New amino-functionalized 1,3-alternate calix[4]arene bis- and mono-(benzo-crown-6 ethers) for pH-switched cesium nitrate extraction

Article abstract of DOI:10.1016/S0040-4039(03)01310-8

Four calix[4]arene benzo-crown-6 ethers functionalized with primary amine groups in various positions have been synthesized. The cesium extraction behavior under alkaline and acidic conditions has been measured for these compounds and compared with that of non-amine containing analogs. Extraction strength when the amine group is neutral is not affected by the amino substituent, but protonation causes a marked decrease in extraction strength, permitting pH-switched back-extraction.

Full text of DOI:10.1016/S0040-4039(03)01310-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5397–5401
New amino-functionalized 1,3-alternate calix[4]arene bis- and
mono-(benzo-crown-6 ethers) for pH-switched cesium nitrate
extraction
Maryna G. Gorbunova, Peter V. Bonnesen,* Nancy L. Engle, Eve Bazelaire, Lætitia H. Delmau and
Bruce A. Moyer
Oak Ridge National Laboratory, PO Box 2008, Mail Stop 6119, Oak Ridge, TN 37831-6119, USA
Received 5 May 2003; accepted 26 May 2003
Abstract—Four calix[4]arene benzo-crown-6 ethers functionalized with primary amine groups in various positions have been
synthesized. The cesium extraction behavior under alkaline and acidic conditions has been measured for these compounds and
compared with that of non-amine containing analogs. Extraction strength when the amine group is neutral is not affected by the
amino substituent, but protonation causes a marked decrease in extraction strength, permitting pH-switched back-extraction.
Published by Elsevier Science Ltd.
Calixarene-crowns or calixcrowns, macrocyclic com-
pounds that combine calixarene and polyether units,
are being studied intensively in many laboratories as
hosts for selective ion recognition. Many variations of
these compounds have been reported, as distinguished
by different crown chain lengths and structures and by
different substituents on the lower and upper rims.1
However, there are only a few papers devoted to the
synthesis and properties of calix[4]crowns with amino
groups.2 We have recently become interested in
calix[4]crowns with pendant primary amines as building
blocks for more complex molecules that might find
utility in a number of applications, among them, metal
ion separation by solvent extraction. Especially useful
would be enhanced release of a bound metal ion upon
protonation of the amino group, thereby increasing the
overall efficiency of binding-release cycles via pH
switching. Calix[4]arene-crown-6 ethers in the 1,3-alter-
nate conformation3 in particular have attracted signifi-
cant interest in recent years as extremely selective
extractants for large alkali metal cations for possible
applications such as nuclear-waste remediation,4 sens-
ing,5 and radiopharmacy.6 In this paper, we report
syntheses of three types of calix[4]arene-crown-6 ethers
categorized according to the location of appended
amino groups attached to the crown-ether moiety, to
the alkoxy substituents, or to the calixarene unit. We
also report a preliminary evaluation of the feasibility of
the use of these compounds as pH-switchable extrac-
tants for cesium nitrate ion pairs.
The synthesis of the amino-substituted calix[4]crowns
of the first type—with the amino group attached to the
crown-ether moiety—was performed according to
Scheme
1.
Bis-1,2-[2%(2%%-hydroxyethoxy)ethoxy]-4-
cyano-benzene 2 was prepared in 74% yield from com-
mercially available 3,4-dihydroxybenzonitrile by
reaction with 2-(2-chloroethoxy)-ethanol in dry
dimethylformamide in the presence of K2CO3.7 Reac-
tion of
2
with methanesulfonyl chloride in
dichloromethane in the presence of Et3N afforded the
dimesylate 38 in 90% yield. It was shown recently that
whereas both dimesylates and ditosylates can be used
for the calixcrown synthesis, using dimesylates can lead
to improved yields.9 Reaction of bis-n-octyloxy-
calix[4]arene 410 with one equivalent of dimesylate 3
was carried out with Cs2CO3 in dry acetonitrile in a
closed heavy-wall glass reaction vessel at 110°C to give
the new 1,3-alternate bis-n-octyloxy-calix[4]arene 4-
cyano-benzo-crown-6 5.11 Reduction of
5
using
(CH3)2S·BH3 in dry THF gave the desired bis-n-octyl-
oxy-calix[4]arene 4-amino-methyl-benzo-crown-6 ether
612 in 90% yield.
