HSAB principle and nickel(II) ion reactivity towards 1-methyhydantoin

Article abstract of DOI:10.1016/j.poly.2011.05.004

1-Methylhydantoin and its novel nickel(II) complex [Ni(H₂O) ₄(1-mhyd)₂] were prepared and identified, by elemental analysis, single crystal X-ray determination and MS methods. In addition, the complex was characterized by spectroscopic (IR, UV-Vis), magnetic and thermal techniques. The ligand reveals an interesting supramolecular architecture with both classical and non-conventional extended HB bonding networks. All rings and chains formed due to this HB bonding are embedded into the undulated pattern. A single crystal X-ray diffraction analysis of the complex shows that the nickel ion is coordinated by deprotonated hydantoin and water ligands in a N ₂O₄ tetragonal arrangement. In the [Ni(H ₂O)₄(1-mhyd)₂] structure both inter and intramolecular hydrogen bonds are created with the participation of water molecules. The ESI-MS method confirmed mono-nuclearity of the complex while electronic spectroscopy proved the tetragonal and pseudooctahedral geometries around the metal ion in the solid state and solution, respectively. By application of the "average environment rule", 10Dq parameters were obtained for the hypothetical, hexa-coordinate [Ni(1-mhyd)₆] approximation or rather more realistic [Ni(1-mhyd)₃] chelate. Based on this the mhyd ligand was ranked in the spectrochemical series close to ammonia. The general consideration of the structure of the hydantoin complexes as a function of the metal ion hardness within the framework of the HSAB theory has been provided. Both the ligand and the complex were found to be non-toxic agents against breast (MCF-7), lung carcinoma epithelial (A549) and mouse fibroblasts (Balb/3T3) cancer cell lines.

Full text of DOI:10.1016/j.poly.2011.05.004

Polyhedron 30 (2011) 2016–2025
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
HSAB principle and nickel(II) ion reactivity towards 1-methyhydantoin
a
b
a
c
´
Mariola Puszynska-Tuszkanow , Marek Daszkiewicz , Gabriela Maciejewska , Zbigniew Staszak ,
d
d
a,
⇑
´
Joanna Wietrzyk , Beata Filip , Maria Cieslak-Golonka
a
_
´
Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
b Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okólna 2, P.O. Box 1410, 50-950 Wrocław, Poland
c
_
Institute of Informatics, Wrocław University of Technology, Wybrzeze Wyspian´skiego 27, 50-370 Wrocław, Poland
d Ludwik Hierszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Science, Rudolf Weigl Str. 12, 53-114 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Methylhydantoin and its novel nickel(II) complex [Ni(H2O)4(1-mhyd)2] were prepared and identified,
by elemental analysis, single crystal X-ray determination and MS methods. In addition, the complex
was characterized by spectroscopic (IR, UV–Vis), magnetic and thermal techniques. The ligand reveals
an interesting supramolecular architecture with both classical and non-conventional extended HB bond-
ing networks. All rings and chains formed due to this HB bonding are embedded into the undulated pat-
tern. A single crystal X-ray diffraction analysis of the complex shows that the nickel ion is coordinated by
deprotonated hydantoin and water ligands in a N2O4 tetragonal arrangement. In the [Ni(H2O)4(1-mhyd)2]
structure both inter and intramolecular hydrogen bonds are created with the participation of water mol-
ecules.
The ESI-MS method confirmed mono-nuclearity of the complex while electronic spectroscopy proved
the tetragonal and pseudooctahedral geometries around the metal ion in the solid state and solution,
respectively. By application of the ‘‘average environment rule’’, 10Dq parameters were obtained for the
hypothetical, hexa-coordinate [Ni(1-mhyd)6] approximation or rather more realistic [Ni(1-mhyd)3] che-
late. Based on this the mhyd ligand was ranked in the spectrochemical series close to ammonia. The gen-
eral consideration of the structure of the hydantoin complexes as a function of the metal ion hardness
within the framework of the HSAB theory has been provided. Both the ligand and the complex were
found to be non-toxic agents against breast (MCF-7), lung carcinoma epithelial (A549) and mouse fibro-
blasts (Balb/3T3) cancer cell lines.
Received 31 January 2011
Accepted 6 May 2011
Available online 13 May 2011
Keywords:
Nickel ion
Hydantoin derivative
Structure
Spectroscopic properties
HSAB theory
Spectrochemical series
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
mhyd)2]Á4H2O, [Pt2(NH3)4(1-mhyd)2]2(NO3)4ÁH2O, [Hg(1-mhyd)2]n,
and {[Ag(1-mhyd)]Á0.5H2O}n [11–14]. In the gold(I) complex the
1-Methylhydantoin (dioxy-creatinine, N-methylhydantoin, N-
methylimidazolidine-2,4-dione) (Scheme 1) belongs to a large
group of compounds generally called hydantoins. Studies on par-
ent hydantoin and its various derivatives are of fundamental and
practical importance due to their physiological action as anticon-
vulsant, antiepileptic, anti-inflammatory and anticancer drugs
[1–4,7,8]. Recently, the potential application of compounds con-
taining a hydantoin fragment for HIV-1 treatment has been also
suggested [5,6]. In addition, 1-methylhydantoin-2-imide (creati-
nine) has been used as a skin cosmetic ingredient [9].
metal ion coordinates two ligands deprotonated at N(3) (Scheme 1)
[11]. In contrast, the crystal structure of other complexes with hyd-
antoins exhibited rather complicated pattern of coordination
modes through deprotonated N(3) of the ring to one metal ion
and O(4) to the other [12,13]. (In addition, some further complica-
tions were found e.g. in the silver complexes due to argentophilic
interactions) [14].
