Synthesis of bis(amidoxime)s and evaluation of their properties as uranyl-complexing agents

Article abstract of DOI:10.1016/j.tet.2018.04.016

Uranium pollution involves high toxicity and radioactivity and, therefore, constitutes a grave threat to human health and the environment. Chelation is an effective method for sequestering uranium. It is well known that chelators based on oxime groups are able to complex uranyl cations efficiently. To this end, various bis(amidoxime)s were synthesized by reaction of hydroxylamine with the corresponding dinitriles. In these compounds the amidoximes are separated by chains of various lengths, some including a heterocycle (pyridine or 1,3,5-triazine). The abilities of these bis(amidoxime)s to complex uranyl cation in water were evaluated by determining their affinity constants and thermodynamic parameters by means of Isothermal Titration Calorimetry (ITC). DFT calculations were also performed, to determine the optimum structures of the complexes formed between uranyl cations and the oximate groups. A tetrakis(amidoxime), also synthesized in this work, shows good affinity for uranium, and a single molecule is able chelate several uranyl cations. These results are of importance for the remediation of uranium-polluted wastewaters, and open up several perspectives for the design and synthesis of new amidoxime compounds.

Full text of DOI:10.1016/j.tet.2018.04.016

Accepted Manuscript
Synthesis of bis(amidoxime)s and evaluation of their properties as uranyl-complexing
agents
Jérémy Stemper, Wei Tuo, Eva Mazarío, Ahmed S. Helal, Alexandre Djurovic, Claude
Lion, Jean-Michel El Hage Chahine, François Maurel, Miryana Hémadi, Thierry Le
Gall
PII:
S0040-4020(18)30384-3
10.1016/j.tet.2018.04.016
TET 29431
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 October 2017
Revised Date: 19 March 2018
Accepted Date: 5 April 2018
Please cite this article as: Stemper Jéé, Tuo W, Mazarío E, Helal AS, Djurovic A, Lion C, El Hage
Chahine J-M, Maurel Franç, Hémadi M, Le Gall T, Synthesis of bis(amidoxime)s and evaluation of their
properties as uranyl-complexing agents, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.016.
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ACCEPTED MANUSCRIPT
Synthesis of bis(amidoxime)s and evaluation of their properties as uranyl-
complexing agents
Jérémy Stemper,a Wei Tuo,a Eva Mazarío,b Ahmed S. Helal,b,c Alexandre Djurovic,a Claude
Lion,b Jean-Michel El Hage Chahine,b François Maurel,b Miryana Hémadi,b Thierry Le Galla,*
aCEA-Université Paris-Saclay, Institut Joliot, Service de Chimie Bioorganique et de
Marquage, Bât. 547, 91191 Gif-sur-Yvette, France
bUniv Paris Diderot, Sorbonne Paris Cité – Interfaces, Traitements, Organisation et
Dynamique des Systèmes, CNRS-UMR 7086, Bât. Lavoisier, 15 rue Jean-Antoine de Baïf,
75205 Paris Cedex 13, France
cDepartment of Nuclear Science and Engineering, Massachusetts Institute of Technology,
USA
thierry.legall@cea.fr
Abstract:
Uranium pollution involves high toxicity and radioactivity and, therefore, constitutes a grave
threat to human health and the environment. Chelation is an effective method for sequestering
uranium. It is well known that chelators based on oxime groups are able to complex uranyl
cations efficiently. To this end, various bis(amidoxime)s were synthesized by reaction of
hydroxylamine with the corresponding dinitriles. In these compounds the amidoximes are
separated by chains of various lengths, some including a heterocycle (pyridine or 1,3,5-
triazine). The abilities of these bis(amidoxime)s to complex uranyl cation in water were
evaluated by determining their affinity constants and thermodynamic parameters by means of
Isothermal Titration Calorimetry (ITC). DFT calculations were also performed, to determine
the optimum structures of the complexes formed between uranyl cations and the oximate
groups. A tetrakis(amidoxime), also synthesized in this work, shows good affinity for
uranium, and a single molecule is able chelate several uranyl cations. These results are of
importance for the remediation of uranium-polluted wastewaters, and open up several
perspectives for the design and synthesis of new amidoxime compounds.
1

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Keywords: Amidoxime; Uranyl; Metal complexation; Affinity constant; Synthesis
1. Introduction
Uranium is the main fuel employed in power plants for the production of nuclear energy.
2+
Uranyl ion (UO2 ) is the form in which uranium is usually found under oxidizing conditions.
The development of ligands able to complex the uranyl ion efficiently has been the subject of
many studies. Such ligands may find application notably for the extraction of uranium from
sea water,1 for the recycling of spent nuclear fuel and for the remediation of uranium-
contaminated soil.2 Uranium and its salts are highly toxic and constitute a major health
problem.3 Indeed, they cause severe damage to kidney and bones, and can accumulate in the
brain.4 Therefore, the removal of uranium from contaminated aqueous solution is of great
importance for the protection of the environment and of mankind.
The various types of ligand that complex the uranyl cation comprise donor atoms, which are
coordinated to the uranium atom in the equatorial plane. They may contain chelating
functions such as carboxylic acid, bis(phosphonate), carboxamide and catechol.4
Ligands containing amidoximes can also complex the uranyl cation; in particular, many
studies dealing with the recovery of uranium from sea water make use of absorbents
containing amidoximes.1 Extraction of uranyl from aqueous solutions by amidoxime-
functionalized ionic liquids,6 by a mesoporous imprinted polymer containing amidoximes7
and by amidoxime-modified mesoporous silica8 has been reported. Interestingly, an η2 (O, N)
coordination of the amidoximate moiety to the uranyl is observed in the X-ray structures of
isolated complexes.6,9 Recently, Vukovic and Hay presented the computer-aided design of
bis(amidoxime)s that are structurally organized for binding the uranyl ion.10 Such compounds
can be valuable for the recovery of uranyl ions, especially if they are grafted on polymers or
on nanoparticles. Uranium sequestration using a bis(amidoxime) grafted on a hydrophilic
backbone was recently reported.11
Here we report the synthesis of a series of bis(amidoxime)s 1a-f, and a tetrakis(amidoxime)
1g, derivatives of which could be employed for uranium sequestration. The two amidoximes
in these compounds are separated by spacers of various lengths which may contain a nitrogen
atom or a heterocycle. In the design of these compounds, the possibility of grafting them, or
analogs of them, onto a polymer or a nanoparticle was taken into account. The uranyl-
complexing abilities of these amidoximes and the corresponding thermodynamic parameters
2