The biscrown analogue, calix[4]arene bis[(4-amino-
methyl)-benzo-crown-6] 8 was obtained in a similar
manner. Thus, reaction of calix[4]arene with two equiv-
alents of dimesylate 3 afforded calix[4]arene bis(4-
* Corresponding author. Tel.: +1-865-574-6715; fax: +1-865-574-4939;
e-mail: bonnesenpv@ornl.gov
0040-4039/03/$ - see front matter. Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)01310-8

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M. G. Gorbuno6a et al. / Tetrahedron Letters 44 (2003) 5397–5401
cyano-benzo-crown-6) 713 in 35% yield. Reduction of 7
afforded the new calix[4]arene biscrown 814 in 60% yield.
The second type of calix[4]arene-crown-6 ether—with
amino-groups attached to the alkoxy groups in posi-
tions 25 and 27 of the calixarene unit—was synthesized
according to Scheme 2. 25,27-Bis(phthalimidoprop-
oxy)calix[4]arene 4-(2-ethylhexyl)benzo-crown-6 11
was prepared in 71% yield from 25,27-bis(3-phthalimido-
propoxy)-calix[4]arene 102a with one equivalent of
ditosylate 915 under the same reaction conditions used
to prepare compounds 5 and 7.16 The phthalimido
groups were removed using the conditions described for
the synthesis of bis(3-aminopropoxy)-calix[4]arene
crown10 to give the new 25,27-bis-(3-aminopropoxy)-
calix[4]arene-4-(2-ethylhexyl) benzo-crown-6 ether 1217
in 83% yield.
The compound of the third type—with one aminomethyl
group attached to the calixarene unit—was synthesized
according to Scheme 3. Bromocalix[4]arene - bis(4 - (2-
ethylhexyl)benzo - crown - 6 - ether) 14 was prepared in
55% yield from bromocalix[4]arene 1318 by reaction with
ditosylate 9 and Cs2CO3 in acetonitrile under the same
reaction conditions described above.19 The bromide was
replaced with a cyano group by treatment of 14 with
CuCN in N-methyl-pyrrolidinone to afford 15 in 72%
yield.20 Reduction of 15 using (CH3)2S·BH3 in dry THF
gave the desired aminomethyl-calix[4]arene bis(4-(2-
ethylhexyl) benzo-crown-6) 16 in 92% yield.21
Scheme 2. Reagents and conditions: (i) Cs2CO3, CH3CN,
110°C, 4 days; (ii) NH2NH2·H2O, EtOH, 110°C.
Scheme 3. Reagents and conditions: (i) Cs2CO3, CH3CN,
110°C, 4 days; (ii) CuCN, NMP, 200°C, 48 h; (iii) (CH3)2S·BH3,
THF, refluxing, 24 h.
Extraction results demonstrated proof-of-principle for
pH-switched extraction and release. The new
calix[4]arene monocrowns 6 and 12 and calix[4]arene
biscrowns 8 and 16 were compared to calixcrowns 1710
and 1810 without amino groups as controls (Fig. 1). The
organic phase in each case consisted of a calixcrown at
2.5 mM in nitrobenzene, a diluent chosen for its high
polarity, which promotes solubility of the calixcrowns
and their complexes and which discourages ion-pairing.
Scheme 1. Reagents and conditions: (i) ClCH2CH2OCH2-
CH2OH, K2CO3, DMF, 80°C, 48 h; (ii) CH3SO2Cl, Et3N,
CH2Cl2, rt, 48 h; (iii) Cs2CO3, CH3CN, 110°C; (iv)
(CH3)2S·BH3, THF, refluxing.

M. G. Gorbuno6a et al. / Tetrahedron Letters 44 (2003) 5397–5401
5399
Figure 1. Calixcrowns used in extraction tests.
The absence or weakening of ion-pairing was expected
to maximize the repulsive effect of the protonated
amino group on binding of the Cs cation. In the case of
the control compounds 17 and 18 without amino
groups, 2.5 mM of tri-n-octylamine (TOA) was also
added to the organic phase to serve as a control for the
presence of an amine group. It may be noted that
alkylation of the benzo group in calix[4]arene-benzo-
crown-6 compounds has only a very minor effect on
cesium extraction strength.6,10
Extractions were carried out from alkaline (1 M
NaNO3, 0.05 M NaOH, 10−4 M CsNO3) and acidic
(0.95 M NaNO3, 0.05 M HNO3, 10−4 M CsNO3)
aqueous solutions containing 137CsNO3 radiotracer
(0.58 mCi/mL). A back-extraction (stripping) of the
organic phase previously contacted with the alkaline
aqueous phase was carried out using an acidic aqueous
phase (0.95 M NaNO3, 0.05 M HNO3) containing no
cesium or tracer. These aqueous conditions were
selected so that the driving force for cesium nitrate
extraction, as controlled by the aqueous nitrate concen-
tration, was approximately constant in all cases. Hence,
differences in extraction behavior on pH swing would
be only due to the pH effect. In each case, equal phase
volumes were equilibrated by gentle agitation in capped
vials for 90 min at 25°C. The cesium distribution ratio
DCs is defined as [Cs]org/[Cs]aq.