All central metal ions in the isolated 1-methylhydantoinate
complexes belong to the soft Lewis acids group (HSAB) [15]. Thus,
it would be of interest:
As complexation to a metal ion usually modifies the biological
activity of a ligand [10], the coordination properties of various hyd-
antoins including 1-mhyd, have been also studied [11–14]. How-
ever, to the best of our knowledge there are only four known
(a) to investigate, if the borderline and hard Lewis acids can
interact with this ligand and if so, how are they bound;
(b) to pursue a more general correlation of the structure of
known metal complexes with other hydantoin derivatives
with the hardness (or softness) of Lewis acids. This may shed
more light on the understanding of the interaction of these
ligands with metal ions.
metal
complexes
with
1-methylhydantoin:
Na[Au(1-
⇑
Corresponding author. Tel.: +48 71 320 22 80; fax: +48 71 320 43 60.
E-mail address: maria.golonka@pwr.wroc.pl (M. Cies´lak-Golonka).
0277-5387/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2011.05.004

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M. Puszynska-Tuszkanow et al. / Polyhedron 30 (2011) 2016–2025
H, 5.07; N, 15.70. Found: C, 27.18; H, 5.15; N, 15.91%. Yield: 21%.
Magnetic moment: 2.77 BM.
2.3. Physicochemical studies
Elemental analyses were performed with a model Perkin–Elmer
Analyzer 2400 (CHN) and AES-ICP 3410 emission spectrometer (Ni)
using appropriate Aldrich standards. IR and FIR spectra of both the
complex and the ligand were recorded as pellets or Nujol mulls
using Perkin–Elmer FTIR 2000 (600–100 cmÀ1) and Perkin–Elmer
1600 spectrophotometer in the range 4000–400 cmÀ1
.
The electronic spectra (5000–30 000 cmÀ1) were measured on a
Cary 500 Scan UV–Vis-NIR Spectrophotometer (Varian) in diffuse
reflectance and absorption in methanol solution modes. In order
to obtain accurate values of the band positions, the spectra were
analyzed using variable digital filter method [18–24] with the fol-
lowing filter parameters: number determining the degree of reso-
lution enhancement,
a = 200.0; the integer number determining
the filter width, N = 10; the increment between points
(step) = 100 cmÀ1. For the d–d transition calculations of the crystal
field the values of Dq (Oh) and Dq, Ds, Dt (D4h) as well as Racah B
parameters for both octahedral and tetragonal symmetries have
been carried out. These calculations were based on the Tanabe-
Sugano diagrams and Perumareddi matrices (without spin–orbit
coupling parameter) for spin allowed transitions [25–27].
Thermogravimetric (TG) and differential thermal analyses
(DTA) were carried out in nitrogen atmosphere, over 40–1000 °C
range with a heating rate of 10° minÀ1 using thermogravimetry
TG-DTA system Setaram SETSYS 16/18. Calcined Al2O3 was used
as the reference material.
Scheme 1. Structure of 1-methylhydantoin (1-mhyd) and its potential binding
sites.
(c) to characterize the strength of 1-methylhydantoinate ligand
through its ranking in the spectrochemical scale; and finally,
(d) due to medical importance of the hydantoins to study cyto-
toxic activity of the ligand alone as well as its metal
complexes.
Magnetic moments were measured using an MSB-MKI instru-
ment (Sherwood Scientific Ltd.) at ambient temperature with
Co[Hg(SCN)4] as the standard.
Electrospray mass spectra (ESI-MS) were obtained in methanol
solution as positive (ESI+) and negative (ESIÀ) ion mode on a
Waters ESI-Q-TOF Premier XE. Additionally, Electron Ionisation
mass spectra (EI) for the ligand were obtained on a Waters GCT
Premier instrument.
In this work we have selected the nickel ion as the Lewis acid
because it belongs to a large group of metal ions exhibiting a bor-
derline hardness while at the same time being biologically inter-
esting [16,17].
As a natural extension of the crystallographic study of the com-
plex, the structure of the ligand has also been determined and re-
ported herein.
