Synthesis of Bis-1,2,4-triazines via Telescoped Condensation of [1,10]-Phenanthroline-2,9-dicarbonitrile with Aromatic 1,2-Dicarbonyls

Article abstract of DOI:10.1002/jhet.2295

(Chemical Equation Presented) Efficient separation of minor actinides from spent nuclear fuel remains a formidable challenge. As part of ongoing efforts to identify effective ligands for separation of toxic radionuclides, a series of bis-1,2,4-triazines, three novel, have been prepared from [1,10]-phenanthroline-2,9-dicarbonitrile in two-telescoped steps without additives, complicated workups, prolonged reaction times, or additional purification.

Full text of DOI:10.1002/jhet.2295

Month 2015
Synthesis of Bis-1,2,4-triazines via Telescoped Condensation of
[1,10]-Phenanthroline-2,9-dicarbonitrile with Aromatic 1,2-Dicarbonyls
a
b
a
*
Serene Tai, Neil J. Williams, and Jesse D. Carrick
aDepartment of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville
Tennessee 38505-0001
bOak Ridge National Laboratory, Oak Ridge, Tennessee 37831
*
E-mail: jcarrick@tntech.edu
Received April 30, 2014
DOI 10.1002/jhet.2295
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Efficient separation of minor actinides from spent nuclear fuel remains a formidable challenge. As part of
ongoing efforts to identify effective ligands for separation of toxic radionuclides, a series of bis-1,2,4-
triazines, three novel, have been prepared from [1,10]-phenanthroline-2,9-dicarbonitrile in two-telescoped
steps without additives, complicated workups, prolonged reaction times, or additional purification.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
pseudo-benzylic hydrogens [6], and is effective in a continuous
flow extraction process.
Efficient chemoselective extraction of minor actinides
present within spent nuclear fuel in an environmentally
responsible way continues to be an area of significant inter-
est for the scientific community. Spent nuclear fuel is
composed of a variety of radionuclides derived from the
lanthanides and actinides. Minor actinides, Am3+ and
Cm3+ specifically, compose just a fraction of the waste
generated from spent nuclear fuel with percentage compo-
sitions less than 0.1 wt% [1]. Although low in composition,
these materials display extremely long half-lives and high
levels of radio toxicity, rendering their effective separation
from lanthanides contained in nuclear waste streams of par-
amount importance [2]. Ongoing research at Oak Ridge
National Laboratory (ORNL), in addition to other efforts
[3], has focused on the evaluation of soft Lewis basic
donor ligands for the effective separation of Am3+ and
Cm3+ from spent nuclear fuel (Fig. 1).
Given the renewed interest in the phenanthroline scaffold
(3) for the development of efficient ligands and solubility
challenges frequently experienced in synthetic preparations,
a direct telescoping procedure of 6 to the corresponding
bis-1,2,4-triazines without additives, extended reaction
times, or additional purification seemed prudent. Often,
construction of bis-1,2,4-triazines employs the use of the ex-
tremely flammable and hazardous anhydrous hydrazine [7].
Herein is described an efficient two-pot (four-step) protocol
using hydrazine hydrate at elevated temperature
Previous work by Kolarik [4] led to the synthesis of 2,6-
bis-(5,6-dialkyl-1,2,4-trizazin-3-yl) pyridines as effective
heterocyclic complexants for An(III) and Ln(III). These
materials also displayed high distribution values in bi-
phasic extraction media. Lanthanides and actinides display
similar electronic properties, rendering chemoselective
separation challenging [5]. In order for any potential ligand
to have utility on scale, current engineering processes seek
a chemoselective moiety, which is stable at low pH, does
not inhibit facile phase separation, possesses one or fewer
Figure 1. Common soft Lewis basic ligand scaffolds.
© 2015 HeteroCorporation

S. Tai, N. J. Williams, and J. D. Carrick
Vol 000
Scheme 1. Synthesis of [1,10]-phenanthroline-2,9-dicarbonitrile.
followed by homogeneous condensation with function-
alized aromatic 1,2-dicarbonyls in polar aprotic solvent.
The desired ligands are obtained directly after treatment
with an anti-solvent in good chemical purity thereby
avoiding further purification via recrystallization or
chromatography. Starting dicarbonitrile 6 was prepared at
ORNL according to the three-step protocol described by
Lewis (Scheme 1) [8].