Figure 2. Cesium extraction results for calixcrowns presented
in Fig. 1 (at 2.5 mM in nitrobenzene) under alkaline and
acidic conditions.
biscrown 16. Stripping under acidic conditions gives
approximately the same value of the cesium distribution
ratio DCs as extraction under nitric acid conditions,
confirming that back-extraction is enhanced. Combina-
tion of high extraction ability under basic conditions
and high stripping efficiency under acidic conditions
make compound 16 an attractive extractant candidate
among the amino substituted calix[4]arene crowns syn-
thesized thus far.
Results presented in Figure
2 demonstrate large
decreases in cesium extraction strength, as much as two
orders of magnitude, upon acidification of the aqueous
phase. Under alkaline conditions, it may be seen that,
except for the bis-amino-propoxy calix[4]crown 12,22
the presence of the amino group does not change DCs
significantly. On extraction from acidic solution, the
controls 17 and 18 exhibit decreased extraction (ca.
2–3-fold), an effect that may be taken as inhibition of
cesium nitrate extraction by a common-ion effect due
to nitric acid extraction. This inhibition is expected in
all cases based on Le Chatelier’s principle and supports
the extraction of cesium nitrate as dissociated ion pairs.
Extraction under the acidic conditions decreases signifi-
cantly for all the amino substituted compounds, and
most significantly for the aminomethyl calix[4]arene
In conclusion, syntheses of the new calix[4]arene-crown-
6 ethers with amino groups in different positions are
reported. Extraction strength when the amino group is
neutral is not affected by the amino substituent, but
protonation causes a marked decrease in extraction
strength, permitting pH-switched back-extraction.
Amino-methyl-calix[4]arene biscrown 16 appeared to be
the most promising extractant. Further studies of the
extraction behavior of the amino substituted
calix[4]arene crowns 6, 8, 12, and 16 and their deriva-
tives are being carried out.

5400
M. G. Gorbuno6a et al. / Tetrahedron Letters 44 (2003) 5397–5401
23°C): (selected) l 118.9 (CN). Anal. Calcd for
Acknowledgements
C15H21NO6: C, 57.87; H, 6.80; N, 4.50. Found: C, 57.86;
H; 7.02; N, 4.49%. 1H and 13C NMR for all other
compounds were obtained under the same conditions
unless otherwise noted.
This research was sponsored by the Environmental
Management Science Program of the Offices of Science
and Environmental Management, US Department of
8. 3: Oil. 1H NMR: l 3.05 (s, 3H) 3.07(s, 3H), 3.83–3.85 (m,
4H), 3.86–3.88 (m, 4H), 3.41–4.22 (m, 4H) 4.38–4.43 (m,
4H), 6.91 (d, J=8.4, 1H), 7.11 (d, J=1.9, 1H), 7.27 (dd,
J=1.9, J=8.4, 1H); 13C NMR: (selected) l 119.6 (CN).
Anal. Calcd for C17H25NO10S2: C, 43.67; H, 5.39; N,
3.00. Found: C; 43.63; H; 5.66; N, 3.08%.
Energy,
under
contract
number
DE-AC05-
0096OR22725 with Oak Ridge National Laboratory,
managed by UT-Battelle, LLC. The participation of
M.G.G. was made possible by an appointment to the
Oak Ridge National Laboratory Postgraduate Program
administered by the Oak Ridge Associated Universities.
9. Talanov, V. S.; Talanova, G. G.; Gorbunova, M. G.;
Bartsch, R. A. J. Chem. Soc., Perkin Trans. 2 2002,
209–215.
10. Sachleben, R. A.; Bonnesen, P. V.; Descazeaud, T.;
Haverlock, T. J.; Urvoas, A.; Moyer, B. A. Solv. Extract.
Solv. Exch. 1999, 17, 1445–1459.
