Hydrolysis and radiation stability of m-xylylene bis-diglycolamide: Synthesis and quantitative study of degradation products by HPLC-APCI +

Article abstract of DOI:10.1002/ejoc.201100443

For nuclear hydrometallurgical separation process development, it is necessary to demonstrate the stability of the extracting systems, since it is well known that radio- and hydrolytic degradation leads to undesirable effects, such as a decrease in selectivity, poorer phase separation and third-phase formation. Recently, we have developed a new family of bis-diglycolamide (bis-DGA) molecules with high distribution coefficients (D) for Eu^III over Am^III. One of these bis-DGA extractants, namely, compound 1, showed high distribution coefficients even under gamma irradiation at 1000 kGy with external ⁶⁰Co sources. We report herein a detailed account on the stability of 1 against radio- and hydrolysis. We have also identified and quantified the sub-products formed during the irradiation process. Qualitative and quantitative analyses of irradiated 1 were performed by HPLC-MS, indicating the presence of seventeen degradation compounds. All fragments (2-18) were identified and synthesized independently. To complete this study, the An ^III and Ln^III extraction properties of these fragments were assessed under the same experimental conditions as those used to evaluate the An^III and Ln^III extraction by irradiated 1. Despite the significance of a decrease in the concentration of 1, Am/Eu D values are still quite high. This means that at least some degradation products also act as efficient extractants. It is relevant to remark that two of the major degradation products (compounds 3 and 11) are stable to radiation and showed high D values for Am^III and Eu^III extraction. Compound 1, an extractant of Am^III and Eu^III from nuclear waste, was irradiated with γ irradiation at 1000 kGy with external ⁶⁰Co sources, resulting in 17 subproducts. These compounds were synthesized and qualitative and quantitative analyses of irradiated 1 were performed. Two of the major degradation products were stable to radiation and showed high D values for Am^III and Eu^III extraction. Copyright

Full text of DOI:10.1002/ejoc.201100443

FULL PAPER
DOI: 10.1002/ejoc.201100443
Hydrolysis and Radiation Stability of m-Xylylene Bis-diglycolamide: Synthesis
and Quantitative Study of Degradation Products by HPLC–APCI+
Hitos Galán,[a] María Teresa Murillo,[a] Rosa Sedano,[b] Ana Núñez,[c] Javier de Mendoza,[d]
Amparo González-Espartero,[c] and Pilar Prados*[a]
Keywords: Bis-diglycolamides / Lanthanides / Actinides / Radiochemistry / Nuclear waste
For nuclear hydrometallurgical separation process develop-
ment, it is necessary to demonstrate the stability of the ex-
analyses of irradiated 1 were performed by HPLC–MS, indi-
cating the presence of seventeen degradation compounds.
tracting systems, since it is well known that radio- and hydro- All fragments (2–18) were identified and synthesized inde-
lytic degradation leads to undesirable effects, such as a de-
crease in selectivity, poorer phase separation and third-phase
formation. Recently, we have developed a new family of bis-
diglycolamide (bis-DGA) molecules with high distribution
coefficients (D) for EuIII over AmIII. One of these bis-DGA
extractants, namely, compound 1, showed high distribution
coefficients even under gamma irradiation at 1000 kGy with
external 60Co sources. We report herein a detailed account
on the stability of 1 against radio- and hydrolysis. We have
also identified and quantified the sub-products formed dur-
ing the irradiation process. Qualitative and quantitative
pendently. To complete this study, the AnIII and LnIII extrac-
tion properties of these fragments were assessed under the
same experimental conditions as those used to evaluate the
AnIII and LnIII extraction by irradiated 1. Despite the signifi-
cance of a decrease in the concentration of 1, Am/Eu D val-
ues are still quite high. This means that at least some degra-
dation products also act as efficient extractants. It is relevant
to remark that two of the major degradation products (com-
pounds 3 and 11) are stable to radiation and showed high D
values for AmIII and EuIII extraction.
tion coefficients (D) for AnIII and LnIII, but also to demon-
strate the stability of the extractant. It is well known that
radio- and hydrolytic degradation during the extraction
process leads to undesirable effects, such as a decrease of
selectivity, poorer phase separation and third-phase forma-
tion. Most often, the new species generated have extracting
properties that markedly differ from those of the original
ligands.[4] Although several technologies have been used to
determine the degradation process,[5] a study to assess the
structure of these compounds has not been performed yet.
Previously, we have described a family of bis-DGA ex-
tractants containing either rigid spacers or flexible alkyl
chains that co-extract AnIII and LnIII. Specifically, com-
pound 1 with a m-xylylene spacer between the di-
glycolamide subunits showed higher selectivity than simple
diglycolamides for EuIII over AmIII extraction from 3 m
solutions of nitric acid in a mixture (95:5 vol.-%) of hydro-
genated tetrapropylene (HTP)/1-octanol (Figure 1).[6]
To evaluate the effect of hydrolysis and extended irradia-
tion on the distribution coefficients, we have studied the
degradation products of 1 by HPLC–APCI+ and fragments
2–18 were identified (Figure 1). These compounds have
been synthesized and their extraction properties have been
assessed separately. Finally, quantification of 1 and its de-
gradation products has been performed by HPLC–APCI+
after irradiation of 1 under different experimental condi-
tions and pretreatments of the organic solutions.
Introduction
One of the strategies used for spent nuclear fuel manage-
ment is the hydrometallurgical treatment of high level-li-
quid waste (HLLW), coming from the PUREX process, in
two steps.[1] The first one consists of co-extraction of tri-
valent actinides (AnIII) and trivalent lanthanides (LnIII) by
the DIAMEX process (DIAMide EXtraction), which re-
moves part of the nitric acid and most of the fission prod-
ucts.[2] The second step, called the SANEX process (Selec-
tive ActiNide EXtraction), separates the AnIII/LnIII
group.[3] In these processes, organic ligands are used as cat-
ion extractants in apolar solvents. Since the system is in
contact with highly radioactive solutions, for process devel-
opment it is not only necessary to demonstrate high extrac-
[a] Departamento de Química Orgánica (C-I),
Facultad de Ciencias, Universidad Autónoma de Madrid
Carretera de Colmenar Viejo 15.3 km, 28049 Madrid, Spain
Fax: +34-91-4973966
E-mail: pilar.prados@uam.es
[b] Servicio Interdepartamental de Investigación (SIDI),
Facultad de Ciencias, Universidad Autónoma de Madrid
Carretera de Colmenar Viejo 15.3 km, 28049 Madrid, Spain
[c] Centro de Investigaciones Energéticas,
Medioambientales y Tecnológicas (CIEMAT),
Avda. Complutense 22, 28040 Madrid, Spain
[d] Institute of Chemical Research of Catalonia (ICIQ),
43007 Tarragona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100443.
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P. Prados et al.
FULL PAPER
Figure 1. Radiolytic degradation products of 1.
chloride with amine 2 in the presence of triethylamine
(Scheme 1).
Results and Discussion
Similar procedures were used to obtain compounds 3, 15
and 16 (Scheme 2).
Synthesis
Compound 1 was prepared according to the procedure
previously described by us.[6] Compound 2 was obtained
from commercially available tert-butyl 3-(aminomethyl)-
benzylcarbamate in two steps by coupling with carboxylic
acid 4[7] followed by hydrolysis of the tert-butoxycabonyl
group (Scheme 1).
Carboxylic acid 19 was prepared from diglycolic anhy-
dride by following the general procedure.[6] Compounds 13
and 14 were synthesized by activation of the corresponding
Compound 9 was obtained by basic hydrolysis of ester
22, which was prepared from methyl [3-(methoxycarbonyl)-
phenyl]methylammonium chloride by coupling with carb-
oxylic acid 4[7] (Scheme 3).
Compound 8 was prepared by coupling of compound 4[7]
with 3-(aminomethyl)benzamide, whereas aldehyde 10 was
synthesized from amine 23[8] by coupling with carboxylic
acid 4[7] followed by hydrolysis of the acetal (Scheme 4).
Ester 5 was prepared by O-alkylation of carboxylic acid
carboxylic acids {19 and 2-[(carbamoyl)methoxy]acetic 4,[7] whereas amide 11 was obtained in two steps from 2-
acid} with EDC·HCl followed by addition of amine 2, (benzyloxy)acetic acid followed by hydrogenolysis of amide
whereas compound 7 was obtained by reaction of acetyl 24 (Scheme 5).
