Determination of composition and instability constants of maltol complexes with iron(III) ions

Article abstract of DOI:10.1023/B:RUCB.0000037841.67079.2b

Complexation of maltol (MH) with Fe³⁺ ions in aqueous solutions was studied. The compositions of [FeMa]²⁺, [FeMa₂] ⁺, and [FeMa₃] complexes were determined by the method of isomolar series, and their instability constants were calculated. The values of the latter were confirmed by the method of apparent deviation from the Bouger - Lambert - Beer law. An increase in the Ma:Fe³⁺ ratio from 1 to 3 decreases the instability constants of the complexes. The [FeMa₃] complex can be considered as a basis for the antianemic drug with a prolonged effect.

Full text of DOI:10.1023/B:RUCB.0000037841.67079.2b

780
Russian Chemical Bulletin, International Edition, Vol. 53, No. 4, pp. 780—784, April, 2004
Determination of composition and instability constants
of maltol complexes with iron(III) ions
I. A. Antipova, S. A. Mukha, and S. A. Medvedevaꢀ
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
1 ul. Favorskogo, 664033 Irkutsk, Russian Federation.
Fax: +7 (395 2) 41 9346. Eꢀmail: msa@irioch.irk.ru
Complexation of maltol (MH) with Fe3+ ions in aqueous solutions was studied. The
compositions of [FeMa]2+, [FeMa2]+, and [FeMa3] complexes were determined by the method
of isomolar series, and their instability constants were calculated. The values of the latter were
confirmed by the method of apparent deviation from the Bouger—Lambert—Beer law. An
increase in the Ma : Fe3+ ratio from 1 to 3 decreases the instability constants of the complexes.
The [FeMa3] complex can be considered as a basis for the antianemic drug with a prolonged
effect.
Key words: maltol, iron(III), complexation, instability constants.
Maltol (3ꢀhydroxyꢀ2ꢀmethylꢀ4ꢀpyrone, MaH) is a
the compositions and instability constants of the comꢀ
plexes formed at different pH of a medium.
natural substance found in several plants (leaves of
Passiflora,1 Japanese Cercis,2 Aralia,3 and
others). Maltol is isolated, as a rule, from
needles of Siberian fir (Abies sibirica L.),
where its content reaches 1—2%.4
The reaction was studied by the spectrophotometric
method using the absorbance of the resulting complexes
at 340—600 nm. Maltol does not absorb in this region of
wavelengths, and the absorbance of iron(III) chloride is
insignificant. This makes it possible to determine directly
the absorbance and, correspondingly, the concentration
of the colored maltol complexes.
Since the maltol structure contains
the hydroxyl and keto groups in the
orthoꢀposition, this γꢀpyrone is an effiꢀ
cient bidentate chelating ligand and can
easily be coordinated with biꢀ and trivalent metal ions to
form bisꢀ and trischelate complexes.5—11 These maltol
compounds can be considered as ionophores capable of
supplying an organism with necessary microelements.
Unlike similar chelating ketoꢀalcohols, maltol has great
advantages from the biological point of view, because it is
a lowꢀtoxicity substance (index LD50 = 1400 mg kg–1),8
manifests antioxidant properties12 (due to which it is used
in food and fragrance industries), and possesses fungiꢀ
static and antibacterial activity.13
The neutral waterꢀsoluble tris(3ꢀhydroxyꢀ2ꢀmethylꢀ
4ꢀpyronato)iron(III) complex is of interest as a potential
medicine for treatment of ironꢀdeficient anemia.10,11
A study of complexation
and stability of this comꢀ
plex is expected to provide
Experimental
Maltol was isolated from needles of Siberian fir (Abies
sibirica L.) using a procedure proposed by us previously.14 The
following reagents were used: FeCl3•6Н2О, HСlO4 (reagent
grade), 25% NH4OH (analytical grade), glacial AcOH (reagent
grade), and bidistilled water.
Electronic spectra were recorded on an SFꢀ26 spectrophoꢀ
tometer. The absorbance of solutions was measured in quartz
cells with layer thicknesses of 1 cm and 0.1 cm (in the dilution
method) using a buffer with the same pH value as a reference
solution. To determine the plots of the absorbance of maltol
vs. pH of the medium and pKa, aqueous solutions of the subꢀ
stance with a concentration of 6.87•10–5 mol L–1 were used.
The pH values of solutions were measured with an EVꢀ74 uniꢀ
versal pHꢀmeter.
To control the pH of the medium, 0.2 М solutions of ammoꢀ
–
nia and perchloric acid were used, because the СlO4 anion is
insight into its behavior in
much less prone to form complexes with iron compared to anꢀ
ions of other acids. The iron salt (FeCl3•6H2O) is readily hydroꢀ
lyzed at pH > 6 to form a precipitate of iron hydroxide. Thereꢀ
fore, an acetate—ammonia buffer was used in some experiments,
because the acetate anion of this buffer forms an easily dissociꢀ
ating complex with FeIII, whose weak absorption can be neꢀ
glected compared to that of the iron(III) complexes with maltol.
the human organism.
The purpose of this
work is to study the comꢀ
plexation of maltol with
iron(III) chloride, includꢀ
ing the determination of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 744—748, April, 2004.
1066ꢀ5285/04/5304ꢀ0780 © 2004 Plenum Publishing Corporation

