Synthesis, spectroscopic and thermal characterization of some transition metal complexes of folic acid

Article abstract of DOI:10.1016/j.saa.2007.10.008

Compounds having general formula: [M(FO)(Cl)_x(H₂O)_y]·zH₂O, where (M = Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II), FO = folate anion, x = 2 or 4, y = 2 or 4 and z = 0, 1, 2, 3, 5 or 15) were prepared. The obtained compounds were characterized by elemental analysis, infrared as well as electronic spectra, thermogravimetric analysis and the conductivity measurements. The results suggested that all folate complexes were formed by 2:1 molar ratio (metal:folic acid) as a bidentate through both of the two carboxylic groups. The molar conductance measurements proved that the folate complexes are electrolytes. The kinetic thermodynamic parameters such as: E*, ΔH*, ΔS* and ΔG* were estimated from the DTG curves. The antibacterial evaluation of the folic acid and their complexes was also done against some Gram positive/negative bacteria as well as fungi.

Full text of DOI:10.1016/j.saa.2007.10.008

Available online at www.sciencedirect.com
Spectrochimica Acta Part A 70 (2008) 916–922
Synthesis, spectroscopic and thermal characterization
of some transition metal complexes of folic acid
M.G. Abd El-Waheda, M.S. Refatb,∗, S.M. El-Megharbela
a Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
b Department of Chemistry, Faculty of Education, Port Said, Suez Canal University, Port Said, Egypt
Received 23 July 2007; received in revised form 13 September 2007; accepted 4 October 2007
Abstract
Compounds having general formula: [M(FO)(Cl)x(H2O)y]·zH2O, where (M = Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II),
FO = folate anion, x = 2 or 4, y = 2 or 4 and z = 0, 1, 2, 3, 5 or 15) were prepared. The obtained compounds were characterized by elemental analysis,
infrared as well as electronic spectra, thermogravimetric analysis and the conductivity measurements. The results suggested that all folate complexes
were formed by 2:1 molar ratio (metal:folic acid) as a bidentate through both of the two carboxylic groups. The molar conductance measurements
proved that the folate complexes are electrolytes. The kinetic thermodynamic parameters such as: E*, ꢀH*, ꢀS* and ꢀG* were estimated from
the DTG curves. The antibacterial evaluation of the folic acid and their complexes was also done against some Gram positive/negative bacteria as
well as fungi.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Folic acid; Infrared spectra; Thermal analysis; Thermodynamic parameters; Conductivity; Antibacterial activity
1. Introduction
ysis FTIR and UV–vis spectra, molar conductance and TGA
techniques. On the other hand, folic acid and their synthesized
complexes were selected to determine its inhibitory effect on
some bacteria as well as fungi.
Folic acid is structurally composed of pteroic acid and glu-
tamic acid connected via an amide linkage (Fig. 1). Several
studies describe the derivatization of folic acid at the c-carboxyl
group of the glutamate moiety [1]. To date folate conjugates of
chemotherapeutic agents [2,3], antisense oligonucleotides and
ribozymes [4,5], immunotherapeutic agents [6,7] have been syn-
thesized and successfully tested in cancer cells overexpressing
the folate receptor (FR) on their surface.
The structural diversity encountered in metal–folate com-
plexes could be attributed to the versatile ligational behavior of
the carboxylate group which can function like a bidentate ligand
binding to a single metal or alternatively as a bridging bidentate
ligand coordinating to two metals or as a monodentate ligand
[8,9]. The three different coordination modes were reported as
shown in Fig. 2 [10].
2. Experimental
2.1. Materials and instrumentation
All chemicals used were of the purest laboratory grade
(Merck) and folic acid was presented from Egyptian Interna-
tional Pharmaceutical Industrial Company (EIPICo.). Carbon
and hydrogen contents were determined using a Perkin-Elmer
CHN 2400. The metal content was found gravimetri-
cally by converting the compounds into their corresponding
carbides.
IR spectra were recorded on Bruker FTIR spectrophotome-
ter (4000–400 cm−1) in KBr pellets. The UV–vis spectra were
studied in the DMSO solvent with concentration (1.0 × 10−3 M)
for the folic acid and their complexes by help of Jenway
6405 spectrophotometer with 1 cm quartz cell, in the range
800–200 nm.