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Hydrolysis and Radiation Stability of a m-Xylylene Bis-diglycolamide
Scheme 1. Synthesis of compounds 2, 7, 13 and 14. TFA = trifluoroacetic acid, EDC = NЈ-(3-dimethylaminopropyl)-N-ethylcarbodiimide.
Scheme 2. Synthesis of compounds 3, 15 and 16.
Scheme 4. Synthesis of compounds 8 and 10.
Scheme 3. Synthesis of compound 9.
The synthesis of 17 was carried out quantitatively from
dioctylamine by using 1H-benzo[d][1,2,3]triazole-1-carbal- obtained from 2-[(carbamoyl)methoxy]acetic acid and di-
dehyde as the acylation agent. Finally, compound 18 was octylamine in the presence of EDC·HCl. (Scheme 6).
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Figure 2. HPLC chromatogram of 1 (0.1 m) in dodecane/1-octanol
(95:5 vol.-%) after 42 d in contact with 3 m HNO3. * Methyl ester
of compound 4, formed during the analytical process.
Scheme 5. Synthesis of compounds 5 and 11.
Scheme 6. Synthesis of compounds 17 and 18.
Stability of 1 towards Hydrolysis
Hydrolysis experiments were performed at 25 °C, using a
0.1 m solution of 1[6] in a mixture of dodecane/1-octanol
(95:5 vol.-%), in contact for 42 days with a 3 m solution of
nitric acid. Samples were analyzed qualitatively by HPLC–
APCI+ after 7, 15, 36, and 42 days. Structures of com-
pounds 2, 5 and the methyl ester of 4 were established from
the mass spectra of all peaks of the chromatograms, show-
ing in all cases a similar qualitative composition (Figure 2).
As expected, hydrolysis takes place on the amide group and
compound 5 was formed from 4 due to the presence of 1-
octanol in the sample. Quantitative analysis of 1 through-
Figure 3. Stability of 1 towards hydrolysis. Organic phase: 1 (0.1 m)
in dodecane/1-octanol (95:5 vol.-%). Aqueous phase: 152Eu and
241Am tracers in 3 m HNO3. ᭿: Am, ᮀ: Eu.
Stability of 1 towards Radiolysis
Initially, the stability of 1 against radiolysis was deter-
out the hydrolysis was performed by HPLC–APCI+; 18.6% mined in three solvents commonly employed in hydrometal-
of 1 remained after 42 days of contact time. This result lurgical processes for actinide partitioning: 1-octanol and
is in contrast with N,N,NЈ,NЈ-tetraoctyldiglycolamide dodecane/1-octanol (90:10 and 95:5 vol.-%). Solutions of 1
(TODGA), which remains stable after four weeks in contact (0.1 m) were pre-equilibrated with 3 m nitric acid and sub-
with 3 m nitric acid.[9] The solvents used in both cases jus- sequently irradiated at 250, 500, 750 and 1000 kGy inte-
tify the different behaviour observed, since for 1 the pres- grated doses (3.7 kGyhϪ1 dose rate) with external 60Co
ence of 1-octanol facilitates hydrolysis, whereas for sources. Non-irradiated samples of 1, under the same con-
TODGA an apolar solvent, dodecane, was employed.
ditions, were stored as references for aging control. Finally,
AmIII and EuIII extraction was performed by using the the distribution coefficients for Am/Eu were determined
organic solutions obtained after the period studied. A (Table 1).
higher decrease in the distribution coefficients of Am (DAm
= 226; 42 days) than for Eu (DEu = 682; 42 d) were obtained tribution coefficients decreased as the integrated doses in-
(Figure 3, Table 1, dose 0). creased. After irradiation at 1000 kGy, samples still showed
The extraction experiments showed that the Am/Eu dis-
Despite the significant decrease in the concentration of high distribution coefficients for AmIII and EuIII, in agree-
1, Am/Eu D values were still quite high. This means that ment with TODGA stability under the same experimental
at least some of the degradation products act as efficient conditions [1000 kGy, dodecane/1-octanol (95:5 vol.-%),
extractants, compounds 2, 4 and 5 are most likely because DAm = 121 and DEu = 458; see the Supporting Infor-
they possess diglycolamide groups that could coordinate to mation]. Nevertheless, these values were lower when 1-oc-
the cation.
tanol was used.
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Hydrolysis and Radiation Stability of a m-Xylylene Bis-diglycolamide
Table 1. Distribution coefficients of 1 irradiated with different inte- with previously identified structures. It can be concluded
grated doses.[a]
that radiolysis takes place mainly at the amide (compounds
2 and 18) and ether functions (compounds 3, 7, 15 and 16).
In addition, benzylic oxidation (compounds 8, 9 and 10)
and octyl chains breaking (compounds 13 and 14) were also
produced.
Dose [kGy] Solvent [vol.-%]
1-octanol
DAm
DEu
22
374
600
10
327
595
7
–
361
5
255
233
3.5
156
180
123
Ͼ1000
Ͼ1000
52
905
880
29
–
996
17
713
885
13
652
780
0
dodecane/1-octanol (90:10)
dodecane/1-octanol (95:5)
1-octanol
Distribution coefficients of AmIII and EuIII for each frag-
ment were determined. Compounds 2, 3, 8, 9, 10, 14 and
18, which still have diglycolamide groups in their structures,
showed high values for DAm and DEu (Table 2). Unfortu-
nately, during extraction a third phase was observed for
compounds 7 and 13, displaying high distribution coeffi-
cients.
250
500
750
1000
dodecane/1-octanol (90:10)
dodecane/1-octanol (95:5)
1-octanol
dodecane/1-octanol (90:10)
dodecane/1-octanol (95:5)
1-octanol
dodecane/1-octanol (90:10)
dodecane/1-octanol (95:5)
1-octanol
dodecane/1-octanol (90:10)
dodecane/1-octanol (95:5)
Table 2. Distribution coefficients of AmIII and EuIII for compounds
1–18.[a]
Compound
DAm
DEu
Compound
DAm
DEu
[a] Organic phase: 1 (0.1 m) in different solvents. Aqueous phase:
241Am and 152Eu tracers in 3 m HNO3.
1
2
600
125
313
Ͼ1000 1 irradiated
180
1.5
780
1.6
526
433
0.18
11
12
13
14
15
16
17
18
3
Ͻ0.001 Ͻ0.001
Qualitative analysis of the irradiated samples (1000 kGy)
was performed by HPLC–APCI+ under different condi-
tions, without solvent (raw), or dissolved in 1-octanol or
dodecane/1-octanol (95:5 vol.-%), previously pre-equili-
brated with 3 m HNO3. The HPLC chromatograms showed
the presence of at least 17 degradation compounds, the
structures of which were assigned from the mass spectra (2–
18, Figure 1).
[b]
[b]
4
0.071
5
Ͻ0.001 Ͻ0.001
262
0.055
0.419
Ͻ0.001 Ͻ0.001
74 277
245
0.102
0.668
[b]
[b]
7
8
232
50
30
Ͼ1000
300
150
9
10
[a] Organic phase: 0.1 m of each compound in a mixture of do-
decane/1-octanol (95:5 vol.-%). Aqueous phase: 241Am and 152Eu
tracers in 3 m HNO3. [b] A third phase was observed.
The relative amounts of the signals varied depending on
the experimental conditions (Figure 4). The results show a
significant decrease in the signal of compound 1 when a
solvent was employed; this was more significant when its
polarity increased. The sample of 1 without solvent dis-
played the highest resistance to radiation, in good agree-
ment with the results obtained for TODGA.[9]
To evaluate the effect of nitric acid during the irradiation
process, quantitative analysis of irradiated samples of 1
(0.1 m) at 500 and 1000 kGy (2.6 kGyhϪ1 dose rate) was
carried out in dodecane/1-octanol (95:5 vol.-%) with and
without pre-equilibration. Initially, calibration curves were
performed with 0.01, 0.1, 0.5 and 1 mm for 1 and for each
synthesized fragment (2–18). Known concentrations of each
compound and mixtures of all of them were employed for
calibration, and the results are in agreement with those for
the initial concentration (see the Supporting Information).