Complexes of maltol with iron(III)
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
781
Table 1. Degrees of dissociation and instability constants of the
iron(III) maltolate complexes determined by the method of
isomolar series
The accuracy of measurements (Tables 1 and 2) was exꢀ
pressed by standard deviations (s).18
Results and Discussion
Complex
pH
α
Кinstab/mol L–1
[FeMa]2+
FeMa2]+
[FeMa3]
1
3
6
0.35
0.16
0.10
1.48•10–4
2.44•10–5
8.70•10–6
Maltol, whose singleꢀcharged anion is a ligand in the
complexes with FeIII, is a weak acid, and its pKa in water
is 8.68.10 The concentration of the ionized form of a weak
acid is known to increase considerably with an increase in
the pH of solution. Therefore, the dependence of the
absorbance of maltol itself in the 220—360 nm region on
the pH of medium was studied first.
In an interval of pH = 1—6, the UV spectra (Fig. 1)
exhibit one absorption maximum with λmax = 275 nm
(logε = 4.242), which is characteristic of the nonꢀdissociꢀ
ated maltol molecule. With an increase in the pH from 7
to 9, the intensity of this absorption maximum decreases
(logε = 4.159 at pH 8) and a new maximum appears at
λmax = 320 nm (logε = 3.044). This maximum is characꢀ
The compositions of the complexes were determined by the
method of isomolar series.15—17 Three isomolar series with pH 1,
3, and 5.5 were prepared. For this purpose, the starting aqueous
solutions of FeCl3•6Н2О and maltol with equal concentrations
(7.9•10–4 mol L–1) were mixed in different ratios, so that the
sum of moles of the substances in solutions of the series reꢀ
mained unchanged. The absorbances of solutions were detected
at λ = 500, 460, and 412 nm, respectively. The compositions of
the complexes formed and their instability constants were deterꢀ
mined by the extrapolation of the initial regions of each "ratio of
components—absorbance" diagram to the intersection point.
Table 2. Degrees of dissociation and instability constants of the iron(III) maltolate complexes determined by the
method of apparent deviation from the Bouger—Lambert—Beer law
Complex
[FeMa]2+
λ/nm
D1
D10
∆
∆
s
α
Кinstab/mol L–1
av
400
410
420
430
440
450
460
470
480
490
500
400
410
420
430
440
450
460
470
480
490
500
400
410
420
430
440
450
460
470
480
490
500
0.37
0.37
0.36
0.35
0.34
0.36
0.39
0.42
0.46
0.48
0.50
0.46
0.46
0.46
0.45
0.44
0.45
0.46
0.48
0.49
0.50
0.49
0.60
0.60
0.60
0.58
0.57
0.57
0.56
0.55
0.53
0.50
0.45
0.27
0.26
0.25
0.23
0.22
0.23
0.25
0.28
0.30
0.32
0.34
0.40
0.405
0.40
0.39
0.39
0.40
0.41
0.43
0.44
0.45
0.44
0.56
0.56
0.56
0.54
0.53
0.53
0.52
0.51
0.50
0.46
0.42
0.27
0.31
0.32
0.33
0.34
0.36
0.36
0.33
0.35
0.33
0.33
0.13
0.12
0.13
0.13
0.11
0.12
0.11
0.10
0.11
0.10
0.10
0.006
0.006
0.006
0.069
0.070
0.071
0.072
0.075
0.30
0.11
0.07
0.025
0.14
1.5•10–4
[FeMa2]+
0.012
0.05
2.0•10–5
[FeMa3]
0.002
0.03
8.4•10–6