Theaimofthepresentworkistoshowtheinteractionbetween
some transition metal ions and folic acid. The composition and
structure of the complexes were identified using: elemental anal-
Molar conductivities of freshly prepared 1.0 × 10−3
∗
Corresponding author.
E-mail address: msrefat@yahoo.com (M.S. Refat).
mol dm−3 DMSO solutions were measured using Jenway
1386-1425/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2007.10.008

M.G.A. El-Wahed et al. / Spectrochimica Acta Part A 70 (2008) 916–922
917
2.2.4. [Ni2(FO)(Cl)2(H2O)2]·15H2O (IV,
C19H51N7O23Cl2Ni2) complex
Like the above procedure of the preparation of complexes, a
methanolic solution of NiCl2·6H2O (0.238 g and 1.0 mmol) was
mixed with an equal volume of folic acid solution (1.0 mmol) in
methanol. The mixture was allowed to stay at room temperature
for about 1 h with constant stirring and then heated on a water
bath at ∼60 ◦C for 30 min. The pale yellow complex was filtered
off, washed several times with hot methanol, dried under vacuo
over anhydrous CaCl2.
2.2.5. [Cu2(FO)(H2O)2(Cl)2]·2H2O (V,
Fig. 1. Structure of folic acid.
C19H25N7O10Cl2Cu2) complex
The copper(II) folate complex was prepared by the same
method used for preparation of the Mn(II) and Co(II) com-
plexes. The weight of CuCl2·H2O was (0.152 g and 1.0 mmol)
mixed with folic acid by (1:1) molar ratio in methanol as
solvent.
2.2.6. [Zn2(FO)(Cl)2(H2O)2] (VI, C19H21N7O8Cl2Zn2)
complex
Fig. 2. Coordination modes of the carboxylate group.
The complex, [Zn(Fo)(Cl)2(H2O)2] was prepared by mix-
ing equal volumes (30 ml) of folic acid (1.0 mmol) with ZnCl2
(0.136 g and 1.0 mmol). The mixture was neutralized by titra-
tion with NaOH to adjust pH at 7.0 and then heated on a water
bath at 60 ◦C with constant stirring for about 45 min. A white
solid complex was precipitated and its amount increased with
increasing time of heating. The obtained precipitate was sepa-
rated, washed several times with hot methanol and then dried in
vacuo over anhydrous CaCl2 and recrystalization occurs using
a mixture of water and methanol (1:1).
4010 conductivity meter. Magnetic measurements were car-
ried out on a Sherwood scientific magnetic balance using Gouy
method.
Thermogravimetric analysis (TGA and DTG) was carried
out in dynamic nitrogen atmosphere (30 ml/min) with a heat-
ing rate of 10 ◦C/min using a Schimadzu TGA-50H thermal
analyzer.
2.2. Synthesis of metal complexes
2.2.7. [Cd2(FO)(Cl)2(H2O)2]·3H2O (VII,
C19H27N7O11Cl2Cd2) and [Hg2(FO)(Cl)2(H2O)2] (VIII,
C19H21N7O8Cl2Hg2) complexes
2.2.1. [Mn2(FO)(H2O)2Cl2]·H2O (I, C19H23N7O9Cl2Mn2)
complex
Preparation of these two complexes followed essentially by
the same procedure as preparation of (I), but the weight of
CdCl2 andHgCl2 were0.201 g, 1.0 mmoland0.271 g, 1.0 mmol,
respectively. The pH was adjusted at 7.0.
Folic acid (0.441 g, 1.0 mmol) was added to 30 ml methanol
and titrated against aqueous sodium hydroxide (0.1 M) to adjust
pH at 7.0, then 10 ml methanolic solution of (0.198 g, 1.0 mmol)
of MnCl2·4H2O was added with continuously stirring, after that
the mixture was warmed at about ∼60 ◦C and then neutralized.
Immediately, the brown precipitate was settled down and filtered
off, washed several times by minimum amounts of hot methanol
and dried under vacuo over anhydrous CaCl2.
2.3. Antibactrial and anti-fungal investigation
From these studies, according to Gupta et al. [11], the hole-
well 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) nutrient agar (NA). The homogeneous suspensions were
pouredintoPetri dishes. Theholes(diameter 4 mm)weredonein
the cool medium. After cooling in these holes, 2 × 10−3 dm3 of
the investigated compounds were applied using a micropipette.
