Heterocyclic substituted thiosemicarbazides and their Cu(II) complexes: Synthesis, spectral characterization, thermal, molecular modeling, and DNA degradation studies

Article abstract of DOI:10.1080/00958972.2012.674519

Four Cu(II) complexes of N¹-phenyl-N²-(pyridin-2-yl) hydrazine-1,2-bis(carbothioamide) (H₂PPS), N-phenyl-2-(2-(pyridin-2- ylcarbamothioyl)hydrazinyl)-2-thioxoacetamide (H₂PBO), N-phenyl-2-(pyridin-2-ylcarbamothi

Full text of DOI:10.1080/00958972.2012.674519

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Heterocyclic substituted
thiosemicarbazides and their Cu(II)
complexes: synthesis, spectral
characterization, thermal, molecular
modeling, and DNA degradation studies
O.A. El-Gammal a , G.M. Abu El-Reash a , S.E. Ghazy a & T. Yousef
b
a Department of Chemistry, Faculty of Science, Mansoura
University, Mansoura 35516, Egypt
b Department of Toxic and Narcotic Drug, Forensic Medicine,
Mansoura Laboratory, Medicolegal Organization, Ministry of
Justice, Egypt
Version of record first published: 05 Apr 2012.
To cite this article: O.A. El-Gammal, G.M. Abu El-Reash, S.E. Ghazy & T. Yousef (2012):
Heterocyclic substituted thiosemicarbazides and their Cu(II) complexes: synthesis, spectral
characterization, thermal, molecular modeling, and DNA degradation studies, Journal of
Coordination Chemistry, 65:10, 1655-1671
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Journal of Coordination Chemistry
Vol. 65, No. 10, 20 May 2012, 1655–1671
Heterocyclic substituted thiosemicarbazides and their Cu(II)
complexes: synthesis, spectral characterization, thermal,
molecular modeling, and DNA degradation studies
O.A. EL-GAMMAL*y, G.M. ABU EL-REASHy, S.E. GHAZYy and T. YOUSEFz
yDepartment of Chemistry, Faculty of Science, Mansoura University,
Mansoura 35516, Egypt
zDepartment of Toxic and Narcotic Drug, Forensic Medicine, Mansoura Laboratory,
Medicolegal Organization, Ministry of Justice, Egypt
(Received 10 August 2011; in final form 17 February 2012)
Four Cu(II) complexes of N1-phenyl-N2-(pyridin-2-yl)hydrazine-1,2-bis(carbothioamide)
(H2PPS), N-phenyl-2-(2-(pyridin-2-ylcarbamothioyl)hydrazinyl)-2-thioxoacetamide (H2PBO),
N-phenyl-2-(pyridin-2-ylcarbamothioyl)hydrazinecarboxamide (H2APO), and 1-(aminoN-(pyr-
idin-2-yl)methanethio)-4-(pyridin-yl)thiosemicarbazide (H2PPY) have been prepared and
characterized by elemental analyses, spectral (infrared (IR), UV-Visible, 1H NMR, and
electron spin resonance (ESR)) as well as magnetic and thermal measurements. Varying the
substituents on the thiosemicarbazide led to remarkable modiEcations of the mode of
coordination. IR spectral data reveal that the ligands are SN bidentate, NON tridentate, or
NSNS tetradendate chelates forming structures in which copper is square-planar or octahedral.
ESR spectra of these complexes are quite similar and exhibit an axially symmetric g-tensor
parameter with g 4 g 4 2.0023 revealing an appreciable covalency with d(x2–y2) as the
k
?
ground-state. Bond lengths, bond angles, HOMO, LUMO, and dipole moments have been
calculated to confirm the geometry of the thiosemicarbazide derivatives and their correspond-
ing complexes. Proton-ligand dissociation and copper-ligand stability constants of all ligands
were calculated pH-metrically. The effect of the compounds on calf thymus DNA was
investigated.
Keywords: Heterocyclic thiosemicarbazides; Copper(II) complexes; Thermal degradation;
Calf thymus DNA
1. Introduction
Thiosemicarbazones are sulfur ligating systems with a range of biological properties
[1–4]. Thiosemicarbazide syntheses can be modified from the parent aldehyde or
ketone, or by substitution at 2C or 1N [5–7]. Thiosemicarbazide complexes have
anticancer and antimicrobial activity owing to their ability to diffuse through the
semipermeable membrane of cell lines [5, 8–10]. The biological activity of copper, a
metal that plays an important role in many biological processes [11], has been the
subject of numerous studies [12–14]. Since Sigman et al. [15] discovered in 1979 that
*Corresponding author. Email: olaelgammal@yahoo.com
Journal of Coordination Chemistry
ISSN 0095-8972 print/ISSN 1029-0389 online ß 2012 Taylor & Francis
http://dx.doi.org/10.1080/00958972.2012.674519