Irradiated samples of 1 and compounds 2–18 were diluted
200 and 100 times with MeOH/1-octanol (90:10 vol-%) and
data were collected in triplicate, and the final concentra-
tions were calculated as the average of the three measure-
ments. Quantitative analysis showed a higher final concen-
tration of 1 in the presence of nitric acid (1000 kGy pre-
equilibrated sample: 13.6 mm, without pre-equilibration:
2.2 mm). Although nitric acid causes partial hydrolysis of 1,
it seems to play a protective role during irradiation. This
result is in contrast with others previously pub-
lished.[10a,10c,10d] To the best of our knowledge, only one
similar behaviour has been reported.[10b]
Figure 4. HPLC chromatograms of 1 after 1000 kGy of integrated
dose. * Methyl ester of compound 4, formed during the analytical
process.
Surprisingly, comparison of data at 500 and 1000 kGy
reveals that fragments 3 and 11 do not degrade with in-
As in the hydrolysis study, the high distribution coeffi- creasing the irradiation dose (Figure 5).
cients found after irradiation indicated that some of the de-
Additionally, an experiment has been carried with com-
gradation products also took part in the extraction. To pounds 3 and 11 irradiated separately. Qualitative analysis
demonstrate this, fragments 2–18 were synthesized and ana- by HPLC–MS of the irradiated samples revealed that nei-
lyzed by HPLC–APCI+ (SCAN method) to confirm that ther compound had been degraded by radiolysis, especially
their mass spectra and retention times were in agreement compound 3 (Figure 6). This is relevant because 3 shows
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P. Prados et al.
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which was produced by cleavage of the ether group. It is
worth emphasizing that compound 11, also arising from
cleavage of the ether group, was obtained in similar concen-
trations under all studied conditions.
Figure 5. Concentration of 1 and fragments 2–18 after irradiation
of 1 (0.1 m) samples in dodecane/1-octanol (95:5 vol.-%), pre-equili-
brated with 3 m HNO3. Black: 1000 kGy, grey: 500 kGy.
Figure 7. Concentration of 1 and fragments 2–18 after irradiation
up to 1000 kGy of 1 (0.1 m) samples in (95:5 vol.-%) dodecane/1-
octanol under several conditions. Black: raw, lines: pre-equili-
brated, grey: no pre-equilibrated, white: in contact.
high distribution coefficients for Am and Eu, in addition to
being stable to radiation. This structure could be considered
as a model to develop a new series of extractants with en-
hanced resistance towards irradiation. This behaviour could
be due to the formation of an enol in the acidic environ-
ment, which in turn would be stabilized by formation of an
intramolecular hydrogen bond.
Conclusions
This study showed that Am/Eu D values of 1 in do-
decane/1-octanol (95:5 vol.-%) pre-equilibrated with 3 m ni-
tric acid were still quite high, even after irradiation up to
1000 kGy, despite the significant decrease in the concentra-
tion of 1. This meant that at least some of the degradation
products also acted as efficient extractants. The presence of
nitric acid during the irradiation procedure prevented fur-
ther degradation of 1. For the first time, the identified hy-
drolytic and radiolytic degradation fragments have also
been synthesized, allowing their extraction properties to be
studied and their concentration after irradiation to be
quantified. It should also be noted that two of the major
degradation products in the mixture (compounds 3 and 11)
were stable to irradiation, showing high capacity to extract
AmIII and EuIII. Compound 3 could be considered as a
model to develop a new series of extractants with enhanced
resistance towards irradiation.
Figure 6. HPLC chromatograms of 3 and 11 in dodecane/1-octanol
(95:5 vol.-%), pre-equilibrated with 3 m HNO3, after 1000 kGy of
integrated dose at 9.5 kGyhϪ1
.
To simulate the irradiation conditions for a counter-cur-
rent extraction process, we repeated the quantification study
up to 1000 kGy (3.1 kGyhϪ1 dose rate) in only one step,
expanding the range of experimental conditions. These ex-
perimental conditions were chosen to compare samples
Experimental Section
General Methods: Solvents were freshly distilled and dried before
with and without solvent [dodecane/1-octanol (95:5 vol.-%), use by standard methods. All chemicals were used as purchased.
The NMR spectroscopy experiments (1H,13C{1H}) were carried
out at 500 (125), 400 (100) or 300 (75) MHz and reported chemical
HTP/1-octanol (95:5 vol.-%)], different treatments (with
and without pre-equilibration with 3 m HNO3, and in con-
shifts (δ) are externally referenced to the residual solvent signal
tact with 3 m HNO3).
and are given in ppm. Mass spectra were recorded on a REFLEX
As expected, no significant differences were found be-
spectrometer by MALDI-TOF, on a VG Autospec spectrometer by
tween the solvents chosen but an important decrease in the
FAB+ or on Waters LCT Premier spectrometer for ESI methods.
concentration of 1 was observed. Figure 7 summarizes the
results. An increase in the concentration of fragments 8, 9,
and 18 was produced when a sample without solvent was
irradiated (raw). For a sample that had not been pre-equili-
Elemental analyses were performed on a LECO CHN 932 micro-
analyser and reported as percentages. TLC was performed on silica
gel Alugram Sil G/UV254 (Macherey–Nagel) sheets. HTP was used
in AREVA’s Reprocessing Plant. N,N-Dioctylacetamide (12)[11] was
brated, a higher concentration of fragment 12 was obtained, obtained according to the procedure described.
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Hydrolysis and Radiation Stability of a m-Xylylene Bis-diglycolamide
General Procedure to Obtain Amides: A solution of the correspond-
ing amine (1 equiv.), in dry CH2Cl2 or DMF was added to a solu-
tion of corresponding acid (1.2 equiv., 0.4 m) and EDC·HCl
(1.2 equiv.), in dry CH2Cl2 and under argon atmosphere, and
stirred for some time at room temp. A solution of 1 m HCl was
added and the mixture was extracted with CH2Cl2. The organic
phase was washed with a solution of 1 m HCl and water, and finally
dried (MgSO4). The solvent was removed under reduced pressure
and the residue was purified by column chromatography.
(533.74): calcd. C 67.51, H 9.63, N 7.87; found C 67.32, H 9.64, N
7.51.
3-({2-[2-(Dioctylamino)-2-oxoethoxy]acetamido}methyl)benzamide
(8): Prepared by coupling of 3-(aminomethyl)benzamide (95.0 mg,
0.63 mmol) and Et3N (0.09 mL, 0.63 mmol) in dry DMF (2.0 mL)
with carboxylic acid 4[7] (271.4 mg, 0.76 mmol) and EDC·HCl
(145.5 mg, 0.76 mmol) in dry CH2Cl2 (3.0 mL). The mixture was
stirred for 24 h and the solvent was removed under reduced pres-
sure. Purification by column chromatography [using a reservoir
Bond Elut (Varian) of 10 mL, with 3 cm silica gel, 95:5 CH2Cl2/
MeOH] gave 8 (212.0 mg, 68 %) as a yellow oil. 1H NMR
2-{2-[3-(Aminomethyl)benzylamino]-2-oxoethoxy}-N,N-dioctyleth-
anamide (2): Prepared by coupling tert-butyl 3-(aminomethyl)benz-
ylcarbamate (1.42 mL, 6.35 mmol) in dry CH2Cl2 (5.0 mL) with
carboxylic acid 4[7] (2.7 g, 7.62 mmol) and EDC·HCl (1.46 g,
7.62 mmol) in dry CH2Cl2 (20.0 mL). The mixture was stirred for
24 h. The organic solution was washed with citric acid and brine.
Purification by flash column chromatography (silica gel, 96:4
CH2Cl2/MeOH) gave tert-butyl 3-({2-[2-(dioctylamino)-2-oxo-
ethoxy]acetamido}methyl)benzylcarbamate as a yellow oil (1.50 g,
41%). This oil was dissolved in CH2Cl2 (20.0 mL) and trifluoro-
acetic acid (0.99 mL) was added. The solution was stirred at room
temp. for 2 h and the solvent was removed under reduced pressure.
