′) =
2.139(2) Å). The dimers form a 1D polymer via the
carboxylic acid group (Zn—O(2) = 1.960(2) Å), and the dis-
torted square pyramidal environment of Zn is completed by
1
a significant upfield shift in the H NMR spectra is observed
for the imine methine proton, from ca. 9 ppm to ca. 8 ppm,
upon coordination of the ligand to the d8 metal centre in
complexes 1. Coordination to the d10 zinc centres resulted in
only minor shifts to ca. 8.9 ppm. More notable, however, is
the absence of the broad OH stretch in the FT-IR spectra
when the ligands are coordinated to the metals.
coordination of
a
DMSO molecule (Zn—O(18)
=
2.130(2) Å) and the imine nitrogen (Zn—N(9) = 2.048(2) Å),
the latter occupying the axial position.
Interestingly, a zwitterionic conformer of complex 3a has
been characterized by an X-ray diffraction study, the molec-
ular structure of which is shown in Fig. 3. Crystallographic
data are given in Table 1, and bond distances and angles are
listed in Table 3. Attempts to grow single crystals of 3a in
DMSO resulted in the loss of one Schiff base ligand, pre-
sumably via protonation by the carboxylic acid group of the
5-ASA moiety, to give the DMSO adduct 4 shown in Fig. 3.
The solvent ligand is coordinated to the hard zinc via the ox-
ygen atom of the DMSO. The remaining coordinated Schiff
Although zwitterionic zinc complexes are relatively well-
known (41–48), Schiff base analogues are much less com-
mon. For instance, Zn(II) complexes of the type
ZnX2(H2salen) (X = Cl, Br, I, NO3, SO4) containing N,N′-
ethylenebis(salicylideneimine) ligands have been reported
previously (49). However, in these complexes the Schiff base
ligand is bound to the metal centre through the negatively
charged phenolic oxygens and not the nitrogen atoms. Re-
lated copper complexes containing only one tridentate Schiff
base ligand have also been reported (50, 51). Complex 4 is
© 2005 NRC Canada

1068
Can. J. Chem. Vol. 83, 2005
Table 3. Selected bond lengths (Å) and angles
Table 2. Bond lengths (Å) and angles (°) for a.
(°) for 4.
Bond lengths (Å)
Bond lengths (Å)
Zn—O(2)a
Zn—O(17)
Zn—N(9)
Zn—O(18)
Zn—O(17)b
Zn—Znb
C(2)—O(8)
C(5)—N(9)
C(7)—O(1)
C(7)—O(2)
O(2)—Zna
N(9)—C(10)
C(12)—O(17)
O(17)—Znb
O(18)—S
C(1)—C(6)
C(1)—C(2)
C(1)—C(7)
C(2)—O(8)
C(2)—C(3)
C(3)—C(4)
C(4)—C(5)
C(5)—C(6)
C(5)—N(9)
C(7)—O(1)
C(7)—O(2)
N(9)—C(10)
C(10)—C(11)
C(11)—C(16)
C(11)—C(12)
C(12)—O(17)
C(12)—C(13)
C(13)—C(14)
C(14)—C(15)
C(15)—C(16)
1.388(2)
1.408(2)
1.477(2)
1.351(2)
1.391(3)
1.373(3)
1.400(2)
1.388(2)
1.417(2)
1.238(2)
1.308(2)
1.307(2)
1.414(2)
1.412(2)
1.430(2)
1.310(2)
1.404(3)
1.372(3)
1.396(3)
1.363(3)
1.9598(16)
1.9796(15)
2.0476(18)
