Efficient synthesis of water-soluble calixarenes using click chemistry

Article abstract of DOI:10.1021/ol047468h

(Chemical Equation Presented) Several water-soluble calix[4]arenes were synthesized via Huisgen 1,3-dipolar cycloaddition between azides and alkynes. Cationic, anionic, and nonionic calixarenes were prepared from a common azidocalixarene intermediate. Azidocalixarenes performed better than alkynylcalixarenes as precursors. The aggregation behavior of the water-soluble calixarenes was studied by ¹H NMR spectroscopy.

Full text of DOI:10.1021/ol047468h

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1035-1037
Efficient Synthesis of Water-Soluble
Calixarenes Using Click Chemistry
Eui-Hyun Ryu and Yan Zhao*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011-3111
zhaoy@iastate.edu
Received December 9, 2004
ABSTRACT
Several water-soluble calix[4]arenes were synthesized via Huisgen 1,3-dipolar cycloaddition between azides and alkynes. Cationic, anionic,
and nonionic calixarenes were prepared from a common azidocalixarene intermediate. Azidocalixarenes performed better than alkynylcalixarenes
as precursors. The aggregation behavior of the water-soluble calixarenes was studied by 1H NMR spectroscopy.
Calixarenes are among the most versatile and useful building
blocks in supramolecular chemistry.1 Water-soluble calix-
arenes attracted considerable attention very early on because
their well-formed hydrophobic cavities make it possible to
study molecular recognition in water. Water-soluble groups
such as sulfonates,2 carboxylic acids,3 amines,4 and phos-
phonates5 have been introduced through various reactions.
More recently, calixarenes have become attractive multivalent
scaffolds for making amphiphiles useful in both biological6,7
and chemical applications.8
compatibility. If the reaction does not give high conversion,
separation of the (highly polar) persubstituted products from
incompletely substituted ones is difficult. Because many of
the biological and chemical applications mentioned above
are influenced by the charge characteristics of water-soluble
calixarenes, it is highly desirable to have a modular synthesis
that can introduce a variety of water-soluble groups without
using protective/deprotective chemistry.
“Click chemistry”10 seems to be particularly suitable for
attaching water-soluble groups. Click reactions are modular,
tolerant of a wide range of solvents and functional groups,
However, synthesis of multivalent water-soluble calix-
arenes represents a considerable challenge.9 Certain reaction
conditions (e.g., sulfonation) have poor functional group
(6) (a) Marra, A.; Scherrmann, M.-C.; Dondoni, A.; Casnati, A.; Minari,
P.; Ungaro, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2479-2481. (b)
Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Casnati, F.; Sansone, F.;
Ungaro, R. Chem. Eur. J. 1997, 3, 1774-1782. (c) Roy, R.; Kim, J. M.
Angew. Chem., Int. Ed. 1999, 38, 369-372. (d) Fulton, D. A.; Stoddart, J.
F. Bioconjugate Chem. 2001, 12, 655-672 and references therein. (e) Pe´rez-
Balderas, F.; Ortega-Mun˜oz, M.; Morales-Sanfrutos, J.; Herna´ndez-Mateo,
F.; Calvo-Flores, F. G.; Calvo-As´ın, J. A.; Isac-Garc´ıa, J.; Santoyo-Gonza´lez,
F. Org. Lett. 2003, 5, 1951-1954. (f) Consoli, G. M. L.; Cunsolo, F.; Geraci,
C.; Sgarlata, V. Org. Lett. 2004, 6, 4163-4166.
(7) (a) Hamuro, Y.; Calama, M. C.; Park, H. S.; Hamilton, A. D. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2680-2683. (b) Park, H. S.; Lin Q.;
Hamilton, A. D. J. Am. Chem. Soc. 1999, 121, 8-13. (c) Casnati, A.;
Sansone, F.; Ungaro, R. Acc. Chem. Res. 2003, 36, 246-254 and references
therein.
(8) (a) Kellermann, M.; Bauer, W.; Hirsch, A.; Schade, B.; Ludwig, K.;
Bo¨ttcher, C. Angew. Chem., Int. Ed. 2004, 43, 2959-2962. (b) Lee, M.;
Lee, S.-J.; Jiang, L.-H. J. Am. Chem. Soc. 2004, 126, 12724-12725.(c)
Ryu, E.-H.; Zhao, Y. Org. Lett. 2004, 6, 3187-3189.
(9) For a review, see: Casnati, A.; Sciotto, D.; Arena, G. In Calixarenes
2001; Asfari, Z., Bo¨hmer, W., Harrowfield, J., Vicens, J., Eds.; Kluwer
Academic Press: Dordrecht, 2001; Chapter 24, pp 440-456.
(1) (a) Gutsche, C. D. In Calixarenes ReVisited, Monograph in Supramo-
lecular Chemistry; Stoddart, J. F., Ed.; Royal Society of Chemistry:
Cambridge, 1998. (b) Mandolini, L., Ungaro, R., Eds. Calixarenes in Action;
Imperial College Press: London, 2000. (c) Asfari, Z., Bo¨hmer, W.,
Harrowfield, J., Vicens, J., Eds. Calixarenes 2001; Kluwer Academic
Press: Dordrecht, 2001.
(2) (a) Shinkai, S.; Mori, S.; Tsubaki, T.; Sone, T.; Mababe, O.
Tetrahedron Lett. 1984, 25, 5315-5318. (b) Shinkai, S. Pure Appl. Chem.
1986, 58, 1523-1528. (c) Shinkai, S.; Araki, K.; Tsubaki, T.; Arimura, R.;
Manabe, O. J. Chem. Soc., Perkin Trans. 1 1987, 2297-2299.
(3) (a) Arduini, A.; Pochini, A.; Reverberi, S.; Ungaro, R. J. Chem. Soc.,
Chem. Commun. 1984, 981-982. (b) Gutsche, C. D.; Alam, I. Tetrahedron
1988, 44, 4689-4694.
(4) (a) Nagasaki, T.; Sisido, K.; Arimura, T.; Shinkai, S. Tetrahedron
1992, 48, 797-804. (b) Shimizu, S.; Kito, K.; Sasaki, Y.; Hirai, C. Chem.
Commun. 1997, 1629-1630.
(5) (a) Almi, A.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R.
Tetrahedron 1989, 45, 2177-2182. (b) Arimura, T.; Nagasaki, T.; Shinkai,
S.; Matsuda, T. J. Org. Chem. 1989, 54, 3766-3768.
10.1021/ol047468h CCC: $30.25
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Published on Web 02/22/2005