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are reported. Density Functional Theory (DFT) calculations were used in order to determine
the optimum structures of the various complexes.
2. Results and discussion
2.1. Synthesis of amidoxime derivatives
Bis(amidoxime)s 1a and 1b were synthesized from the corresponding dinitriles (Scheme 1).
The treatment of benzamide 212 with hydroxylamine hydrochloride in the presence of
NaHCO313 did not afford the expected compound 1a, but a mixture of benzamide 2 and cyclic
adduct 3. After recrystallization, 3 was isolated in 21% yield. Compound 3, which is
analogous to glutaramide dioxime,14 could also be a good ligand for uranyl cation. Eventually
bis(amidoxime) 1a was obtained in 84% yield by treatment of 2 with an aqueous solution of
hydroxylamine in ethanol at room temperature. Likewise, treatment of benzamide 415 afforded
bis(amidoxime) 1b. A similar procedure was employed for the preparation of other
amidoximes.
Scheme 1. Synthesis of compounds 3, 1a and 1b. Reagents and conditions: a. H2NOH.HCl,
NaHCO3, EtOH, 80 °C, 4 h, 21% after recrystallization; b. NH2OH (50 wt% in H2O), EtOH,
RT, 20 h (1a: 84%, 1b: 98%).
As shown in Scheme 2, another benzamide-bis(amidoxime), in which the two chelating
functions are separated by eleven atoms, was obtained in two steps from N,N-bis(2-
hydroxyethyl)benzamide (5).16 The diol was reacted with two equivalents of acrylonitrile,
leading to dinitrile 6, resulting from a double Michael addition. However, the product was
obtained as a mixture with inseparable acrylonitrile oligomers. It was then converted to the
corresponding bis(amidoxime) 1c, which was purified by chromatography.
3

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Scheme 2. Synthesis of bis(amidoxime) 1c. Reagents and conditions: a. acrylonitrile, t-
BuONa, t-BuOH, RT, 18 h, 71% (not pure); b. NH2OH (50 wt% in H2O), EtOH, RT, 71%.
In pyridines with two amidoxime substituents in the ortho positions, the pyridine nitrogen
atom could also participate in the complexation of the uranyl ion. Two such compounds were
prepared. In the first, 1d, both amidoxime functions are directly bonded to the pyridine ring,
while in the second, 1e, they are separated from the heterocyclic ring by methylene groups
(Scheme 3). Diester 7 serves as the precursor for both bis(amidoxime)s. Treatment of 7 with
aqueous ammonia in methanol, followed by dehydration, afforded dinitrile 8,17 which was
converted to 1d18 in 89% yield. Dinitrile 919 was obtained in three steps from diester 7
(reduction to a diol, conversion of the diol to a dibromide, and reaction of the latter with
potassium cyanide). The expected bis(amidoxime) 1e was then obtained from 9 in 81% yield.
HO
OH
O
O
N
N
a
b
N
N
NC
CN
N
CN
MeO
OMe
H2N
NH2
7
1d
8
OH OH
CN
H2N
N
N
NH2
N
c
b
7
N
9
1e
Scheme 3. Synthesis of bis(amidoxime)s 1d and 1e. Reagents and conditions: a. (1) 28% aq.
NH3, MeOH, RT, 24 h, 67%; (2) (CF3CO)2O, Et3N, THF, RT, 4 h, 90%; b. NH2OH (50 wt%
in H2O), EtOH, RT, 48 h (1d: 89%, 1e: 83%); c. (1) NaBH4, EtOH, 0 °C, then RT, 15 h, 71%;
(2) 48% HBr, reflux, 16 h, 23%; (3) KCN, 18-crown-6, CH3CN, 80 °C, 15 h, 81%.
As in the case of the pyridine derivatives, the complexation of the uranyl ion by 1,3,5-
triazines substituted by two amidoximes functions could involve a nitrogen atom of the
heterocyclic ring. Such compounds can be synthesized from readily available cyanuric
chloride (10), and the third hydrogen can be replaced by a substituent which could be used to
4

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graft the triazine onto a polymer or a nanoparticle. We chose to prepare compound 1f, which
comprises a di(hydroxyethyl)amino moiety, expected to enhance the water solubility of the
compound (Scheme 4). Compound 1f was synthesized in four steps. One equivalent of the
bis(tert-butyldimethylsilyl) ether of diethanolamine20 was reacted with 10 in the presence of
Hunig’s base, leading to the corresponding dichloride, which was converted to dinitrile 11 in
51% yield by reaction with potassium cyanide at room temperature. At higher temperatures,
degradation occurred. Reaction with hydroxylamine, followed by treatment with acid to
remove the silyl ethers, afforded the expected bis(amidoxime) 1f.
Scheme 4. Synthesis of bis(amidoxime) 1f. Reagents and conditions: a. (1)
HN(CH2CH2OTBS)2, EtNiPr2, THF, -78 °C to RT, 3 h, 88%; (2) KCN, CH3CN, RT, 51%; b.
(1) NH2OH (50 wt% in H2O), EtOH, RT, 48 h, 96%; (2) 1N HCl, EtOH, RT, 1 h, 95%.
Finally, another triazine derivative, compound 1g, comprising four amidoximes, was also
synthesized (Scheme 5). Cyanuric chloride 10 was treated with two equivalents of
iminodiacetonitrile, leading to tetranitrile 12. The remaining chlorine atom was replaced by a
phenoxy group by treatment of 12 with sodium phenoxide. The four nitriles of 13 were
transformed into amidoxime functions under the conditions previously employed, affording
product 1g in 77% yield.
5

