Synthesis and characterization of disubstituted arylcyanoximes and their several metal complexes

Article abstract of DOI:10.1016/j.ica.2007.10.019

A series of new disubstituted halogenated arylcyanoximes was synthesized using nitrosation reaction of the respective phenylacetonitriles by CH₃-ONO at room temperature in isopropanol. Six synthesized colorless arylcyanoximes containing two F and/or Cl atoms at 2-, 4-, 5- and 6-positions were characterized by means of NMR, IR, UV-Vis spectroscopy and pK_a studies. Crystal structures were determined for four cyanoximes and revealed the presence of only the syn-isomers for fluorinated compounds in a solid state, while the chlorinated arylcyanoxime exists as anti-isomer in the crystal. However, five out of the six protonated arylcyanoximes HL exist as a mixture of syn- and anti-isomers in solutions. Deprotonation of HL with NaOC₂H₅ in ether solutions leads to yellow NaL which were used as precursors for the synthesis of a series of monovalent Ag, Tl and bivalent Pd, Pt complexes. Seven palladium and platinum arylcyanoximates of [M(HL)₂Cl₂] composition were synthesized and characterized. Obtained colored compounds are non-electrolytes in solution. However, in EtOH and DMSO solutions Pt(II) cyanoximates undergo two consecutive solvolysis reactions. First order rate constants were measured at 294 K for complexes in both solvents. Binding modes of the cyanoxime ligands and the possible solid state structures of the obtained coordination compounds are suggested on a basis of their IR spectra and MM-2 calculations. Because of their structural resemblance to the cisplatin family of anticancer drugs, synthesized Pd/Pt arylcyanoximates were tested in vitro against human colon carcinoma WiDr cell line using cis-[Pt(NH₃)₂Cl₂] as positive control. Results showed that two Pd(II) and Pt(II) cyanoximates containing oximino(2,4-dichlorophenyl)acetonitrile exhibit cytotoxicity at 0.25 mM concentrations.

Full text of DOI:10.1016/j.ica.2007.10.019

Available online at www.sciencedirect.com
Inorganica Chimica Acta 361 (2008) 1983–2001
www.elsevier.com/locate/ica
Synthesis and characterization of disubstituted arylcyanoximes
and their several metal complexes
a,
a
b
c
Nikolay Gerasimchuk *, Leon Goeden , Paul Durham , Charles Barnes ,
d
e
e
John F. Cannon , Svitlana Silchenko , Ismael Hidalgo
a
Department of Chemistry, Temple Hall 456, Missouri State University, Springfield, MO 65897, USA
b
Biology Department, Temple Hall 234, Missouri State University, Springfield, MO 65897, USA
Department of Chemistry, University of Missouri-Columbia, Chemistry Building 125, Columbia, MO 65211, USA
c
d
Department of Chemistry and Biochemistry, Brigham Young University, Benson Science Building 100, Provo, UT 84602, USA
e
Absorbtion Systems, Inc., 436 Creamary Way, Suite 600 Exton, PA 19341-2554, USA
Received 8 August 2007; accepted 9 October 2007
Available online 24 October 2007
Dedicated to Prof. Anatoliy Brusilovets (Kiev State University) on occassion of his retirements
Abstract
A series of new disubstituted halogenated arylcyanoximes was synthesized using nitrosation reaction of the respective phenylaceto-
nitriles by CH3–ONO at room temperature in isopropanol. Six synthesized colorless arylcyanoximes containing two F and/or Cl atoms
at 2-, 4-, 5- and 6-positions were characterized by means of NMR, IR, UV–Vis spectroscopy and pKa studies. Crystal structures were
determined for four cyanoximes and revealed the presence of only the syn-isomers for fluorinated compounds in a solid state, while the
chlorinated arylcyanoxime exists as anti-isomer in the crystal. However, five out of the six protonated arylcyanoximes HL exist as a mix-
ture of syn- and anti-isomers in solutions. Deprotonation of HL with NaOC2H5 in ether solutions leads to yellow NaL which were used
as precursors for the synthesis of a series of monovalent Ag, Tl and bivalent Pd, Pt complexes. Seven palladium and platinum arylcy-
anoximates of [M(HL)2Cl2] composition were synthesized and characterized. Obtained colored compounds are non-electrolytes in solu-
tion. However, in EtOH and DMSO solutions Pt(II) cyanoximates undergo two consecutive solvolysis reactions. First order rate
constants were measured at 294 K for complexes in both solvents. Binding modes of the cyanoxime ligands and the possible solid state
structures of the obtained coordination compounds are suggested on a basis of their IR spectra and MM-2 calculations. Because of their
structural resemblance to the cisplatin family of anticancer drugs, synthesized Pd/Pt arylcyanoximates were tested in vitro against human
colon carcinoma WiDr cell line using cis-[Pt(NH3)2Cl2] as positive control. Results showed that two Pd(II) and Pt(II) cyanoximates con-
taining oximino(2,4-dichlorophenyl)acetonitrile exhibit cytotoxicity at 0.25 mM concentrations.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: Cyanoximes; Silver(I); Thallium(I); Palladium(II); Platinum(II); IR-, NMR, UV–Vis spectroscopy; X-ray analysis
1. Introduction
between different subclasses of oximes and their precursors
is shown in Scheme 1. Cyanoximes-compounds with gen-
eral formula HO–N@C(CN)–R (R = electron withdrawing
group)-represent a new class of biologically active mole-
cules [5] that are capable of binding to different metal ions
[6]. Presence of the CN-group significantly increases their
acidity and makes them better ligands as compared to con-
ventional monoximes. Organic compounds that contain
˜N–NO or ˜C@N–O fragments have been known to be
Oximes represent versatile organic molecules that were
extensively used as excellent ligands in analytical [1], inor-
ganic [2,3] and bioinorganic chemistry [4]. The relationship
*
Corresponding author. Tel.: +1 417 836 5165; fax: +1 417 836 5507.
E-mail address: NNGerasimchuk@missouristate.edu (N. Gerasim-
chuk).
0020-1693/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2007.10.019

1984
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
biologically active compounds. Thus, N-oxides and N-
ketone
R'
acetonitrile
NC
aldehyde
nitrosoureas represent established anticancer drugs
Tirapazamineꢁ [7], Lomustineꢁ and Carmustineꢁ [8],
KF25706 [9] (Scheme 2A), while oximes are known antibi-
otics Althyomycin [10] and Caerulomycin [11], insecticides
[12], antimicrobial [13,14] and growth-regulating agents
[5] (Scheme 2B). The activity of the Caerulomycin family
of antibiotics is attributed to their irreversible binding as
tridentate chelating ligands biologically important metal
ions such as Zn, Fe and Co (Scheme 2B). Some of the
arylcyanoximes also have shown interesting biological
activity [15]. However, their metal complexes have not been
examined on that matter since they are largely unknown.
Synthesis and investigation of spectroscopic and structural
properties of a group of Tl(I) arylcyanoximates was
recently published [16]. Continuous search for new ligands
H
R
R
R
O
O
H
R
R'
R
NC
HO
R
N
N
N
HO
HO
aldoxime
ketoxime
cyanoxime
Scheme 1.
_
A
O
+
N
O
O
Cl
Cl
Cl
+
N
H
N
N
N
H
N
N
N
NH
2
O_
O
O
carmustine
lomustine
tirapazamine
B
antibiotics:
OH
H
OCH
3
O
O
N
OR
N
N
H
N
S
N
HO N
H
H
OCH
3
N
S
O
N
HO
Caerulomycin B (R=H) and
Caerulomycin C (R=CH3)
Althiomycin
new anticancer drug:
incecticides:
OH
N
CH
R'
N
3
OH O
O
SR'
R
R, R' R" = alkyl;
X = O, S
R"
R"
O
O
HO
O
Cl
N
R'
N
N
X
SR'
R
OH
KF 25706
thioximes and their esters
growth regulating and
antimicrobial agents:
herbicide antidots:
R
R
X
X
NC
N
R = H, CH
X = O, S
NC
HO
3
X
N
X = O, S, NH, N-CH
N
HO
3
2-hetarylcyanoximes
amide-cyanoximes
Scheme 2.

