Synthesis, characterization and antiplasmodial evaluation of cyclopalladated thiosemicarbazone complexes

Article abstract of DOI:10.1016/j.jorganchem.2013.02.024

Cyclopalladated thiosemicarbazone complexes arising through chelation of the tridentate thiosemicarbazone ligand via the ortho-carbon of the aryl ring, the imine nitrogen and the thiolate sulfur were synthesized with the phosphorus ligand occupying the fo

Full text of DOI:10.1016/j.jorganchem.2013.02.024

Journal of Organometallic Chemistry 736 (2013) 19e26
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis, characterization and antiplasmodial evaluation of cyclopalladated
thiosemicarbazone complexes
,
,
Muneebah Adams a, Carmen de Kock b, Peter J. Smith b, Kelly Chibale a c, Gregory S. Smith a
*
a Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa
b Division of Pharmacology, Department of Medicine, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory 7925, South Africa
c Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclopalladated thiosemicarbazone complexes arising through chelation of the tridentate thio-
semicarbazone ligand via the ortho-carbon of the aryl ring, the imine nitrogen and the thiolate sulfur
were synthesized with the phosphorus ligand occupying the fourth coordination site of the palladium(II)
ion. These complexes were prepared by cleavage of the bridging PdeS bonds of previously reported
tetranuclear complexes with phosphorus ligands such as PTA and aminophosphines. The cyclopalladated
complexes along with their free ligands were screened for antiplasmodial activity against two Plasmo-
dium falciparum strains, NF54 (chloroquine-sensitive) and Dd2 (chloroquine-resistant), exhibiting
inhibitory effects in the low micromolar range.
Received 28 December 2012
Received in revised form
13 February 2013
Accepted 19 February 2013
Keywords:
Bioorganometallic chemistry
Thiosemicarbazone
Cyclopalladation
Ó 2013 Elsevier B.V. All rights reserved.
Antiplasmodial activity
1. Introduction
reported herein is brought about through oxidative addition of the
ortho CeH bond of an aryl group present in the ligand (Fig. 1).
Probing the application of platinum group metal-based com-
pounds as biological agents has increased exponentially within the
field of inorganic and organometallic research [1e4]. One of the
leading diseases being targeted by researchers is malaria, an in-
fectious parasitic disease estimated to have affected over 200
million people in 2010 [5]. However, despite the success of anti-
malarial drug regiments, these treatments are steadily losing their
efficacy as resistance to current drug treatments increases [6]. This
has led to the search for new and effective antimalarial drugs,
particularly to combat the rising resistance [7e9].
Thiosemicarbazones are Schiff-base compounds well-known for
their pharmacological properties, such as antitumour [10e15],
antiviral [16,17], antibacterial [18] and especially for their use as
antiparasitic [10,11,19e24] agents. Their ability to chelate endoge-
nous metals such as Fe(III) which may be required for the function
of certain metal dependent enzymes, inhibits parasite growth
[25,26].
However, in addition to the aforementioned method, cyclo-
metallation may occur through transmetallation (via lithiation of
the starting compound) as well the oxidative addition of a CeBr
bond [27,32]. The biological evaluation of these types of complexes
is still relatively new, though promising results have been reported
[10,33,34].
This study aims to expand on work previously carried out within
our research group on cyclopalladated complexes [19]. The new
cyclopalladated thiosemicarbazone complexes reported herein are
discussed in terms of the synthesis, characterization and anti-
plasmodial evaluation.
2. Results and discussion
2.1. Synthesis and characterization of phosphine ligands and the
palladium(II) complexes
On the other hand, chemistry associated with the preparation of
cyclometallated complexes is well established, especially those
prepared via CeH activation [27e32]. The cyclopalladated system
The iminophosphine ligand (L1) is a known compound syn-
thesized via a reported method [35]. The iminophosphine ligand L2
was prepared via a Schiff-base condensation reaction between (2-
diphenylphosphino)benzaldehyde and p-phenylenediamine in
methanol (Scheme 1) [33e35]. Reduction of the iminophosphine
ligands (L1, L2) using sodium borohydride produced the amino-
phosphine ligands (L3, L4). The phosphine ligands (L1, L3) were
* Corresponding author.
E-mail address: Gregory.Smith@uct.ac.za (G.S. Smith).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.02.024

20
M. Adams et al. / Journal of Organometallic Chemistry 736 (2013) 19e26
spacer are observed as a singlet at 6.88 and 6.14 ppm for compounds
R2
L2 and L4 respectively. The observation of a singlet is due to the
symmetry of the compounds about a two-fold rotation axis.
Compounds L3 and L4 are similar in structure and thus com-
N
NR3R4
N
M
L
parable trends were observed in the 13C{1H} NMR spectra. In the 13
C
R1
{1H} NMR spectra of L3 and L4, several carbon atoms situated close
to phosphorus are observed as doublets due to coupling with
phosphorus. For compounds L3 and L4, the signal for CH2eNH is
observed as a doublet at 52.7 (3JCP ¼ 20.7 Hz) and 46.1 ppm
(3JCP ¼ 25.7 Hz) respectively due to the three bond coupling
experienced with phosphorus. The signals for the carbon atoms of
the propyl chain are observed in the aliphatic region at 51.4, 23.2
and 11.9 ppm respectively for compound L3. The aromatic carbons
of the rigid spacer in compound L4 are observed as singlets at 139.7
and 113.5 ppm, which corroborate the statement that the com-
pound is symmetrical.
S
Fig. 1. The general structure of a cyclometallated complex. M ¼ metal; L ¼ ligand;
R1 ¼ aryl group; R2, R3, R4 ¼ H, alkyl or aryl group.
isolated as yellow oils, whereas the diphosphine ligands (L2, L4)
were isolated as yellow solids, in relatively high yields (88e94%).
These aminophosphine ligands along with 1,3,5-triaza-7-
phosphaadamantane (PTA) were the phosphorus-donor ligands
chosen as precursors for the targeted cyclopalladated complexes.