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Scheme 5. Synthesis of tetrakis(amidoxime) 1g. Reagents and conditions: a.
iminodiacetonitrile, BzCl, EtNiPr2, THF, RT, 20 h, 65%; b. Phenol, NaH, THF, RT, 2.5 h,
84%; c. NH2OH (50 wt% in H2O), EtOH, RT, 48 h, 77%.
2.2. Complexation studies
Nano-isothermal Titration Calorimetry (ITC) was used to measure directly the heat gained or
lost during the association of the synthesized molecules (L) with uranyl cation in water. This
allowed us to determine, in a single experiment, the thermodynamic binding parameters: the
affinity constant (Ka), the stoichiometry (n), and the enthalpy and entropy of formation (ꢀrH°
and ꢀrS°) of the complex formed between L and uranyl cation [equation (1)].
2+
2+
L + nUO2
[L-(UO2 )n]
(eq. 1)
ꢄꢅ
ꢁ
ꢇ
L − (ꢂꢃꢄ )ꢆ
with Kꢀ =
ꢁ
ꢄꢅꢇꢆ
ꢁꢈꢇ ꢂꢃꢄ
In Figure 1 are presented the ITC curves for the complexation of uranyl cation by compounds
1c and 1f at T = 298 K and at pH 6.5; this pH value was chosen to avoid any precipitation of
uranyl species. In both cases, a regular heat variation with uranium concentration is observed,
which establishes the interaction between L and the cation. The contribution of TꢀrS° is lower
than that of ꢀrH°; complex formation is enthalpy-driven and the reaction is exothermic (ꢀrH°
< 0). The negative value of ꢀrS° suggests that an ordered chelator-cation complex is formed.
6

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Fig. 1. Isothermal titration calorimetry (ITC) curves for the formation of complexes between
amidoximes 1c and 1f and uranyl cation.
Table 1 summarizes the thermodynamic data obtained for all the amidoxime derivatives
synthesized. For the molecules from 1a-1e, the fitting was performed according to the
"independent" model which implies one binding site. All the ligands exhibit a very good
affinity for uranyl cation, with log Ka > 4. Ligands 1a, 1b, 1d and 1e complex uranyl cations
with a metal/ligand stoichiometry of 0.5/1. The two amidoxime groups of one ligand molecule
are unable to complex one uranyl cation, probably because of the rigidity of the molecules,
and one uranyl cation is shared by two different ligands. However, in the case of molecule 1c,
where the arms are longer and therefore flexible, the metal/ligand stoichiometry is 1/1. In this
molecule, one cation is complexed with one molecule of ligand. For 1f and 1g, multiple-site
fitting was performed. Indeed, in 1f, in addition to the two amidoxime groups, two alcohol
functions are involved in the complexation of the cation, which leads to the possibility of two
different binding sites. The affinity for the amidoxime sites is much higher than that for the
alcohol sites. The tetrakis(amidoxime) 1g was best fitted with the multiple-site model. The
two amidoxime groups complex a single cation with a higher affinity (log Ka1 = 5.9, n1 = 1.2),
leaving two isolated amidoxime groups which are able to complex cations by sharing with
other ligand molecules, with a lower affinity (log Ka2 = 3.8, n2 = 0.6). These amidoxime
7

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derivatives, and especially 1f and 1g, are very efficient chelators (log Ka > 5.7) for uranyl
cations, since each ligand can complex more than one cation. A higher value of log K1 (11.1)
has been reported for the uranyl complex of acetamidoximate,14,21 DFT calculations were in
agreement with the observed value.14 The discrepancies compared to the values observed in
our study may be attributed to the different pH at which the complexation constants were
recorded.
Table 1. Thermodynamic constants for the complexation of amidoxime derivatives 1a-g.a
Amidoxime log Ka
n
ꢀrH° (kJ.mol-1)
-39.9 ±0.8
TꢀrS° (kJ.mol-1)
-11.3 ± 0.9
-5.9 ± 0.5
1ab
1bb
1cb
1db
1eb
1fc
5.0 ± 0.1
0.7 ± 0.1
1.2 ± 0.1
0.6 ± 0.1
0.6 ± 0.2
0.5 ± 0.1
4.4 ± 0.1
5.1 ± 0.1
5.1 ± 0.2
4.7 ± 0.1
-31.2 ± 1.1
-48.7 ± 1.5
-50.9 ± 1.2
-64.2 ± 1.8
-19.6 ± 0.8
-21.8 ± 0.7
-37.2 ± 1.0
5.7 ± 0.3 (log Ka1) 1.0 ± 0.1 (n1) -11.9 ± 0.8 (ꢀrH1) +20.6 ± 0.9 (TꢀrS1)
3.0 ± 0.1(log Ka2) 1.0 ± 0.1 (n2) -63.1 ± 1.3 (ꢀrH2) -45.9 ± 1.8 (TꢀrS2)
5.9 ± 0.3 (log Ka1) 1.2 ± 0.2 (n1) -12.1 ± 0.9 (ꢀrH1) +22.1 ± 0.8 (TꢀrS1)
3.8 ± 0.3 (log Ka2) 0.6 ± 0.2 (n2) -96.2 ± 1.4 (ꢀrH2) -74.6 ± 1.2 (TꢀrS2)
1fc
1gc
1gc
a log of the affinity constant (log Ka), stoichiometry (n), reaction enthalpy (ꢀrH°), and reaction
entropy (ꢀrS°) at T = 298 K and pH 6.5. b For compounds 1a-1e, the values were obtained
using the "independent fitting" model. c For compounds 1f and 1g, the values were obtained
using the "multiple-site fitting" model.
2.3. Quantum mechanical approach
Uranyl complexes with different ligands have been widely studied in the framework of
Density Functional Theory (DFT), which is a particularly powerful method for obtaining
information about their geometries and energies.
The linear uranyl cation exists in solution as a complex ion with ligands equatorially bonded
to the uranium. If there are no ligands in the solution, water molecules make up the first
coordination shell. Although the number of water ligands can vary from 4 to 6, several
8

