Diethanolammonium protic ionic liquids - promising buffers for the synthesis of 68Ga- labelled radiopharmaceuticals

Article abstract of DOI:10.1016/j.molliq.2021.117029

Fifteen new protic ionic liquids based on diethanolammonium (DEA) salts of carboxylic acids have been synthesized and identified using a complex of physicochemical methods (NMR, FT-IR spectroscopy, elemental, thermal analysis). The crystal structure of di

Full text of DOI:10.1016/j.molliq.2021.117029

Journal of Molecular Liquids xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Diethanolammonium protic ionic liquids - promising buffers for the
synthesis of 68Ga- labelled radiopharmaceuticals
b
c
b
Yulia A. Kondratenko a, , Dmitrii O. Antuganov , Andrey A. Zolotarev , Michail A. Nadporojskii ,
⇑
Valery L. Ugolkov a, Tatyana A. Kochina a
a Grebenshchikov Institute of Silicate Chemistry RAS, Nab. Makarova, 2, Saint-Petersburg, 199034, Russian Federation
b Granov Russian Research Center of Radiology & Surgical Technologies, 197758 Leningradskaya str. 70, Pesochny, Saint-Petersburg, Russian Federation
c Institute of Earth Sciences, St. Petersburg State University, University Emb., 7/9, 199034, Saint- Petersburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Fifteen new protic ionic liquids based on diethanolammonium (DEA) salts of carboxylic acids have been
synthesized and identified using a complex of physicochemical methods (NMR, FT-IR spectroscopy, ele-
mental, thermal analysis). The crystal structure of diethanolammonium salts of benzoic and 1-hydroxy-
2-naphthoic acids was determined for the first time by XRD. A comparative analysis of the conformations
of DEA cations was carried out. The effectiveness of synthesized DEA ionic liquids as buffer agents was
demonstrated on 68Ga-radiolabeling reactions with different chelators and clinically approved peptides.
Ó 2021 Elsevier B.V. All rights reserved.
Received 15 March 2021
Revised 1 July 2021
Accepted 15 July 2021
Available online xxxx
Keywords:
Protic ionic liquids
Room-temperature ionic liquids
Diethanolamine
Cation conformation
Buffer activity
Radiolabeling
PET
1. Introduction
separation of gas mixtures, to the synthesis of different nanostruc-
tures, nanoparticles, etc. [9–13]. In biochemistry, RTILs are often
Ionic liquids (ILs) are a great class of compounds consisting of
bulky organic cations and protic acid anions with melting points
below the boiling point of water [1,2]. ILs isolated in the liquid
state at room temperature (below 25 °C) are usually referred to a
special group À room temperature ionic liquids (RTILs) [3]. No
solid phase formation in RTILs can be attributed to the weak inter-
actions between the constituent ions, which cause a low tendency
to crystallize [4]. One of the most important and promising appli-
cations of RTILs is their usage as environmentally friendly solvents
(‘‘green solvents”) in catalysis and synthesis. The phase-out of toxic
organic solvents is the leading tendency of green chemistry. Com-
pared with traditional organic solvents, the usage of RTILs as sol-
vents (co-solvents) has several advantages associated with their
unique physical and chemical properties. These properties include
negligible vapor pressure, chemical, thermal, electrochemical sta-
bility, and good miscibility with various inorganic, organic, and
polymer compounds [5–8]. In practical terms, RTILs are widely
used to absorb gases such as CO2, CO, H2, SO2, H2S, etc., to efficient
used as a stabilizing medium for selective and enzymatic reactions
[14–16].
Recently, ILs, possessing self-buffering capacity, have been
assigned to a separate class À Good’s buffer ILs (GB-ILs). Typically,
these ILs contain Good’s buffers (GBs) as cations or anions. GBs,
first described by N. Good and colleagues in 1966, are buffers with
suitable characteristics (pKa: 6.0–8.0; high solubility, non-toxic,
etc.) for biological and biochemical research [17]. Cholinium-
based GB-ILs are effective stabilizers and preservation media for
recombinant small RNAs [18]. Cholinium ILs are biodegradable,
non-toxic, and can support the function and structure of different
biomolecules [19–21]. Extensive studies of the buffer properties,
biocompatibility, biological activity, and toxicity of GB-ILs contain-
ing cholinium, tetra-butylphosphonium, tetra-alkylammonium
cations, and GBs anions were carried out in works [2,22–26].