After incubation for 24 h in a thermostat at 25–27 ◦C, the inhi-
bition (sterile) zone diameters (including disc) were measured
and expressed in mm. An inhibition zone diameter over 7 mm
indicates that the tested compound is active against the bacteria
under investigation.
2.2.2. [Fe2(FO)(Cl)4(H2O)4]·7H2O (II,
C19H29N7O17Cl4Fe2) complex
A similar procedure as that described for complex (I) was
carried out, by mixing (1.0 mmol) of folic acid with FeCl3·2H2O
(0.162 g and 1.0 mmol).
2.2.3. [Co2(FO)(H2O)2(Cl)2]·3H2O (III,
C19H27N7O11Cl2Co2) complex
A pale yellow complex, [Co2(Fo)(H2O)2(Cl)2]·3H2O was
prepared during the reaction of (1.0 mmol) folic acid with
0.257 g and 1.0 mmol of CoCl2·6H2O by a method similar to
that described above.
The antibacterial activities of the investigated compounds
were tested against Escherichia coli (Gram −ve), Bacillus sub-

918
M.G.A. El-Wahed et al. / Spectrochimica Acta Part A 70 (2008) 916–922
strongly supported with the elemental analysis data, where Cl−
ions are detected by addition of AgNO3 solution, inside the coor-
dination sphere of the complexes by the degradation of the all
complexes using nitric acid.
tilis (Gram +ve) and anti-fungal (Trichoderma and Penicillium
activities).
3. Results and discussion
The results of the elemental analysis and some physical
characteristics of the obtained compounds were discussed.
The complexes are air-stable, with high-melting points, insol-
uble in H2O and most of organic solvents except for DMSO
and DMF are slightly soluble. The elemental analysis data of
the complexes indicate that the 2:1 (metal:ligand) stoichiome-
try with general formula: [M2(FO)(H2O)x(Cl)y]·nH2O (where
M = Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and
Hg(II), and x = 2 in the case of all complexes except for Fe(III)
x = 4, y = 2.
3.2. Infrared spectra
The essential infrared data are summarized in Table 1. Folic
acid exhibits a very strong absorption band at 1694 cm−1 due
to the stretching vibration of ν(C O) of free ketonic of the
carboxylic group. This group is shifted or disappeared in the
spectra of its complexes. Interestingly, there are two bands
which appeared at the range of 1514–1564 cm−1 and corre-
sponded to νas(COO−) and the other band is exhibited within the
range of 1333–1352 cm−1 assigned to νs(COO−). Accordingly,
the antisymmetric and symmetric stretching vibration modes
(νas(COO−), and νs(COO−)) of the COO− group, the structure
of our complexes could be elucidated [13]. The direction of the
frequency shift of the νas(COO−) and the νs(COO−) bands with
respect to those of the free ion depends on the coordination mode
of the COO− group with the metal ion.
Nakamoto and McCarthy [14] have established that if the
coordination is monodentate (structure I) the νas(COO−) and
νs(COO−) will be shifted to higher and lower frequencies,
respectively. Whereas, if the coordination is chelating biden-
tate (structure II) or bridging bidentate (structure III) both
νas(COO−) and νs(COO−) frequencies will change in the
same direction because the bond orders of both C O bonds
would change by the same amount. Based on these facts and
3.1. Molar conductivities of metal chelates
The molar conductivity values for the folate complexes
in DMSO solvent (1.0 × 10−3 mol) were in the range of
53.50–93.70 ꢁ−1 cm−1 mol−1, suggesting them to be elec-
trolytes in nature. Conductivity measurements provide a method
of testing the degree of ionization of the complexes, the molecu-
lar ions that is a complex liberates in solution (in case of presence
of anions outside the coordination sphere), the higher will be
its molar conductivity and vice versa [12]. It is clear from the
obtained data that the complexes present seem to be electrolytes.