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1985
for potential Zn-dependent metallo-proteases inhibitors
and cytotoxic metallocomplexes has warranted exploration
of new organic ligands and investigation of their metal
complexes.
In this paper we report: (1) synthesis and characteriza-
tion of a series of new disubstituted arylcyanoximes, their
Na+, Tl+ salts, Ag+ and bivalent palladium and platinum
complexes, and (2) results of in vitro cytotoxicity evaluation
of the obtained bivalent Pd and Pt compounds against
WiDr human colon carcinoma cell line.
3 was reached. The data from all three titration curves were
analyzed using the RefinementPro software (provided with
the Sirius Analytical Instruments multifunctional titration
station) and presented in Table 1. Results indicate that
studied compounds represent weak organic acids as com-
pared to benzoic acid and its derivatives, but similar in
strength with substituted phenols. At the same time pro-
tonated disubstituted arylcyanoximes, due to the presence
of the CN-group, by a factor of ꢀ10000 stronger acids
than conventional monoximes and dioximes [20]. No direct
correlations between the number of halogen atoms
attached to the phenyl group, or their positions, or Ham-
mett parameters [21] and pKa values of the arylcyanoximes
were found at present time. Solutions of disubstituted
arylcyanoximes in ethanol, acetone and DMSO are non-
electrolytes evidencing the absence of ionization.
2. Results and discussion
2.1. Characterization of new cyanoxime ligands
2.1.1. Acid–base properties of the arylcyanoximes in
solutions
In general, values of acidity for the arylcyanoximes were
not known prior to this study. This group of organic
ligands only recently has been synthesized [17] and their
metal binding properties just started to be examined
[18,19]. Since the solubility of protonated disubstituted
arylcyanoximes HL was found to be low, CH3OH was cho-
sen as a co-solvent for pKa studies. Potentiometric titration
of HL was conducted in triplicate using ꢀ2 mg samples
which were first dissolved in 5 mL of 80% aqueous metha-
nol with the following addition of 9 mL of DI water. The
pH of the system was automatically adjusted to 11 by add-
ing of 0.5 M KOH solution. The titration with 0.5 M HCl
solution was performed automatically until the pH value of
2.1.2. NMR spectra
1
The exact assignment of signals in H and 13C NMR
spectra was carried out using 2D COSY and HMQC meth-
ods. Five out of six synthesized dihalogen substituted arylc-
yanoximes demonstrate in solutions the presence of both
syn- and anti-isomers. Thus, 13C{1H} NMR spectra of pro-
tonated arylcyanoximes HL in DMSO-d6 solutions contain
a double set of signals with the exception of H(2,5-diF-
PhCO), representing a monoisomeric compound. The exact
assignment of the NMR signals of the individual isomers
within the mixture was conducted for H(2,4-diCl-PhCO)
and H(2,4-diF-PhCO) (since those molecules contain sensi-
tive to the syn-configuration hydrogen atoms at ortho-posi-
tion) using 2D NOE and HMQC (1H–13C) correlation
experiments. Proton NMR spectra of the arylcyanoxi-
mes—that represents an isomeric mixture in dry DMSO-
d6—also show the presence of two broadened signals at
ꢀ14 ppm at room temperature. Contrary to the several
cyanacetamides [22], there is no thermally induced inter-
conversion of isomers in the mixture (Scheme 3A). For
example, the ratio between isomers does not change upon
heating the DMSO solutions of H(2,4-diCl-PhCO) and
H(2,6-diCl-PhCO) up to 120 ꢂC, evidencing the coexistence
of both isomers in solutions. The ratio between syn- and
Table 1
pKa values for synthesized dihalogen-substituted arylcyanoximes mea-
sured at 25 1 ꢂC
Compound
pKa
H(2,4-diF-PhCO)
H(2,6-diF-PhCO)
H(2,5-diF-PhCO)
H(2Cl-6F-PhCO)
H(2,4-diCl-PhCO)
H(2,6-diCl-PhCO)
6.49 0.04
6.28 0.01
6.52 0.01
5.93 0.01
6.44 0.02
6.17 0.01
Hal
Hal
A
+ t
NC
N
Hal
NC
N
Hal
Hal = F and Cl atoms at
2,4-, 2,5- and 2,6-, positions
HO
OH
syn-
anti-
B
_
N
Hal
Hal
Hal
Hal
Hal
NC
N
Hal
NC
Hal
NC
N
Hal
+ base
C
N
Hal
NC
N
Hal
_
_
_
- baseH+
O
O
N
O
HO
O
colorless
yellow
Scheme 3.

1986
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
Y
Y
Y
A
anti-
F
X
X
X
1) +HCl, pH~4
+ Na, + R-ONO
R.T., +N2
syn-
anti-
F
2) - NaCl, + ether (extr.)
F
i-PrOH;
N
CN
CN
N
CN
N
CN
F
O-Na+
OH
OH
HO
syn-
N
CN
X and Y are: F and Cl atoms at 2,4-, 2,5- and 2,6-positions
+20oC
+30oC
+40oC
+50oC
F
F
F
F
F
F
CN
N
CN
CN
N
N
14.4
14.0
13.6
OH
OH
OH
Chemical shift (ppm)
H(2,4-diF-PhCO)
H(2,6-diF-PhCO)
H(2,5-diF-PhCO)
B
anti-
Cl
syn-
F
F
anti-
syn-
N
CN
F
Cl
CN
Cl
Cl
CN
Cl
F
HO
F
OH
N
CN
N
N
CN
N
OH
OH
OH
+20oC
H(2Cl-6F-PhCO)
H(2,4-diCl-PhCO)
H(2,6-diCl-PhCO)
+30oC
+50oC
Scheme 4.
anti-isomers and an effect of heat on solutions of other cyan-
oximes in DMSO-d6 is present in SM 1 (Supplementary
material). At the same time, the variable temperature H
1
14.8
14.4
14.0
NMR spectra of fluorinated compounds—such as H(2,4-
diF-PhCO), H(2,6-diF-PhCO), and H(2Cl-6F-PhCO) in
DMSO solutions—demonstrates the coalescence of signals
that correspond to the protons of the oxime groups
(Fig. 1), indicating proton exchange between the two iso-
mers. 13C NMR spectra of solutions of these compounds still
show two sets of signals at elevated temperatures. By using
the values of peaks’ separation of individual isomers in the
absence of exchange and coalescence temperatures the ther-
modynamic parameters for the process (Table 2) were calcu-
lated using the following equations:
Chemical shift (ppm)
Fig. 1. Fragments of variable temperature 1H NMR spectra of H(2,4-diF-
PhCO) (A) and H(2,6-diF-PhCO) (B) in DMSO-d6 at room temperature
showing proton exchange between the two isomers.
cyclization reaction with the formation of halogen-substi-
tuted benz(isoxazoles) [18] (SM 2). A detailed description
of these interesting reactions is out of the scope of this
paper and publication of these results is forthcoming.
pffiffiffi
ꢀ
ꢁ
2.1.3. Structures of protonated ligands
¼
2
kBTc
h
ꢁDG
Þ
eð
RT
c
kc ¼ p
ðva ꢁ vbÞ kc ¼ v
The crystal structures of four out of six new dihalogen-
substituted arylcyanoximes were determined (Table 3). The
top and side views of these molecules are presented in
Fig. 2 and the geometrical parameters of the cyanoxime
fragment are shown in Table 4. There are two crystallo-
graphically independent molecules in the structure of
H(2,6-diF-PhCO). Both adopt the same configuration
and have similar geometries. All studied compounds are
non-planar and show different values of dihedral angles a
between planar haloaryl- and cyanoxime-fragments reflect-
ing the steric bulkiness of the haloaryl-group at 2- and 2,6-
positions. The smallest value of a = 43.7ꢂ was determined
2
va and vb frequencies of individual signals
kc
kB
Tc
h
rate of proton exchange
Bolzmann constant
coalescence temperature
Plank’s constant
Interestingly, heating of the DMSO solutions of the fluo-
rinated compounds such as H(2,4-diF-PhCO), H(2,6-diF-
PhCO) and H(2Cl-6F-PhCO) resulted in intramolecular

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1987
Table 2
for the H(2,5-diF-PhCO) which has free of halogen atom 6-
position. The H(2,6-diCl-PhCO) has the largest value of
dihedral angle a = 77.1ꢂ (Fig. 2) having the two chlorine
atoms at both 2- and 6-positions on the phenyl group. It is
important to note that all fluorinated arylcyanoximes adopt
in the crystal state a rare syn-configuration. Only one similar
configuration was documented earlier for the 2-oximino-
cyanomethyl(4-methylthiazole), HTLCO [23]. Valence
angles between the N1–C7–C(phenyl group) in fluorinated
cyanoximes with syn-geometry are less than expected 120ꢂ
angles for the sp2-hybridized carbon atom (Table 4). H-bon-
Thermodynamic parameters for proton exchange between the two isomers
in DMSO-d6 solutions of fluorinated disubstituted arylcyanoximes
obtained from variable temperature 1H NMR experiments
b
Compound
Dma (Hz)
Tc (ꢂC)
kc (sꢁ1
)
DEc (KJ/mol)
H(2,6-diF-PhCO)
H(2,4-diF-PhCO)
H(2Cl-6F-PhCO)
a
42.1
63.5
129.5
30
40
70
94
141
287
62
63
68
1
1
1
Separation of signals in the absence of fast exchange at room
temperature.
b
Coalescence temperature.
Value of the activation energy DE was set here as equal to DG value.
c
¼
Table 3
Crystal data and structure refinement for the obtained new disubstituted arylcyanoximes
Parameter
H(2,5-diF-PhCO)
H(2,6-diF-PhCO)
H(2Cl-6F-PhCO)
H(2,6-diCl-PhCO)
Chemical formula
Formula weight (g/M)
Experiment temperature (K)
Crystal system
C8H4F2N2O
182.13
173(2)
monoclinic
P21/n
C8H4F2N2O
182.13
296(2)
monoclinic
P21/n
C8H4ClFN2O
198.58
173(2)
monoclinic
C2/c
C8H4Cl2N2O
215.03
173(2)
tetragonal
P4321
Space group
˚
a (A)
3.7176(4)
16.8592(19)
12.3818(14)
90
95.904(2)
90
771.92(15)
4
1.567
7.6997(17)
17.156(3)
12.2802(17)
90
98.916(14)
90
1602.5(5)
8
1.510
9.2125(15)
11.5840(19)
16.204(3)
90
103.152(3)
90
1683.9(5)
8
1.567
7.8047(9)
7.8047(9)
31.713(7)
90
90
90
1931.8(5)
8
1.479
0.630
864
˚
b (A)
˚
c (A)
a (ꢂ)
b (ꢂ)
c (ꢂ)
3
˚
Volume (A)
Z
Dcalc (Mg/m3)
Absorption coefficient (mmꢁ1
F(000)
)
0.139
368
0.134
736
0.426
800
Final R indices [I > 2r(I)]
R indices (all data)
R1 = 0.0487
R1 = 0.0907
R1 = 0.0482
R1 = 0.1007
R1 = 0.444
R1 = 0.0489
R1 = 0.0619
R1 = 0.0769
Fig. 2. Molecular structures of dihalogen substituted arylcyanoximes: (A) – H(2,5-diF-PhCO), (B) – H(2,6-diF-PhCO), (C) – H(2Cl-6F-PhCO),
(D) – H(2,6-diCl-PhCO); an ORTEP drawing at 50% probability of thermal ellipsoids.