2.4. X-ray structure determination
Diffraction data for (L1) and (1) were collected on a Oxford Dif-
fraction four-circle single crystal diffractometer equipped with a
CCD detector using graphite-monochromated Mo K
a radiation
2. Experimental
(k = 0.71073 Å). The raw data were integrated with the CRYSALIS Data
Reduction Program (version 1.172.32.6) and included the absorp-
tion correction. The intensities were corrected for Lorentz and
polarization effects. Crystal structures were solved by the direct
methods and refined by a full-matrix least-squares method using
SHELXL-97 program [28]. All non-hydrogen atoms were refined with
anisotropic displacement parameters. The H-atoms were located
from the difference Fourier maps and refined assuming a ‘ride-
on’ model.
2.1. Crystallization of 1-methylhydantoin (L1)
Crystals suitable for a single crystal X-ray diffraction determina-
tion were obtained by slow recrystallization of the compound (Al-
drich Co.) from acetonitrile. Anal. Calc. for C4H6N2O2 (L1)
(Mr = 114.11 g/mol): C, 42.12; H, 5.26; N, 24.55. Found: C, 42.00;
H, 4.82; N, 24.04%. Yield: 75%. Colour: white.
2.2. Preparation of [Ni(H2O)4(1-mhyd)2] (1)
2.5. Antiproliferative activity
Blue crystals of (1) were prepared as follows: 0.1 mM (0.240 g)
of NiCl2Á6H2O dissolved in 10 cm3 of water was added to 0.2 mM
(0.280 g) of 1-methylhydantoin dissolved also in 10 cm3 of water.
Finally, to adjust pH value to ꢀ8.0, 1 cm3 of 0.05 M KOH aqueous
solution was added. The obtained bright blue solution was allowed
to evaporate at room temperature to ca. 10 cm3 of volume. After
72 h, blue crystals of X-ray measurement quality were obtained.
The product was filtered off and dried in vacuum. The crystals were
stable at room temperature and soluble in methanol, DMSO and
DMF. Anal. Calc. for C8H18NiN4O8 (Mr = 356.95 g/mol): C, 26.91;
The anti-proliferative tests were performed in vitro on human
cancer cell lines MCF-7 (breast adenocarcinoma), A549 (non-small
cell lung carcinoma) and mouse fibroblast cell line (Balb/3T3).
Twenty-four hours before addition of the tested compounds, the
cells were plated in 96-well plates (Sarstedt, Germany) at density
of 104 cells per well and cultured in the mixture medium. The
breast cancer cells were cultured in Eagle medium supplemented
with 2 mM glutamine (Sigma–Aldrich Chemie GmbH, Steinheim,
Germany), amino acids and insulin (Sigma–Aldrich Chemie GmbH,
Steinheim, Germany). The lung carcinoma cells were cultured in

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M. Puszynska-Tuszkanow et al. / Polyhedron 30 (2011) 2016–2025
Table 2
the mixture of RPMI 1640 and Opti-MEM (1:1) medium (where
RPMI and Opti-MEM are standard reagents used for cell culture
[29]). In this case the RPMI 1640 was supplemented with 2 mM
glutamine. The fibroblast cells were cultured in Dulbecco medium
supplemented with 4 mM glutamine and glucose. All media were
supplemented with 100 mg/cm3 streptomycin (Polfa, Tarchomin,
Selected bond lengths [Å] and angles [°] for 1-methylhydantoin (L1) and [Ni(H2O)4(1-
mhyd)2] (1).
Bond lengths [Å]
Angles [°]
(L1)
N(3)–H(3)
N(1)–C(1)
N(1)–C(2)
C(2)@O(2)
N(3)–C(2)
N(3)–C(4)
C(4)@O(4)
0.931(19)
1.444(2)
N(3)–C(4)–O(4)
C(4)–N(3)–H(3)
C(2)–N(3)–H(3)
N(1)–C(2)–O(2)
N(3)–C(2)–O(2)
N(1)–C(2)–N(1)
C(2)–N(1)–C(1)
111.87(13)
126.4(10)
121.6(10)
127.47(13)
124.60(13)
107.91(13)
123.51(14)
Poland), 100 l
g/cm3 penicillin (Polfa, Tarchomin, Poland), 5%
1.3323(18)
1.2278(18)
1.3915(18)
1.3595(19)
1.2110(18)
(A549) or 10% (MCF-7, Balb/3T3) fetal bovine serum (Sigma–Al-
drich Chemie GmbH, Steinheim, Germany). The cells were cultured
at 37 °C in humid atmosphere saturated with 5% CO2.