Diethanolamine (DEA) and its N-derivatives are promising alka-
nolamines for the production of alkanolammonium RTILs. Aqueous
DEA solutions are extensively used to remove the acid gases, par-
ticularly CO2 and H2S, from natural or refinery gas processing and
coal gasification [27]. DEA is used in cosmetic products and surfac-
tants as a wetting agent and emulsifiers [28]. DEA is used in med-
icine as a buffer and regulator for some drugs [29,30]. It should also
⇑
Corresponding author at: Grebenshchikov Institute of Silicate Chemistry RAS,
nab. Makarova, 2, St. Petersburg, 199034 Russia.
E-mail address: kondratencko.iulia@yandex.ru (Y.A. Kondratenko).
https://doi.org/10.1016/j.molliq.2021.117029
0167-7322/Ó 2021 Elsevier B.V. All rights reserved.
Please cite this article as: Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al., Diethanolammonium protic ionic liquids - promising buffers for the syn-
thesis of 68Ga- labelled radiopharmaceuticals, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2021.117029

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
be noted that DEA salts are the closest analogs of tris(2-
hydroxyethyl)ammonium (TEA) salts, which are commonly known
as protatranes (atrane skeleton with intramolecular hydrogen
bonds N+HÁ Á ÁOH). Due to extensive studies on the biological activ-
ity of protatranes, new immunomodulators, adaptogens, and
growth-stimulating agents for medicine and agriculture have been
developed [31–33]. Recent structural studies [34] of the crystal
structure of TEA salts have shown that TEA cations are character-
ized by two conformations - tricyclic (endo-conformation) and
bicyclic (endo-exo-conformation). However, the conformation of
DEA cations and the cation–anion interactions in DEA salts is virtu-
ally unknown.
This study aimed to obtain and characterize new protic ILs con-
taining diethanolammonium cations and carboxylic acid anions.
Several works have shown that DEA-containing ILs can be used
as green solvents, precatalyst-precursors in Heck reaction with
PdCl2 [35], for the synthesis of cyclic carbonates without additional
co-catalyst and co-solvents [36]. However, the usage of DEA ILs as
buffers is almost unknown.
2.4. X-ray data collection
X-ray diffraction data sets of DEA salts 1 and 4 were carried out
via a Rigaku «XtaLAB Synergy» diffractometer (CuK radiation, k =
a
1.54184 Å). The main crystallographic data and refinement details
are summarized in Table 1. Structures 1 and 4 were solved by
direct methods and refined by full-matrix least-squares methods
using the SHELXL program [46] as incorporated in the OLEX2 pro-
gram package [47]. The carbon- and nitrogen-bound H atoms were
placed in calculated positions and included in the refinement in the
‘riding’ model approximation. All H atoms bonded to O atoms were
located in the difference Fourier map. Empirical absorption correc-
tion was applied in CrysAlisPro [48] program. CCDC 2,063,813 and
2,063,814 contains supplementary crystallographic data on this
paper and can be obtained free of charge via www.ccdc.cam.ac.
uk/structures/
2.5. Buffer properties
One of the priorities is the usage of ILs as buffer agents in radio-
pharmaceuticals, in particular, for the synthesis of 68Ga-labelled
compounds. The gallium-68 isotope is one of the most important
and valuable in PET diagnostics due to its optimal decay properties
and simple binding to chelating groups of bioactive molecules
[37,38]. At the same time, as a rule, the formation of a Ga-
chelator bond is possible only in a narrow pH range (3.5–4.5)
[39]. Therefore, it is necessary to use buffers to maintain the
desired pH. The HEPES buffer (2-[4-(2-hydroxyethyl)piperazin-1-
yl]ethanesulfonic acid) is most commonly used to produce 68Ga-
radiopharmaceuticals [40,41]. However, the European Pharma-
copoeia defines 200 mg of HEPES as the maximum permissible daily
value in solutions for parenteral administration [42]. Our previous
works [43–45] showed that alkanolammonium protic ILs, in partic-
ular TEA, TRIS (tris(hydroxymethyl)methyl ammonium), PDA (N-
phenyldiethanolammonium), and TPA (tris(2-hydroxypropyl)am
monium) salts, are effective buffer agents in 68Ga-radiolabeling
reactions of chelators and clinically approved peptides. Their effi-
ciency is significantly higher than that of the HEPES buffer under
low-temperature radiolabeling conditions (37 °C) [44]. Here we
focused on the synthesis and investigation of the buffer properties
of DEA-containing ILs.
«High-temperature» 68Ga-Radiolabeling of bifunctional chelating
agents (BCAs). p-SCN-Bn-DOTA was labelled with [68Ga]Ga3+ in a
water solution of DEA salt and an additive of EtOH at 95 °C for
10 min. The detailed description is presented in Supplementary
data.
«Low-temperature» 68Ga-Radiolabeling. Precursor (chelator or
peptide, Table S1) was labeled with [68Ga]Ga3+ in a water solution
of DEA salt and an additive of acetone at 37 °C for 15 min. The
detailed description is presented in Supplementary data.