Also the molar conductance values indicate that the anions may
be exhibits inside the coordination sphere. These results were
Table 1
IR frequencies (cm−1) of folic acid (FO) and its metal complexes
Assignments
Compound
FO
I
II
III
IV
V
VI
VII
VIII
ν(OH); H2O
3544
3415
3322
3106
2926
2840
3344
3381
3385
3379
3377
3353
3338
3419
ν(NH)
νas(CH)
3180
3083
2927
2865
2723
–
3175
3090
2930
2870
2770
–
3190
2920
3200
2940
3200
3030
2930
2860
2805
–
3170
3008
2915
2860
2810
–
3170
3000
2910
2867
3200
3050
2927
2863
2810
–
νs(CH)
2820
2750
–
2850
2805
–
ν(COOH)
νas(COO−)
1694
1565
1544
1483
1453
1413
1338
1294
1230
1191
1160
1134
1106
971
–
1545
1564
1543
1544
1548
1522
1514
1563
δ(CH)
1448
1409
1445
1407
1444
1404
1448
1406
1446
1401
1453
1402
1451
1403
1456
1401
νs(COO−)
νas(CC)
ν(CN)
1339
1301
1187
1108
1337
1303
1188
1127
1345
1300
1185
1103
1352
1277
1187
1102
1333
1295
1184
1108
1339
1188
1127
1105
1342
1184
1102
1335
1295
1180
1121
νs(CC)
δ(CC)
952
786
759
585
519
950
768
968
767
669
579
416
945
768
666
582
466
955
769
669
585
521
963
786
993
786
951
768
764
ν(M–O)
–
582
520
580
453
578
457
576
516

M.G.A. El-Wahed et al. / Spectrochimica Acta Part A 70 (2008) 916–922
919
Table 2
Asymmetric and symmetric stretching vibrations of the carboxylate group
Compound
νas(COO−)
νs(COO−)
ꢀν = νas(COO−)−νs(COO−)
Bonding mode
FO
1565
1564
1543
1544
1548
1522
1514
1545
1563
1453
1339
1337
1345
1352
1333
1339
1342
1335
112
225
206
199
196
189
175
203
228
Bidentate
Bidentate
Bidentate
Bidentate
Bidentate
Bidentate
Bidentate
Bidentate
Bidentate
[Mn2(FO)(H2O)2Cl2]·H2O (I, C19H23N7O9Cl2Mn2)
[Fe2(FO)(Cl)4(H2O)4]·7H2O (II, C19H29N7O17Cl4Fe2)
[Co2(FO)(H2O)2(Cl)2]·3H2O (III, C19H27N7O11Cl2Co2)
[Ni2(FO)(Cl)2(H2O)2]·15H2O (IV, C19H51N7O23Cl2Ni2)
[Cu2(FO)(H2O)2(Cl)2]·2H2O (V, C19H25N7O10Cl2Cu2)
[Zn2(FO)(Cl)2(H2O)2] (VI, C19H21N7O8Cl2Zn2)
[Cd2(FO)(Cl)2(H2O)2]·3H2O (VII, C19H27N7O11Cl2Cd2)
[Hg2(FO)(Cl)2(H2O)2] (VIII, C19H21N7O8Cl2Hg2)
comparison the νas(COO−) and νs(COO−) frequencies of the
folate complexes by the νas(COO−) and νs(COO−) frequen-
cies of sodium carboxylate [15], as shown in Table 2, man
can say that all the prepared complexes are chelating bidentate
structure.
convenient with experimental values [17] obtained for square
planner complexes.
3.4. Electronic absorption spectra
The stretching broadband vibration of OH− group ν(O–H)
occurred as expected [16] at the range ∼3400 cm−1. The angu-
lar deformation motions of the coordinated water in the hydrated
folate complexes can be classified into four types of vibrations:
δb (bend), δr (rock), δt (twist) and δw (wag). The assignments
of these motions in all complexes are as follows: The bend-
ing motion, δb(H2O), is assigned to its characteristic band
around at ∼1600 cm−1 (from medium to very strong band).
The rocking motions, δr(H2O), is assigned at ∼760 cm−1 and
the wagging motion, δw(H2O), is observed at ∼600 cm−1. The
twisting motion, δt(H2O), is observed at above 600 cm−1. It
should be mentioned here that these assignments for both the
bond stretches and angular deformation of the coordinated water
molecules fall in the frequency regions reported for related com-
plexes [14].
The spectra of free folic acid and their complexes in DMSO
are followed. There are two detected absorption bands at around
(225 and 240 nm) and (256, 290 and 355 nm) assigned to ␲–␲*
andn–␲*intraligandtransitions, respectively. Thefirstbands are
probably due to a ␲–␲* of the alkyl group as well as aromatic
rings, but the other bands are due to presence of COOH, –NH,
NH2 and C O groups [18]. After complexation, they are shifted
to ca. 20–30 nm and ∼25 nm, for ␲–␲* and n–␲*, respectively,
confirming the complexation of metal ions via carboxylic group.
