Crystal structure, DFT, spectroscopic and biological activity evaluation of analgin complexes with Co(ii), Ni(ii) and Cu(ii)

Article abstract of DOI:10.1039/c4dt02366h

Reaction of analgin (NaL) with Co(ii), Ni(ii) and Cu(ii) salts in ethanol affords complexes of the type [ML₂], which were characterized by elemental analysis, FT IR, UV-Vis, EPR, TG/DTA, magnetic susceptibility and conductance measurements. The copper(ii) complex crystallizes in the orthorhombic Pbca space group. Analgin behaves as a mono-negatively tridentate ligand via pyrazolone O, sulfonate O and tertiary amino groups. The interaction of the tertiary nitrogen with Mⁿ⁺ ions is the main factor which determines the stability of complexes as revealed from natural bond orbital analysis data, where the binding energy of [ML₂] decreases with an increase in the bond length of the M-N bond. Time-dependent density functional theory calculations were applied in order to realize the electronic structures and to explain the related experimental observations. The anti-bacterial activity was studied on Staphylococcus aureus and Escherichia coli. Coordination of analgin to Ni(ii) and Cu(ii) leads to a significant increase in its antibacterial activity as compared with the Co(ii) complex. This journal is

Full text of DOI:10.1039/c4dt02366h

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Crystal structure, DFT, spectroscopic and
biological activity evaluation of analgin complexes
with Co(II), Ni(II) and Cu(II)†
Cite this: Dalton Trans., 2014, 43,
15950
Ahmed M. Mansour
Reaction of analgin (NaL) with Co(II), Ni(II) and Cu(II) salts in ethanol affords complexes of the type [ML2],
which were characterized by elemental analysis, FT IR, UV-Vis, EPR, TG/DTA, magnetic susceptibility and
conductance measurements. The copper(II) complex crystallizes in the orthorhombic Pbca space group.
Analgin behaves as a mono-negatively tridentate ligand via pyrazolone O, sulfonate O and tertiary amino
groups. The interaction of the tertiary nitrogen with Mn+ ions is the main factor which determines the
stability of complexes as revealed from natural bond orbital analysis data, where the binding energy of
[ML2] decreases with an increase in the bond length of the M–N bond. Time-dependent density func-
tional theory calculations were applied in order to realize the electronic structures and to explain the
related experimental observations. The anti-bacterial activity was studied on Staphylococcus aureus and
Escherichia coli. Coordination of analgin to Ni(II) and Cu(II) leads to a significant increase in its antibacterial
activity as compared with the Co(II) complex.
Received 4th August 2014,
Accepted 28th August 2014
DOI: 10.1039/c4dt02366h
www.rsc.org/dalton
The mode of action involves the hydrolysis to 4-methyl-
aminoantipyrine, with the latter further converted to other
Introduction
Analgin (dipyrone, metamizole or novalgin) (Scheme 1) is the metabolites by various enzymatic reactions.5 Analgin
sodium salt of [(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)- forms the active constituent of several drugs and a binary
methylamino]methanesulfonate. This drug presents antipyre- mixture with acetylsalicyclic acid and paracetamol. Several
tic and analgesic activity1 as well as other beneficial effects analytical techniques such as UV-Vis6 and fluorescence spec-
such as a vascular smooth muscle relaxant, anti-apoptotic, troscopy,7 HPLC,8 flow injection analysis,9 and polarogra-
and anti-convulsant.2 Analgin has both spasmolytic action and phy10 were applied for the determination of analgin in the
analgesic effect that makes it a favorable drug for colic pain.3 pharmaceuticals.
However, the administration of analgin may be associated with
So far, pyrazolone and its derivatives were acknowledged to
severe effects such as chemical intolerance and agranulocytosis.4 possess a wide range of industrial and pharmaceutical appli-
cations, which have attracted considerable scientific and
applied interest.11,12 Thus, it was essential for inorganic che-
mists to shed more light on the coordination behavior of
analgin. To the best of my knowledge, no X-ray crystal data for
metal complexes of analgin were reported in the literature,
which makes the structures of these compounds ambiguous.