1656
O.A. El-Gammal et al.
copper ions complexed to 1,10-phenanthroline were capable of cleaving DNA [16],
copper complexes with a nitrogen donor heterocyclic ligand have been used widely to
improve nuclease activity [17–21], mostly because of their ability to break the DNA
chain in the presence of H2O2 and reducing agents [22]. In this work, we study the
coordination chemistry of substituted thiosemicarbazides, N1-phenyl-N2-(pyridin-
2-yl)hydrazine-1,2-bis(carbothioamide)
(H2PPS),
N-phenyl-2-(pyridin-2-ylcarba-
mothioyl) hydrazinecarboxamide (H2PBO), 1-(amino(thioformyl)-N-phenylform)
-4-(pyridin-2-yl)thiosemicarbazide (H2APO), and 1-(aminoN-(pyridin-3-yl)metha-
nethio)-4-(pyridin-yl)thiosemicarbazide (H2PPY) to correlate their structures with
their ability to degrade DNA.
2. Experimental
2.1. Materials and physical measurements
All chemicals were purchased from Aldrich and Fluka and used without purification.
Elemental analyses (C, H, and N) were performed on a Perkin-Elmer 2400 analyzer. All
compounds were within ꢀ0.5% of the theoretical values. Melting points were
determined in open capillaries on an electrothermal melting point apparatus
1
(Electrothermal Engineering Ltd., Essex, UK) and are uncorrected. H NMR spectra
were recorded in DMSO-d6 on a JEOL JNM LA 300 WB spectrometer at 300 MHz
using TMS (tetramethylsilane) as an internal standard (chemical shift in ꢀ ppm) and the
infrared (IR) spectra of the ligands were recorded as KBr discs on a Mattson 5000
FTIR spectrophotometer. Magnetic susceptibilities were measured with a Sherwood
scientific magnetic susceptibility balance at 298 K. Thermogravimetric measurements
(TGA, DTA, 20–1000ꢁC) were recordedꢂo1n a DTG-50 Shimadzu thermogravimetric
analyzer at a heating rate of 10ꢁC min and nitrogen flow rate of 20 mL minꢂ1
.
Electron spin resonance (ESR) spectra were obtained on a Bruker EMX spectrometer
working in the X-band (9.78 GHz) mode with 100 kHz modulation frequency. The
microwave power and modulation amplitudes were set at 1 mW and 4 Gauss,
respectively. The low field signal was obtained after four scans with 10-fold increase in
the receiver gain. A powder spectrum was obtained in a 2 mm quartz capillary at room
temperature.
2.2. Synthesis of the ligands
4-(2-Pyridyl)-3-thiosemicarbazide (1) was synthesized as reported earlier [23].
Derivatives (2–5) were prepared by heating ethanolic solution of 4-(2-pyridyl)-3-
thiosemicarbazide (1) (1.6 g, 100 mmol) with an equimolar amount of phenyl isothio-
cyanate, phenyl isocyanate, benzoyl isothiocyanate, and 2-pyridyl isothiocyanate,
respectively.
2.2.1. H2PPS (2). Yield 78%; m.p.: 178–180ꢁC, C13H13N5S2 (303.41): Calcd C 51.46,
H 4.32, N 23.08, S 21.14; found C 51.13, H 4.25, N 22.96, S 21.11. IR (KBr): ꢁ/ꢀ ¼ 1223,

Cu(II) thiosemicarbazides
1657
1
0
850 (C¼S), 3099 (NH)a,a , 3160 (NH)b,c, 1569 (C¼N)py, and 1598 (C¼C). H NMR
0
ꢀ ¼ 15.4 (s,1H,SH), 11.10, 10.97 (s,1H,NHa,a ), 8.27, 8.25 (d, J ¼ 1.2 Hz,1H,NHb,c), 8.26
(d, J ¼ 5.4 Hz, 1H, pyridine H6), 7.85 (dd, J ¼ 6.9, 5.4 Hz, 1H, pyridine H4), 7.65 (dd,
J ¼ 6.9, 4.8 Hz, 1H, pyridine H5), 7.37–7.50 (d, J ¼ 5.4 Hz, 1H, pyridine H3), 7.00–7.35
(m, 5H, Ph ring).
2.2.2. H2PBO (3). Yield 79%; m.p.: 267–270ꢁC, C14H13N5OS2 (331.42): Calcd C
50.74, H 3.95, N 21.13, O 4.83, S 19.35; found C 50.35, H 3.47, N 21.78, O 4.71, S 19.31.
0
IR (KBr): ꢁ/ꢀ ¼ 1243, 865 (C¼S), 3158, 3100 (NH)a,a , 3239 (NH)b,c, 1542 (C¼N)py,
1
0
1675 (C¼O), and 1604 (C¼C). H NMR ꢀ ¼ 11.09, 10.53 (s,1H,NHa,a ), 9.54, 8.20
(d,1H,NHb,c), 8.27 (d, J ¼ 8.1 Hz, 1H, pyridine H3), 2 (d, J ¼ 5.1 Hz, 1H, pyridine H6),
7.55 (dd, J ¼ 6.3, 5.7 Hz, 1H, pyridine H4), 7.78 (dd, J ¼ 7.5, 6.3 Hz, 1H, pyridine H5),
7.12–7.23 (m, 5H, Ph ring).
2.2.3. H2APO (4). Yield 81%; m.p.: 180–182ꢁC, C13H13N5OS (287.34): Calcd C
54.34, H 4.56, N 24.37, O 5.57, S 11.16; found C 54.15, H 4.45, N 23.98, O 5.78, S 11.11.
0
IR (KBr): ꢁ/ꢀ ¼ 1247, 800 (C¼S), 3170, 3104 (NH)a,a , 3220 (NH)b,c, 1641 (C¼N)py,
1672 (C¼O), and 1600 (C¼C). 1H NMR: ꢀ ¼ 15.8 (s,1H,SH), ꢀ ¼ 11.9, 11.30
0
(s,1H,NHa,a ), 8.36, 8.09 (d,1H,NHb,c), 8.23 (dd, J ¼ 8.7, 6 Hz, 1H, pyridine H5), 8.01
(d, J ¼ 5.3 Hz, 1H, pyridine H6), 7.9 (d, J ¼ 6.4 Hz, 1H, pyridine H3), 7.66 (dd, J ¼ 6.1,
4.8 Hz, 1H, pyridine H4), 7.0–7.64 (m, 5H, Ph ring).
2.2.4. H2PPY (5). Yield 82%; m.p.: 307–310ꢁC, C12H12N6S2 (304.06): Calcd C 47.35,
H 3.97, N 27.61, S 21.07; found C 47.02, H 4.05, N 27.86, S 21.31. IR (KBr): ꢁ/ꢀ ¼ 1218,
1
0
875 (C¼S), 3174 (NH)a,a , 3234 (NH)b,c, 1562 (C¼N)py, and 1604 (C¼C). H NMR
0
ꢀ ¼ 15.4 (s,1H,SH), 11.10 (s,1H,NHa,a ), 8.29, 8.28 (d, J ¼ 3.9, 1H, NHb,c), 8.21 (d,
J ¼ 6.2 Hz, 1H, pyridine H6), 8.17 (d, J ¼ 7.4 Hz, 1H, pyridine H3), 7.88 (dd, J ¼ 5.5,
3.3 Hz, 1H, pyridine H5), 7.85 (dd, J ¼ 6.6, 5.4 Hz, 1H, pyridine H4).
2.3. Synthesis of Cu(II) complexes
Ethanolic solution of thiosemicarbazides (1.0 mmol) and hydrated copper chloride
(1.0 mmol) was refluxed for 2–3 h. The precipitates that formed were filtered off, washed
with hot ethanol followed by diethyl ether, and dried in a vacuum desiccator over
anhydrous CaCl2. The complexes have high melting points and are insoluble in
common organic solvents and soluble in DMF or DMSO.
2.3.1. [Cu(HPPS)Cl(H2O)2] (6). Anal. Calcd for C13H14CuN5OS2Cl: C 37.23, H 3.36,
N 16.69, S 15.29, Cu 15.2, Cl 8.45; Found: C 37.59, H 3.18, N 17.05, S 15.43, Cu 15.4, Cl
8.15. Main IR peaks (KBr, cmꢂ1): ꢁ(NH)a,a 3120, 3070; ꢁ(NH)b,c 3230; ꢁ(C¼N)py 1616;
0
ꢁ/ꢀ (C¼S)a,a 1232, 860; ꢁ(C¼N)* 1600; ꢁ(C–S) 646; UV-Vis (DMF, cmꢂ1) 35,211.
0
2.3.2. [Cu(HPBO)Cl(H2O)2] (7). Anal. Calcd for C14H16CuN5O3S2Cl: C 36.12, H
3.46, N 15.04, S 13.77, Cu 13.6, Cl 4.61; Found: C 36.33, H 3.78, N 15.55, S 13.48, Cu
13.4, Cl 7.81. Main IR peaks (KBr, cmꢂ1): ꢁ(NH)a,a 3187; ꢁ(C¼O) 1673; ꢁ(C¼N)py
0