2.1296(17)
2.1387(16)
3.1381(5)
1.352(3)
1.427(3)
1.254(3)
1.261(3)
1.9597(16)
1.295(3)
1.341(3)
2.1387(16)
1.5149(17)
1.785(3)
S—C(20)
S—C(19)
1.786(3)
Bond angles (°)
O(2)a-Zn-O(17)
O(2)a-Zn-N(9)
O(17)-Zn-N(9)
O(2)a-Zn-O(18)
O(17)-Zn-O(18)
N(9)-Zn-O(18)
O(2)a-Zn-O(17)b
O(17)-Zn-O(17)b
N(9)-Zn-O(17)b
O(18)-Zn-O(17)b
O(2)a-Zn-Znb
145.61(7)
121.03(7)
93.03(7)
91.32(7)
93.35(6)
90.18(7)
89.02(7)
80.79(7)
98.26(7)
169.93(6)
120.59(5)
42.28(5)
97.54(5)
135.07(4)
38.51(4)
117.79(19)
123.54(19)
118.25(14)
120.35(19)
117.84(15)
121.61(14)
126.8(2)
Bond angles (°)
C(6)-C(1)-C(2)
C(6)-C(1)-C(7)
C(2)-C(1)-C(7)
O(8)-C(2)-C(3)
O(8)-C(2)-C(1)
C(3)-C(2)-C(1)
C(4)-C(3)-C(2)
C(2)-C(3)-H(3)
C(3)-C(4)-C(5)
C(6)-C(5)-C(4)
C(6)-C(5)-N(9)
C(4)-C(5)-N(9)
C(5)-C(6)-C(1)
O(1)-C(7)-O(2)
O(1)-C(7)-C(1)
O(2)-C(7)-C(1)
C(10)-N(9)-C(5)
N(9)-C(10)-C(11)
C(16)-C(11)-C(10)
C(16)-C(11)-C(12)
C(10)-C(11)-C(12)
O(17)-C(12)-C(13)
O(17)-C(12)-C(11)
C(13)-C(12)-C(11)
C(14)-C(13)-C(12)
C(13)-C(14)-C(15)
C(16)-C(15)-C(14)
C(15)-C(16)-C(11)
119.19(16)
121.21(15)
119.58(16)
117.92(16)
122.10(16)
119.98(16)
120.26(17)
123.2(11)
120.33(17)
119.64(16)
117.10(15)
123.25(15)
120.58(16)
122.87(16)
121.51(16)
115.60(15)
127.25(15)
122.31(16)
120.27(16)
119.12(17)
120.60(16)
122.42(16)
119.24(16)
118.34(16)
120.54(18)
121.36(19)
119.61(18)
121.02(18)
O(17)-Zn-Znb
N(9)-Zn-Znb
O(18)-Zn-Znb
O(17)b-Zn-Znb
C(6)-C(5)-N(9)
C(4)-C(5)-N(9)
C(7)-O(2)-Zna
C(10)-N(9)-C(5)
C(10)-N(9)-Zn
C(5)-N(9)-Zn
N(9)-C(10)-C(11)
N(9)-C(10)-H(10)
O(17)-C(12)-C(13)
O(17)-C(12)-C(11)
C(12)-O(17)-Zn
C(12)-O(17)-Znb
Zn-O(17)-Znb
116.6
119.2(2)
122.94(19)
118.62(13)
125.57(14)
99.21(6)
119.87(10)
105.27(13)
104.83(12)
98.85(14)
S-O(18)-Zn
O(18)-S-C(20)
O(18)-S-C(19)
C(20)-S-C(19)
aSymmetry transformations used to generate
equivalent atoms: –x, –y + 1, –z + 1.
bSymmetry transformations used to generate
equivalent atoms: –x, –y + 1, –z.
unique, however, in that it contains only one zwitterionic
bidentate Schiff base ligand where the third coordination site
is occupied by a solvent molecule.
Antifungal activity
As mentioned previously, the ability of metal Schiff base
complexes to inhibit fungal growth is well-documented (34–
© 2005 NRC Canada

Bourque et al.
1069
Fig. 4. View of compound 4, showing the polymeric nature.
Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms and DMSO molecules have been omitted for clarity.
neering Research Council of Canada (NSERC), and Mount
Allison University for financial support. We also thank Dan
Durant and Roger Smith for their expert technical assistance
and anonymous reviewers for helpful comments.
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