The known thiosemicarbazone ligands, 3,4-dichloroaceto-
phenone thiosemicarbazone (L5) and 3,4-dichloropropiophenone
thiosemicarbazone (L6), were used in the synthesis of the reported
tetranuclear complexes [Pd(3,4-dichloroacetophenone thiosemicar-
bazone)]4 (1) and [Pd(3,4-dichloropropiophenone thiosemicarba-
zone)]4 (2) [19,36]. The molecular structures of 1 and 2 have not been
reported before.
The synthesis of complexes 3e6 was accomplished through
cleavage of the bridging PdeS bond (Scheme 2) in the core of the
tetranuclear complex (1, 2) by the appropriate phosphorus-
containing ligand. Complexes 3e6 were isolated as yellow solids
in moderate to high yields in the range 40e94%.
Further confirmation is given by the singlets displayed in the 31P
{1H} NMR spectra, where the signals shifted upfield from ꢀ13.9 (L1)
and ꢀ12.2 (L2) ppm to ꢀ16.1(L3) and ꢀ16.9 (L4) ppm respectively.
Infrared spectral analysis of the iminophosphine ligand 3 revealed
an absorption band at 1610 cmꢀ1 for the imine (C]N) bond. No
absorption band is observed in the region characteristic of C]N
stretchings for the aminophosphine ligands L3 and L4, whilst aweak
absorption band is observed at 3405 and 3427 cmꢀ1 respectively, in
the region for NeH stretching frequency of secondary amines. This
confirms reduction of the C]N bond. EIþ-mass spectra displayed
molecular ion peaks at m/z 653 and 656 respectively for L2 and L4.
Cleavage of the bridging PdeS bond by the phosphine ligands is
seen in the 1H NMR spectra (3, 5, 6) where the signal for the aro-
matic proton Ha is now observed as a doublet (4JHP w 3.66 Hz)
between 6.13 and 7.10 ppm, while the signal for 4 is observed as a
broad signal. Compounds 3 and 4 contain the PTA ligand, and thus a
singlet associated with the PCH2N protons was observed at ca.
4.27 ppm. The NCH2N protons are in an AB spin system resulting in
two doublets corresponding to the different environments expe-
rienced by the axial and equatorial NCH2N protons [37e39]. The
doublet associated with the protons in the axial and equatorial
protons are observed around 4.44 and 4.58 ppm respectively for 3
and 4. In the 1H NMR spectra of 4 and 5, the aromatic protons are
observed in the range 7.00e7.74 ppm. Compound 5 maintains the
two-fold symmetry displayed by L2 and L4 which is evident by the
singlet observed for the protons of the aromatic spacer.
In the 1H NMR spectra of the iminophosphine ligands L1 and L2,
the signal corresponding to the imine proton is observed as a doublet
(4JHP w 5.00 Hz) at ca. 9.00 ppm. Reduction of the imine bond using
sodium borohydride is confirmed by the absence of the imine peak in
the 1H NMR spectra of L3 and L4, and the appearance of the signals
for the eCH2eN and secondary amine (CH2eNHe) protons. The
signals for the aromatic protons are observed in the range 6.76e
8.19 ppm. The protons of the propyl chain are observed upfield in the
aliphatic region. For compound L3, the CH3 protons are observed as a
triplet (J ¼ 7.44 Hz) at 0.73 ppm due to coupling with the adjacent
CH2 protons. The eCH2e protons are observed as a multiplet at
1.26 ppm for L3, while the remaining NeCH2e protons are observed
as a triplet (J ¼ 7.40 Hz) at 2.39 ppm. The protons of the rigid aromatic
H2N
c
L1: R = CH2CH2CH3
b
d
i
*
+
PPh2
OR
a
L2: R =
N
CHO
R
N
e
PPh2
PPh2
H2N
NH2
1 equiv.
or 2 equiv.
ii
c
L3: R = CH2CH2CH3
d
b
a
H
N
*
PPh2
L4: R =
R
N
H
e
PPh2
Scheme 1. (i) L2: MeOH, reflux, 6 h; (ii) L3: MeOH, NaBH4, ambient temp. 3 h; L4: DCM:MeOH (75:25% v/v), NaBH4, ambient temp. 6 h.

M. Adams et al. / Journal of Organometallic Chemistry 736 (2013) 19e26
21
b
Cl
Cl
N
NH2
N
Pd
2
S
H
N
g
a
Ph2P
PPh2
Pd
c
N
H
Cl
Cl
S
6
f
d
N
e
H2N
N
iii
R
R
H
N
Cl
Cl
NH2
Cl
Cl
N
NH2
N
N
S
Pd
S
L5: R = CH3
L6: R = CH2CH3
4
1: R = CH3
2: R = CH2CH3
ii
i
b
a
R
Cl
Cl
N
NH2
b
N
Pd
Cl
Cl
N
NH2
4
N
Pd
P
S
4
S
Ph2P
a
c
N
H
3: R = CH3
5
N
N
f
d
4: R = CH2CH3
N
e
Scheme 2. (i) Acetone, PTA (4 equiv.), reflux, 3 h; (ii) Acetone, L3 (4 equiv.), ambient temp. 3 h; (iii) Acetone/DCM, L4 (2 equiv.), ambient temp. 5 h.