The in vitro cytotoxic effect of all compounds was examined
after 96-h exposure of the cultured cells to varying concentrations
of the tested compounds, using the SRB assay for adherent cells
[29]. The results are presented as the IC50 value (inhibitory con-
(1)
Ni–OW1
Ni–OW2
Ni–N(3)
Ni–OW1#1
Ni–OW2#2
Ni–N(3)#3
2.0605(14)
2.1239(14)
2.1005(17)
2.0605(14)
2.1239(14)
2.1005(17)
N(3)#1–Ni–N(3)
N(3)#1–Ni–OW1#1
N(3)#1–Ni–OW1
N(3)–Ni–OW1#1
N(3)–Ni–OW1
OW2#1–Ni–OW2
OW1#1–Ni–OW2#1
OW1–Ni–OW2#1
N(3)#1–Ni–OW2#1
N(3)–Ni–OW2#1
OW1#1–Ni–OW2
OW1–Ni–OW2
180.00(9)
89.82(6)
90.18(6)
90.18(6)
89.82(6)
180.00
89.62(6)
90.38(6)
91.00(6)
89.00(6)
90.38(6)
89.62(6)
89.00(6)
91.00(6)
180.00(8)
centration 50%), i.e. the concentration (l
g/cm3) of tested agent
which inhibits proliferation of 50% of cancer cells population). A
compound showing activity lower than 50% measured for
100 l
g/cm3 was considered an inactive agent [29]. IC50 values
were calculated separately for each experiment. Each compound
was re-tested at every concentration in triplicate in a single exper-
iment, which was repeated 3 times.
N(3)#1–Ni–OW2
N(3)–Ni–OW2
OW1#1–Ni–OW1
3. Results and discussion
The interaction of nickel(II) chloride with 1-methylhydantoin in
aqueous solution resulted in precipitation of the mononuclear
complex: trans-[Ni(H2O)4(mhyd)2] (1). Its structure determination
revealed tetragonally distorted coordination polyhedron around
the metal ion involving two N(3) atoms, one from each 1-meth-
ylhydantoinate anion and the O atoms of four water molecules.
Symmetry codes: #1 Àx, Ày + 1, Àz + 1.
The distances and angles around the heterocyclic hydantoin
ring are in good agreement and compare well with those found
in the parent hydantoin and its various derivatives like e.g. 5,5-di-
methyl(diphenyl) hydantoins [30–33]. The hydantoin ring in 1-
mhyd can be classified as essentially planar. The C(2)@O(2) bond
length is slightly longer than the C(4)@O(4) distance (Table 2),
apparently because only the O(2) atom participates in the hydro-
gen bonding network whereas the O(4) atom remains free
3.1. Crystal structure of the 1-methylhydantoin (L1)
The results of the X-ray analysis for 1-methylhydantoin are
shown in Tables 1–3 and illustrated in Fig. 1.
Table 1
Crystal data and structure refinement parameters for 1-methylhydantoin (L1) and [Ni(H2O)4(mhyd)2] (1).
Compound
(L1)
(1)
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system, space group
Unit cell dimensions
a (Å)
C4H6N2O2
114.11
295(2)
0.71073
Monoclinic, P21/c
C8H18N4NiO8
356.97
295(2)
0.71073
Monoclinic, P21/c
5.6010(10)
12.178(3)
8.090(2)
6.9349(5)
12.1963(11)
8.0162(8)
b (Å)
c (Å)
b (°)
105.64(2)
531.4(2)
4, 1.426
0.116
240
96.29(1)
673.9(1)
2, 1.759
1.487
Volume (Å3)
Z, Dcalc (g/cm3)
Absorption coefficient (mmÀ1
F(0 0 0)
)
372
Crystal size (mm)
h Range for data collection (°)
Limiting indices
0.37 Â 0.35 Â 0.35
3.35–27.48
À7 6 h 6 7
À15 6 k 6 15
À10 6 l 6 10
4850/1215 [Rint = 0.0755]
99.2%
0.32 Â 0.28 Â 0.23
3.34–27.48
À9 6 h 6 9
À15 6 k 6 15
À10 6 l 6 10
9589/1524 [Rint = 0.0512]
99.1%
Reflections collected/unique
Completeness to h
Absorption correction
None
Numerical
Maximum and minimum transmission
Refinement method
0.886 and 0.721
Full-matrix least-squares on F2
1524/0/98
Full-matrix least-squares on F2
1215/0/98
0.963
Data/restraints/parameters
Goodness-of-fit on F2
1.01.1087
Final R indices [I > 2
R indices (all data)
r
(I)]
R1 = 0.0403, wR2 = 0.1068
R1 = 0.0583, wR2 = 0.1165
0.034(11)
0.181 and À0.160
R1 = 0.0321, wR2 = 0.0897
R1 = 0.0366, wR2 = 0.0923
None
0.387 and À0.512
Extinction coefficient
Largest differences in peak and hole (e ÅÀ3
)

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Table 3
(Fig. 1b, Table 3). The most prominent pattern of hydrogen bonds is
the centrosymmetric ring R22(8) formed by the classic N–HÁ Á ÁO
interactions. The O(2) atom takes part also in the C–HÁ Á ÁO interac-
tion. This non-conventional hydrogen bonding connects 1-methyl-
hydantoin molecules together resulting in a binary chain pattern,
C22(10) (Fig. 1b). Other binary chain patterns can be also distin-
guished. However, neither of them describes the large ring,
R46(22). All of the rings and chains are part of undulated pattern
of hydrogen bonding parallel to the (À1 0 2) plane. Since the
N(3)–H(3)Á Á ÁO(2) interaction (not shown in Fig. 1) is in plane of
the 1-methylhydantoin molecule, the undulation is associated
with the weak non-conventional C(5)–H(52)Á Á ÁO(2) moiety and
sp3 hybridisation of the C(5) atom.
