Polyhedron 18 (1999) 3695–3702www.elsevier.nl / locate /poly

Synthesis, characterization and antifungal activity of group 12 metal4complexes of 2-acetylpyridine- N-ethylthiosemicarbazone (H4EL) and 2-

4acetylpyridine-N-oxide- N-ethylthiosemicarbazone (H4ELO)a b a , a*˜ ´Elena Bermejo , Rosa Carballo , Alfonso Castineiras , Ricardo Domınguez , C. Maichle-

c c d¨ ¨Mossmer , Joachim Strahle , Douglas X. Westa ´ ´Universidad de Santiago de Compostela, Departamento de Quımica Inorganica, Facultad de Farmacia, Campus Universitario Sur, E-15706

Santiago de Compostela, Spainb ´ ´Universidad de Vigo, Departamento de Quımica Inorganica, Lagoas-Marcosende, E-36200 Vigo, Spain

c ¨ ¨ ¨ ¨Institut f ur Anorganische Chemie der Universitat Tubingen, Auf der Morgenstelle 18, D-72076 Tubingen, GermanydDepartment of Chemistry, Illinois State University, Normal, IL 61790-4160, USA

Received 30 June 1999; accepted 29 September 1999

Abstract

4Reaction of group 12 metal halides in ethanol with the thiosemicarbazones 2-acetylpyridine- N-ethylthiosemicarbazone (H4EL) and42-acetylpyridine-N-oxide- N-ethylthiosemicarbazone (H4ELO) produced the compounds [M(H4EL)X ] and [M(H4ELO)X ] [M5Zn(II),2 2

1 13Cd(II) or Hg(II), X5Cl, Br or I]. The ligands and complexes were characterized by elemental analysis and by IR and NMR ( H, C,113 199Cd, Hg) spectroscopy, and the structures of H4ELO?H O and the complexes [Cd(H4EL)I ]?2DMSO, [Hg(H4EL)Br ]–DMSO,2 2 2

[Zn(H4ELO)Cl ] and [Zn(H4ELO)Br ] were determined by X-ray diffraction. The metal centers in the complexes have coordination2 2

number five, H4EL and H4ELO behaving as neutral NNS- and ONS-tridentate ligands, respectively. The coordination polyhedra are closeto tetragonal pyramids, the degree of distortion towards trigonal bipyramids was estimated by t calculation. Against the pathogenic fungiAspergillus niger and Paecilomyces variotii, the mercury complexes of H4ELO had activities that at some doses exceeded that of nystatin. 1999 Elsevier Science Ltd. All rights reserved.

4Keywords: 2-Acetylpyridine- N-ethylthiosemicarbazone; Group 12 metal(II) complexes; X-ray structures

1. Introduction coordination chemistry of the heterocyclic thiosemicar-4bazones 2-acetylpyridine- N-ethylthiosemicarbazone

4Thiosemicarbazones are known to have a wide range of (H4EL) and 2-acetylpyridine-N-oxide- N-biological applications [1–5]. Heterocyclic thiosemicar- ethylthiosemicarbazone (H4ELO), with a view to correlat-bazones have attracted the greatest attention, particularly ing their structures with their antifungal activity.those in which the ring is bound through position 2, asbonding through positions 3 and 4 renders the compoundsinactive. The results of a number of conformational studiesof these thiosemicarbazones show that the thione form isthe most common, and that the azomethine group canadopt various positions in relation to the heterocyclic ring(Z, E and E9 isomers) [6], which may affect chemicalbehavior. The third donor atom, present in the ring ofheterocyclic thiosemicarbazones (N in the case of thepyridine ring, O in the case of pyridine N-oxide) makes

2. Experimentalthem potentially tridentate. In this work we studied the

2.1. General*Corresponding author. Tel.: 134-981-594-636; fax: 134-981-547-163.

˜E-mail address: qiac01@usc.es (A. Castineiras) Elemental analyses (C, H, N) were carried out with a

0277-5387/99/$ – see front matter 1999 Elsevier Science Ltd. All rights reserved.PI I : S0277-5387( 99 )00309-5

3696 E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702

Carlo Erba 1108 microanalyser. Melting points were for X-ray diffraction analysis were obtained (X5Cl, Br).¨measured with a Buchi apparatus. Infrared spectra were Crystals of [Cd(H4EL)I ]?2DMSO and [Hg(H4EL)Br ]?2 2

21recorded using KBr discs (4000–400 cm ) and nujol DMSO were obtained by recrystallization from DMSO.21between polythene films (500–100 cm ) with Mattson

