Complexes of Group 12 Metals with 2-Acetylpyridine 4N-Dimethylthiosemicarbazone and with 2-Acetylpyridine-N-oxide 4N-Dimethylthiosemicarbazone: Synthesis, Structure and Antifungal Activity

Article abstract of DOI:10.1515/znb-1999-0613

Reaction in ethanol of group 12 metal halides with 2-acetylpyridine ⁴N-dimethylthiosemicarbazone (H4DML) and with 2-acetylpyridine-N-oxide ⁴N-dimethylthiosemicarbazone (H4DMLO) afforded complexes of the forms [M(H4DML)X₂] (1 - 9) and [M(H4DMLO)X₂] (10 - 18) (M = Zn^II, Cd^II or Hg^II; X = Cl, Br or I). H4DMLO and the complexes of both thiosemicarbazones have been characterized by elemental analysis and by IR and ¹H, ¹³C and ¹¹³Cd NMR spectroscopy, and the crystal structures of [Cd(H4DML)Cl₂] (4), [Cd(H4DML)I₂] (6), H4DMLO, [Hg(H4DMLO)Cl₂] (16) and [Hg(H4DMLO)Br₂] (17) have been determined by X-ray diffractometry. In all the H4DML complexes, the thiosemicarbazone acts as an N,N,S-tridentate ligand, and the coordination polyhedra of the pentacoordinate metals are more or less distorted tetragonal pyramids. H4DMLO is an O,N,S-tridentate ligand for zinc and cadmium halides and an N,S-bidentate ligand for mercury halides, in which the mercury atom has coordination number four and a distorted trigonal pyramidal environment. In assays of antifungal activity against Aspergillus niger and Paecilomyces variotii, H4DML was more active than nystatin, and its complex with ZnCl₂ also showed good activity against A. niger, neither H4DMLO nor any of its complexes inhibited the growth of either pathogen.

Full text of DOI:10.1515/znb-1999-0613

Complexes of Group 12 Metals with 2-Acetylpyridine 4N-Dimethyl-
thiosemicarbazone and with 2-Acetylpyridine-N-oxide 4N-Dimethyl-
thiosemicarbazone: Synthesis, Structure and Antifungal Activity
Elena Bermejoa, Rosa Carballob, Alfonso Castiñeirasa’*, Ricardo Domínguez3,
Anthony E. Libertad, Cäcilia Maichle-Mössmer0, and Douglas X. Westd
a Universidad de Santiago de Compostela, Departamento de Qufmica Inorgäánica, Facultad de
Farmacia, Campus Universitario Sur, E-15706 Santiago de Compostela, Spain
b Universidad de Vigo, Departamento de Qufmica Inorgänica,
Lagoas-Marcosende, E-36200 Vigo, Spain
c Institut für Anorganische Chemie der Universität Tübingen,
Auf der Morgenstelle 18, D-72076 Tübingen, Germany
d Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
* Reprint requests to Prof. Dr. A. Castineiras. E-mail: qiacOl @usc.es
Z. Naturforsch. 54 b, 777-787 (1999); received December 29, 1998
2-Acetylpyridine
4
A^-Dimethylthiosemicarbazone, 2-Acetylpyridine-ALoxide /V-Dimethyl-
4
thiosemicarbazone, Group 12 Metal(II) Complexes, ll3Cd NMR Data
Reaction in ethanol of group 12 metal halides with 2-acetylpyridine ^-dimethylthio-
semicarbazone (H4DML) and with 2-acetylpyridine-N-oxide W-dimethylthiosemicarbazone
4
(H4DMLO) afforded complexes of the forms [M(H4DML)X2] (1 - 9) and [M(H4DMLO)X2]
(10 - 18) (M = Zn", Cd11 or Hg11; X = Cl, Br or I). H4DMLO and the complexes of both
thiosemicarbazones have been characterized by elemental analysis and by IR and 'H, i3C and
1
l3Cd NMR spectroscopy, and the crystal structures of [Cd(H
4
DML)Cl
2
] (4), [Cd(H
4
DML)l ]
2
(6), H4DMLO, [Hg(H4DMLO)Cl2] (16) and [Hg(H DMLO)Br
4
2
] (17) have been determined
by X-ray diffractometry. In all the H4DML complexes, the thiosemicarbazone acts as an N,N,S-
tridentate ligand, and the coordination polyhedra of the pentacoordinate metals are more or less
distorted tetragonal pyramids. H4DMLO is an 0,N,S-tridentate ligand for zinc and cadmium
halides and an N,S-bidentate ligand for mercury halides, in which the mercury atom has coor-
dination number four and a distorted trigonal pyramidal environment. In assays of antifungal
activity against Aspergillus niger and Paecilomyces variotii, H4DML was more active than nys-
tatin, and its complex with ZnCF also showed good activity againstA. niger; neither H4DMLO
nor any of its complexes inhibited the growth of either pathogen.