Oxidation of commercially sourced 2,9-dimethyl-[1,10]-
phenanthroline with SeO2 afforded the requisite dialdehyde
5. One-pot hydroxamic acid formation followed by
Scheme 2. Bis-hydrazonamide formation.
Table 1
Synthesis of bis-1,2,4-triazines via telescoped condensation.
Entry
Dicarbonyl (2.20 equiv)
Solvent
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Anti-solvent
H2O
Temp (°C)
Time (h)
16
Yielda (%)
Product
16
1
8 R1 = H
R2 = H
78
78
78
78
78
78
78
78
75
29
50
55
75
85
40
0
2
3
4
5
6
7
8
9 R1 = H
R2 = CH3
10 R1 = H
R2 = CHCH2
11 R1 = H
R2 = F
12 R1 = H
R2 = Cl
13 R1 = H
R2 = Br
H2O
16
17
H2O
16
18b
19
H2O
16
H2O
16
20
—
16
21
14 R1 = OMe
R2 = H
15 R1 = H
R2 = NMe2
H2O
16
22
H2O
16
23
aOver four steps.
bDecomposes at ambient temperature.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Bis-1,2,4-triazines via Telescoped Condensation of
[1,10]-Phenanthroline-2,9-dicarbonitrile with Aromatic 1,2-Dicarbonyls
Figure 3. Spectral data for structure 16. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Figure 2. Spectral data for structure 7. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
sulfonation and elimination at elevated temperature afforded
dinitrile 6 in 36% isolated yield over three steps. Lewis
described the preparation of bis-hydrazonamide 7 using
hydrazine hydrate at ambient temperature and a reaction time
of 14 days. A modest increase of the reaction temperature to
40°C afforded 7 in quantitative conversion (1H-NMR) and
isolated yield after 16 h (Scheme 2).
Condensation of 7 with a series of aromatic dicarbonyls
(8–15) with varying functionality and substitution was
explored leading to the formation of 16, 17, and 21 described
elsewhere [9] and four novel heterocycles 18–20, and 22
(Table 1).
Dissolution of 7 (Fig. 2) in NMP followed by addition of
the desired 1,2-dicarbonyl afforded a homogeneous mix-
ture that produced the listed heterocycle after heating
overnight at 78°C. Treatment of the crude mixtures with
water as an anti-solvent afforded ligands (16–22)
(Figs. 3–7) in 29–85% yield over two reaction pots (four
steps) from 7.
condensation with the electronic nature of the substituent
on the aromatic 1,2-dicarbonyl. Inductive electron-
withdrawing substituents (entries 4–6) resulted in favorable
condensation and yield. Inductively electron-donating sub-
stituents such as entry 2 did not afford the desired ligand in
good yield. Aromatic 1,2-dicarbonyl 10 was not commer-
cially available and was prepared via Suzuki–Miyaura
coupling of the corresponding Br-derivative 13 with
potassium vinyltrifluoroborate according to the Molander
procedures [10]. While the divinylbenzil 10 was stable, the
resulting condensation product rapidly decomposed at
ambient temperature. In entry 8, possessing the strong-
resonance donating N,N-dimethylamino substituent no
conversion to the desired bis-1,2,4-triazine was afforded
[11]. 4,4′-Dimethoxybenzil was also screened under this
protocol and afforded a complex mixture of products.
CONCLUSIONS
In summary, an operationally simple and efficient
synthesis of useful bis-1,2,4-triazines derived from
[1,10]-phenanthroline-2,9-dicarbonitrile has been achieved.
Highlights of this work include quantitative conversion of
RESULTS AND DISCUSSION
After optimization of the reaction conditions listed in
Table 1, a general trend emerged paralleling ease of
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S. Tai, N. J. Williams, and J. D. Carrick
Vol 000
Figure 4. Spectral data for structure 19. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Figure 5. Spectral data for structure 20. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
6 to 7 without additives or prolonged reaction times, efficient
homogeneous condensation with aromatic 1,2-dicarbonyls
containing electron-withdrawing substituents under mild
conditions, and effective isolation of the desired ligands in
reasonable yields over four steps from 7 without purification.
Distribution studies on ligands synthesized are ongoing at
ORNL. Solubility of ligands in process relevant solvents
remains at the forefront of synthetic efforts, and additional
ligand syntheses are ongoing in this laboratory.
referenced to the residual solvent signal: chloroform (δ 7.26),
DMSO-d6 (δ 2.50) for 1H and chloroform (δ 77.0) and
DMSO-d6 (δ 39.5) for 13C. Physical property data for 5, 6, and
17 have been previously reported.