The 13C{1H} NMR spectra displayed the signal for the thiolate
carbon downfield at ca. 177.0 ppm when compared to that observed
for the tetranuclear complexes. A doublet (4JHP w 9.76 Hz) is dis-
played in the spectra for 5 and 6. The imine carbons are observed in
the range 163.6e172.4 ppm while the aromatic carbon atoms
resonate in the range 114.0e164.0 ppm. As seen with other com-
plexes containing the PTA ligand, the carbon atoms NCH2N and
PCH2N resonate as doublets at 72.4 (3JCP ¼ 7.40 Hz) and 51.5
ꢁ
ꢀ
Fig. 2. The molecular structure of 1. Hydrogen atoms have been omitted for clarity. Selected bond lengths (A) and angles ( ): Pd(1)eN(1) 2.002(3); Pd(1)eC(1) 1.998(3); Pd(1)eS(1)
2.3637(9); Pd(1)eS(4) 2.3194(9); S(1)eC(9) 1.787(4); N(1)eC(7) 1.303(4); N(2)eC(9) 1.303(4); N(1)ePd(1)eC(1) 81.24(13); N(1)ePd(1)eS(1) 83.15(8); S(4)ePd(1)eS(1) 100.56(3);
C(1)ePd(1)eS(4) 94.91(10); N(1)ePd(1)eS(4) 175.63(8); C(1)ePd(1)eS(1) 164.06(11).

22
M. Adams et al. / Journal of Organometallic Chemistry 736 (2013) 19e26
Table 1
Crystal data and structure refinement data for complexes 1, 4 and 5.
1.3C4H8O
4
5.2CHCl3
Empirical formula
Formula weight
Temperature (K)
C48H52Cl8N12O3Pd4S4
1682.46
173(2)
C16H21Cl2N6PPdS
537.72
173(2)
C33H33Cl8N4PPdS
938.66
173(2)
ꢀ
Wavelength (A)
0.71073
0.71073
0.71073
Crystal system
Space group
Monoclinic
P21/n
16.4634(9)
9.1883(5)
38.962(2)
90
93.4590(10)
90
5883.1(6)
4
1.900
1.762
3328
0.18 ꢂ 0.17 ꢂ 0.16
2.06e28.40
ꢀ22 ꢃ h ꢃ 19;
ꢀ10 ꢃ k ꢃ 12;
ꢀ52 ꢃ l ꢃ 52
67,481
Monoclinic
C2/c
35.7802(19)
6.9559(4)
16.2229(9)
90
92.3610(10)
90
4034.2(4)
8
1.771
1.383
2160
0.09 ꢂ 0.08 ꢂ 0.07
2.28e28.44
ꢀ47 ꢃ h ꢃ 47;
ꢀ9 ꢃ k ꢃ 9;
ꢀ21 ꢃ l ꢃ 21
35,350
Triclinic
P-1
ꢀ
a (A)
11.7431(9)
12.8847(11)
14.7987(11)
69.656(2)
84.069(2)
72.202(2)
1999.0(3)
2
ꢀ
b (A)
ꢀ
c (A)
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
3
ꢀ
V (A )
Z
Dcalc (Mg mꢀ3
)
1.542
1.120
924
Absorption coefficient (mmꢀ1
F (000)
)
Crystal size (mm3)
0.07 ꢂ 0.08 ꢂ 0.12
q
Range for data collection (ꢁ)
1.8e28.3
Index range
ꢀ15 ꢃ h ꢃ 14;
ꢀ17 ꢃ k ꢃ 17;
ꢀ11 ꢃ l ꢃ 19
21,501
Reflections collected
Independent reflections [R(int)]
Data/restraints/parameters
Goodness-of-fit on F2
Transmission
14,734 [0.0604]
14,734/0/723
1.011
0.7658, 0.7422
R1 ¼ 0.0365,
wR2 ¼ 0.0681
R1 ¼ 0.0598,
wR2 ¼ 0.0758
0.722 and ꢀ0.520
5077 [0.0666]
5077/0/244
1.009
0.9094, 0.8857
R1 ¼ 0.0291,
wR2 ¼ 0.0586
R1 ¼ 0.0443,
wR2 ¼ 0.0644
0.469 and ꢀ0.457
9946 [0.041]
9946/21/414
1.042
0.9256, 0.8772
R1 ¼ 0.0664,
wR2 ¼ 0.1719
R1 ¼ 0.0928,
wR2 ¼ 0.1909
1.98 and 1.51
Final R indices [I > 2
s(I)]
R indices (all data)
ꢀꢀ3
Largest difference in peak and hole (e A
)
(1JCP ¼ 15.5 Hz) ppm for 3 and 4. The eCH2eN carbon atom of
compound 5 and 6 resonates as a doublet at 52.8 (3JCP ¼ 12.8 Hz)
and 47.9 (3JCP ¼ 14.8 Hz) ppm respectively [37e39].
centrosymmetric triclinic system with P-1 space group. The for-
mation of the expected two 5-membered rings are observed as the
thiosemicarbazone ligand chelates to the palladium(II) centre in a
tridentate C,N,S-mode [10,49]. Upon formation of compound 1, the
bonds N(1)eC(7) and N(2)eC(9) have equal bond lengths of
For the phosphorus-containing cyclopalladated complexes (3e
6),
a
singlet was observed in the 31P{1H} NMR spectra
ꢀ
at ꢀ49.5, ꢀ49.6, 29.5 and 29.0 ppm respectively, which is downfield
from the free phosphine ligands. Infrared spectral analysis of 3e6
displayed two absorption bands in the region typical of C]N bonds
between 1559 and 1641 cmꢀ1. The lower energy absorption band
corresponds to the metal-coordinated imine (through the nitrogen
atom), while the higher energy absorption band is assigned to the
newly formed C]N bond.
1.303(4) A, which confirms the formation of the second C]N bond
(Fig. 2). Upon formation of the mononuclear complexes, the fourth
coordination site on the metal is occupied by the phosphorus ligand.
The metal-coordinated imine bond is slightly shorter than that
observed for compound 1, while the second C]N bond is slightly
longer (Figs. 2e4). The chelation of the ligand in the thiolate form is
confirmed when comparing the length of the SeC bond to that of
other thiosemicarbazone ligands and palladium(II) complexes.
Complexes 1, 4 and 5 have SeC bond lengths of 1.787(4), 1.768(3)
and 1.755(6) respectively. Previously published molecular struc-
EIþ- and ESIþ-mass spectra were recorded for compounds 3e6,
which displayed a peak corresponding to the molecular ion.