Instruments model CYGNUS-100 FTIR spectrophotome- 2.5. Crystal structure determinations1 13ters. H and C NMR spectra were recorded in DMSO-d6

with a Brucker WM-300 spectrophotometer using TMS as All X-ray data were collected on an Enraf-Nonius113 199internal reference. Cd and Hg NMR spectra were CAD4 diffractometer. The unit cell dimensions were

obtained with a Brucker WM-250 spectrophotometer, obtained from a least-squares fit to setting angles of 2522using approximately 10 M DMSO solutions, and 0.1 M reflections (SET4) [13]. Reduced-cell calculations did not

Cd(ClO ) and HgMe , respectively, as references. Mass indicate higher lattice symmetry [14]. Crystal data and4 2 2

spectra of the ligands were recorded on a Kratos MS-50 details of data collections are listed in Table 1. Data weremass spectrometer using the FAB technique (matrix: 3- corrected for Lorentz-polarization effects and for observednitrobenzylalcohol). 2-Acetylpyridine, 4-ethyl-3- linear decay of the reference reflections. Absorption cor-thiosemicarbazide, ZnBr , CdCl ?H O, CdBr ?4H O, rections (DIFABS [15] or c-scans [16]) were applied for2 2 2 2 2

CdI , HgBr , HgI (Aldrich), HgCl (Merck) and ZnCl , all compounds. The structures were solved by automated2 2 2 2 2

ZnI (Ventron) were used without prior purification. The Patterson or direct methods [17] and subsequent difference2

ligands were prepared using the general method for Fourier techniques and refined on F (SDP/VAX) [18] or2condensation of amines with aldehydes or ketones as F (SHELXL97) [19] by full-matrix least-squares tech-

described by Klayman et al. [7–11]. niques with anisotropic displacement factors for all non-hydrogen atoms. All hydrogen atoms were located from

4 difference Fourier maps and refined isotropically (H4ELO2.2. 2-Acetylpyridine- N-ethylthiosemicarbazone (H4EL)and [Zn(H4ELO)Cl ]) or were included in the refinement2

in calculated positions riding on their carrier atomsA solution of 2-acetylpyridine (7.56 g, 0.062 mol) in 50([Cd(H4EL)I ], [Hg(H4EL)Br and [Zn(H4ELO)Br ).2 2 2ml of ethanol was slowly added to a solution of 4-ethyl-3-Neutral atom scattering factors and anomalous dispersionthiosemicarbazide (7.44 g, 0.062 mol) in 100 ml of warmcorrections were taken from the International Tables forwater. The mixture was refluxed for 2 h. The white productX-ray Crystallography [20]. Geometrical calculations andwhich formed was filtered off and recrystallized fromillustrations were performed or generated with theethanol. Yield, 92%; m.p. 1438C. C H N S (222.09):10 14 4 SHELXL97 [19], ZORTEP [21] and PLATON [22] pack-calc.: C, 54.2; H, 6.3; N, 25.2; found: C, 54.2; H, 6.4; N,

1 1 ages.25.5; MS-FAB, m /z (%): [L1H] , 223(100); [L] ,222(25.6).

3. Results and discussion42.3. 2-Acetylpyridine-N-oxide- N-ethylthiosemicarbazone4(H4ELO) Reaction of the N-monosubstituted thiosemicarbazones

H4EL and H4ELO with halides of group 12 metals inThe N-oxide of 2-acetylpyridine was prepared by oxida- ethanol afforded the complexes listed in Table 2 in good

tion with hydrogen peroxide by the method described by yields. These compounds are yellow, stable in air and justWinterfeld and Zickel [12]. The synthesis of H4ELO was slightly soluble in common organic solvents, and haveanalogous to that of H4EL. After room-temperature re- melting points ranging from 160 to 3138C and mi-crystallization, crystals suitable for X-ray analysis were croanalytical data consistent with 1:1 metal:ligand ratios.obtained by storing the mother liquor at low temperature. Their spectroscopic properties in the solid state (IR) and in

1 13 113 199Yield, 90%; m.p., 1028C. C H N OS (238.08): calcd.:10 14 4 solution ( H, C, Cd and Hg NMR) are reportedC, 48.6; H, 6.1; N, 22.7; found: C, 47.3; H, 6.1; N, 22.1; below, as are the crystal structures of the thiosemicar-

1 1MS-FAB, m /z (%): [L1H] , 239(100); [L] , 238(9). bazones and of the complexes [Cd(H4EL)I ],2