Binary complexes of the type ML2 (M = CoII, NiII, CuII, and
ZnII) and Cd(NaL)2Cl2 were reported by Tatwawadi,13 who
assumed the interaction of analgin with Mn+ as a bidentate
ligand. Several mixed-ligand complexes of VOII, CrIII, MnII,
Scheme 1 Synthesis of [ML2] complexes (NaL = analgin drug).
CoIII, NiII, MoII, WO2VI, and HgII metal ions were also syn-
thesized and characterized by Maurya et al.14 supposing that
Chemistry Department, Faculty of Science, Cairo University, Gamaa Street,
analgin coordinated through only the pyrazolone O atom.
Besides, the reaction between analgin and FeIII in the presence
Giza 12613, Egypt. E-mail: inorganic_am@yahoo.com, mansour@sci.cu.edu.eg;
Fax: +20 2 35728843; Tel: +2 02 01222211253
of different anions was followed by means of UV, IR, and pH-
†Electronic supplementary information (ESI) available. CCDC 986306. For ESI
metric titrations.15 The composition and stability of HgII com-
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
plexes were pH-metrically studied,16 where the development of
c4dt02366h
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complexes assumed to proceed through only the pyrazole ring
O and SO3 group.
Table 1 Crystal data and structure refinement for 3
Molecular formula
C26H32CuN6O8S2
The search for new effective antimicrobial agents is of para-
mount importance, but the discovery of new drugs having
completely new chemical structures is time consuming and
expensive. Thus, molecular structure modification is better
and desirable. Analgin presents a chemical structure that
favors chemical modifications by means of complexation with
some transition metal ions. In the present study, Co(II), Ni(II)
and Cu(II) complexes of the analgin antipyretic drug were syn-
thesized, characterized, and tested for their biological activity
against Staphylococcus aureus and Escherichia coli. Structural
properties have been studied both experimentally and theoreti-
cally and are correlated here. Natural bond orbital (NBO) ana-
lysis has also been performed to provide details of the type of
hybridization and the nature of bonding in the studied com-
plexes. With the aim of understanding the electronic struc-
tures of the complexes and the related experimental
observations, TD-DFT calculations were applied.
Formula weight
Crystal system
Space group
Color
Wavelength (Å)
Unit cell dimensions (Å, °)
a
b
c
α
β
γ
V
Z
684.25
Orthorhombic
Pbca
Green
0.7107
10.607(2) Å
15.644(3) Å
17.786(4) Å
90.00°
90.00°
90.00°
2951.3 (10) Å3
4
T (K)
298
1.540
0.941
1420.0
Dx (g cm−3
)
Absorption coefficient (mm−1
F(000)
)
Theta range for collection
Index range
Absorption correction
Max. and min. transmission
Minimum/maximum transmission
Refinement method
Criterion
Data/parameters/restraints
Goodness of fit on F2
R(all)
R(gt)
wR(ref)
wR(gt)
Reflections (all)
Reflections (gt)
27.478–2.910
h = 0→13, k = 0→20, l = 0→23
Multi-scan
0.708 and 0.589
0.613/0.403
Full matrix least squares on F2
I > 2.00σ(I)
3339/199/0
1.029
0.0904
0.0458
0.1279
0.1079
3339
Results and discussion
Structural characterization
The reaction of Co(NO3)2·6H2O, Ni(CH3COO)2·4H2O, and
Cu(NO3)2·3H2O with two equivalents of analgin in ethanol
affords pink (1), blue (2) and crystalline green (3) complexes of
the type [ML2] in that order (Scheme 1). These complexes were
characterized by elemental analysis, TG/DTA, IR, EPR, UV-Vis,
and magnetic and conductance measurements. However,
unambiguous proof of the tridentate behavior of analgin via
pyrazolone O, sulfonate O and tertiary amino group to the
metal ions finally came from the single crystal X-ray analysis of
complex 3. Relevant parameters are listed in Table 1 and the
molecular structure of [CuL2] is shown in Fig. 1. Among the
various vibrational bands of analgin, studies of the CvO, C–N,
and SO3 modes were found to be useful in determining the
coordination sites. The FT IR spectrum of analgin showed a
strong CvO stretching band at 1660 cm−1, which shifted to a
lower wave number, 1604 (1), 1611 (2), and 1600 (3), suggesting
the participation of the CvO group in the coordination sphere
of the metal ions. The assignment of the stretching bands of
the C–N and SO3 groups in the region between 1400 and
1000 cm−1 is not easily interpreted owing to their overlap
with the aromatic bands. Therefore, it was necessary to
compare first the spectrum of analgin with that of phenazole,
which have a similar structure, but without attaching the
–N(CH3)CH2SO3Na group to position 4 of the pyrazolone ring.