Introduction
in which the azomethine nitrogen is bound to a het-
erocyclic moiety, especially those in which the het-
erocycle is bound at position
, leaving the het-
2
Thiosemicarbazones and their complexes with
metals have acquired importance due to their po- eroatom as a third potential donor. For example,
tentially useful biological activities [1], Although
free thiosemicarbazones act by chelating metal ions,
their complexes can somewhat paradoxically have
greater activity, or can combine the primary ac-
tivity of the ligand with beneficial secondary ef-
fects. This may come about by the complexes sim-
ply supplying biologically essential metals, which
become available to the organism upon cleavage
of the complex; by activation of the ligand, or by
the metal bringing about the inactivation of mech-
anisms of resistance [2]. Among the thiosemicar-
bazones with greatest therapeutic potential are those
4
A^-disubstituted thiosemicarbazones derived from
-acetylpyridine efficiently inhibit the growth of
2
Aspergillus niger [3, 4]. This has spurred the syn-
thesis and structural and biological characterization
of both other Ar-disubstituted thiosemicarbazones
and their complexes, usually their complexes with
transition metals [5]. As part of our on-going re-
search on the coordination chemistry of thiosemi-
carbazones with non-transition metals, we have syn-
thesized and characterized complexes of group 1 2
4
metals with 2-acetylpyridine-
carbazone (H4DML) and with 2-acetylpyridine-AL
4
A^-dimethylthiosemi-
0932-0776/99/0600-0777 $ 06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
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E. Bermejo et al. • Complexes of Group 12 Metals
778
Table I. Analytical data,
No. Compound
Colour M. p.
(°C)
N (%)
— Found (Calcd) —
Yield
(%)
C(%)
H (%)
colours and melting points
of complexes of Zn(II),
Cd(II) and Hg(II) with
H4DML and H4DMLO.
yellow
1
2
302 33.9 (33.5) 3.8 (3.9) 16.0(15.6) 71
[Zn(H4DML)Cl2]
[Zn(H4DML)Br2]
[Zn(H4DML)F]
[Cd(H4DML)Cl2]
yellow 294
77
6 8
27.2(26.8) 2.9 (3.1) 12.8(12.5)
yellow
yellow 288
10.2 (10.4)
3.2 (3.5) 13.5 (13.8) 70
3
4
5
6
7
8
9
299 22.5 (22.2) 2.5 (2.5)
29.6 (29.6)
74
65
6 8
[Cd(H4DML)Br,] yellow 286 24.6 (24.3) 2 . 6
yellow 20.8 (20.4) 2.1 (2.4) 9.4 ( 9.5)
[Hg(H4DML)Cl->] orange 228 24.9 (24.3) 2 . 6
(
2
.8
) 11.4(11.3)
[Cd(H4DML)I2]
285
orange 232 20.9 (20.6)
orange 236 17.8(17.7) 1.9 (2.1) 8.1 ( 8.3)
yellow 224
11.9(11.4)
9.7 ( 9.7)
(
2
. )
8
[Hg(H4DML)Bri]
[Hg(H4DML)F]
2.2 (2.4)
79
74
3.7 (3.7) 14.9(15.0) 72
10 [Zn(H4DMLO)Cl2]
11 [Zn(H4DMLO)Br?]
31.9 (32.1)
yellow
yellow
yellow
yellow
yellow
yellow
72
65
248 25.9 (26.5) 3.0 (3.1) 1 2 . 1
(
(
1 2
.
0
)
)
12
2.5 (2.5) 1 0
.0
1 0
.0
[Zn(H4DMLO)I2]
179 21.7 (21.5)
12.9(13.3) 71
10.4(11.0) 79
13 [Cd(H4DMLO)Cl2]
14 [Cd(H4DMLO)Br2]
15 [Cd(H4DMLO)I2]
16 [Hg(H4DMLO)Cl2]
196 27.6 (28.5) 3.5 (3.3)
192 23.3 (23.5)
192 20.2 (18.9) 2.0 (2.3) 8.9 ( 9.3)
198 23.6 (23.6) 2 . 6 ) 11.0(10.9)
2.4 (2.7)
75
73
(
2 8
.
17 [Hg(H4DMLO)Br2] yellow 197
18 [Hg(H4DMLO)I2]
9.5 ( 9.4) 76
76
2 0 . 0
(
2 0
.
1
) 2.3 (2.3)
yellow
8 . 2
(
8
. )
1
188 17.4(17.3) 2 . 1 . )
(
2
0
Fig. 1. Prespective view of the
molecule 4 showing the atom num-
bering scheme and the co-ordi-
nation geometry about cadmium.
Thermal ellipsoids enclose 50%
probability level. Hydrogen atoms
are drawn with an arbitrary BIS0 =
1.5 A
2
and represented by open cir-
cles.
oxide
4
Ar-dimethylthiosemicarbazone (H4DMLO), plexes are stable under air and moderately soluble
in common organic solvents; their melting points
which were chosen so as to allow evaluation of how
coordination behaviour and antifungal activity are range from 179 to 302 °C.
affected when the possibility of coordination via
the pyridine N atom of H4DML is replaced by the
possibility of coordination via an O atom.