General experimental conditions.
[1,10]-Phenanthroline-
2,9-dicarbonitrile (100 mg, 0.434 mmol, 1.00 equiv) was slurried
in hydrazine hydrate-65% max (0.30 mL, 8.00 equiv) and
anhydrous ethanol (2 mL) at 0°C. The mixture was heated to
40°C for 16 h. The bis-hydrazonamide was isolated via vacuum
1
filtration as a white-crystalline solid. H-NMR conversion of 6
to 7 was quantitative in DMSO-d6. The bis-hydrazonamide was
telescoped to the condensation step without additional
purification. Thus, 7 was dissolved in the polar aprotic solvent
listed, and the required 1,2-dicarbonyl (2.20 equiv) was charged
in one portion followed by heating to 78°C for 16 h. After
cooling to ambient temperature, the homogenous mixture was
treated with 1 mL of water, and the resulting crystalline material
was isolated by vacuum filtration and dried under reduced
pressure to constant mass at 100°C.
EXPERIMENTAL
All reagents were purchased from U.S. chemical suppliers,
stored according to published protocols, and used as received
unless indicated otherwise. All experiments were performed in
oven-dried glassware under an inert atmosphere of Ar except
where indicated. All reported yields are listed for pure compounds
as judged from 1H-NMR spectroscopy over four total steps from
the corresponding bis-1,2,4-hydrazonamide unless otherwise
indicated. Infrared spectral data were obtained on a Varian
(Palo Alto, CA) Excalibur 3100 FT-IR spectrometer. All 1H-
and 13C-NMR data were acquired on a Bruker (Billerica, MA)
Avance 500 MHz or Varian Mercury 300 MHz NMR spectrome-
ter. All chemical shifts are reported using the δ scale and are
Bis-hydrazonamide (7). [1,10]-Phenanthroline-2,9-dicarbonitrile
(100 mg, 0.434 mmol, 1.00 equiv) was slurried in hydrazine
hydrate-65% max (0.30 mL, 8.00 equiv) and anhydrous ethanol
(2mL) at 0°C. The mixture was heated to 40°C for 16h. The bis-
hydrazonamide was isolated via vacuum filtration as a yellow-
1
crystalline solid. H-NMR conversion of 6 to 7 was quantitative
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Bis-1,2,4-triazines via Telescoped Condensation of
[1,10]-Phenanthroline-2,9-dicarbonitrile with Aromatic 1,2-Dicarbonyls
Figure 7. Spectral data for structure 22. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Figure 6. Spectral data for structure 21. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
in DMSO-d6. The bis-hydrazonamide was telescoped to the
condensation without additional purification. IR (solution; CHCl3)
2,9-Bis-[5,6-bis-(4-chloro-phenyl)-[1,2,4]triazin-3-yl]-[1,10]
phenanthroline (20). IR (solution, CHCl3) cmÀ1 3057, 1593,
1479, 1377, 1089, 1004, 831, 1H-NMR (300 MHz, CDCl3) δ
9.00 (d, J = 9.0 Hz, 2H), 8.54 (d, J = 6.0 Hz, 2H), 8.00 (s, 2H),
7.92 (d, J = 9.0 Hz, 4H), 7.70 (d, J = 9.0 Hz, 4H), 7.70 (d,
J = 9.0 Hz, 4H), 7.45 (d, J = 6.0 Hz, 4H), 7.43 (d, J = 6.0 Hz,,
4H), 13C-NMR (75 MHz, CDCl3) δ 160.6, 155.7, 155.6, 152.3,
146.4, 137.5, 137.4, 136.5, 133.5, 131.7, 130.8, 129.9, 129.2,
129.1, 127.8, 123.1, HRMS 778.0738 (EI) m/z = (778.0721
calculated for C42H22Cl4N8).
cmÀ1 1H-NMR (300 MHz, DMSO-d6) δ 8.38 (d, J = 8.60Hz,
,
2H), 8.28 (d, J = 8.50Hz, 2H), 7.95 (s, 2H), 6.15 (br-s, 4H), 5.65
(br-s, 4H), 13C-NMR (75 MHz, DMSO-d6) δ 151.7, 143.9, 143.6,
136.5, 128.6, 126.5, 119.4, HRMS (EI) m/z = 294.1346
(294.1341) calculated for C14H14N8.