2072
Fig. 1 Molecular structure of complex 3 with ellipsoids drawn at the
50% probability level.
In general, the non-coordinated anionic SO3 shows two bands corresponding to asymmetric and symmetric modes.18 In
due to the asymmetric and symmetric stretching modes.17 On addition, the νss(SO) at 1051 cm−1 in analgin was shifted to
coordination to the metal ion, three ν(SO) bands are observed 1019 (1), 1022 (2), and 1030 cm−1 (3) suggesting the contri-
as the C3v-symmetry is broken. Comparison of analgin with bution of SO3 in the complex formation. The ν(C–N) in the
phenazole showed two new bands at 1182 and 1051 cm−1 uncoordinated analgin was found at 1343 cm−1, and shifted to
assigned to νss(SO), while the asymmetric mode is overlapped. ≈1331 cm−1 in complexes. The most noteworthy observation is
In complexes, the SO3 group gave rise to a doublet structure at that the anion of the metal salt has no role in the complex for-
(1265, 1166) (1), (1263, 1169) (2), and (1245, 1196 cm−1) (3) mation, as the IR spectra of the complexes which were pre-
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3
pared from either the chloride or acetate salts are typical. n–π* (CvO) and A2g→3T1g (F) (ν2), respectively, in an octa-
Therefore, analgin behaves as a N,O,O tridentate ligand hedral geometry. The μeff of 2 is found to be 3.70μB (298 K) in
towards Mn+ ions.
the presence of spin–orbital coupling.24 This value exceeds the
21
For complexes 1 and 3, the thermal decompositions start spin-only value, but is not as high as μs+L
.
This happens
from 270 and 236 °C with a continuous weight loss in the because the electric fields of atoms, ions, and molecules sur-
temperature range of 270–546 and 236–561 °C respectively. rounding the metal ion in its compounds restrict the orbital
Three endothermic stages at 253, 383, and 513 °C for 1 and at motion of the electrons so that the orbital angular momentum
220, 269, and 478 °C for 3 were identified and assigned to and hence the orbital moments are partially quenched. For
organic ligand decomposition with high percentage of the octahedral Cu(II) complexes, it has been established that the
final residues (18.24% for 1 and 16.37% for 3) at 1100 °C. The split of 2Eg and 2T2g states of the 2D ground state may keep the
2
2
2
final residue may be considered to be CoS2 (calcd 17.99%; 1) three B1g→2A1g (ν1), B1g→2B2g (ν2) and B1g→2Eg (ν3) elec-
and carbonized CuS (calcd 15.72%; 3).19 The simultaneous tronic transitions unresolved in the spectra of the elongated
TG/DTA of 2 showed that the thermal decomposition takes tetragonal or rhombic distortion (D4h symmetry) geometries.
place via three complicated stages maximized at 274, 411, and Complex 3 showed four bands in DMF at 270, 375, 485, and
475 °C. These steps bring the total mass loss up to 88.73% of 780 nm. The broad band at 780 nm can be assigned in terms
the parent complex. Such mass loss is close to the calculated of overlapping of the ν1–ν3 bands in an octahedral geometry.
value (89.08%) expected for the formation of NiO as a final The band at 485 nm has LMCT character, which may be ori-
residue.
ginated from the SO3 group, while those at 270 and 375 nm
are attributed to π–π*/aromatic and n–π*(CvO), respectively.