1658
O.A. El-Gammal et al.
1562; ꢁ/ꢀ (C¼S)a,a 1221, 854; ꢁ(C¼N)* 1612; ꢁ(C–S) 646; UV-Vis (DMF, cmꢂ1) 32,258;
0
28,409; 18,050.
2.3.3. [Cu(HAPO)Cl](H2O) (8). Anal. Calcd for C13H18CuN5O4SCl: C 35.54, H 4.13,
N 15.04, S 13.77, Cu 14.50, Cl 8.10; Found: C 35.66, H 4.05, N 15.55, S 13.48, Cu 14.45,
Cl 8.30. Main IR peaks (KBr, cmꢂ1): ꢁ(NH)a,a 3244; ꢁ(NH)b,c 3115; ꢁ(C¼N)py 1621; ꢁ/ꢀ
0
(C¼S)a,a 1232, 865; ꢁ(C¼N)* 1567; UV-Vis (DMF, cmꢂ1) 35,211; 32,467; 27,624;
0
23,585; 19,685; 15,291.
2.3.4. [Cu(HPPY)Cl (H2O)2] (9). Anal. Calcd for C12H15CuN6O2S2Cl: C 32.84, H
3.45, N 19.16, S 14.63, Cu 14.4, Cl 8.1; Found: C 32.63, H 3.8, N 19.34, S 14.28, Cu
13.4, Cl 8.8. Main IR peaks (KBr, cmꢂ1): ꢁ(NH)a,a 3187; ꢁ(C¼N)py 1562; ꢁ/ꢀ (C¼S)a,a
0
0
1221, 840; ꢁ(C¼N)* 1612; ꢁ(C–S) 656; UVꢂVis (DMF, cmꢂ1) 35,211; 31,847; 29,585;
25,126; 19,157.
2.4. pH metric studies
The experimental procedure involves pH-metric titrations of solution mixtures against
standardized NaOH (9.2 ꢃ 10ꢂ3 mol Lꢂ1) in 50% (v/v) dioxane-water at (298, 303, and
308 K) and at constant ionic strength of (ꢂ ¼ 0.1, 0.15, and 0.2 mol Lꢂ1 KCl). The
solution mixtures (i–iii) were prepared as follows:
(i) 1.25 mL (1.1 ꢃ 10ꢂ2 mol Lꢂ1
)
HCl þ 1.25 mL (0.1, 0.15, and 0.2 mol Lꢂ1
HCl þ 1.25 mL (0.1, 0.15, and 0.2 mol Lꢂ1
)
KCl þ 10 mL twice-distilled H2O.
(ii) 1.25 mL (1.1 ꢃ 10ꢂ2 mol Lꢂ1
)
)
KCl þ 2.5 mL (5 ꢃ 10ꢂ3 mol Lꢂ1) H2PPS, H2PBO, H2APO, and H2PPY þ 10 mL
twice-distilled H2O.
(iii) 1.25 mL (1.1 ꢃ 10ꢂ2 mol Lꢂ1
)
HCl þ 1.25 mL (0.1, 0.15, and 0.2 mol Lꢂ1
)
KCl þ 2.5 mL (5 ꢃ 10ꢂ3 Cu2þ solution) þ 0.5 mL (5 ꢃ 10ꢂ3 mol Lꢂ1) metal ion in
twice-distilled water þ 9.5 mL H2O.
The total volume was adjusted to 25 mL by adding dioxane in each case. The pH-
meter readings in 50% (v/v) dioxane mixture are corrected according to the Van Uitert
and Hass relation [24].
2.5. DNA interaction studies
A solution of 2 mg of calf thymus DNA (ct-DNA) was dissolved in 1 mL of sterile
distilled water. Stock concentrations of the ligands and complexes were prepared by
dissolving 2 mg mLꢂ1 in DMSO. Equal volumes from each compound and DNA were
mixed thoroughly and kept at room temperature for 2–3 h. The effect of the chemicals
on the DNA was analyzed by agarose gel electrophoresis. Loading dye (2 mL) was
added to 15 mL of the DNA mixture before being loaded into the well of agarose gel.
The loaded mixtures were fractionated by electrophoresis, visualized by UV and
photographed [25].