2,9-Bis-(5,6-diphenyl-[1,2,4]triazin-3-yl)-[1,10]-phenanthroline
(16). IR (solution; CHCl3) cmÀ1 3633, 3392, 3055, 1618, 1486,
1
1443, 1379, 1221, 1135, H-NMR (300 MHz, CDCl3) δ 9.05 (dd,
J= 8.40, 4.00 Hz, 2H), 8.61 (d, J= 8.40 Hz, 2H), 8.05 (s, 2H), 7.93
(d, J= 7.50 Hz, 4H), 7.73 (d, J= 7.50 Hz, 4H), 7.55–7.44 (m, 12H),
13C-NMR (75 MHz, solvent) δ 160.8, 156.6, 156.3, 146.6, 137.6,
135.4, 130.9, 130.4, 130.1, 130.0, 129.7, 128.7, 128.7, 127.9, 123.4,
HRMS (EI) m/z = 642.2271 (642.2280 calculated for C42H26N8).
2,9-Bis-[5,6-bis-(4-fluoro-phenyl)-[1,2,4]triazin-3-yl]-[1,10]
phenanthroline (19). IR (solution, CHCl3) cmÀ1 3070, 1602, 1487,
1381, 1227, 1160, 841, 1H-NMR (500 MHz, DMSO-d6-373 K) δ 8.87
(d, J= 10.0 Hz, 2H), 8.83 (d, J= 5.0 Hz, 2H), 8.25 (s, 2H), 7.79 (br-t,
J=5.0Hz, 4H), 7.71 (br-t, J= 5.0 Hz, 4H), 7.34 (t, J= 10.0 Hz, 4H),
7.26 (t, J= 10.0 Hz, 4H), 13C-NMR (125 MHz, DMSO-d6-373 K) δ
164.6 (d, J = 150Hz (1J C-F)), 162.6 (d, J = 150 Hz (1J C-F)),
161.2, 155.8, 155.1, 152.9, 146.2, 138.0, 132.8, 132.7, 132.1,
132.0, 129.9, 128.2, 123.5, 116.1, 116.0, 115.8, 115.7, HRMS
(EI) m/z = 714.1916 (714.1904 calculated for C42H22F4N8).
2,9-Bis-[5,6-bis-(4-bromo-phenyl)-[1,2,4]triazin-3-yl]-[1,10]-
phenanthroline (21). IR (solution, CHCl3) cmÀ1 3037, 1586,
1
1477, 1362, 1147, 1069, 831, H-NMR (300 MHz, CDCl3) δ 9.03
(d, J= 9.0 Hz, 2H), 8.65 (d, J= 9.0 Hz, 2H), 8.07 (s, 2H), 7.88–7.81
(m, 4H), 7.69–7.58 (m, 12H), 13C-NMR (75 MHz, CDCl3) δ 160.4,
155.2, 154.6, 152.2, 145.9, 137.8, 133.4, 132.5, 132.3, 131.3,
129.9, 127.8, 126.2, 124.9, 123.0, HRMS (ESI) m/z = 954.8793
(954.8779 calculated for C42H23Br4N8 [M + H]).
2,9-Bis-[5,6-bis-(3-methoxy-phenyl)-[1,2,4]triazin-3-yl]-[1,10]
phenanthroline (22).
IR (solution, CHCl3) cmÀ1 2935, 2832,
1580, 1482, 1379, 1038, 861, 785, 1H-NMR (500 MHz, DMSO-d6-
373 K) δ 8.88 (d, J= 10.0 Hz, 2H), 8.83 (d, J= 10.0 Hz, 2H), 8.25
(s, 2H), 7.39 (t, J = 10.0 Hz, 2H), 7.35–7.17 (br-m, 10H),
7.10–7.05 (m, 4H), 3.74 (s, 6H), 3.68 (s, 6H), 13C-NMR
(125 MHz, DMSO-d6-373 K) δ 161.0, 159.2, 159.0, 156.2,
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S. Tai, N. J. Williams, and J. D. Carrick
Vol 000
[5] (a) Dam, H. H.; Reinhoudt, D. N.; Verboom, W. Chem Soc
Rev 2007, 36, 367; (b) Ekberg, C.; Fremvik, A.; Retegan, T.;
Skarnemark, G.; Foreman, M. R. S.; Hudson, M. J.; Englund, S.;
Nilsson, M. Radiochimica Acta 2008, 96, 225; (c) Kolarik, Z. Chem
Rev 2008, 108, 4208; (d) Steppert, M.; Cisařova, T.; Fanghänel, T.;
Geist, A.; Lindqvist-Reis, P.; Panak, P.; Štĕpnička, P.; Trumm, S.;
Walther, C. Inorg Chem 2012, 51, 591; (e) Lewis, F. W.; Harwood, L. M.;
Hudson, M. J.; Distler, P.; John, J.; Stamberg, K.; Nunez, A.; Galan, H.;
Espartero, A. G. Eur J Org Chem 2012, 1509; (f) Cotton, S.