[Hg(H4EL)Br ] and [Zn(H4ELO)X2] where X5Cl, Br.2

2.4. Synthesis of complexes3.1. Description of crystal structures

To a solution of each thiosemicarbazone in warmethanol, was added an equimolar solution or suspension of The most relevant bond lengths and angles of thethe corresponding metal salt in ethanol. The mixture was thiosemicarbazones moiety in H4EL [6] and H4ELO arestirred for about 1 week, after which time the yellow solid listed in Table 3. Like similar thiosemicarbazones [23,24],which formed was filtered off, washed with ethanol, and both have E conformations with the thiosemicarbazonevacuum dried. After slow concentration of the filtrates at moiety directed away from the pyridyl nitrogen atomroom temperature, crystals of [Zn(H4ELO)X ], suitable (Figs. 1 and 2).2

E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702 3697

Table 1aCrystal and structure refinement data for H4ELO and the complexes of H4EL with CdI and HgBr and of H4ELO with ZnCl and ZnBr2 2 2 2

Compound [Cd(H4EL)I ]?2DMSO [Hg(H4EL)Br ]?DMSO2 2

Empirical formula C H CdI N O S C H Br HgN OS14 26 2 4 2 3 12 20 2 4 2

Formula weight 744.81 660.85˚Wavelength (A) 0.71073 0.70930

Crystal size (mm) 1.5030.4530.45 0.5030.3030.25Crystal shape Plate PlateCrystal system Triclinic Monoclinic

¯Space group P1 (No. 2) P2 /n (No. 14)1˚a (A) 9.319(8) 14.386(2)˚b (A) 10.742(10) 8.3199(4)˚c (A) 13.340(14) 16.693(3)

a (8) 97.68(5) 90.000(2)b (8) 103.22(5) 99.416(6)g (8) 103.79(5) 90.000(2)

3˚V (A ) 1237(2) 1971.0(4)3Z, D (Mg/m ) 2, 2000 4, 2.227calcd.

F(000) 712 1240u range (8) 3.00–26.00 2.99–27.90Temperature (K) 293(2) 223(2)h /h 0/11 21/18min max

k /k 213/13 0/10min max

l /l 216/16 222/21min max21

m (mm ) 3.65 12.080Max. /min. transmissions 1.229/0.702 0.999/0.939Refl. collected /unique 5149/4525 5264/4718Data /parameters 4235/244 4717/199Final R 0.056 0.045Final wR2 0.063 0.085GOOF 0.947 1.158

23˚Max. Dr (e A ) 2.253 1.421

Compound H4ELO–H O [Zn(H4ELO)Cl ] [Zn(H4ELO)Br ]2 2 2

Empirical formula C H N O S C H Cl N OSZn C H Br N OSZn10 16 4 2 10 14 2 4 10 14 2 4

Formula weight 256.32 374.61 463.50˚Wavelength (A) 0.71073 1.54056 0.71073

Crystal size (mm) 0.4030.1530.10 0.3530.2030.20 0.2030.1530.10Crystal shape Prism Plate PrismCrystal system Monoclinic Monoclinic MonoclinicSpace group P2 (No. 4) P2 /n (No. 14) P2 /n (No. 14)1 1 1

˚a (A) 7.294(2) 8.394(1) 8.525(2)˚b (A) 7.367(1) 14.196(1) 14.070(2)˚c (A) 12.084(4) 12.857(1) 13.525(4)

a (8) 90.00(2) 90.000(2) 90.00(2)b (8) 103.57(1) 103.972(5) 102.00(1)g (8) 90.00(2) 90.000(2) 90.00(2)

3˚V (A ) 631.2(3) 1486.8(3) 1586.8(6)3Z, D (Mg/m ) 2, 1.349 4, 1.674 4, 1.940calcd.

F(000) 272 760 904˚u range (A) 3.26–30.92 5.00–69.00 3.08–29.91

Temperature (K) 293(2) 293(2) 293(2)h /h 0/10 210/10 0/11min max

k /k 0/10 21/17 0/19min max

l /l 217/16 21/15 218/18min max21

m (mm ) 0.254 6.901 6.712Max. /min. transmissions 0.975/0.904 0.779/0.398 0.553/0.347Refl. collected /unique 2281/2138 3542/2329 4852/4575Data /parameters 2138/218 2329/229 4575/174Final R 0.043 0.031 0.048Final wR2 0.110 0.033 0.095GOOF 1.030 1.072 0.961

23˚Max. Dr (e A ) 0.379 0.419 0.662a ˚The unit cell measurements of the other [Cd(H4EL)X ] were as follows: [Cd(H4EL)Cl ]?2DMSO, a58.373(6), b58.835(6), c515.157(11) A,2 2

a 586.12(7), b 584.83(9) and g 578.67(6)8; and [Cd(H4EL)Br ]?2DMSO, isotypic with [Cd(H4EL)I ]?2DMSO, a58.719(8), b510.133(8), c52 2˚13.888(11) A, a 597.27(6), b 5103.70(8) and g 5101.46(8)8.

