Triethanolammonium salts of biologically active carboxylic acids

Article abstract of DOI:10.1134/S1070363215120075

Triethanolammonium salts (protatranes) of biologically active carboxylic acids (nicotinic, cinnamic, benzoic, salicylic, oxalic, malonic, succinic, malic, citric) were synthesized in yields exceeding 90%. The structure of the synthesized compounds was studied by IR spectroscopy and X-ray diffraction analysis.

Full text of DOI:10.1134/S1070363215120075

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 12, pp. 2710–2714. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © Yu.A. Kondratenko, Т.А. Kochina, V.S. Fundamensky, Yu.G. Vlasov, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85,
No. 12, pp. 1978–1982.
Triethanolammonium Salts
of Biologically Active Carboxylic Acids
Yu. A. Kondratenkoa, Т. А. Kochinaa,b, V. S. Fundamenskyc, and Yu. G. Vlasovb
a Grebenshchikov Institute of Silicate Chemistry, Russian Academy of Sciences,
nab. Makarova 2, St. Petersburg, 199034 Russia
e-mail: kondratencko.iulia@yandex.ru
b St. Petersburg State University, St. Petersburg, Russia
c St. Petersburg State Institute of Technology (Technical University), St. Petersburg, Russia
Received May 14, 2015
Abstract—Triethanolammonium salts (protatranes) of biologically active carboxylic acids (nicotinic,
cinnamic, benzoic, salicylic, oxalic, malonic, succinic, malic, citric) were synthesized in yields exceeding 90%.
The structure of the synthesized compounds was studied by IR spectroscopy and X-ray diffraction analysis.
Keywords: triethanolamine, biologically active carboxylic acids, protatranes
DOI: 10.1134/S1070363215120075
Earlier it was found that the conversion of bio-
logically active carboxylic acids into their triethanol-
ammonium salts NH+(CH2CH2OH)3X– (X– = anion of
carboxylic acid) strongly increases their biological
activity and expands the spectrum of their action
[1–10]. Even the first representative of this class of
compounds, triethanolammonium salt of 2-methyl-
Owing to the structure, and by analogy with
silatranes, the triethanolammonium salts of protic acids
were named “protatranes” [14]. Apparently, just the
atrane structure determines biological activity of protatranes.
In the present work, the earlier unknown triethanol-
ammonium salts of carboxylic acids having a wide
spectrum of activity (antibacterial, antimicrobial, anti-
septic, antitoxic, antitumor, etc.) were synthesized in
order to obtain potentially biologically active compounds.
phenyloxyacetic
acid
[2-CH3C6H4OCH2COO]–·
[NH(CH2CH2OH)3]+ (drug “Trecrezan”) showed much
higher growth-regulating activity for plants and
animals than the original acid [6, 7]. Trecrezan
possesses immunomodulating and adaptogenic effect,
stimulates the cell and humoral immunity and the
system of interferones-α and -γ, sustains the work
capacity of the organism and increases the resistance to
climate and toxic loads [8–10].
Protatranes 1–9 (Table 1) were synthesized in high
yields by interaction of triethanolamine with the
corresponding acids using the known procedure [16,
17] by reflux of the mixture of the corresponding
carboxylic acid and triethanolamine in methanol
during 1 h. The obtained compounds are water-soluble
colorless solids (1–3, 5–7) or viscous liquids (4, 8, 9)
(Scheme 1).
From the X-ray structural analysis data [11–13],
triethanolammonium cation has a tricyclic atrane struc-
ture closed by three intramolecular hydrogen bonds
(“Chinese lantern”), where X is the anion of a protic acid.
It should be noted that the reaction of carboxylic
acids with triethanolamine in the presence of 1,3-
dicyclohexylcarbodiimide and catalytic amounts of
dimethylaminopyridine leads to the formation of full
esters of triethanolamine [15]:
H
H
O
O
H
RO
OR
X−
OH
N
N
+
OR
2710

