Synthesis and Solid-State Characterization of Zn(II)
Metal Complex with Acetaminophen
IONUT LEDETI1, GEORGETA SIMU1, GABRIELA VLASE5, GERMAINE SAVOIU2, TITUS VLASE5, LENUTA-MARIA SUTA3,
CALIN POPOIU6*, ADRIANA FULIAS4
1
University of Medicine and Pharmacy “Victor Babeº”, Faculty of Pharmacy, Department of Physical Chemistry, 2 Eftimie Murgu
Sq., 300041, Timiºoara, Romania
2
University of Medicine and Pharmacy “Victor Babeº”, Faculty of Pharmacy, Department of Anatomy,, 2 Eftimie Murgu Square ,
300041, Timiºoara, Romania
3
University of Medicine and Pharmacy “Victor Babeº”, Faculty of Pharmacy, Department of Pharmaceutical Technology,
3 Eftimie Murgu Sq., 300041, Timiºoara, Romania
4
University of Medicine and Pharmacy “Victor Babeº”, Faculty of Pharmacy, Department of Analytical Chemistry, 2 Eftimie
Murgu Sq., 300041, Timiºoara, Romania
5
West University of Timisoara, Research Centre for Thermal Analysis in Environmental Problems, 16 Pestalozzi Str., 300115,
Timisoara, Romania
6
University of Medicine and Pharmacy “Victor Babeº”, Faculty of Medicine, 2 Eftimie Murgu Sq., 300041, Timisoara, Romania
This paper describes the synthesis and characterization of a coordination compound of Zn(II) with
acetaminophen. The complex was characterized by elemental analysis, FTIR-UATR spectroscopy and TGDTG-HF technique. Correlating the obtained data, it was proven that acetaminophen acts as a bidentate
ligand, namely by the hydroxyl group and by the carbonyl group. By the thermal analysis and spectroscopy, it
was proven that the final decomposition product, at 450 °C is ZnO.
Keywords: zinc(II) complex, acetaminophen, paracetamol, thermal behavior, spectroscopy
Acetaminophen (Paracetamol, N-(4-hydroxyphenyl)
acetamide) is a derivative of 4-aminophenol and is one of
the most frequently commercialized antipyretic and
analgesic agent without medical prescription.
Acetaminophen is used as an active ingredient in different
pharmaceutical formulations with different routes of
administration, such as tablets and capsules, suspension,
intravenous and intramuscular form, as well as rectal
suppositories [1,2].
Acetaminophen (ACPH) is commonly used as a main
ingredient in cold and influenza pharmaceutical
formulations [3] and is recommended in treatment of
headache, toothache, rheumatism and neuralgia [4,5]. In
combination with other active substances, acetaminophen
can also be used in the amelioration of post-operative pain
[6] or providing palliative care for patients that suffers for
advanced forms of neoplasms.[7].
Even if ACPH is not considered an NSAID due to the fact
that its anti-inflammatory activity is considered weak
comparative to other drugs in this class, studies had shown
that ACPH is a selective cyclooxygenase-2 inhibitor [8].
The chemical structure of acetaminophen (ACPH) is
presented in figure 1.
The interaction between metal ions and
pharmaceuticals is an attractive field of research, due to
the fact that in vivo, metal ions can interact with
pharmaceutical ligands that appear in living systems. It is
known that the cations can bind to enzymes, proteins and
other biological ligands [9].
O
HO
NH
Fig. 1. The structure of acetaminophen (ACPH)
The chemistry of coordination compounds is a domain
that has known a rapid development in the last decade.
Metal coordination compounds that contain active
substances as ligands are the base of inorganic medicinal
chemistry and represent a highly developing domain with
enormous potential for applications in medicine,
engineering or agriculture [10].
The design of small organic ligands as drugs in order to
interact with a metalloenzyme was previously reported
[11,12]. The biochemistry of zinc-containing enzymes and
their imbalance in vivo can be associated with several
diseases including arthritis and cancer, so the targeting of
the zinc active site can be considered a key step in the
strategy of drug design. Enzymatic zinc is an attractive
target because of the diversity of its structural and catalytic
roles in enzymes [13].
Even if literature data contains extremely numerous
references to the synthesis, characterization and biological
activity of coordination compounds containing transitional
cations such as Fe(III), Co(II), Ni(II), Cu(II), Pt(II) or Zn(II)
and active substances as ligands, complexes derived from
ACPH were less studied. According to this, we set our goal
in the synthesis and solid-state characterization of a
coordination compound containing Zn(II) as central ion
and ACPH as ligand.