Hydrogen bonds geometry in 1-methylhydantoin (L1) and [Ni(H2O)4(1-mhyd)2] (1) [Å
and °].
D–HÁ Á ÁA
d(HÁ Á ÁA)
d(DÁ Á ÁA)
<(DHA)
(L1)
N(3)–H(3)Á Á ÁO(2)#1
C(1)–H(13)Á Á ÁO(4)#2
C(5)–H(52)Á Á ÁO(2)#3
1.888(19)
2.75(3)
2.8148(17)
3.450(2)
173.5(16)
136(2)
2.598(19)
3.455(2)
147.2(13)
Symmetry codes: #1 Àx, Ày, Àz; #2 x + 1, Ày + 1/2, z + 1/2; #3 Àx + 1, y + 1/2,
Àz + 1/2
(1)
OW1–H(1W1)Á Á ÁO(2) #1
1.88
1.86
1.93
1.97
2.673(2)
2.658(2)
2.803(2)
2.794(2)
146.7
156.8
178.6
172.7
OW1–H(2W1)Á Á ÁO(4)
OW2–H(1W2)Á Á ÁO(4)#2
OW2–H(2W2)Á Á ÁO(2)#3
Overall, the hydrogen bonding architecture of 1-methylhydan-
toin differs significantly from the 5,5-disubstituted analogues,
Symmetry codes: #1 Àx, Ày + 1, Àz + 1; #2 Àx, y + 1/2, Àz + 3/2; #3 Àx + 1, Ày + 1,
Àz + 1.
Fig. 1. (a) Atomic numbering scheme for 1-methylhydantoin. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of
arbitrary radii. (b) Hydrogen bonding pattern parallel to the (À1 0 2) plane shows (c) undulated feature.

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2020
Fig. 2. (a) Molecular structure of [Ni(H2O)4(1-mhyd)2]. (b) The chain and ring patterns constructed by O2W–H1W2Á Á ÁO4 hydrogen bonds viewed along the a-axis.
Table 4
Thus, the ligands create tetragonal coordination sphere around
the metal centre with the 1-mhyd anions arranged in a trans posi-
tion. The Ni–N and Ni–OW1 bond lengths are shorter than Ni–OW2
distances (Table 2) and they are similar to those found in the pre-
viously reported [Ni(NH3)2(H2O)2(pht)2] and [Ni(H2O)4(pht)2]
(pht = 5,5-diphenylhydantoin) [34,35]. The real point group sym-
metry of the [Ni(H2O)4(mhyd)2] molecule is Ci. However, the corre-
sponding interatomic angles within the coordination sphere differ
insignificantly from the ideal octahedral values and the geometric
parameters of the trans-[NiN2O4] chromophore correlate with the
D4h point group symmetry.
The water molecule, OW1, forms two intramolecular hydrogen
bonds (Table 3), both denoted by the S(6) graph set (Fig. 2a). Since
the two OW1 water molecules which are present in the coordina-
tion sphere of the nickel(II) ion are related to each other by the
inversion centre, four intramolecular hydrogen bonds are created
in one molecule of [Ni(H2O)4(mhyd)2] (Fig. 2). The second indepen-
dent water molecule OW2, participates in the inter-molecular
hydrogen bonding networks. It is noteworthy, that one OW2–
H1W2Á Á ÁO4 hydrogen bond creates a unitary chain pattern, C(6),
and it also forms separately a large ring pattern, R44(24), (Fig. 2b).
Overall, the complexes [Ni(H2O)4(1-mhyd)2] (1) and [Ni(H2O)4
(pht)2] [35] have equivalent compositions and similar structures.
However, they exhibit a different arrangement of HB networks. For
example, in the former, the N1 atom, being methylated, cannot form
hydrogen bonds.
Selected IR bands for the 1-methylhydantoin and the complex: [Ni(H2O)4(mhyd)2]
(1).
(L1)
(1)
Assignment [36,37]
3140w
–
m
m
m
m
m
(N(3)–H)
(H2O) for (1)
(C–H)
(C@O)
(C@O)
3368w
3086w 2810w
1723w
1666s
1609s
–
1479m
–
1396s
–
3045w 2955w
1768m
1709m
–
1592w
1499s
1414s
1374w
1350m
–
d(H2O) for (1)
d(C–N–H)
d(C–N–H)
d(N–H)
m
(C–N)
(H2O)
1300m
806m
442s
–
–
–
q
m
m
(M–O)
(M–N)
324s
Abbreviations: vs, very strong; s, strong; m, medium; w, weak; vw, very weak.
because the N1 atom cannot participate in hydrogen bonding net-
work as a donor of proton.