The residue was dissolved in CH2Cl2, and the organic phase was
washed with NaHCO3 and water, and finally dried (MgSO4) to give
2 (1.21 g, 98%) as a yellow oil. 1H NMR (500 MHz, CDCl3, 25 °C):
3
(300 MHz, CDCl3, 25 °C): δ = 8.17 (t, JH,H = 6.3 Hz, 1 H, NH),
3
7.83 (s, 1 H, ArH), 7.76 (d, JH,H = 7.5 Hz, 1 H, ArH), 7.44–7.28
(m, 2 H, ArH), 7.09 (br. s, 1 H, NH), 6.11 (br. s, 1 H, NH), 4.51
(d, 3JH,H = 6.3 Hz, 2 H, CH2N), 4.24 (s, 2 H, CH2O), 4.10 (s, 2 H,
CH2O), 3.30–3.16 (m, 2 H, CH2N), 3.11–2.98 (m, 2 H, CH2N),
1.58–1.37 (m, 4 H, CH2), 1.36–1.12 (m, 20 H, CH2), 0.90–0.76 (m,
6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, DEPT, 25 °C): δ =
169.8, 169.4, 168.3 (CO), 138.5, 133.8 (Ar), 130.9, 128.7, 126.8,
125.9 (ArH), 71.8, 69.4 (CH2O), 46.9, 46.3, 42.4 (CH2N), 31.8,
29.7, 29.3, 29.20, 29.16, 29.1, 28.9, 27.5, 27.0, 26.8, 22.58, 22.56
(CH2), 14.0 (CH3) ppm. MS (FAB+, m-NBA): m/z (%) = 490.3
(100) [M + H]+. C28H47N3O4 (489.69): calcd. C 68.68, H 9.67, N
8.58; found C 68.61, H 9.52, N 8.29.
3
δ = 8.00 (br. s, 1 H, NH), 7.29–7.25 (m, 2 H, ArH), 7.18 (d, JH,H
2-[2-(3-Formylbenzylamino)-2-oxoethoxy]-N,N-dioctylacetamide
(10): Prepared by coupling of 23[8] (2.21 g, 12.35 mmol), carboxylic
acid 4[7] (3.40 g, 14.83 mmol) and EDC·HCl (2.84 g, 14.82 mmol)
in dry CH2Cl2 (100.0 mL). The mixture was stirred for 24 h. Purifi-
cation by column chromatography [using a reservoir Bond Elut
(Varian) of 10 mL, with 3 cm silica gel, 95:5 CH2Cl2/MeOH] gave
2-{2-[3-(1,3-dioxolan-2-yl)benzylamino]-2-oxoethoxy}-N,N-di-
octylacetamide as a yellow oil (3.91 g, 61%). HCl (0.1 m, 2.0 mL)
was added to a solution of this oil (1.05 g, 2.02 mmol) in CH3CN
(35.0 mL) and the mixture was stirred for 24 h at room temp. The
solvent was removed under reduced pressure and the residue was
partitioned in CH2Cl2/H2O. The organic phase was washed with
NaHCO3 and H2O and finally dried (MgSO4). The solvent was
removed under reduced pressure to give 10 (932.0 mg, 97%) as a
3
= 7.5 Hz, 2 H, ArH), 4.48 (d, JH,H = 6.0 Hz, 2 H, CH2N), 4.21
(s, 2 H, OCH2), 4.11 (s, 2 H, OCH2), 3.84 (s, 2 H, CH2N), 3.26 (t,
3JH,H = 7.6 Hz, 2 H, CH2N), 3.05 (t, 3JH,H = 7.7 Hz, 2 H, CH2N),
1.87 (br. s, 2 H, NH2), 1.55–1.43 (m, 4 H, CH2), 1.32–1.19 (m, 20
H, CH2), 0.90–0.83 (m, 6 H, CH3) ppm. 13C NMR (125 MHz,
CDCl3, DEPT, 25 °C): δ = 169.5, 168.1 (CO), 138.6 (Ar), 128.8,
126.5, 126.3, 126.2 (ArH), 71.9, 69.5 (CH2O), 46.8, 46.3, 46.2, 42.8
(CH2N), 31.83, 31.76, 29.4, 29.3, 29.28, 29.25, 29.20, 28.9, 27.6,
27.0, 26.9, 22.7, 22.6 (CH2), 14.1 (CH3) ppm. MS MALDI-TOF
(dithranol): m/z (%) = 476.3 (100) [M + H]+. C28H49N3O3·1/
2MeOH·1/2CH2Cl2 (534.20): calcd. C 65.20, H 9.81, N 7.87; found
C 65.40, H 9.37, N 7.26.
2-(2-{3-[(2-Hydroxyacetamido)methyl]benzylamino}-2-oxoethoxy)-
N,N-dioctylacetamide (3): Prepared by coupling 20[12] (350.0 mg,
1.23 mmol) in dry CH2Cl2 (5.0 mL) with carboxylic acid 4[7]
(661.0 mg, 1.85 mmol) and EDC·HCl (355.0 mg, 1.85 mmol) in dry
CH2Cl2 (5.0 mL). The mixture was stirred for 48 h to give 2-[2-(3-
{[2-(benzyloxy)acetamido]methyl}benzylamino)-2-oxoethoxy]-
N,N-dioctylacetamide (417.0 mg, 54%). Then, a hydrogen flow was
passed through a solution of this compound (417.0 mg, 0.67 mmol)
and 10% Pd/C (catalytic amount) in EtOH (25.0 mL) for 30 min.
The mixture was stirred under a hydrogen atmosphere at room
temp. for 12 h. The mixture was filtered through Celite and the
solvent was removed under reduced pressure. The residue was puri-
fied by column chromatography (silica gel, 97:3 Ǟ 95:5 CH2Cl2/
MeOH) to give 3 (220.0 mg, 63 %) as a yellow oil. 1H NMR
1
yellow oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 9.92 (s, 1 H,
3
CHO), 8.46 (br. s, 1 H, NH), 7.76 (s, 1 H, ArH), 7.69 (d, JH,H
=
3
7.6 Hz, 1 H, ArH), 7.52 (d, JH,H = 7.9 Hz, 1 H, ArH), 7.40 (t,
3JH,H = 7.6 Hz, 1 H, ArH), 4.50 (d, JH,H = 6.0 Hz, 2 H, CH2N),
3
4.19 (s, 2 H, CH2O), 4.08 (s, 2 H, CH2O), 3.27–3.14 (m, 2 H,
CH2N), 3.06–2.92 (m, 2 H, CH2N), 1.52–1.35 (m, 4 H, CH2), 1.31–
1.05 (m, 20 H, CH2), 0.86–0.70 (m, 6 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, DEPT, 25 °C): δ = 192.2 (CHO), 170.0, 168.3
(CO), 139.7, 136.7 (Ar), 133.9, 129.2, 129.0, 128.4 (ArH), 72.1, 69.7
(CH2O), 46.8, 46.3, 42.3 (CH2N), 31.8, 29.3, 29.20, 29.16, 29.12,
28.9, 27.5, 27.0, 26.8, 22.6 (CH2), 14.1 (CH3) ppm. MS (FAB+, m-
NBA): m/z (%) = 475.3 (100%) [M + H]+. C28H46N2O4 (474.68):
calcd. C 70.85, H 9.77, N 5.90; found: C, 69.98, H, 9.81; N, 5.61.
(500 MHz, CDCl3, 25 °C): δ = 7.99 (br. s, 1 H, NH), 7.28–7.15 (m, N,N-Dioctyl-2-{2-[3-({2-[2-(octylamino)-2-oxoethoxy]acetamido}-
3
4 H, ArH), 7.12 (br. s, 1 H, NH), 4.46 (d, JH,H = 6.0 Hz, 4 H,
methyl) benzylamino]-2-oxoethoxy}acetamide (13): Prepared by cou-
CH2N), 4.37 (br. s, 1 H, OH), 4.21 (s, 2 H, CH2O), 4.09 (s, 2 H, pling of amine 2 (200.0 mg, 0.42 mmol) in dry CH2Cl2 (5.0 mL)
CH2O), 4.07 (s, 2 H, CH2OH), 3.32–3.23 (m, 2 H, CH2N), 3.11– with carboxylic acid 19 (155.0 mg, 0.63 mmol) and EDC·HCl
3.03 (m, 2 H, CH2N), 1.78 (br. s, 1 H, OH), 1.58–1.42 (m, 4 H, (121.0 mg, 0.63 mmol) in dry CH2Cl2 (5.0 mL). The mixture was
CH2), 1.35–1.17 (m, 20 H, CH2), 0.92–0.83 (m, 6 H, CH3) ppm.