1988
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
Table 4
Selecteda bond lengths and valence angles (ꢂ) for the cyanoxime fragment in several structurally characterized disubstituted arylcyanoximes
˚
˚
Distance (A)
Angle (ꢂ)
Distance (A)
Angle (ꢂ)
H(2,5-diF-PhCO)
O(1)–N(1) 1.369
N(1)–C(7) 1.293
N(2)–C(8) 1.141
C(1)–C(7) 1.486
C(7)–C(8) 1.448
H(2,6-diF-PhCO)
O(1)–N(1) 1.362
N(1)–C(7) 1.287
N(2)–C(8) 1.136
C(4)–C(7) 1.477
C(7)–C(8) 1.441
C(7)–N(1)–O(1) 111.7
N(1)–C(7)–C(8) 112.1
N(1)–C(7)–C(1) 129.2
C(8)–C(7)–C(1) 118.7
N(2)–C(8)–C(7) 178.2
C(7)–N(1)–O(1) 111.4
N(1)–C(7)–C(8) 114.2
N(1)–C(7)–C(4) 128.2
C(8)–C(7)–C(4) 117.6
N(2)–C(8)–C(7) 175.9
H(2Cl-6F–PhCO)
O(1)–N(1) 1.364
N(1)–C(7) 1.289
N(2)–C(8) 1.139
C(1)–C(7) 1.484
C(7)–C(8) 1.447
a
H(2,6-diCl-PhCO)
O(1)–N(1) 1.352
N(1)–C(7) 1.323
N(2)–C(8) 1.134
C(1)–C(7) 1.474
C(7)–C(8) 1.439
C(7)–N(1)–O(1) 112.6
N(1)–C(7)–C(8) 111.9
N(1)–C(7)–C(1) 127.9
C(8)–C(7)–C(1) 120.1
N(2)–C(8)–C(7) 178.9
C(7)–N(1)–O(1) 108.1
N(1)–C(7)–C(8) 124.0
N(1)–C(7)–C(1) 116.2
C(8)–C(7)–C(1) 119.8
N(2)–C(8)–C(7) 177.2
Geometry of the phenyl group with attached halogen atoms is normal and not shown.
ing is essential for packing the arylcyanoximes into crystal.
Thus, infinite polymeric chains of molecules are formed
due to the H-bonds between the nitrogen atoms of the cyano-
and the oxime groups in all structurally characterized arylc-
yanoximes (Fig. 3). A ‘‘slipped’’ p–p stacking interactions
between the haloaryl-fragments provide additional stabiliza-
tion of the structures in all cases and are responsible for the
interesting lattice architecture.
formation of a yellow conjugated anionic species (Scheme
3B). Contrary to sodium salts, tetrabutylammonium cya-
noximates were not isolated in a solid state; rather, they
were studied in solutions. The color of anions originates
from n ! p* transition in the nitroso-chromophore [24]
with typical values of the molar extinction e ranging from
20 to 200 dm3 cmꢁ1 Mꢁ1. A position of this transition in
UV–Vis spectra is solvent dependent [22,25,26] (SM 3).
Thus, all six dihalogen-substituted anionic arylcyanoximes
clearly exhibit a negative solvatochromic effect [27] associ-
ated with polarity difference in molecules being in ground
and excited states. The alkali metal salts ML of other ionic
cyanoximates [28] in solid state adopt planar structures in
which bond lengths indicate conjugation between func-
tional groups in the anions. The delocalization of a nega-
tive charge throughout the anion can be described using
several resonance forms (Scheme 3B) where most of them
have nitroso character [29,30]. New arylcyanoximes dis-
cussed in this paper follow the same trend (SM 4). It is
important to note in context of the charge delocalization
and conjugation discussion that the 13C NMR spectra of
ionic NaL (L = synthesized dihalogen-substituted arylc-
yanoximes) in DMSO-d6 contain only one set of signals,
reflecting the absence of syn-/anti-isomerism in anionic spe-
cies due to rotation around C–NO bond (Scheme 3B).
2.1.4. Anionic cyanoximes
The deprotonation of colorless cyanoximes with
N(C4H9)4OH in solutions in different solvents leads to a
2.2. Characterization of metal complexes
2.2.1. Sodium salts and monovalent Tl and Ag complexes
Synthesized dihalogen-substituted arylcyanoximes rep-
resent weak organic acids able to bind different metal ions.
Thus, arylcyanoximes easily form ionic salts of ML compo-
sition (M = Na+, Tl+) and covalent AgL complexes [16–
19].
Sodium and thallium(I) salts form 1:1 eletrolytes in
water, DMSO, EtOH and DMF evidencing complete dis-
sociation of these ionic salts in solutions. The m(N–O)
vibrations of the oxime group in the IR spectra are of high
intensity due to a significant change in the dipole moment,
while m(C@N) vibrations have medium to low intensity in
the IR spectra [31]. Both these vibrations do not have
Fig. 3. Hydrogen bonding in the structure of anti-H(2,6-diCl-PhCO) (A)
and crystal packing diagram for syn-H(2,5-diF-PhCO) (B).

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
, cm-1
1989
ν
1400
1300
1200
1100
1000
900
1600
1500
ν
(C=N)
HL
ν
(N-O)
R
NC
HO
C
N
ML
_
R
NC
O
C
N
as(CNO)
ν
s(CNO)
ν
M = Na+, K+, Rb+, Cs+
Scheme 5.
defined place in the IR spectra of the protonated arylcyan-
oximes HL, and typically move in the range up to ꢀ150
cmꢁ1 in both directions from their position observed in
acetone–oxime, (CH3)2C@N–OH [31,32]. Deprotonation
of the ˜C@N–OH group of cyanoximes leads to significant
redistribution of the electron density and change position
of bands in the IR spectra of the ionic Na+ salts (Scheme
5; SM 5–7). Since the electron density (and bond lengths
[28,33]) in the CNO fragment in the anions Lꢁ practically
leveled, the assignment of vibrations was suggested by
Ko¨hler [34] and Lampeka [35] to be as asm(CNO) and
sm(CNO), respectively.
Both sodium and thallium salts possess yellow color due
to the n!p* transitions in the ˜C–NO chromophores of
the cyanoxime anions. Unfortunately, in spite of numerous
efforts, we did not succeed in growing suitable for the X-ray
analysis crystals of the TlL and AgL. Therefore, binding
mode of anions in these complexes was deduced after anal-
ysis of their IR spectra (Table 5; and SM 5–7) using previ-
ously established spectroscopic criteria for the oxime/
nitroso-group coordination [32,36–40]. No change in inten-
sity and position of the m(C„N) stretching vibrations in
spectra of NaL and TlL indicated absence of the anion
binding via cyano-group in the latter compounds. Values
of frequencies for both vibrations with participation of
the oxime group for the obtained in this work TlL are prac-
tically identical to those for structurally characterized thal-
lium(I) complexes with monosubstituted arylcyanoximes
[16,17]. Therefore, we suggest for the disubstituted arylc-
yanoximes reported in this work binding mode III (Table
5) in their Tl(I) complexes which have structural motif
depicted in Scheme 6A.
conductivity is lower than expected for the 1:1 electrolytes
indicating partial dissociation of compounds which reflects
stronger binding between Ag+ and arylcyanoxime anion.
Silver(I) complexes of disubstituted arylcyanoximes also
possess yellow-orange color and were found to be very light
sensitive. Careful analysis of the IR spectra of AgL con-
cluded that they have positions of the asm(CNO) and
sm(CNO) vibrations similar to those in Ag(ECO)
[ECO@NC–C(NO)–C(O)OEt] [41] crystal structure of
which recently has been determined [42]. Thus, there is
ꢀ20–40 cmꢁ1 increase in frequency of the m(C„N) stretch
in the IR spectra of described here silver(I) disubstituted
arylcyanoximates in comparison with their ionic Na-salts.
This high energy shift unequivocally indicates the partici-
pation of the cyano-group in coordination [43]. Both
sm(CNO) and sm(CNO) vibrations underwent ꢀ30
10 cmꢁ1 decrease in frequencies consistent with engage-
ment of the nitroso-group into metal binding type V (Table
6). This is a clear manifestation of the bridging function of
the cyanoxime anion using both nitrogen and oxygen
atoms of the CNO-group parallel to that in Ag(ECO)
(SM 20) and other silver(I) cyanoximates [33,44]. Similari-
ties of their IR spectra allowed us to suggest polymeric
structure of the AgL (L = disubstituted arylcyanoximates)
presented in Scheme 6B leaving the proof of correctness for
such assessments to be validated when crystallographic
information will become available.
Numerous attempts to synthesize bivalent first row tran-
sition metal complexes (Co, Cu, Fe and Ni) did not lead to
isolable stoichiometric compounds. We attribute this fact
to inability of disubstituted arylcyanoximes to act as che-
lating ligands, therefore, causing instability of the formed
metal complexes containing monodentate oxime ligand in
solutions.
Six silver(I) complexes also form conductive solutions in
polar aprotic donor solvents, but the value of electrical