782
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Antipova et al.
D320 (rel. units)
D (rel. units)
4
0.6
0.5
0.4
0.3
0.2
0.1
1
1.2
3
2
3
0.8
0.4
2
4
1
5
410
460
510
560
λ/nm
250
280
310
340
λ/nm
Fig. 3. Electronic spectra of a mixture of aqueous solutions of
FeCl3•6Н2О and maltol (molar ratio 1 : 5) at pH 1 (1), 2 (2),
3 (3), and 5—9 (4) of the medium.
Fig. 1. Electronic spectra of aqueous solutions of maltol
(6.87•10–5 mol L–1) at pH 1—5 (1), 7 (2), 8 (3), 9 (4), and
10 (5) in the medium.
(3.95•10–4 mol L–1) and a fivefold excess of maltol
(1.97•10–3 mol L–1) for different pH values (Fig. 3). For
detection of the complexes, λ = 412 nm was chosen. The
plot of the absorbance (D412) vs. pH of the solution is
presented in Fig. 4. The shape of the curve indicates the
stepwise formation of three complexes with different opꢀ
tical properties. The observed jumps of the absorbance
and comparison of the plots presented in Figs. 3 and 4
suggest the following. In a region of pH 1—2 a complex of
maltol with Fe3+ ions (1) is formed, and its spectrum is
teristic of the Ma– anion, and its intensity increases with
an increase in the pH (logε = 4.167 for pH 8). For
pH 10—10.5, the maximum at λ = 275 nm disappears,
and the single maximum at λ = 320 nm is observed in the
spectrum.
The plot of the absorption intensity of maltol at λ =
320 nm vs. pH of the medium (Fig. 2) allows one to find
the pH value corresponding to the 50% dissociation of the
substance, when КHR = [H+].16 This point corresponds to
the halfꢀsum of the absorbances of the acid and salt forms
of the substance for the equal concentrations
characterized by the absorption maximum with λmax
=
500 nm. Complex 2 with λmax = 460 nm is formed in a
region of pH 3—4, and complex 3 with λmax = 412 nm is
formed at pH 5—6. The formation of various complexes is
confirmed by the color of solutions changing from vioꢀ
let (1) to red (2) and then to yellow (3). The decrease in
the absorbance at pH 8—10 indicates that hydrolysis of
the starting salt FeCl3•6Н2О occurs predominantly in
this medium.
Dm = 0.5(DHR + DR–).
For maltol Dm = 0.5(0.05 + 1.05) = 0.55. The abscissa
of this point corresponding to pH 8.6 shows a correlation
with the pKa value, because in this point pH = pKa.
To study the reaction of maltol with iron(III) chloride,
we recorded electronic spectra of solutions of the comꢀ
plexes formed at a constant concentration of FeCl3•6Н2О
The compositions of the complexes were determined
by the method of isomolar series.15 Three isomolar series
D320 (rel. units)
D412 (rel. units)
1.0
0.8
0.6
0.4
0.2
0.6
0.4
3
5
7
9
pH
3
5
7
9
11
13 pH
Fig. 4. Absorbance of a mixture of aqueous solutions of
FeCl3•6Н2О and maltol (molar ratio 1 : 5) vs. pH of the meꢀ
dium at λ = 412 nm.
Fig. 2. Absorbance of an aqueous solution of maltol
(6.87•10–5 mol L–1) vs. pH of the medium at λ = 320 nm.

Complexes of maltol with iron(III)
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
783
differed by the pH value: the first series had pH 1, the
second series had pH 3, and the third series was characꢀ
terized by pH 5.5. These pH values were chosen, because
a noticeable amount of the Fe3+ ions, which are not bound
in the corresponding [FeMan](3 – n)+ complex, remains
under these conditions. This corresponds graphically (see
Fig. 4) to a rise of the region of the absorbance curve
attributed to this complex. The absorbance was measured
at λ = 500, 460, and 412 nm corresponding to the absorpꢀ
tion maxima of the complexes. As can be seen from the
data in Fig. 5, the maximum absorbance is observed for
ratios of volumes of the starting solutions of FeCl3•6Н2О
and maltol of 5 : 5 (see Fig. 5, a), 3.3 : 6.6 (see Fig. 5, b),
and 2.5 : 7.5 (see Fig. 5, c). This corresponds to the
following compositions of the Fe3+—Ma complexes:
1 : 1 (1), 1 : 2 (2), and 1 : 3 (3). The complexes can be
presented by the common formula [FeMan](3 – n)+. The
stepwise formation of the complexes occurs via Scheme 1.
Scheme 1
Fe3+ + НМа
[FeMa]2+ + Н+
[FeMa2]+ + Н+
[FeMa]2+ + НМа
[FeMa2]+ + НМа
D500 (rel. units)
D0
[FeMa3] + Н+
a
0.4
Fe3+ + n HМа
[FeMan](3 – n)+ + n Н+
D1
HMa is the maltol molecule, and Ma is the singleꢀcharged maltol
anion
0.2
The instability constants of the [FeMan](3 – n)+ comꢀ
plexes were determined by the equation8
2
Кinstab = α С/(1 – α),
2
4
6
8
V(Fe3+)/mL
where C is the concentration of the solution/mol L–1, α is
the degree of dissociation of the complex determined by
the formula
D460 (rel. units)
D0
0.6
0.4
0.2
D1
b
α = D0 – D1/D0,
where D0 is the absorbance corresponding to the complex
when dissociation is completely absent and D1 is the abꢀ
sorbance corresponding to the maximum in the curve for
an isomolar series.
The instability constants of the [FeMan](3 – n)+ comꢀ
plexes are presented in Table 1.
Since the method of isomolar series gives reliable reꢀ
sults only when one and the simplest complex (1 : 1) is
formed, the method of apparent deviation from the
Bouger—Lambert—Beer law was additionally used to conꢀ
firm the Кinstab values obtained.15—17
2
4
6
8
V(Fe3+)/mL
D412 (rel. units)
D0
0.8
D1
c
Three mixtures of solutions of the reacting compoꢀ
nents were prepared. Solutions had an equal starting conꢀ
centration of 7.9•10–3 mol L–1) with Fe3+ : Ma ratios of
1 : 1 (pH = 1), 1 : 2 (pH = 3), and 1 : 3 (pH = 6), which
corresponded to the [FeMa]2+, [FeMa2]+, and [FeMa3]
complexes. The spectra of the resulting solutions were
recorded in a region of 400—600 nm to obtain the D1
value in a cell with a layer thickness of 0.1 cm. The soluꢀ
tions were tenfold diluted (n = 10), and the absorbance
(D10) was determined in a cell with a layer thickness
of 1 cm. The relative change in absorbance (∆) was calcuꢀ
lated for each chosen wavelength by the formula
0.6
0.4
0.2
2
4
6
8
V(Fe3+)/mL
Fig. 5. Absorbances of aqueous solutions of mixtures of
FeCl3•6Н2О and maltol (overall volume 10 mL) for the molar
ratios of the components of the isomolar series at pH = 1 (a),
3 (b), and 5.5 (c).
∆ = D1 – D10/D1.