Cu(II) thiosemicarbazides
1659
Scheme 1. Molecular modeling of H2PPS.
Scheme 2. Molecular modeling of H2PBO.
Scheme 3. Molecular modeling of H2APO.
Scheme 4. Molecular modeling of H2PPY.
2.6. Molecular modeling
To gain better insight on the molecular structure of the ligands (schemes 1–4) and
complexes (schemes 5–8), geometric optimization and conformational analysis have
been performed using MMþ [26] force field as implemented in HyperChem 8 [27].

1660
O.A. El-Gammal et al.
Scheme 5. Molecular modeling of [Cu(HPPS)Cl(H2O)2] complex.
Scheme 6. Molecular modeling of [Cu(HPBO)Cl(H2O)2] complex.
Scheme 7. Molecular modeling of [Cu(HAPO)Cl](H2O) complex.
Scheme 8. Molecular modeling of [Cu(HPPY)Cl(H2O)2] complex.
3. Results and discussion
3.1. Synthesis and spectroscopy
In continuation of our previous work on pyridine chemistry [28], we synthesized some
new thiosemicarbazide derivatives containing the pyridine ring (scheme 9).

Cu(II) thiosemicarbazides
1661
S
S
H
N
NH2
RX
+
N
N
H
N
H
N
N
H
N
H
RX
1
2(a-d)
3(a-d)
R
ph
X
A
B
C
D
NCS
NCOS
NCO
NCS
ph
ph
2-py
4
4
1
1
S
H
H
S
H
H
5
6
3
2
5
6
3
2
C
N
N
a'
b
N
a
N
a
C
N
N
a'
b
N
c
c
C
S
C
O
N
1
N
C
S
N
2
1
H
H
2
H
H
N1-phenyl-N2-(pyridin-2-yl)hydrazine-1,2-bis(carbothioamide)
N-phenyl-2-(2-(pyridin-2-ylcarbamothioyl)hydrazinyl)-2-thioxoacetamide
(H2PBO)
(H2PPS)
4
4
S1
C
H
H
S
C
H
H
N
5
6
3
2
3
2
5
6
a
N
b
N
a
b
N
N
c
a'
c
a'
N
C
O
N
N
C
S
N
N
1
1
2
H
H
N
H
H
N-phenyl-2-(pyridin-2-ylcarbamothioyl)hydrazinecarboxamide
1-(aminoN-(pyridin-2-yl)methanethio)-4-(pyridin-2-yl)thiosemicarbazide
(H2APO)
(H2PPY)
Scheme 9. The synthesized thiosemicarbazide derivatives.
3.2. IR spectra
IR spectra of the free ligands show three bands in the region 3234–3100 cmꢂ1
0
attributable to stretching modes of the (NH)a,a and ꢁ(NH)b,c groups. The stretching
and out-of-plane ring deformation modes (ꢁ/ꢀ) of the pyridine ring are observed at
ꢄ1560 and 620–635 cmꢂ1 [29]. Strong bands due to stretching vibration of ꢁ(C¼N)
(azomethine) in H2PPS and H2PBO thiosemicarbazides are at 1646 and 1641 cmꢂ1
,
respectively; this band was difficult to recognize in H2PPY because it is overlapped with
ꢁ(C¼C) of the pyridine ring. The stretching and bending vibrations (ꢁ/ꢀ) of the C¼S
groups are observed as strong bands at 1218–1247 cmꢂ1 and 840–865 cmꢂ1, respectively
[30, 31]. As these ligands contain two C¼S groups, (C¼S)1 and (C¼S)2, we propose that
(C¼S)1 is in the thione form and (C¼S)2 in the thiol form as confirmed by the existence
of additional bands at ꢅ2600 and 660 cmꢂ1 in the spectra of the aforementioned ligands
assignable to ꢁ(C–S) and ꢁ(SH). This assumption is further supported by the absence of
bands due to ꢁ(C¼N) (azomethine), ꢁ(C–S), and ꢁ(SH) in the IR spectrum of the
starting (4-pyridyl thiosemicarbazide) [32] and the absence of the SH signal in the
1H NMR spectrum of H2APO.
Also, the appearance of ꢀ (C–S) in H2PPY at higher wavenumber, 683 cmꢂ1, than
that of other ligands may be due to presence of pyridyl groups which act as electron-
withdrawing groups.