3. Results and discussion
3.1. Characterization of DEA salts 1–15
The target products, diethanolammonium salts 1–15 (Fig. 1),
were prepared by the interaction of DEA with corresponding car-
boxylic acids in methanol. Most synthesized DEA salts were vis-
cous liquids at room temperature. Only four DEA salts 1, 4, 6,
and 12 were isolated as hygroscopic powders or crystals. The struc-
ture and composition of the synthesized samples were confirmed
by the NMR, elemental analysis, and FTIR spectroscopy (see Supple-
mentary data).
The 1H NMR spectra of synthesized compounds were measured
in DMSO d6 due to the good solubility of DEA salts in this solvent
(Figs. S1, Supplementary data). No broadened peaks were observed
in the region above 10.0 ppm indicated the complete reaction con-
version. Two multiplets in the region from 2.7 to 3.8 ppm were
attributed to protons of NCH2 (2.72–3.13 ppm) and OCH2 groups
(3.45–3.79 ppm) of two hydroxyethyl branches of DEA cations.
The broadened signal in the region of 3.90–7.18 ppm relates to
the H-signals of the ammonium and OH groups. The multiplet sig-
nals in the 6.60–9.04 ppm region correspond to the aromatic pro-
tons of anions in salts 1–7. The peak area ratio between the cation
and anion signals confirmed the structure of the synthesized salts,
and in the case of salts of dicarboxylic acids, gave clear information
about the actual cation/anion ratio in the resulting substance. In
the 13C NMR spectrum, characteristic signals of carbon atoms of
DEA cation were observed in the region of 49.0–50.3 ppm (NCH2)
and 56.4–58.3 ppm (OCH2). The carbon signals of aromatic frag-
ments of anions 1–7 were located in the range from 111.2 to
162.2 ppm. The carbon signals from the COO– and COOH groups
have appeared in the range 165.2–177.5 ppm.
2. Experimental
2.1. Materials
All the chemicals were purchased from commercial sources and
used without further purification. The details are given in the Sup-
plementary data.
2.2. Synthesis of DEA salts
DEA salts 1–15 (Fig. 1) were first synthesized by interaction of
diethanolamine with the corresponding carboxylic acid in metha-
nol at boiling with constant stirring for 2 h. More details on the
synthesis and characterization of the synthesized DEA salts (yields,
NMR (13C, 1H) spectroscopy, and elemental analysis data) are given
in Supplementary data.
2.3. Methods
In the FTIR spectra of all synthesized DEA salts 1–15, a very
Newly prepared salts were characterized by a complex of meth-
ods: FT-TR, Elemental analysis, Thermal analysis (TG, DTG, DSC, IC),
and NMR (1H, 13C). The details are given in the Supplementary data.
broadened region of 3440–3140 cmÀ1 with no noticeable maxima,
associated with stretching bands
m(OH) of DEA cations and some
anions, containing OH groups (3, 4, 14, and 15) was observed.
2

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
Fig. 1. Synthesized diethanolammonium salts 1–15.
Table 1
Crystallographic data and refinement parameters for DEA salts 1 and 4.
Diethanolammonium salts
1
4
Crystal data
Chemical formula
Mr
C
11H17NO4
C15H19NO5
293.31
227.26
Crystal system, space group
a, b, c (Ǻ)
Monoclinic, P21/n
7.1787(3), 24.3908(7), 7.7064(3)
90, 114.183(5), 90
1230.93(9)
Monoclinic, P21/n
7.2256(5); 29.381(2); 7.7024(5)
90, 115.099(8), 90
1480.8(2)
a, b, c (°)
V (Å3)
Z
4
4
Radiation type
CuK
0.776
a
(k = 1.54184 Å)
CuK
0.825
a (k = 1.54184 Å)
m (mmÀ1
)
Crystal size (mm)
Data collection
0.16 Â 0.11 Â 0.06
0.18 Â 0.13 Â 0.05
Diffractometer
Temperature K
Rigaku «XtaLAB Synergy»
100
Rigaku «XtaLAB Synergy»
100
Absorption correction
Multi-scan
Multi-scan
T
min, Tmax
0.865, 1.000
9470, 2336, 2061
0.0654
0.443, 1.000
9145, 2803, 2224
0.0616
No. of measured, independent and observed [I > 2r(I)] reflections
Rint
hmin, hmax
Refinement
3.624, 70.441
3.008, 70.457
R[F2 > 2
r
(F2)], wR(F2), S
0.0477, 0.1435, 1.153
0.0639, 0.2063, 1.112
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
2336
154
0
mixed
0.307, À0.278
2803
199
0
Mixed
0.308, À0.404
D
qmax
,
D
qmin (eǺÀ3
)
3

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
The nature of intermolecular interactions is indicated by the shift
of the stretching vibrations of m(OH) groups in the FTIR spectra.