1. However, no reaction occurred at room temperature, and
complex mixtures formed at 60 °C.16
Scheme 1. Preparation of Water-Soluble Calix[4]arenesa
We then explored the second route using azidocalixarene
4 and water-soluble alkynes (5a-c). Reactions proceeded
very smoothly under similar conditions. One distinctive
advantage of this route is that the alkyne-coupling side
reaction16 at most would consume some of 5 but otherwise
cause no harm to the calixarene precursor 4. Another
advantage is in the preparation of the water-soluble alkynes
5a-c, which could be synthesized from readily available
starting materials in high yields and stored in a freezer
indefinitely.17 High stability is particularly important from
the standpoint of safety, because potentially explosive, small
organic azides have to be used in the other route involving
alkynylcalixarenes.18
In general, the coupling reaction between 4 and 5 was
complete within 24 h at 60 °C in THF/EtOH/H2O (1/2/2).
Calixarene 6a was purified by simple precipitation into
acetone, and 6b/6c was purified by reverse-phase column
chromatography with aqueous methanol as the eluent. The
isolated yield in general was about 80%. We also performed
the reactions using copper(I) iodide as the catalyst in the
presence of organic bases such as diisopropylethylamine, but
the reactions were not as clean.
The solubility of the resulting calixarene (6a-c) varied
greatly. The nonionic 6a, to our surprise, was not soluble at
all in water.19 Anionic calixarene 6b was soluble in water
but insoluble in methanol, acetone, acetonitrile, and tetrahy-
drofuran. Cationic 6c had solubility properties quite similar
to 6b in most solvents except methanol, in which it was quite
soluble.
a Reagents: (a) propargyl bromide, NaH; (b) CuSO4, sodium
ascorbate; (c) ethyl bromoacetate, K2CO3; (d) LiAlH4; (e) MsCl,
Et3N; (f) NaN3.
simple to perform, and very high yielding. Click reactions
have already been used successfully to prepare enzyme
inhibitors in situ,11 to functionalize surfaces,12 and to
synthesize dendritic polymers.13 In this communication, we
report the preparation of water-soluble calixarenes using the
Huisgen 1,3-dipolar cycloaddition of an azide and an alkyne
to form a triazole,14 one of the most efficient click reactions
to date.15
To attach water-soluble groups via the cycloaddition, we
can potentially employ calixarenes functionalized with either
alkynes or azido groups (Scheme 1). We first attempted the
synthesis of 3 because its precursor 2 could be prepared in
one step from commercially available tert-butylcalix[4]arene
Calixarenes 6b and 6c were soluble in water probably
because of micelle formation. To study their aggregation
1
behavior, we recorded their H NMR spectra at different
concentrations in D2O. This method requires a minimal
amount of material and has been used previously in the
characterization of similar water-soluble calixarenes.20
When the concentration of anionic 6b was increased from
0.2 to 5 mM, the chemical shifts of several hydrogens
changed significantly. The largest change in the chemical
shift was observed for the endo methylene bridge (ArCH2-
Ar) hydrogens. Significant changes were observed above 1
(16) Large difference in the solubility of 2 and azidoacetic acid was
probably responsible for the poor results. High temperature might have
promoted the side reaction, homocoupling of alkynes; see: (a) Cadiot, P.;
Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. D., Ed.; Marcel
Dekker: New York, 1969; pp 597-648. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3064. (c) Ref 15.