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2+
experimental and quantum mechanical studies indicate that the UO2(H2O)5 complex
predominates in aqueous solution.22
The complexes of uranyl with the seven amidoximes (L), 1a-g, were constructed by H2O-
amidoxime exchange from the UO2(H2O)52+ complex. Upon complexation, it has been shown
that amidoximes deprotonate to form neutral complexes. For this reason, DFT calculations
2+
were performed starting with the UO2(H2O)5 complex, and several water molecules were
replaced by one or two amidoximate ligands.
The optimized structures of the different species are shown in Figure 2. In all structures of the
mono- and bis(amidoximate) complexes the uranyl unit is linear, and both the water
molecules and the amidoximates are symmetrically distributed in the equatorial plane
perpendicular to the O=U=O axis. The amidoximate acts as a bidentate ligand, binding the
uranyl through the N-O bond in a η2 motif. This result is in agreement with several theoretical
and experimental studies9,23 and confirms the accepted view about the coordination of the
2+
deprotonated amidoxime with UO2 .
(
)
The distances between U and O or N in the complexes ꢂꢃꢄꢈ ꢃꢉꢄ are all around 2.3 Å,
except for 1d (Figure 2). This indicates a strong interaction between uranyl and ligand,
leading to charge transfer from the latter to the former. Interestingly, in the bi-deprotonated
amidoxime complex with 1d the U-O distance is significantly longer. This is probably
because the geometry of the bis-amidoximate unit in this ligand cannot accommodate the
coordination site of uranyl. In all the calculated structures, the oximate N-O and C-N
distances are close to 1.350 Å and 1.300 Å, respectively, indicating a partially delocalized
oximate group.24
1a
U…O1=2.953 Å
U…O2=2.305 Å
U…N1=2.376 Å
U…N2=2.400 Å
U…O1=2.317 Å
U…O2=2.318 Å
U…N1=2.307 Å
U…N2=2.308 Å
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1b
N…HO1=1.910 Å
O2H…N=1.906 Å
U…O1=2.285 Å
U…O1=2.287 Å
U…O2=2.275 Å
U…N1=2.368 Å
U…N2=2.394 Å
U…O2=2.281 Å
U…N1=2.393 Å
U…N2=2.408 Å
1c
O1H…OU=1.836 Å
O2H…OU=1.832 Å
U…O1=2.271 Å
U…O2=2.275 Å
U…N1=2.369 Å
U…N2=2.408 Å
U…O1=2.281 Å
U…O2=2.282 Å
U…N1=2.409 Å
U…N2=2.409 Å
1d
U…O1=2.274 Å
U…O2=2.260 Å
U…N1=2.391 Å
U…N2=2.420 Å
U…O1=3.393 Å
U…O2=3.404 Å
U…N1=2.530 Å
U…N2=2.536 Å
1e
U…O1=2.271 Å
U…O2=2.269 Å
U…N1=2.392 Å
U…N2=2.415 Å
U…O1=2.296 Å
U…O2=2.307 Å
U…N1=2.380 Å
U…N2=2.407 Å
1f
10

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O1H…OU=2.009 Å
O2H…OU=2.014 Å
U…O1=2.268 Å
U…O2=2.278 Å
U…N1=2.422 Å
U…N2=2.393 Å
U…O1=2.274 Å
U…O2=2.291 Å
U…N1=2.388 Å
U…N2=2.375 Å
1g
N1H…OU=2.186 Å
N2H…OU=2.127 Å
U…O1=2.276 Å
U…O2=2.276 Å
U…N1=2.390 Å
U…N2=2.381 Å
U…O1=2.288 Å
U…O2=2.306 Å
U…N1=2.353 Å
U…N2=2.384 Å
Fig. 2. Optimized structures of complexes between uranyl cation and bi-deprotonated
(
)
(
)
amidoxime ꢂꢃꢄꢈ ꢃꢉꢄ (left) and two mono-deprotonated amidoximes ꢂꢃꢄꢈꢄ ꢃꢉꢄ (right).
Bond distances (Å) are listed with the structures, and the subscripts 1 and 2 indicate the left or
right atom of the oximate ligand, respectively. The color code is: C gray, H white, O red, and
N blue.
From an energetic point of view, the ability of a ligand to complex uranyl can be determined
from DFT calculations by using the following equations (2) and (3) for mono- and
bis(amidoximate) complexes, respectively.
Table 2. Enthalpies of reaction of the complexes [UO2L(OH2)] and [UO2L2(OH2)] calculated
from equations (2) and (3).
Stoichiometry
∆rH
(kcal.mol-1)
-90.2
Amidoxime
n=1
n=2
n=1
n=2
n=1
n=2
n=1
n=2
n=1
n=2
1a
-77.2
-92.2
-81.8
-82.2
-54.6
-61.9
-65.1
-88.3
1b
1c
1d
1e
-83.3
11