3.2. Crystal structure of trans-[Ni(H2O)4(1-mhyd)2] (1)
Complex (1) crystallizes in a centrosymmetric space group
(Table 1) with the nickel(II) ion positioned on the inversion centre.
The asymmetric unit contains one 1-methylhydantoinate anion
and two water molecules. The six coordination sphere of the
nickel(II) ion is completed by two additional water molecules
and 1-mhyd anion generated by the inversion (Fig. 2).
3.3. Infrared spectra
Table 4 presents the most important IR vibrations for both the
ligand and (1), together with proposed assignments. In the IR spec-
trum of [Ni(H2O)4(mhyd)2] (1) one may expect some new bands

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Fig. 3. Mass spectrum (ESI-MS) for 1-mhyd (L1) in methanol.
Fig. 4. Mass spectrum (EI) and fragmentation scheme for 1-mhyd (L1).
appearing due to M–L vibrations and some changes in the organic
ligand, e.g. disappearance of the N(3)–H(3) vibrations. In addition,
the bathochromic shift of the mC@O vibrations due to formation of
In FTIR spectra of the complex new bands at 324 cmÀ1 and
442 cmÀ1 were assigned to
tions, respectively [38,39].
m(M–N) and m(M–O) stretching vibra-
the HB between CO and H2O molecules can be expected (Fig. 2a).
As IR spectra of solid 1-mhyd are not available, the interpretation
was made on the basis of its known solution spectra and spectrum
of the parent hydantoin [36,37].
The comparative analysis of the IR spectra of 1-mhyd and its
Ni(II) complex confirmed the expected bathochromic shift of
3.4. Mass spectrometry
Two spectrometric techniques were used to characterize the li-
gand: ESI-MS and EI. The first one is used for molecular mass deter-
mination while the second one to show the fragmentation pattern.
The ESI-MS spectrum of (L1) (Fig. 3) shows a molecular peak at
m/z 115.0625, which can be assigned to the protonated ligand
[(L1)H]+. Additionally, the presence of ligand dimer has been also
detected (Fig. 3).
1-mhyd decomposes during the EI processes producing various
ions, among them two of significant intensity: at m/z 86.0498 and
71.0397 (Fig. 4). These particular forms are attributed to the loss of
m
(C4@O(4)) and m(C2@O(2)) vibrations in (1) (Table 4), equal to
ca. 40 cmÀ1. The change of the band positions and their intensities
in (1) is related mainly to the hydrogen bond formation involving
carbonyl oxygen atoms and OW1 and OW2 of coordinated water
molecules (Fig. 2a). The bands at 3368 cmÀ1 and 806 cmÀ1 in the
spectrum of (1), were assigned to the stretching
ing (H2O) vibrations of water, respectively.
m(H2O) and rock-
q

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M. Puszynska-Tuszkanow et al. / Polyhedron 30 (2011) 2016–2025
2022
Fig. 5. ESI-MS spectra of complex (1) in methanol. Theoretically calculated isotope (top) and experimental (bottom) patterns of peaks with m/z 451.0737 assigned as
[Ni(CH3OH)4(1-mhyd)2 + K]+.
CO (À28u) and/or NHCO (À43u), both fragments of 1-mhyd. This
mode of decomposition was observed also for other hydantoin
derivatives [40,41]. Carbon monoxide originates from C(4)@O(4)
fragments earlier identified with isotopic labelling techniques
[42]. The pathway of fragmentation indicates that the CH3 substi-
tuent remains in the final residue upon ligand decomposition. Fur-
thermore, it supports the earlier findings of poor stability of
hydantoin [40].
The molecular formula of complex (1) was corroborated by sig-
nals at m/z 451.0737 assigned to [Ni(CH3OH)4(1-mhyd)2 + K]+ (see
Fig. 5 and Section 2). The presence of methanol molecules in the
observed peak results from substitution of water with this solvent
during dissolution of the complex. For verification, complex (1)
was additionally dissolved in acetonitrile but this did not show
the solvent effect. Fig. 5 shows a comparison of the theoretically
calculated nickel isotope envelope of peaks with the experimental
results.
symmetry 10Dq has a slightly different meaning being de facto one
of three parameters i.e. Dq, Ds, or Dt, describing the CF splitting
(Table 5), the comparative analysis for Oh and D4h symmetries
was made taking into account only the Racah B parameter. Based
on the data in Table 5, it can be concluded that for the pseudooc-
tahedral symmetry (solution) the B parameters are 48 cmÀ1 lower
than those for D4h, Thus, in the solid phase (D4h), the ionicity of M–
L bonds was higher than in solution. This may be a result of greater
‘‘individuality’’ of the species in the solution phase.
Generally, CF and Racah B values obtained here for the [NiN2O4]
chromophore in (1) were found to be comparable to those for Ni(II)
complexes reported previously [43].
