Synthesis and structure of complexes between ascorbic acid and amino acids

Full text of DOI:10.1023/A:1014055027825

Pharmaceutical Chemistry Journal
Vol. 35, No. 9, 2001
SYNTHESIS AND STRUCTURE OF COMPLEXES BETWEEN
ASCORBIC ACID AND AMINO ACIDS
M. A. Nadtochii1 and T. A. Melent’eva1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 9, pp. 49 – 50, September, 2001.
Original article submitted January 25, 2001.
+
Interacting with amino acids, ascorbic acid (I) readily
+
RO CCH2 NH3
NH3(CH ) COOH
forms complexes of the ammonium salt type. Many of such
compounds possess valuable pharmacological properties and
are used as medicinal preparations [1, 2]. For example, the
complexes of ascorbic acid with g-aminobutyric acid (GABA)
and cobalt or iron produce anticonvulsant action [3].
For the targeted synthesis of ascorbic acid complexes po-
ssessing therapeutic properties, it is necessary to establish re-
lationships between the physicochemical properties and bio-
logical activity of these compounds. In particular, it was fo-
und that there is a direct correlation between redox potentials
of the chelate complexes of Fe and Co with I and methylmet-
hionine, on the one hand, and their antihypoxant activity, on
the other hand [4]. However, the physicochemical properties
of the complexes between ascorbic acid and amino acids are
still insufficiently studied.
We have synthesized the complexes of I with seven ami-
no acids containing one or two amino groups, or an amino
group and a thio group (Table 1). The complexes of I with
glycine (IIa), b-alanine (IIIa), GABA (IIIb), lysine (IV), met-
hionine (Va), and acetylmethionine (Vb) were obtained by
heating aqueous solutions of I with the corresponding amino
acids. The complex between I and glycine ethylate (complex
IIb) was obtained by etherification of complex IIa.
2 n
O
–
–
O
OH
O
OH
H
H
O
O
O
O
HO CH
CH2OH
IIà, IIb
HOCH
CH2OH
IIIà, IIIb
n = 2 (a), 3 (b)
R = H (a); R = C2H5 (b)
+
H3C S(CH2)2CH(COCH)NHR
H
NH3(CH2)4CH(COOH)NH2
–
O
OH
O
OH
H
H
O
O
O
O
HOCH
HOCH
CH2OH
CH2OH
Và, Vb
IV
R = H (a); COCH3 (b)
ONa
OH
H
O
O
HOCH
CH2OH
VI
In order to determine the structures of the synthesized
complexes, we measured their IR absorption spectra (Tab-
le 2). In the IR spectra of complexes II – IV, the absorption
bands due to C=O and C=C groups in the acid I ring are shif-
ted toward lower vibration frequencies as compared to the
spectrum of pure ascorbic acid. Previously [5], we demonst-
rated that the conversion of I into sodium ascorbate (VI) is
also accompanied by a low-frequency shift of the C=O and
C=C vibration frequencies (Table 2). The low-frequency
shift of nC=O and nC=C reaches maximum in the IR spectrum
of salt VI, which is indicative of an increase in the degree of
ionization. The shifts of bands of the spectra of complexes
II – IV are proportional to the ability of their NH2 groups to
attach protons (i.e., to the increase in pK2).
The introduction of lysine leads to a change in the IR ab-
sorption spectrum analogous to the effect of GABA, which
confirms that lysine is attached to I with a g-amino group.
The addition of glycine or its ethyl ether to I leads to a decre-
ase in the frequency of C=O and C=C vibrations, which is
more pronounced than might be expected taking into account
the pK2 value of glycine (Table 2). As is known [6], a favo-
rable mutual spatial arrangement of the acid I ring and a sub-
stituent at C-3 may lead to the formation of an additional
hydrogen bond between a COOH group of the substituent
and the 5-OH group of I. We suggested that the attachment of
glycine or its ethyl ether to I may also lead to the formation
of an additional hydrogen bond and, hence, of complexes IIa
and IIb.
1
The IR absorption spectra of the complexes between I
and methionine or acetylmethionine (Va, Vb) exhibit no shift
State Research Institute of Vitamins, State Unitary Enterprise, Moscow,
Russia.
518
0091-150X/01/3509-0518$25.00 © 2001 Plenum Publishing Corporation