The μeff of 3, corrected for diamagnetic and temperature-inde-
pendent paramagnetic contributions, is 2.57μB (298 K). This
value is higher than the spin-only value expected for non-inter-
Electronic structure, magnetic and EPR measurements
The crystal field theory of high spin octahedral Co(II) com-
plexes20 predicted three spin allowed d–d transitions, namely
3
acting CuII ions (S = 1/2, t2g6eg ), but is in the acceptable range
4T1g→4T2g(F) (ν1), T1g→2A2g (ν2) and T1g→4T2g(P) (ν3). The
electronic spectrum of 1 showed only one band in DMSO at
275 nm as well as a shoulder at 420 nm assigned to the π–π*/
aromatic system and n–π*(CvO)/4T1g→4T2g(P) (ν3), respect-
ively. The effective magnetic moment (μeff) of 4.71μB for
complex 1 further complements the electronic spectral find-
ings as this value lies in the acceptable experimental range
(4.10–5.20μB) for high spin cobalt(II) complexes.21 The elec-
4
4
for Cu(II) complexes.21
The X-band EPR spectrum of 3 in the solid state (Fig. 2) at
298 K exhibits typical four line noticeable 63/65Cu (I = 3/2)
hyperfine splitting with g = 2.320 (A = 143 × 10−4 cm−1) and
k
k
g⊥ = 2.074 characteristic of mononuclear copper(II) complexes
having rhombic-octahedral with the elongation of the axial
bonds or square-based pyramidal symmetries and dx2−y2
orbital in the ground state. This spectrum is usually obtained
with a large ligand like analgin that increases the Cu–Cu dis-
tance and decreases the line width.25 The geometric parameter
G, which is a measure of the exchange of interactions between
the copper centers in a powdered sample, has been calcu-
3
tronic ground state of octahedral Ni(II) complexes is A2g and
three spin-allowed transitions: A2g→3T2g (ν1), A2g→3T1g(F)
3
3
(ν2), and A2g→3T1g(P) (ν3) are expected.22 Some octahedral
3
Ni(II) complexes23 showed a weak broad band at about 790 nm
corresponding to the spin-forbidden A2g→1Eg transition.
3
lated26 as G = (g − 2.0023)/(g⊥ − 2.0023). According to
Complex 2 displayed three bands in DMSO at 275, 400 and
535 nm assigned to the internal ligand transitions, MLCT/
k
Hathaway27 if G > 4, the exchange interaction is negligible and
Fig. 2 EPR spectrum of complex 3.
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G < 4 indicates exchange interaction. The value of G is found each other through O2SO⋯H–C with a distance of 2.734 Å
to be 4.32 indicating the absence of moderate exchange inter- (Fig. 3b).
actions among the copper molecules in the solid state.
DFT/TD-DFT
Crystal structure
To obtain an insight into the geometrical and electronic struc-
tures of the investigated complexes, [ML2] (M = Co(II), Ni(II),
and Cu(II)) were optimized (Fig. S1†) at the DFT/B3LYP level of
theory starting from the X-ray structure coordinates of the
Cu(II) complex. The complexes were characterized as local
minima through harmonic frequency analysis. Selected calcu-
lated bond lengths and angles are compared in Table S1.†
Good agreement was found for the Cu–O bonds, while the
value of the Cu–N bond is overestimated by the DFT method.
The M–N bond distance increases from Ni to Co and then Cu.