Their shift to a lower frequency region indicates the formation of
hydrogen-bound associates. Based on the data obtained (Table 2),
in the case of DEA salts 1–3, 5–7, 9, 11, 13–15 with
m-
(OH) < 3220 cmÀ1, strong hydrogen-bound associates are formed.
In the FTIR spectra of DEA salts 4, 8, 10, and 12 stretching vibra-
tions of the m .
(OH) groups were slightly higher than 3300 cmÀ1
This difference may be due to the formation of intramolecular
hydrogen bonds involving OH - and –COOH groups of anions. In
the case of DEA salts 12, the stretching band
m(OH) is highly
intense and has two maxima, which may also indicate the forma-
tion of polymer associates (for example, due to the formation of
anionic chains: HOOC-COO–Á Á ÁHOOC-COO–), which are character-
ized by very intense and wide bands.
The medium and weak bands with individual maxima in the
frequency region from 3070 to 2820 cmÀ1 are assigned to stretch-
ing frequencies of the m(CH2) and m(CH) cations and anions. m
(NH+2)
groups appear in 2700–2400 cmÀ1 region as broadened low-
intensity bands (Figs. S2.1–2.15). The carboxylate groups exhibit
two strong asymmetric (
m
as(COO–)) and relatively strong symmet-
ric (m
s(COO–)) stretching bands at 1640–1540 cmÀ1 and 1440–
1370 cmÀ1, respectively. In the FTIR spectra of DEA salts 1–7, the
bands with peaks at 1640–1440 cmÀ1 are assigned to the stretch-
ing frequencies of the aromatic groups. In the FTIR spectra of DEA
salts of dicarboxylic acids 8, 10, 12, and 14, the band in the 1740–
1710 cmÀ1 region corresponds to the stretching of the COOH
group. The presence of this band confirms the formation of acidic
salts of the composition [DEA][O2CRCOOH]. The absence of a band
at1740-1710 cmÀ1 in the FTIR spectra of DEA salts 9, 11, 13, and 15
indicates that DEA salts of the composition [DEA]2[O2CRCO2] are
formed. FTIR spectra of DEA ILs 1–15 and the assignment of some
bands are shown in Figs. S2.1-S2.15 and Table 2.
Fig. 2. X-ray crystal structure of 1, showing the atom labeling scheme.
3.2. Single crystal XRD structure of DEA salts
The crystal structure of two DEA salts 1 and 4 was solved by
single-crystal XRD. The unit cell of salts 1 and 4 contains one
cation–anion pair (Fig. 2, Fig. 3). In contrast to TEA salts, whose
cations contain an –NH+ group bound to three hydroxyethyl
branches, DEA cations contain an –NH+2 group and two hydrox-
yethyl branches. As a result, the two hydrogen atoms of the ammo-
nium group form two intramolecular H-bonds with O atoms of the
hydroxyethyl groups. Thus, each hydroxyethyl group is directed to
two different hydrogen atoms of the ammonium group, which
leads to their different orientation relative to each other (Fig. 2,
Fig. 3). This structural feature significantly distinguishes DEA salts
Fig. 3. X-ray crystal structure of 4, showing the atom labeling scheme.
Table 2
Some stretching bands in FTIR spectra of DEA salts 1–15 (cmÀ1).
No.
m(OH)
m
(CH),
m
(CH2)
m(CAr
)
m
(COOH)
m(COO)
1
2
3
4
5
6
7
8
3200 (br.)
3140 (br.)
3180 (br.)
3350 (br.)
3170 (br.)
3195 (br.)
3195 (br.)
3320 (br.)
3160 (br.)
3300 (br.)
3160 (br.)
3440, 3390 (br.)
3220 (br.)
3195 (br.)
3180 (br.)