Experimental part
All chemicals were of analytical grade. Acetaminophen
and anhydrous zinc chloride were obtained from SigmaAldrich and used as received. The composition of the metal
complex (C, H, N and Cl) was obtained by means of
elemental analysis using an Vario El Cube analyzer. The
Zn(II) content was determined by complexonometric
titration with EDTA, in buffer solution (NH3/NH4Cl) at pH ~
10, in the presence of Eriochrome Black T as indicator, by
a standard analytical procedure.
* email: [email protected]
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Table 1
ELEMENTAL ANALYSIS DATA
Thermal analysis of prepared complex was carried out
by TG-DTG-HF method using a Perkin-Elmer DIAMOND
equipment. Samples about 7 mg were heated in aluminium
crucibles, up to 550 °C at a heating rate β=10 °C·min-1, in
dynamic air atmosphere.
Melting point was determined on a Böetius PHMK (Veb
Analytik Dresden) instrument, and thin-layer
chromatography was carried out on silica gel-coated plates
60F254 Merck using hexane:methanol 3:7 as eluant. The
FTIR spectra of acetaminophen and metallic complex with
Zn were obtained on the Perkin Elmer SPECTRUM 100
spectrometer using the U-ATR technique on 4000 - 650
cm-1 spectral range and in KBr pellet on a Jasco FT/IR-410
spectrophotometer for the product of thermal
decomposition of Zn(II) complex, respectively, on 4000400 cm-1 spectral range.
Synthesis of the metal complex
The complex was obtained in the reaction of ACPH and
zinc chloride in aqueous medium. To a solution (100 mL)
containing anhydrous zinc chloride (0.409g, 3 mmol) in
water, solid ACPH (0.907g, 6 mmol) was added. The
mixture was stirred at r.t. until the dissolution of ACPH
occurred, then heated under reflux for 6h. The mixture was
allowed to cool down at room temp., and then approx. 70
mL of solvent (water) was removed under reduced
pressure (40°C / 10 mmHg). The coordination compound
precipitated as an amorphous solid, which was filtered off
under vacuum, washed with distilled water (3 x 5 mL) and
dried for 48 h at 30 °C.
[Zn(ACPH)2(OH2)2]2+ 2Cl- metal complex
Amorphous whitish solid (1.234 g, 2.6 mmol, yield
86.7%), m.p. (Böetius)= 114 °C (decomp.), TLC one spot;
Chemical formula: C 16 H 22 Cl 2N 2O 6Zn; molar mass:
474.46 g/mol;
FTIR (UATR, cm-1): 3741-2921 (large), 3322, 1694, 1651,
1561, 1505, 1436, 1369, 1324, 1227, 1143, 1014, 835, 805,
732, 682.
Results and discussions
According to our knowledge, literature data mention the
synthesis and characterization only of a few complexes of
ACPH [5,14-15]. The complex with the formula
[Zn(ACPH) 2(OH2)2]2+ 2Cl- was obtained. ACPH ligand
coordinates to Zn2+ in the stoichiometric ratio 2:1 by the
oxygen atoms from phenolic hydroxyl and amidic carbonyl.
The elemental analysis data of the investigated complex
are shown in table 1.
Spectroscopic description
Evidence for complex formation was obtained by
comparing the infrared spectra of the free acetaminophen
and complex in the region of 4000-650 cm-1 (fig. 2).
By the analysis of FTIR spectrum of free ligand (ACPH),
one can notice several characteristic absorption bands at
3322 cm-1 and 3160-3108 cm-1 which can be assigned to
the stretching vibrations of –NH and -OH groups,
respectively.
The strong absorption band at 1650 cm-1 in the spectrum
of ACPH can be assigned to stretching of C=O functional
group. These three functional groups (-NH, -OH and –C=O)
were analysed due to the fact that they can act as donors
in the dative bond for the formation of the complex, so a
modification of their relative intensity and/or position in
spectrum can be expected.
By the analysis of the FTIR spectrum of Zn(II) metal
complex, the maximum of several bands have been shifted
to different wavenumbers or they modified their aspect.