ꢀ
tures reported bond lengths of approximately 1.684 A for the ligand
2.2. Molecular structures of 1, 4 and 5
ꢀ
and 1.782 A for the palladium(II) complexes [40,41]. The SeC bond
lengths reported for complexes 1, 4 and 5 is consistent with single
Single crystals, crystallized with three molecules of tetrahy-
drofuran, were obtained via the slow evaporation of a solution of
compound 1 dissolved in tetrahydrofuran/hexane. Single crystals of
4 were obtained by the slow diffusion of hexane into a tetrahy-
drofuran solution of 4. The slow diffusion of hexane into a solution
of 5 dissolved in chloroform allowed for the formation of suitable
crystals with two molecules of chloroform. The molecular struc-
tures of 1, 4 and 5 were elucidated using single-crystal X-ray
diffraction and validates the spectroscopic and analytical charac-
terization of the mononuclear (4 and 5) complexes, as well as the
molecular structure of the previously described tetranuclear com-
plex 1 which has not yet been reported. The molecular structure of
1, 4 and 5 are shown in Figs. 2e4 and the crystallographic data is
given in Table 1.
bond character, i.e. chelation in the thiolate form. The lengthening of
ꢀ
ꢀ
the PdeN bonds of compounds 4 (2.022(2) A) and 5 (2.033(5) A)
ꢀ
compared to compound 1 (2.002(3) A) is indicative of the trans effect
induced by the introduction of a phosphorus ligand.
Compounds 1, 4 and 5 have a slightly distorted square-planar
geometry around the palladium(II) centre (Figs. 2e4). The bond
angles between adjacent coordinating atoms are close to the ex-
pected value of 90ꢁ, in the range 80.71(10)e101.45(8)ꢁ. This
observed geometry is comparable to that in related complexes
[19,29,42,43].
2.3. Antiplasmodial activity
Compound 1 and 4 crystallizes in a monoclinic systemwith space
groups P21/n and C2/c respectively, while compound 5 is packed in a
The thiosemicarbazone ligands (L5, L6) and their corresponding
cyclopalladated complexes (1e6) were evaluated for antiplasmodial

M. Adams et al. / Journal of Organometallic Chemistry 736 (2013) 19e26
23
Table 2
IC50 values for compounds L5, L6 and 1e6 against the P. falciparum strains NF54
(CQS) and Dd2 (CQR).
a
IC50
(mM)
Compound
NF54
Dd2
RIb
L5
L6
1
2
14.1 ꢄ 0.34
19.0 ꢄ 2.18
Inactive
9.82 ꢄ 0.78
4.46 ꢄ 0.74
Inactive
0.70
0.23
NDc
ND
Inactive
Inactive
3
4
5
6
1.93 ꢄ 0.04
1.81 ꢄ 0.11
1.76 ꢄ 0.074
Inactive
2.69 ꢄ 0.22
1.73 ꢄ 0.16
1.59 ꢄ 0.053
54.56 ꢄ 3.83
0.22 ꢄ 0.016
1.39
0.96
0.90
ND
CQDP
0.031 ꢄ 0.006
7.10
a
IC50: compound concentration causing 50% inhibition of parasitaemia in vitro.
RI: resistance index ¼ [IC50 (Dd2)]/[IC50 (NF54)].
ND: not determined.
b
c
On the other hand compounds 3e5 exhibit comparable inhibi-
tory activity in both strains, with IC50 values in the range 1.59e
2.69 M. An enhancement of activity is clearly observed for the
m
mononuclear complexes (3e5) compared to the free mono-
thiosemicarbazone ligands (L5, L6).
The rationale behind the synthesis of polynuclear complexes
was to determine if an enhancement in antiplasmodial activity
would be observed with an increase in the number of metal centres.
However, the data collected for polynuclear complexes should be
read with caution before a definite correlation can be made be-
tween the activity displayed and the number of metal centres.
Compound 6, which contains a diphosphine ligand, allowing for the
synthesis of a binuclear complex, exhibits only moderate activity
Fig. 3. The molecular structure of 4. Hꢁydrogen atoms have been omitted for clarity.
ꢀ
Selected bond lengths (A) and angles ( ): Pd(1)eN(1) 2.022(2); Pd(1)eC(1) 2.024(3);
Pd(1)eP(1), 2.2412(7); Pd(1)eS(1) 2.3397(7); S(1)eC(10) 1.768(3); N(2)eC(10)
1.310(3); N(1)eC(7) 1.302(3); N(1)ePd(1)eC(1) 80.71(10); N(1)ePd(1)eS(1) 83.19(6);
C(1)ePd(1)eP(1) 101.45(8); P(1)ePd(1)eS(1) 95.16(2); C(1)ePd(1)eS(1) 163.28(8);
N(1)ePd(1)eP(1) 170.63(6).
(IC50 ¼ 54.56 ꢄ 3.83
mM) against the Dd2 strain in comparison to
activity against the Plasmodium falciparum strains, NF54 (chloro-
quine-sensitive) and Dd2 (chloroquine-resistant). The control drug
used in the experiment was chloroquine diphosphate (CQDP), and
the results are displayed inTable 2. Compounds L5 and L6 were more
the mononuclear complexes 3e5. However, against the NF54 strain
compound 6 displays weak potency at the tested concentration
(1000 ng/ml). Based on the data available for the Dd2 strain, the
proposed enhancement of activity is not observed moving from the
mononuclear complexes (3e5) to the binuclear complex (6). It may
well be that correlation (or lack thereof) may be strain-dependent
and/or compound-specific. For this reason a larger number of
complexes need to be synthesized and tested against a broader
range of drug-sensitive and drug-resistant strains of the malaria
parasite P. falciparum.
active in the Dd2 strain (4.46 and 9.82
mM respectively) than in the
NF54 strain (14.1 and 19.0 M respectively), The tetranuclear com-
m
plexes 1 and 3 (Scheme 2) were inactive against the NF54 and Dd2
strains at the highest tested concentrations (1000 ng/ml).