Molecular structures
The molecular structures of [Cd(H
4
DML)Cl ]
2
(4) and [Cd(H4DML)I2] DMSO (6 + DMSO) are
shown in Figs 1 and 2, respectively, Table II lists
Results and Discussion
Table I lists the yields, elemental analyses, the chief bond lengths and angles of their thiosemi-
colours and melting points of the compounds ob- carbazone moieties, and Table III the lengths of,
tained by reacting H4DML or H4DMLO with group and angles between, their coordination bonds. In
12 metal halides in ethanolic media. All the analyti- both compounds H4DML is N,N,S-tridentate, so
that the metal atom is pentacoordinated to two nitro-
cal data indicate metal/ligand ratios of 1:1. All com-
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779
E. Bermejo et al. ■Complexes of Group 12 Metals
Table III. Coordinating lengths (A) and angles (°) in com-
plexes of Cd(II) and Hg(II) with H4DML and H4DMLO.
Table II. Selected bond lengths (A) and bond angles (°)
in the thiosemicarbazone ligands.
4
6 +
H4-
16
17
17
4
6+DMSO 16
DMSO DMLO
2.424(2)
2.546(2)
2.563(2)
2.454(4)
—
2.480(2)
2.455(3)
2.575(3)
2.308(6)
2.405(8)
2.761(1)
2.751(1)
2.592(2)
2.364(5)
2.376(5)
M-X(l)
M-X(2)
M-S(l)
M-N(l)
M-N(2)
C(6)-N(2)
N(2)-N(3)
N(3)-C(7)
C(7)-S(l)
C(7)-N(4)
0( l)-N(l)
1.278(9) 1.279(7) 1.316(4) 1.286(11) 1.290(16)
1.38(1) 1.385(7)1.350(3) 1.373(9) 1.390(13)
1.364(9) 1.374(8) 1.358(4) 1.347(11) 1.322(16)
1.709(8)1.703(6) 1.706(3) 1.725(8) 1.715(13)
1.29(1) 1.311(8) 1.347(4) 1.345(10) 1.352(15)
2.462(3)
2.423(2)
—
2.540(7)
2.569(15)
—
—
N(l)-M-X(l)
94.1(2)
N(l)-M-X(2) 103.9(2)
96.5(1)
102.5(1)
—
—
1.315(3) 1.333(10) 1.330(18)
—
—
N(l)-C(5)-C(6) 116.0(6) 116.8(5) 121.6(3) 118.6(8) 121.4(12)
C(5)-C(6)-N(2) 113.9(7) 114.8(5) 120.5(2) 125.9(8) 125.1(11)
C(6)-N(2)-N(3) 120.1(7) 119.1(5) 121.4(2) 116.3(7) 117.2(10)
N(2)-N(3)-C(7) 118.8(7) 117.7(5) 112.2(2) 120.4(7) 120.7( 10)
N(3)-C(7)-S(l) 123.8(7) 122.7(4) 125.7(2) 124.7(6) 125.9(10)
N(3)-C(7)-N(4) 116.4(7) 116.2(5) 112.4(2) 116.3(7) 115.5(11)
S(l)-C(7)-N(4) 119.8(5)121.1(5)122.0(2)118.9(6) 118.6(11)
—
—
N(l)-M-N(2)
N(2)-M-X(l)
N(2)-M-X(2) 107.6(2)
X(l)-M-X(2) 105.5(1)
S(l)-M-X(l) 106.11(8)
67.6(3)
145.2(2)
67.1(2)
145.4(2)
98.0(2)
115.58(2)
109.1(2)
96.6(2)
107.03(9) 109.15(6)
108.6(3)
96.1(3)
126.4(1)
102.21(4) 128.74(9)
S(l)-M-X(2) 108.08(9) 108.54(4) 123.50(8) 124.0(1)
S(l)-M-N(l) 135.5(2)
S(l)-M-N(2)
73.7(2)
131.6(1)
72.5(1)
—
—
74.7(3)
C(5)-N(l)-0(1) —
C(l)-N(l)-0(1)—
—
—
120.5(2)120.7(7) 119.9(11)
118.7(2)118.7(7) 120.9(11)
75.3(2)
Table IV. Distortion r from ideal tetragonal pyramidal
coordination in 4 and . bpt = ideal trigonal bipyramid,
6
p-t = ideal tetragonal pyramid.
Compound /?[N(2)-Cd-X(l)] a[S(l)-Cd-N(l)] \ß - a\
r
9.7
13.8
60.0
0.0
0.16
0.23
1.00
0.00
4
145.2
145.4
120.0
180.0
135.5
131.6
180.0
180.0
6+DMSO
bpt
p-t
complexes of cadmium halides with other thiosemi-
carbazones [7, ]. The Cd-Npy distance is shorter
8
in the chloride than in the iodide [2.308(6) A as
against 2.364(5) A], and in both compounds the
Cd-Npy bond is shorter, and therefore stronger, than
the C d - N a z o m e th in e bond (Table III). However, the
Cd-N and Cd-halogen distances are in general all
similar to those found in other complexes of cad-
mium(II) halides with thiosemicarbazones contain-
ing a pyridine ring [7,
8
]. Of the various possi-
ble conformations of thiosemicarbazones derived
from 2-acetylpyridine [9, 10], H4DMLO adopts
that of the polar resonance form E' (Fig. 3), prob-
ably because this structure, in which the proton
transfers from N3 to the azomethine nitrogen N2,
allows the formation of a bifurcated intramolec-
ular hydrogen bond between N2 and the sulphur
and oxygen atoms [N2-H-0, 1.02(4), 1.77(4) and
2.532(4) A, 127(3)°; N2-H-S, 1.02(4), 2.29(5) and
2.867(3) A, 114(3)°]. The chief bond lengths and
angles of H4DMLO (Table II) are in general similar
Fig. 2. Molecular structure of asymmetrical unit of
+DMSO. Details as in Fig. 1.