The bond angles slightly differ by 2–3°. This happens because
the calculations are performed in the gaseous state, whereas
packing molecules with inter- and intra-molecular interactions
are treated in the experimental measurements. The nature of
the electronic transitions observed in the UV-Vis spectra of the
complexes has been studied by time-dependent DFT. The
lowest 30 singlet-to-singlet spin-allowed excitation states were
calculated using the same functional and basis set for the geo-
metry optimization. In the model structures of the investigated
complexes, to reduce the computer time, the phenyl ring and
two methyl groups attached to the pyrazolone ring were
replaced by H atoms. The calculated d–d excitation wave-
lengths, energies of other excitation transitions ( f > 0.002) and
their assignments are tabulated in Table S2.† As expected, the
d–d transitions are forbidden and their oscillator strengths are
also close to 0.0. In the 320–800 nm region, the stimulated
spectrum of the Co(II) complex showed three forbidden tran-
sitions at 761, 533 and 484 nm as well as a highest energy
band at 335 nm corresponding to H(β) → L+2(β), H(β) →
L+5(β), H−1(β) → L+5(β) and H(β) → L(β) (H: HOMO and
L: LUMO). The HOMOs are mainly composed of Co d charac-
ter, and the LUMO orbital is of Co dz2nature (Table S3†). The
transition energy at 761 nm has a ground state composed of
Co d character, whereas the excitation state is of pyrazolone π*
orbitals forming a MLCT. Similarly, the low oscillator strength
X-ray single-crystal diffraction data revealed that complex 3
crystallizes in the orthorhombic Pbca space group. A view of
the molecular structure of 3 is shown in Fig. 1. Selected crystal-
lographic data are presented in Table 2. The six-coordinated
Cu(II) ion is arranged in a slightly distorted octahedral geome-
try, where two analgin molecules lying in a trans-conformation
are acting as tridentate chelators forming four stable five-mem-
bered rings. An inversion centre of symmetry is found at the
copper atom, where the two ligands are adjusted in a linear
way, but pointing in opposite directions. The structure is
coplanar, where the bond angles O2–Cu–O2i, N9–Cu–N9i, and
O13–Cu–O13i equal 180°. The coordination sphere consists of
two pyrazolone oxygen atoms [CuO2 = 2.007(2) Å], two N atoms
[CuN9 = 2.009(2) Å] and two oxygen atoms [CuO13 = 2.321(2)
Å] of SO3 groups. The two covalent Cu–O13 bond lengths are
equal, but they are longer than the Cu–O2 bond distances.
As shown in Table 2, the distortion around the copper atom
is low, where the bond angles are slightly deviating from
those of a regular octahedron. In the crystal packing, it is poss-
ible to observe π–π stacking interactions between the ring
planes (Fig. 3a), and also the molecules are cross-linked to
Table 2 Selected experimentally determined bond lengths (Å) and
angles (°) for complex 3
Bond length (Å)
Angles (°)
Cu–O2
Cu–O2i
Cu–N9
Cu–N9i
Cu–O13
Cu–O13i
2.007 (2)
2.007 (2)
2.099 (2)
2.099 (2)
2.321 (2)
2.321 (2)
O2–Cu–O2i
N9–Cu–N9i
O13–Cu–O13i
O2–Cu–N9
O2–Cu–O13
N9–Cu–O13
O2–Cu–O13i
O2–Cu–N9i
N9–Cu–O13i
180.00 (5)
180.00 (13)
180.00 (5)
87.66 (8)
92.17 (9)
83.71 (9)
87.82 (9)
92.34 (8)
96.29 (9)
Fig. 3 (a) A view showing the π–π stacking interactions of the phenyl rings; (b) cross-linking of copper complexes to each other through
O2SO⋯H–C.
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transitions at 533 and 484 nm are MLCT to the π* system of The bands at 569 and 526 nm are of LMCT character, originat-
the SO3 groups. The band at 335 nm can be assigned to dxz ing from the pyrazolone rings and SO3 groups and going to
→
dz2 in an octahedral structure. The HOMO–LUMO gap in 1 is Cu dz2. The highest energy bands at 462, 426, and 347 nm with
4.22 eV, which is higher than that of 2. The TD-DFT spectrum significant oscillator strengths are all of π–π* character.
of 2 displayed three transitions at 484, 415 and 409 nm with
Natural bond orbital (NBO) analysis
oscillator strengths of 0.0002, 0.0017, and 0.0011, respectively.
HOMO and HOMO−1 show predominantly 3d character. According to NBO,28 the electronic arrangement of Co in 1 is:
HOMO−4, which is lower than HOMO by 3.65 eV, results from [Ar]4s0.203d7.564p0.414d0.015p0.01 with 8.167 valence electrons.
