Synthesis and characterization of norfloxacin-transition metal complexes (group 11, IB): Spectroscopic, thermal, kinetic measurements and biological activity

Article abstract of DOI:10.1016/j.saa.2006.12.078

The investigation of the new structures of Ag(I), Cu(II) and Au(III) complexes, [Ag₂(Nor)₂](NO₃)₂, [Cu(Nor)₂(H₂O)₂]SO₄·5H₂O and [Au(Nor)₂ (H₂O)₂]Cl₃ (where, Nor = norfloxacin) was done during the reaction of silver(I), copper(II) and gold(III) ions with norfloxacin drug ligand. Elemental analysis of CHN, infrared, electronic, ¹H NMR and mass spectra, as well as thermo gravimetric analysis (TG and DTG) and conductivity measurements have been used to characterize the isolated complexes. The powder XRD studies confirm the amorphous nature of the complexes. The norfloxacin ligand is coordinated to Ag(I) and Au(III) ions as a neutral monodentate chelating through the N atom of piperidyl ring, but the copper(II) complex is coordinated through the carbonyl oxygen atom (quinolone group) and the oxygen atom of the carboxylic group. The norfloxacin and their metal complexes have been biologically tested, which resulted in norfloxacin complexes showing moderate activity against the gram positive and gram negative bacteria as well as against fungi.

Full text of DOI:10.1016/j.saa.2006.12.078

Available online at www.sciencedirect.com
Spectrochimica Acta Part A 68 (2007) 1393–1405
Synthesis and characterization of norfloxacin-transition metal
complexes (group 11, IB): Spectroscopic, thermal,
kinetic measurements and biological activity
Moamen S. Refat∗
Department of Chemistry, Faculty of Education, Suez-Canal University, Port Said, Egypt
Received 1 December 2006; accepted 16 December 2006
Abstract
The investigation of the new structures of Ag(I), Cu(II) and Au(III) complexes, [Ag2(Nor)2](NO3)2, [Cu(Nor)2(H2O)2]SO4·5H2O and [Au(Nor)2
(H2O)2]Cl3 (where, Nor = norfloxacin) was done during the reaction of silver(I), copper(II) and gold(III) ions with norfloxacin drug ligand.
Elemental analysis of CHN, infrared, electronic, 1H NMR and mass spectra, as well as thermo gravimetric analysis (TG and DTG) and conductivity
measurements have been used to characterize the isolated complexes. The powder XRD studies confirm the amorphous nature of the complexes.
The norfloxacin ligand is coordinated to Ag(I) and Au(III) ions as a neutral monodentate chelating through the N atom of piperidyl ring, but
the copper(II) complex is coordinated through the carbonyl oxygen atom (quinolone group) and the oxygen atom of the carboxylic group. The
norfloxacin and their metal complexes have been biologically tested, which resulted in norfloxacin complexes showing moderate activity against
the gram positive and gram negative bacteria as well as against fungi.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Norfloxacin; Gold(III) complex; Biological activity; Kinetic data; Infrared spectra
1. Introduction
and spectroscopic methods, and with detailed biological data
[3–6].
Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-
dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Norfloxacin belongs to the family of molecules known as the
Fluoroquinolones, and is a wide-ranging drug used in treating
bacterial infections of the urinary tract, the respiratory tract,
and the skin, amongst others. It is also known to be effective
in treating diarrhea and can in addition treat conjunctivitis
when it is administered in the form of eye drops. Norfloxacin is
not, however, effective against infections involving anaerobic
bacteria (e.g., yeast, athlete’s foot).
When dealing with the interaction between drugs and metal
ions in living systems, a particular interest has been given
to the interaction of metal ions with antibiotics. Antibiotics
that interact with metal ions constitute a class of drugs which
have been widely used in medicine both towards human beings
and animals [1,2]. In particular, the interaction between tran-
sition metals and ␤-lactamic antibiotics such as cephalexin
has been recently investigated by several physicochemical
Many drugs possess modified pharmacological and toxico-
logical properties when administered in the form of metallic
complexes. Probably the most widely studied cation in this
respect is Cu(II), since a host of low-molecular-weight copper
complexes have been proven beneficial against several diseases
such as tuberculosis, rheumatoid, gastric ulcers, and cancers
[7–10]. There has been a tremendous growth of drugs from
quinolone family, which began with the discovery of nalidixic
acid some over 40 years ago. Since then, the exponential growth
of this family has produced more than ten thousand analogues
[11].
The coordination chemistry of these drugs with metal ions
of biological and pharmaceutical importance is of considerable
interest. Norfloxacin (Nor; Fig. 1) was considered the best of
the third generation quinolone family. There have been sev-
eral reports about the synthesis and crystal structure of metal
complexes with quinolone derivatives [12–15].
Quinoloneantibioticscanparticipateintheformationofcom-
plexes in a number of ways [16–20]. In case of isolated drugs,
these complexes in acidic media usually contain singly and/or
doubly protonated quinolones that are incapable of bonding to
∗
Tel.: +20 127649416.
E-mail address: msrefat@yahoo.com.
1386-1425/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2006.12.078