1662
O.A. El-Gammal et al.
In H2APO, the sharp band at 3521 cmꢂ1 may be due to ꢁ(OH) in addition to the
ꢁ(CO) band at 1675 cmꢂ1, suggesting the keto–enol tautomerism.
IR spectra of the investigated Cu(II) complexes show that H2PPS, H2PBO, H2APO,
and H2PPY coordinate as mono-negative tridentate through (C¼N) of pyridine, N of
NHb, and one of the (C¼S) groups adjacent to N4 in the thiol form (H2PPS, H2PBO,
and H2PPY) or enolized carbonyl group in H2APO.
This chelation is supported by the shift of deformation mode of the pyridine ring
either to lower or higher wavenumber, indicative of coordination of the metal to
pyridine [33], and the band due to thioamide(4) at 840–875 either shifts to lower
wavenumber [34] or disappears with simultaneous appearance of a new band assignable
to ꢁ(C–S), suggesting coordination via C¼S either in the thione form
[Cu(HPPS)Cl(H2O)2] or the thiol form [Cu(HPBO)Cl(H2O)2] and [Cu(HPPY)
Cl(H2O)2] [35]. The shift of ꢁ(N–N) to higher wavenumber is further evidence for
coordination via (NH)b. In the IR spectrum of [Cu(HAPO)Cl](H2O), CS bands at the
same position suggest that they do not participate in coordination and the disappear-
ance of the band at 3363 cmꢂ1 due to the (C–OH) mode, in addition to a new band at
533 cmꢂ1 due to ꢁ(Cu–O), reveals this mode of coordination.
In all the complexes, a band at 480–424 cmꢂ1 assigned to ꢁ(Cu–N) supports the
proposed mode of coordination. IR spectra of all complexes exhibit ꢁasym and ꢁsym(OH)
and D(H2O) vibrations at ꢄ3399–3450 cmꢂ1 and a weak shoulder at 1625 cmꢂ1
,
respectively, suggesting water [36]. Broad bands at 875–850 cmꢂ1 and ꢄ540–550 refer to
Pr(H2O) and Pw(H2O) vibrations and support that water is coordinated, confirmed by
TGA studies.
3.3. 1H NMR spectra
1H NMR spectra of H2PPS, H2PBO, H2APO, and H2PPY in DMSO-d6 show signals at
ꢀ ¼ (10.30–10.90), (11.09–11.90), (8.09–8.25), (8.27–9.54), and (15.40, 15.80) ppm
0
assignable to (NH)a,,a , (NH)b,c, and SH protons, respectively. The peak of (NH)a,,a
0
,
disappears and the intensity of the (NH)b,c peak decreases on addition of D2O, which
suggests that they are easily exchangeable. These protons shift downfield because they
0
hydrogen bond with N of pyridine and S of CS. The protons of (NH)a and (NH)a
appear as singlets as expected since the NH protons are decoupled from nitrogen and
protons from adjacent atoms. (NH)b and (NH)c show coupling with the adjacent
hydrogen as doublets. This coupling can be attributed to the low NH exchange rate.
Signals attributed to pyridyl appear at ꢀ ¼ 8.26 (d, J ¼ 5.40 Hz, 1H, pyridine H6), 7.85
(dd, J ¼ 6.9, 5.4 Hz, 1H, pyridine H4), 7.65 (dd, J ¼ 6.9, 4.8 Hz, 1H, pyridine H5), and
7.35–7.50 (d, J ¼ 5.4 Hz, 1H, pyridine H3) for H2PPS, 8.23 (dd, J ¼ 8.7 Hz, 1H, pyridine
H5), 8.01 (d, J ¼ 5.3 Hz, 1H, pyridine H6), 7.9 (d, J ¼ 6.4 Hz, 1H, pyridine H3), 7.66
(dd, J ¼ 6.1 Hz, 1H, pyridine H4) for H2PBO, 8.23 (dd, J ¼ 8.7 Hz, 1H, pyridine H5),
8.01 (d, J ¼ 5.3 Hz, 1H, pyridine H6), 7.9 (d, J ¼ 6.4 Hz, 1H, pyridine H3), 7.66 (dd,
J ¼ 6.1 Hz, 1H, pyridine H4) for H2APO, and 8.21 (d, J ¼ 6.2 Hz, 1H, pyridine H6), 8.17
(d, J ¼ 7.4 Hz, 1H, pyridine H3), 7.88 (dd, J ¼ 5.5 Hz, 1H, pyridine H5), 7.85 (dd,
J ¼ 7.3 Hz, 1H, pyridine H4) for H2PPY [37]. The signal at ꢀ (8.01–8.22) ppm for
pyridine H6 in all thiosemicarbazides is superimposed with that of some NH (NH)b,c
protons. Also, spectra of H2PPS, H2PBO, and H2APO at 7.00–7.64 ppm due to phenyl
protons appear as complicated multiplets. A signal at ꢀ 15.4 ppm in the spectrum of

Cu(II) thiosemicarbazides
1663
Table 1. Magnetic moment and electronic spectra of the Cu(II) complexes of H2PPS, H2PBO, H2APO, and
H2PPY.
Compound
H2PPS
Solvent
Band position (cmꢂ1
)
ꢂeff (B.M.)
DMF
Nujol
35,211; 31,847; 29,069
–
–
[Cu(HPPS)Cl(H2O)2]
DMF
35,211; 28,089; 26,178
18,587; 16,077
23,364; 20,408; 17,301
1.78
Nujol
H2PBO
DMF
Nujol
35,461; 32,680; 29,070
–
–
2.03
–
[Cu(HPBO)Cl(H2O)2]
H2APO
DMF
Nujol
32,258; 28,409; 18,050
25,000; 30,675; 17,606
DMF
Nujol
35,211; 32,051
–
[Cu(HAPO)Cl](H2O)
H2PPY
DMF
Nujol
35,211; 32,467; 27,624
23,585; 19,685; 15,291
1.54
DMF
Nujol
35,971; 28,409; 22,321
35,211; 30,120; 18,050
–
[Cu(HPPY)Cl(H2O)2]
Nujol
DMF
35,211; 31,847; 29,585
25,126; 19,157
1.83
H2PPY due to SH and a signal at ꢀ 12.80 ppm due to OH in H2APO confirm the thiol–
enol tautomerism in solution.
3.4. Electronic spectra and magnetic moments
The absorption bands and the magnetic moments of the thiosemicarbazides and their
Cu(II) complexes in DMF and Nujol mull are recorded in table 1. The spectra exhibit
bands at 35,111–35,971 cmꢂ1 and 30,120–32,680 cmꢂ1 assignable to ꢃ ! ꢃ* and n ! ꢃ*
transitions, respectively [38]. Charge transfer is observed in spectra of complexes with a
new n ! ꢃ* band at 28,089–29,585 cmꢂ1. The charge transfer band assigned to
(S ! Cu) [38, 39] in [Cu(HPPS)Cl(H2O)2], [Cu(HPBO)Cl(H2O)2], and [Cu(HPPY)
Cl(H2O)2] appeared at higher energies (22,320–25,000 cmꢂ1) in Nujol possibly due to
coordination via sulfur. The d–d transition bands for [Cu(HPPS)Cl(H2O)2],
[Cu(HPBO)Cl(H2O)2], and [Cu(HPPY)Cl(H2O)2] at 18,050–19,685 cmꢂ1 in DMF and
at 17,301–18,116 cmꢂ1 in Nujol are consistent with octahedral complexes. For
[Cu(HAPO)Cl](H2O), the band due to d–d transition appeared at 15291 cmꢂ1 in
DMF confirming a square-planar environment. These geometries will be further
confirmed by ESR spectra. Magnetic moment values fall in the range reported for d9
Cu(II) complexes.
3.5. ESR spectra
ESR spectra of Cu(II) complexes provide information about hyperfine and super-
hyperfine structures which are important in studying the metal ion environment in