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n=1
n=2
n=1
n=2
-75.3
-70.1
-72.4
-56.1
1f
1g
+ Lꢄꢋ ⇌ UOꢄL OHꢄ + 4(OHꢄ) (eq. 2)
ꢁ
ꢇꢅꢄ
(
)
(UOꢄ(OHꢄ)ꢊ
ꢋ
ꢁ
ꢇꢅꢄ
(
)
(
)
(UOꢄ(OHꢄ)ꢊ
+ 2L ⇌ UOꢄLꢄ OHꢄ + 4 OHꢄ
(eq. 3)
It should be noted that these energies cannot be directly compared with experimental values
since the thermodynamics for the deprotonation of the ligand have not been calculated. As
indicated in Table 2, reactions (1) and (2) are both exothermic, whatever the nature of the
ligand, suggesting a high complexing character of amidoxime toward uranyl cation, as
inferred from experimental data.
3. Conclusion
We have synthesized several compounds containing two amidoxime functions and one
compound containing four. By an experimental approach, we have shown that all these
compounds complex uranyl cation with high affinities. These amidoxime derivatives are
clearly good candidates for uranium uptake. By a theoretical approach we have elucidated the
optimized structures for the different complexes. We are pursuing our approach by selecting
the ligands with the highest affinities (1a, 1f, 1g) for grafting onto the surface of magnetic
nanoparticles in order to remove uranium from contaminated wastewaters or soils by
magnetic harvesting.25
4. Experimental section
4.1. Synthesis
4.1.1. General. Non-aqueous reactions were performed in an inert atmosphere using a balloon
filled with argon. TLC: Silica Gel 60F254 plates with detection by UV light and by an aqueous
solution of KMnO4. Column chromatography was carried out with Combiflash Serlabo Rf75
(silica gel columns RediSep® Rf, 35-60 µm). Melting points were recorded using a Büchi B-
540 apparatus. High-resolution mass spectra (HRMS) were performed on a Bruker maXis
mass spectrometer by the "Fédération de Recherche" ICOA/CBM (FR2708) platform." IR
1
spectra were recorded using a Spectrum Two FT-IR spectrometer (Perkin-Elmer). H NMR
and 13C NMR spectra were recorded on a Bruker Advanced 400 spectrometer at 400.133 and
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100.624 MHz for 1H and 13C, respectively. Chemical shifts (
δ) are in parts per million and are
referenced to residual H in the deuterated solvent; coupling constants (J) are in Hertz.
4.1.2. [(3Z,5Z)-3,5-Bis(hydroxyimino)piperazin-1-yl](phenyl)methanone (3)
Hydroxylamine hydrochloride (556 mg, 8.0 mmol, 4 equiv.) and NaHCO3 (672 mg, 8.0
mmol, 4 equiv.) were added to a solution of N,N-bis(cyanomethyl)benzamide12 (2; 398 mg,
2.0 mmol, 1 equiv.) in ethanol (10 mL). The brown suspension was heated at 80 °C for 4 h.
After cooling to room temperature, the solvent was removed under vacuum. THF and brine
were added and, after dissolution of all the solids, the layers were separated. The aqueous
phase was extracted four times with THF and the combined organic phases were dried over
MgSO4, filtered and concentrated under vacuum. The resulting solid was recrystallized from
ethanol to yield the title compound as a white powder (103 mg, 21%); mp 218-219 °C (dec.);
IR: νmax 3394, 3306, 2918, 1670, 1636, 1365, 1276, 1074, 926, 641, 587 cm−1; δH (DMSO-d6)
10.38 (s, 2H, OH), 8.30 (s, 1H, NH), 7.53-7.42 (m, 5H, H-Ar), 4.33 (br s, 4H, CH2); δC
(DMSO-d6) 169.8 (CO), 140.9 (2C, C(NH)NOH), 134.6 (CCO), 130.9 (CH-Ar para), 129.1
(2C, CH-Ar meta), 127.6 (2C, CH-Ar ortho); HRMS (ESI): [M+H]+, found 249.0992.
C11H13N4O3 requires 249.0988.
4.1.3. General procedure for the preparation of amidoximes from nitriles by treatment with
an aqueous hydroxylamine solution.
A 50 wt% solution of hydroxylamine in water (8.0 mmol, 4 equiv., 2 equiv./nitrile function)
was added to a solution of dinitrile (2.0 mmol, 1 equiv.) in ethanol (10 mL), and the solution
was stirred for 20 h at room temperature. The solvent was evaporated under vacuum. The
resulting compound was either chromatographed on silica gel or washed with an appropriate
solvent and recrystallized.
4.1.4. N,N-Bis[(Z)-2-amino-2-(hydroxyimino)ethyl]benzamide (1a)
N,N-Bis(cyanomethyl)benzamide (2; 398 mg, 2.0 mmol, 1 equiv.) and 50 wt% hydroxylamine
in water (490 µL, 8.0 mmol, 4 equiv.) were used following the general procedure. The
resulting solid was recrystallized from ethanol to yield the title compound as brown crystals
(444 mg, 84%); mp 173-174 °C; IR: νmax 3486, 3372, 3233, 2844, 1660, 1553, 1464, 1275,
1011, 918, 798, 721, 691 cm−1; δH (DMSO-d6) 9.30 (br s, 1H, OH), 9.18 (br s, 1H, OH), 7.51-
7.41 (m, 5H, H-Ar), 5.45 (s, 4H, NH2), 4.03 (br s, 2H, CH2N), 3.80 (br s, 2H, CH2N); δC
13

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(DMSO-d6) 171.8 (CO), 149.5 (C(NH)NOH), 148.8 (C(NH)NOH), 136.3 (CCO), 130.1 (CH-
Ar para), 128.6 (2C CH-Ar meta), 127.1 (2C CH-Ar ortho), 48.5 (CH2), 45.5 (CH2); HRMS
(ESI): MH+, found 266.1252. C11H16N5O3 requires 266.1253.
4.1.5. N,N-Bis[(Z)-3-amino-3-(hydroxyimino)propyl]benzamide (1b)
N,N-Bis(2-cyanoethyl)benzamide19 (4; 454 mg, 2.0 mmol, 1 equiv.) and 50 wt%
hydroxylamine in water (490 µL, 8.0 mmol, 4 equiv.) were used following the general
procedure. The resulting solid was washed with diisopropyl ether, to yield the title compound
as a white solid (576 mg, 98%); mp 60-61 °C; IR: νmax 3453, 3323, 3173, 2826, 1657, 1594,
1427, 1358, 1317, 1025, 927, 703 cm−1; δH (DMSO-d6) 8.88-8.84 (m, 2H, OH), 7.42-7.40 (m,
3H, H-Ar), 7.33-7.31 (m, 3H, H-Ar), 5.44 (br s, 2H2, NH2), 5.29 (br s, 2H2, NH2), 3.59 (br s,
2H, CH2-N), 3.36 (br s, 2H, CH2-N), 2.32 (br s, 2H, CH2C(NH2)NOH), 2.16 (br s, 2H,
CH2C(NH2)NOH); δC (DMSO-d6) 171.0 (CO), 151.2 (C(NH)NOH), 150.4 (C(NH)NOH),
137.6 (CCO), 129.4 (CH-Ar para), 128.7 (2C CH-Ar meta), 126.7 (2C CH-Ar ortho), 46.8
(CH2N), 42.4 (CH2N), 30.7 (CH2C(NH2)NOH), 29.5 (CH2C(NH2)NOH); HRMS (ESI): MH+,
found 294.1571. C13H20N5O3 requires 294.1566.
4.1.6. N,N-Bis[2-(2-cyanoethoxy)ethyl]benzamide (6)
A 0.22 M solution of sodium tert-butoxide was prepared by adding sodium (15.3 mg) to
anhydrous tert-butanol (3 mL). This mixture was stirred overnight at room temperature (until
total dissolution of sodium). Acrylonitrile (398 µL, 6.0 mmol, 5 equiv.) and the previously
prepared solution of tert-butoxide (540 µL, 0.12 mmol, 0.1 equiv.) were successively added to
a solution of N,N-bis(2-hydroxyethyl)benzamide16 (5; 250 mg, 1.20 mmol, 1 equiv.) in 0.5
mL of anhydrous tert-butanol. After stirring for 24 h at room temperature, the volatiles were
removed under vacuum to give an orange oil. Chromatography on silica gel (1/1 to 1/9
heptane/ethyl acetate) yielded a pale yellow oil containing the desired product and an
unidentified oligomer of acrylonitrile (270 mg, 71%). The product was used without further
purification; IR: νmax 3059, 2875, 2249, 1625, 1460, 1416, 1114, 786, 735, 707 cm−1; δH
(DMSO-d6) 7.51-7.24 (m, 5H), 3.73-3.53 (m, 6H), 3.54-3.35 (m, 6H), 2.79-2.66 (m, 4H); δC
(DMSO-d6) 171.4, 137.2, 129.4, 128.6, 127.0, 119.7, 119.6, 68.2, 65.5, 53.3, 49.1, 44.4, 18.5;
HRMS (ESI): [M+H]+, found 316.1657. C17H22N3O3 requires 316.1653.
4.1.7. N,N-Bis{2-[(Z)-3-amino-3-(hydroxyimino)propoxy]ethyl}benzamide (1c)
14