1394
M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
Fig. 1. Structure of norfloxacin (Nor) and zwitterionic structure.
the metal ions and in these cases only electrostatic interaction
was observed between the drug and the metal ions [16–18]. On
the other hand [19–21], it was found that neutral quinolones in
the zwitterionic state are capable of forming simple complexes
(bidentate chelating). The quinolones can also act as bridging
ligands and thus are capable of forming polynuclear complexes
[20,21].
from different sources. AgNO3 (99%, Fluka Co.), CuSO4·6H2O
(99.5%, Fluka Co.) and KAuCl4 (99%, Aldrich Co.) were used
without further purification.
2.2. Synthesis
All the complexes are prepared as following with different
ratios dependent on the type of metal used.
A group 11 element is one in the series of elements in group
11 (IUPAC style) in the periodic table, consisting of transition
metals which are the traditional coinage metals of copper (Cu),
silver (Ag), and gold (Au). They are also known as the “noble
metals”; the short-lived transactinide roentgenium (Rg) is also
a member of group 11. They are all relatively inert, corrosion-
resistant metals which have been used for minting coins, hence
their name. These metals, especially silver, have unusual proper-
ties that make them essential for industrial applications outside
of their monetary or decorative value. They are all excellent
conductors of electricity. The most conductive of all metals are
silver, copper, and gold in that order. Silver is also the most
thermally conductive and the most light reflecting element. Sil-
ver also has the unusual property in that the tarnish that forms
on silver is still highly electrically conductive. Copper is used
extensively in electrical wiring and circuitry. Gold contacts are
sometimes found in precision equipment for their ability to
remain corrosion-free. Silver is used widely in mission-critical
applications as electrical contacts and is also used in photogra-
phy (because silver nitrate reverts to metal on exposure to light),
agriculture, medicine, audiophile, and scientific applications.
The synthesis and characterization of new metal complexes
with quinolone antibacterial agents are of great importance for
understanding the drug-metal ion interaction and for their poten-
tial pharmacological use.
2.3. [Ag2(Nor)2](NO3)2
A solution of 1.0 mmol (0.169 g) AgNO3 in 5 ml of distilled
water was added to a solution of 1.0 mmol (0.319 g) of nor-
floxacin ligand in 25 ml acetone. The resulting mixture was
heated ∼50 ◦C under reflux on a water bath for about 12 h
and then cooled. The resulted complex was separated from the
reaction mixture by filtration, washed with boiling water then
acetone and dried in vacuo over CaCl2.
2.4. [Cu(Nor)2(H2O)2]SO4·5H2O
Norfloxacin (0.639 g, 2 mmol) in mixed solvent (50/50%) of
methanol/water was stirred at room temperature for 20 min and
CuSO4·6H2O (0.268 g, 1 mmol) was added. Upon continuous
stirring the color of the heterogeneous mixture started to change
from bluish white to green, and after 8 h a pale green solution
and a light green precipitate were observed. Precipitation was
completed in 20 h. The solid complex was filtered and washed
with MeOH and dried in vacuo over CaCl2.
2.5. [Au(Nor)2(H2O)2]Cl3
A hot aqueous solution (25 ml) of KAuCl4 (0.378 g, 1 mmol)
was added to a hot acetone (75 ml) solution of the norfloxacin
ligand (0.957 g, 3 mmol). The resulted mixture was stirred under
reflux for 24 h where upon the metal complex was precipitated.
The pale yellow solid complex was filtered and washed several
times with boiled water, then acetone, and dried in vacuo over
CaCl2.
The isolation and characterization of the Ag(I), Cu(II) and
Au(III) complexes is reported in this paper. Mid-infrared spec-
troscopy, 1H NMR and mass spectra, and thermal analysis have
been used to interpretation the proposed structures of the com-
plexes that resulted from this interaction.
2. Experimental
2.1. Reagents
3. Measurement methods
Norfloxacin used in this study were obtained from the
Egyptian International Pharmaceutical Industrial Company
(EIPICO). All chemicals used for the preparation of the com-
plexes were of analytical reagent grade, commercially available
Elemental analysis was carried out by standard micro meth-
ods using a Perkin-Elmer CHN 2400, and the metal contents
were determined gravimetrically by ignition weighted samples
in atmospheric air to constant weight and definite structures. IR