A resistance index (RI) value <1 may suggest that cross resis-
tance with chloroquine is unlikely and/or that these complexes will
be active against drug resistant strains of the parasite [44]. The RI
values of the tested compounds are determined relative to chlo-
roquine, and are calculated by dividing the IC50 values for the CQR
(Dd2) strain by that of the CQS (NF54) strain. The RI values were
calculated for the aryl-derived compounds, and found to be lower
than the value for chloroquine diphosphate. All compounds, with
the exception of 3, displayed lower RI values compared to CQ.
3. Conclusions
Imino- and amino-phosphine ligands as well as four new
cyclopalladated thiosemicarbazone complexes containing phos-
phorus ligands have been synthesized and characterized. These
complexes were evaluated for their antiplasmodial activity against
two P. falciparum strains. The mononuclear complexes displayed
activity in the low micromolar range, which was significantly
more potent than that observed for the binuclear complex. As
observed with other cyclopalladated complexes, the biological
data for the mononuclear complexes is promising, and thus
modifications of these mononuclear complexes may lead to
enhanced activity.
Fig. 4. The molecular structure of 5. Hydrogen atoms have been omitted for clarity.
The propyl chain was disordered and the carbon atoms 29 and 30 were refined with
equal site occupancy factors of one-third each. Selected bond lengths (A) and angles
ꢀ
(ꢁ): Pd(1)eN(1) 2.033(5); Pd(1)eC(5) 2.029(4); Pd(1)eP(1) 2.2571(14); Pd(1)eS(1)
2.3181(15); S(1)eC(1) 1.755(6); N(2)eC(1) 1.331(8); N(1)eC(2) 1.298(7); N(1)ePd(1)e
C(5) 81.34(18); N(1)ePd(1)eS(1) 83.24(13); C(5)ePd(1)eP(1) 96.42(14); P(1)ePd(1)e
S(1) 99.11(5); C(5)ePd(1)eS(1) 164.47(14); N(1)ePd(1)eP(1) 171.14(15).

24
M. Adams et al. / Journal of Organometallic Chemistry 736 (2013) 19e26
4. Experimental
slow addition of sodium borohydride (0.0157 g, 0.415 mmol). The
reaction mixture was stirred at ambient temperature for 6 h. The
solvent was removed, the contents redissolved in dichloro-
methane (25 mL), extracted using water (20 mL), and the organic
layer was collected. The organic layer was washed with water
(4 ꢂ 20 mL), and once again collected, and dried over anhydrous
MgSO4. The solvent was reduced to precipitate a yellow powder
which was collected by suction filtration, washed with hot hexane
and dried in vacuo. Yield: 0.0543 g, 94%. Melting point: 194.8e
4.1. General remarks
All reagents and solvents were purchased from commercial
suppliers and used without further purification. Thiosemicarbazone
ligands (L5, L6) [36], K2[PdCl4] [45], the cyclopalladated tetranuclear
complexes (1,2) [19], as well as the iminophosphine ligand (L1) [35]
were prepared using reported methods. Nuclear magnetic reso-
nance (NMR) spectra were recorded on either a Varian Mercury
XR400 MHz (1H: 399.95 MHz) or Bruker Biospin GmbH (1H:
400.22 MHz, 13C: 100.65 MHz, 31P: 162.00 MHz) spectrometer at
ambient temperature. 1H and 13C{1H} NMR chemical shifts are
referenced to the deuterated solvent. Infrared (IR) spectra were
determined using a PerkineElmer Spectrum 100 FT-IR spectrom-
eter, and were recorded using KBr pellets. Elemental analyses (C, H, S
and N) were recorded on a Thermo Flash 1112 Series CHNS-O Ana-
lyser. Electron Impact (EI) mass spectrometry was carried out on a
JEOL GCmateII. Electrospray Ionisation (ESI) mass spectrometry was
also carried out on a Waters API Quattro Micro triple quadrupole
mass spectrometer in the positive mode. Melting points were
determined on the Büchi Melting Point apparatus B-540.
198.5 ꢁC. 1H NMR (399.95 MHz, DMSO-d6):
d
(ppm) ¼ 7.60 (m, 4H,
3
Hd); 7.41 (m, 12H, PPh2); 7.31 (t, JHH ¼ 7.80 Hz, 2H, Hc); 7.24 (m,
3
8H, PPh2); 7.17 (t, JHH ¼ 7.60 Hz, 2H, Hb); 6.76 (dd, JHH ¼ 7.51,
4.76 Hz, 2H, Ha); 6.14 (s, 4H, He); 5.30 (br s, 2H, NH); 4.19 (br s,
4H, eCH2eN). 13C NMR (100.65 MHz, DMSO-d6):
d
(ppm) ¼ 144.1
2
(d, JCP
¼
22.0 Hz, CAreCH2); 139.7 (CAreNH); 135.7 (d,
1JCP ¼ 10.3 Hz, PPh2); 134.4 (d, 1JCP ¼ 14.7 Hz, CArePPh2); 133.5 (d,
2JCP ¼ 19.8 Hz, PPh2); 132.2 (Cd); 131.3 (d, JCP ¼ 9.46 Hz, Ca);
2
129.0 (Cc); 128.8 (d, 3JCP ¼ 6.60 Hz, PPh2); 127.0 (d, 4JCP ¼ 4.40 Hz,
PPh2); 126.7 (Cb); 113.5 (Ce); 46.1 (d, 3JCP ¼ 25.7 Hz, eCH2eN). 31
P
NMR (162.00 MHz, CDCl3):
d
(ppm) ¼ ꢀ16.9. FT-IR (KBr, cmꢀ1):
n
¼ 3427 (w, NeH); 1517 (s, C]C). MS-EIþ: m/z 656 ([M]þ, 40%);
655 ([M ꢀ H]þ, 100%).