As the 10Dq parameter is a measure of the ligand strength, it is
also of interest to rank 1-methylhydantoin in the spectrochemical
series of ligands [27]. By application of the ‘‘average environment
rule’’ [44] i.e. based on the expression
{4
[Ni(H2O)6]2+ + 2 [NiL6]4À} the values for 10Dq for hypothetical
[Ni(1-mhyd)6]4À (assuming a monodentate coordination) can be
estimated and it was found to be equal to 10750 cmÀ1. (The
val-
D[Ni(H2O)4L2] = 1/6
D
D
D
3.5. Electronic spectra of complex (1)
ues for [Ni(H2O)4L2] and Ni(H2O)6]2+ are 9250 cmÀ1 (this work) and
8500 cmÀ1 [27], respectively). As a matter of fact, due to the size of
the ligand and its more than one donor atoms, a more realistic for-
mula for the compound should be [Ni(1-mhyd)3]À chelate.
Thus, 1-methylhydantoin can be placed in the spectrochemical
series for the octahedral NiL6 (and pseudooctahedral Ni(L–L)3)
complexes with one type of ligand as follows (the magnitudes of
splitting in cmÀ1 given in brackets):
H2O (8500) < py (10 150) < NH3(10 750) < 1-mhyd (10 750) < en
(11 700) < bpy (12 650).
The position of 1-mhyd close to ammonia suggests that the
average environment rule can be applicable to this complex. Thus,
on the spectrochemical scale the 1-mhyd was found to be a rather
moderately strong one.
The crystallographic data revealed that microsymmetry of the
nickel surroundings in complex (1) is tetragonal (D4h). The splitting
of the first d–d band in the reflectance spectra is in line with this
approach (Fig. 6a). However, in solution, the bands exhibit only
some asymmetry (Fig. 6b) thus for this phase the analysis assum-
ing pseudooctahedral approximation has been carried out. Addi-
tionally, the value of the
e coefficient (6.5) is in line with the
respective values for [Ni(A2B4)] [27,59]. In the literature both ap-
proaches i.e. pseudooctahedral and tetragonal were used in the
interpretation of the [Ni(A2B4)] complexes (see for example
[59,60]). As there is no clear criterion we adopt here a distinct
splitting of the d–d bands (at least one) in the spectrum as a con-
dition for a tetragonality. The results are presented in Scheme 2,
Table 5 and Fig. 6. For solution phase (pseudooctahedral symme-
try) the crystal field splitting (10Dq) and Racah B parameter (a
measure of interelectronic repulsion) were obtained from the Tan-
abe–Sugano diagram (Table 5) [27]. In view of the fact that for D4h
The value of the experimental magnetic moment obtained for
the nickel(II) complex is 2.77 lB (see Section 2). This value is
slightly lower than those usually observed for nickel(II) octahedral
complexes (leff 2.90, lso 2.83 lB) [45–47]. The lowering of l value

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M. Puszynska-Tuszkanow et al. / Polyhedron 30 (2011) 2016–2025
Fig. 6. Spectrum of [Ni(H2O)4(1-mhyd)2] in the solid phase (a) and methanol (b).
can be attributed to the real symmetry of (1) which is lower than
Oh [27].
3.7. Complexes of hydantoins with ‘‘soft’’, ‘‘borderline’’ and ‘‘hard’’
Lewis acids
The literature search showed that 1-methylhydantoin complex
with Ni(II) (1) is the first isolated species of this ligand with the
borderline metal cation (HSAB). The others examples are very soft
(Au+) and soft (Pt2+, Ag+, Hg2+) (Table 6).
Analysis of the binding modes of metal ion complexes with
other hydantoins (Table 6) provides some general observations
on the structure of their first coordination spheres in relation to
the metal ionic radius and its hardness. The following relationships
have been observed:
3.6. Thermal decomposition
The main goal of thermogravimetric studies was to confirm
(indirectly) the presence and position of water molecules in the
complex (1). Generally, the loss of coordinated water is manifested
through endothermic effect in the range between 140 and 230 °C
while the water of crystallization is released earlier i.e., between
50 and 120 °C [48,49]. TG and DTA data for the complex (1) showed
the weight loss between 140 and 220 °C, which is attributable to
the elimination of four water molecules from the first coordination
sphere (mass loss 20.17%, 22.74%, calculated and found, respec-
tively). This observation is supported by the enthalpy changes
(endothermic effect – 32 kJ/mol) related to the complete loss of
coordination water in (1). The observed weight loss during the next
step is in accordance with the calculated value for the release of
two hydantoin molecules (55.13% and 58.86% calculated and
found, respectively). The subsequent decomposition occurs be-
tween 220 and about 600 °C, leading finally to NiO (exp. solid res-
idue 22.13 calcd. 20.90%).
(a) For a very soft (Au+) and a very hard (K+) cations (both are
very large, see Table 6) the coordination of hydantoins is
monodentate through N and O atoms, respectively.
(b) The same mode of coordination is valid for small borderline
cations (Ni2+ and Zn2+) but exclusively through N atoms.