6
gen, one sulphur and two halogen atoms. The co-
ordination polyhedron is in both cases a distorted
tetragonal pyramid, the distortion towards a trigo-
nal bipyramid (as measured by r [ ]) being greater
6
to those found in
semicarbazone (H4ML) [
2
-acetylpyridine
4
/V-methylthio-
for the larger halogen atom (Table IV). The Cd-S
distances (Table III) are similar to those found in
8
], except that, in keeping
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780
E. Bermejo et al. • Complexes of Group 12 Metals
Fig. 3. Molecular
structure of the
H4DMLO show-
ing the intra-mo-
lecular hydrogen
bonding N-H-O.
Fig. 4. Perspective view of the
molecule 16.
tate, coordinating via the sulphur and azomethine
nitrogen atoms. The metal is accordingly tetra-
coordinate, and its coordination polyhedron is a
distorted trigonal pyramid with the mercury atom
in the same plane as the halogen and sulphur
atoms. The distortion of the polyhedron is illustrated
by the S-Hg-N2 angles, 75.3(2)° in the chloride
and 74.7(3)° in the bromide. The Hg-N distances
with the observed conformation, they show greater
delocalization of charge, affecting the whole
thiosemicarbazone chain, in H4DMLO. In particu-
lar, the N-N distance, 1.350(3) A, is much less than
the 1.44 A of a single N-N bond. Figs 4 and 5 show
the molecular structures of [Hg(H4DMLO)Cb] and
[Hg(H
4
DMLO)Br
2
] respectively; bond lengths and
angles in the ligand moieties are listed in Table II,
and those involving the metal atom in Table III. are similar to that of [Hg(H
4
ML)Cl
2
]-2
DMSO
[
8
], and the Hg-halogen distances are not signif-
In these isotypic compounds H4DMLO is biden-
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E. Bermejo et al. ■Complexes of Group 12 Metals
781
Fig. 5. Perspective view of the
molecule 17.
icantly different from those found in other com- to higher frequencies than in the free ligand, as do
plexes of mercury halides with ligands binding the in-plane and out-of-plane deformation bands of
via thiocarbonyl sulphur atoms [11]. However, the the pyridine ring, an inequivocal sign of coordi-
Hg-S distances are about 0.1 A shorter than in nation via the pyridine nitrogen atom [18]. Thus
H4DML is tridentate in all the complexes studied,
[Hg(H4ML)Cl
2
]-2DMSO [ ], in which the ligand
8
is tridentate. In comparison with the free ligand, as was confirmed by the X-ray studies of two of
the H4DMLO moieties of the mercury complexes the cadmium compounds. In the zinc and cadmium
have longer N2-N3 and C7-S bonds and shorter complexes of H4DMLO, coordination via the pyri-
C6-N2 and N3-C7 bonds (Table II), which may be dine-./V-oxide oxygen atom is reflected by the shifts
attributed to alteration of charge delocalization as to lower frequencies of zz(N-O) and <5(N-0) (Ta-
the result of coordination to the metal. In addition, ble V) [19]. Thus H4DMLO is 0,N,S-tridentate in
the proton has returned to N3, where it establishes these complexes. The v(N -0) bands of the mer-
a hydrogen bond with the pyridine-iV-oxide oxy- cury compounds were impossible to identify, and
gen atom but not with the sulphur atom [N3-H-0:
1.02(4), 1.77(4) and 2.532(4) A, 127(3)°].
the bands attributed to <5(N-0) are too weak for sure
conclusions to be drawn from them, but the ab-
sence of i^(Hg-O) bands from the 500 - 100 cm- 1
region (Table VI) suggests that the O atom is not
involved in coordination. Thus H4DMLO appears
to be N,S-bidentate in these mercury complexes, as
was confirmed by the X-ray studies of the chloro
and bromo compounds.
Infrared spectra
Table V lists the main IR bands of the ligands
and complexes in the 4000 - 400 cm- 1 region. In
all the complexes, coordination via the azomethine
nitrogen is reflected by the z/(C=N) [12 - 14] and
The 500 - 100 cm- 1 spectra of most of the com-
i/(N-N) [15, 16] bands shifting to higher frequen- plexes show two bands assigned on the basis of
published data to u(M-N) (at 340 - 370 cm "1) and
^(M-S) (at 280 - 320 cm-1). The spectra of the
cies, and coordination via the sulphur by a shift in
u(CS) to lower frequencies [17]. In the H4DML
complexes (Table V), the i/(CN) band also shifts zinc and cadmium complexes of H4DMLO show
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782
E. Bermejo et al. • Complexes of Group 12 Metals
Table V. Main IR bands (4000
<5(NO) u(CS)
Compound z/(NH)
i/(CN)
1500m
i/(NN)
HNO)
- 500 cm-1) of H4DML and
H4DMLO and their com-
plexes with Zn(II), Cd(II) and
Hg(II).