(17) Alkyne 5a was prepared by ring opening of δ-gluconolactone with
propargylamine in 97% yield. Alkynes 5b and 5c were prepared in 92 and
80% yields by nucleophilic substitution of propargyl bromide by sodium
sulfite and trimethylamine, respectively. See Supporting Information for
experimental details.
(10) Kolb, H. C., Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004-2021.
(11) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic´, Z.; Carlier, P.
R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 1053-1057.
(12) (a) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.-H.
J. Am. Chem. Soc. 2002, 124, 14397-14402. (b) Bryan, M. C.; Fazio, F.;
Lee, H.-K.; Huang, C.-Y.; Chang, A.; Best, M. D.; Calarese, D. A.; Blixt,
O.; Paulson, J. C.; Burton, D.; Wilson, I. A.; Wong, C.-H. J. Am. Chem.
Soc. 2004, 126, 8640-8641. (c) Collman, J. P.; Devaraj, N. K.; Chidsey,
C. E. D. Langmuir 2004, 20, 1051-1053.
(13) (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel,
A.; Voit, B.; Pyun, J.; Fre´chet, J. M. J.; Sharpless, K. B.; Fokin, V. V.
Angew. Chem., Int. Ed. 2004, 43, 3928-3932. (b) Helms, B.; Mynar, J. L.;
Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 2004, 126, 15020-
15021.
(18) Azidoacetic acid 3 was synthesized by reacting bromoacetic acid
with sodium azide in water and was used directly without further
purification; see: Dyke, J. M.; Groves, A. P.; Morris, A.; Ogden, J. S.;
Dias, A. A.; Oliveira, A. M. S.; Costa, M. L.; Barros, M. T.; Cabral, M.
H.; Moutinho, A. M. C. J. Am. Chem. Soc. 1997, 119, 6883-6887.
(19) A similar calixarene functionalized with tris(hydroxymethyl)-
aminomethane moieties at the lower rim was reported to have a solubility
of <10-5 M in water, see: Sgura, M.; Sansone, F.; Casnati, A.; Ungaro,
R. Synthesis 2001, 2105-2112.
(14) Huisgen, R.; Knorr, R.; Mobius, L.; Szeimies, G. Chem. Ber. 1965,
98, 4014-4021.
(15) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(20) Shinkai, S.; Arimura, T.; Araki, K.; Kawabata, H. J. Chem. Soc.,
Perkin Trans. 1 1989, 2039-2045.
1036
Org. Lett., Vol. 7, No. 6, 2005

9). This is not a surprise because, other than carrying
opposite charges, the trimethylammonium and sulfonate
headgroups are quite similar.
In summary, we have applied click chemistry to the
synthesis of water-soluble calixarenes. Because of possible
side reactions between the alkynes, couplings between
nonpolar azides and water-soluble alkynes gave much better
results than those between nonpolar alkynes and water-
soluble azides. The highly selective nature of the alkyne-
azide cycloaddition should make this click reaction a general
method to introduce polar groups without protective/depro-
tective chemistry.
Figure 1. 1H NMR data for 6b (2) and 6c (9) as a function of
concentration of the calixarene in D2O: (a) chemical shift of the
endo ArCH2Ar hydrogens and (b) line width of the phenyl hydrogen
signal vs concentration.
Acknowledgment. Acknowledgment is made to the
donors of the Petroleum Research Fund, administered by the
American Chemical Society, and to Iowa State University
for support of this research.
mM (Figure 1a). The signals also became substantially
broader above this concentration. Analysis of the line widths
(Figure 1b) gave the same critical micelle concentration
(CMC) of 1 mM. The CMC of the cationic calixarene 6c
was also about 1 mM (see Figure 1a and b, data shown in
Supporting Information Available: Experimental details
and NMR spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL047468H
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