References
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11. 5: Solid, m.p. 124–126°C; 1H NMR: l 0.92 (t, J=7.0,
6H), 1.17–1.36 (br m, 24H), 3.45–3.57 (m, 8H), 3.74 (s,
8H), 3.70–3.81 (m, 8H), 4.10–4.18 (m, 4H), 6.62 (t, J=
7.5, 2H), 6.76 (t, J=7.5, 2H), 6.97-7.05 (m, 9H), 7.20 (d,
J=1.9, 1H), 7.33 (dd, J=1.9, J=8.4, 1H); 13C NMR:
(selected) l 38.05 (ArCH2Ar), 118.07 (CN). Anal. Calcd
for C59H73NO8: C, 76.67; H, 7.96; N, 1.66. Found: C;
76.38; H, 8.00; N, 1.73%.
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12. 6: Solid, m.p. 238–240°C; 1H NMR: l 0.91 (t, J=7.0,
6H), 1.10–1.56 (br m, 24H), 3.25–4.45 (m, 20H), 3.75 (s,
8H), 6.65 (br t, J=7.2, 2H), 6.79 (br t, J=7.2, 2H) 6.92
(br s, 2H), 7.00–7.04 (br m, 9H); 13C NMR: (selected) l
38.31 (ArCH2Ar), 43.67 (CH2NH2). Anal. Calcd for
C59H77NO8·2H2O: C, 73.48; H, 8.48; N, 1.45. Found: C,
73.84; H, 8.37; N, 1.41%.
13. 7: Solid, m.p. 258–260°C; 1H NMR: l 3.50–3.65 (m,
12H), 3.78 (s, 8H), 3.68–3.83 (m, 12H), 4.10–4.20 (m,
8H), 6.67 (t, J=7.5, 4H), 6.99 (d, J=8.3, 2H), 7.04-7.10
(m, 8H), 7.20 (d, J=1.4, 2H), 7.34 (dd, J=1.4, J=8.3,
2H); 13C NMR: (selected) l 38.27 (ArCH2Ar), 118.54
(CN). Anal. Calcd for C58H58N2O12: C, 71.44; H, 6.00;
N, 2.87. Found: C, 71.56; H 6.08; N, 2.94%.
14. 8: Solid, m.p. 237–239°C; 1H NMR: l 3.48–3.63 (m,
16H), 3.64–3.74 (m, 8H) 3.77 (s, 8H), 3.84 (s, 4H),
4.06–4.20 (m, 8H), 6.70 (t, J=7.5, 4H), 6.90–7.04 (m,
6H), 7.06 (d, J=7.5, 8H); 13C NMR: (selected) l 38.38
(ArCH2Ar), 46.80 (CH2NH2). Anal. Calcd for
C58H66N2O12: C, 70.86; H, 6.77; N, 2.85. Found: C,
70.60; H, 6.81; N, 2.78%.
15. 9: Engle, N. L.; Bonnesen P. V.; Tomkins, B. A.; Haver-
lock, T. J.; Moyer, B. A. To be submitted to Solv. Extr.
Ion Exch.
4. (a) Dozol, J.-F.; Simon, N.; Lamare, V.; Rouquette, H.;
Eymard, S.; Tournois, B.; De Marc, D.; Macias, R. M.
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Delmau, L. H.; Moyer, B. A.; Leonard, R. A. Solvent
Extr. Ion Exch. 2000, 18, 1079–1108.
5. (a) Ji, H.-F.; Dabestani, R. T.; Brown, G. M.; Sachleben,
R. A. Chem. Commun. 2000, 833–834; (b) Casnati, A.;
Giunta, F.; Sansone, F.; Ungaro, R.; Montalti, M.;
Prodi, L.; Zaccheroni, N. Supramol. Chem. 2001, 13,
419–434.
16. 11: Solid, m.p. 107–109°C; 1H NMR: l 0.85–0.90 (m,
6H), 1.23–1.35 (br m, 8H), 1.50–1.65 (m, 5H), 2.48 (m,
2H), 2.56–2.62 (m, 4H), 3.4–3.9 (m, 16H), 3.78 (s, 8H),
4.00–4.25 (m, 4H), 6.65 (t, J=7.5, 2H), 6.70–6.94 (m,
5H), 7.04 (br d, J=7.5, 8H), 7.65–7.70 (m, 4H), 7.76–7.82
(m, 4H); 13C NMR: (selected) l 38.26 (ArCH2Ar), 168.53
(C=O). Anal. Calcd for C72H76N2O12: C, 74.46; H, 6.60;
N, 2.41. Found: C, 74.24; H, 6.68; N, 2.35%.