1990
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
Table 5
tion metal complexes have [M(HL)2Cl2](H2O)n composi-
tion (M = Pd, Pt; n = 0 or 1). These compounds have
received special attention in our work due to their resem-
blance of famous cisplatin family anticancer drugs.
Results of IR spectroscopic studies of synthesized disubstituted arylcyan-
oximes and their metal derivatives
Ligand
Compound
Assigned frequencies, cmꢁ1 in the:
Cyano-group CNO-fragment
2.2.3. Solid state IR-spectroscopy
m(C„N)
m(C@N) m(N–O)
Despite numerous attempts, we were unable to grow sin-
gle crystals of Pd/Pt arylcyanoximates suitable for X-ray
analysis. Therefore, structural considerations (such as the
binding mode of the cyanoxime ligand to the metal center)
for the obtained transition metal complexes were made
upon careful analysis of their solid state IR spectra. The
results of the IR spectroscopic investigation of the obtained
ligands HL and their Pd/Pt-derivatives are summarized in
Table 5, while the rest of the data can be found in SM
5–7. Contrary to the amide-cyanoximes [22,25,45] mono-
substituted and disubstituted arylcyanoximes are not capa-
ble of forming chelate rings: they belong to a group of
ligands that use exclusively the oxime group for coordina-
tion to the metal center [17,18]. A schematic representation
of established coordination modes for oximes is shown in
Table 6. These coordination modes were directly linked
to their IR spectroscopic signatures. Summarized in
Table 6 observations were made using 15N labels incorpo-
rated into the ˜CNO-group and also based upon a compar-
ison of crystallographic data with available spectroscopic
information and theoretical calculations [32,36–40]. The
binding mode II (Table 6) of the cyanoxime ligands in syn-
thesized Pd(II) and Pt(II) complexes presented in this paper
was deduced according to the established criteria of the
cyanoximes coordination [39], extensive literature data
for other transition metal complexes [46], and carried out
in this work MM-2 calculations. The solutions’ electrical
conductivity studies evidenced the non-electrolyte nature
of the obtained complexes and suggest the binding mode
II for the compounds (Table 6).
F
HL
NaL
TlL
AgL
2240
2222
2207
2238
2218
1478
1182a
1413
1256a
1423
983
1010a
1105
1112a
986
F
Pt(HL)2Cl2H2O
CN
N
OH
HL
2250, 2235b
2210
2208
2246
1411
981
1014a
1138
1110a
1004
NaL
TlL
AgL
1170a
c
F
F
–
1252a
1440
CN
N
Pd(HL)2Cl2 Æ xH2O 2214
OH
HL
2246
1408
978
1005a
1142
1118a
1010
NaL
TlL
AgL
2206, 2215b
2212
1165a
c
F
F
Cl
CN
–
2234
1254a
1390
N
Pt(HL)2Cl2 Æ xH2O 2210
OH
HL
NaL
TlL
AgL
Pt(HL)2Cl2
Pd(HL)2Cl2
2246
2214
2210
2248
2234
2234
1475
1009
1030a
1143
1120a
1002
1004
1170a
c
F
1255a
1470
1470
CN
N
OH
Cl
HL
NaL
TlL
AgL
Pt(HL)2Cl2
Pd(HL)2Cl2
2194
2202
2202
2238
2220
2218
1405
980
1000a
1137
1128a
981
1170a
c
1263a
1420
1430
Cl
CN
N
994
OH
HL
2248
2210
2208
2246
1350
1155
c
973
1068
1152
1117
2.2.4. Platinum group metal complexes in solutions
NaL
TlL
AgL
Synthesized bivalent Pt and Pd disubstituted arylcya-
noximates are soluble in ethanol, acetone and DMSO. Sta-
bility and integrity of metal complexes in solutions is an
important issue that has implications on biological studies
[47]. Therefore, we investigated the behavior of several
coordination compounds in solutions during 24 h using
methods of UV–Vis spectroscopy, and electrical conductiv-
ity measurements in absolute ethanol and DMSO. Data of
the latter method for 1 mM solutions of Pd/Pt arylcyanox-
imates in ethanol and DMSO evidenced the non-electrolyte
nature of the obtained complexes with insignificant (<10%)
conductivity rising during that time period (SM 8). Careful
analysis of UV–Vis spectra of the same complex com-
pounds in ethanol and DMSO indicated the presence of
two close isosbestic points that originated at different
times. A full set of recorded in kinetic mode UV–Vis spec-
tra for [Pt{H(2,4-diF-PhCO)}2Cl2] and [Pt{H(2,4-diCl-
PhCO)}2Cl2] is shown in SM 9 and SM 10, while fragments
of selected spectra and monitored time traces are displayed
Cl
Cl
CN
1265
N
OH
Assigned as asm(CNO) and m(CNO) vibrations according to [34,35].
Perhaps due to two crystallographically different positions in the
a
s
b
lattice.
c
Overlapped with Nujol.
2.2.2. Bivalent Pd/Pt complexes
Only seven out of twelve palladium and platinum disub-
stituted arylcyanoximates were obtained from aqueous
solutions. It is noteworthy that the protonated HL do
not react with the transition metal sources K2[MCl4]
(M = Pd, Pt) in aqueous solutions. However, the anionic
cyanoximates do react with K2[MCl4] since Lꢁ are better
nucleophiles in substitution reactions at square-planar
metal centers. Synthesized and characterized seven transi-

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1991
Hal
Hal
A
Hal
Hal
N
C
C
N
N
N
O
O
Tl
Tl
Tl
Tl
O
O
n
N
N
N
N
C
C
Hal
Hal
Hal
Hal
B
Hal
Hal
Hal
Hal
Hal
Ag
Hal
C
C
C
N
N
N
Ag
N
Ag
N
N
Ag
O
O
O
Ag'
Ag'
Ag'
n
Scheme 6.
in Figs. 4 and 5. All kinetic experiments were conducted at
294 K three times.
Considering the results of an electrical conductivity
studies and data of UV–Vis spectroscopic observations, it
is evident that in ethanol and DMSO solutions two consec-
utive solvolysis reactions take place:
in ethanol (Table 7). At 21 ꢂC it takes 12–20 min to com-
plete the first ligand substitution reaction in pure DMSO,
which is consistent with the t1/2 values and is in agreement
with k1values observed by Lippard and co-workers [47] for
the trans-complexes of Pt(II). However, in our case solvent
molecules substitute the cyanoximes molecules, which,
apparently, are weakly bound to the metal center. It is
important to note that there were no changes observed in
UV–Vis spectra within 6 h when quickly prepared (ꢀ10 s;
0.1 mL) DMSO solutions of the Pt cyanoximates were
mixed with water (3.0 mL) in the cuvette. Therefore,
DMSO solutions of bivalent Pd and Pt complexes for
in vitro cytotoxicity studies were quickly prepared fresh
each time prior to the testing, and immediately added to
the cell culture in order to avoid prolonged exposure of
compounds to organic solvent [47] as described in Section
3. Based on results of kinetic studies and literature data
(trans-effect) [48,49] we suggest the trans-geometry for the
obtained Pt(II) cyanoximates. Proton NMR spectroscopy
turned out to be not informative for studies of bivalent
platinum and palladium cyanoximates in solutions.
k1
½PtðHLÞ2Cl2ꢂ þ Solv !½PtðHLÞðSolvÞCl2ꢂ þ HL
ð1Þ
ð2Þ
k2
½PtðHLÞðSolvÞCl2ꢂ þ Solv !½PtðSolvÞ2Cl2ꢂ þ HL
HL = disubstituted arylcyanoxime ligands
Solv = EtOH, DMSO
Values of the first order rate constants for the observed
reactions 1 and 2 are shown in Table 7. In both studied sol-
vents the first cyanoxime substitution reaction is signifi-
cantly faster than the second reaction. Thus, in ethanol
solutions the second solvolysis reaction is slower ꢀ4.5
times for the [Pt{H(2,4-diF-PhCO)}2Cl2], and ꢀ10 times
for the [Pt{H(2,4-diCl-PhCO)}2Cl2] (Table 7). The differ-
ence in both steps of solvolysis is not great for DMSO solu-
tions: the reaction 1 is approximately 1.7 times faster than
the reaction 2. However, overall solvolysis of investigated
metal complexes in DMSO is considerably faster than that
2.2.5. Optimization of geometry: MM-2 calculations
The optimization of geometry MM-2 calculations were
carried out for two platinum complexes [Pt{H(2Cl-6F-

1992
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
Table 6
Binding modes of cyanoximes and related compounds in metal complexes
Ligand
status
Binding mode
Compound
Ref.
Oxime-form
SbPh4L (L = ACOꢁ, BCOꢁ, DCOꢁ)
SnMe3(TLCO)
[40,57]
[58]
R
I
Fe(TPP)(CCO)
[37]
N
O
NC
NC
M
Ni(DMG)2 DMG = dimethylglyoxime
PtHL(DMSO)Cl HL = phenylaldoxime
[46a,46b,46c]
[46d]
R
II
M
N
O
H
Tl(2Cl-PhCO)
Tl(4Br-PhCO)
[17]
[16]
R
III
N
NC
O
M
M
M
R
Nitroso-
form
NiEn2L2
[32]
[36]
[59]
[60]
[61]
IV
M(CCO){PPh3}2 (M = Pd, Pt; L = CCOꢁ)
ePy4(CCO)2
M
N
NC
Ni(ACO)2 Æ x2H2O
Cu(DCO)2 Æ xH2O
O
R
Ag(BCO), Ag(CCO)
Tl(PCO)
Tl(TDCO)
[44]
[39a]
[62]
M
N
NC
V
O
M
Tl(TLCO)
UO2L2
L = 1-nitroso-2-naphtol
[63]
[64]
R
N
NC
VI
M
O
CH3
Br
CH3
N
CH3
H2N
NC
O
S
N
N
S
N
O
N
CN
O
H3C
H3C
Cl
N
N
NC
N
NC
NC
N
NC
N
NC
N
NC
N
NC
N
NC
O-
OH
OH
OH
OH
OH
OH
OH
OH
CCO-
HTLCO
HACO
HPCO
HBCO
HTDCO
HDCO
H(2Cl- & 4Br-PhCO)
PhCO)}2Cl2] and [Pt{H(2,4-diCl-PhCO)}2Cl2] using PC
adapted the CACHE 6.0 program (Molecular Structure
Group, Fujitsu Inc.) and geometrical parameters for the
ligands available from their crystal structures [25]. This
program package has been known for its accurate predic-
tion [50] of geometry for both organic and coordination

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1993
Fig. 5. Solvolysis of 1 mM solution of [Pt{H(2,4-diCl-PhCO)}2Cl2]
in DMSO at 294 K. (A) – the reaction time trace monitored at 307 nm;
(B) – fragments of UV–Vis spectra recorded during the first 7 min with
shown inset for the first isosbestic point; (C) – fragments of spectra
recorded within the last 50 min of the reaction with the inset showing the
second isosbestic point.
Fig. 4. Solvolysis of 1mM solution of [Pt{H(2,4-diF-PhCO)}2Cl2] in
ethanol at 294 K. (A) – time trace at 295 nm; (B) – fragment of UV–Vis
spectra during first 180 min of the reaction with the inset indicating the
first isosbestic point; (C) – fragments of spectra recorded at later times
with the inset showing the second isosbestic point.
compounds. There were four principal initial settings used:
(1) a complex of the trans-geometry with the cyanoxime
molecule either in syn- or anti-configuration, and (2) a com-
plex of the cis-geometry with the cyanoxime molecule hav-
ing syn- or anti-configuration. All geometry optimizations
were carried out for the isolated (‘‘gas-phase’’) molecules
of coordination compounds without taking into consider-
ation any intermolecular interactions. The selection of the
particular structure was based on the calculated minimal
value of the molecule total formation energy after several
routes of geometry optimization when the program has
normally stopped. The general structural motif for the
obtained platinum group metal cyanoximates is shown in
Fig. 6. Suggested trans-geometry of Pt(II) arylcyanoxi-
mates is based on indirect evidence from kinetics of solvol-
ysis studies. It is interesting to note the pronounced