4.1.1. Synthesis of N1,N4-bis(2-(diphenylphosphino)benzylidene)
benzene-1,4-diamine (L2)
4.1.4. Synthesis of [Pd(3,4-dichloroacetophenone
thiosemicarbazone)(PTA)] (3)
2-(Diphenylphosphino)benzaldehyde (0.101 g, 0.346 mmol) was
added to methanol (15 mL), followed by the addition of benzene-
1,4-diamine (0.0186 g, 0.172 mmol). The reaction mixture was
refluxed at 68 ꢁC for 6 h, and stirred overnight at ambient tem-
perature to yield a yellow suspension. A light yellow powder was
collected by suction filtration, washed with hexane and dried in
vacuo. Yield: 0.0985 g, 88%. Melting point: 206.4e210.4 ꢁC. 1H NMR
Compound 1 (0.300 g, 0.205 mmol) was suspended in
acetone (15 mL), followed by the addition of 1,3,5-triaza-7-
phosphaadamantane (0.123 g, 0.781 mmol) to the reaction
flask. The reaction mixture was refluxed at 60 ꢁC for 3 h, and
cooled to ambient temperature. The yellow powder was
collected by suction filtration, washed with acetone and diethyl
ether, and dried in vacuo. Yield: 0.383 g, 94%. Melting point:
(399.95 MHz, CDCl3):
d
(ppm) ¼ 9.06 (d, 4JHP ¼ 5.10 Hz, 2H, HC]N);
243.0e248.4 ꢁC. 1H NMR (399.95 MHz, DMSO-d6):
d
(ppm) ¼ 7.27
8.19 (m, 2H, Hd); 7.45 (t, 3JHH ¼ 7.80 Hz, 2H, Hc); 7.33 (m, 22H, PPh2
(s, 1H, Hb); 7.10 (d, 4JHP ¼ 3.42 Hz, 1H, Ha); 7.02 (s, 2H, NH2); 4.59
(d, JHP ¼ 12.4 Hz, 3H, NCH2(eq)N); 4.44 (d, JHP ¼ 13.2 Hz, 3H,
NCH2(ax)N); 4.27 (s, 6H, PCH2N); 2.21 (s, 3H, CH3). 13C NMR
& Hb); 6.94 (m, 2H, Ha); 6.88 (s, 4H, He). 31P NMR (162.00 MHz,
CDCl3):
d
(ppm) ¼ ꢀ22.2. FT-IR (KBr, cmꢀ1):
n
¼ 3435 (w, NeH);
1610 (m, C]N). MS-EIþ: m/z 653 ([M]þ, 40%); 652 ([M ꢀ H]þ, 94%).
(100.65 MHz, DMSO-d6):
163.6 (CArePd); 153.2 (CAreCN); 136.4 (CeCl); 130.6 (CeCl);
d
(ppm) ¼ 177.2 (CeS); 163.7 (C]N);
3
4.1.2. Synthesis of N-(2-(diphenylphosphino)benzyl)propan-1-
amine (L3)
127.2 (Ca); 127.1 (Cb); 72.4 (d, JCP ¼ 7.40 Hz, NCH2N); 51.5 (d,
1JCP ¼ 15.5 Hz, PCH2N); 13.6 (CH3). 31P NMR (162.00 MHz, DMSO-
Compound L1 (0.0635 g, 0.192 mmol) was dissolved in dry
methanol (20 mL), followed by the slow addition of sodium boro-
hydride (0.0127 g, 0.336 mmol). The reaction mixture was stirred at
ambient temperature for 3 h. The solvent was removed, the con-
tents of the flask quenched with water (20 mL), and extracted with
dichloromethane (3 ꢂ 20 mL). The organic layer was collected,
washed with water (2 ꢂ 15 mL), and dried over anhydrous MgSO4.
The solvent was removed to afford a yellow oil which was dried in
vacuo. Yield: 0.0583 g, 91%. 1H NMR (399.95 MHz, CDCl3):
d6):
d
(ppm) ¼ ꢀ49.5. FT-IR (KBr, cmꢀ1):
¼ 3414 (m, NeH); 1624
n
(m, C]N); 1574 (w, C]N); 1488 (w, C]C aromatics). Elemental
analysis for C15H19Cl2N6PdPS: Found C 35.0, H 3.46, N 16.4, S
5.91%; Calculated C 34.4, H 3.66, N 16.0, S 6.12%. EIþ-MS: m/z 524
([M]þ, 4%).
4.1.5. Synthesis of [Pd(3,4-dichloropropiophenone
thiosemicarbazone)(PTA)] (4)
Compound 4 was synthesised following a procedure similar to
that described for 3. Compound 2 (0.0253 g, 0.166 mmol) was
reacted with PTA (0.109 g, 693 mmol) to yield a yellow solid.
Yield: 0.265 g, 74%. Melting point: 235.9e239.4 ꢁC. 1H NMR
d
(ppm) ¼ 7.58 (m, 1H, Hd); 7.40 (m, 1H, Hc); 7.23 (m, 10H, PPh2);
7.09 (t, 3JHH ¼ 7.64 Hz, 1H, Hb); 6.83 (dd, JHH ¼ 7.32, 4.39 Hz, 1H, Ha);
3.90 (s, 2H, ꢀCH2eN); 2.39 (t, 3JHH ¼ 7.40 Hz, 2H, NeCH2e); 1.72 (br
s, 1H, NH); 1.26 (m, 2H, eCH2e); 0.73 (t, 3JHH ¼ 7.44 Hz, 3H, eCH3).
(399.95 MHz, DMSO-d6):
d
(ppm) ¼ 7.27 (br s, 1H, Hb); 7.11 (br s,
13C NMR (75.46 MHz, CDCl3):
d
(ppm) ¼ 144.6 (d, JCP ¼ 24.1 Hz,
1H, Ha); 7.05 (s, 2H, NH2); 4.58 (d, JHP ¼ 12.8 Hz, 3H, NeCH2(eq)e
N); 4.44 (d, JHP ¼ 12.8 Hz, 3H, NeCH2(ax)eN); 4.26 (s, 6H, PCH2N);
2.70 (q, 3JHH ¼ 7.60 Hz, 2H, CH2); 1.02 (t, 3JHH ¼ 7.60 Hz, 3H, CH3).