3698 E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702

Table 2aAnalytical data and some properties of the complexes with H4EL and H4ELO

Compound Colour M.p. Yield Analysis (%)(8C) (%)

C H N

[Zn(H4EL)Cl ] Yellow 306 62 34.1(33.5) 3.6(3.9) 15.5(15.6)2

[Zn(H4EL)Br ] Yellow 313 62 27.4(26.8) 2.6(3.1) 12.4(12.5)2

[Zn(H4EL)I ] Yellow 296 67 22.8(22.2) 1.6(2.6) 10.4(10.4)2

[Cd(H4EL)Cl ] Yellow 300 67 29.7(29.6) 3.4(3.5) 13.7(13.8)2

[Cd(H4EL)Br ] Yellow 303 65 24.5(24.3) 2.4(2.8) 11.2(11.3)2

[Cd(H4EL)I ] Yellow 189 62 20.6(20.4) 1.9(2.4) 9.7(9.6)2

[Hg(H4EL)Cl ] Yellow 237 74 24.6(24.3) 2.3(2.8) 11.3(11.4)2

[Hg(H4EL)Br ] Yellow 230 63 20.9(20.6) 1.8(2.4) 9.7(9.6)2

[Hg(H4EL)I ] Yellow 160 59 18.0(17.7) 1.4(2.1) 8.1(8.3)2

[Zn(H4ELO)Cl ] Yellow 256 53 32.2(32.1) 3.7(3.7) 14.9(15.0)2

[Zn(H4ELO)Br ] Yellow 261 55 26.0(25.9) 2.9(3.0) 11.9(12.1)2

[Zn(H4ELO)I ] Yellow 249 67 21.8(21.5) 2.3(2.5) 10.0(10.1)2

[Cd(H4ELO)Cl ] Yellow 247 78 27.9(27.3) 3.8(3.2) 12.6(12.8)2

[Cd(H4ELO)Br ] Yellow 239 59 23.4(23.5) 2.7(2.7) 10.8(12.0)2

[Cd(H4ELO)I ] Yellow 218 66 19.9(19.9) 2.1(2.3) 9.0(9.3)2

[Hg(H4ELO)Cl ] Yellow 181 62 24.1(23.6) 3.1(3.8) 10.8(11.0)2

[Hg(H4ELO)Br ] Yellow 186 68 20.5(20.1) 2.3(2.3) 8.8(9.4)2

[Hg(H4ELO)I ] Yellow 200 66 17.4(17.3) 1.8(2.0) 8.0(8.1)2

a Calculated values are in parentheses.

Table 3˚Selected lengths (A) and angles (8) in free and complexed H4EL, H4ELO

aH4EL [Cd(H4EL)I ]?2DMSO [Hg(H4EL)Br ]?DMSO H4ELO?H O [Zn(H4ELO)Cl ] [Zn(H4ELO)Br ]2 2 2 2 2

C(6)–N(2) 1.287(2) 1.289(9) 1.276(10) 1.287(3) 1.289(5) 1.282(6)N(2)–N(3) 1.370(2) 1.369(9) 1.359(9) 1.372(3) 1.370(4) 1.368(6)N(3)–C(7) 1.364(2) 1.373(9) 1.344(11) 1.368(3) 1.359(4) 1.367(7)C(7)–S(1) 1.676(2) 1.683(9) 1.715(8) 1.687(2) 1.688(4) 1.686(6)C(7)–N(4) 1.326(3) 1.322(9) 1.318(11) 1.315(3) 1.320(4) 1.311(7)N(1)–O(1) – – – 1.316(3) 1.321(4) 1.327(5)N(1)–C(5)–C(6) 115.9(2) 116.9(8) 116.8(7) 117.7(2) 122.2(3) 121.9(5)C(5)–C(6)–N(2) 114.7(2) 113.2(9) 114.6(7) 114.3(2) 118.5(3) 118.3(5)C(6)–N(2)–N(3) 119.4(2) 119.2(1) 121.0(7) 115.9(2) 116.9(3) 117.7(4)N(2)–N(3)–C(7) 118.3(2) 119.7(7) 120.6(7) 120.4(2) 120.2(3) 120.0(4)N(3)–C(7)–S(1) 120.1(2) 124.2(6) 123.0(7) 118.2(2) 122.5(2) 122.7(4)N(3)–C(7)–N(4) 115.7(2) 113.7(8) 116.3(7) 116.7(2) 114.2(4) 114.5(5)S(1)–C(7)–N(4) 124.2(1) 122.1(8) 120.6(7) 125.1(2) 123.4(3) 122.7(5)C(5)–N(1)–O(1) – – – 119.9(2) 123.1(3) 122.3(4)C(1)–N(1)–O(1) – – – 119.4(2) 115.7(3) 116.2(4)

a Ref. [6].