The disappearance or superpose of the characteristic bands
of –OH stretching vibrations from 3160-3108 cm-1 and the
appearance of o broad signal between 3730 cm-1 and 2926
cm-1 indicates both the involvement of the –OH group in
the formation of the coordination complex and suggest
the presence of water in its structure, fact sustained by the
thermal behaviour of the complex. As can be noticed, the
sharp band from 3322 cm-1 suggests that the –NH group is
not involved in the formation of Zn(II)-ACPH complex. A
significant shifting to a higher wavenumber (from 1650
cm-1 up to 1694 cm-1) of the characteristic stretching band
of C=O functional group suggest that coordination occurs
through this group. A comparative analysis of the
corresponding wavenumbers of other bands from ACPH
and metal complex reveals only insignificants shifting (at
± 3 cm -1) and cannot be assigned to involvement in
coordination bonds. In order to sustain the formation of the
metal complex, two new absorption bands at 682 cm-1
Fig. 2. FTIR spectra of (1) ACPH-pure ligand;
(2)- [Zn(ACPH)2(OH2)2]2+ 2Cl-
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Fig. 3. FTIR spectra for the decomposition
product of Zn(II)-ACPH complex at 550 °C
(1) and pure ZnO(2)
Fig. 4. The thermoanalytical curves TG/DTG/HF
obtained in air at β=10 °C·min-1 for the analysed
Zn(II) complex.
Table 2
THERMOANALYTICAL DATA OF THE
ANALYSED COMPLEX
and 732 cm-1 in the spectrum of the Zn(II) complex were
observed, without a correspondence in the spectrum of
pure ACPH. These two new bands can be tentatively
assigned to stretching vibrations of zinc-oxygen bonds,
namely C=O→Zn and HO→Zn.
In order to determine the decomposition product by the
thermal treatment of the Zn(II)-ACPH complex at 550 °C,
an FTIR spectra was drawn up. The bands present in this
spectrum suggest the formation of a simple inorganic
product, characterised by a reduced number of bands. By
the comparison with the FTIR spectrum of pure ZnO, it
was proven that the decomposition product is ZnO and
traces of organic fragments from ACPH are no longer
present (fig. 3).
Thermal decomposition
In our previous studies [16-22], the importance of
hyphenated techniques (TG-DTG-HF-FTIR) in the solid-state
characterization of pharmaceuticals and their compatibility
with excipients was proven. According to this, we aimed
towards the characterization of complex by thermal
analysis. The TG/DTG/HF curves of [Zn(ACPH)2(OH2)2]2+
2Cl- obtained during heating in air are shown in figure 4.
The first mass loss on the thermogravimetric curve
occurring in the 100-140 °C range corresponds to the loss
REV. CHIM. (Bucharest) ♦ 64 ♦ No. 10 ♦ 2013
of 2 moles water (calculated mass loss =7.59 %;
experimental mass loss=8.34 %). The dehydration is
accompanied by a weak endothermic peak on the HF
curve (HFpeak=126 °C) according to the loss of two water
molecules. This fact may point a relatively weak bonding
of water molecules in the complex structure. According to
literature [23] lattice water is removed at temperatures
below 100oC, whereas coordinated water is eliminated
within 110-275 °C temperature range. As a conclusion to
this, the two water molecules should correspond to the
coordination water, not to lattice water.
After the water elimination, a decomposition process
with a continuous mass loss takes place until 500°C. The
anhydrous zinc complex is stable up to 220°C. The solid
residue obtained during thermal decomposition of
complex is in agreement with formation of ZnO (calculated
mass loss=17.15%, experimental mass loss=19.04%). The
thermal analysis results of the new Zn(II) complex with
acetaminophen, determined in non-isothermal conditions
are summarized in table 2.
According to spectroscopic data, and by corroboration
to thermal behaviour of complex and the results from
elemental analysis, a proposed structure for the metal
complex is presented in figure 5.
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1129
OH
HN
O
H2O
Zn2+
OH2
2Cl -
O
HO
NH
Fig. 5. The proposed structure of [Zn(ACPH)2(OH2)2]2+ 2Clcomplex
Conclusions
In our study, a Zn(II)-ACPH coordinative compound was
synthesized and characterized by elemental analysis, FTIR
spectroscopy and TG-DTG-HF technique. It was proven
that the formation of complex occurs by both –OH and –
C=O groups from ACPH. From TG data obtained in air
atmosphere, three main stages of decomposition can be
observed. In the first step, water molecules are released,
followed by the decomposition of anhydrous complex by
the degradation of organic ligand. By TG technique and
FTIR, it was proven that pure ZnO is the final decomposition
product, which is obtained at a reasonable temperature of
450°C.
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Manuscript received: 25.07.2013
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