1664
O.A. El-Gammal et al.
Table 2. ESR data of some Cu(II) complexes at room temperature.
Complex
g
g
?
A ꢃ 10ꢂ4 (cmꢂ1
)
G
g /A
k
ꢄ2
ꢅ2
k
k
k
[Cu(HPPS)Cl(H2O)]
2.28
2.29
2.25
2.23
2.06
2.06
2.08
2.07
165
168
–
4.60
3.30
3.12
3.20
138
136
–
0.80
0.73
–
0.90
0.74
–
[Cu(HPBO)Cl(H2O)](H2O)
[Cu(HAPO)Cl](H2O)3
[Cu(HPPY)Cl(H2O)](H2O)
150
148
0.71
0.87
complexes, i.e., the geometry, nature of the ligation sites and degree of covalency of the
metal ligand bonds (Supplementary material). The spin Hamiltonian parameters of the
complexes with Cu(II), S ¼ 1/2, I ¼ 3/2, were calculated and are summarized in table 2.
Room temperature solid state ESR spectra of these complexes are similar and exhibit
axially symmetric g-tensor parameters with g 4 g 4 2.0023 revealing an appreciable
k
covalency with d(x2–y2) as the ground-state [40], characteristic of square-planar, square-
?
pyramidal or octahedral stereochemistry [41].
In axial symmetry the g-values are related by the expression G ¼ (g – 2)/(g – 2) ¼ 4,
k
?
where G is the exchange interaction parameter. According to Hathaway and Billing [42],
if G is greater than 4, the exchange interaction between copper(II) centers in the solid
state is negligible, whereas when it is less than 4, considerable exchange interaction is
indicated. The calculated G values (Supplementary material) show G 4 4 for
[Cu(HPPS)Cl(H2O)2] and less than 4 for [Cu(HPBO)Cl(H2O)2], [Cu(HAPO)Cl](H2O),
and [Cu(HPPY)Cl(H2O)2] [43].
A band corresponding to forbidden magnetic dipolar transition for [Cu(HPBO)
Cl(H2O)2], [Cu(HPPS)Cl(H2O)2], and [Cu(HPPY)Cl(H2O)2] is not observed at half-
field (ca 1600 G, g ¼ 4.0), revealing mononuclear Cu(II) complexes [44]. Superhyperfine
structures for these complexes are not seen at higher fields excluding any interaction of
the nuclear spins of nitrogen (I ¼ 1) with the unpaired electron density on Cu(II).
The absorption for [Cu(HAPO)Cl](H2O) consists of a broad band centered at g ¼ 2,
attributable to dipolar broadening and enhanced spin lattice relaxation [45]. This line
broadening is probably due to insufficient spin exchange narrowing toward the
coalescence of four copper hyperfine lines to a single line; similar powder ESR line
shapes have been observed for many square-planar or distorted octahedral dimeric
Cu(II) complexes with strong intra-dimer spin-exchange interaction [46]. Hyperfine
splitting due to the spin of copper was not detected because of the broadness. These
observations confirm occurrence of super exchange coupling between Cu(II) ions in the
dimeric complexes, consistent with the subnormal effective magnetic moment values
which may refer to sulfur coordination [47].
The tendency of A to decrease with concomitant increase of g is an index of
k
tetrahedral distortion in the coordination sphere of copper. To quantify the degree of
k
distortion of the Cu(II) complexes, we selected f(ꢄ) ¼ g /A obtained from the ESR
k
k
spectra. Values of 110–120 are typical for planar complexes, while the range 130–150 is
characteristic of slight to moderate distortion and 180–250 cm–1 indicate considerable
distortion [48, 49]. The ratio g /A for [Cu(HPBO)Cl(H2O)2], [Cu(HPPS)Cl(H2O)2], and
k
k
[Cu(HPPY)Cl(H2O)2] are 136, 138, and 148, respectively, demonstrating significant
dihedral angle distortion in the xy-plane, consistent with distorted octahedral geometry
around the copper site.

