Synthesis of a Water-Soluble, Soft N-Donor BTzBP Ligand Containing only CHON

Article abstract of DOI:10.1055/s-0040-1707163

A hydrophilic ligand that contains only C, H, O, and N substituents and uses a 6,6′-bis(1 H -1,2,3-triazol-4-yl)-2,2′-bipyridine (BTzBP) structural core has been synthesized. The effect of adding water-soluble groups onto extractant ligands has been extensively studied to facilitate the efficient partitioning of 4f and transuranic 5f elements for the treatment of spent nuclear fuel. Soft, N-donor ligands exhibit greater binding affinities for the trivalent actinides over the trivalent lanthanides, making BTzBP ligands an ideal candidate in the search for extractants to be used on an industrial scale. To date, hydrophobic BTzBPs have been shown to exhibit physical and chemical properties that might be conducive to nuclear waste processing conditions. However, hydrophilic BTzBPs have yet to be reported. Herein, we show the synthesis of a hydrophilic BTzBP ligand featuring cationic water solubilizing groups attached to the bipyridal rings.

Full text of DOI:10.1055/s-0040-1707163

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Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
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Synlett
S. A. Labb et al.
Letter
Synthesis of a Water-Soluble, Soft N-Donor BTzBP Ligand Containing
Only CHON
Samantha A. Labb
Conner J. Masteran
Savannah G. Albright
Bakr Ali
Hayley A. Chapman
Yijie Cheng
Rachel M. Cusic
Nathan B. Hartlove
Alissa N. Marr
Miranda Timmons
Seth J. Friese*
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Salisbury University, 1101 Camden Ave., Salisbury, MD 21801,
USA
sjfriese@salisbury.edu
Received: 26.05.2020
Accepted after revision: 31.05.2020
Published online: 24.06.2020
Prior to Am/Cm transmutations, the neutron scavenging
lanthanides must first be eliminated.
1,2
DOI: 10.1055/s-0040-1707163; Art ID: st-2020-d0054-l
Due to the nearly identical chemical behavior of the
An(III) and Ln(III), development of efficient separation
methods is challenging. Both the An and Ln have predomi-
nate trivalent oxidation states, similar ionic radii that de-
crease with increasing atomic number across groups, and
Abstract A hydrophilic ligand that contains only C, H, O, and N sub-
stituents and uses
a 6,6′-bis(1H-1,2,3-triazol-4-yl)-2,2′-bipyridine
(
BTzBP) structural core has been synthesized. The effect of adding wa-
ter-soluble groups onto extractant ligands has been extensively studied
to facilitate the efficient partitioning of 4f and transuranic 5f elements
for the treatment of spent nuclear fuel. Soft, N-donor ligands exhibit
greater binding affinities for the trivalent actinides over the trivalent
lanthanides, making BTzBP ligands an ideal candidate in the search for
extractants to be used on an industrial scale. To date, hydrophobic
BTzBPs have been shown to exhibit physical and chemical properties
that might be conducive to nuclear waste processing conditions. How-
ever, hydrophilic BTzBPs have yet to be reported. Herein, we show the
synthesis of a hydrophilic BTzBP ligand featuring cationic water solubi-
lizing groups attached to the bipyridal rings.
3
similar ionic bonding in complexes. However, it has been
demonstrated that complexing ligands containing donor at-
oms softer than oxygen (e.g., nitrogen, sulfur) exhibit great-
er binding affinities for An(III) than Ln(III) as a result of co-
3+
valent interactions between Am and soft N-donor hetero-
4
cycles. Thus, the number of syntheses of ligands containing
N-donor atoms have increased due to the interest in devel-
oping better An(III)/Ln(III) separation methods.
An interesting array of new molecules have been report-
ed during the past 25 years, and processes for their use have
arisen but, to date, none have reached the stage of full-scale
Key words BTzBP, separations, actinide, lanthanide, solvent ex-
traction, CHON, triazolyl
5
application. One could conclude from the present status
To meet the increasing demand for clean and reliable
energy, the production of electricity through nuclear ener-
gy is an integral element to meet the baseload needs for the
future. As a side effect, there will be an increase in the nu-
clear waste inventory and, with no long-term storage op-
tions, waste management solutions need to be developed.