1994
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
Table 7
Values of the first order rate constants for solvolysis of two moderately in vitro cytotoxic Pt(II) cyanoximates in DMSO and ethanol at 294 K
Complex
Solvent
EtOH
DMSO
[Pt{H(2,4-diF-PhCO)}2Cl2]
[Pt{H(2,4-diCl-PhCO)}2Cl2]
k1 = 2.5 · 10ꢁ6 1.8 · 10ꢁ7
k1 = 9.6 · 10ꢁ5 2.7 · 10ꢁ7
k2 = 5.5 · 10ꢁ7 1.2 · 10ꢁ8
k2 = 5.9 · 10ꢁ5 3.5 · 10ꢁ7
k1 = 5.1 · 10ꢁ6 2.3 · 10ꢁ7
k2 = 5.0 · 10ꢁ7 1.4 · 10ꢁ8
k1 = 1.2 · 10ꢁ4 2.3 · 10ꢁ6
k2 = 7.2 · 10ꢁ5 6.2 · 10ꢁ7
attractive interactions between the oxime OH group and Cl
ions coordinated to Pt(II), or F atom on the aryl group of
the cyanoxime regardless of the syn-, anti-conformation of
the ligand or cis-, trans-geometry of the complex (Fig. 6,
SM 11 and SM 12).
thesized Pd and Pt cyanoximates was tested at
concentration 0.01 mM, 0.1 mM, 0.25 mM and 0.50 mM.
Protonated cyanoxime ligands HL itself did not show
any cytotoxicity.
The least active coordination compounds among studied
complexes were found to be Pd (II) and Pt(II) cyanoxi-
mates with the fluorinated ligands H(2,4-diF-PhCO) and
H(2,5-diF-PhCO). Bivalent palladium and platinum com-
plexes bearing chlorine-containing cyanoxime ligands
showed cytotoxicity with the most effective being
[Pt{H(2,4-diClPhCO)}2Cl2] and [Pd{H(2,4-diCl-PhCO)}2-
Cl2] at 0.25 mM concentration leading in a massive cell
death. These two complexes demonstrated antiproliferative
activity against WiDR cells found to be ꢀ20% of that for
cisplatin at similar conditions
2.2.6. In vitro antiproliferative activity studies for Pd(II)
and Pt(II) cyanoximates
Synthesized bivalent palladium and platinum cyanoxi-
mates of [M(HL)2Cl2] composition contained coordinated
chloride anion and resemble known cytotoxic cisplatin
family drugs. Therefore, it was interesting to examine anti-
proliferative activity for seven synthesized Pt(II) and Pd(II)
complexes using human cancer cells. We selected for these
studies colon carcinoma WiDR cells which are not resistant
to cisplatin. These are the first known arylcyanoximates
ever tested in vitro against human cancer cell line. Details
of the cytotoxicity protocol as well as relevant tables and
actual cell pictures are presented in SM 13–17 of Support-
ing material, respectively. The DMSO was found to be the
most suitable for making solutions for in vitro studies since
ethanol even at low concentrations exhibits certain cyto-
toxicity itself [51,52]. Antiproliferative activity of the syn-
3. Experimental
3.1. Solvents and reagents
Solvents used for carrying out reactions and crystalliza-
tions were HPLC grade and employed without further
purification. Acetone, ethanol and DMSO employed in
kinetic and conductivity studies were additionally dried
according to standard procedures [31]. The inorganic salts
of bivalent palladium and platinum were purchased from
Sigma–Aldrich: cis-diamineplatinum(II) dichloride (Sigma,
P
4394), potassium tetrachloropalladate(II) (Aldrich
#205796), and potassium tetrachloroplatinate(II) (Aldrich,
#20675), while metallic Na and NaNO2 were obtained
from FLUKA. The initial dihalogen-substituted phenyl-
acetonitriles NC–CH2–R can be synthesized using different
routes [17]. Commercially available precursors, such as 2,4-
dichlorophenylacetonitrile, 2,6-dichlorophenylacetonitrile,
2-chloro-6-fluorophenlyacetonitrile,
2,4-difluorophenyl-
acetonitrile, 2,5-difluorophenylacetonitrile, and 2,6-difluor-
ophenylacetonitrile from Sigma–Aldrich were of good
quality and were used in this work without additional
purification. Neat organic nitrite CH3–ONO was obtained
fresh before every nitrosation reaction according to pub-
lished procedures [53]. The organic base used for deproto-
nation of ligands during UV–Vis spectroscopic studies was
tetrabutylammonium hydroxide as 1.0 M solution in
methanol (Sure-Seal, Aldrich). Silicagel-on-glass plates
with indicator (Merk) were used for TLC using EtOAc/
hexane = 1:4 mobile phase. Elemental analysis for the
Fig. 6. Suggested structures of platinum arylcyanoximate: MM-2 opti-
mized geometry of the trans-[Pt{H(2Cl-6F-PhCO)}2Cl2]; the cyanoxime
adopts syn-configuration. (A)
– top view and (B) – side views;
Etot = ꢁ4.22 kcal/mol. Coloring scheme: green – Cl, yellow – F, red
– O, blue – N, grey – C, large light grey – Pt. (For interpretation of the
references in color in this figure legend, the reader is referred to the web
version of this article.)

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1995
C,H,N content of the obtained Na, Pt and Pd complexes
3.2.3. X-ray crystallography
were done by Atlantic Microlab, Inc (Norcross, GA).
Crystal and molecular structures were determined for
four disubstituted arylcyanoximes: H(2,5-diF-PhCO),
H(2,6-diF-PhCO), H(2Cl-6F-PhCO) and H(2,6-diCl-
PhCO). Suitable single crystals were grown from dilute
solutions (aqueous, mixture of organic solvents) upon slow
solvent evaporation. A single crystal was mounted on a
thin glass fiber using viscous oil and then cooled to the data
collection temperature (173 K) for the three compounds,
while a single crystal of the H(2,6-diF-PhCO) was studied
at room temperature (Table 3). A Bruker SMART CCD
diffractometer operating in x-scans mode was used for data
3.2. Physical methods
3.2.1. Instrumentation
Melting points (without correction) for ligands and Na+
salt derivatives were obtained by using a Mel-Temp II
apparatus (Thomas Hoover) in open capillary tubes. Elec-
trical conductivity measurements for several complexes and
organic ammonium salts were carried out in 1 mM solu-
tions in an anhydrous acetone, ethanol and DMSO using
the YSI Conductance–Resistance meter Model 34. Solu-
tions of tetrabutylammonium bromide, tetraphenylphos-
phonium bromide (as 1:1 electrolytes) and hydrazonium
dichloride (as 1:2 electrolyte) were used for the electrode
calibration. Measurements of pKa values for synthesized
benz(2-hetroaryl)cyanoximes were carried out using a Sir-
ius Analytical Instruments automated titration station
(Sussex, UK) equipped with a temperature-controlled bath.
Since protonated cyanoximes HL are poorly soluble in
water, all measurements were conducted in mixed solvent
systems using methanol as solubilizing co-solvent. Ateno-
lolꢃ and Lidocaineꢃ (from Aldrich) were used for calibra-
tion of the instrument [54]. Measurements consisted of the
three-step multi-stage titration in water/CH3OH mixtures
from 18.9 wt% to 23.8 wt% content of organic solvent with
ionic strength adjusted to 0.15 with KCl. The pH in titra-
tion experiments ranged from 3 to 11. The values were
extrapolated to ‘‘zero’’ CH3OH content to obtain an aque-
ous pKa value using the Yasuda–Shedlovsky procedure
(Table 1).
˚
collection using Mo Ka radiation (k = 0.71070 A). The
data were corrected for decay and absorption using the
SADABS program [55]. Direct methods structure solutions,
difference Fourier calculations, and full-matrix least
squares refinements against F2 were performed with SHEL-
XL-97 program package. All non-hydrogen atoms were
refined with anisotropic displacement parameters, while
hydrogen atoms were placed in geometrically idealized
positions and refined using a riding model. The crystal
and refinement data for the studied compounds are listed
in Table 3. An ORTEP program package [56] was used to
draw figures of crystal structures. Respective .CIF files
*
for studied compounds are available (Supporting material).
3.3. Synthesis of organic ligands
The route for preparation of the disubstituted arylcyan-
oximes is shown in Scheme 4. Side reactions associated
with the initial nitrosating agent, unfortunately, were
encountered during this preparation. Isolated, spectroscop-
ically and structurally characterized examples of products
of the side reactions are shown in SM 2. The commercial
products – alkylnitrites – from Aldrich were of poor qual-
ity. Therefore, alkylnitrites n-C3H7–ONO or CH3–ONO
must be prepared fresh before use, and small quantities
(5–20 g) of it were made each time prior to use in oximes
syntheses according to published procedures [53]. Previ-
ously, we successfully used nitrosation reaction at basic
conditions for the synthesis of monosubstituted arylcyan-
oximes [17–19] and some amide-cyanoximes [22,45]. The
typical procedure for the synthesis of dihaloganeted arylc-
yanoximes is presented below.
3.2.2. Spectroscopic methods
1H and 13C NMR spectra of protonated (HL) and depro-
tonated (NaL) ligands were recorded using a Varian Gemini
200 MHz NMR spectrometer in DMSO-d6 (with 0.1%
TMS). Variable temperature (in DMSO-d6 from 296 to
406 K in 10o 0.1o steps) (Table 2), and 2D NMR experi-
ments (HMQC, COSY and HSQC–NOESY) for HL and
NaL were conducted using the Avance DRX-500 BRU-
KER NMR spectrometer. IR spectra for the solid ligands,
HL, their Na+ salt derivatives and the Pt(II)/Pd(II) com-
plexes were recorded in KBr pellets in the range of 4000–
400 cmꢁ1 with an FT-IR Nicolet Magna 550 spectrometer
(with OMNIC 1.20 software) (Table 5). UV–Vis spectra
of solutions of protonated HL and deprotonated Lꢁ disub-
stituted arylcyanoximes were recorded in several organic
solvents (CH3OH, EtOH, n-PrOH, t-BuOH, DMSO,
DMF, acetone, CH3CN) and H2O. UV–Vis spectra were
obtained using an Agilent 8453E UV–Vis Spectroscopy Sys-
tem at 294 K in the range of 190–1100 nm in 1 mm and 1 cm
quartz cuvettes (Starna). Kinetic of solvolysis of Pt(II) cya-
noximates was recorded as spectroscopic changes of their
1 mM solutions in dried DMSO and EtOH in 1 mm cells
(Table 7). Similar solutions (10 mL) were used for the mon-
itoring of an electrical conductivity within 24 h.
3.4. Synthesis of oximino(2,6-difluorophenyl)acetonitrile,
H(2,6-diF-PhCO)
Metallic sodium (0.754 g; 0.033 mol) was dissolved at
room temperature and under N2 protection in 300 mL of
isopropanol. The starting 2,6-difluorophenylacetonitrile,
NC–CH2–C6H3F2 (5.000 g; 0.033 mol), was dissolved in
50.0 mL of isopropanol and then added to the sodium iso-
propoxide solution. Gaseous methylnitrte, CH3ONO, gen-
erated on site from cold aqueous solutions of NaNO2,
methanol and H2SO4 [53], was bubbled through the mix-
ture of NaOC3H7 and NC–CH2–C6H3F2 in i-propanol