M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
1395
spectra were recorded on a Genesis II FT-IR spectrophotometer
was also tested, as well as the pure solvent. The concentration
of each solution was 1.0 × 10−3 mol dm3. Commercial DMSO
was employed to dissolve the tested samples.
(KBr discs) in the v = 400–4000 cm−1 range. H NMR spec-
1
tra were recorded on a Varian Gemini 200 MHz spectrometer
using DMSO-d6 as solvent. Mass spectra (MS) were taken on a
AEI MS 30 mass spectrometer at 70 eV. TG-DTG measurements
were made in an N2 atmosphere between room temperature and
800 ◦C using a Shimadzu TGA-50H. Electronic spectra were
obtained using a Shimadzu UV-spectrophotometer model 1601
PC with a 1 cm quartz cell. Molar conductivities in DMSO at
10−3 mol dm−3 concentration were measured on a Jenway 4010
conductivity meter. The X-ray diffraction patterns of the cop-
per(II) complex were recorded with a Rikagu diffractometer
using Cu K␣ radiation.
Decomposition of complexes was performed in concentrated
HNO3; after decomposition, thesampleswerediluted withwater
to 100 ml, and qualitative presence of Cl− and SO4− ions in the
samplesAu(III)andCu(II))wasdeterminedbymeansofAgNO3
and BaCl2, respectively. The decomposition of gold compound
was found to contain Cl− ions, and their concentration was
determined with an ion selective electrode.
4. Results and discussion
The analytical data and physical properties of the Nor ligand
and coordination compounds are listed in Table 1.The results
from Table 1 show that the ligand coordinate to the Ag(I) and
(Cu(II) and Au(III)) ions in a 1:1 and 1:2 molar ratio, respec-
tively. All compounds are stable in air. The melting points of
the complexes are higher than that of the ligand revealing that
the complexes are much more stable than ligand. The molar
conductance values (Table 1) of the complexes lay in the range
13.31–34.00 ꢀ−1 cm2 mol−1 (at 25 ◦C), which indicates that the
compounds are of slightly increasing in electrolytic nature than
ligand [22]. The products were insoluble in water, ethanol, chlo-
roform, acetone, cyclohexane, and 2-propanol.
4.1. Infrared spectra
3.1. Antibacterial investigation
The assignments of IR bands (Fig. 2 and Table 2) were made
by comparing the spectra of the complexes with those of the free
ligand Norfloxacin.
For these investigations the filter paper disc method was
applied. The investigated isolates of bacteria were seeded in
tubes with nutrient broth (NB). The seeded NB (1 cm3) was
homogenized in the tubes with 9 cm3 of melted (45 ◦C) nutri-
ent agar (NA). The homogeneous suspensions were poured
into Petri dishes. The discs of filter paper (diameter 5 mm)
were ranged on the cool medium. After cooling on the formed
solid medium, 2 × 10−5 dm3 of the investigated compounds
were applied using a micropipette. After incubation for 24 h
in a thermostat at 25–27 ◦C, the inhibition (sterile) zone diam-
eters (including disc) were measured and expressed in mm. An
inhibitionzonediameterover8 mmindicatesthatthetestedcom-
pounds are active against some of the bacteria and fungi under
investigation.
The antibacterial activities of the investigated compounds
were tested against Escherichia Coli, Bacillus subtilis, and
Pseudomonas aerruguinosa as well as some kinds of fungi
Aspergillus flavus, Fusarium solani, and Penicillium verrcosum.
At the same time with the antibacterial and antifungal investi-
gations of the Ag(I), Cu(II), and Au(III) complexes, the ligand
Brown powdered solid of silver(I)-Nor compound was pre-
pared in 75% yield by refluxing of 1:1 mixture of AgNO3 and
H-Nor in acetone/water at ∼50 ◦C for 12 h (Scheme 1).
The infrared spectrum of the new complex,
[Ag2(Nor)2](NO3)2, in KBr disc is shown in Fig. 2A and
its band assignments are given in Table 2. The IR spectrum of
silver compound shows distinct bands of v(C O); (COOH), and
v(C O), which are similar to those of free norfloxacin, indicat-
ing the presence of uncoordinated Ocarboxylate and Oketo in Ag(I)
compound. The molecular structure of [Ag2(Nor)2](NO3)2
consists of cationic mononuclear units of 2[Ag(H-Nor)]+ and
weekly coordinated anionic 2NO3−. The H-Nor ligand in Ag(I)
compound acts as a neutral monodentate to coordinate to Ag
atom by N atom of piperidyl ring, and 4-oxo and 3-carboxylate
oxygen atoms do not take in the coordination. Unlike in
other known complexes of H-Nor ligand [23–25], only N of
the piperidyl ring in H-Nor coordinates to the silver ion in
Ag-Nor compound. This bonding mode was unexpected and, to
this knowledge, unprecedented in quinolone drug interactions
Table 1
Elemental analyses and physical properties of the compounds
Complexes
Molecular Yield (%)
weight
Color
mp (◦C) Analysis (%) found (calculated)
Λa (ꢀ−1 cm2 mol−1
)
C
H
N
Nor, C16H18FN3O3
[Ag2(Nor)2](NO3)2,
319
978
–
75
Yellow
Brown
232
247
59.45 (60.18)
40.62 (39.26)
5.54 (5.68)
4.41 (3.68)
12.89 (13.16)
11.30 (11.45)
10.16
34.00
C32H36F2N8O12Ag2
[Cu(Nor)2(H2O)2]SO4·5H2O, 924
77
73
Light green 265
Pale yellow 318
41.22 (41.56)
40.38 (39.26)
5.46 (5.41)
4.13 (4.09)
8.93 (9.09)
8.77 (8.59)
19.73
13.31
C32H50F2N6O17SCu
[Au(Nor)2(H2O)2]Cl3,
C32H40F2N6O8Cl3Au
978
a
Measured in 10−3 M DMSO solutions at room temperature.