Fig. 2. Perspective drawing and atomic numbering scheme of thethiosemicarbazone H4ELO.

The values of the bond lengths and angles are within theFig. 1. Perspective view of H4EL molecule, showing 50% probabilityranges expected for this kind of thiosemicarbazone [23,24].ellipsoids for the non-hydrogen atoms and the numbering scheme of the

atoms in the molecule. The bond lengths reflect extensive electron delocalization

E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702 3699

involving both the thiosemicarbazone moiety and thearomatic heterocycle.

H4ELO crystallizes with a water molecule involved inintermolecular hydrogen bonding. For example, the oxygenof the water molecules from the equivalent positions2 x 1 1, y 2 1/2, 2 z 1 2 and 2 x, y 2 1/2, 2 z 1 2 arehydrogen-bonded to both the thioamide nitrogen [N(4)–

˚H(40)? ? ?O; 0.85(4), 2.33(4), 3.029(4) A and 140(3)8] andthe hydrazinic nitrogen [N(3)–H(30)? ? ?O; 0.77(3),

˚2.31(3), 3.044(4) A and 161(3)8], respectively.Fig. 3. Molecular structure of [Cd(H4EL)I ].2Relevant bond distances and angles in the thiosemicar-

bazone fragments and coordination spheres are listed inTables 3 and 4, respectively, for the DMSO-solvatedcomplexes [CdH4EL)I ]?2DMSO and [Hg(H4EL)Br ]?2 2

DMSO, and for the zinc complexes [Zn(H4ELO)Cl and2

[Zn(H4ELO)Br ]. Figs. 3–6 show the molecular structures2

of these complexes.In all four complexes, the metal has a coordination

number of five binding two halide ions, the sulfur andazomethine nitrogen atoms of the thiosemicarbazone, andeither the pyridine nitrogen (when the ligand is H4EL) orthe pyridine N-oxide oxygen (when the ligand is H4ELO). Fig. 4. Molecular structure of [Hg(H4EL)Br ].2

The t values [25], listed in Table 5 show that thecoordination geometry is closer to tetragonal pyramidalthan to trigonal bipyramid with the ligand atoms and ahalide ion at the base of the pyramid and the second halideion at the apex. Distortion toward trigonal bipyramidalgeometry is much greater in the H4ELO complexes than inthe H4EL compounds. This is in keeping with the generaltrend among other complexes of group 12 metal halideswith this kind of thiosemicarbazone [23,24,26]: Cd and Hgcomplexes with an M(NNS)X nucleus usually have a2

quite clear tetragonal pyramidal geometry, whileZn(ONS)X complexes exhibit strong distortion towards Fig. 5. Molecular structure of [Zn(H4ELO)Cl ].2 2

Table 4˚Bond lengths (A) and angles (8) around the metallic centre of each complex

[Cd(H4EL)I ]?2DMSO [Hg(H4EL)Br ]?DMSO [Zn(H4ELO)Cl ] [Zn(H4ELO)Br ]2 2 2 2

M–X(1) 2.748(1) 2.565(10) 2.252(1) 2.392(1)M–X(2) 2.748(1) 2.573(11) 2.366(1) 2.514(1)M–S(1) 2.591(2) 2.560(3) 2.363(2) 2.362(2)M–N(1) 2.350(8) 2.475(7) – –M–N(2) 2.398(9) 2.547(7) 2.250(3) 2.271(4)M–O(1) – – 2.017(3) 2.010(3)N(1)–M–X(1) 97.3(2) 93.6(2) – –N(1)–M–X(2) 100.3(2) 98.4(2) – –N(1)–M–N(2) 66.3(2) 62.9(2) – –N(2)–M–X(1) 138.8(3) 137.5(2) 99.16(7) 96.6(1)N(2)–M–X(2) 100.2(3) 98.1(2) 151.64(7) 155.4(1)X(1)–M–X(2) 120.34(4) 121.21(4) 108.66(4) 107.49(3)S(1)–M–X(1) 100.61(7) 107.06(6) 111.78(4) 114.85(6)S(1)–M–X(2) 104.55(7) 107.95(7) 94.22(4) 94.18(5)S(1)–M–N(1) 136.0(3) 129.8(2) – –S(1)–M–N(2) 73.9(2) 71.5(2) 80.14(7) 79.9(1)O(1)–M–X(1) – – 108.09(7) 109.5(1)O(1)–M–X(2) – – 87.86(7) 89.6(1)O(1)–M–N(2) – – 78.17(9) 77.4(1)S(1)–M–O(1) – – 136.96(7) 131.9(1)