Partitioning and Transmutation (P&T) of spent nuclear fuel
is a rational approach to the challenge of reducing the vol-
that there may well be room for new approaches based on
advanced reagents. For implementation on an industrial
scale, reagents must satisfy numerous criteria, making li-
gand design challenging. These reagents must selectively
extract An(III) over Ln(III), be sufficiently soluble in the de-
sired solvent, and be resistant to acid hydrolysis and radi-
olysis. Ideally, the reagent should also consist exclusively of
C, H, O, and N (the ‘CHON’ principle) so that wastes may be
incinerated when they can no longer be used, without gen-
erating corrosive by-products.6
1
ume and radiotoxicity of high-level waste. A major techno-
logical challenge for this option is the ability to efficiently
separate the transuranic elements (Am, Cm, Np) from the
ever-present fission product lanthanides (La–Ho and Y).2
Of the nitrogen-containing ligands studied for the pur-
pose of conducting liquid-liquid separations, a large num-
ber of bis-triazinyl bipyridines (BTBPs) and bis-triazinyl
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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Synlett
S. A. Labb et al.
Letter
phenanthrolines (BTPhens; Figure 1A) have been intensive-
ly investigated due to their selectivity for An(III) over Ln(III)
in acidic media and to evaluate how structural features af-
fect separations and to overcome slow rates of extraction,
tridentate N-donor ligand
tetradentate N-donor ligand
N
N
N
N
N
N
poor solubility in nonpolar diluents, and acidic or radiolyt-
N
N
N
ic/hydrolytic instability observed for this ligand class.7–9
N
N
N
N
N
N
A
B
=
neutral water-solubilizing group
N
N
N
N
N
N
Figure 2 Core structures of hydrophilic triazolyl based tri- and tetra-
dentate ligands
R
N
N
N
R
N
N
N
N
N
R'
N
N
R'
R
R
A
B
Figure 1 General structure of BTBP, BTPhen, and BTzBP N-donor ligands
synthesis of a new hydrophilic BTzBP ligand introducing a
new water-solubilizing group to these ligand classes by in-
corporating cationic trimethyl ammonium groups on the
backbone of the bipyridyl group, while remaining CHON
compliant (Scheme 1).
To address the challenge of stability, previous investiga-
tions focused on the synthesis of novel hydrophobic tetra-
dentate nitrogen-based complexants by combining 1,2,3-
triazolyl rings with the favorable binding configuration of a
bipyridine core. These BTzBP ligands (Figure 1B) have been
shown to extract An(III) over Ln(III) selectively (SFAm/Eu ca.
NO3
NMe3
3
Me N
NO3
7
0) with the use of a cation exchanging co-extractant (2-
N
N
N
N
bromohexanoic acid), have good metal-binding kinetics,
and be resistant to degradation in highly acidic and oxida-
tive media. These results establish the essential viability
of this class of complexants and suggest avenues for addi-
tional improvements.
Me
N
Me
N
N
N
N
Me
N
N
Me
10
HN
N
Scheme 1 Hydrophilic BTzBP ligand with a cationic water-solubilizing
group
Recently, the innovative Selective ActiNide EXtraction
(i-SANEX) process has shown promise for the extraction of
both An(III) and Ln(III) into the organic layer using
N,N,N′,N′-tetraoctyldiglycolamide (TODGA), followed by the
back-extraction of the An(III) into the aqueous layer with
Installation of the triazolyl unit onto the bipyridyl back-
bone involves two general synthetic pathways. The use of
‘click’ chemistry utilizing azides has provided many conve-
11
15
an appropriate hydrophilic ligand. A diverse array of triaz-
inyl BTP, BTBP, and BTPhen ligands using sulfonates as the
solubilizing groups have been made and have demonstrated
nient syntheses for a variety of triazolyl scaffolds. In this
synthesis, a small R group (Me) was used at the N1 position.
However, azides with a low carbon-to-nitrogen ratio are
12
16
marked selectivity for An(III) over Ln(III). However, the
use of sulfonates is not ideal for incineration and would
highly reactive and can be explosive. While methyl azide
reagents have been synthesized in situ to be used in click
6
17
generate additional waste streams post processing. In con-
chemistry, modifying and adding a triazolyl unit directly
trast, only a limited number of hydrophilic ligands have
been made that combine the beneficial features of the tri-
azolyl unit of the BTzBP ligands with water-solubilizing
groups.
provided a high yielding and safer method to scale the reac-
tion up to a multigram scale.
The key synthetic step is a Stille coupling between the
triazolyl and bipyridyl units. Using 1,2,3-triazole as the
starting point, modification of the N1 and C5 positions of
compound 1 is necessary in order to add the required SnBu3
group at the C4 position, allowing for the correct arrange-
ment of the nitrogen atoms to form the binding pocket.