ACCEPTED MANUSCRIPT
Dinitrile 6 (500 mg, 1.59 mmol, 1 equiv.) and 50 wt% hydroxylamine in water (389 µL, 6.34
mmol, 4 equiv.) were used following the general procedure. The product was purified on
silica gel (95/5 to 9/1 CH2Cl2/MeOH) to afford the title compound as a colorless oil (430 mg,
71%); IR: νmax 3322, 3174, 2829, 1655, 1594, 1426, 1357, 1025, 924, 702 cm−1; δH (DMSO-
d6) 8.81 (s, 2H, HO-N), 7.44-7.40 (m, 3H, H-Ar), 7.37-7.34 (m, 2H, H-Ar), 5.37 (s, 2H, H-
NH), 5.34 (s, 2H, H-NH), 3.60 (br s, 4H, CH2O), 3.48-3.35 (m, 8H, CH2O and CH2N), 2.25-
2.16 (m, 4H, CH2C(NH2)NOH); δC (DMSO-d6) 171.4, 150.9, 150.8, 137.3, 129.3, 128.7,
127.1, 68.2, 68.0, 49.2, 44.6, 31.8; HRMS (ESI): [M+H]+, found 382.2085. C17H28N5O5
requires 382.2082.
4.1.8. (2Z,6Z)-N'2,N'6-Dihydroxypyridine-2,6-bis(carboximidamide) (1d)
Dinitrile 817 (844 mg, 6.54 mmol, 1 equiv.) and 50 wt% hydroxylamine in water (1.60 mL,
26.2 mmol, 4 equiv.) were used following the general procedure. The resulting solid was
washed with diethyl ether to yield the title compound18 as a white solid (1.13 g, 89%); mp 220
°C; IR: νmax 3483, 3355, 3089, 2791, 1654, 1630, 1560, 1387, 1075, 955, 827, 645 cm−1; δH
(DMSO-d6) 9.83 (s, 2H, HO-N), 7.84-7.71 (m, 3H, H-Ar), 6.27 (br s, 4H, NH2); δC (DMSO-
d6) 150.0 (2C, Car-N or C(NOH)NH2), 149.4 (2 C, Car-N or C(NOH)NH2), 137.0 (CH para),
119.6 (2C, CH meta); HRMS (ESI): MH+, found 196.0827. C7H10N5O2 requires 196.0834.
4.1.9. (1Z,1'Z)-2,2'-(Pyridine-2,6-diyl)bis(N'-hydroxyacetimidamide) (1e)
Dinitrile 919 (450 mg, 2.86 mmol, 1 equiv.) and 50 wt% hydroxylamine in water (705 µL,
11.5 mmol, 4 equiv.) were used following the general procedure. The resulting solid was
washed with diisopropyl ether to yield the title compound as a white solid (532 mg, 83%); mp
190 °C (dec.); IR: νmax 3448, 3330, 3172, 2778, 1660, 1595, 1573, 1457, 1349, 982, 915, 884,
763, 621 cm−1; δH (DMSO-d6) 8.98 (s, 2H, HO), 7.65 (t, J = 7.7 Hz, Car-H para), 7.18 (d, J =
7.7 Hz, 2H, Car-H meta), 5.47 (br s, 4H, NH2), 3.42 (s, 4H, CH2); δC (DMSO-d6) 156.8 (2C,
Car-N), 151.0 (2C, C(NOH)NH2), 137.1 (Car-H para), 120.8 (2C, Car-H meta), 39.6 (2C,
CH2); HRMS (ESI): MH+, found 224.1140. C9H14N5O2 requires 224.1069.
4.1.10. N,N-Bis{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4,6-dichloro-1,3,5-triazine-2-amine
A solution of bis{2-[(tert-butyldimethylsilyl)oxy]ethyl}amine20 (1.947 g, 5.83 mmol, 1
equiv.) in anhydrous THF (10 mL) was slowly added to a solution of cyanuric chloride (1.076
g, 5.83 mmol, 1 equiv.) and diisopropylethylamine (0.983 mL, 1 equiv.) in anhydrous THF
15