Some complexes have a band at range ∼360 nm may be assigned
to the ligand to metal charge transfer [19,20].
3.5. Thermogravimetric analysis
Thermal analysis curves (TG/DTG) of the folic acid and their
transition metal complexes are studied and interpreted as follows
The folic acid ligand melts at 493 K with simultaneous
decomposition. The first mass loss was observed at 368 K. From
the TG curve, it appears that the sample decomposes in three
stages over the temperature range 368–1073 K. The first step
occurs at 298–368 K with a mass loss of (obs. = 8.04% and
calc. = 7.70%). The second step starts at 523 K and ends at 994 K
with a mass loss (obs. = 32.90% and calc. = 33.10%). The last
one within the range 994–1027 K was accompanied by mass loss
(obs. = 57% and calc. = 56.4%). From the corresponding DTG
curve, three endothermic peaks are noted. The first maximum is
at 368 K and the second, third at 523 and 994 K, respectively.
The thermal decomposition of Mn complex occurs also
at three steps. The first degradation step take place in the
range of 298–319.5 K and it is corresponds to the elimina-
tion of 3H2O molecules beside 0.5N2 molecule due to weight
3.3. Magnetic measurements
Magnetic measurements were carried out according to the
Gauy method. The calculations were evaluated by applying the
equations:
ꢀ
cl(R − R0)
χg =
,
χm = χgMWt, μeff = 2.828 χmT
109M
where χ is mass susceptibility per g of sample; c is the calibration
constant; R is the balance reading for the sample and tube; R0 is
the balance reading for the empty tube; M is the weight of the
sample in g.
The magnetic moments of Ni and Cu complexes at T = 300 K
and their corresponding hybrid orbitals are given in Table 3.
The observed values of the effective magnetic moments μeff are
Table 3
Magnetic moment of the Ni(II) and Cu(II) complexes
Complex
μeff (μB)
Hybrid orbitals
Stereochemistry
Found
Calculated
[Ni2(FO)(Cl)2(H2O)2]·15H2O
[Cu2(FO)(H2O)2(Cl)2]·2H2O
0.00
1.85
0.00
1.50
dsp2
dsp2
Square planner
Square planner

920
M.G.A. El-Wahed et al. / Spectrochimica Acta Part A 70 (2008) 916–922
loss (obs. = 9.84% and calc. = 10.09%). The second step falls
in the range of 319.5–620 K which is assigned to loss of
C6H12O2 (organic rest) with a weight loss (obs. = 17.29% and
calc. = 17.2%). The last decomposition step within the range
620–1073 K was accompanied by mass loss (obs. = 39.63% and
calc. = 38.43%) which is assigned to loss of C3H5N6O4Cl2
(organic rest). The (2MnC2 + 6C) is the final product remains
stable till 1073 K.
The thermal decomposition of Fe complex occurs com-
pletely in three steps. The first step ranged at 298–369 K
corresponding to the loss of 11H2O molecules and CH2O
organic molecule, representing weight loss (obs. = 25.63%
and calc. = 25.59%). The second and third steps occurring
at 369–736 and 763–1073 K corresponding to the loss of
C2H5N7O5 (organic part) and two chlorine molecules, rep-
resenting weight loss (obs. = 39.02% and calc. = 40.30%).
The 2FeC2 + 12C is the final product remains stable till
1073 K.
The Co complex decomposed in three steps. The first
step ranged at 298–324 K corresponding to the loss of
5H2O molecules representing weight loss (obs. = 12.96% and
calc. = 12.53%). The second step occurring at 324–625 K cor-
responding to the loss of C6H12O6 organic molecule, the
weight loss associated with this stage (obs. = 25.35% and
calc. = 25.07%). The final step of decomposition occurs at a tem-
perature range from 636 to 1073 K. The weight loss at this step
is obs. = 25.24% and calc. = 25.77%. Associated with the loss
of CH5N7 (organic moiety) and chlorine molecule. The final
residue at the end of this stage is 2CoC2 + 8C.
To make sure about the proposed formula and structure for
the new Ni complex, thermogravimetric (TG) and differential
thermogravimetric analysis (DTG) was carried out for this com-
plex under N2 flow. The thermal decomposition of the nickel(II)
complex proceeds approximately with main three degradation
steps. The first stage occurs at maximum temperature of 341 K.