_
—
—
—
—
—
—
—
—
—
_
—
—
—
—
—
—
—
—
—
921 w
903m
910w
914w
908w
904w
904w
903m
906m
903m
H4DML
2947sh, 2908m
980w
3253w, 3096w
3310w, 3059w
3316w, 3054w
322 lw
1
1017w
1013w
1 0 1 lw
1015w
1013w
1013w
1009w
1007w
1005w
2
1562vs
1562vs
1561vs
1555vs
1557vs
1545vs
1537vs
1532vs
3
4
5
6
7
8
9
3312w, 307lw
3314w, 3068w
3092w
3092w
3092w
3072m, 3034m, 2930m 1500m
3199m
1038w 852w 802w
H4DMLO
1244vs
1215m
—
853w 780w
1049w 84lw 785w
10
1576s
3182m, 3075m
3175mw, 3061w
3214w, 3061w
3343w, 3119w, 3069w
3329m, 3111 w, 3078w
3038w
11
12
1574vs 1204s
1576vs 1213m
1568vs 1219m
1564vs 1204s
—
8 6 6
w 795w
1057w 833w 793w
1042w 839w 795w
13
14
15
16
17
18
81 lw
760w
769w
1208s 1053w 939w
1561vs
1537m
1537s
—
—
—
8 6 6
w
w
1065w
3030w
3109w
1063w 8 6 6
1537w
85lw 764w
1055m
Table VI. Main IR
Compound
!/(MX)s i/(MN)
i/MS)
i/(MO)
i/(MI)MMCl)
i/(MBr)/i/(MCl)
KMX)«
bands (500-100 cm- 1)
of the complexes
of Zn(II), Cd(II) and
Hg(II) with H4DML
and H4DMLO and ra-
tios between the M-X
stretching frequencies
of complexes with dif-
ferent halogen ligands
(where two z/(M-X)
bands were observed,
the mean was used).
-- _ _
_
1
283
207
187
266
186
158
278
179
149
286
214
181
242
166
146
283
170
149
272
191
172
253
170
142
235
169
136
240
171
136
—
363
365
366
365
358
357
350
350
347
370
368
366
355
359
359
363
359
351
—
—
—
—
—
—
—
—
—
2
294
293
—
0.72
—
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
0.65
—
—
—
282
280
287
287
284
0 . 6 8
—
0.58
—
—
—
0 . 6 8
—
0.55
—
—
314 425
312 418
312 406
316 427
307 417
—
0.73
—
0.60
—
—
—
—
0.69
—
—
298
319
314
307
404
—
0.60
—
—
—
—
—
—
0.60
—
—
—
0.53
a band between 400 and 430 cm
“
1
that does not attributed to z/(M-X) exhibit i/(M-Br)/^(M-Cl) and
appear in those of the mercury complexes and ap- z/(M-I)/z/(M-Cl) ratios in keeping with published
pears to be due to z/(M-O) [20], and thus to confirm values [21; Table VI].
that the ligand coordinates via the oxygen atom in
these complexes. The fact that the i'(M-S) bands
of the H4DML complexes lie at lower wavenum-
1H NMR spectra
bers than those of the analogous H4DMLO com-
plexes is probably attributable to the M -0 bond
being more covalent than the M-Npy bond, and
also by 6 , 6 bichelate rings vs. 5,6 bichelate rings.
Finally, the bands between 140 and 275 cm- 1
Table VII lists the 'H NMR signals of the lig-
ands and complexes as assigned on the basis of
published data [13, 22- 25], In both ligands, and
in some of the mercury complexes, the N3 pro-
ton (N2H in H4DMLO) has more than one signal,
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E. Bermejo et al. • Complexes of Group 12 Metals
783
Table VII. 'H NMR signals ( , ppm) of H4DML, H4DMLO and their complexes with Zn(II), Cd(II) and Hg(II).
6
Compound
H(l)
N(3)H
NMe
H(2)
H(3)
H(4)
CMe
H4DML
3.32-
3.30- 3.08
3.18- 311
—
8.70-8.57
8.65 - 8 . 6 8
8.81 -8.64
8.71
7.49- 7.36
7.63 - 7.51
7.77- 7.57
7.73
7.82-7.80
7.97
8.14
8.14
8.14
8.16
8.15
8.07
8 . 0 2
8.02 - 7.97
8 . 1 1
2.37
14.66-9.61
3.30
—
—
1
—
—
2
8 . 2 1
2.38
—
3
8 . 2 1
4
8 . 6 8
7.77
8 . 2 0
2.36
2.37
2.37
2.38
2.37
2.37
2.24
—
10.98
10.99
1 0 . 8 8
9.41
—
3.11
5
8.71
8.73
7.80
7.80
7.72- 7.55
7.70- 7.51
8 . 2 2
3.15
6
8 . 2 0
3.14
7
8
9
8.74 - 8.65
8.71 - 8.61
8.69
8.13
8 . 1 1
3.17- 3.12
3.15
7.54
10.47-9.41
9.65 - 8.29*
—
3.14
7.68 -
7.48
7.56
7.56
7.62
8 . 0 1
8 . 2 0
H4DMLO
10
11
8.47
7.59
7.71
7.74
7.84
7.76
7.61
7.62
7.84
7.87
7.85
7.97
7.93
7.93
8 . 0 2
3.29- 3.26
3.27
8.52
—
8.49
2.07
3.26
12
3.26
8.55
2.13
8.40
8.64
8.75
—
—
13
14
15
16
17
18
8.43
7.59- 7.49
7.50
7.98-7.89
7.88
7.89
8 . 0 2
3.28
8.42
2.07
2.07
2.29
2.30
2.07
3.28
8.43
7.51
3.28
8.50
10.84-8.66
12.16-8.66
8.65
3.25
7.59
8.50
7.60
8 . 0 1
3.26
8.47
7.56
8 . 0 1
3.27
*N(2)H.