(c) Soft cations but smaller than Au+ can coordinate through N
to one metal ion and O to the other forming a coordination
polymer.
It can be stated that the HSAB principle is valid for hydantoin
complexes as a very soft Au+ does not interact with oxygen,
whereas soft Lewis acids have preference for both donors, conse-
quently forming polynuclear forms [57]. On the contrary, a very
Summing up, the results of analysis, IR and solid state electronic
spectra, mass spectroscopy and thermal data are consistent with
the structure determined by X-ray analysis for (1).

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M. Puszynska-Tuszkanow et al. / Polyhedron 30 (2011) 2016–2025
Scheme 2. Correlation diagram (d8 configuration) for Oh and D4h symmetries (a) and the effect of filtration of the solid state spectrum of (1) (b).
Table 5
its nickel complex are inactive in the inhibition of cell proliferation.
The band positions, assignment of the electronic spin-allowed transitions in the
In general, hydantoins are found to be cytotoxically inactive but
the complexation to a metal ion e.g. Ag+ may produce strong pro-
liferative agents [14,58]. This activity was found to be also a cell
line selective [58]. The present work shows no cytotoxic activity
of both the ligand and its Ni complex.
spectra and crystal field and Racah B parameters for [Ni(H2O)4(mhyd)2] (1) (in cmÀ1).
Absorption
Reflectance
Transition from ground state (3A2g
)
a
Oh
D4h
3T2g (3F)
9000
3Eg
8450
3B2g
3A2g
3E2g
3A2g
3Eg
11 300
13 900
16 050
24 800
26 600
3T1g (3F)
3T1g (3P)
15 100
25 300
4. Summary and conclusions
1-Methylhydantoin interacts with Ni(II) ion to form a mononu-
clear mixed ligand species of the formula trans-[Ni(H2O)4L2]. The
single crystal X-ray diffraction data revealed an interesting HB net-
work both in the free ligand (classic and non-conventional) and in
the complex (conventional intramolecular bonding). The analysis
of electronic spectra showed the significance of the phase and
the adopted symmetry model in the calculation of the crystal field
parameters. In the spectrochemical series 1-methylhydantoin was
found to be positioned close to ammonia, i.e. appearing as a mod-
erately ligand. Both 1-methylhydantoin and its nickel complex
exhibited no cytotoxic activity in vitro against three cancer cell
lines.
Comparative analysis of the mixed ligand Ni(II) complex with 1-
methylhydantoin and other hydantoin derivative complexes shows
dependence of the mode of ligand binding upon metal ion hard-
ness in the frame of the HSAB theory. Both very soft and very hard
Lewis acids coordinate this ligand through only one donor atom:
nitrogen and oxygen, respectively. With soft acids polynuclear spe-
cies were formed due to binding through N(3) donor atom to one
metal central atom and oxygen atom to the other. For borderline
Lewis acids the coordination is mononuclear again. The results of
the current work combined with the literature data can be used
as the basis for further studies on the structural dependence of
hydantoin complexes upon metal hardness.
CF and Racah parameters
a
Oh
D4h
Dq
B
925
841
–
1148
889
329
172
ÀDt
Ds
–
a
Resolved with the digital filtration.
hard cation (K+) shows, as expected, preference for the oxygen
atom of the ligand.
The borderline small cations (Zn2+, Ni2+) bind to nitrogen atom
of the ligand with formation of mononuclear complexes.
As the above observations are based on limited data, more stud-
ies are needed to verify the information included in Table 6.
3.8. Antiproliferative activity
The compounds 1-mhyd (L1) and its Ni(II) complex (1) were
subjected to cytotoxic activity tests carried out in vitro against
three cancer cell lines: breast (MCF-7), lung (A549) and mouse cell
line fibroblasts mouse fibroblast cell line (Balb/3T3). The results re-
vealed that in the studied concentration range both the ligand and

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M. Puszynska-Tuszkanow et al. / Polyhedron 30 (2011) 2016–2025
Table 6
The mode of ligand coordination in hydantoin derivatives in relation to metal hardness [50,51] and ionic radius [52].
Metal ion
Hardness (
g
)
Ionic radius (pm)
Donor atoms coordinated to the metal ions
References
1-Methylhydantoin
5,5-Diphenylhydantoin
5,5-Dimethylhydantoin
Soft
Au+
Ag+
5.4
6.9
7.7
8.0
137
115
102
86
N(3)
–
–
–
–
–
–
–
–
[11]
[14]
[13]
[12]
N(3), O(4)
N(3), O(4)
N(3), O(4)
Hg2+
Pt2+
Border line
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Acknowledgments
´
The authors are thankful to Ms. E. Mróz and Dr. A. Adach for
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analysis, respectively. The helpful comments and language correc-
tion from Dr. W. Roth are greatly acknowledged. The author (MPT)
wishes to acknowledge the Polish Ministry of Higher Education
and Science for financial support (grant no. NN204 331037). Grant
from Wrocław University of Technology is also acknowledged.
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