3060, 2950, 2830
3060, 3030, 2950, 2820
3050, 2940, 2820
3040, 2960, 2890
3060, 2960, 2820
3060, 3030, 2960, 2920, 2860
3050, 2960, 2930, 2850
3050, 2960, 2830
3070, 2960, 2830
3040, 2960, 2820
3060, 2950, 2820
3030, 2960, 2890, 2825
3060, 2940, 2830
3060, 2950, 2830
3070, 2950, 2820
1590, 1440
1640, 1490, 1450
1620, 1480, 1450
1620, 1510, 1480, 1440
1600, 1450
1590, 1490, 1450
1580, 1490
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1710
–
1710
–
1740
–
1710
–
1540, 1370
1540, 1370
1570, 1380
1580, 1400
1550, 1370
1590, 1400
1580, 1400
1550, 1390
1540, 1380
1570, 1405
1550, 1430
1640, 1430
1570, 1440
1560, 1390
1560, 1380
9
10
11
12
13
14
15
br. – broadened
4

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
Fig. 4. Two possible conformations of DEA cations: conformation I on the example of DEA benzoate 1 (a) and conformation II on the example of DEA 2-bromophenolate (b)
[55]
from TEA and TPA salts [34,45,49], in which the hydroxyalkyl
branches are oriented relative to a single hydrogen atom of the
ammonium group (–NH+).
DEA 2-bromophenolate [55] and DEA picrate (b, Table 3) [51]. As
can be seen from Table 3, the distances between one hydrogen
atom and the two O atoms of the two hydroxyethyl branches
(Fig. 4a) in the case of conformation I differ significantly and gen-
erally vary in the range of 2.40–3.47 Å. The opposite trend was
observed in the case of conformation II, in which the distance
between one hydrogen atom and oxygen atoms is approximately
the same and varies in the range of 2.48–2.82 Å (for the oriented
branches) and 2.93–3.65 Å (for the distant branches). The differ-
ence in the structure of the two conformations (I and II) of DEA
cations are shown in Fig. 4.
When compared with other structures from the literature, the
conformation found in salts 1 and 4, in which each hydroxyethyl
group is directed to two different HN atoms (conformation I,
Fig. 4a), is typical and the most prevalent for DEA salts. In particu-
lar, a similar conformation for DEA cations was found in the DEA 4-
nitrobenzoate [50], picrate (a, Table 3) [51], [Fe(Cp(PPh2)(CpPO3-
H)]- [52], FeCl4- [53], CoCl24- [43], Diclofenac [54]. However, accord-
ing to the literature, a conformation in which two hydroxyethyl
branches are oriented relative to only one of the two ammonium
hydrogen atoms (conformation II, Fig. 4b) can also occur among
DEA salts. In particular, this conformation was found in two salts:
The difference in the structure of DEA cations (conformations I
and II) significantly affects the intermolecular hydrogen bonding.
In particular, in DEA salts 1 and 4 with conformation I type, the
Table 3
Some geometric parameters in DEA cations.
Anion
Type of conformation,
Fig. 4
d(OÁ Á ÁHa), Å
d(OÁ Á ÁHb), Å
d(NÁ Á ÁO), Å
Ref.
Benzoate, 1
I
2.66
3.12
2.94
2.54
2.66
3.17
3.09
2.56
3.37
2.99
2.45
3.20
2.97
2.56
2.63
3.11
2.91
2.58
2.61
3.19
2.63
2.48
3.14
2.72
2.882(2)
2.866(2)
2.859(3)
2.862(3)
2.869(2)
2.883(2)
2.890(2)
2.898(2)
2.986(2)
2.824(2)
2.864(2)
2.970(2)
–
1-hydroxy-2-naphthoate, 4
4-nitrobenzoate
picrate (a)
I
–
I
[50]
[51]
[51]
[52]
I
picrate (b)
II
I
FeCl-4
I
I
I
2.44
3.47
2.62
3.25
3.24
2.82
2.97
2.40
3.23
2.65
2.51
3.27
2.763(6)
2.817(6)
2.919(3)
2.954(3)
2.877(4)
3.061(4)
[53]
[53]
[54]
CoCl24-
Diclofenac
2-bromophenolate
II
2.82
2.73
2.93
3.65
3.194(2)
2.814(2)
[55]
5

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
cationic dimers were formed due to hydrogen bonds via the NH2+
group of one cation and the hydroxyethyl group of the neighboring
cation from another column. The second H atom of the ammonium
group also forms H-bonds, but only with the O atom of the COO–
group. Thus, DEA cations form columns along the c-axis (in the
case of salt 1) and along the a-axis (in the case of salt 4), which
are hydrogen-bonded to DEA cations from adjacent columns
directly (dimer formation) or through H-bonds with anions (Figs. 5,
6). The main difference between 1 and 4 is the presence of an
intramolecular H-bond between the OH-group and the O atom of
boxylate groups of the 1-hydroxy-2-naphthoate anion. This
assumption is consistent with the results of the X-ray diffraction
experiment. In salt 12, either anionic chains HOOC-COO–ÁÁÁHOOC-
COO– or intramolecular bonds –COO–ÁÁÁHOOC– are probably
formed, which is also confirmed by FTIR spectroscopy.