1996
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
within 10 min. The reaction mixture’s color changed to yel-
low, and the mixture was kept overnight at ꢀ4 ꢂC. The sol-
vent was removed and the remaining yellow solid residue of
NaL* (L = 2,6-diF-PhCO) was dried at room temperature
under vacuum. The solid NaL was re-dissolved in 50 mL of
water and the solution was slowly acidified with 1.0 M
HCl. At pH ꢀ 7 white precipitate started to appear in the
flask. The precipitate of HL was filtered, washed with water
and dried in a desiccator resulting in 5.124 g (0.028 mol) of
the cyanoxime at 86% yield. M.p. = 99–100 ꢂC, Rf = 0.29
(EtOAc/hexane = 1:4). C8H4F2N2O requires: C, 52.76; H,
2.21; N, 15.38. Found: C, 52.71; H, 2.18; N, 15.43%.
NMR spectra evidenced the mixture of syn (ꢀ50%) and
anti (ꢀ50%) isomers. Data for syn-isomer: 1H NMR,
ppm: 14.46 (1H, s, oxime group); 7.68 (1H, ten lines multi-
plet); 7.30 (2H, seven lines multiplet); 13C NMR, ppm.:
160.00 (carbon at 2-position; 1J(13C–19F) = 254 Hz,
3J(13C–19F) = 5.1 Hz), 112.74 (carbon at 3-position;
requires: C, 52.76; H, 2.21; N, 15.38. Found: C, 52.80; H,
2.26; N, 15.47%. Only one isomer (syn) in solutions. H
1
NMR, ppm: 14.29 (1H, s, oxime group); 7.49 (1H, multi-
plet, ddd); 7.45 m (2H, multiplet, ddd). 13C NMR, ppm.:
158.39 – carbon at 2-position (1J(13C–19F) = 242 Hz,
4J(13C–19F) = 2.1 Hz), 155.69 – carbon at 5-position
(1J(13C–19F) = 248 Hz, 4J(13C–19F) = 2.3 Hz), 126.12 –
oxime carbon, 119.82 – carbon at 3-position (2J(13C–19F)
= 24.3 Hz, 3J(13C–19F) = 8.9 Hz), 119.41 – ipso-carbon
(2J(13C–19F) = 12.9 Hz, 3J(13C–19F) = 8.2 Hz), 118.96 –
carbon
at
4-position
(2J(13C–19F) = 22.8 Hz,
3J(13C–19F) = 8.2 Hz), 115.34 – carbon at 6-position
(2J(13C–19F) = 26.5 Hz, 3J(13C–19F) = 2.5 Hz), 110.06 –
CN-group. UV–Vis spectrum, kmax (EtOH)/nm, e/
dm3 Mꢁ1 cmꢁ1: 204 nm (e = 16080 dm3 Mꢁ1 cmꢁ1), 259
(7320). X-ray quality needle-like crystals were obtained
by slow cooling in thermostat hot solution of compound
in CCl4.
4
2J(13C–19F) = 20.5 Hz, J(13C–19F) = 4.3 Hz), 110.01 (car-
bon at 4-position), 134.05 (ipso-carbon; 2J(13C–19F) =
10.8 Hz), 123.91 (oxime carbon), 105.62 (CN-group).
Mass-spectrometry: for C8H4F2N2O found (required) –
182.0299 (182.0292). UV–Vis spectrum, kmax (EtOH)/nm,
e/dm3 Mꢁ1 cmꢁ1: 210 (5900), 244 (5550). X-ray quality
needle-like crystals were obtained by slow evaporation of
its aqueous solution.
3.4.3. Oximino(2-chloro-6-fluorophenyl)acetonitrile,
H(2Cl-6F-PhCO)
Colorless needles; yield 45%, m.p. = 119–120 ꢂC,
Rf = 0.38 (EtOAc/hexane = 1:4). C8H4FClN2O requires:
C, 48.39; H, 2.03; N, 14.11. Found: C, 48.33; H, 2.09; N,
14.23%. NMR spectra indicate mixture of syn (73%) and
anti (27%) isomers in DMSO-d6. The following data for
Other cyanoximes follow:
1
syn-isomer. H NMR, ppm: 14.51 (1H, s, oxime group);
7.66 (1H, multiplet at 5-position; 3J(1H–1H) = 8.5 Hz,
3J(1H–19F) = 8.51 Hz); 7.53 (1H, doublet at 3-position;
3J(1H–1 H) = 8.5 Hz); 7.45 (1H, multiplet at 4-position;
3J(1H–1H) = 7.5 Hz, 4J(1H–19F) = 1.0 Hz). 13C NMR,
ppm.: 159.31 – carbon at 6-position (1J(13C–19F) = 251
3.4.1. Oximino(2,4-difluorophenyl)acetonitrile, H(2,4-diF-
PhCO)
Colorless crystalline substance; yield = 89%, m.p. = 64–
65 ꢂC, Rf = 0.37 in EtOAc/hexane = 1:4 mobile phase.
C8H4F2N2O requires: C, 52.76; H, 2.21; N, 15.38. Found:
C, 52.80; H, 2.24; N, 15.47%. NMR spectra evidenced
the mixture of syn (60%) and anti (40%) isomers in
DMSO-d6. Data for syn-isomer: 1H NMR, ppm: 14.12
(1H, s, oxime group); 7.75 (1H, multiplet at 6-position;
Hz), 134.07
–
carbon at 4-position (3J(13C–19F) =
9.6 Hz), 132.79 – carbon at 2-position (3J(13C–19F) = 4.6
Hz), 126.32 – carbon at 3-position (4J(13C–19F) = 3.0
Hz), 126.26 – oxime carbon, 116.32 – carbon at 1-position
(2J(13C–19F) = 20.7 Hz), 115.85 – carbon at 5-position
(2J(13C–19F) = 21.3 Hz), 114.72 – CN-group. UV–Vis spec-
trum, kmax (EtOH)/nm, shoulders at 214 and 261 nm.
5
3J(1H–1 H) = 8.0 Hz, J(1H–1 H) = 2.0 Hz, 4J(1H–19F) =
8.5 Hz); 7.47 (1H, multiplet at 5-position; 3J(1H–1
4
3
H) = 8.5 Hz, J(1H–1 H) = 2.5 Hz, J(1H–19 F) = 11.5 Hz,
5J(1H–19F) = 3.0 Hz); 7.25 (1H, multiplet at 3-position;
3J(1H–1H) = 8.0 Hz, 4J(1H–19F) = 6.5 Hz). 13C NMR,
ppm.: 163.87 – carbon at 2-position, (1J(13C–19F) =
3.4.4. Oximino(2,4-dichlorophenyl)acetonitrile, H(2,4-diCl-
PhCO)
251 Hz, J(13C–19F) = 12.3 Hz), 159.82 – carbon at 4-posi-
Colorless fibrous crystalline substance; yield 95%,
3
tion (1J(13C–19F) = 255 Hz, 3J(13C–19F) = 12.8 Hz), 131.09
m.p. = 151 ꢂC,
Rf = 0.34
(EtOAc/hexane = 1:4).
–
carbon
at
6-position
(3J(13C–19F) = 10.4 Hz,
C8H4Cl2N2O requires: C, 44.68; H, 1.87; N, 13.03. Found:
C, 44.71; H, 1.98; N, 13.23%. NMR spectra show mixture
of anti (70%) and syn (30%) isomers in DMSO-d6. Pre-
0
3 J(13C–19F) = 4.0 Hz), 126.31 – oxime carbon, 113.17 –
ipso-carbon (2J(13C–19F) = 22.0 Hz, J(13C–19F) = 3.3 Hz),
4
1
110.28 – CN-group, 105.82 – carbon at 3-position
(2J(13C–19F) = 25.9 Hz), 105.62 – carbon at 5-position
(2J(13C–19F) = 25.1 Hz, 4J(13C–19F) = 2.0 Hz). UV–Vis
spectrum, kmax (EtOH)/nm, e/dm3 Mꢁ1 cmꢁ1: 261 (6200).
sented data for anti-isomer. H NMR, ppm: 14.24 (1H, s,
oxime group), 7.82 (1H, s, at 3-position), 7.66 (1H, multi-
plet, at 5-position), 7.58 (1H, at 6-position). 13C NMR,
ppm.: 136.71 – carbon at 2-position, 132.92 – carbon at
3-position, 132.45 – carbon at 4-position, 130.36 – carbon
at 5-position, 128.64 – carbon at 6-position, 127.70 – oxime
carbon, 110.13 – CN-group. UV–Vis spectrum, kmax
(EtOH)/nm, e/dm3 Mꢁ1 cmꢁ1: ꢀ225 nm shoulder, 265 nm
(e = 11200 dm3 Mꢁ1 cmꢁ1).
3.4.2. Oximino(2,5-difluorophenyl)acetonitrile, H(2,5-diF-
PhCO)
Colorless needle-type crystals; yield = 91%, m.p. = 64–
67 ꢂC, Rf = l0.24 (EtOAc/hexane = 1:4). C8H4F2N2O