1.858
0.751
1.736
1.421
the π system of the pyrazolone rings (Table S4†). The two The occupancies of Co 3d are: dxy
dxz
dyz
dx2−y2
LUMOs (LUMO and LUMO+1) are lying close to HOMO with a dz21.794. The calculated natural charge was found to be 0.821 as
small energy gap (0.81 eV) between HOMO and LUMO. These a result of electron density donation from two tridentate mole-
orbitals are a mixture of π* orbitals resulting from the two co- cules. Similarly, the electronic configuration of the Ni atom in
ordinated pyrazolone moieties. Hence, the electronic tran- 2 is [Ar]4s0.203d8.604p0.395p0.01 with about one electron more in
sitions: H−1 → L (484 nm)/H → L+1 (409 nm) and H−4 → L the d sub-shell (9.189) compared with complex 1, indicating
(415 nm) are MLCT and π–π* characters, respectively. The cal- that the quantity of the electron density donation from the two
culated spectrum of 3 is characterized by three lowest energy ligands is the same or slightly more excess in the NiII center.
1.984
1.512
1.919
1.326
electronic transitions at 809, 569, and 526 nm assigned to The occupancies of Ni 3d are: dxy
dxz
dyz
dx2−y2
H(β) → L, H−1(β) → L, and H−3(β) → L, respectively. As shown dz21.857. For complex 3, the electronic arrangement of Cu is
in Fig. 4, the MOs from HOMO−3 to LUMO are mainly of Cu d [Ar]4s0.243d9.334p0.375p0.01 distributed as 18 core electrons,
character and energetically well separated from the next lower 9.935 valence electrons (on 4s, 3d, and 4p atomic orbitals) and
occupied MOs. The LUMO orbital with β-spin is mainly of Cu 0.010 Rydberg electrons (mainly on the 5p orbital) giving a
dz2 character, whereas the HOMO orbital is coming from the total of 27.945 electrons and leaving 1.053. The occupancies
1.985
1.529
1.873
1.965
Cu dxy. Hence, the electronic transition at 809 nm is assigned of Cu 3d are: dxy
dxz
dyz
dx2−y2
dz21.973. The
to dxy → dz2 characteristic of the octahedral Cu(II) complexes. strength of interactions between the metal ion and donor sites
can be estimated by the second order perturbation theory. The
larger the E2 value, the more intensive is the interaction
between electron donors and electron acceptors. For complex
1, the E2 values are 290, 120, and 280 cal mol−1 for LP(2)-
O2→RY*(2)Co/LP(2)O39→RY*(2)Co, LP(1)N4→RY*(2)Co/LP(1)-
N41→RY*(2)Co and LP(3)O5→RY*(2)Co/LP(3)O43→RY*(2)Co,
in that order. These M–L interactions have energies of 230,
490, and 70 cal mol−1 in 2, and 420, 30 and 120 cal mol−1 in
complex 3, respectively. Binding energies are defined as the
total energy of the complex minus the sum of total energies of
the most stable isolated moieties.29 Complex 2 is more stable
than 1 by ≈2.813 kcal mol−1 and than 3 by 22.615 kcal mol−1
.
Thus, the stronger the binding capability is, the more stable
the complex will be, and the higher the metal binding selecti-
vity of a ligand to the metal ions will be. The interaction of the
tertiary nitrogen with Mn+ is the main factor determining the
stability of the studied complexes, where the binding energy
decreases with an increase of the M–N bond distance.
Antibacterial activity
The antimicrobial activities of analgin and its complexes were
studied using two microbes S. aureus and E. coli and compared
to tetracycline which was used as a standard. Preliminary
screening was carried out at 20 mg mL−1. In classifying the
antibacterial activity as Gram-positive or Gram-negative, it
would be expected that a much greater number of drugs would
be active against Gram-positive than Gram-negative bacteria.30
Analgin showed lower activity against S. aureus (G+) than tetra-
cycline, and was inactive against E. coli. It is clear from the
inhibition zone diameter data of the investigated complexes
that the antibacterial activity of analgin is affected by the type
of the divalent cation. Coordination of analgin to Co(II) did not
Fig. 4 Theoretical electronic absorption transitions of complex 3.
