Heterodimerization studies of calix[4]arene derivatives in polar solvents

Article abstract of DOI:10.1021/ol060612+

Several calix[4]arene derivatives propylated on the lower rim and substituted on the upper rim with amino or carboxyl groups have been synthesized. Examples include calixarenes substituted with alanino (C- and N-linked), amino, carboxy, carboxyphenyl, and

Full text of DOI:10.1021/ol060612+

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2913-2915
Heterodimerization Studies of
Calix[4]arene Derivatives in Polar
Solvents
Joshua S. Sasine, R. Elizabeth Brewster, Kevin L. Caran,
Adrienne M. Bentley, and Suzanne B. Shuker*
Department of Chemistry and Biochemistry, Georgia Institute of Technology,
Atlanta, Georgia 30332
suzy.shuker@chemistry.gatech.edu
Received March 13, 2006
ABSTRACT
Several calix[4]arene derivatives propylated on the lower rim and substituted on the upper rim with amino or carboxyl groups have been
synthesized. Examples include calixarenes substituted with alanino (C- and N-linked), amino, carboxy, carboxyphenyl, and amidino groups.
The self-assembly of these derivatized calixarenes into heterodimers has been studied by NMR in DMSO-d6 or CD3OD with 5% aqueous
phosphate buffer.
Molecular recognition is a rapidly growing field centered
around the synthesis and study of molecules capable of
recognizing and binding one another through intermolecular
interactions such as hydrogen bonds, π-stacking, hydrophobic
interactions, electrostatic interactions, and van der Waals
interactions. These molecules have a wide variety of ap-
plications, including catalysis, drug delivery, chiral separa-
tion, biocatalysis, and supramolecular assembly. One par-
ticular area that has received considerable attention is the
design and synthesis of self-assembling capsules. A self-
assembling capsule is a supramolecular structure made up
of two or more molecules that come together through non-
covalent, reversible interactions to form an enclosed cavity.
If an appropriate guest molecule is mixed in with the
monomers, the guest will be encapsulated within the cavity.
synthesis of dimers that assemble through ionic interactions
in polar solvents has been reported.2 In these cases, the
dimerization is favored by the increased bond strength of
ionic bonds over hydrogen bonds. Here, we report the
synthesis of calixarene derivatives that utilize ionic interac-
tions to form heterodimers in polar solvent.
(1) For dimers formed through hydrogen bonds in nonpolar solvents,
see: (a) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. J. Am. Chem. Soc.
1997, 119, 12670-12672. (b) Castellano, R. K.; Nickolls, C.; Rebek, J.,
Jr. J. Am. Chem. Soc. 1999, 121, 11156-11163. (c) Castellano, R. K.;
Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1996, 118, 10002-
10003. (d) Mogck, O.; Bo¨hmer, V.; Vogt, W. Tetrahedron 1996, 52, 8489-
8496. (e) Mogck, O.; Pons, M.; Bo¨hmer, V.; Vogt, W. J. Am. Chem. Soc.
1997, 119, 5706-5712. (f) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P.
Angew. Chem., Int. Ed. 2001, 40, 2382-2426. (g) Rinco´n, A. M.; Prados,
P.; de Mendoza, J. J. Am. Chem. Soc. 2001, 123, 3493-3498. (h) Rebek,
J., Jr. Chem. Commun. 2000, 637-643. (i) Shimizu, K. D.; Rebek, J., Jr.
Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 12403-12407. (j) Schalley, C. A.;
Castellano, R. K.; Brody, M. S.; Rudkevich, D. M.; Siuzdak, G.; Rebek, J.,
Jr. J. Am. Chem. Soc. 1999, 121, 4568-4579. (k) Vysotsky, M. O.;
Thondorf, I.; Bo¨hmer, V. Angew. Chem., Int. Ed. 2000, 39, 1264-1266.
For dimers formed through hydrogen bonds in polar solvents, see: (l)
Atwood, J. L.; Barbour, L. J.; Jerga, A. Chem. Commun. 2001, 2376-
2377. (m) Shivanyuk, A.; Rebek, J., Jr. Chem. Commun. 2001, 2374-2375.
(n) Vysotsky, M. O.; Thondorf, I.; Bo¨hmer, V. Chem. Commun. 2001,
1890-1891.
To utilize capsules and complexes for biological applica-