The weight loss associated with this stage (obs. = 11.94% and
calc. = 11.56%) corresponding to the loss of 6H2O. The sec-
ond step occurs at the maximum temperature 623 K. The weight
loss at this step (obs. = 14.08% and calc. = 15.42%) associated
with the loss of 8H2O. The final decomposition stage occurs at
the maximum temperature 759 K. The weight loss at this step
(obs. = 39.35% and calc. = 39.73%) associated with the loss of
C3H23N7O9 organic part and chlorine. The final residue at the
end of this stage is 2NiC2 + 12C.
As mentioned above in the copper(II) complex, the zinc(II)
folate complex, also has three decomposition steps. These
steps located in the range between 298–328, 328–636 and
636–1073 K and the weight loss for the first step (obs. = 9.40%
and calc. = 10.34%) due to the loss of 2H2O + 2NH3. The second
decomposition stage occurs at the maximum temperature 636 K.
The weight loss at this step is (obs. = 18.7% and calc. = 18.17%)
associated with the loss of C4H5N5 organic part. The weight
loss of the final decomposition stage is (obs. = 36.69% and
calc. = 36.05%) associated with the loss of C6H6O6organic part
and chlorine molecule. The final residue at the end of this stage
is 2ZnC2 + 5C.
The thermal decomposition of Cd complex proceeds with
three main degradation steps. The first step of the degrada-
tion occurs at maximum temperature of 322 K in the range
of 298–630 K is accompanied by weight loss (obs. = 9.30%
and calc. = 8.72%) correspond to the loss of 4H2O. The sec-
ond decomposition stage occurs at the maximum temperature
of 630 K. The weight loss at this step (obs. = 9.90% and
calc. = 9.69%) associated with the loss of C2H8O3 organic part.
The final decomposition stage occurs at the maximum tempera-
ture of 1054 K. The weight loss at this step is (obs. = 29.33% and
calc. = 29.46%) associated with the loss of NH3 + 3N2 + 4H2O
and chlorine molecule. The final residue at the end of this stage
is 2CdC2 + 13C.
The thermal decomposition data obtained support the pro-
posed structure and indicate that the thermal decomposition
of Hg complex proceeds with three main degradation steps.
The first step occurs at a temperature maximum of 328 K. The
weight loss found associated with this step (obs. = 10.80% and
calc. = 9.92%) and may be attributed to the loss of the organic
moiety (CH3NO2). The second step of decomposition occurs
at a temperature maximum of 626 K. The weight loss found at
this step (obs. = 16.29% and calc. = 16.25%) corresponds to the
loss of C4H10O6 (organic moiety). The final step of decompo-
sition occurs at a temperature range from 1054–1073 K. The
weight loss at this step is (obs. = 21.34% and calc. = 21.70%)
associated with the loss of C4H4N6 (organic moiety) and chlo-
rine molecule. The final residue at the end of this stage is
2HgC2 + 6C.
3.6. Kinetic studies
In recent years, there has been increasing interest in determin-
ing the rate-dependent parameters of solid-state non-isothermal
decomposition reactions by analysis of TG curves [21–27]. Most
commonly used methods are the differential method of Freeman
and Carroll [21] integral method of Coat and Redfern [22] and
the approximation method of Horowitz and Metzger [25].
In the present investigation, the general thermal behaviors
of the folate complexes in terms of stability ranges, peak tem-
peratures and values of kinetic parameters, are discussed. The
kinetic parameters have been evaluated using the Coats–Redfern
equation:
The thermal degradation of the Cu complex occurs in mainly
three degradation stages. The first stage of decomposition occurs
at a temperature maximum of 565 K. The weight loss found
associated with this step (obs. = 8.81% and calc. = 10.14%)
and may be attributed to the loss of 4H2O. The second step
of decomposition occurs at a temperature maximum of 839 K.
The weight loss found at this step equals to (obs. = 17.73% and
calc. = 17.61%) corresponds to the loss of C2H5O6 (organic
moiety). Final step occurring at 636–1073 K is corresponding to
the loss of C7H12N7 organic moiety and chlorine molecule rep-
resenting weight loss (obs. = 37.81% and calc. = 37.21%).
The final thermal products obtained at 1073 K are
2CuC2 + 6C.