784
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Antipova et al.
Being. Environment. Universe"] (Irkutsk, 2001), Irkutsk, 2001,
115 (in Russian).
9. M. T. Achmet, C. S. Frampton, and J. Silver, J. Chem. Soc.,
Dalton Trans., 1988, 1159.
The degrees of dissociation of the complexes were found
by the formula15
α =∆av/100.5 – 1,
10. A. Stefanovic, J. Havel, and L. Sommer, Coll. Czech. Chem.
Commun., 1968, 33, 4198.
where α is the degree of dissociation of the nonꢀdiluted
complex and 10 is the number of dilution times of the
starting solution. We calculated the instability constants
of the complex using the dilution law based on α and the
initial concentration of the complex (C):
11. S. A. Mukha, Tez. dokl. XIII Zimnei mezhdunar. molodezhn.
nauch. shkoly "Perspektivnye napravleniya fizikoꢀkhimicheskoi
biologii i biotekhnologii" [Proc. XIII Winter Intern. Youth
Scientific School "Promising Directions of Physicochemical
Biology and Biotechnology"] (Moscow, 2001), Moscow, 2001,
81 (in Russian).
2
Кinstab = α С.
12. I. V. Babenkova, Yu. O. Teselkin, S. A. Medvedeva, N. A.
Tyukavkina, Yu. A. Kolesnik, L. B. Rebrov, V. A. Bykov,
S. A. Mukha, and I. A. Antipova, Voprosy biologicheskoi
meditsinskoi i farmatsevticheskoi khimii [Problems of Biologiꢀ
cal Medical and Pharmaceutical Chemistry], 2001, 4, 22 (in
Russian).
13. S. A. Medvedeva, Ph. D. (Chem.) Thesis, Institute of Orꢀ
ganic Chemistry, Siberian Branch, Russian Academy of Sciꢀ
ences, Irkutsk, 1973, 138 pp. (in Russian).
The Кinstab values obtained by the methods of apparent
deviation (see Table 2) and isomolar series (see Table 1)
agree well.
Thus, the stability of the complexes increases in the
series [FeMa]2+, [FeMa2]+, and [FeMa3]. The trisꢀ
maltolate complex formed in an interval of pH 5.5—8 is
most stable and can be considered as a basis for an antiꢀ
anemic medicine with a prolonged effect.
14. RF Pat. 2171805, 2001; RZhKhim. [Abstract J. Chem.], 2002,
02.02—190.203P (in Russian).
15. A. K. Babko, Fizikoꢀkhimicheskii analiz kompleksnykh
soedinenii v rastvorakh [Physicochemical Analysis of Comꢀ
plexes in Solutions], Izd. Akad. Nauk UkrSSR, Kiev, 1955,
104 (in Russian).
16. М. I. Bulatov and I. P. Kalinkin, Prakticheskoe rukovodstvo
po fotometricheskim metodam analiza [Practical Guide on Phoꢀ
tometric Methods of Analysis], Khimiya, Leningrad, 1986,
280 (in Russian).
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Received June 3, 2003;
in revised form November 24, 2003