Making the desired compound 1 is complicated by the
fact that the 1,2,3-triazole exists as two interconverting iso-
mers. As a result, substitution of any desired group on the
nitrogen atom makes two different isomers at the N1 and
N2 positions in different ratios depending on the conditions
used. Wang et al. have shown how substituents and sol-
vents affect the alkylation and acylation of 1,2,3-triazoles
and 4,5-dibromo-1,2,3-triazoles.18 As the size of the sub-
stituent increased, so did the yield of isomer 2. Similarly,
The PyTri series of ligands have shown good solubility
in water and dilute HNO solutions (ca. 150–200 mM) while
3
13
exhibiting good SF(Eu/Am) = 100 (Figure 2A). On the other
hand, the BTrzPhen ligands (Figure 2B) gave a SF(Eu/Am) about
half that of the PyTri ligands, but with a ligand concentra-
tion eight times less (solubility is ca. 10 mM in 0.3–3.0 M
HNO solutions). In addition, the BTrzPhen ligands also ex-
3
14
hibited SF(Cm/Am) of 2.5.
With the BTzBP ligands having ideal physical and chem-
ical characteristics in organic solvents and the BTrzPhen li-
gands exhibiting preferential binding of Cm over Am, mak-
ing a hydrophilic BTzBP ligand is an important advance-
ment for these ligand classes. Herein, we report the
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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S. A. Labb et al.
Letter
the larger Br on the 4,5-dibromo-1,2,3-triazole led to an in-
crease in the yield of isomer 2. Interestingly, when Wang et
al. decreased the temperature from room temperature to
be used without further purification. Therefore, the desired
Stille reagent 4 can be made from 1,2,3-triazole in four
steps with good to high yields.
0
°C, the reaction further favored the formation of isomer 2
1
) BuLi
1) BuLi
–78 °C
(Scheme 2).
Br
Br
Br
Bu3Sn
N
N
N
N
N
N
–78 °C
N
N
N
N
2) MeI
MeI
Na2CO3
2) Bu3SnCl
N
N
H
1B
3
4
X
X
N
N
X
X
N
N
N
N
Scheme 3 Modification of the 4- and 5-position of the triazolyl unit
N
N
1
2
) Br2, H2O
) MeI, Na2CO3
NH
1
1
A: X = H
B: X = Br
2A: X = H
2B: X = Br
To install the triazolyl rings onto the bipyridyl backbone
forming the tetra-aza framework, a Stille coupling reaction
between compounds 4 and 5 was carried out in toluene at
Scheme 2 Methylation of the 1,2,3-triazolyl unit and the dibromina-
tion of C4 and C5
110 °C for 18 h (Scheme 4). During this time, the product 6
Therefore, to increase the amount of the desired isomer
B, the reaction was heated in a screwcap vial at 25, 100,
precipitated out of the solution and was collected via filtra-
tion to give an isolated yield of 70%.
1
and 110 °C for 1 h. Isolated yields of the desired isomer 1B
increased from 49, 57, to 60%, respectively. In fact, H NMR
1
O
O
O
O
analysis of the crude reaction mixture after heating at
PdCl (PPh )
PPh3
2
3
2
O
O
110 °C showed a 2.0:1 ratio of isomer 1B/2B, effectively
N
O
Cl
N
O
N
showing an equal statistical probability of substituting at
the N1 vs. N2 positions.
Bu3Sn
N
N
N
N
N
N
N
N
Cl
For both compounds 1A and 1B, the C5 position is the
more reactive position. Ohta et al. have shown that subse-
quent deprotonation and reactions of 1A can take place first
N
N
5
6
1
2
) LAH, 0 °C
) HBr, H2SO4
19
at the C5 and then at the C4 position. However, these
yields were typically less than 60%, and, in the case of sub-
stituting a methyl group, it was less than 50%. As an alter-
native approach, bromination of the 1,2,3-triazole was ex-
plored.
Br
X
Me3N
X
Bromination of the 1,2,3-triazole was carried out in a
N
Br
N
N
N
NMe3
N
Me3N
N
N
N
water/bromine mixture, resulting in the precipitation of
N
N
N
N
0
4
,5-dibromo-1,2,3-triazole as a white solid.2 Bromine was
CH2Cl2
added twice to the filtrate to ensure complete bromination,
which gave an overall yield of 98%. Attempts were first
made to carry out the modification of 1B by adding a hy-
drogen at the C5 position. However, when the subsequent
halide exchange reaction was attempted at the C4 position,
deprotonation of the hydrogen at the C5 position was kinet-
ically competitive to the halide exchange at C4, resulting in
N
N
N
N
8
8
A: X = Br
B: X = NO3
AgNO3
7
Scheme 4 Four-step synthesis to make the hydrophilic BTzBP N-donor
ligand
the substitution of the Bu Sn group at both the C4 and C5
positions.