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alter the toxicity, but the formation of complexes 2 and 3 and heated to reflux (1–3 h), where pink Co(II) (1), blue Ni(II)
results in excellent activity against the resistant E. coli (G−), as (2) and crystalline green Cu(II) (3) complexes were precipitated.
well as S. aureus bacterium. The activity of 2 and 3 did not dis- Diffusion of analgin solution to Cu2+ ions in ethanol gave
criminate between the tested organisms. The higher toxicity of green crystals suitable for X-ray structure analysis. Lower molar
2 and 3 can be explained by Tweedy’s chelation theory,31 conductance values (in DMF) were reported for the complexes
which explicated that the lipophilicity of the free organic compared with the reported values32 for 1 : 1 (65–90 Ω−1 cm2
ligand is changed by reducing the polarizability of the Mn+ ion mol−1) and 1 : 2 (130–170 Ω−1 cm2 mol−1) electrolytes in DMF,
via the L→M donation, and the possible electron delocaliza- indicating their non-electrolytic nature.
tion over the complexes. Lipophilicity is an important factor
• Complex
1
(C26H32CoN6O8S2): Yield: 73%: %Calcd
associated with the membrane permeation in biological (%Found). C, 45.95 (45.48); H, 4.75 (4.77); N, 12.37 (12.63). FT IR:
systems: the higher the lipophilicity, the easier the penetration 1604, ν(CvO); 1331, ν(C–N); 1256 νass(S–O); 1166 νss(S–O); and
in the cell through the cellular membrane.
1019 νss(S–O) cm−1. UV-Vis (DMF): 275 and 420 nm. μeff = 4.71μB
(298 K). Molar Cond. (10−3 M, DMF): 13.51 Ω−1 cm2 mol−1
• Complex (C26H32N6NiO8S2): Yield: 77%: %Calcd
.
2
(%Found). C, 45.96 (45.39); H, 4.75 (4.78); N, 12.37 (13.50). FT
Conclusion
IR: 1611, ν(CvO); 1331, ν(C–N); 1263 νass(S–O); 1169 νss(S–O);
Co(II), Ni(II), and Cu(II) complexes of the analgin antipyretic and 1022 νss(S–O), cm−1. UV-Vis (DMF): 275, 400 and 535 nm.
drug were prepared in good yields, characterized, and tested μeff
for their biological activity against S. aureus and E. coli. 13.01 Ω−1 cm2 mol−1
Unequivocal proof of the tridentate nature of analgin came • Complex
=
3.70μB (298 K). Molar Cond. (10−3 M, DMF):
.
3
(C26H32CuN6O8S2): Yield: 68%: %Calcd
from the X-ray crystallography data. The M(II) ion is arranged (%Found). C, 45.64 (44.80); H, 4.71 (4.64); N, 12.28 (12.27). FT
in a slightly distorted octahedral geometry, where two analgin IR: 1600, ν(CvO); 1331, ν(C–N); 1245 νass(S–O); 1196 νss(S–O);
molecules are acting as tridentate chelators forming four and 1030 νss(S–O), cm−1. UV-Vis (DMF): 270, 375, 485 and
stable five-membered rings. The experimental studies were 780 nm. μeff = 2.57μB (298 K). Molar Cond. (10−3 M, DMF):
complemented by quantum chemical calculations. Coordi- 18.12 Ω−1 cm2 mol−1
.
nation of analgin to Co(II) did not alter the toxicity, but the
formation of Ni(II) and Cu(II) complexes results in excellent
activity against the tested organisms.
X-ray diffraction analysis
Crystallographic data were collected on an Enraf-Nonius CAD4
single crystal X-ray diffractometer with graphite monochro-
mated Mo-Kα radiation (λ = 0.71073 Å) at 298 K. All the diffr-
acted intensities were corrected for Lorentz-polarization and
absorption.33,34 The structure was solved using the SIR9235
computer program in the space group Pbca and then refined
Experimental
Synthesis of complexes
Instruments. FT IR spectra were recorded as potassium with the SHELX software package.36 All hydrogen atoms were
bromide pellets using a Jasco FTIR 460 plus in the range of included in calculated positions. The figures involving hydro-
4000 to 200 cm−1. Elemental microanalysis was performed gen-bonds and packing were drawn using Mercury.37 Crystallo-
using Elementer Vario EL III. TG/DTA analysis was performed graphic data have been deposited with the Cambridge
under a nitrogen atmosphere (20 mL min−1) in a platinum cru- Crystallographic Data Center as supplementary publication no.
cible with a heating rate of 10 °C min−1 using a Shimadzu CCDC 986306 for complex 3.