The thermal decomposition of DEA salt 1 begins after 135 °C
and proceeds through one notable stage. The mass loss was
À90.2% at 324° C. In this temperature range, the DSC curve shows
a strong endothermic effect at 207° C with an active release of
water vapor on the ion current (IC) curve. Further, in the tempera-
ture range of 226–324 °C, small and broadened exothermic effects
have appeared with the active release of carbon dioxide as the
decomposition products, i.e., the substance burns. In the tempera-
ture range of 398–529 °C, the organic residue is burned out, as evi-
denced by the exothermic effect on the DSC curve at 496 °C.
The thermal decomposition of salts 4 and 6 proceeds in a simi-
lar way. The first stage at the temperature of 118–335 °C (salt 4)
and 145–389 °C (salt 6) is the main stage of thermal decomposi-
tion, at which the mass loss is À84.2% and À88.3%, respectively.
In this temperature range, the DSC curves exhibit strong endother-
mic effects with maxima at 166 (4), 191, and 274 °C (6), followed
by exothermic effects with maxima at 314 °C (salt 4) and 326 °C
(salt 6). Thus, at this stage, thermal decomposition accompanied
by the evaporation process (endothermic effect with the release
of water vapor and carbon dioxide) and subsequent oxidation of
the organic residue (exothermic effect) occurs. Further, after
388 °C, as in the case of salt 1, combustion of the organic residue
occurs, as evidenced by the strong exothermic effect at 520 (salt
4) and 495 (salt 6) °C and the release of carbon dioxide on the IC
curve. At the second stage of thermal decomposition, the mass loss
was À13.22% in the temperature range 388–574 °C (salt 4) and
À7.55% in the temperature range 389–545 °C (salt 6).
the carboxylate (O14-HÁ Á ÁO13
) in the 1-hydroxy-2-naphthoate
anion (Fig. 6). Hydrogen bonding parameters in structures of DEA
salts 1 and 4 are shown in Table 4.
It should be mentioned that in DEA 2-bromophenolate with the
cation conformation II [55], there are no H-bonds via the cations
involving the NH+2 group. Instead, the cations form chains through
H-bonds via the hydroxyl groups of two adjacent cations. In the
structure of DEA picrate (conformation type II) [51], cationic chains
are also formed (instead of dimers) only involving the ammonium
group, as in salts 1 and 4.
3.3. Thermal stability
The thermal behavior of four DEA salts 1, 4, 6, and 12 isolated in
solid form was studied in the temperature interval from 40 to
600 °C by complex thermal analysis (Fig. S3.1–3.4). The thermal
decomposition of all the synthesized DEA compounds begins after
the melting of the samples and proceeds via 1–2 noticeable stages
of mass loss. The visible endothermic peaks at 50 (1), 69 (4), 48 (6),
and 88 (12), which correspond to the melting process, are observed
on the DSC-curves of all the studied DEA salts. Thus, all synthesized
DEA salts isolated in both solid and liquid form are protic ILs.
Figs. S4.1-S4.4 (Supplementary data) shows the values of the melt-
ing enthalpy for DEA salts 1, 4, 6, and 12. As can be seen, the melt-
ing enthalpy for DEA salt 1 was 4.65 J/g, for salt 4–30.42 J/g, for salt
6–17.79 J/g, and for salt 12–24.05 J/g. The larger the value of heat
of fusion, the stronger the intermolecular binding forces in the
solid. The difference in the melting enthalpy indicates that salts
4 and 12 with the highest melting enthalpy have stronger inter-
and/or intramolecular forces compared to salts 1 and 6. This is
probably due to the absence of additional intramolecular hydrogen
bonds in DEA salts 1 and 6 compared to salts 4 and 12. In the case
of salt 4, this is an intramolecular bond between the OH– and car-
In contrast to salts 1, 4, and 6, the thermal decomposition of salt
12 at the temperature of 108–303 °C proceeds through two notice-
able stages (Fig. S3). At the first decomposition stage (108–208 °C),
the mass loss was À30.08%. The DSC curve shows a broadened
endothermic peak at 160° C followed by the simultaneous release
of H2O and CO2. At the next stage, in the temperature interval of
208–303 °C on the DSC curve, an endothermic effect is observed
at 242 °C, which then passes into an exothermic peak at 266 °C.
The mass loss at the second decomposition stage was À61.4%. In
other words, the thermal decomposition at the second stage con-
tinues with the active release of water and carbon dioxide, which,
Fig. 5. Supramolecular architecture of DEA salt 1 with hydrogen bonding interactions.
6

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
Fig. 6. Supramolecular architecture of DEA salt 4 with hydrogen bonding interactions.
Table 4
Hydrogen bonding geometry for DEA salts 1 and 4 (Å, °).