2
C
C
AreCH2); 136.6 (d, 1JCP ¼ 10.1 Hz, PPh2); 135.6 (d, 1JCP ¼ 13.5 Hz,
2
ArePPh2); 133.9 (d, JCP ¼ 20.1 Hz, PPh2); 133.6 (Cd); 129.3 (d,
2JCP ¼ 5.20 Hz, Ca); 128.8 (Cc); 128.7 (PPh2); 128.5 (d, 3JCP ¼ 6.87 Hz,
PPh2); 127.1 (Cb); 52.7 (d, 3JCP ¼ 20.7 Hz, eCH2eN); 51.4 (NeCH2e);
23.2 (eCH2e); 11.9 (eCH3). 31P NMR (121.47 MHz, CDCl3):
13C NMR (100.65 MHz, DMSO-d6):
d
(ppm) ¼ 177.4 (CeS); 168.3
(C]N); 164.2 (CArePd); 151.9 (CAreCN); 136.6 (CeCl); 130.6 (Ce
Cl); 127.2 (Ca); 127.0 (Cb); 72.4 (d, 3JCP ¼ 7.40 Hz, NCH2N); 51.5 (d,
d
(ppm) ¼ ꢀ16.1. FT-IR (solution, CH2Cl2, cmꢀ1):
n
¼ 3405 (w, NeH).
1JCP
¼
15.5 Hz, PCH2N); 20.0 (CH2); 11.5 (CH3). 31P NMR
(162.00 MHz, DMSO-d6):
d
(ppm) ¼ ꢀ49.6. FT-IR (KBr, cmꢀ1):
4.1.3. Synthesis of N1,N4-bis(2-(diphenylphosphino)benzyl)
benzene-1,4-diamine (L4)
Compound L2 (0.0572 g, 0.0876 mmol) was dissolved in dry
dichloromethane:methanol (75:25% v/v, 20 mL), followed by the
n
¼ 3440 (br, NeH); 1641 (w, C]N); 1559 (w, C]N); 1497 (w, C]
C aromatics). Elemental analysis for C16H22Cl2N6PdPS: Found C
35.8, H 4.14, N 16.1, S 5.48%; Calculated C 35.7, H 4.12, N 15.6, S
5.95%. EIþ-MS: m/z 538 ([M]þ, 2.4%).

M. Adams et al. / Journal of Organometallic Chemistry 736 (2013) 19e26
25
4.1.6. Synthesis of [Pd(3,4-dichloroacetophenone
thiosemicarbazone)(N-(2-(diphenylphosphino)benzyl) propan-1-
amine)] (5)
cooling system (Oxford Cryostat). Cell refinement and data reduc-
tion were performed using the program SAINT [46]. The data were
scaled and absorption correction performed using SADABS [47]. The
structure was solved by direct methods using SHELXS-97 [47] and
refined by full-matrix least-squares methods based on F2 using
SHELXL-97 [47] and using the graphics interface program X-Seed
[48,49]. The programs X-Seed and POV-Ray [50] were both used to
prepare molecular graphic images. All non-hydrogen atoms were
refined anisotropically. All hydrogen atoms were placed at calcu-
Compound L3 (0.131 g, 0.393 mmol) was dissolved in dry
acetone (10 mL), followed by the addition of compound 1 (0.143 g,
0.0973 mmol). The reaction mixture was stirred at ambient tem-
perature for 3 h. The volume of the solution was reduced, and the
solid precipitated with the addition of hexane. The solid was pu-
rified using column chromatography (silica, Ethyl acetate:hexane,
1:1). The yellow powder was collected by suction filtration, and
washed with diethyl ether. Yield: 0.108 g, 40%. Melting point:
ꢀ
ꢀ
lated positions with CeH distances ranging from 0.95 A to 0.99 A
ꢀ
and NeH distance 0.88 A and refined as riding on their parent
179.7e184.1 ꢁC. 1H NMR (399.95 MHz, DMSO-d6):
d
(ppm) ¼ 7.74
atoms with Uiso (H) ¼ 1.2 or 1.5 Ueq (C or N).
(m, 1H, Hf); 7.49 (m, 11H, Hc & PPh2); 7.32 (t, 3JHH ¼ 7.70 Hz, 1H, Hd);
7.23 (s, 1H, Hb); 7.00 (m, 1H, He); 6.90 (br s, 2H, NH2); 6.13 (d,
4.3. Antiplasmodial screening
4JHP ¼ 3.85 Hz, Ha); 4.13 (s, 2H, eCH2eNH); 2.28 (m, 2H, NHeCH2e
3
CH2); 2.26 (s, 3H, CH3); 0.71 (t, JHH ¼ 7.28 Hz, 3H, CH2eCH3). 13
C
The test samples were tested in triplicate on one occasion
against chloroquine sensitive NF54 and chloroquine resistant Dd2
strain of P. falciparum. Continuous in vitro cultures of asexual
erythrocyte stages of P. falciparum were maintained using a modi-
fied method of Trager et al. [51] Quantitative assessment of anti-
plasmodial activity in vitro was determined via the parasite lactate
dehydrogenase assay using a modified method described by Makler
et al. [52] The test samples were prepared to a 20 mg/ml stock
solution in 100% DMSO and sonicated to enhance solubility. Sam-
ples were tested as a suspension if not completely dissolved. Stock
solutions were stored at ꢀ20 ꢁC. Further dilutions were prepared on
the day of the experiment. Chloroquine diphosphate (CQDP) was
used as the reference drug in the experiment. A full doseeresponse
was performed for all compounds to determine the concentration
inhibiting 50% of parasite growth (IC50 value). The samples were
tested at a starting concentration of 100,000 ng/ml, which was then
serially diluted 2-fold in complete medium to give 10 concentra-
tions; with the lowest concentration being 2 ng/ml. The same
dilution technique was used for all samples. The highest concen-
tration of solvent to which the parasites were exposed to had no
measurable effect on the parasite viability (data not shown). The
IC50 values were obtained using a non-linear doseeresponse curve
fitting analysis via Graph Pad Prism v.4.0 software.