3700 E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702

binding to Zn forces the ring to rotate about the C(5)–C(6)bond. Another important difference, of course, is that theH4ELO complexes feature both five- and six-memberedchelate rings and the H4EL complexes two five-memberedrings. With respect to this, six-membered chelate ringsdeviate from planarity while five-membered chelate ringsgenerally do not.

Curiously, whereas in the CdI complex of H4EL (Fig.2

3) the terminal ethyl carbon C(9) is trans to the thioamidecarbon C(7) (and to the sulfur atom), in the HgBr2

complex (Fig. 4) it is cis; and both these conformationsFig. 6. Molecular structure of [Zn(H4ELO)Br ].2differ from that of free H4EL (Fig. 1). Similarly, although

trigonal bipyramidal geometry [no structures are available the relationship between the C(8)–C(9) bond and thefor Zn(NNS)X , Cd(ONS)X or Hg(ONS)X ]. This does thioamide group in the ZnCl complex of H4ELO is the2 2 2 2

21 21not seem to be due to Cd and Hg being larger than same as in the free ligand (Figs. 2 and 5), in the ZnBr221Zn , but rather to the orientation of the bonding electron complex C(9) is trans to C(7) and the sulfur atom. It is

pair on the donor atom of the thiosemicarbazone heterocy- difficult to attribute these differences to factors other thancle. the packing constraints on the terminal ethyl group.

The Cd–S, Cd–I and Cd–N distances in [Cd(H4EL)I ]?2

2DMSO agree with the values found in complexes ofcadmium(II) halides with similar thiosemicarbazones 3.2. Infrared spectra[23,26,27]. Similarly, in the mercury(II) complex, theHg–S, Hg–N and Hg–Br bond lengths are within the The most significant IR bands of H4EL [32], H4ELO

21ranges normally recorded for complexes of mercury(II) and their complexes in the region 4000–400 cm arehalides with ligands in which the donor atoms are a available as supplementary data. In all the complexes

21 21thiocarbonyl sulfur and nitrogen [23,28,29]. The tendency n(C=N) (at 1580 cm in H4EL and at 1553 cm into axial distortion of the compounds [Zn(H4ELO)X ] is H4ELO) shifts to higher wave numbers [33] and n(C=S)2

21 21seen in the difference between the two Zn–X distances — (at 824 cm in H4EL and at 822 cm in H4ELO) tothe shorter is approximately of the same order of mag- lower wave numbers [34], reflecting coordination via the

˚nitude as those found in terminal Zn–Cl (2.257 A) and azomethine nitrogen and the thiocarbonyl sulfur.˚Zn–Br (2.378 A) bonds [29] while the other is about 0.12 In the H4EL complexes, unequivocal proof that coordi-

A longer — and in the fact that the Zn–N distance is nation occurs through the pyridine ring nitrogen [35],significantly longer than in complexes of zinc with hy- increasing the double bond character of the C–C and C–N

˚ ˚drazines (2.158 A) [30] or Schiff bases (1.998 A) [31]. bonds in the ring, is provided by the shifts to higher wave˚The Zn–S distances, of about 2.36 A, are slightly longer numbers of the bands involving n(C=C) and n(C=N) and

that those present in other zinc complexes containing of the in-plane and out-of-plane ring deformation bands21 21ligands in which the donor atom is thiocarbonyl S (2.300 [a(CCC) shifts from 619 cm in H4EL to 637–654 cm

21A) [30], while the Zn–O distances (Table 3) are slightly in the complexes, f(CC) from 407 cm to 409–41621shorter than those in hexacoordinated complexes of zinc cm ]. The IR spectra therefore confirm that H4EL, like

˚with pyridine N-oxides (2.076 A) [18]. similar thiosemicarbazones [7–12,14], is NNS-tridentate inThe most marked geometrical difference between the all the complexes that have been studied.

ligands in these complexes is that H4EL is planar and In most Cd and Zn H4ELO complexes, n(N–O) andH4ELO considerably less so (Fig. 2). This appears to be d(N–O) have lower wave numbers than in the free ligand