To eliminate the mixture of products being formed, a
methyl group was added first in place of hydrogen by carry-
ing out the halide exchange reaction on 1B with n-BuLi at –
The final sequence in the synthesis was to covert the es-
ter into the ammonium salt to enhance its hydrophilicity.
The ester was reduced with lithium aluminum hydride to
yield the diol (66% yield). Conversion of the hydroxyl groups
into an appropriate leaving group, Br, with HBr in H SO al-
3
2
4
7
(
8 °C and then quenching the reaction with MeI to make 3
92% yield) (Scheme 3). Overall, use of the brominated 1B
proved to be more efficient (91% over two steps) than the
lowed for the formation of 7 in 85% yield.
The last step was to substitute the leaving group with a
trimethylamine group to form the bis-trimethyl ammoni-
um salt. This was accomplished by adding trimethylamine
to a dichloromethane suspension of 7. After stirring for 24
h, removal of the solvent left 8a in 99% yield. Conversion
into the nitrate salt 8b was carried out by dissolving 8a in
water and adding AgNO3.21 Filtration and removal of the
19
direct substitution from 1A (<50%). Then, in a similar
fashion, the Bu Sn group was added by the halide exchange
with n-BuLi at –78 °C followed by quenching the reaction
with Bu SnCl, giving the desired Stille reagent 4 that could
3
3
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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S. A. Labb et al.
Letter
solvent gave the final CHON-compliant water-soluble, N-
donor BTzBP ligand.
(3) (a) Cotton, S. In Lanthanide and Actinide Chemistry.; J. Wiley &
Sons Ltd: Chichester, 2006. (b) Katz, J. J.; Morss, L. R.; Edelstein,
N. M.; Fuger, J. In The Chemistry of the Actinide and Transactinide
Elements, Vol. 1; Katz, J. J.; Morss, L. R.; Edelstein, N. M.; Fuger, J.,
Ed.; Springer: Dordrecht, 2006, 1–17.
A survey of the solubility of 8a in different concentra-
tions of nitric acid (the desired solvent for the An/Ln target
ions) showed that, even in de-ionized water, the ligand has
a molar solubility of ca. 35 mM (ca. 3× greater than that ob-
served for the BTrzPhen ligands). This increases slightly to
(
4) (a) Choppin, G. R. J. Alloys Compd. 2002, 344, 55. (b) Jarvinen, G.
D.; Barrans, R. E.; Schroeder, N. C.; Wade, K. L.; Jones, M. M.;
Smith, B. F.; Mills, J. L.; Howard, G.; Freiser, H.; Muralidharan, S.
In Separation of f Elements; Nash, K. L.; Choppin, G. R., Ed.;
Plenum Press: New York, 1995.
ca. 5 mM in 1 M HNO . However when the concentration of
3
HNO was increased to 2 and 4 M, an even more substantial
3
(
(
(
5) (a) Leoncini, A.; Huskens, J.; Verboom, W. Chem. Soc. Rev. 2017,
increase in solubility to ca. 175 and >780 mM, respectively,
was observed. A preliminary analysis of these solutions
46, 7229. (b) Hudson, M. J.; Harwood, L. M.; Laventine, D. M.;
Lewis, F. W. Inorg. Chem. 2013, 52,07 3414. (c) Panak, P. J.; Geist,
A. Chem. Rev. 2013, 113, 1199.
1
showed no degraded or hydrolyzed products by H NMR
spectroscopy after four weeks at room temperature.
In conclusion, this new, water-soluble, CHON-compli-
ant, N-donor BTzBP ligand can be made in a high yielding
and readily purified route. The change in nature and place-
ment of the solubilizing group on these classes of ligands
increases its solubility by ca. threefold compared to the
BTrzPhen ligands, making this ligand an excellent candidate
for future extraction and solution studies.
6) (a) Hudson, M. J. Czech. J. Phys. 2003, 53, A305. (b) Madic, C.;
Hudson, M. J. In High-level Liquid Waste Partitioning by Means of
Completely Incinerable Extractants; EUR 18038, European Com-
mission: Luxembourg, 1998.
7) (a) Zaytsev, A. V.; Bulmer, B.; Kozhevnikov, V. N.; Sims, M.;
Modolo, G.; Wilden, A.; Waddell, P. G.; Geist, A.; Panak, P. J.;
Wessling, P.; Lewis, F. W. Chem. Eur. J. 2020, 26, 428. (b) Distler,
P.; Stamberg, K.; John, J.; Harwood, L. M.; Lewis, F. W. J. Chem.