ꢂ
ꢃ
ꢁ
ꢁ
α
T
dα
(1 − α)n
A
ϕ
E∗
2
=
exp
−
dt
(1)
RT
0
T
1

M.G.A. El-Wahed et al. / Spectrochimica Acta Part A 70 (2008) 916–922
921
This equation on integration gives
ꢄ
ꢅ
ꢄ
ꢅ
ln(1 − α)
E∗
AR
ϕE∗
ln −
= −
+ ln
(2)
T2
RT
A plot of left-hand side (LHS) against 1/T was drawn. E* is
the energy of activation (J mol−1) and calculated from the slop
and A (s−1) from the intercept value. The entropy of activation
ꢀS* (J K−1 mol−1) was calculated by using the equation:
ꢂ
ꢃ
Ah
ꢀS∗ = R ln
(3)
kBTs
where kB is the Boltzmann constant, h is the Plank’s constant
and Ts is the DTG peak temperature [28].
The Horowitz–Metzger equation is an illustrative of the
approximation methods.
ꢆ
Fig. 3. Statistical representation for biological activity of folic acid and its
complexes.
1 − (1 − α)1−n
1 − n
E∗θ
2.303RTs2
log
=
,
for n = 1
(4)
3.7. Antimicrobial activity
When n = 1, the LHS of Eq. (4) would be log[−log(1 − α)]. For a
first-order kinetic process the Horowitz–Metzger equation may
be written in the form:
The results of antimicrobial activities (bacteria and fungi)
in vitro of the folic acid ligand and their complexes (Fig. 3)
show that, the [Hg2(FO)(Cl)2(H2O)2] test complex have high
activities against Penicillium > Trichoderma > E. coli. On the
other hand, the cadmium(II), cobalt(II) and nickel(II) folate
complexes have antimicrobial activities against B. subtilis, Tri-
choderma and Penicillium, respectively. These results clearly
obviously that, some metal ions after complexation give the
sensitive nature for the ligand against some bacteria and fungi.
ꢄ
ꢂ
ꢃꢅ
ꢂ
ꢃ
w␣
wy
E∗θ
2.303RTs2
log log
=
− log 2.303
where θ = T − Ts, wy = w␣ − w, w␣ = mass loss at the
completion of the reaction; w = mass loss up to time t. The
plot of log[log(w␣/wy)] vs. θ was drawn and found to be linear
from the slope of which E* was calculated. The pre-exponential
factor, A, was calculated from the equation:
E∗
RTs2
A
=
ϕ exp(−E∗/RTs)
The entropy of activation, ꢀS*, was calculated from Eq. (3).
The enthalpy activation, ꢀH*, and Gibbs free energy, ꢀG* were
calculated from ꢀH* = E*−RT and ꢀG* = ꢀH*−TꢀS*, respec-
tively.
ꢀG is positive for reaction for which ꢀH is positive and
ꢀS is negative. The reaction for which ꢀG is positive and
ꢀS is negative considered as unfavorable or non-spontaneous
reactions.
Reactions are classified as either exothermic (ꢀH < 0) or
endothermic (ꢀH > 0) on the basis of whether they give off
or absorb heat. Reactions can also be classified as exergonic
(ꢀG < 0) or endergonic (ꢀG > 0) on the basis of whether the free
energy of the system decreases or increases during the reaction.
The thermodynamic data obtained with the two methods are
in harmony with each other. The activation energy of Mn2+ and
Hg2+ complexes is expected to increase in relation with decrease
in their radii [29]. The smaller size of the ions permits a closer
approachoftheligand. Hence, the E valuein the firststageforthe
Mn2+ complex is higher than that for the other Hg2+ complex.
The correlation coefficients of the Arrhenius plots of the
thermal decomposition steps were found to lie in the range of
0.9845–0.9999, showingagoodfitwithlinearfunction. Itisclear
that the thermal decomposition process of all folate complexes
is non-spontaneous, i.e., the complexes are thermally stable.
Fig. 4. The mode of chelation of the folate complexes.

922
M.G.A. El-Wahed et al. / Spectrochimica Acta Part A 70 (2008) 916–922
[7] B.K. Cho, E.J. Roy, T.A. Patrick, D.M. Kranz, Bioconjug. Chem. 8 (1997)
3.8. Structure of the folate complexes
338.