Table 2
IR frequencies (cm−1) and assignments for: Nor and Ag(I), Cu(II), and Au(III) compounds
Nor
Ag(I)
Cu(II)
Au(III)
Assignments
3399 ms
3428 s, br
3399 vs, br
3463 vs, br
3162 ms, 3040 vw, 2991 w,
sh, 2927 w, 2856 w
v(N H) + vas(O H); H2O
vs(O H); H2O, v (C H), v ( NH2 )
+
3267 vw, 3228 vw, 3189 vw,
3130 vw, 3021 w, 2927 m,
2823 w, 2796 w 2764 w,
2723 m, 2696 vw, 2654 w,
2617 w, 2511 w, 2468 m
1727 sh, 1716 ms
–
3246 w, br, 3122 w, br
3058 vw, 2990 vw, 2925 mw,
2852 mw, 2759 vw, 2644 vw,
2510 w
3197 s, br, 3114 sh, 2991 mw,
2918 w, 2851 mw, 2765 w,
2720 sh, 2653 w, 2544 mw,
2495 w
1716 s
–
–
1725 s
–
v(C O): (COOH)
vas(COO−)
1619 vs
1630 vs, 15 1552 w
1482 vs, 1454 m
1396 s
1307 vw
1277 vw, 1263 s, 1248 vw
1201 m, 1192 m
1153 vw, 1142 w 1132 w,
1115 w, 1095 m, 1076 m,
1051 vw, 1036 ms, 1024 w,
1005 m, 982 m
1628 vs, 1584 ms 1547 ms
1497 s, 1462 s
1384 vs
1338 w, sh
1274 s, 1250 w, sh
1192 s
1582 s, 1549 sh
1483 vs
1397 sh, 1386 s
1336 s
1629 vs, 1580 vw
1483 vs, 1460 sh
1397 s
1348 w, 1326 vw
1268 vs
1183 w
1128 w, 1097 vw 1087 ms,
1025 s
v(C O) + δb(H2O) Phenyl breathing modes
-
CH; deformation of CH2 − v(N O): NO3
vs(COO−) + v(N O): NO3
δb(CH2)
1266 vs
v(C C)
1179 s, 1142 w
1122 mw, 1096 w 1030 s,
962 vw
v(C O) v(C N)
δr(CH2) v(N O): NO3
−
1126 w, 1109 w 1031 s
972 w, 935 ms, 916 m, 899 m,
887 m, 858 w, 823 ms,
804 ms
926 s, 899 sh, 827 s, 804 s
923 vs, 814 vs, 782 mw
958 w, 924 s, 900 mw, 819 vw,
809 s
CH-bend; phenyl
δb(COO−) + δ(NO2): NO3
v(M–O) + v(M–N) ring deformation
−
750 s, 706 m
758 m, 738 w, 700 w
663 m, 623 s, 556 w, 525 w,
501 w, 436 w
732 s, 700 ms
652 vw, 619 vs 562 w, 544 w
515 w, 483 w, 408 mw
747 ms, 677 w
614 ms, 554 vw, 530 vw,
499 w, 453 w
667 w, 631 w, br, 569 ms,
524 w, 499 m, 474 m,
453 vw, 430 ms
(a): s = strong, w = weak, m = medium, sh = shoulder, v = very, br = broad; (b): v, stretching; δ, bending.

M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
1397
Scheme 1. [Ag2(Nor)2](NO3)2 compound.
towards metal ions. Accordingly, the most probable geometrical
structure of this complex is shown in Scheme 1, where NO3
tra of the copper(II) complex and the norfloxacin free ligand
(∼1700–1300 cm−1) is selected and assigned, as shown in
Fig. 2B. In contrast to the assignments data of Nor and
−
acts as a bridged bidentate ligand while the two Nor molecules
exist as monodentate ligands. A related mononuclear complex
of norfloxacin with silver(I), [Ag(H-Nor)2]NO3, was reported
by Li et al. [26] to be formed in the reaction of silver nitrate
with norfloxacin by 1:2 ratio in concentrated aqueous NH3
at 100 ◦C for 8 h. The characteristic stretching vibrations of
bridged bidentate nitrato group, NO3−, is observed at 1384 and
1031 cm−1 attributed to vas(NO2) and vs(NO2), respectively,
[27,28]. The stretching motion of v(N O) is observed at
1462 cm−1 as a strong band, while the two bending motion
of the type δ(NO2) are well resolved and observed at 758 and
663 cm−1 as medium bands.
Cu(II)/Nor complex shows no absorption band at ∼1700 cm−1
,
characteristic of the v(C O) vibration of the carboxylic group,
that is indicative of the involvement of the carboxyl group in the
coordination with copper ion. The peak at 1619 cm−1 is absent
in the spectrum data of the free Nor and can be assigned to
the asymmetric stretching vibration of the carboxylate group,
vas(COO−). The spectrum of [Cu(Nor)2(H2O)2]SO4·5H2O
complex also has strong intensity band at 1386 cm−1. This band
is absent in spectrum of Nor and interpretive to the symmetric
vibration of the vs(COO−) group.
Deacon and Phillips [29] have studied the criteria that can
be used to distinguish between the three binding states of the
carboxylate complexes. These criteria are: (i) ꢁv > 200 cm−1
Concerning the [Cu(Nor)2(H2O)2]SO4·5H2O complex,
(Scheme 2) the most important region in the infrared spec-

1398
M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
Scheme 2. [Cu(Nor)2(H2O)2]SO4·5H2O.
(where ꢁv = [vas(COO−) − vas(COO−)]) this relation was
found in case of unidentate carboxylato complexes, (ii) biden-
tate or chelating carboxylato complexes exhibit ꢁv significantly
smaller than ionic values (ꢁv < 100 cm−1), and finally, (iii)
bridging complexes show ꢁv comparable to ionic values
(ꢁv ∼ 150 cm−1). The observed ꢁv for the copper complex
is 233 cm−1, which confirm a unidentate interaction of the
carboxylate group. The infrared spectral data of the Cu/Nor
complex show a very strong broad band at 3399 cm−1 and
medium weak to weak bands at 2851 and 2495 cm−1. These
bands can be assigned to the vibrations of the quaternized
nitrogen of the piperazinyl group, which indicated that the zwit-
terionic form of Nor is involved in the coordination to the copper
ion investigated [30]. However, the vibrations of the free sul-
phate group [27] in this complex [Cu(Nor)2(H2O)2]SO4·5H2O,
can be assigned as follows: two bands with strong intensities
1630 cm−1(vs); (2) the band at 1717 cm−1, due to the carboxylic
group, wasdetectedin thespectrumof thegold complex, indicat-
ing that this moiety does not participate in the bonding to metal
ion; (3) however, the technique permitted a definitive conclusion
about the participation of the ketone group in the bonding to the
metal, the corresponding band was recorded at 1630 cm−1 in the
spectrum of Nor, and a band close to this position (1629 cm−1
)
in the spectrum of the complex could be due to the ketone group
uncoordinated to the metal ion. Similar to [Ag2(Nor)2](NO3)2
compound, the N atom of the piperidyl ring takes part in the
coordination to metal ion (Au(III)) (Scheme 3 and Table 2).
4.2. Electronic spectra
Electronic spectra of the three complexes and Nor were
recorded in the 200–800 nm region in DMSO (Fig. 3). Two
peaks appear at 285 nm (band I) and 335 nm (band II) in the
ligand, attributed to n-␲* and ␲–␲* transitions (these transi-
tions occur in case of unsaturated hydrocarbons which contain
carbon atom attached with oxygen atom as in carboxylic and
ketone groups). The electronic spectra of complexes Ag+ and
Au3+ are similar to each other and are also similar to that of
ligand; these facts show that after formation of the complexes,
the two bands I and II in the electronic spectra are not affected,
obviously suggesting that the ligand has not changed to the zwit-
occur in the region above 1000 cm−1 at 1179 and 1030 cm−1
,
and very strong band at 923 cm−1 are assigned to the differ-
ent symmetric and antisymmetric bond vibrations, v(SO42−),
while the bending motion of ␦(SO42−) is assigned to the band
at 619 cm−1
.
Fig. 2C shows the IR spectra of [Au(Nor)2(H2O)2]Cl3 com-
plex. On comparing the main IR frequencies of gold complex
with that of Nor, the following were found: (1) there were two
absorption peaks in the ligand Nor, i.e., 1716 cm−1(ms) and