Thermodyn. 2020, 141, 105955. (c) Afsar, A.; Babra, J. S.; Distler,
P.; Harwood, L. M.; Hopkins, I.; John, J.; Westwood, J.; Selfe, Z. Y.
Heterocycles 2020, 101, 209. (d) Williams, J.; Dehaudt, J.;
Bryantsev, V. S.; Luo, H.; Abney, C. W.; Dai, S. Chem. Commun.
Funding Information
2
017, 53, 2744.
We gratefully acknowledge the National Science Foundation (MRI No.
(
8) (a) Foreman, M. R. S. J.; Hudson, M. J.; Geist, A.; Madic, C.; Weigl,
M. Solvent Extr. Ion Exch. 2005, 23,05 645. (b) Aneheim, E.;
Gruner, B.; Ekberg, C.; Foreman, M. R. S. J.; Hajkova, Z.;
Lofstrom-Engdahl, E.; Drew, M. G. B.; Hudson, M. J. Polyhedron
1827905) for financial support to purchase a 400 MHz NMR spec-
trometer console and autosampler, and additional research support
by the National Science Foundation: Bridges for SUCCESS (No.
0969428) and Salisbury University.
N
ati
o
n
a
lS
c
i
e
n
c
e
F
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n
d
ati
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n
(0
9
6
9
4
2
8)Nati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(1
8
2
7
9
0
5)
2013, 50, 154. (c) Lofstrom-Engdahl, E.; Aneheim, E.; Ekberg, C.;
Skarnemark, G. J. Radioanal. Nucl. Chem. 2013, 296, 733.
9) (a) Drew, M. G. B.; Foreman, M. R. S. J.; Hill, C.; Hudson, M. J.;
Madic, C. Inorg. Chem. Commun. 2005, 8, 239. (b) Nilsson, M.;
Ekberg, C.; Foreman, M. R. S.; Hudson, M.; Liljenzin, J. O.;
Modolo, G.; Skarnemark, G. Solvent Extr. Ion Exch. 2006, 24, 823.
(
Acknowledgment
The authors are grateful to Ken Nash and former members of the
Nash Group for their many discussions that provided impetus for this
work.
(c) Lewis, F. W.; Harwood, L. M.; Hudson, M. J.; Drew, M. G. B.;
Desreux, J. F.; Vidick, G.; Bouslimani, N.; Modolo, G.; Wilden, A.;
Sypula, M.; Vu, T.-H.; Simonin, J.-P. J. Am. Chem. Soc. 2011, 133,
1
3093.
Supporting Information
(
10) (a) Muller, J. M.; Galley, S. S.; Albrecht-Schmitt, T. E.; Nash, K. L.
Inorg. Chem. 2016, 55,21 11454. (b) Muller, J. M.; Nash, K. L.
Solvent Extr. Ion Exch. 2016, 34, 322.
11) (a) Modolo, G.; Wilden, A.; Geist, A.; Magnusson, D.; Malmbeck,
R. Radiochim. Acta 2012, 100, 715. (b) Modolo, G.; Wilden, A.;
Kaufholz, P.; Bosbach, D.; Geist, A. Prog. Nucl. Energy 2014, 72,
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707163.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
(
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(
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A.; Panzeri, W.; Boubals, N.; Berthon, L.; Charbonnel, M.-C.;
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Commun. 2017, 53, 5001.
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1
(21) Characterization Data for 8b: H NMR (D O 400 MHz):  = 2.63
2
(15) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41,14 2596.
(s, 6 H), 3.20 (s, 18 H), 4.00 (s, 6 H), 4.69 (s, 4 H), 8.01 (s, 2 H),
13
8.18 (s, 2 H). C NMR (100 MHz, D O):  = 9.2, 34.5, 52.9, 67.6,
2
(
16) (a) Bräse, S.; Gil, C.; Zimmerman, V. Angew. Chem. Int. Ed. 2005,
122.8, 124.6, 134.8, 138.1, 141.8, 151.4, 155.2. IR (ATR): 669.1,
750.1, 872.9, 902.2, 934.0, 977.3, 1067.3, 1113.4, 1162.8,
1277.9, 1326.0, 1480.8, 1560.3, 1606.1, 2910, 2955, 3035, 3373
44, 5188. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem. Int. Ed. 2001, 40, 2004.
–1
+2
(17) Velázquez, H. D.; Garcia, Y. R.; Vandichel, M.; Madder, A.;
cm . HRMS (ESI): m/z [M] calcd for C26H38N10: 245.1635;
Verpoort, F. Org. Biomol. Chem. 2014, 12, 9350.
found: 245.1630.
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–E