Synthesis and Structure of Complexes between Ascorbic Acid and Amino Acids
519
TABLE 2. Structural Characteristics of Complexes between Ascor-
TABLE 1. Yields and Physicochemical Characteristics of Com-
bic Acid and Amino Acids
plexes between Ascorbic Acid and Amino Acids
20
D
Compound nC=O, cm – 1 nC=C, cm – 1
pK2
Amino acid
–
Empirical
formula
[a]
Compound
Yield, %
M.p., °C
I
1753
1725
1730
1735
1730
1730
1755
1755
1702
1670
1655
1655
1660
1665
1665
–
IIa
85
63
137 – 138
148 – 149
145 – 146
125 – 126
136.5 – 140
153 – 154
116 – 117
+ 26
C8H13NO8
IIa
IIb
IIIa
IIIb
IV
Va
Vb
VI
9.86
–
Glycine
IIb
IIIa
IIIb
IV
C10H17NO8
C9H15NO8
Glycine ethylate
b-Alanine
GABA
85
+ 37
+ 47
+ 21
+ 12
+ 14
10.36
10.43
10.53
9.21
85
C10H17NO8
C12H22N2O8
C11H19NO8S
C13H21NO9S
72.5
84
Lysine
Va
Methionine
Acetylmethionine
–
Vb
83
1595
–
of the vibration frequencies of C=O groups in I (Table 2).
The complex between I and methylmethionine described in
[3] was assigned a structure containing the O–H…S bond.
We suggested that methionine and acetylmethionine are at-
tached to the 3-OH group in I also via a hydrogen bond of the
O–H…S type, thus forming complexes Va and Vb. As is
known [7], the greater the difference in atomic electronegati-
vities, the higher the polarity of interatomic bonds. The elect-
ronegativities of H and S atoms are 2.1 and 2.5, respectively.
This corresponds to a low polarity of the O–N…S bond and
explains the absence of a shift in the nC=O frequency of the
acid I ring in complexes Va and Vb (Table 1). Additional evi-
dence for the proposed structure of these complexes is that
acetylmethionine can hardly form a complex of the ammoni-
um salt type with I, albeit methionine can, in principle, form
such a complex. However, the frequencies of C=O vibrations
in the IR spectra of both complexes coincide, which indicates
that the two amino acids form complexes of the same struc-
tural type.
(0.02 mole) of GABA and 3.52 g (0.02 mole) of ascorbic
acid (Table 1).
Ascorbic acid – lysine complex (IV). To a solution of
33 g (0.25 mole) of lysine in 300 ml of distilled water were
added a solution of 44 g (0.25 mole) of ascorbic acid in
200 ml of water and 5 g of activated charcoal, after which the
mixture was stirred and filtered. Then the solution was eva-
porated in a rotor-film evaporator at 40 – 50°C until a dense
syrup was obtained. To this residue was added 50 ml of ace-
tone and the mixture was cooled down to 0°C. The precipita-
te was filtered and dissolved in ethanol. Finally, ethanol was
distilled off at 50°C, after which the residue of compound IV
was washed with acetone and dried (Table 1).
Ascorbic acid – methionine complex (Va). To a soluti-
on of 3 g (0.02 mole) of methionine in 20 ml of acetone was
added a solution of 3.59 g (0.02 mole) of ascorbic acid in
20 ml of water. The solution was distilled off in a rotor-film
evaporator and the residue was triturated with acetone to ob-
tain compound Va (Table 1).
Thus, we have established that different amino acids attac-
hed to ascorbic acid may form complexes of various types.
Ascorbic acid – acetylmethionine complex (Vb). Com-
pound Vb was obtained silimilarly to Va, proceeding from
3.82 g (0.02 mole) of acetylmethionine and 3.59 g
(0.02 mole) of ascorbic acid (Table 1).
EXPERIMENTAL PART
Ascorbic acid – glycine ethylate complex (IIb). A mix-
ture of 2.06 g (0.02 mole) of complex IIa and 15 ml of etha-
nol was heated until ethanol evaporated. The residue was tri-
turated with acetone to obtain compound IIa (Table 1).
The IR spectra were measured on a Perkin-Elmer model
180 spectrophotometer using samples pelletized with KBr.
The data of elemental analyses (C, H, N, S) correspond to the
results of calculations using empirical formulas.
Ascorbic acid – glycine complex (IIa). To a solution of
1.50 g (0.02 mole) of glycine in 25 ml of distilled water was
added 3.52 g (0.02 mole) of ascorbic acid. After complete
dissolution of the acid, water was distilled off in a rotor-film
evaporator at 80 – 85°C. The flask with a residue was cooled
on ice and the obtained crystals were triturated with acetone.
Finally, compound IIa was filtered and dried (Table 1).
Ascorbic acid – b-alanine complex (IIIa). Compound
IIIa was obtained similarly to IIa, proceeding from 1.78 g
(0.02 mole) of b-alanine and 3.52 g (0.02 mole) of ascorbic
acid (Table 1).
REFERENCES
1. T. A. Melent’eva and A. M. Taber, A Review of Information [in
Russian], Medbioekonomika, Moscow (1991), Issue 2,
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2. P. A. Seik, Int. J. Vit. Nutr. Res., Suppl., 27, 259 – 305 (1985).
3. Ya. D. Fridman,
S. V. Alkeeva,
and
N. V. Dolgashova,
Khim.-Farm. Zh., 22(6), 425 – 428 (1988).
4. Ya. D. Fridman, Khim.-Farm. Zh., 23(11), 1310 – 1313 (1989).
5. J. Hvoslef and P. Kleaboe, Acta Chem. Scand., 25(8),
3043 – 3053 (1971).
6. W. Wenner, J. Org. Chem., 14, 22 – 25 (1949).
7. T. I. Temnikova, A Treatise on Theoretical Foundations of Or-
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Ascorbic acid – GABA complex (IIIb). Compound IIIb
was obtained similarly to IIa, proceeding from 2.06 g