[8] R.C. Mehrotra, R. Bohra, Metal Carboxylates, Academic Press, London,
1983.
[9] R.C. Mehrotra, A. Singh, Prog. Inorg. Chem. 46 (1997) 239.
[10] G.B. Deacon, R.J. Phillips, Coord. Chem. Rev. 33 (1980) 227.
[11] R. Gupta, R.K. Saxena, P. Chatarvedi, J.S. Virdi, J. Appl. Bacteriol. 78
(1995) 378.
Finally on the basis of the above studies, the suggested struc-
tures of the folate complexes can be represented in Fig. 4.
4. Conclusion
[12] K. Burger, Coordination Chemistry: Experimental Methods, Butterworth
Group, Britain, 1973.
[13] M.A. Mesubi, J. Mol. Struct. 81 (1982) 61.
[14] K. Nakamato, P.J. McCarthy, Spectroscopy and Structure of Metal Chelate
Compounds, John Wiley, New York, 1968, p. 268.
[15] R. Goto, T. Takenaka, J. Chem. Soc. Jpn. 84 (1963) 392.
[16] L.S. Gelfand, F.J. Iaconianni, L.L. Pytlewski, A.N. Speca, C.M. Mikulski,
N.M. Karayannis, J. Inorg. Nucl. Chem. 42 (1980) 377.
[17] A. Earnshow, Introduction to Magneto Chemistry, Academic Press, New
York, 1968.
[18] G.D. Fasman, Handbook of Biochemistry and Molecular Biology, Nucleic
Acids, I, CRC Press, pp. 65–215.
[19] R.H. Holm, F.A. Cotton, J. Am. Chem. Soc. 80 (1958) 5658.
[20] F.A. Cotton, C.W. Wilkinson, Advanced Inorganic Chemistry, third ed.,
Interscience Publisher, New York, 1972.
[21] E.S. Freeman, B. Carroll, J. Phys. Chem. 62 (1958) 394.
[22] A.W. Coats, J.P. Redfern, Nature 201 (1964) 68.
[23] T. Ozawa, Bull. Chem. Soc. Jpn. 38 (1965) 1881.
[24] W.W. Wendlandt, Thermal Methods of Analysis, Wiley, New York,
1974.
The complexation between transition metal ions like (Mn(II),
Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II)) with
folic acid produced 2:1 molar ratio (metal:folic acid) as a biden-
tate via both two carboxylic groups and give general formula:
[M(FO)(Cl)x(H2O)y]·zH2O, where FO = folate anion; x = 2 or 4,
y = 2 or4 and z = 0, 1, 2, 3, 5 or15. Theresulted folatecompounds
were assigned by infrared and electronic spectra. Thermogravi-
metric analysis and kinetic thermodynamic parameters have
proved the thermal stability feature of folate complexes. The
antimicrobial activities of the transition metal complexes of folic
acidrecordedasignificanteffectagainstsomebacteriaandfungi.
References
[1] W.J. Guo, G.H. Hinkle, R.J. Lee, J. Nucl. Med. 40 (1999) 1563.
[2] C.A. Ladino, R.V.J. Chari, L.A. Bourret, N.L. Kedersha, V.S. Goldmacher,
Int. J. Cancer 73 (1997) 859.
[3] J.W. Lee, J.Y. Lu, P.S. Low, P.L. Fuchs, Bioorg. Med. Chem. 10 (2002)
2397.
[4] J. Matulic-Adamic, M. Sanseverino, L. Beigelman, Tetrahedron Lett. 43
(2002) 4439.
[5] C.P. Leamon, S.R. Cooper, G.E. Hardee, Bioconjug. Chem. 14 (2003) 738.
[6] D.M. Kranz, T.A. Patrick, K.E. Brigle, M.J. Spinella, E.J. Roy, Proc. Natl.
Acad. Sci. U.S.A. 92 (1995) 9057.
[25] H.W. Horowitz, G. Metzger, Anal. Chem. 35 (1963) 1464.
[26] J.H. Flynn, L.A. Wall, Polym. Lett. 4 (1966) 323.
[27] P. Kofstad, Nature 179 (1957) 1362.
[28] J.H.F. Flynn, L.A. Wall, J. Res. Natl. Bur. Stand. A 70 (1996) 487.
[29] N.K. Tunali, S. Ozkar, Inorganic Chemistry, Pub No. 185, Gazi University
Publication, Ankara, 1993.