D-HÁ Á ÁA
D-H (Å)
HÁ Á ÁA (Å)
DÁ Á ÁA (Å)
\ D-HÁ Á ÁA, °
1
N4-HBÁ Á ÁO16
N4-HAÁ Á ÁO7
O7-HÁ Á ÁO15
O1-HÁ Á ÁO16
4
0.89
0.89
0.92
0.91
1.87
2.07
1.75
1.84
2.729(1)
2.879(2)
2.664(2)
2.750(2)
162.6
150.9
176(3)
172(3)
N18-HAÁ Á ÁO21
N18-HBÁ Á ÁO12
O21-HÁ Á ÁO13
O15-HÁ Á ÁO12
O14-HÁ Á ÁO13
0.89
0.89
0.82
0.88
1.04
2.04
1.90
1.87
1.91
1.57
2.855(3)
2.711(2)
2.686(2)
2.789(2)
2.541(2)
151.2
150.2
172.4
173(4)
152(4)
after 242 °C, turns into the combustion of the organic residue. After
303 °C, a monotonous mass loss was observed on the TG curve, as
in the case of compound 1. The exothermic effect with two peaks at
444 and 513 °C appears on the DSC-curve, i.e. as in the case of com-
pounds 1, 4 and 6, the organic residue is burned out.
Table 5
Melting and decomposition temperatures of DEA (1, 4,
hydroxyalkylammonium salts.
6
and 12) and some
Td, °C
Compound
M.P., °C*
1 [DEA]Benz
[TEA]Benz
[TPA]Benz
50
92
87
159
69
48
119
88
70
119
126
135
169
113
139
118
145
149
108
129
156
142
Our earlier works [45,56,57] allow us to compare the actual
results with the thermal stability data of hydroxyalkylammonium
salts (TEA, TRIS, TPA) containing similar anions (benzoate, 2-
methylphenoxyacetate, and hydrogenoxalate). As can be noted
from Table 5, the melting of DEA salts compared with TEA, TRIS,
TPA salts begins much earlier (except for DEA and TEA
hydrogenoxalate). For example, in benzoates, the melting point
of DEA salt is three times less than in the case of TRIS salt (Table 5).
Thus, a slight increase in the melting point on going from DEA to
TEA and TPA salts and a significant increase on going to TRIS salts
were observed. The initial decomposition temperature, on the con-
trary, practically did not change when the hydroxyalkylammonium
cation was replaced.
[TRIS]Benz
4 [DEA]–OH-Nph
6 [DEA]Crez
[TRIS]Crez
12 ([DEA]HOxal
[TEA] HOxal
[TPA] HOxal
[TRIS] HOxal
*
corresponds to the maximum endothermic effect on the DSC curve
95–100 °C [58]. Under ‘‘high-temperature” conditions (95 °C,
10 min), radiochemical conversions (RCCs) were > 75% for ILs 1–
4 and 6–9.
3.4. Buffer properties
The experimental data (Fig. 7) indicates that when using hydrox-
yalkylammonium salts of dicarboxylic acids, in particular, salts of
oxalic, malonic, and malic acids, we no observed target complex
68Ga-chelator formation, i.e., RCC = 0. Probably, this is due to the
high tendency of 68Ga-oxalate (malonate or malate) complex for-
mation. An exception is DEA salts of succinic acid 8 and 9. The usage
of these DEA salts led to the production of 68Ga complexes with the
Investigations of buffer properties were carried out in several
stages. In the first stage, we studied the formation of 68Ga complex
with chelator p-SCN-Bn-DOTA in a media of DEA ILs 1–15 accord-
ing to our previously developed method [43]. It is commonly
known that 68Ga forms stable complexes with 1,4,7,10-tetraazacy
clododecane-1,4,7,10-tetraacetic acid (DOTA) upon heating to
7

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
Fig. 7. RCCs for high- and low-temperature reactions of p-SCN-Bn-DOTA with 68Ga in a media of ILs 1–15 (* - precipitation upon mixing with 0.1 M HCl. Prior to TLC analysis
reaction was neutralized with 2 M Na2CO3).
p-SCN-Bn-DOTA chelator with a very high RCC (over 80%). Appar-
ently, the formation of gallium succinate is not preferred (the pos-
sible structure of the complex is a seven-membered ring), i.e.,
succinate anions did not affect the 68Ga-radiolabeling. The differ-
ence between DEA buffers of succinic and malic acids can be asso-
ciated with the presence of an additional OH group in malate,
which, along with the carboxylate group, coordinates gallium to
form a more stable complex (six-membered ring) compared to suc-
cinate (seven-membered ring). Thus, DEA salts of the most dicar-
boxylic acids (DEA salts 10–15) are inapplicable as buffers for
68Ga-radiolabeling. In addition, 68Ga-radiolabeling reactions with
DEA salt of nicotinic acid as buffer did not observed, possibly due
to the chelation of pyridine nitrogen with 68Ga.