stirred for 24 h. Purification by column chromatography (silica gel,
1
13C NMR (125 MHz, CDCl3, DEPT, 25 °C): δ = 172.2, 169.3, 98:2 CH2Cl2/MeOH) gave 13 (217.0 mg, 73%) as a yellow oil. H
168.1 (CO), 138.7, 138.5 (Ar), 128.7, 126.8, 126.7, 126.0 (ArH), NMR (300 MHz, CDCl3, 25 °C): δ = 8.16 (br. s, 1 H, NH), 7.33–
71.3, 70.0, 62.2 (CH2O), 46.8, 46.3, 42.5 (CH2N), 31.7, 31.6, 29.3,
29.13, 29.07, 28.8, 27.5, 26.9, 26.8 (CH2), 14.0 (CH3) ppm. MS 4.51 (d, JH,H = 5.9 Hz, 4 H, CH2N), 4.27 (s, 2 H, CH2O), 4.15 (s,
(FAB+, m-NBA): m/z (%) = 534.4 (100) [M + H]+. C30H51N3O5
2 H, CH2O), 4.12 (s, 2 H, CH2O), 4.07 (s, 2 H, CH2O), 3.40–3.25
7.15 (m, 4 H, ArH), 6.92 (br. s, 1 H, NH), 6.64 (br. s, 1 H, NH),
3
Eur. J. Org. Chem. 2011, 3959–3969
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3965

P. Prados et al.
FULL PAPER
(m, 4 H, CH2N), 3.20–3.15 (m, 2 H, CH2N), 1.60–1.40 (m, 6 H, (CH2), 13.7 (CH3) ppm. MS (FAB+, m-NBA): m/z (%) = 464.2 (17)
CH2), 1.39–1.15 (m, 30 H, CH2), 0.94–0.82 (m, 9 H, CH3) ppm.
[M + H]+, 408 (18) [M+ – C4H8], 364 (8) [408 – CO2], 307 (19)
13C NMR (75 MHz, CDCl3, DEPT, 25 °C): δ = 169.7, 168.6, 168.4,
[M+ – 157], 57 (100) [C4H8]+. C25H41N3O5 (463.61): calcd. C 64.77,
168.2 (CO), 138.9, 138.4 (Ar), 129.0, 126.9, 126.8, 126.7 (ArH), H 8.91, N 9.06; found C 64.47, H 8.85, N 8.91.
71.7, 71.14, 71.06, 69.4 (CH2O), 46.8, 46.2, 42.8, 42.6 (CH2N), 39.1,
2-(Benzyloxy)-N,N-dioctylacetamide (24): Prepared by coupling of
31.8, 31.7, 29.6, 29.3, 29.23, 29.19, 29.15, 28.9, 27.6, 27.0, 26.94,
26.85, 22.61, 22.58 (CH2), 14.1 (CH3) ppm. MS (FAB+, m-NBA):
m/z (%) = 703.4 (100) [M + H]+. C40H70N4O6·H2O (721.07): calcd.
C 66.63, H 10.07, N 7.77; found C 66.75, H 9.84, N 8.07.
N,N-dioctylamine (0.45 mL, 1.50 mmol), 2-(benzyloxy)acetic acid
(250.0 mg, 1.50 mmol) and EDC·HCl (317.1 mg, 1.65 mmol) in dry
CH2Cl2 (15.0 mL). The mixture was stirred for 24 h. Then, a solu-
tion 10% of citric acid was added and the mixture was extracted
with CH2Cl2. The organic phase was washed with brine and water
and finally dried (Na2SO4). The solvent was removed under re-
2-[2-(3-{[2-(2-Amino-2-oxoethoxy)acetamido]methyl}benzylamino)-
2-oxoethoxy]-N,N-dioctylacetamide (14): Prepared by coupling of
amine 2 (200.0 mg, 0.42 mmol), 2-[(carbamoyl)methoxy]acetic acid duced pressure and the residue was triturated in hexane to give 24
(67.2 mg, 0.51 mmol) and EDC·HCl (96.7 mg, 0.51 mmol) in dry
DMF (2.5 mL). The mixture was stirred for 72 h. Purification by
column chromatography [using a reservoir Bond Elut (Varian) of
(378.2 mg, 65 %) as a yellow oil. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.44–7.27 (m, 5 H, ArH), 4.65 (s, 2 H, CH2Ar), 4.18 (s,
2 H, CH2CO), 3.41–3.28 (m, 2 H, CH2N), 3.26–3.15 (m, 2 H,
10 mL, with 3 cm silica gel, 95:5 CH2Cl2/MeOH] gave 14 CH2N), 1.64–1.45 (m, 4 H, CH2), 1.40–1.16 (m, 20 H, CH2), 0.96–
(175.0 mg, 70%) as yellow oil. 1H NMR (300 MHz, CDCl3, 25 °C):
0.83 (m, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, DEPT,
δ = 8.18 (br. s, 1 H, NH), 7.62 (br. s, 1 H, NH), 7.25–7.02 (m, 5
25 °C): δ = 168.6 (CO), 137.6 (Ar), 128.4, 128.1, 127.8 (ArH), 73.2
H, ArH, NH), 6.10 (br. s, 1 H, NH), 4.45–4.32 (m, 4 H, CH2N), (OCH2Ar), 69.0 (CH2CO), 47.1, 45.7 (CH2N), 31.81, 31.75, 29.4,
4.20 (s, 2 H, CH2O), 4.04 (s, 2 H, CH2O), 3.98 (s, 2 H, CH2O), 29.28, 29.25, 29.2, 29.0, 27.6, 27.1, 26.8, 22.64, 22.61 (CH2), 14.1
3.89 (s, 2 H, CH2O), 3.31–3.17 (m, 2 H, CH2N), 3.10–2.97 (m, 2
H, CH2N), 1.58–1.40 (m, 4 H, CH2), 1.36–1.12 (m, 20 H, CH2),
(CH3) ppm. MS (FAB+, m-NBA): m/z (%) = 390.3 (100) [M +
H]+. C25H43NO2 (389.61): calcd. C 77.07, H 11.12, N 3.60; found
0.94–0.78 (m, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, DEPT, C 77.04, H 11.03, N 3.77.
25 °C): δ = 171.7, 169.9, 168.8, 168.3 (CO), 138.8, 138.5 (Ar), 128.8,
Octyl 2-[2-(dioctylamino)-2-oxoethoxy]acetate (5): 1-Iodooctane
126.72, 126.65 (ArH), 71.6, 70.9, 70.5, 69.4 (CH2O), 46.8, 46.3,
42.7 (CH2N), 31.8, 31.7, 29.23, 29.15, 28.9, 27.6, 27.0, 26.9, 22.59,
22.57 (CH2), 14.0 (CH3) ppm. MS (FAB+, m-NBA): m/z (%) =
591.2 (100) [M + H]+. Purity by HPLC–MS 81.9%.
(0.22 mL, 1.23 mmol) was added to a mixture of compound 4[7]
(400.0 mg, 1.12 mmol) and Cs2CO3 (401.0 mg, 1.23 mmol) in dry
DMF (12.0 mL) under argon atmosphere. The mixture was stirred
at room temp. for 24 h (TLC 98:2 CH2Cl2/MeOH). Finally, 1 m
HCl and H2O were added and the solution was stirred for 20 min.
2-(2-Amino-2-oxoethoxy)-N,N-dioctylacetamide (18): Prepared by
coupling of N,N-dioctylamine (1.36 mL, 4.51 mmol), 2-[(carb- The solution was extracted with CH2Cl2 and washed with NaHSO3
amoyl)methoxy]acetic acid (500.0 mg, 3.76 mmol) and EDC·HCl
(864.2 mg, 4.51 mmol) in dry 1,2-dichloroethane (15.0 mL). The
mixture was stirred at 40 °C for 9 h and then 12 h at room temp.