M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
1399
Scheme 3. [Au(Nor)2(H2O)2]Cl3 compound.
that appears at m/z 108 should be assigned to silver metal Ag+.
These results are again consistent with the presence of direct
metal–ligand bonding in silver complex.
terionic form. In the copper(II) complex, the peak at 285 nm has
hyperchromic effect to high absorbance than the ligand, and it
should be assigned that carboxylic group and ketone groups are
involved in the complexation.
4.4. Powder X-ray diffraction
4.3. Mass spectra
X-ray patterns of the copper(II) complex recorded at
2θ = 0–90 range were shown in Fig. 5. All the complexes are
powder solids (amorphous). The resulted complexes are slightly
soluble in DMF and DMSO and are decomposed in diluted solu-
tions of all strong acids. Attempts to prepare single crystals were
unsuccessful.
In the mass spectra of [Ag2(Nor)2](NO3)2, intense mass
peaks at m/z 319, 275, 233, 161, 107, and 56 were observed
(Fig. 4). The first mass peak corresponds to the [H-Nor]+ ion
and the second one proceeds by loss of CO2 from the molec-
ular ion at m/z 275 with intensity 72%, then the elimination of
C2H4N, leads to the formation of an ion at m/z (%), 233 (100%),
which is the base peak of the spectrum (Scheme 4). On compari-
son between the Nor (ligand) and Ag–Nor complex, it is clearly
obvious that the peak that refers to molecular ion m/z 319 of
Nor ligand is present in the silver(I) complex, and the new peak
4.5. 1H NMR spectra
1
The H NMR spectra presented the persuasive confirma-
1
tion of the coordination modes. Thus, the H NMR spectrum

1400
M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
Scheme 4. Mass fragmentation route of Norfloxacin ligand.
of Cu(II) complex on comparing with that of the free nor-
floxacin indicates that Nor acts as bidentate ligand through the
ring carbonyl oxygen atom and one of the oxygen atoms of
the carboxylic group. On the other hand, the reaction of nor-
floxacin with KAuCl3 yields an unusual mononuclear complex
[Au(Nor)2(H2O)2]Cl3 in which the local coordination environ-
ment around Au(III) ion with N–Au–N coordinated feature.
Fig. 6 shows 1H NMR spectra of copper(II) and gold(III)
complexes, which were carried out in DMSO-d6 as a sol-
vent. Concerning [Cu(Nor)2(H2O)2]SO4.·5H2O complex, the
data obtained are in agreement with the suggested coordina-
tion through the carboxylic group (absent the hydrogen signal
of (COOH) in this case), and due to different chemical envi-
ronments two signals are recorded for the quaternized nitrogen
11.00 ppm, respectively, except an increasing/decreasing in the
chemical shift of protons of piperazine and aromatic rings com-
pared with the donor alone. This shift is due to the complexation
and difference in the configuration of complexes than ligand.
4.6. Thermal studies
The norfloxacin of Ag(I), Cu(II), and Au(III) complexes are
stable at room temperature and can be stored for several months
without any changes. Ag(II), Cu(II), and Au(III) complexes of
norfloxacin were studied by thermogravimetric analysis from
ambient temperature to 800 ◦C N2 atmosphere. The TG curves
were redrawn as mg mass loss versus temperature (TG) curves
and also as the rate of loss of mass versus temperature (DTG)
curves. Typical TG and DTG curves are presented in Fig. 7, and
the temperature ranges and percentage mass losses of the decom-
position reaction are given in Table 4, together with evolved
moiety and theoretical percentage mass losses.
(
+NH2) at δ 2.51 and 2.75 ppm. The peak at δ 3.55 ppm
was assigned to water molecules within the complex, which
was not detected in the spectra of free norfloxacin ligand.
1
Table 3 summarizes the H NMR spectral data of free Nor,
[Cu(Nor)2(H2O)2]SO4·5H2O and [Au(Nor)2(H2O)2]Cl3 com-
pounds. The CH2 group quartet has a total intensity of two
units with the values of δ 4.56, 4.67, 4.70, and 4.78 ppm, while
the CH3 group (triplet) has three units of intensity with the
value of δ 1.41, 1.43 and 1.46 ppm. The 1H NMR spectrum of
a solution of [Au(Nor)2(H2O)2]Cl3 solid complex in DMSO-
d6 showed frequencies at ␦ 1.33, 2.00, 3.45, 2.82, 4.48, 4.51,
7.03, 7.07, 7.75, 7.78, 7.82, and 8.85 ppm and these are the
same places as those of free donor, Nor (the signal of carboxylic
group not affected and the presence of δH; NH signal) located
at δ 1.13, 2.00, 3.55, 2.78, 3.10, 3.47, 5.93, 7.12, 8.01, and
The overall loss of mass from the TG curves
is 97.74% for Nor, 71.25% for [Ag2(Nor)2](NO3)2,
82.39% for [Cu(Nor)2(H2O)2]SO4·5H2O and 80.35% for
[Au(Nor)2(H2O)2]Cl3. All the complexes show two or three
stages of mass loss in their TG/DTG curves. The first mass
loss corresponds to the formation of their respective anhydrous
compounds. While the second, third, and fourth mass loss is
due to the decomposition of counter ions and Nor molecules.
The end-products were confirmed with infrared spectra.
Norfloxacin melts at 232 ◦C with simultaneous decompo-
sition. The first mass loss was observed at 125 ◦C in the TG
Table 3
1H NMR spectral data of free Nor, [Cu(Nor)2(H2O)2]SO4.5H2O and [Au(Nor)2(H2O)2]Cl3 compounds
Nor
[Cu(Nor)2(H2O)2]SO4.·5H2O
[Au(Nor)2(H2O)2]Cl3
Assignments
1.13
1.41, 1.43, 1.46
1.33
δ H, CH3
2.0
–
–
2.00
–
δ H, NH; Piperazine
δ H, +NH2
2.51, 2.75
–
3.55
3.45
δ H, H2O
2.78, 3.10, 3.47
5.93, 7.12, 8.01
11.00
4.56, 4.67, 4.70, 4.78
7.20, 7.29, 7.92, 7.95
–
2.82 4.51, 4.48
7.03, 7.07, 7.75, 7.78, 7.82
8.85
δ H, CH2; Piperazine δ H, CH2; CH2CH3
δ H, CH aromatic
δ H, COOH