TRIETHANOLAMMONIUM SALTS OF BIOLOGICALLY ACTIVE CARBOXYLIC ACIDS
2711
Scheme 1.
N(CH2CH2OH)3 + HX (H2X) → [NH(CH2CH2OH)3]+ X–
1–6
2N(CH2CH2OH)3 + H2X → [NH(CH2CH2OH)3]2+ X2–
7, 8
3N(CH2CH2OH)3 + H3X → [NH(CH2CH2OH)3]3+ X3–
9
−
−
COO
COO
−
−
COO
COO
OH
(4),
−
Xn−
=
(2),
(3),
OOC
(1),
COOH (5),
N
−
OH
H2C CH
COOH
CH2
HO COO
−
−
−
(8),
OOC
COO (9).
OOC
H2C
OOC
(7),
CH2
(6),
C
C
−
−
−
−
H2
H2
COO
OOC
COO
In the IR spectra of protatranes 1–9 a wide band of
ν(ОН) vibrations is observed in the range 3360–
3060 cm–1 (Table 2) caused by the vibrations of three
hydroxy groups of the cation, whose oxygen atoms are
involved in the formation of hydrogen bonds with the
N+H hydrogen atom, and the hydrogen atoms at these
oxygens, with anion X–. The relative position of the ν
(ОН) frequencies allows assessing the strength of the
hydrogen bonds of the hydroxy groups with the
carboxylate anion. In the IR spectra of protatranes 4
and 6 the ν(ОН) bands appear at lower frequencies
(3060 and 3140 cm–1), than in the spectra of other
protatranes (3240–3360 cm–1). This is indicative of a
higher strength of hydrogen bonds formed by the OH
groups of the protatrane cation with the carboxylic
group of anion X–. In the spectrum of pure tri-
ethanolamine the ν(ОН) vibrations appear at 3311 cm–1
as a strong wide band (∆ν1/2 ≈ 400 cm–1) [16]. A wide
band of ν(N+H) is present in all spectra in the range
2800–3000 cm–1.
It was known that the degree and nature of
interaction between the cation and anion in proptatrane
is reflected in the frequencies of symmetric and
asymmetric vibrations ν(COO–) [16, 18]. The dif-
ference between these values (∆ν) is used as a criterion
of the structure of the molecule. Using the methods of
IR spectroscopy and X-ray analysis it was shown that
the value of ∆ν > 200 cm–1 points to a significant
asymmetry of the carboxylic group, while the value of
∆ν < 200 cm–1 is indicative of its approximate sym-
metry [18]. The molecule of protatrane 5 is charac-
terized by the vibration bands of the carboxylate anion
at 1640 [νas(СОO–)] and 1410 cm–1 [νs(СОO–)]
(Table 2). The value of ∆ν equal to 230 cm–1 points to
a significant asymmetry of the carboxylic group. For
Table 1. Elemental analysis, melting points, and yields of protatranes 1–3 and 5–7a
Found, %
Calculated, %
Comp. Yield,
mp,
°С
Formula
no.
%
C
H
N
C
H
N
1
91
57–59
52.41
8.10
10.43
C12H20N2O5
52.93
7.70
10.29
2
3
5
6
7
95
94
90
90
95
70–72
92–93
70–73
87–89
74–75
60.40
58.71
40.12
42.68
46.12
8.27
8.19
6.90
7.84
9.18
4.90
5.32
6.19
5.47
6.84
C15H23NO5
C13H21NO5
C8H17NO7
C9H19NO7
C16H36N2O10
60.59
57.55
40.17
42.68
46.15
7.79
7.80
7.16
7.56
8.71
4.71
5.16
5.86
5.53
6.73
а Protatranes 4, 8, and 9 were obtained with a yield of 99% as a liquids.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 12 2015

2712
KONDRATENKO et al.
of the IR spectroscopy data. Thus, in protatrane 5, one
Table 2. IR spectra of protatranes 1–9
oxygen atom of the oxalate anion forms two hydrogen
bonds: with the OH group of the cation and with
another molecule of the oxalate anion, whereas the
second oxygen atom is linked only with one OH group
of the cation (structure А). A similar structure with
nonequivalent binding of the carboxylate anion can be
expected in the case of protatranes 3, 7, and 9 with
∆ν > 200 cm–1 (Table 2). In protatrane 6 with ∆ν =
190 cm–1 each oxygen atom of the carboxylic group
forms two hydrogen bonds: one with two OH groups
of the two cations, and another one with the cation and
with malonate anion (structure B). It can be assumed
that other protatranes 1, 2, 4, 8 with ∆ν < 200 cm–1
have the structure close to that of protatrane 6, or they
have the structure in which each oxygen atom of the
carboxylic group forms one hydrogen bond with the
cation or another anion (Scheme 2).
Comp.
no.
ν(СОО–), cm–1
∆ν, cm–1 ν(ОН), cm–1
1
1590
1410
1410
1400
1380
1410
1400
1410
1380
1370
180
150
200
190
230
170
230
190
210
3350
3355
3350
3060
3360
3140
3350
3240
3240
2
1560
1600
1570
1640
1570
1640
1570
1580
3
4
5
6
7
8
9
protatrane 6, ∆ν = 170 cm–1, shows, on the contrary, an
approximate symmetrical binding of the carboxylate
anion. In the spectra of protatranes 5 and 6 also the
stretching vibration bands of the carboxylic group
ν(СООН) appear at 1720 and 1710 cm–1 respectively.
In general, the region of 1500–700 cm–1 in the spectra
of protatranes 1–9 resembles that in the spectrum of
triethanolamine and differs by the presence of much
more intense bands at 1500–1000 cm–1, in most cases
shifted to higher frequencies (bending vibrations of the
methylene groups).
Therefore, the structure of triethanolammonium
salts of carboxylic acids (protatranes) 1–9 depends on
the type and strength of hydrogen bonds between the
protatrane cation and carboxylate anion, which affects
the frequencies of stretching vibrations of OH- and
СOO– groups. The results of X-ray analysis prove this
conclusion.
EXPERIMENTAL
IR spectra of protatranes in KBr or in microlayer
(for liquids) were obtained on an IR Fourier
Investigation of protatranes 5 and 6 by the X-ray
method confirmed the conclusions made on the basis
Scheme 2.
H
H
O
O
H
C
O
O
H
H
CH2
H
C
O
O
C
O
O
C
H
N
O
H
H
O
O
H
N
N
O
H
O
H
O
H
O
O
H
H
O
H
O
H
H
O
H
O
C
H
H
H
O
O
H
O
H
O
O
CH2
O
C
O
N
N
C
C
O
O
O
O
А
B
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 12 2015

TRIETHANOLAMMONIUM SALTS OF BIOLOGICALLY ACTIVE CARBOXYLIC ACIDS
2713
Fig. 1. Crystalline structure of protatrane 5.
Fig. 2. Crystalline structure of protatrane 6.
spectrometer Nicolet 8700 (Thermo Scientific). Elemental
analysis was performed on a C,H,N-analyzer Euro
EA3028-НТ. For X-ray analysis colorless mono-
crystals were chosen of 0.21 × 0.13 × 0.18 and 0.25 ×
0.16 × 0.09 mm size. The analysis was performed on a
Supernova (Agilent Technologies, Oxford Diffraction)
diffractometer with CuKα-radiation.
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