Purification by column chromatography [using a reservoir Bond
(40%) and brine, and dried (Na2SO4). Solvent was removed under
reduced pressure and the residue was purified by flash column
chromatography (silica gel, 98:2 CH2Cl2/MeOH) to give 5
1
(380.0 mg, 72%) as a colourless oil. H NMR (300 MHz, CDCl3,
Elut (Varian) of 60 mL, with 5 cm silica gel, 95:5 CH2Cl2/MeOH] 25 °C): δ = 4.23 (s, 2 H, CH2O), 4.19 (s, 2 H, CH2O), 4.09 (t, 3JH,H
gave 18 (683.0 mg, 51 %) as a yellow oil. 1H NMR (300 MHz,
= 6.8 Hz, 2 H, CH2O), 3.29–3.20 (m, 2 H, CH2N), 3.18–3.10 (m,
CDCl3, 25 °C): δ = 7.80 (br. s, 1 H, NH), 5.50 (br. s, 1 H, NH), 2 H, CH2N), 1.63–1.58 (m, 2 H, CH2), 1.53–1.40 (m, 4 H, CH2),
4.25 (s, 2 H, CH2O), 4.08 (s, 2 H, CH2O), 3.36–3.24 (m, 2 H,
CH2N), 3.14–3.03 (m, 2 H, CH2N), 1.60–1.45 (m, 4 H, CH2), 1.37–
1.32–1.12 (m, 30 H, CH2), 0.87–0.77 (m, 9 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, DEPT, 25 °C): δ = 170.1, 167.9 (CO), 69.4, 67.9,
1.18 (m, 20 H, CH2), 0.92–0.83 (m, 6 H, CH3) ppm. 13C NMR 64.8 (CH2O), 46.9, 45.6 (CH2N), 31.69, 31.66, 29.24, 29.20, 29.1,
(75 MHz, CDCl3, DEPT, 25 °C): δ = 172.7, 168.3 (CO), 71.9, 69.8
28.9, 28.5, 27.5, 26.9, 26.7, 25.7, 22.5 (CH2), 13.9 (CH3) ppm. MS
(CH2O), 47.0, 46.4 (CH2N), 31.9, 31.8, 29.4, 29.31, 29.26, 29.1, (FAB+, m-NBA): m/z (%) = 470.4 (100) [M + H]+. C28H55NO4
28.9, 27.7, 27.1, 27.0, 26.9, 22.6 (CH2), 14.2 (CH3) ppm. MS (469.74): calcd. C 71.59, H 11.80, N 2.98; found C 71.67, H 11.88,
(FAB+, m-NBA): m/z (%) = 357.4 (100) [M + H]+. C20H40N2O3
(356.54): calcd. C 67.37, H 11.31, N 7.86; found C 67.55, H 11.36,
N 7.77.
N 3.01.
2-{2-[3-(Acetamidomethyl)benzylamino]-2-oxoethoxy}-N,N-dioctyl-
acetamide (7): A solution of 2 (300.0 mg, 0.63 mmol) and Et3N
(0.176 mL, 1.26 mmol) in dry CH2Cl2 (5.0 mL) was added drop-
wise to a solution of acetyl chloride (0.067 mL, 0.95 mmol) in dry
CH2Cl2 (10.0 mL) stirred at 0 °C under argon atmosphere. The
mixture was stirred at room temp. for 12 h. The organic solution
was washed with 1 m HCl and water, and finally dried (MgSO4).
tert-Butyl 3-({2-[2-(Octylamino)-2-oxoethoxy]acetamido}methyl)-
benzylcarbamate (21): Prepared by coupling of tert-butyl 3-(ami-
nomethyl)benzylcarbamate (1.35 mL, 8.46 mmol), 19 (1.48 g,
6.07 mmol) and EDC·HCl (1.16 g, 6.07 mmol) in dry CH2Cl2
(30.0 mL). The mixture was stirred for 36 h. Purification by column
chromatography (6 ϫ 10 cm silica gel, 100 % Ǟ 95:5 CH2Cl2/ The solvent was removed under reduced pressure to afford 7
1
MeOH) gave 21 (1.47 g, 50%) as a yellow oil. 1H NMR (300 MHz,
(204.0 mg, 63%) as an oil. H NMR (300 MHz, CDCl3, 25 °C): δ
CDCl3, 25 °C): δ = 7.35–7.17 (m, 4 H, ArH), 6.98 (br. s, 1 H, NH), = 8.09 (br. s, 1 H, NH), 7.35–7.16 (m, 4 H, ArH), 6.05 (br. s, 1 H,
6.62 (br. s, 1 H, NH), 5.05 (br. s, 1 H, NH), 4.48 (d, 3JH,H = 5.9 Hz, NH), 4.50 (d, 3JH,H = 6.0 Hz, 2 H, CH2N), 4.43 (d, 3JH,H = 5.6 Hz,
3
2 H, CH2N), 4.30 (d, JH,H = 6.0 Hz, 2 H, CH2N), 4.08 (s, 2 H,
2 H, CH2N), 4.26 (s, 2 H, CH2O), 4.15 (s, 2 H, CH2O), 3.36–3.25
CH2O), 4.01 (s, 2 H, CH2O), 3.34–3.21 (m, 2 H, CH2N), 1.57–1.47 (m, 2 H, CH2N), 3.15–3.06 (m, 2 H, CH2N), 2.04 (s, 3 H, CH3),
(m, 2 H, CH2), 1.47 [s, 9 H, C(CH3)3], 1.39–1.19 (m, 10 H, CH2), 1.62–1.44 (m, 4 H, CH2), 1.40–1.18 (m, 20 H, CH2), 0.98–0.84 (m,
0.95–0.83 (m, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, DEPT, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, DEPT, 25 °C): δ =
25 °C): δ = 168.1, 167.9, 155.6 (CO), 139.3, 137.8 (Ar), 128.7, 126.3, 170.0, 169.5, 168.1 (CO), 138.8, 138.6 (Ar), 128.9, 127.1, 126.90,
126.2 (ArH), 79.3 [OC(CH3)3], 70.8, 70.7 (CH2O), 44.0, 42.5, 38.7 126.85 (ArH), 71.8, 69.5 (CH2O), 46.8, 46.2, 43.6, 42.7 (CH2N),
(CH2N), 31.4, 29.1, 28.8, 28.7 (CH2), 28.0 [OC(CH3)3], 26.5, 22.2 31.8, 31.7, 29.3, 29.24, 29.21, 29.16, 28.9, 27.6, 27.0, 26.9 (CH2),
3966
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3959–3969

Hydrolysis and Radiation Stability of a m-Xylylene Bis-diglycolamide
23.22 (CH3CO), 22.61, 22.58 (CH2), 14.1 (CH3) ppm. MS (FAB+,
CH2N), 2.05 (s, 3 H, CH3CO), 1.56–1.46 (m, 2 H, CH2), 1.39–1.22
m-NBA): m/z: (%) = 518.2 (100) [M + H]+. C30H51N3O4 (517.74): (m, 10 H, CH2), 0.94–0.83 (m, 3 H, CH3) ppm. 13C NMR
calcd. C 69.59, H 9.93, N 8.12; found C 69.30, H 9.92, N 7.90.
(75 MHz, CDCl3, DEPT, 25 °C): δ = 170.3, 168.6, 168.4 (CO),
139.1, 138.5 (Ar), 129.1, 126.9, 126.8 (ArH), 71.1, 71.0 (CH2O),
43.4, 42.8, 39.1 (CH2N), 31.8, 29.5, 29.22, 29.18, 26.9 (CH2), 23.2
(CH3CO), 22.6 (CH2), 14.1 (CH3) ppm. MS (FAB+, m-NBA): m/z
(%) = 406.3 (100) [M + H]+. C22H35N3O4 (405.53): calcd. C 65.16,
H 8.70, N 10.36; found C 65.31, H 8.70, N 10.35.