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1997
3.4.5. Oximino(2,6-dichlorophenyl)acetonitrile, H(2,6-diCl-
PhCO)
in 3.5 mL of ethanol under N2 protection. The sodium eth-
oxide solution was added at once to the HL solution under
intensive stirring resulting in an immediate precipitation of
yellow NaL in the flask (route 1, Scheme 7). The precipitate
was filtered, washed with cold ethyl ether and dried under
vacuum giving 0.665 g (0.003 mol) of NaL (yield = 60%).
All sodium salts of dihalogen-substituted arylcyanoxi-
mes represent yellow hygroscopic powdery solids that are
soluble in water, DMF, DMSO, and pyridine; they are
insoluble in propanol, chlorocarbons and hexane. Yields,
and data of element content determination for other syn-
thesized NaL, are presented in SM 18.
Colorless microcrystalline substance; yield 60%,
m.p. = 94–96 ꢂC, Rf = 0.29 (EtOAc/hexane =;1:4). C8H4-
Cl2N2O requires: C, 44.68; H, 1.87; N, 13.03. Found: C,
44.75; H, 1.94; N, 13.12%. NMR spectra evidenced the
mixture of syn (45%) and anti (55%) isomers. Data for
anti-isomer are shown. 1H NMR, ppm: 14.41 (1H, s, oxime
group), 7.68 (2H, multiplet), 7.59 (1H, multiplet). 13C
NMR, ppm.135.26 – carbons at 2,6-positions, 133.26 – car-
bons at 3,5-positions, 129.07 – carbon at 4-position, 127.27
carbon at 1-position, 129.64 – oxime carbon, 114.29 – CN-
group. UV–Vis spectrum, kmax (EtOH)/nm, e/dm3
Typical preparation of thallium(I) salts is presented
below
M
ꢁ1 cmꢁ1: 216 nm (e = 15080 Mꢁ1 cmꢁ1), 269 nm shoul-
der. Block-type single crystals, suitable for X-ray analysis,
were obtained during slow evaporation within ꢀ2 weeks of
the ethyl ether/CCl4 solvent mixture.
3.5.2. Synthesis of thallium(I) oximino(2,4-
difluorophenyl)acetonitrile, Tl(2,6-diF-PhCO)
All synthesized cyanoximes are weak organic acids and
represent colorless crystalline substances that are soluble
in ether, alcohols, acetone, ethylacetate, DMSO, DMF,
acetonitrile, and chlorocarbons, sparingly soluble in water,
but not soluble in hydrocarbons. Dissolution protonated
cyanoximes HL in amines (pyridine, triethylamine, ethy-
lenediamine) leads to the formation of yellow solutions of
deprotonated cyanoximate anions Lꢁ.
287.7 mg (0.61 mmol) of Tl2CO3 were dissolved in
15 mL of water and mixed with 250.4 mg (1.2 mmol) of
Na(2,6-diF-PhCO) dissolved in 20 mL of water (route 3,
Scheme 7). The yellow solution was heated to boil for
ꢀ5 min and then filtered into the large mouth test tube
immersed into the Dewar flask containing preheated to
95 ꢂC water and left to cool. After several days yellow/
orange fibrous thin crystals of the Tl(I) complex appeared
in the test tube. The compound was filtered, washed with
5 mL of cold water and dried in desiccator charged with
H2SO4(c). Yield 68%; complex decomposes during heating
above 160 ꢂC. Anal. Calc. for C8H3F2N2OTl: C, 24.92;
H, 0.78; N, 7.27. Found: C, 24.50; H, 0.81; N, 7.35%.
Other Tl(I) disubstituted arylcyanoximates follow:
Tl(2,4-diF-PhCO): yellow fibrous solid, yield 75%.
Anal. Calc. for C8H3F2N2OTl: C, 24.92; H, 0.78; N, 7.27.
Found: C, 24.79; H, 0.83; N, 7.15%.
3.5. Preparation of sodium, thallium(I) salts and transition
metal complexes
The following paragraph describes typical methods of
synthesis of ionic sodium salts that are used as precursors
for the preparation of Pd(II) and Pt(II) cyanoximates,
and also preparation of monovalent Tl and Ag complexes
(Scheme 7).
Tl(2,5-diF-PhCO): dark-yellow needles, yield 82%.
Anal. Calc. for C8H3F2N2OTl: C, 24.92; H, 0.78; N, 7.27.
Found: C, 24.97; H, 0.81; N, 7.36%.
3.5.1. Sodium salt of oximino(2-chloro-6-
fluorophenyl)acetonitrile, Na(2Cl-6F-PhCO)
One gram (0.005 mol) of the starting oxime H(2Cl-6F-
PhCO) was dissolved in 100 mL of ethyl ether. Sodium
metal (0.116 g; 0.005 mol) was thinly sliced and dissolved
Tl(2Cl-6F-PhCO): yellow microcrystalline solid, yield
70%. Anal. Calc. for C8H3FClN2OTl: C, 23.90; H, 0.75;
N, 6.97. Found: C, 24.07; H, 0.78; N, 7.14%.
Tl(2,4-diCl-PhCO): dark-yellow fibrous solid, yield
65%. Anal. Calc. for C8H3Cl2N2OTl: C, 22.96; H, 0.72;
N, 6.70. Found: C, 23.11; H, 0.77; N, 6.85%.
AgL
Tl(2,6-diCl-PhCO): yellow solid, yield 88%. Anal. Calc.
for C8H3Cl2N2OTl: C, 22.96; H, 0.72; N, 6.70. Found: C,
22.81; H, 0.82; N, 6.73%.
Actual photographs of some of the thallium(I) arylcya-
noximates are shown in SM 19.
Synthesized Tl(I) complexes are soluble in DMSO,
DMF and pyridine and its homologs, sparingly soluble in
cold water, and insoluble in ethanol, acetone, chlorohydro-
carbons and aromatic hydrocarbons.
4
+ AgNO3
R.T., H2O
5
+ K2[MCl4]
R.T., H2O
1
NaL
[M(HL)2Cl2] x nH2O
+ NaOC2H5
R.T., ether
R.T., H2O; M = Pd, Pt; n = 0, 1
3
+ Tl2CO3
R.T., H2O
HL
- CO2
3.5.3. Synthesis of silver(I) oximino(2,4-difluorophenyl)
acetonitrile, Ag(2,4-diF-PhCO)
The sodium salt of the ligand was the precursor for the
preparation of the Ag(I) complex (route 4, Scheme 7).
2
+ Tl2CO3
95oC, H2O
TlL
Scheme 7.