ACCEPTED MANUSCRIPT
(50 mL) cooled at -78 °C. The reaction mixture was stirred for 15 min at -78 °C, then allowed
to warm at room temperature and stirred for 3 h. After concentration under vacuum,
dichloromethane (50 mL) was added. The organic phase was washed with water (3 x 15 mL),
then dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by
silica gel chromatography (heptane/ethyl acetate: 97/3 to 95/5) to yield the title compound as
white crystals (2.475 g, 88%); mp 60.3 °C; IR: νmax 2955, 2930, 2854, 1570, 1460, 1089, 828,
771 cm−1; δH (CDCl3) 3.82 (s, 8H, CH2), 0.89 (s, 18H, CH3Si), 0.05 (s, 12H, CH3C); δC
(CDCl3) 169.8 (CCl), 164.7 (C(N2)N), 60.3 (CH2O), 51.4 (CH2N), 25.8 (CH3C), 18.1 (CCH3),
-5.4 (CH3Si). HRMS (ESI): MH+, found 481.1984. C19H39Cl2N4O2Si2 requires 481.1983.
4.1.11. 6-(Bis{2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-1,3,5-triazine-2,4-dicarbonitrile
(11)
Potassium cyanide (106.7 mg, 1.64 mmol, 4 equiv.) was added to a solution of the dichloride
prepared above (200 mg, 0.41 mmol, 1 equiv.) in anhydrous acetonitrile (4 mL) under argon.
The suspension was stirred at room temperature for two days and then concentrated under
vacuum. Dichloromethane (25 mL) and water (15 mL) were added. After decantation, the
phases were separated and the organic phase was washed with water (2 x 15 mL), then dried
(MgSO4), filtered and concentrated under vacuum. The residue was purified by silica gel
chromatography (heptane/ethyl acetate: 100/0 to 95/5) to yield the title compound as yellow
crystals (98 mg, 51%); mp 79.8 °C; IR: νmax 2954, 2929, 2854, 2252, 1595, 1553, 1472, 1483,
1104, 807, 837, 828, 772 cm−1; δH (CDCl3) 3.91-3.86 (m, 4H, CH2O), 3.85-3.81 (m, 4H,
CH2N), 0.90 (s, 18H, CH3Si), 0.05 (s, 12H, CH3C); δC (CDCl3) 163.1 (CCN), 152.6
(C(N2)N), 113.6 (CN), 60.1 (CH2O), 51.6 (CH2N), 25.7 (CH3C), 18.1 (C(CH3)3Si), -5.5
(CH3Si); HRMS (ESI): MH+, found 463.2670. C21H39N6O2Si2 requires 463.2667.
4.1.13. 6-(Bis{2-[(tert-butyldimethylsilyl)oxy]ethyl}amino)-N'2,N'4-dihydroxy-1,3,5-triazine-
2,4-bis(carboximidamide)
The dinitrile prepared above (100 mg, 0.21 mmol, 1 equiv.) and 50 wt% hydroxylamine in
water (53 µL, 0.86 mmol, 4 equiv.) were used following the general procedure. The resulting
solid was washed with diethyl ether, to yield the title compound as a white powder (110 mg,
96%); mp 246.3 °C; IR: νmax 3494, 3340, 2952, 2928, 2855, 1658, 1556, 1509, 1094, 976,
834, 773, 718 cm−1; δH (DMSO-d6) 10.38 (s, 2H, OH), 6.01 (s, 4H, NH2), 3.79 (s, 4H, CH2-
O), 3.33 (s, 4H, CH2-N), 0.82 (s, 18H, CH3Si), -0.03 (s, 12H, CH3C); δC (DMSO-d6) 165.5
16

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(C(NOH)NH2), 164.6 (C(N2)CNH2), 148.7 (C(N3)), 60.7 (CH2O), 50.7 (CH2N), 26.1 (CH3C),
18.2 (C(CH3)3Si), -5.1 (CH3Si); HRMS (ESI): MH+, found 529.3097. C21H45N8O4Si2 requires
529.3096.
4.1.14.
(2Z,4Z)-6-[Bis(2-hydroxyethyl)amino]-N'2,N'4-dihydroxy-1,3,5-triazine-2,4-
bis(carboximidamide) (1f)
A solution of the bis(amidoxime) prepared above (20 mg, 37.8 µmol, 1 equiv) in ethanol (1.6
mL) and 1N HCl (0.5 mL) was stirred for 45 min, then ethanol was removed under vacuum.
The aqueous phase was washed with diethyl ether (2 x 1 mL). Concentration under vacuum
afforded the title compound as a slightly yellow powder (10.8 mg, 95%); mp 246.3 °C; IR:
ν
max 2952, 2422, 2237, 1679, 1574, 1496, 1025, 894, 749 cm−1; δH (D2O) 3.95 (br s, 4H), 3.84
(br s, 4H); δC (D2O) 164.3 (C(NOH)NH2), 159.4 (C(N2)CNH2), 152.8 (C(N3)), 58.2 (CH2O),
49.8 (CH2N); HRMS (ESI): MH+, found 301.1367. C9H17N8O4 requires 301.1367.
4.1.15. 2,2'-[(4-{[2-(
2-yl)azanediyl]diacetonitrile (12)
λ λ
2-azanylidene)-2 3-ethyl](cyanomethyl)amino}-6-chloro-1,3,5-triazin-
To a solution of cyanuric chloride (500 mg, 2.71 mmol, 1 equiv.) and diisopropylethylamine
(0.92 mL, 5.42 mmol, 2 equiv.) in 10 mL THF cooled at 0 °C, was added dropwise a solution
of iminodiacetonitrile (515 mg, 5.42 mmol, 2 equiv.) in 5 mL THF. After 20 h stirring at
room temperature, the organic solvent was removed under vacuum. The residue was purified
by silica gel chromatography (heptane/ethyl acetate: 1/1) to yield the title compound as a
white solid (536 mg, 65%); mp 217-218 °C; IR: νmax 3009, 2953, 2256, 1560, 1518, 1407,
1234, 806, 739 cm−1; δH (DMSO-d6) 4.89 (s, 4H), 4.79 (s, 4H); δC (DMSO-d6) 169.8 (C),
164.7 (2C), 116.2 (CH2), 116.0 (CH2), 36.7 (2CH2); HRMS (ESI): MH+, found 302.0664.
C11H9ClN9 requires 302.0664.
4.1.16. 2,2',2'',2'''-[(6-Phenoxy-1,3,5-triazine-2,4-diyl)bis(azanetriyl)]tetraacetonitrile (13)
Sodium hydride (60% dispersion in mineral oil, 111 mg, 2.78 mmol, 1.2 equiv.) was
suspended in dry THF (3 mL) under argon at 0 °C. A solution of phenol (261 mg, 2.78 mmol,
1.2 equiv.) in dry THF (3 mL) was added slowly enough to prevent the excessive formation of
foam. The resulting mixture was then stirred 10 min at 0 °C and a solution of tetranitrile 12
(700 mg, 2.32 mmol, 1 equiv.) in dry THF (3 mL) was added dropwise. After 2.5 h stirring at
room temperature, a saturated aqueous solution of NH4Cl was poured into the flask and the
17