M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
1401
Fig. 3. Electronic spectra of: [Ag2(Nor)2](NO3)2; [Cu(Nor)2(H2O)2]SO4·
5H2O and [Au(Nor)2(H2O)2]Cl3 compounds.
Fig. 4. Mass spectra of (A): Nor ligand and (B): [Ag2(Nor)2](NO3)2 compound.
range 575–726 ◦C with a maximum at 650 ◦C and is accom-
panied by a weight loss of 19.56%, and may be attributed to
the loss of pyrrole ring, 2C2H2 + 1/2N2 + 1/2H2, in reasonable
agreement with the theoretical value of 21.00%.
The TG of the [Ag2(Nor)2](NO3)2 complex reveals a mass
loss in the temperature range 25–275 ◦C corresponding to the
formation of 2Ag(Nor). The next decomposition step occurs in
Fig. 2. Infrared spectra of: (A) [Ag2(Nor)2](NO3)2 compound; (B)
[Cu(Nor)2(H2O)2]SO4·5H2O compound; (C) [Au(Nor)2(H2O)2]Cl3 com-
pound.
profile. The TG/DTG profiles of ligand are shown in Fig. 7.
From TG curves, it appears that the sample decomposes in three
stages over the range 25–726 ◦C. The first decomposition occurs
between 25 and 270 ◦C with a mass loss of 8.38% and the sec-
ond decomposition starts at 270 ◦C and ends at 575 ◦C with a
69.80% mass loss. The next decomposition step occurs in the
Fig. 5. X-ray powder diffraction of [Cu(Nor)2(H2O)2]SO4·5H2O complex.

1402
M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
The TG curve of [Cu(Nor)2(H2O)2]SO4·5H2O complex
shows an initial mass loss in the temperature range 25–275 ◦C
correspondingtothedecompositionofthecomplextoanhydrous
complex by the loss of five uncoordinated water molecules.
This is followed by another mass loss in the tempera-
ture range 275–470 ◦C due to the thermal decomposition of
[Cu(Nor)2(H2O)2]SO4 to [Cu(Nor)]SO4. The mass loss at the
last stage in the temperature range 470–657 ◦C is due to the
decomposition of [Cu(Nor)]SO4 to copper(II) sulfate by the
decomposition of the second norfloxacin molecule.
The [Au(Nor)2(H2O)2]Cl3 complex is thermally stable up
to 265 ◦C. The mass loss at the first stage in the temperature
range 25–350 ◦C corresponds to the decomposition of the com-
plex to [Au(Nor)2]Cl3. The mass loss at the second stage in the
temperature range 350–700 ◦C is due to the decomposition of
[Au(Nor)2]Cl3 to metallic gold. A horizontal plateau on the TG
curve for the complex indicate the decomposition of organic
part of the chelate in the last step leaving residue of metallic
at the final temperature. The final weight of residues corre-
spond to the corresponding metallic or/and metal oxides [31]
as end-products. The decomposition temperatures of the com-
plexes are higher than that of the ligands (Table 4) and indicate
that the thermal stability of the complexes are increased due to
Fig. 6. 1H NMR spectra of: (A) [Cu(Nor)2(H2O)2]SO4·5H2O; (B)
[Au(Nor)2(H2O)2]Cl3.
the temperature range 275–525 ◦C and corresponds to the ther-
mal decomposition of 2Ag(Nor) to (AgF + Ag(Nor)). The last
decomposition step occurs in the temperature range 525–773 ◦C
and corresponds to the formation of 2AgF.
Fig. 7. TG and DTG curves of: (A) Norfloxacin ligand; (B) [Ag2(Nor)2](NO3)2; (C) [Cu(Nor)2(H2O)2]SO4·5H2O; (D) [Au(Nor)2(H2O)2]Cl3.