3-({2-[2-(Dioctylamino)-2-oxoethoxy]acetamido}methyl)benzoic
Acid (9): KOH (41.7 mg, 0.74 mmol) was added to a solution of 22
(250.0 mg, 0.50 mmol) in THF/EtOH (40 mL, 7:1) stirred at room
temp. The mixture was stirred at 70 °C for 3 h. The solvent was
eliminated under reduced pressure and the residue was partitioned
in CH2Cl2/HCl (1 m). The organic solution was washed with water
and finally dried (MgSO4). The solvent was removed under reduced
pressure to give 9 (196.9 mg, 81%) as a colourless oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 8.26 (br. s, 1 H, NH), 7.90–7.80 (m,
2-Hydroxy-N-[3-({2-[2-(octylamino)-2-oxoethoxy]acetamido}meth-
yl)benzyl]acetamide (16): Trifluoroacetic acid was added (0.88 mL,
11.43 mmol) to a solution of 21 (1.06 g, 2.29 mmol) in CH2Cl2
(13.0 mL) stirred at room temp. The mixture was heated at 40 °C
for 3 h. Solvent was removed under reduced pressure, and the resi-
due was dissolved in CH2Cl2. The organic solution was washed
with NaHCO3 and water, and finally dried (MgSO4). Solvent was
removed under reduced pressure to give N-[3-(aminomethyl)
benzyl]-2-[2-(octylamino)-2-oxoethoxy]ethanamide (0.896 g, quan-
titative) as yellow oil. Then, 2-(benzyloxy)acetic acid (201.5 mg,
1.15 mmol) was added at room temp. under an argon atmosphere
to a solution of this oil (350.0 mg, 0. 96 mmol) and EDC·HCl
(221.5 mg, 1.15 mmol) in dry CH2Cl2 (10.0 mL). The mixture was
stirred for 48 h at room temp. Then, 1 m HCl was added and the
mixture was extracted with CH2Cl2. The organic phase was washed
with 1 m HCl and water, and finally dried (MgSO4). The solvent
was removed under reduced pressure, and the residue was purified
by column chromatography (silica gel, 98:2 Ǟ 95:5 CH2Cl2/MeOH)
to give 2-(benzyloxy)-N-[3-({2-[2-(octylamino)-2-oxoethoxy]acet-
amido}methyl)benzyl]acetamide (378.0 mg, 77%). A hydrogen flow
was passed through a solution of this compound (378.0 mg,
0.74 mmol) and 10% Pd/C (catalytic amount), in EtOH (15.0 mL)
for 30 min. The mixture was stirred under a hydrogen atmosphere
at room temp. for 3 h. The mixture was filtered through Celite and
the solvent was removed under reduced pressure to give 16
(251.0 mg, 80%) as a yellow oil. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.34 (br. s, 1 H, NH), 7.24–7.15 (m, 4 H, ArH), 7.09
3
3
2 H, ArH), 7.46 (d, JH,H = 7.9 Hz, 1 H, ArH), 7.30 (t, JH,H
=
3
7.7 Hz, 1 H, ArH), 4.48 (d, JH,H = 5.5 Hz, 2 H, CH2N), 4.21 (s,
2 H, CH2O), 4.10 (s, 2 H, CH2O), 3.30–3.15 (m, 2 H, CH2N), 3.10–
2.95 (m, 2 H, CH2N), 1.55–1.35 (m, 4 H, CH2), 1.30–1.10 (m, 20
H, CH2), 0.90–0.75 (m, 6 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3, DEPT, 25 °C): δ = 170.6, 170.0, 169.0 (CO), 139.1 (Ar),
132.9 (ArH), 130.7 (Ar), 129.6, 129.3, 129.0, (ArH), 72.1, 69.9
(CH2O), 47.4, 46.8, 43.0 (CH2N), 32.23, 32.17, 29.8, 29.7, 29.64,
29.60, 29.3, 28.0, 28.4, 27.3, 23.0 (CH2), 14.5 (CH3) ppm. MS
(FAB+, m-NBA): m/z (%) = 491.3 (100) [M + H]+. C28H46N2O5
(490.68): calcd. C 68.54, H 9.45, N 5.71; found C 68.54, H 9.43, N
5.27.
2-Hydroxy-N,N-dioctylacetamide (11): A hydrogen flow was passed
through a mixture of 24 (378.2 mg, 0.97 mmol) and 10 % Pd/C
(catalytic amount) in EtOH (12.0 mL) for 30 min. The mixture was
stirred under a hydrogen atmosphere at room temp. for 7 h. Then,
the mixture was filtered through Celite, and the solvent was elimin-
ated under reduced pressure and the residue was purified by flash
column chromatography (silica gel, 99:1 CH2Cl2/MeOH) to give 11
(223.2 mg, 77 %) as a yellow oil. 1H NMR (500 MHz, CDCl3,
25 °C): δ = 4.13 (s, 2 H, CH2OH), 3.69 (s, 1 H, OH), 3.38–3.33 (m,
2 H, CH2N), 3.07–3.02 (m, 2 H, CH2N), 1.70–1.50 (m, 4 H, CH2),
1.45–1.15 (m, 20 H, CH2), 1.00–0.75 (m, 6 H, CH3) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 171.0 (CO), 59.7 (CH2O), 46.1, 45.8,
(CH2N), 31.8, 31.7, 29.3, 29.2, 29.1, 28.5, 27.5, 27.0, 26.8, 22.6
(CH2), 14.0 (CH3) ppm. MS (FAB+, m-NBA): m/z (%) = 300.3
(100) [M + H]+. Purity by HPLC–MS 94.4%.
3
(br. s, 1 H, NH), 6.72 (br. s, 1 H, NH), 4.47 (d, JH,H = 5.6 Hz, 4
H, CH2N), 4.08 (s, 4 H, CH2O), 3.99 (s, 2 H, CH2O), 3.28–3.19
(m, 2 H, CH2N), 2.43 (br. s, 1 H, OH), 1.57–1.42 (m, 2 H, CH2),
1.36–1.18 (m, 10 H, CH2), 0.93–0.80 (m, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, DEPT, 25 °C): δ = 173.3, 169.4, 169.2 (CO),
138.6, 138.5 (Ar), 128.9, 126.8, 126.7, 126.4 (ArH), 70.69, 70.65
(CH2O), 61.9 (CH2OH), 42.7, 42.6, 39.3 (CH2N), 31.8, 29.7, 29.4,
29.23, 29.18, 28.4, 26.9, 22.6 (CH2), 14.1 (CH3) ppm. MS (FAB+,
m-NBA): m/z (%) = 422.1 (25) [M + H]+. C22H35N3O5·1/3H2O
(427.53): calcd. C 61.80, H 8.41, N 9.83; found C 61.86, H 8.30, N
9.73.
N-[3-(Acetamidomethyl)benzyl]-2-[2-(octylamino)-2-oxoethoxy]acet-
amide (15): Trifluoroacetic acid (0.88 mL, 11.43 mmol) was added
to a solution of 21 (1.06 g, 2.29 mmol) in CH2Cl2 (13.0 mL) stirred
at room temp. The mixture was heated at 40 °C for 3 h. Solvent
was removed under reduced pressure, and the residue was dissolved
in CH2Cl2. The organic solution was washed with NaHCO3 and
water, and finally dried (MgSO4). Solvent was removed under re-
duced pressure to give N-[3-(aminomethyl)benzyl]-2-[2-(oct-
N,N-Dioctylformamide (17):
A solution of N,N-dioctylamine
(100.0 mg, 0.41 mmol) in dry THF (3.0 mL) under argon atmo-
ylamino)-2-oxoethoxy]acetamide (0.896 g, quantitative) as a yellow sphere was added dropwise to a solution of 1H-benzo[d][1,2,3]tri-
oil. A solution of this oil (250.0 mg, 0.69 mmol) and Et3N azole-1-carbaldehyde (57.6 mg, 0.39 mmol) in dry THF (2.5 mL).
(0.19 mL, 1.38 mmol) in dry CH2Cl2 (5.0 mL) was added dropwise
The mixture was stirred at room temp. for 40 min. The solvent was
to a solution of acetyl chloride (0.073 mL, 1.03 mmol) in dry removed under reduced pressure and the residue was dissolved in
CH2Cl2 (10.0 mL) stirred at 0 °C under an argon atmosphere. The
mixture was stirred for 24 h at room temp. The organic solution
was washed with 1 m HCl and water, and finally dried (MgSO4).
The solvent was removed under reduced pressure and the residue
was purified by column chromatography (silica gel, 99:1 Ǟ 96:4
CH2Cl2 (10.0 mL). The organic solution was washed with 2 m
NaOH and water, and dried (MgSO4). The solvent was removed
under reduced pressure to give 17 (101.8 mg, 98%) as a colourless
1
oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 8.03 (s, 1 H, CHO),
3.36–3.22 (m, 2 H, CH2N), 3.20–3.14 (m, 2 H, CH2N), 1.60–1.44
(m, 4 H, CH2), 1.37–1.14 (m, 20 H, CH2), 0.94–0.79 (m, 6 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3, DEPT, 25 °C): δ = 162.7 (CHO),
47.5, 42.2 (CH2N), 31.8, 31.7, 29.3, 29.20, 29.15, 28.7, 27.3, 27.0,
26.5, 22.61, 22.60 (CH2), 14.0 (CH3) ppm. MS (FAB+, m-NBA)
m/z (%) = 270.3 (100) [M + H]+. Purity by HPLC–MS 99.3%.