tions, they must self-assemble and be soluble in polar, protic
solvents. Although there are many examples of self-as-
sembling dimers in nonpolar solvent, these compounds utilize
hydrogen bonding1 and the addition of small amounts of
polar solvent often disrupts the complex. Recently, the
10.1021/ol060612+ CCC: $33.50
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We have prepared a number of calix[4]arene derivatives
substituted on the upper rim with amino or carboxyl groups,
including C-linked alaninocalix[4]arene 1,3 N-linked alanino-
calix[4]arene 2, anilinocalix[4]arene 3,4 carboxycalix[4]arene
4, carboxyphenylcalix[4]arene 5, and amidinocalix[4]arene
11. Calix[4]arene derivatives 1 and 3 are shown in Figure
1. The syntheses of 2, 4, 5, and 11 are shown in Schemes
1-3.
was then converted to the acid fluoride 7 using diethylami-
nosulfur trifluoride (DAST) in methylene chloride. tert-Butyl
protected alanine was coupled to 7 using triethylamine in
methylene chloride to afford the protected alaninocalix[4]-
arene 8. Deprotection of 8 with trifluoroacetic acid (TFA)
in methylene chloride yielded the desired product, N-linked
alaninocalix[4]arene 2.
Scheme 2. Synthesis of Carboxyphenylcalix[4]arene 5
Figure 1. Previously synthesized calix[4]arene derivatives.
Carboxyphenylcalix[4]arene 5 was prepared in two steps
from bromocalix[4]arene 96 (Scheme 2). Suzuki coupling
of 9 with p-cyanophenylboronic acid was accomplished in
THF/water using palladium tetrakis(triphenylphosphine) and
sodium carbonate. Hydrolysis of the resulting nitrilophenyl-
calix[4]arene 10 with potassium hydroxide in EtOH/water
affords compound 5 in excellent yield.
N-Linked alaninocalix[4]arene was synthesized in four
steps from nitrilocalix[4]arene 6 (Scheme 1), which was
Scheme 1. Synthesis of Alaninocalix[4]arene 2 and
Carboxycalix[4]arene 4
Scheme 3. Synthesis of Amidinocalix[4]arene 11
Amidinocalix[4]arene 11 was synthesized from nitrilocalix-
[4]arene in one step using an alkylchloroaluminum amide6
(Scheme 3). The aluminum reagent was prepared in situ from
trimethyl aluminum and ammonium chloride in dichloroet-
hane.7
The self-assembly of these derivatized calixarenes into
heterodimers was studied by NMR in DMSO-d6 or CD3OD
with 5% aqueous phosphate buffer. Anilinocalix[4]arene 3
does not dimerize with either 2 or 4 in the DMSO/buffer,
pH 4.3 mixture. In contrast, C-linked alaninocalix[4]arene
1 does form a complex with 2, 4, and 5 in DMSO/buffer,
pH 6.5 (Figure 2).
prepared following the procedure from Pinkhassik et al.5 The
nitrile was hydrolyzed with potassium hydroxide in EtOH/
water to form carboxycalix[4]arene 4. The acid derivative 4
(2) For dimers formed through ionic interactions in polar solvents, see:
(a) Corbellini, F.; Di Costanzo, L.; Crego-Calama, M.; Geremia, S.;
Reinhoudt, D. N. J. Am. Chem. Soc. 2003, 125, 9946-9947. (b) Corbellini,
F.; Fiammengo, R.; Timmerman, P.; Crego-Calama, M.; Versluis, K.; Heck,
A. J. R.; Luyten, I.; Reinhoudt, D. N. J. Am. Chem. Soc. 2002, 124, 6569-
6575. (c) Grawe, T.; Schrader, T.; Gurrath, M.; Kraft, A.; Osterod, F. J.
Phys. Org. Chem. 2000, 13, 670-673. (d) Hamelin, B.; Jullien, L.; Derouet,
C.; du Penhoat, C. H.; Berthault, P. J. Am. Chem. Soc. 1998, 120, 8428-
8447. (e) Lee, S. B.; Hong, J.-I. Terahedron Lett. 1996, 37, 8501-8504.
(f) Zadmard, R.; Schrader, T.; Grawe, T.; Kraft, A. Org. Lett. 2002, 4,
1687-1690.
(3) Brewster, R. E.; Shuker, S. B. J. Am. Chem. Soc. 2002, 124, 7902-
7903.
(4) Matthews, S. E.; Saadioui, M.; Bo¨hmer, V. J. Prakt. Chem. 1999,
341, 264-273.
(5) Pinkhassik, E.; Sidorov, V.; Stibor, I. J. Org. Chem. 1998, 63, 9644-
9651.
(6) Corbellini, F.; Fiammengo, R.; Timmerman, P.; Crego-Calama, M.;
Versluis, K.; Heck, A. J. R.; Luyten, I.; Reinhoudt, D. N. J. Am. Chem.
Soc. 2002, 124, 6569-6575.
2914
Org. Lett., Vol. 8, No. 14, 2006