M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
1403
Table 4
Thermo analytical results for the investigated compounds
Samples
Stage
TG results temp
peak (◦C)
DTG results temp.
range (◦C)
Weight loss(%)
Found
Evolved moiety
C2H4
HF + 4C2H2 + CO + CO2 + N2
2C2H2 + 0.5H2 + 0.5N2
Calculated
Nor
I
II
III
25–270
270–575
575–726
125
335
650
8.38
69.80
19.56
8.78
70.22
21.00
Ag/Nor
Cu/Nor
Au/Nor
I
II
25–275
275–525
525–773
> 773
250
375
600
11.97
30.54
28.74
28.75
12.68
30.67
30.67
25.97
2NO2 + O2
8C2H2 + 0.5N2 + 2NO + H2O
8C2H2 + 0.5N2 + 2NO + H2O
2AgF
III
Residue
I
II
25–275
275–470
470–657
> 657
45, 90, 240
290, 425
575
9.55
38.21
34.63
17.61
9.75
38.44
34.53
17.28
5H2O
2H2O + Nor
Nor
III
Residue
CuSO4
I
II
25–350
350–700
> 700
320
375
3.74
76.16
19.65
3.68
76.61
20.16
2H2O
3/2Cl2 + 2Nor
Au
Residue
the ligand coordinating with metal ions to form stable complexes
(Table 4).
The norfloxacin ligand and their Ag(I), Cu(II), and Au(III)
complexes have been evaluated for their antifungal activity. The
minimal inhibitory concentration values listed in Table 7 show
that all the test compounds have lower antifungal activity against
Aspergillus flavus and Fusarium solani types except for Peni-
cillium verrcosum type, which have higher antifungal activity
comparable to the respective ligand.
4.7. Kinetics data
Coats–Redfern [32] and Horowitz–Metzger [33] are the
two methods mentioned in the literature related to decom-
position kinetics studies; these two methods are applied in
this study. From the TG curves, the activation energy, E, pre-
exponential factor, A, entropies, ꢁS, enthalpy, ꢁH, and Gibbs
freeenergy, ꢁG, werecalculatedbywell-knownmethods;where
ꢁH = E − RT and ꢁG = ꢁH − T ꢁS.
The linearization curves of Coats–Redfern and
Horowitz–Metzger methods are shown in Fig. 8. Kinetic
parameters for the first stages, calculated by employing the
Coats–Redfern and Horowitz–Metzger equations, are summa-
rized in Table 5, together with the radii of metal ions. The
results show that the values obtained by various methods are
comparable.
The kinetic data obtained with the two methods are in har-
mony with each other. The activation energy of Ag(I), Cu(II),
and Au(III) compounds is expected to increase in relation with
decrease in their radii [34]. The smaller size of the ions permits
a closer approach of the ligand. Hence, the E value in the first
stages for the Cu(II) complex is higher than that for the other
complexes [35,36].
4.8. Biological activities
The results of antibacterial activities in vitro of the ligand
and the complexes are shown in Table 6. From the results we
can see that when the content of the ligand and the complexes
was 1.0 × 10−3 mol dm3, they had no inhibitory activity against
G(−) Escherichia coli. The ligand showed no inhibitory activity
against G(−) Pseudomonas aeruginosa, while the complexes
showed obvious inhibitory activity. The inhibitory activity of
the three complexes in comparison with ligand against G(+)
Bacillus subtilis was decreased.
Fig. 8. Kinetic parameter of [Cu(Nor)2(H2O)2]SO4·5H2O compound.