1998
N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
Thus, 250.1 mg (1 mmol) of Na(2,4-diF-PhCO) were dis-
solved in 20 mL of water, while silver nitrate (AgNO3),
(208.3 mg; 1 mmol) was dissolved in 5 mL of water. The
two solutions were then mixed under stirring. The reaction
was carried out in the dark to prevent a photodegradation
of the Ag(2,4-diF-PhCO). Thick yellow precipitate
appeared immediately after the mixing. Solution was stir-
red for ꢀ10 min then filtered, and precipitate was washed
with cold water, methanol, and ether. The Ag-salt
appeared to be slightly soluble in methanol; dry product
was kept from ambient light in a desiccator using protec-
tion of aluminum foil since the complex is very light sensi-
tive. The amount of isolated dry Ag(2,4-diF-PhCO):
0.278 g (79% yield). Anal. Calc. for C8H3AgF2N2O: C,
33.25; H, 1.05; N, 9.69. Found: C, 33.49; H, 1.03; N, 9.75%.
Other Ag(I) disubstituted arylcyanoximates follow:
Ag(2,6-diF-PhCO): yellow-orange solid, yield 92%.
Anal. Calc. for C8H3AgF2N2O: C, 33.25; H, 1.05; N,
9.69. Found: C, 33.31; H, 1.12; N, 9.82%.
of the potassium tetrachloroplatinate(II) in 6 mL of
water under an intensive stirring at the ratio of K2PtCl4/
NaL 1:2. The reaction mixture was left to stir for 24 h.
The reaction mixture gained a yellow color and fine yellow
precipitate was filtered, washed with cold water and
dried in a vacuum desiccator. Yield of yellow Pt[H(2,4-
diCl-PhCO)2]Cl2was 31%. Anal. Calc. for C16H8Cl6N4-
O2Pt: C, 27.61; H, 1.16; N, 8.05. Found: C, 28.14; H,
1.47; N, 8.18%.
Other platinum group metal complexes follow:
Pt[H(2,4-diF-PhCO)2]Cl2 Æ xH2O: yellow solid, yield
63%. Anal. Calc. for C16H10Cl2F4N4O3Pt: C, 29.64; H,
1.55; N, 8.64. Found: C, 29.50; H, 1.41; N, 8.55%.
Pt[H(2Cl-6F-PhCO)2]Cl2 Æ xH2O: yellow solid, yield
18%. Anal. Calc. for C16H10Cl4F2N4O3Pt: C, 28.21; H,
1.48; N, 8.23. Found: C, 28.09; H, 1.50; N, 8.17%.
Pt[H(2,5-diF-PhCO)2]Cl2: brown solid, yield 32%.
Anal. Calc. for C16H8Cl2F4N4O2Pt: C, 30.49; H, 1.28; N,
8.89. Found: C, 31.83; H, 1.51; N, 9.34%.
Ag(2,5-diF-PhCO): dark-yellow solid, yield 85%. Anal.
Calc. for C8H3AgF2N2O: C, 33.25; H, 1.05; N, 9.69.
Found: C, 33.22; H, 1.17; N, 9.61%.
Pd[H(2,4-diCl-PhCO)2]Cl2: reddish/orange, yield 95%.
Anal. Calc. for C16H8Cl6N4O2Pd: C, 31.64; H, 1.33; N,
9.22. Found: C, 31.12; H, 1.33; N, 9.08%.
Ag(2Cl-6F-PhCO): yellow solid, yield 80%. Anal. Calc.
for C8H3AgClFN2O: C, 31.46; H, 0.99; N, 9.17. Found: C,
31.29; H, 1.04; N, 9.26%.
Pd[H(2,5-diF-PhCO)2]Cl2: orange solid, yield 78%.
Anal. Calc. for C16H8Cl2F4N4O2Pd: C, 35.48; H, 1.49; N,
10.35. Found: C, 36.55; H, 1.16; N, 10.61%.
Ag(2,4-diCl-PhCO): yellow solid, yield 80%. Anal. Calc.
for C8H3AgCl2N2O: C, 29.85; H, 0.94; N, 8.70. Found: C,
30.03; H, 1.01; N, 8.76%.
Ag(2,6-diCl-PhCO): orange solid, yield 88%. Anal.
Calc. for C8H3AgCl2N2O: C, 29.85; H, 0.94; N, 8.70.
Found: C, 29.97; H, 0.98; N, 8.82%.
Pd[H(2,6-diF-PhCO)2]Cl2 Æ xH2O:
reddish/orange,
yield 63%. Anal. Calc. for C16H10Cl2F4N4O3Pd: C, 34.34;
H, 1.80; N, 10.01. Found: C, 34.04; H, 1.56; N, 9.84%.
The synthesized transition metal complexes are poorly
soluble in water, soluble in acetone and ethanol, and well
soluble in donor solvents such as DMF, DMSO and
pyridine.
According to the results of magnetic susceptibility mea-
surements (Gouy method; Johnson Matthew Mark-III
magnetometer; K3[Cr(oxalate)3] as calibrant), all obtained
bivalent platinum and palladium complexes represent dia-
magnetic at 296 K substances with square-planar geome-
tries of the metal centers.
Obtained silver(I) compounds are light sensitive, insolu-
ble in CHCl3, CH2Cl2, aromatic hydrocarbons and slightly
soluble in organic solvents such as acetone and CH3OH,
but well dissolve aqueous ammonia, dimethylamine solu-
2ꢁ
tion, pyridine, DMSO and DMF, thiosulfate S2O3
solution.
3.5.4. Bivalent Pd and Pt cyanoximates
Fine colored precipitates of complexes were obtained in
aqueous solutions at room temperature upon mixing of
K2[MCl4] (M = Pd, Pt) with two equivalents of sodium
salts of dihalogen substituted arylcyanoximates (route 5,
Scheme 7). Seven out of twelve possible complexes were
synthesized using this method. The Pd(II)-arylcyanoxi-
mates formed much faster and with better yields compared
to their Pt(II) analogs, where precipitation was com-
plete within hours. This is contrary to the quick forma-
tion of bivalent palladium and platinum complexes with
amide-containing cyanoximates that formed five-mem-
bered chelate metallocycles observed earlier [22,45].
Typical preparation for the platinum(II) complex is pre-
sented below.
3.5.6. In vitro cytotoxicity studies
Antiproliferative activity of the obtained disubstituted
arylcyanoximes and their Pd(II) and Pt(II) complexes
was examined using a WiDR human colon carcinoma cell
line (ATTC, catalog #CCL-218) following in general the
basic procedures and operations with animal cells [51,52].
We developed and successfully used slightly different
protocol and data collection for our in vitro experiments
details of which are presented in SM 3 and SM 4. Several
solutions of different concentration (0.01 mM, 0.1 mM,
0.25 mM, 0.50 mM, 0.75 mM and 1.0 mM) were prepared
for the testing. Since rapid solvolysis of cisplatin and
related compounds in pure DMSO [47] had been
previously established, Pd and Pt cyanoximates were
quickly dissolved in DMSO within 20 seconds and then
appropriate aliquots were mixed with aqueous buffer dur-
ing one minute and added to plated cells. No re-precipi-
tation of complexes in the 24-well plates was observed.
3.5.5. Synthesis of Pt[H(2,4-diCl-PhCO)2]Cl2
100.8 mg (4.25 · 10ꢁ4 mol) of NaL were dissolved in
4 mL of water and mixed with 87.1 mg (2.10 · 10ꢁ4 mol)

N. Gerasimchuk et al. / Inorganica Chimica Acta 361 (2008) 1983–2001
1999
During all in vitro experiments, WiDr cells were used in
the exponential phase of their growth, and were allowed
to grow 24 h after being plated before any compounds
were added to the medium. All in vitro studies of synthe-
sized compounds and control substances (cisplatin,
DMSO) were conducted in duplicate. The viable/non-via-
ble stained cells count method was used for the evalua-
tion of cytotoxicity of the synthesized compounds.
Digital pictures of cells were taken with an Olympus
DP70 digital camera attached to an Olympus BX41
Microscope at 100· magnification. Three random views
were photographed with subsequent cell counts and data
analysis.
placement was observed in these solutions. Kinetics of
these first order reactions was measured using UV–Vis
spectroscopy. In both solvents the first cyanoxime sub-
stitution reaction is significantly faster (4.5–10 times)
than the second reaction. The overall solvolysis of inves-
tigated metal complexes in DMSO by factor of 20–110
faster than that in ethanol.
6. Results of in vitro cytotoxicity studies of synthesized
arylcyanoximes and their Pd and Pt complexes on
human colon carcinoma WiDr cell line showed absence
of cytotoxicity of the uncomplexed ligands and all metal
complexes at low concentrations (0.01–0.1 mM). Two
bivalent palladium and platinum cyanoximates con-
taining H(2,4-diCl-PhCO) showed the greatest anti-
proliferative activity at 0.25 mM concentrations
found to be ꢀ20% of that for cisplatin at the same
conditions.
4. Conclusions
1. High-yield preparation of new disubstituted arylcyan-
oximes was developed using the nitrosation reaction
at basic conditions despite several side reactions. Six
new synthesized arylcyanoximes were characterized
by means of NMR, IR and UV–Vis spectroscopy.
Crystal structures were determined for four cyanoxi-
mes and it was found that the fluorinated compounds
adopt rare syn-configuration in solid state. Neverthe-
less, five out of six protonated arylcyanoximes HL
exist as a mixture of syn- and anti-isomers in solu-
tions. No interconversion between the two isomers
was observed upon heating of their solutions in
DMSO-d6.
2. Six thallium(I) and six silver(I) dihalogenated
arylcyanoximates were synthesized from protonated
ligands HL and Na-salts respectively. Obtained coor-
dination polymers were characterized using spectro-
scopic methods. The cyanoxime anions perform
bridging function upon coordination utilizing the
oxime group (Tl+), or cyano-group and the oxime
groups (Ag+) as deduced from their IR-spectra analo-
gous to several structurally characterized thallium and
silver cyanoximates.
Acknowledgments
L.G. thanks the MSU Department of Chemistry for
funding part of this research. Also, L.G. is especially grate-
ful to Mrs. Elizabeth Cartwriter and Mrs. Marcie Abbey
for their help with cytotoxicity studies. The authors thank
to Prof. Bryan Breyfogle (MSU) for his assistance with the
electrical conductivity system and to Mrs. Sarah Neuens-
wander (KU) for high-field NMR spectroscopic measure-
ments. N.G. is grateful for the financial support received
from the American Chemical Society (PRF Award #
390790-B3), and also to Mr. Michael Frizell for valuable
technical assistance.
Appendix A. Supplementary material
Summary of the NMR spectra for HL and NaL and
effect of heat on solutions (SM 1); products of encoun-
tered during nitrosation side reactions (SM 2); represen-
tative data for cyanoximates’ solvatochromism (SM 3);
charge delocalization in anions (SM 4); tables of IR-
spectra of synthesized compounds (SM 5–SM 9); data
of solutions electrical conductivity studies of two Pd
and Pt complexes (SM 10); UV–Vis spectra of the two
Pt complexes in kinetic mode (SM 11, SM 12); results
of MM-2 optimization of geometry calculations (SM
13, SM 14); cytotoxicity protocol (SM 15, SM 16);
photographs of controls used in in vitro experiments
(SM 17); actual photos of WiDR cells with added
Pt-cyanoximate (SM 18); chart with the cytotoxicity data
for several Pd and Pt cyanoximates (SM 19); composi-
tion and properties of NaL (SM 20); optical and EM
photographs of some of the TlL crystals (SM 21);
X-ray structure of related Ag(I) complex (SM 22). An
X-ray crystallographic files (CIF) for all reported struc-
tures. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.ica.2007. 10.019.
3. First-row transition metals ions do not form isolable
coordination compounds with studied disubstituted
arylcyanoximes due their inability to form chelate-type
complexes common for other cyanoximes.
4. Seven new bivalent Pd and Pt arylcyanoximates of gen-
eral formula [M(HL)2Cl2] were synthesized and studied
using IR, UV–Vis spectroscopy and the solutions’ elec-
trical conductivity. Monodentate binding mode of the
cyanoxime ligands via nitrogen atom of the oxime frag-
ment are suggested based on data of their IR spectra and
MM-2 calculations with optimization of geometry. A
square-planar geometry for the obtained coordination
compounds with Cl anions and monodentate cyanoxi-
mes being in trans-position to each other was offered
as a solid state structure.
5. Both Pd and Pt complexes are non-electrolytes in etha-
nol and DMSO. Nevertheless, a stepwise solvolysis of
the Pt(II) arylcyanoximates leading to the oxime dis-

2000
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