Cu(II) thiosemicarbazides
1665
Molecular orbital coefficients, ꢄ2 (a measure of the covalency of the in-plane ꢆ-
bonding between a copper 3d orbital and the ligand orbitals) and ꢅ2 (covalent in-plane
ꢃ-bonding), were calculated by using the following equations [50–53]:
À
Á
À
Á
ꢄ2 ¼ A =0:036 þ g ꢂ 2:0023 þ 3=7ð g ꢂ 2:0023Þ þ 0:04,
k
k
?
À
Á
ꢅ2 ¼ g ꢂ 2:0023 E= ꢂ 8ꢇꢄ2,
k
where ꢇ ¼ ꢂ828 cmꢂ1 for free copper ion and E is the electronic transition energy.
As a measure of the covalency of the in-plane ꢆ-bonding, ꢄ2 ¼ 1 indicates complete
ionic character, whereas ꢄ2 ¼ 0.5 denotes 100% covalent bonding with the assumption
of negligibly small values of overlap integral. ꢅ2 gives an indication of the covalency of
the in-plane ꢃ-bonding. The smaller ꢅ2, the larger is the covalency of the bonding.
Values of ꢄ2 and ꢅ2 for [Cu(HPBO)Cl(H2O)2], [Cu(HPPS)Cl(H2O)2], and
[Cu(HPPY)Cl(H2O)2] indicate that the in-plane ꢆ-bonding and in-plane ꢃ-bonding
are covalent, which originates from thiolato sulfur binding incorporating greater
covalency in the metal–ligand bonding through delocalized dꢃ–pꢃ in-plane ꢃ-bonding as
evidenced from higher ꢅ2 values [54]. Data for [Cu(HAPO)Cl](H2O) show that in-plane
ꢆ-bonding and in-plane ꢃ-bonding are ionic. For square-planar geometry, the lower
values of ꢅ2 compared to ꢄ2 indicate that in-plane ꢃ-bonding is more covalent than the
in-plane ꢆ-bonding, consistent with other reported values [55–58].
3.6. Molecular modeling
The molecular structure and atom-numbering of ligands and its Cu(II) complex are
shown in schemes 1–8.
From data recorded in Supplementary tables (S1–S9) for bond lengths and angles,
one can conclude the following: (1) bond angles of the thiosemicarbazide are altered
upon coordination with largest effects on S(9)–C(8)–N(10), C(8)–N(10)–N(11), N(10)–
N(11)–C(12), and C(4)–N(7)–C(8) angles which are reduced from 123.3ꢁ, 116.8ꢁ, 123.3ꢁ,
and 127.6ꢁ in H2PPS to 97.6ꢁ, 127.5ꢁ, 107.5ꢁ, and 106ꢁ for [Cu(HPPS)Cl(H2O)2]; N(10)–
N(11)–C(12) and N(11)–C(12)–S(13) from 124ꢁ and 126.1ꢁ in H2PBO to 115ꢁ and
119.6ꢁ for [Cu(HPBO)Cl(H2O)2]; C(5)–C(4)–N(7) and N(10)–N(11)–C(12) from 126.6ꢁ
and 122.5ꢁ in H2APO to 121.6ꢁ and 114.3ꢁ for [Cu(HAPO)Cl](H2O), and N(11)–C(12)–
S(13) and N(11)–C(12)–N(14) from 123.6ꢁ and 115.6ꢁ in H2PPY to 118.4ꢁ and 122.5ꢁ
for [Cu(HPPY)Cl(H2O)2] [59]. (2) All bond angles in the complexes are close to
octahedral geometry except for [Cu(HAPO)Cl](H2O), which has a square-planar
geometry. (3) All groups taking part in coordination, C¼S, N–H, (C¼N)py, and (C¼O),
have bonds longer than in the ligand. (4) The presence of two water molecules in trans
position for [Cu(HPPY)Cl(H2O)2]. (5) Lower highest occupied molecular orbital
(HOMO) energy values show weaker electron donation while higher HOMO energy
implies a good electron donor. Lowest unoccupied molecular orbital energy represents
the ability of a molecule receiving electron [60].
3.7. Thermogravimetric studies
The stages of decomposition, temperature range, decomposition product, and weight
loss percentages of complexes are given in table 3. A glance at the table indicates that

1666
O.A. El-Gammal et al.
Table 3. Decomposition steps with temperature range and weight loss for ligands and their copper
complexes.
Weight loss
Compound
H2PPS
Temperature range (ꢁC)
Removed species
Found (%)
Calcd (%)
141–228
229–371
513–691
691–800
ꢂPy þ NH
30.84
45.76
9.58
30.68
45.18
9.8
ꢂPy þ NH þ CS
ꢂN2H2
CS (residue)
13.8
14.5
[Cu(HPPS)Cl(H2O)2]
190–279
280–390
391–527
528–754
754–800
ꢂ2H2O þ HCl
ꢂPy
16.78
17.65
5.85
30.17
29.55
16.57
17.85
5.95
30.44
29.19
ꢂCN
ꢂCN2H þ NH þ Ph
CuS þ S (residue)
H2PBO
0–210
210–370
370–700
ꢂPy þ NH
ꢂC3H3S2O
C6H5
28.58
48.16
23.28
28.09
48.64
23.27
[Cu(HPBO)Cl(H2O)2]
188–292
292–441
441–695
695–800
ꢂ2H2O
7.87
35.65
25.69
30.79
7.94
35.85
25.37
30.84
ꢂCl þ Py þ N2H2 þ 2C
ꢂC6H5 þ NH þ N þ C
CuO þ 2S (residue)
H2APO
126–217
217–344
344–700
ꢂC5H5N2 þ N2H2
ꢂC6H5 þ CO þ NH
CS (residue)
42.15
41.11
16.74
42.85
41.82
15.34
[Cu(HAPO)Cl](H2O)
21–137
137–258
258–397
397–570
570–776
776–800
ꢂH2O
4.03
31.77
19.63
6.51
10.93
27.13
4.47
31.88
19.12
6.69
10.17
27.8
ꢂPy þ Cl þ NH
ꢂC6H5
ꢂNH þ C
ꢂN2H þ C
CuO þ S (residue)
H2PPY
188–246
246–400
400–700
ꢂN2H2
10.57
60.96
28.78
9.86
61.18
28.96
ꢂ2Py þ N2H2
2CS (residue)
[Cu(HPPY)Cl(H2O)2]
290–467
467–660
660–800
ꢂ2H2O þ Cl
16.71
54.16
29.13
16.30
54.56
29.12
ꢂ2Py þ N4H3 þ 2C
Cu þ 2S (residue)
thermal stabilities of ligands increase on complex formation. TGA curves of
[Cu(HPPS)Cl(H2O)2] as a representative example (Supplementary material) display
five degradation steps. The first at 190–279ꢁC with weight loss of 16.78 (Calcd 16.57%)
is attributed to loss of the two lattice water molecules and Cl. The second step with
weight loss of 17.65 (Calcd 17.85%) at 280–390ꢁC corresponds to removal of pyridine.
The third step at 391–557ꢁC with weight loss of 5.85 (Calcd 5.95%) is for removal of
CN. The fourth step (558–754ꢁC) can be ascribed to elimination of CN4H fragment
with weight loss of 30.17 (Calcd 30.44%). The residual is CuS þ S (found 29.55,
Calcd 29.19%).
3.8. pH metric studies
ꢀ
The average number of protons associated with ligand na was calculated at different
pH-values using the Irving–Rossotti equation [61] and used to draw proton-ligand