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aqueous phase was extracted twice with ethyl acetate. The combined organic phases were
dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica
gel chromatography (heptane/ethyl acetate: 7/3 to 4/6) to yield the title compound as brown
crystals (702 mg, 84%); mp 146-147 °C; IR: νmax 3005, 1567, 1547, 1488, 1394, 1209, 940,
814, 775, 690 cm−1; δH (CDCl3) 7.46 (t, J = 7.8 Hz, 2H, H-Ar meta), 7.32 (t, J = 7.4 Hz, 1H,
H-Ar para), 7.19 (d, J = 7.6 Hz, 2H, H-Ar ortho), 4.60 (m, 8H, CH2N); δC (CDCl3)
171.1 (C(N2)O), 166.0 (2C, C(N2)N), 151.5 (Car-O), 129.6 (2C, CH meta), 126.3 (CH para),
121.5 (2C, CH ortho), 114.0 (2C, CN), 113.9 (2C, CN), 35.7 (2C, CH2), 35.5 (2C, CH2);
HRMS (ESI): MH+, found 360.1327. C17H14N9O requires 360.1321.
4.1.17. (1Z,1'Z,1''Z,1'''Z)-2,2',2'',2'''-[(6-Phenoxy-1,3,5-triazine-2,4-diyl)bis(azanetriyl)]tetra-
kis(N'-hydroxyacetimidamide) (1g)
Tetranitrile 13 (200 mg, 0.56 mmol, 1 equiv.) and 50 wt% hydroxylamine in water (274 µL,
4.48 mmol, 8 equiv.) were used following the general procedure. The resulting solid was
washed with diethyl ether, to yield the title compound as a white solid (212 mg, 77%); mp
157-158°C; IR: νmax 3472, 3344, 2870, 1661, 1566, 1488, 1206, 890, 808, 603 cm−1; δH
(DMSO-d6) 9.13 (s, 2H, OH), 9.08 (s, 2H, OH), 7.42 (t, J = 7.4 Hz, 2H, H-Ar meta), 7.24 (t, J
= 7.2 Hz, 1H, H-Ar para), 7.19 (d, J = 7.2 Hz, 2H, H-Ar ortho), 5.41 (s, 4H, NH2), 5.20 (s,
4H, NH2), 4.07 (s, 4H, CH2) 3.95 (s, 4H, CH2); δC (DMSO-d6) 170.6 (C(N2)O), 166.8 (2C,
C(N2)N), 152.5 (Car-O), 150.0 (2C, CH2C(NH2)NOH),149.3 (2C, CH2C(NH2)NOH), 129.9
(2C, CH meta), 125.7 (CH para), 122.1 (2C, CH ortho), 46.8 (2C, CH2), 46.3 (2C, CH2);
HRMS (ESI): MH+, found 492.2179. C17H26N13O5 requires 492.2180.
4.2. Complexation studies
Thermodynamic assays were carried out in water by using a Nano-Isothermal Titration
Calorimeter (Nano-ITC, TA Instruments, USA) with an active cell volume of 0.988 mL and a
250 µl stirring syringe. Nano-ITC uses a semiconductor thermoelectric heating and cooling
system to precisely control temperature and a single removable syringe assembly for efficient
and accurate distribution of the titrant reagent. The power curve (heat flow as a function of
time) was integrated by means of the NanoAnalyze program to obtain the overall heat
produced or absorbed during the reaction. All solutions were thoroughly degassed by stirring
under vacuum. Titrations were performed at 298 K and pH 6.5 by an automated sequence of
50 injections, each of 5 µL uranyl acetate solutions (1.2 mM), into the sample cell containing
18

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the amidoxime solution (0.1 mM). The injections were spaced by 300 s to ensure complete
equilibration. Three titrations were carried out for each measurement. The reported
experimental data are the best-fit values.
4.3. Density Functional Theory (DFT) calculations
DFT calculations of the geometries, vibrational frequencies, and electronic structures of the
uranyl complexes with the amidoxime ligands were performed with the Gaussian 09 software
package26 using the PBE1PBE1 functional.27 The Stuttgart/Dresden small core (SC)
relativistic effective core pseudo-potential (RECP), replacing 60 core electrons,28 was used for
the U atom, and the total electron 6-311+G(d,p) basis set was used for the C, H, O and N
atoms. Frequencies at the same level were calculated to verify that the optimized geometries
are local minima on the potential energy surfaces and to obtain the thermodynamic quantities
of the reaction (enthalpies of reaction). Solvation effects of water were taken into account by
means of the polarizable continuum model using the integral equation formalism variant
(IEFPCM)29 with default convergence criteria.
Acknowledgments
Financial support by the Agence Nationale de la Recherche (ANR-13-SECU-0001) for the
project DECRET is gratefully acknowledged. The authors are grateful to Dr. John S. Lomas
for constructive discussions.
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Synthesis of bis(amidoxime)s and evaluation of their properties as uranyl-complexing
agents
Jérémy Stemper,a Wei Tuo,a Eva Mazarío,b Ahmed S. Helal,b,c Alexandre Djurovic,a Claude
Lion,b Jean-Michel El Hage Chahine,b François Maurelb, Miryana Hémadi,b Thierry Le Galla,*
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