21 21mainly due to the tetrahedral oxygen atom, which upon (at 1223 cm and 849 cm , respectively), suggesting

Table 5Deviation from tetragonal pyramidal coordination geometry (t values)

Compound b(N–M–X) a(S–M–N/O) b 2 a t 5 (b 2 a) /60

[Cd(H4EL)I ] 138.8 136.0 2.8 0.052

[Hg(H4EL)Br ] 137.5 129.8 7.7 0.0132

[Zn(H4ELO)Cl ] 151.6 137.0 14.6 0.242

[Zn(H4ELO)Br ] 155.4 131.9 23.5 0.392atbp 120.0 180.0 60.0 1.00

btp 180.0 180.0 0.0 0.00a Trigonal bipyramid.b Tetragonal pyramidal.

E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702 3701

coordination through the N-oxide oxygen. Although these bazones with an N-oxide group [24,26]. In most complexesbands do not undergo significant shifts in the Hg complex- the ring carbon atoms are deshielded (more markedly in

21es, the band near 400 cm in the spectra of HgI and the H4EL complexes than the H4ELO, but in some cases2

HgBr derivatives, which may be due to n(M–O), means one or other of the carbons ortho to the nitrogen atom,2

that the mercury complexes also may involve coordination C(1) and C(5), is slightly shielded.via oxygen.

21In most spectra, two bands in the 380–320 cm and 113 1993.5. Cd and Hg NMR spectra21310–270 cm regions that are not present in the spectrumof the free ligand probably correspond to n(M–N) and

Only the H4EL complexes of cadmium were sufficientlyn(M–S), respectively. As in the case of other group 12 113soluble for Cd NMR spectra to be recorded. In eachhalo-complexes with thiosemicarbazones which contain the

case, a single signal appeared (at 372.8, 349.9 and 281.6pyridine N-oxide group [24,26], coordination via oxygen is

ppm for the chloro, bromo and iodo complexes, respective-suggested in the spectra of almost all the complexes of

ly). The metal atom is in each case less deshielded than in21H4ELO by a band close to 400 cm that is attributable tothe corresponding halide (CdX ), most markedly in the21 2n(M–O). Finally, two bands in the 300–130 cm region,case of the chloro complex [40]. These findings are

assigned to metal–halogen stretching exhibit n(M–Br) /consistent with those obtained for other complexes of

n(M–Cl) and n(M–I) /n(M–Cl) frequency ratios similar to 4cadmium(II) halides with 2-acetylpyridine N-alkyl- andthese reported for other complexes of this type [24,26]. 4N-arylthiosemicarbazones [23,24].

[Hg(H4EL)Cl ] was the only complex soluble enough to21 1993.3. H NMR spectra allow the recording of an Hg NMR spectrum. The

single signal at 21269.4 ppm, indicates that there is only1The H NMR signal assignments proposed for the free one kind of coordination environment. The chemical shift

ligands and their complexes on the basis of previously shows shielding relative to both HgCl and the analogous2

reported spectra [33,36–39] are available as supplementary complex [Hg(H4ML)Cl ] [23].2

data. The presence of the N(3)H signal in the spectra ofthe complexes implies that neither ligand is deprotonated,

3.6. Antifungal activityand the general shift of this signal to lower fields than inthe free ligand reflects coordination through the

In a previous study [32], H4EL appeared to have aazomethine nitrogen. The N(4)H signal (at 8.64 ppm in

certain activity against Aspergillus niger but its complexesH4EL and 8.51 ppm in H4ELO) undergoes a downfield

with transition metals were inactive. In this study, the onlyshift that is very marked in the mercury(II) complexes,

active H4EL complexes were the zinc compounds, andindicating coordination via the sulfur atom. The downfield

even these were only active at very high doses (Table 6).shifts of the signals of the pyridine protons H(1), H(2) and

However, the H4ELO mercury complexes had activitiesH(3) as a result of coordination via N(1) or O are, asexpected, smaller for the H4ELO complexes than for the

Table 6H4EL compounds.Antifungal activity data of active compounds

a200 400 600 1000133.4. C NMR spectraAspergillus niger

c13 H4EL 6.0 6.0 7.5 11.5The C NMR signals assignments proposed [36,38,39]

[Zn(H4EL)Cl ] 6.0 6.0 9.3 –2for the free ligands and those complexes that were soluble [Zn(H4EL)Br ] 6.0 6.0 9.8 –2

enough to allow the recording of spectra are available as [Hg(H4EL)Cl ] 6.0 11.5 13.3 12.52