Cu(II) thiosemicarbazides
1667
formation curves, which indicated that the maximum na is ꢅ2 revealing that the
investigated ligands have two dissociable protons of NHb and NHc, respectively. An
inspection of the results in table 4 reveals the following:
(1) Effect of substituent: pK1 values of the ligands are influenced by the inductive effect
of the substituent. The pK values under the same conditions of temperature and
ionic strength can be arranged as H2APO 4 H2PPS 4 H2PPY 4 H2PBO, attrib-
uted to hydrogen-bond formation. The first three compounds form two hydrogen
bonds and the last one forms three hydrogen bonds, and as a result it is difficult to
lose Hþ, so the pK is high. On substituting carbonyl by thione, the pK value
decreases as oxygen is more electronegative than sulfur. The presence of pyridyl in
H2PPY (i.e., electron withdrawing) decreases the electron density more effectively
than phenyl, giving a stronger hydrogen bond and, consequently, smaller pK.
(2) Effect of ionic strength: There is an increase in pK with increasing ionic strength of
the medium, consistent with that reported [62].
(3) Effect of temperature: pKa values decrease with increasing temperature, i.e., the
acidity of ligands increase with increasing temperature.
(4) The stepwise stability constants of complexes: The values (table 5) decrease with
increasing temperature, indicating that complexation is unfavorable with increasing
temperature.
(5) Thermodynamic parameters: DGꢁ values are positive, indicating non-spontaneous
character of the dissociation processes. DSꢁ values were negative, indicating that
dissociation is entropically unfavorable due to disorder of the solvent around the
ligand [63]. Positive values of DHꢁ indicate that dissociation of ligands is
endothermic.
‘‘Supplementary material’’ shows that DGꢁ values are negative, indicating sponta-
neous chelation. Negative values of DSꢁ indicate that complexation is entropically
unfavorable while negative values of DHꢁ suggest that chelation is accompanied by
generation of heat, indicating that the processes are exothermic, i.e., complexation is
favorable at lower temperature.
3.9. DNA degradation studies
DNA cleavage reactions generally occur through three pathways, namely oxidative
strand cleavage by abstraction of a sugar hydrogen (s), hydrolytic cleavage involving
the phosphate, and by base oxidations primarily directed at guanine. Irradiation is one
methodology for inducing DNA cleavage [64]. For the sulfur containing thiosemi-
carbazides thio or thione moieties exhibit efficient intersystem crossing to the triplet
state 3(n–ꢃ*) and/or 3(ꢃ–ꢃ*). Such state with a longer lifetime can either cause damage
to DNA directly or can activate oxygen from its triplet state (3O2) to the cytotoxic
singlet state (1O2) [65, 66]. Examining DNA degradation assay for H2PPS, H2PBO,
H2APO, and H2PPY, and their corresponding Cu(II) complexes revealed variability on
their immediate damage on the ct-DNA (figure 1). The results show that either DNA in
DMF (þve control) or DNA treated with 2, 3, 4, and 5 showed no effect through the
incubation period, whereas 6 exhibited partial degradation, judged by the rate of DNA
migration in the gel. DNA disappeared completely after treatment with 7, 8, and 9 due
to direct contact of these complexes with DNA, which is necessary to degrade it. The

1668
O.A. El-Gammal et al.

Cu(II) thiosemicarbazides
1669
Table 5. The stability constants of Cu(II) complexes in 50% (v/v) dioxane-water and KCl at different
temperatures.
Dissociation constant
298 K
303 K
308 K
Compound
ꢂ (mol Lꢂ1
)
log K1
log K2
log K1
log K2
log K1
log K2
Cu(II) þ H2PPS
0.1
0.15
0.2
18.58
–
16.20
11.30
7.36
10.98
16.83
–
14.87
9.77
14.16
8.59
11.36
–
–
3.32
9.93
6.57
Cu(II) þ H2PBO
Cu(II) þ H2APO
Cu(II) þ H2PPY
0.1
0.15
0.2
17.71
18.72
–
6.91
9.85
13.31
15.42
–
–
6.38
12.43
12.07
14.01
–
–
3.96
13.21
13.80
0.1
0.15
0.2
18.42
12.52
15.93
9.75
7.65
10.31
16.06
–
–
8.92
12.29
11.16
14.91
9.16
–
6.43
6.96
10.74
0.1
0.15
0.2
19.70
14.68
14.45
11.20
–
10.64
16.29
13.37
13.98
8.34
–
11.38
15.43
–
–
8.23
7.47
6.49
Figure 1. Effect of free ligands and their Cu(II) complexes on the DNA in vitro.
data suggest that conjugation between the thio and imine make them inefficient,
3
possibly by reducing the triplet state (n–ꢃ*) and/or the (ꢃ–ꢃ*) lifetime of the sulfur
ligand in an enolic form. The absence of such conjugation in 6, 7, 8, and 9 in addition to
the near planarity of the chelate ring enhances the photosensitization and consequently
can either cause damage of DNA directly or activate oxygen. Therefore, 7 and 8 can be
used as a promising anti-tumor agent in vivo to inhibit the DNA replication in the
cancer cells and not allow the tumor to further grow [67].
4. Conclusion
Based on the elemental analysis and spectral data for Cu(II) complexes of H2PPS,
H2PBO, H2APO, and H2PPY, the substituents modify the coordination. The ligands

1670
O.A. El-Gammal et al.
coordinate to copper as SN bidentate, NON tridentate, or NSNS tetradendate, forming
structures in which each copper is square-planar or octahedral. ESR spectra of these
complexes are quite similar, exhibiting axially symmetric g-tensor parameters with
g 4 g 4 2.0023 revealing d(x2ꢂy2) as ground-state. Thermal degradation indicated
k
?
high stability of the formed chelates. Also, pH-metric studies were carried out at
different temperatures and ionic strengths, and revealed the effect of the substituent on
the dissociation constants of the thiosemicarbazides. At a given temperature, pK values
are in the order H2APO 4 H2PPS 4 H2PPY 4 H2PBO. DNA degradation assay for
H2PPS, H2PBO, H2APO, and H2PPY and their corresponding Cu(II) complexes
showed that the existence of conjugation in the thiosemicarbazides reduced the triplet
state lifetime of the sulfur ligand in the thiol form, so they were unable to cause damage
on DNA. Absence of such conjugation in the Cu(II) complexes enhanced their ability to
cause DNA cleavage. [Cu(HPBO)Cl(H2O)](H2O) and [Cu(HAPO)Cl](H2O)3 have the
highest degradation ability.
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