in all cases. For 9-member cyclic BCA NCS-MP-NODA (entry 5,
Table 6), complex formation yields vary from 44% to 70% for stud-
ied ILs. For acyclic BCAs (p-SCN-Bn-DTPA and HBED, entry 6 and 8,
Table 6), almost quantitative RCCs were observed only in a media
of buffer 1. The exception is chelator p-SCN-Bn-DFO (entry 7,
Table 6) where RCC for buffer 1 was only 40%, whereas, in buffers
2, 6, and 8, we observed RCCs up to 71%. Thus, based on reactions
with ‘‘model” BCAs, diethanolammonium benzoate 1 was chosen
as the most promising buffer agent.
Approbation of buffer 1 was carried out for clinically relevant
peptides (Fig. S5.2–5.3, Table S1) for PET visualization prostate
cancer (DOTA-PSMA-617, DOTA-AMBA, NOTA-AMBA) and neu-
roendocrine tumors (DOTA-TATE, DOTA-NOC, NOTA-JR11, DOTA-
JR11) [59,60]. RCC in buffer 1 was compared with the same for
HEPES which is the most widely used buffer in the chemistry of
68Ga [40]. In the case of NOTA-substituted peptides and, surpris-
ingly, DOTA-PSMA-617, there were no differences in RCCs. Other
results were observed regarding the labeling of DOTA-substituted
peptides. It was shown that if the reaction was carried out under
37 °C, then IL 1 surpass HEPES as a buffer for radiolabeling
(Fig. 8). The exception is DOTA-JR11, where no reaction was
observed for both buffers, while at 70 °C RCC reaches 75–80% for
both buffers.
For further evaluation, 68Ga-DOTA complex formation was car-
ried out under our developed ‘‘low-temperature” protocol (37 °C,
15 min, acetone as co-solvent) [44]. As a result, reactions proceed
only in a media of DEA salts 1, 2, 6, and 8. Thus, these DEA salts
were chosen for further study.
In a second stage, we studied interactions of 68Ga with cyclic (p-
NCS-Bz-DOTA-GA, p-SCN-Bn-NOTA, p-NCS-benzyl-NODA-GA, NCS-
MP-NODA) and acyclic (p-SCN-Bn-DTPA, p-SCN-Bn-DFO, and
HBED) BCAs (Table S1) in a media of buffers 1, 2, 6 and 8
(Fig. S5.1). The results are presented in Table 6.
As a result, the most appropriate reactions for 68Ga with 12-
member cyclic BCAs were carried out in ILs 1 and 8 (entry 1–2,
Table 6). Also, for 9-member cyclic BCAs, p-SCN-Bn-NOTA, and p-
NCS-Bz-NODA-GA (entry 3–4, Table 6) high RCCs were observed
Besides, for buffer 1, its pH profile (Fig. S5.4), buffering pH
range, and buffer capacity data were measured [2,24,26]. These
results confirmed that in aqueous media, newly synthesized DEA
benzoate retains its buffering potential.
Table 6
RCCs for reactions of 68Ga with BCAs (Table S1) in a media of ILs 1, 2, 6, and 8.
Entry
BCA
RCC, % (n = 3) for different buffers
1
2
6*
8
1
2
3
4
5
6
7
8
p-SCN-Bn-DOTA
p-NCS-Bz-DOTA-GA
p-SCN-Bn-NOTA
p-NCS-Bz-NODA-GA
NCS-MP-NODA
p-SCN-Bn-DTPA
p-SCN-Bn-DFO
HBED
68.5 4.6
65.2 4.7
81.9 2.4
84.8 6.7
44.4 2.6
95.3 1.1
40.7 4.5
96.4 0.4
24.0 5.9
0
34.5 3.6
23.6 1.4
83.0 2.3
75.7 2.1
57.5 6.2
0
50.7 6.8
45.5 11.4
94.8 0.7
83.5 1.1
51.5 4.4
0
90.2 1.4
78.5 1.9
69.7 2.2
35.8 1.8
66.4 1.3
49.3 4.1
66.1 3.6
64.6 2.3
70.8 3.8
82.6 3.7
*
precipitation upon mixing with 0.1 M HCl. Prior to TLC analysis reaction was neutralized with 2 M Na2CO3
8

Y.A. Kondratenko, D.O. Antuganov, A.A. Zolotarev et al.
Journal of Molecular Liquids xxx (xxxx) xxx
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