17. 12: Solid, m.p. 124–126°C; 1H NMR: l 0.83–0.89 (m,
6H), 1.23–1.32 (br m, 8H), 1.50–1.63 (m, 5H), 2.40–2.50
(m, 2H), 3.40–3.90 (m, 32H), 4.00–4.30 (m, 4H), 6.68 (t,
J=7.5, 2H), 6.70–6.95 (m, 5H), 7.00–7.20 (m, 8H); 13C
NMR: (selected) l 38.00 (ArCH2Ar), 41.11 (CH2NH2).
Anal. Calcd for C56H72N2O8·H2O: C, 73.18; H, 8.13; N,
3.04. Found: C, 73.39; H, 7.85; N, 2.96%.
6. Haverlock, T. J.; Mirzadeh, S.; Moyer, B. A. J. Am.
Chem. Soc. 2003, 125, 1126–1127.
1
7. 2: Solid, m.p. 74–76°C; H NMR (400.13 MHz; CDCl3,
23°C): l 3.62–3.79 (m, 8H), 3.86–3.95 (m, 4H), 4.15–4.25
(m, 4H), 6.90 (d, J=8.4, 1H), 7.10 (d, J=1.8, 1H), 7.27
(dd, J=1.8, J=8.4, 1H); 13C NMR (100.61 MHz; CDCl3,

M. G. Gorbuno6a et al. / Tetrahedron Letters 44 (2003) 5397–5401
5401
18. Casnati, A.; Fochi, M.; Minari, P.; Pochini, A.; Reggiani,
M.; Ungaro, R.; Reinhoudt, D. N. Gazz. Chim. Ital. 1996,
126, 99–106.
(s, 2H); 13C NMR: (selected) l 37.38 (ArCH2Ar), 37.72
(ArCH2Ar), 119.94 (CN). Anal. Calcd for C73H91NO12: C,
74.65; H, 7.81; N, 1.19. Found: C, 74.66; H, 7.73; N, 1.09%.
21. 16: Solid, m.p. 106–108°C; 1H NMR: l 0.83–0.90 (m, 12H),
1.10–1.35 (br m, 16H), 1.45–1.60 (br m, 2H), 2.40–2.52 (br
m, 4H), 3.48–3.80 (m, 26H), 4.00–4.20 (m, 10H), 4.40–4.50
(br m, 2H), 4.59 (br s, 2H), 6.16 (br s, 1H), 6.65 (t, J=7.5,
1
19. 14: Solid, m.p. 82–84°C; H NMR: l 0.87 (t, 12H), 1.27
(br s, 16H), 1.45–1.60 (br m, 2H), 2.40–2.60 (br m, 4H),
3.40–3.90 (m, 32H), 4.05–4.12 (m, 4H), 4.14–4.25 (m, 4H),
6.68 (t, J=7.4, 4H) 6.70–6.85 (m, 4H), 6.88 (d, J=8.1, 2H),
7.00–7.15 (m, 6H), 7.22 (s, 2H); 13C NMR: (selected) l
37.49 (ArCH2Ar), 37.81 (ArCH2Ar). Anal. Calcd for
C72H91BrO12: C, 70.40; H, 7.47. Found: C, 70.15; H, 7.37%.
20. 15: Solid, m.p. 93–95°C; IR (deposit from CH2Cl2 solution
on KCl plate, cm−1): w 2255 (CN); 1H NMR: l 0.87 (t, 12H),
1.27 (br s, 16H), 1.45–1.60 (br m, 2H), 2.40–2.52 (m, 4H),
3.44–3.82 (m, 32H), 4.00–4.20 (m, 8H), 6.62 (t, J=7.5, 2H),
6.65–6.83 (m, 6H), 6.88 (m, 2H), 7.00–7.10 (m, 6H), 7.46
2H), 6.68–6.95 (m, 9H), 7.02–7.10 (m 4H), 7.24 (s, 2H); 13
C
NMR: (selected) l 37.48 (ArCH2Ar), 37.74 (ArCH2Ar),
44.62 (CH2NH2). Anal. Calcd for C73H95NO12·2H2O: C,
72.18; H, 8.15; N, 1.18. Found: C, 72.63; H, 8.15; N, 1.18%.
22. The weaker extraction by 12 implies an additional effect,
which we suggest may arise from a negative allosteric
influence of intramolecular hydrogen binding. This possi-
bility is under investigation.