No dimerization was observed between amidinocalix[4]-
arene 11 and carboxycalix[4]arene 4 or N-linked alaninocalix-
[4]arene 2 (Table 1).
All of the heterodimers were analyzed using Job plots,
and a representative plot of 1 and 2 is shown in Figure 3.
Figure 2. NMR dilution studies of C-linked alaninocalix[4]arene
1 with N-linked alaninocalix[4]arene 2, carboxycalix[4]arene 4, and
carboxyphenylcalix[4]arene 5 in DMSO-d6/5% phosphate buffer
at pH 6.5.
The dimerization of these derivatives is attributed to the
larger difference in pKa’s of protonated 1 (pKa ∼ 9) and 2,
Figure 3. Job plot of the aryl protons of C-linked alaninocalix-
[4]arene 1 with N-linked alaninocalix[4]arene 2 in DMSO-d6/5%
phosphate buffer at pH 6.5.
Table 1. Heterodimer Association Constants
heterodimers
Ka (M-1
)
solvent
All of the Job plots have a maximum at approximately 0.5,
indicating the assembly of a supramolecular structure with
a 1:1 monomer ratio. The NMR spectra from both the Job
plots and the dilution studies have sharp peaks that are
consistent with the formation of heterodimers rather than
larger assemblies, which would be expected to have broader
peaks in the NMR spectra.
1 + 2
1 + 5
1 + 4
3 + 2
3 + 4
11 + 2
11 + 4
5040
4410
1200
a
DMSO-d6/5% buffer, pH 6.5
DMSO-d6/5% buffer, pH 6.5
DMSO-d6/5% buffer, pH 6.5
DMSO-d6/5% buffer, pH 4.3
DMSO-d6/5% buffer, pH 4.3
CD3OD/5% buffer, pH 8.8
DMSO-d6/5% buffer, pH 8.8
a
a
a
In summary, this paper describes the ability of calix[4]-
arene derivatives to self-assemble into heterodimers in polar
solvents with association constants of 5000-1000 M-1.
Although the calix[4]arene derivatives are water soluble as
monomers, the heterodimers are not. We are currently
synthesizing calix[4]arene derivatives with alcohols on the
lower rim to increase the water solubility.
a No dimerization observed.
4, and 5 (pKa ∼ 5) compared to that of 3 (pKa ∼ 4.7) and 2,
4, and 5. The monomers with the largest pKa difference,
N-linked and C-linked alaninocalix[4]arene, form the tightest
binding heterodimer (Ka ) 5040 M-1).2 Carboxyphenylcalix-
[4]arene also forms a strong heterodimer with 1 (Ka ) 4410
M-1),8 followed by carboxycalix[4]arene (Ka ) 1200 M-1).8
It is interesting to note that addition of the phenyl spacers
to the calix[4]arene scaffold increases the size of the hetero-
dimer with little effect on its ability to dimerize (Table 1).
Acknowledgment. We thank NSF (0316801) and the
Georgia Institute of Technology for financial support.
Supporting Information Available: Experimental pro-
cedures, NMR data, 1H NMR spectra, and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Garigipati, R. S. Tetrahedron Lett. 1990, 31, 1969-1972.
(8) All of the association constants were calculated using the method
described in: Nakano, M.; Nakano, N. I.; Higuchi, T. J. Phys. Chem. 1967,
71, 3954-3959.
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Org. Lett., Vol. 8, No. 14, 2006
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