1
CH2Cl2/MeOH) to afford 15 (235.4 mg, 85%) as an oil. H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.38–7.21 (m, 4 H, ArH), 6.81 (br.
s, 1 H, NH), 6.48 (br. s, 1 H, NH), 5.97 (br. s, 1 H, NH), 4.52 (d,
3JH,H = 6.0 Hz, 2 H, CH2N), 4.45 (d, 3JH,H = 5.9 Hz, 2 H, CH2N),
4.13 (s, 2 H, CH2O), 4.06 (s, 2 H, CH2O), 3.34–3.23 (m, 2 H,
Eur. J. Org. Chem. 2011, 3959–3969
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3967

P. Prados et al.
FULL PAPER
2-[2-(Octylamino)-2-oxoethoxy]acetic Acid (19): 1-Octylamine
(3.06 mL, 20.68 mmol) was added to a solution of diglycolic anhy-
dride (2.40 g, 20.68 mmol) in dry THF (25.0 mL, 0.8 m) stirred at
room temp. The mixture was kept under the same conditions for
48 h. The mixture was washed three times with 1 m HCl and water.
The organic phase was dried (Na2SO4) and the solvent was re-
moved. Petroleum ether was added to the resulting orange oil and
a white solid appeared. The precipitate was filtered, dried and puri-
fied by column chromatography (95:5 CH2Cl2/MeOH) to give 19
Hydrolytic Procedure: The stability studies of 1 against hydrolysis
were performed by using six samples (700 μL) of the organic phase
[0.1 m of 1 in a mixture of dodecane/1-octanol (95:5 vol.-%)] pre-
equilibrated with 3 m nitric acid, which were contacted with an
equal volume of 3 m nitric acid as the aqueous phase. Mixtures
were agitated for 5, 12, 19, 26, 36 and 42 d, respectively, with an
oscillating mixer at 900 rpm at room temp. [(22Ϯ2) °C]. After this
period, 241Am and 152Eu extraction was assessed by following ex-
traction procedure described.
1
(980.0 mg, 19%) as a colorless wax. H NMR (400 MHz, CDCl3,
Irradiation Procedure: The stability studies of 1 against irradiation
were performed at the CIEMAT Nayade facility, which was a pool
1.2 m2 by 4.5 m deep. It consisted of 60 sources of 60Co distributed
in six lots with a total activity of 1.1ϫ1014 Bq, with a dose rate of
2.6–9.5 kGyhϪ1. The irradiation container used provided homo-
geneous irradiation flux. The 2 mL bottles were sealed with a plas-
tic lid that was loosely screwed on to allow potential over-pressure
to level out. No volume decrease was observed during the irradia-
tions, hence evaporation of the solvent was assumed to be negligi-
ble. The AmIII and EuIII extraction with the irradiated samples of
1 were assessed immediately after irradiation. The bottles were then
stored in a freezer while awaiting further HPLC–MS analyses.
25 °C): δ = 6.75 (br. s, 1 H, NH), 4.21 (s, 2 H, OCH2), 4.12 (s, 2
H, OCH2), 3.33–3.28 (m, 2 H, CH2N), 1.55–1.50 (m, 2 H, CH2),
1.30–1.27 (m, 10 H, CH2), 0.90–0.86 (m, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 172.2 (CO2 H), 170.2 (CONH), 70.5,
68.2 (OCH2), 39.2 (CH2N), 31.7, 29.2, 29.13, 29.10, 26.8, 22.6
(CH2), 14.0 (CH3) ppm. HRMS (ES): m/z calcd. for C12H22NO4
244.1549 [M+]; found 244.1551.
Methyl
3-({2-[2-(Dioctylamino)-2-oxoethoxy]acetamido}methyl)-
benzoate (22): A solution of [3-(methoxycarbonyl)phenyl]methana-
minium chloride (850.0 mg, 4.21 mmol) and Et3N (1.75 mL,
12.6 mmol) in dry CH2Cl2 (5.0 mL) was added to a mixture of 4[7]
(1.96 g, 5.48 mmol) and benzotriazole-1-yloxytrispyrrolidinophos-
phonium hexafluorophosphate (PyBOC; 2.85 g, 5.48 mmol) in dry
CH2Cl2 (5.0 mL) at room temp. The mixture was stirred under the
same conditions for 24 h. Then, a solution of 1 m HCl was added
and the mixture was extracted with CH2Cl2. The organic phase was
washed with 1 m HCl and water, and finally dried (MgSO4). The
solvent was removed under reduced pressure and the residue was
purified by column chromatography (silica gel, 95:5 CH2Cl2/
MeOH) to give 22 (1.33 mg, 63%) as a yellow oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 8.25 (br. s, 1 H, NH), 7.97–7.91 (m,
HPLC–APCI+ Procedure: HPLC–MS studies were performed by
using an HPLC–MS Agilent 1100 (Quadrupole detector 6120A)
with a Protonsil C-8 column (50ϫ2 mm, 5 μm) at 40 °C using a
gradient of mobile phase [(A: 0.1 vol.-% CH3CN/HCOOH), (B:
0.1 vol.-% H2O/HCOOH)] in the APCI+ ionization mode (SCAN).
Samples from irradiation were used without pre-evaporation and
were diluted in (90:10) MeOH/1-octanol until 10–3 m. Calibration
curves and verification of these curves were realized with 1 and
with each of the synthesized fragments. A quantitative study was
carried out by HPLC–APCI+ (SIM mode) by using irradiated sam-
ples of 1, which were diluted 100 and 200 times. Data were collected
in triplicate and the final concentrations of all fragments were cal-
culated as the average of the different dilutions.
3
3
2 H, ArH), 7.52 (d, JH,H = 7.7 Hz, 1 H, ArH), 7.39 (t, JH,H
=
3
7.7 Hz, 1 H, ArH), 4.54 (d, JH,H = 6.0 Hz, 2 H, CH2N), 4.24 (s,
2 H, CH2O), 4.15 (s, 2 H, CH2O), 3.90 (s, 3 H, OCH3), 3.29–3.24
(m, 2 H, CH2N), 3.09–3.03 (m, 2 H, CH2N), 1.60–1.40 (m, 4 H,
CH2), 1.35–1.15 (m, 20 H, CH2), 0.95–0.85 (m, 6 H, CH3) ppm.
13C NMR (75 MHz, CDCl3, DEPT, 25 °C): δ = 169.7, 168.1, 166.9
(CO), 138.8 (Ar), 132.3 (ArH), 130.4 (Ar), 128.8, 128.7, 128.5
(ArH), 72.0, 69.6 (CH2O), 52.1 (CH3O), 46.8, 46.2, 42.5 (CH2N),
31.8, 31.7, 29.3, 29.24, 29.21, 29.15, 28.9, 27.6, 27.0, 26.9, 22.6
(CH2), 14.0 (CH3) ppm. MS (FAB+, m-NBA): m/z (%) = 505.3
(100) [M + H]+. C29H48N2O5·1/4H2O (509.21): calcd. C 68.40, H
9.60, N 5.50; found C 68.39, H 9.35, N 5.53.
Supporting Information (see footnote on the first page of this arti-
cle): Spectral characterization data (1–18). HPLC–MS data of the
qualitative and quantitative studies. Distribution coefficients of
AmIII and EuIII by TODGA after irradiation.
Acknowledgments
This work was financially supported by grants from the European
Projects EUROPART (FI6W-CT-2003-508854) and ACSEPT
(Contract Number: FP7-CP-2007-211267) and ENRESA.
Extraction Procedure: Solutions were prepared by dissolving
weighed amounts of the corresponding compounds in the appropri-
ate volume (700 μL) of corresponding solvent up to 0.1 m. Clear
organic solutions were pre-equilibrated twice for 5 min with the
same volume (700 μL) of the aqueous phase having the same nitric
acid concentration (3 m) as the aqueous phase to be used in the
subsequent extraction experiment. Nitric acid solutions were pre-
pared by diluting concentrated nitric acid (65%) with ultrapure
water (18 MΩcmϪ1). The behaviour of trivalent actinides and lan-
thanides were simulated by 241Am and 152Eu, respectively, which
were supplied by Isotope Products Laboratories, California (USA).
The extraction experiments were performed by mixing the aqueous
phase (500 μL) and the pre-equilibrated organic phase (500 μL) for
30 min. Both phases were separated by centrifugation at 5000 rpm
and 400 μL aliquots of each phase were spiked and conditioned
into a 5 mL glass vial for high- and low-energy gamma spectrome-
try measurements (Canberra-Packard, CIEMAT, Spain), using the
γ lines at 59.5 and 121.8 keV for 241Am and 152Eu determination,
respectively. The distribution coefficients (DMIII) were calculated as
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Received: March 30, 2011
Published Online: June 27, 2011
Eur. J. Org. Chem. 2011, 3959–3969
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3969