DTG-60H simultaneous DTG/TG apparatus. Magnetic measure-
ment was carried out on a Sherwood scientific magnetic
DFT calculations
balance using the Gouy method,30 and Hg[Co(SCN)4] was used Geometry optimizations of complexes 1–3 in the gas phase
as a calibrant. Electronic spectra were scanned on a Shimadzu were carried out by the DFT/B3LYP method combined with the
Lambda 4B spectrophotometer in both DMSO and DMF solu- LANL2DZ basis set38 using Gaussian 03,39 where the singlet
tions. A digital Jenway 4310 conductivity meter with a cell con- state was assigned to complex 2 and the doublet state to both
stant of 1.02 was used for the molar conductance study. 1 and 3. The starting geometry for optimization was con-
X-band EPR measurements were performed on solid samples structed based on crystallographic data without any symmetry
at 298 K using a Bruker EMX spectrometer. The magnetic restriction. The complexes were characterized as local minima
modulation frequency was 100 kHz and the microwave power through harmonic frequency analysis. Electronic transitions
was set to 0.201 mW. The g-values were obtained by referen- were calculated by TD-DFT.40 Natural bond orbital (NBO) ana-
cing to a diphenylpicrylhydrazyl (DPPH) sample with g = lysis and the analysis of frontier molecular orbitals were per-
2.0036. The modulation amplitude was set at 4 Gauss while formed at the same level of theory.
the microwave frequency was determined as 9.775 GHz.
Synthesis. Two mmol of analgin (646 mg) and one mmol of
Antibacterial activity
Co(NO3)2·6H2O (291 mg), Ni(CH3COO)2·4H2O (248 mg), or The antimicrobial activities of the test samples were deter-
Cu(NO3)2·3H2O (241 mg) were dissolved in ethanol (15 mL) mined by a modified Kirby–Bauer disc diffusion method41
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under standard conditions using Mueller-Hinton agar
medium (tested for composition and pH), as described by
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and Escherichia coli as a Gram-negative bacterium. A solution
Rev., 2005, 249, 2909–2945.
of 20 mg mL−1 of each compound (free ligand, metal com- 12 J. S. Casas, M. S. García-Tasende, A. Sánchez, J. Sordo and
plexes and the standard drug tetracycline) in DMSO was pre-
A. Touceda, Coord. Chem. Rev., 2007, 251(11–12),
1561–1589.
pared for testing. Centrifuged pellets of bacteria from a 24 h
old culture containing approximately 104–106 CFU mL−1 13 S. V. Tatwawadi, A. P. Singh and K. K. Narang, Indian
(colony forming unit) were spread on the surface of Mueller
Hinton agar plates. Then the wells were seeded with 10 mL of
J. Chem., Sect. A: Inorg., Bio-inorg., Phys., Theor. Anal. Chem.,
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the prepared inocula to have 106 CFU mL−1. Petri plates were 14 (a) R. C. Maurya and S. Rajput, Synth. React. Inorg. Met.-
prepared by pouring 100 mL of seeded nutrient agar. DMSO
(0.1 mL) alone was used as the control under the same con-
ditions for each microorganism, subtracting the diameter of
the inhibition zone resulting with DMSO from that obtained
in each case. The antimicrobial activities could be calculated
as the mean of three replicates.
Org. Chem., 2003, 33(10), 1877–1894; (b) R. C. Maurya,
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Acknowledgements
I thank Dr Krzysztof Radacki, Julius-Maximilians-Universität
Würzburg, Germany, for refining the crystal structure of com-
pound 3.
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