Table VIII. 13C NMR signals of H4DML, H4DMLO and their complexes with Zn(II), Cd(II) and Hg(II).
Compound
C(2)
C(4)
C(3)
C(5)
C(
6
)
C(60)
C(7)
C(
8
)
C(9)
C(l)
H4DML
150.35
1 2 0 . 2 2
136.73 124.41
140.70 125.80
155.32 148.76 12.15
182.13 42.42 34.59
179.24 41.42 34.58
178.49 41.80 34.56
—
—
—
1
122.73
123.89 141.18
124.10 141.37 126.27
148.68
147.29 14.76
—
—
—
2
148.87
149.54
126.94
—
—
—
—
—
—
—
—
14.84
14.93
3
147.61
148.31
178.23
177.73
177.70
177.68
4
149.47 124.38
140.77 126.92
5
149.40 124.64
140.89 127.06 152.17 147.97 15.11
140.92 126.86 151.56 147.83 15.10
6
149.08 124.67
—
—
—
—
—
—
—
—
—
—
7
8
9
149.30 124.68 139.98
15.09- 13.24
14.98 -
13.98
41.37 34.62
41.80 34.60
41.12 34.62
—
126.33
126.14
—
—
13.12
149.03 124.43
148.46 121.46 139.56 125.23
—
—
—
139.80
H4DMLO
125.01
128.00 126.00
140.50 14.57
184.50 34.59
—
—
—
—
—
34.77
—
10
12
17
125.00 128.96 126.26
141.49
—
—
—
127.55 125.85
126.83 131.51
126.11
126.79 131.50 128.73 150.54 140.77
140.22
141.73
—
144.64
143.36
144.57
140.77
172.91
128.68 150.49
130.18 128.07 149.43 140.15
17.08
16.84
171.64
172.38
18
—
—
130.01 128.00 148.75
possibly due to its involvement in hydrogen bonding
The signals of the H4DML pyridine ring pro-
(as found in the solid state in some cases) or to there tons (H I-4) undergo considerable downfield shifts
being several different isomers of the ligands in so- upon complexation, showing coordination via the
lution, more than one of which may coordinate to pyridine nitrogen. The ring proton signals of the
mercury in this state. In general, the N3H signals of H4DMLO complexes naturally provide little infor-
mation about coordination via the pyridine-V-oxide
oxygen atom. The methyl groups on the thioamide
nitrogen atom give rise to two signals in each ligand
the complexes lie downfield from the corresponding
signals of the free ligands, reflecting coordination
via the azomethine nitrogen.
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784
E. Bermejo et al. ■Complexes of Group 12 Metals
Table IX. Antifungal activity of H4DML and its com-
(NMe in Table VII): at 3.32 and 3.30 ppm in
H4DML and at 3.29 and 3.26 ppm in H4DMLO.
The presence of just one NMe signal in the spectra
of most of the complexes shows that these methyls
are magnetically equivalent in these compounds, no
doubt due to free rotation about the N4-C7 bond be-
ing allowed by the reduction of its bond order upon
complexation.
plexes with Zn(II) and Cd(II).
Concentration (/./g ml ')
2 0 0
a
1 0 0 0
Aspergillus niger
18.2
14.7
15.2
17.3
H4DML [4]
1
2
8.9
9.5
1 0 . 2
9.0
Nystatinh
Paecilomyces variotti
13C NMR spectra
H4DML
31.5
11.5
1 1 . 2
9.8
10.3
7.8
18.5
6 . 0
Table VIII lists the l?C NMR signals of the lig-
ands and complexes that were soluble enough for
interpretable spectra to be obtained, as assigned on
the basis of published data [22,25]. The shielding
of C7 in all the complexes is attributable to coor-
dination via the sulphur atom, and the deshielding
of C60, the methyl carbon bound to the azomethine
group, to coordination via the azomethine nitrogen.
In the pyridine ring of the H4DML complexes, the
carbons ortho to the heteroatom are shielded and
the others deshielded, which can be regarded as re-
flecting coordination via the pyridine nitrogen. No
such effects can be expected to be caused by coordi-
nation via O in the H4DMLO complexes, for which
the general deshielding of the pyridine ring carbons
throws no light on coordination behaviour.
1
2
3
4
5
6
10.5
6 . 0
6.3
7.0
8.3
1 2 . 8
12.5
25.2
Nystatin
a Diameter of growth inhibition zone (6.0 indicates no
inhibition);bcommercially avalilable therapeutic agent.
inhibit the growth of A. niger dose-dependently and
rather better than nystatin [4], and was only assayed
against P. variotii, against which it showed activ-
ity that was considerably greater than that of nys-
tatin and was dose-dependent up to 600 /ig-ml-1.