3
NMR (100.65 MHz, DMSO-d6):
d
(ppm) ¼ 177.2 (d, JCP ¼ 9.43 Hz,
2
CeS); 172.4 (C]N); 163.7 (CArePd); 163.6 (d, JCP ¼ 4.70 Hz, CAre
3
CH2); 153.2 (CAreCN); 145.2 (d, JCP ¼ 11.4 Hz, Cf); 135.9 (d,
1JCP ¼ 8.10 Hz, CArePPh2); 135.0 (d, 1JCP ¼ 12.8 Hz, PPh2); 132.6 (Cc);
2
131.7 (Ce); 131.3 (CeCl); 130.8 (CeCl); 130.7 (d, JCP ¼ 8.10 Hz,
4
2
PPh2); 130.1 (d, JCP ¼ 3.40 Hz, PPh2); 129.3 (d, JCP ¼ 10.1 Hz, Ca);
3
127.2 (d, JCP ¼ 8.10 Hz, PPh2); 127.0 (Cd); 126.7 (Cb); 56.2 (NHe
CH2eCH2); 52.8 (d, 3JCP ¼ 12.8 Hz, CH2eNH); 51.5 (CH2eCH2eCH3);
13.7 (CH3); 12.0 (CH2eCH3). 31P NMR (162.00 MHz, DMSO-d6):
d
(ppm) ¼ 29.5. FT-IR (KBr, cmꢀ1):
¼ 3435 (w, NeH); 3318 (w, Ne
n
H); 1618 (m, C]N); 1582 (w, C]N). Elemental analysis for
C31H31Cl2N4PdPS$H2O$2C3H6O$½n-C6H14: Found C 50.8, H 5.17, N
5.92, S 3.59%; Calculated C 50.7, H 4.94, N 6.39, S 3.66%. ESIþ-MS: m/
z 700 ([M]þ, 45%); 701 ([M þ H]þ, 100%).
4.1.7. Synthesis of [Pd2(3,4-dichloroacetophenone
thiosemicarbazone)2(N1,N4-bis(2-(diphenylphosphino)benzyl)
benzene-1,4-diamine)] (6)
Compound L4 (0.0413 g, 0.0629 mmol) was suspended in an
acetone:dichloromethane (80:20% v/v, 10.0 mL) mixture, followed
by the addition of compound 1 (0.0459 g, 0.0313 mmol). The re-
action mixture was stirred at ambient temperature for 5 h. The
yellow powder was collected by suction filtration, washed with
hexane and diethyl ether, and dried in vacuo. Yield: 0.0507 g, 58%.
Melting point: 246.5e249.3 ꢁC. 1H NMR (399.95 MHz, DMSO-d6):
Acknowledgements
d
(ppm) ¼ 7.50 (m, 24H, Hc & Hf & PPh2); 7.35 (t, 3JHH ¼ 7.50 Hz, 1H,
Financial support from the University of Cape Town and the
National Research Foundation (NRF) of South Africa is gratefully
acknowledged. We thank the Anglo American Platinum Limited for
the kind donation of palladium salts. The South African Research
Chairs initiative of the Department of Science and Technology
administered through the NRF is gratefully acknowledged for
support (K.C.).
Hd); 7.21 (s, 1H, Hb); 7.08 (m, 1H, He); 6.91 (br s, 2H, NH2); 6.18 (d,
4JHP ¼ 3.70 Hz, Ha); 5.87 (s, 4H, HAr); 5.32 (br s, 2H, NH); 4.65 (br s,
2H, eCH2eNH); 2.24 (s, 3H, CH3). 13C NMR (100.65 MHz, DMSO-d6):
3
d
(ppm) ¼ 177.1 (d, JCP ¼ 10.1 Hz, CeS); 164.0 (C]N); 163.5 (d,
2JCP ¼ 4.71 Hz, CAreCH2); 163.3 (CArePd); 153.3 (CAreCN); 144.6 (d,
3JCP ¼ 11.4 Hz, Cf); 140.0 (NHeCH2e); 135.7 (d, 1JCP ¼ 7.40 Hz, CAre
PPh2); 135.0 (d, 1JCP ¼ 12.1 Hz, PPh2); 133.0 (d, JCP ¼ 3.40 Hz, Cc);
2
4
131.8 (Ce); 130.8 (CeCl); 130.3 (CeCl); 130.1 (d, JCP ¼ 3.89 Hz,
Appendix A. Supplementary material
2
3
PPh2); 129.3 (d, JCP ¼ 10.4 Hz, PPh2); 128.6 (d, JCP ¼ 8.17 Hz, Ca);
127.0 (d, 3JCP ¼ 10.8 Hz, PPh2); 126.8 (Cd); 126.5 (Cb); 114.0 (eCH2e
CCDC 923955, 923956 and 923957 contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
CH3); 47.9 (d, JCP ¼ 14.8 Hz, eCH2eNH); 13.8 (CH3). 31P NMR
3
(162.00 MHz, DMSO-d6):
d
(ppm) ¼ 29.0. FT-IR (KBr, cmꢀ1):
n
¼ 3483 (w, NeH); 3380 (w, NeH); 1597 (m, C]N); 1574 (w, C]N).
Elemental analysis for C62H52Cl4N8Pd2P2S2$½H2O: Found C 53.6, H
4.13, N 7.52, S 3.92%; Calculated C 53.2, H 3.75, N 8.01, S 4.58%. ESIþ-
MS: m/z 1391 ([M þ H]þ, 12%); 1390 ([M]þ, 10%).
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