Comprehensive Coordination Chemistry II; Elsevier: Oxford,
2004; Vol 3, p 93.
[6] Hill, C.; Guillaneux, D.; Berthon, L.; Madic, C. J Nucl Sci
Tech 2002, 309.
[7] Trumm, S.; Geist, A.; Panak, P. J.; Fanghanal, T. Solvent Extr
Ion Exch 2011, 29, 213.
[8] Lewis, F. W.; Harwood, L. M.; Hudson, M. J.; Drew, M. G. B.;
Desreux, J. F.; Viddick, G.; Bouslimani, N.; Modolo, G.; Wilden, A.;
Sypula, M.; Vu, T.-H.; Simonin, J.-P. J Am Chem Soc 2011,
133, 13093.
155.6, 152.8, 145.9, 137.7, 136.7, 129.6, 129.6, 129.5, 128.0,
123.3, 121.7, 121.7, 116.6, 115.4, 115.0, 55.2, 55.2, HRMS (EI)
m/z = 762.2768 (762.2703 calculated for C46H34N8O4).
Acknowledgments. Financial support for this project was provided
by a grant from the Fuel Cycle Research and Development program,
Office of Nuclear Energy, U.S. Department of Energy, and the TTU
Department of Chemistry. Support from NSF-RUI 9970016 is
gratefully acknowledged for the acquisition of the department’s
300 MHz NMR spectrometer. The authors would also like to
thank Dr. Markus W. Voehler (VU) for acquisition of NMR data
for 19 and 22. Profs. Dale D. Ensor and Janet G. Coonce (TTU)
and Dr. Laetitia H. Delmau (ORNL) are acknowledged for helpful
discussions. The University of Alabama and Dr. Qiaoli Liang
(UA) are gratefully acknowledged for acquisition of HRMS data.
REFERENCES AND NOTES
[9] (a) Laventine, D. M.; Afsar, A.; Hudson, M. J., Harwood, L. M. He-
terocycles 2012, 86, 1419; (b) Afsar, A.; Laventine, D. M.; Harwood, L. M.;
Hudson, M. J.; Geist, A. Chem Comm 2013, 49, 8534.
[10] 10 was synthesized from 5 undeÀr modified Suzuki–Miyaura
conditions with PdCl2, PPh3, CH2CHBF3 K+, Cs2CO3, THF/H2O,
90°C, 14 h, in 70% isolated yield as a green solid. Molander, G. A.;
Brown, A. R. J Org Chem 2006, 71, 9681.
[1] McKibben, J. M. Radiochimica Acta 1984, 36, 3.
[2] (a) Bremer, A.; Ruff, C. M.; Girnt, D.; Müllich, U.; Rothe, J.;
Roesky, P. W.; Panak, P. J.; Karpov, A.; Müller, T. J. J.; Denecke, M. A.;
Geist, A. Inorg Chem 2012, 51, 5199; (b) Ruff, C. M.; Müllich, U.;
Geist, A.; Panak, P. J Dalton Trans 2012, 41, 14594.
[3] Hudson, M. J.; Harwood, L. M.; Laventine, D. M.; Lewis, F. W.
Inorg Chem 2013, 52, 3414.
[11] A subsequent experiment in DMF also did not afford the
desired ligand after treatment with 1,2-bis-(4-dimethylamino-phenyl)-
[4] (a) Kolarik, Z.; Müllich, U.; Gassner, F. Solvent Extr Ion Exch
1999, 17, 1155; (b) Kolarik, Z.; Müllich, U.; Gassner, F. Solvent Extr Ion
Exch 1999, 17, 23.
ethane-1,2-dione. In both cases, the hydrazonamide
observed in the crude reaction mixture. Further optimization was
not investigated.
2
was
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DOI 10.1002/jhet