Of the complexes, which were tested at doses of
2 0
0
and 1 0
0
0
/ig-ml-1 , only the zinc and cad-
mium compounds were active against P. variotii,
and only [Zn(H4DML)Cl2] and [Zn(H4DML)Br2]
against A. niger. In all these cases the activity shown
was greater than that of the corresponding complex
113Cd. NMR spectra
Only the H4DML complexes were soluble
enough for ll3Cd NMR spectra to be recorded.
The spectra of the chloro, bromo and iodo com-
plexes show single signals at 379.2, 375.5 and
295.1 ppm respectively, reflecting deshielding with
respect to the corresponding cadmium dihalide in
DMSO [26] (especially in the case of the chloro
complex). The nuclide is also more deshielded in
of the
was greater at the higher dosage used. Against A.
niger [Zn(H DML)Br ] was somewhat more active
4
N-monomethylated ligand H4ML [
8
], and
4
9
than nystatin or H4DML at the lower dosage, but
somewhat less active than these agents at the higher.
Against P. variotii the complexes were all signifi-
cantly less active than nystatin and H4DML.
the
4
N-disubstituted complexes than in the corre-
ML)X ] complexes [ ], possibly
sponding [Cd(H
4
2
8
due to the different strength of the Cd-S bond and
to steric hindrance by the methyls on N4.
Experimental
Elemental analyses (C, N, H) were performed with a
Carlo Erba 1108 microanalyser. Melting points were de-
termined in a Büchi apparatus. IR spectra were recorded
on a Mattson Instruments Cygnus 100 FTIR spectrometer
Antifungal activity
The activity of the compounds against the
pathogenic fungi Aspergillus niger and Pae-
cilomyces variotii was assayed in comparison
with the commercially available antifungal agent
nystatin. No activity whatsoever was shown by
H4DMLO or its complexes. H4DML is known to
using KBr pellets for spectra run from 4000 to 400 cm
- 1
and polyethylene-sandwiched Nujol mulls for the range
500 - 100 cm“ 1. 'H and 13C NMR spectra in (CD3)2SO
were recorded on a Brücker WM-300 spectrometer with
TMS as internal reference 11 ’Cd NMR spectra of 10- 2 M
.
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E. Bermejo et al. ■Complexes of Group 12 Metals
785
Table X. Crystal structure refinement data for H4DMLO and the complexes 4, 6, 16 and 17.
4
Compound
H 4D M L O
6 + DMSO
17
16
Empirical formula
Formula weight
Crystal size [mm]
Wavelength [A]
Crystal shape
Crystal system
Space group
a [A]
b [A]
c [A]
a [° ]
ß 1°]
C10H,4N4OS
238.31
0.50x0.10x0.10 0.30x0.20x0.20
0.71073
needle
monoclinic
P2\/c (No. 14)
6.9799(4)
11.0524(8)
15.3255(13)
—
98.736(6)
—
1168.56(15)
4, 1.355
504
CioH,4CdCl2N4S
405.63
C]oH14Br2HgN4 0 S
598.72
0.40x0.20x0.10
0.71073
prism
Ci2H2oCdl2N4OS2
666.67
0.50x0.40x0.30
0.70930
prism
monoclinic
P2\/n (No. 14)
11.129(3)
15.352(1)
12.313(3)
—
100.27(1)
—
2070.0(8)
4, 2.139
1256
C,oH|4Cl2HgN4OS
509.80
0.50x0.30x0.20
0.71073
prism
triclinic
P\ (No. 2)
7.840(3)
9.184(4)
11.005(5)
84.26(3)
88.45(3)
70.86(4)
744.9(6)
2, 2.273
480
0.71073
prism
triclinic
P\ (No. 2)
7.835(2)
9.242(4)
10.757(4)
84.87(3)
82.44(3)
65.12(3)
700.1(5)
2, 1.924
400
triclinic
P\ (No. 2)
7.898(3)
9.374(4)
11.152(4)
84.62(3)
89.39(3)
72.06(3)
781.9(5)
2, 2.543
552
7 1°1
V[A3]
Z, Dcaicd. [Mg/m3]
F(000)
9 Range [°]
Temperature [K]
3.26 - 26.95
213
3.00 - 30.00
293
3.0 - 28.0
213
3.14-31.00
213
3.07 - 27.05
213
-1 /8
0 / 14
-19/19
0.262
0 /1 0
-1 / 14
0 /2 0
-1 6 / 16
4.24
-1 /1 1
-1 / 10
-11/11
-1 4 /1 4
15.082
^min/^max
^min/^max
Anin//max
-1 / 12
-15/15
2.08
-1 2 /1 3
-15 / 15
10.827
p [mm- 1]
Max./min. transmissions 0.724 / 0.275
0.902 / 0.636
3024 / 2983
0.0416
2983 / 164
0.047
0.983 / 0.672
5906 / 4374
0.022
4295 / 200
0.0354
0.570/0.105
5667/4741
0.0458
4741 / 213
0.0550
0.603/0.132
4155/3401
0.0545
3401 / 175
0.0572
Refl. collected/unique
3160/2534
0.0455
2534/201
0.0536
^int
Data / parameters
Final R
Final wR2
GOOF
0.057
1.128
0.0354
1.295
0.1034
1.000
0.1323
1.035
0.1147
1.016
Max. A p [eA-3 ]
0.184
0.321
0.950
2.027
2.330
solutions in DMSO were run on a Brücker WM-250 spec-
trometer and referred to 0.1 M Cd(C1 0 4 .The mass spec-
tra of the ligands were obtained by FAB using a Kratos
MS-50 apparatus, with nitrobenzylalcohol as matrix.