[Hg(H4EL)Br ] 10.0 10.8 10.5 11.3supplmentary data. The signals attributed to the ethyl 2

[Hg(H4EL)I ] 8.0 11.5 13.8 16.32group attached to the thioamide nitrogen atom, C(8) andbNysatin 9.0 10.7 12.8 17.3C(9), are deshielded in the complexes, confirming that in

DMSO solution coordination via the sulfur atom is main- Paecilomyces variotiitained. The thiocarbonyl carbon, C(7), is shielded princi- [Zn(H4EL)Cl ] 6.0 8.2 9.3 13.82

[Zn(H4EL)Br ] 6.0 7.1 8.5 11.8pally in the mercury(II) complexes (from 177.64–178.00 2

[Zn(H4EL)I ] 6.0 7.8 10.0 12.72ppm to 171.57–173.08 ppm). The signal of azomethine[Hg(H4EL)Cl ] 6.0 12.5 13.0 12.12carbon, C(6), shifts to a higher field in the H4EL complex-[Hg(H4EL)Br ] 10.0 14.0 13.0 8.12es (from 147.89 ppm in the free ligand to 146.68–147.58 [Hg(H4EL)I ] 8.8 12.2 12.3 19.02

ppm in the complexes) and to a lower field in H4ELO Nysatin 12.8 14.5 16.5 25.2complexes (from 139.76 ppm in the ligand free to 139.83– a Diameters of growth inhibition zone (6.0 indicates no inhibition).

b139.92 ppm in the complexes), as has also been observed Commercially available therapeutic agent.cfor other complexes of halides with group 12 thiosemicar- Ref. [28].

3702 E. Bermejo et al. / Polyhedron 18 (1999) 3695 –3702

[13] J.L. de Boer, A.J.M. Duisenberg, Acta Crystallogr., Sect. A 40that against Aspergillus niger at some doses exceeded that(1984) 410.of the commercial therapeutic agent nystatin. Since

[14] A.L. Spek, J. Appl. Crystallogr. 21 (1988) 578.[Hg(H4PLO)I ] is also active against these pathogenic2 [15] N. Walker, D. Stuart, Acta Crystallogr., Sect. A 39 (1983) 158.4fungi (H4PLO52-acetylpyridine-N-oxide N-phenyl- [16] A.C.T. North, D.C. Phillips, F.S. Mathews, Acta Crystallogr., Sect.thiosemicarbazone [24]), it is clear that mercury com- A 24 (1968) 351.

4plexes with N-monosubstituted thiosemicarbazones con- ¨[17] G.M. Sheldrick, SHELXS86, University of Gottingen, 1986.[18] B.A. Frenz and Associates, and Enraf-Nonius, SDP/VAX Structuretaining the pyridine N-oxide group, such as H4ELO and

Determination Package, V.2.2, College Station, TX, 1986.H4PLO, are more active than complexes of group 124 ¨ ¨[19] G.M. Sheldrick, SHELXL97, Universitat Gottingen, 1997.metals with N-disubstituted thiosemicarbazones contain-

[20] A.J.C. Wilson, in: International Tables for X-Ray Crystallography,ing a non-oxygenated 2-acetylpyridine moiety (H4EL, Vol. C, Kluwer Academic, Dordrecht, 1995, Tables 4.2.6.8 andH4PL, H4DML) [23,26]. 6.1.1.4.

[21] L. Zsolnai, ZORTEP, University of Heidelberg, 1997.[22] A.L. Spek, Acta Crystallogr., Sect. A 46 (1990) C34.

˜ ´[23] E. Bermejo, R. Carballo, A. Castineiras, R. Domınguez,, A.E.Supplementary data¨Liberta, C. Maichle-Mossmer, M.M. Salberg, D.X. West, Eur. J.

Inorg. Chem. (1999) 965.Supplementary data (excluding structure factors) are ˜ ´[24] E. Bermejo, R. Carballo, A. Castineiras, R. Domınguez, C. Maichle-

available from the Cambridge Crystallographic Data Cen- ¨ ¨Mossmer, J. Strahle, D.X. West, Z. Anorg. Allg. Chem. 625 (1999)tre, 12 Union Road, Cambridge CB2 1EZ, UK on request, 961.

[25] A.W. Addison, T.N. Rao, J. Reedijk, J. van Rijn, G.C. Verschoor, J.quoting the deposition numbers 116780 to 116784. Addi-Chem. Soc., Dalton Trans. (1984) 1349.tional supplementary data (five tables of IR and NMR

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