1404
M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
Table 5
Kinetic data on the studied compounds for stage I
Compounds
Nor
Ionic radius/pm
–
Parametersa
From Coats–Redfern eq.
From Horowitz–Metzger eq.
E
A
ꢁS
ꢁH
ꢁG
r
9.36 × 104
2 × 101
9.66 × 104
8.68 × 101
−3.79 × 101
9.33 × 104
1.08 × 105
0.9817
−5.01 × 101
9.03 × 104
1.10 × 105
0.9853
Ag/Nor
Cu/Nor
Au/Nor
a
126
73
E
A
ꢁS
ꢁH
ꢁG
4.70 × 104
3.74 × 104
−1.62 × 102
4.24 × 104
1.31 × 105
0.9815
4.89 × 104
2.24 × 102
−2.05 × 102
4.43 × 104
1.57 × 105
0.9822
E
A
ꢁS
ꢁH
ꢁG
6.26 × 104
2.67 × 107
−1.04 × 102
5.97 × 104
9.59 × 104
0.9737
6.77 × 104
2.37 × 108
−8.59 × 101
6.48 × 104
9.47 × 104
0.9768
85
E
A
ꢁS
ꢁH
ꢁG
5.23 × 104
2.67 × 1026
−2.55 × 102
3.18 × 105
1.66 × 105
0.9878
5.39 × 104
3.40 × 1027
−2.76 × 102
3.25 × 105
1.61 × 105
0.9863
Units of parameters: E in kJ mol−1, A in s−1, ꢁS in J mol−1 k−1, ꢁH and ꢁG in kJ mol−1
.
Table 6
[2] J. Klostersky, D. Danean, D. Weerts, Chemotherapy 18 (1973) 191.
[3] J.R. Anacona, J. Coord. Chem. 54 (2001) 355.
[4] J. Lozano, J. Borras, J. Inorg. Biochem. 31 (1987) 187.
[5] F.M. Abdel-Gawad, N.M. el-Guindi, M.N. Ibrahim, J. Drug Res. 17 (1987)
197.
[6] M.I.H. Helaleh, E.S.M. Nameh, An. Quim. Int. Ed. 94 (1998) 160.
[7] J.R.J. Sorenson, J. Med. Chem. 19 (1976) 135.
[8] D.H. Brown, A.E. Lewis, W.E. Smith, J.W. Teape, J. Med. Chem. 23 (1980)
729.
Antibacterial activity data for Nor and its compounds
Compound
Bacillus subtilis
P. aeruginosa
E. coli
Nor
++++
+++
+++
+++
+
−
−
−
−
Ag/Nor
Cu/Nor
Au/Nor
++
+++
++
(−) NO antibacterial activity, (+) mild activity, (++) moderate activity, (+++)
[9] D.R. Williams, The Metals of Life, Van Nostrand Reinhold, London,
1971.
marked activity, (++++) strong marked activity.
[10] M. Ruiz, L. Perello, R. Ortiz, A. Castineiras, C. Maichlemossmer, E. Can-
ton, J. Inorg. Biochem. 59 (1995) 801.
[11] S.E. Castillo-Blum, N. Barba-Behrens, Coord. Chem. Rev. 196 (2000)
3.
Table 7
Antifungal activity data for Nor and their compounds
Compound Aspergillus flavus Fusarium solani Penicillium verrcosum
[12] I. Turel, I. Leban, N. Bukovee, J. Inorg. Biochem. 66 (1997) 241.
[13] I. Turel, L. Golic, P. Bukovee, J. Inorg. Biochem. 71 (1998) 53.
[14] P. Yang, J.B. Li, Y.N. Tian, K.B. Yu, Chin. Chem. Lett. 10 (1999)
879.
[15] G. Wu, G. Wang, X. Fu, L. Zhu, Molecules 8 (2003) 287.
[16] I. Turel, I. Leban, G. Klintschar, N. Bukovec, S. Zalar, J. Inorg. Biochem.
66 (1997) 77.
[17] I. Turel, K. Gruber, I. Leban, N. Bukovec, J. Inorg. Biochem. 61 (1996)
197.
[18] I. Turel, I. Leban, M. Zupancic, P. Bukovec, K. Gruber, Acta Crystallog,
Sect. C: Cryst. Struct. Commun. 52 (1996) 2443.
[19] Z.F. Chen, R.J. Xiong, J.L. Zuo, Z. Guo, X.Z. You, K.H. Fun, J. Chem.
Soc., Dalton Trans. 22 (2000) 4013.
Nor
−
−
−
−
−
−
−
−
++
Ag/Nor
Cu/Nor
Au/Nor
+++
+++
++++
(−) NO antibacterial activity, (+) mild activity, (++) moderate activity, (+++)
marked activity, (++++) mtrong marked activity.
Acknowledgements
The author is deeply grateful to the member staff of Depart-
ment of Microbiology, Egyptian International Pharmaceutical
Industrial Company (EIPICO), for performing the antimicrobial
evaluation.
[20] J. Al-Mustafa, Acta Chim. Slov. 49 (2002) 457.
[21] M. Ruiz, L. Perello, J.S. Cario, R. Ortiz, S.G. Granda, M.R. Diaz, E. Canton,
J. Inorg. Biochem. 69 (1998) 231.
[22] W.J. Geary, Coord. Chem. Rev. 7 (1971) 81.
[23] Z.-F. Chen, B.-Q. Li, Y.-R. Xie, R.-G. Xiong, X.-Z. You, X.-L. Feng, Inorg.
Chem. Commun. 4 (2001) 346.
References
[24] L.-Z. Wang, Z.-F. Chen, X.-S. Wang, Y.-H. Li, R.-G. Xiong, X.-Z. You,
Chin. J. Inorg. Chem. 18 (2002) 1185.
[1] A. Zaki, E.C. Schreiber, I. Weliky, J.R. Knill, H.J. Hubsher, J. Clin. Phar-
macol. 14 (1974) 1180.

M.S. Refat / Spectrochimica Acta Part A 68 (2007) 1393–1405
1405
[25] Z.-F. Chen, H. Liang, H.-M. Hu, Y. Li, R.-G. Xiong, X.-Z. You, Inorg.
Chem. Commun. 6 (2003) 241.
[30] R.M. Silverstein, G.C. Bassler, T.C. Morril, Spectroscopic Identification of
Organic Compounds, fifth ed., Wiley, 1991.
[26] Y.-X. Li, Z.-F. Chen, R.-G. Xiong, Z. Xue, H.-X. Ju, X.-Z. You, Inorg.
Chem. Commun. 6 (2003) 819.
[31] W.W. Wendlandt, Thermal Methods of Analysis, Interscience, New York,
1964.
[27] K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination
Compounds, Wiley, New York, 1978.
[28] S.D. Ross, Inorganic Infrared and Raman Spectra, McGraw Hill, London,
1972.
[32] A.W. Coats, J.P. Redfern, Nature 201 (1964) 68.
[33] H.H. Horowitz, G. Metzger, Anal. Chem. 35 (1963) 1464.
[34] G. Avsar, N. Kulcu, H. Arslan, Tur. J. Chem. 26 (2002) 607.
[35] G.S. Sodhi, Therm. Chim. Acta 120 (1987) 107.
[36] H.S. Sangari, G.S. Sodhi, Therm. Chim. Acta 171 (1990) 49.
[29] G.B. Deacon, R.J. Phillips, Coord. Chem. Rev. 33 (1980) 227.