C10H14N4S (222.31)
Calc C 54.0 H 6.4 N 25.2%,
Found C 53.0 H6.1 N 24.9%.
)2
MS-FAB (m/z,%): [L+H]+, 223(100); [L]\ 222(36).
2-Acetylpyridine-N-oxide AN-dimethylthiosemicarb-
azone, H4DMLO: 2-Acetyl pyridine-N-oxide was pre-
pared as per Winterfeld and Zickel [28] by oxidation of
Reagents: 2-Acetylpyridine, 4-dimethyl-3-thiosemi-
carbazide, ZnBn, CdChhbO, CdBr
2
-4
H2
0
,Cdl
2
, HgBr
2
and Hgl (all from Aldrich), HgCh (from Merck), and
2
2
-acetylpyridine with hydrogen peroxide, and was used
ZnCh and Znh (both from Ventron) were all used with-
to synthesize H4DMLO by a procedure analogous to that
described above for H4DML. Crystals suitable for X-ray
diffraction studies were obtained upon storing the mother
liquor of the recrystallization step at low temperature,
yield 36%, m. p. 229 °C.
out prior purification.
Synthesis of the ligands
The ligands were prepared using Klayman et al.'s, [27]
general method for condensation of amines with aldehy-
des or ketones, as follows.
C,oH14N40S (238.31)
Calc C 50.4 H 5.9 N 23.5%,
2-Acetylpyridine AN-dimethylthiosemicarbaz.one,
H4DML: A solution of 2-acetylpyridine (10.16 g,
0.08 mol) in 50 ml of ethanol was slowly added to a solu-
tion of4-dimethyl-3-thiosemicarbazide (10.0 g, 0.08 mol)
in 100 ml of hot water. After refluxing for 4 h, the yellow
product was filtered out and recrystallized from ethanol,
yield 33%, m. p. 156 °C.
Found C 49.9 H 5.8 N 22.9%.
MS-FAB (m/z,%): [L+H]+, 239(100); [L]\ 238(26).
Synthesis of the complexes
To a solution of the appropriate thiosemicarbazone in
hot ethanol was added an equimolar amount of the appro-
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786
E. Bermejo et al. ■Complexes of Group 12 Metals
priate metal salt dissolved or suspended in ethanol. The
refinement are given in Table X. Data were corrected for
Lp effects and for observed linear decay of the reference
reflections. An empirical absorption correction (DIFABS)
], [31] was applied for all compounds. The structures were
mixture was stirred for about
solids formed were filtered out, washed with ethanol
and vacuum dried. Monocrystals of [Cd(H DML)Cl
1
week, and the coloured
4
2
[Hg(H4DMLO)Cl2] and [Hg(H4DMLO)Br2] suitable for solved by automated Patterson or direct methods and sub-
X-ray diffraction studies were obtained by slow evapo-
sequent difference Fourier techniques (SHELXS8 6 ) [32]
ration of solvent from the corresponding filtrates. Single
and refined on F(SDP/VAX) [33] or F2(SHELXL97) [34]
crystals of [Cd(H
crystallization from DMSO.
4
DML)l
2
] DMSO were obtained by re- by a full-matrix least-squares procedure using anisotropic
displacement parameters. Hydrogen atoms were located
from difference Fourier maps and refined isotropically
in H4DMLO and 16, or were included in the refinement
X-ray crystallography
Crystals of H4DMLO, 4,6.16 and 17 suitable for X-ray in calculated positions riding on their carried atoms in
diffraction were mounted on glass fibers and transferred to 4, 6 and 17. Neutral atom scattering factors and anoma-
lous dispersion corrections were taken from the Interna-
tional Tables for X-Ray Crystallography [35]. Geomet-
an Enraf Nonius CAD4 diffractometer. Accurate unit-cell
parameters and an orientation matrix were determined by
least-squares refinement of the setting angles of a set of rical calculations and illustrations were performed with
the SHELXL97 [34], ZORTEP [36] and PLATON98 [37]
package. Further details of structure analysis are available
from the Fachinformationszentrum Karlsruhe GmbH.,
D-76344 Eggenstein-Leopoldshafen (Germany), on quot-
ing the depository numbers CSD-410560 - CSD-410564.
well-centered reflections (SET4) [29] in the range 7.87
- 14.81 (H4DMLO), 7.81 - 14.86 (4), 7.23 - 13.35 (6),
7.25 - 14.90 (16) and 6 . 6 6 - 13.85 (17). Reduced-cell
calculations did not indicate higher lattice symmetry [30].
Crystal data and details of the data collection and
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787
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