Carboxylate anion selective receptor with glycoluril molecular scaffold

Article abstract of DOI:10.1016/j.tetlet.2004.05.040

Glycoluril based tweezer-type receptor has been designed and synthesized. Anion binding studies carried out using ¹H NMR and UV-vis revealed that this compound displays good affinities for Y-shaped anions such as acetate and benzoate, while bin

Full text of DOI:10.1016/j.tetlet.2004.05.040

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5225–5228
Carboxylate anion selective receptor with
glycoluril molecular scaffoldq
Jongmin Kang,* Jee-hye Jo and Sungjae In
Department of Applied Chemistry, Sejong University, Seoul 143-747, South Korea
Received 31 March 2004; revised 3 May 2004; accepted 10 May 2004
1
Abstract—Glycoluril based tweezer-type receptor has been designed and synthesized. Anion binding studies carried out using H
NMR and UV–vis revealed that this compound displays good affinities for Y-shaped anions such as acetate and benzoate, while
binding spherical-shaped anions and tetrahedral-shaped anions only weakly.
ꢀ 2004 Elsevier Ltd. All rights reserved.
While the selective recognition of cations was one of the
main challenges in the early days of supramolecular
chemistry,1 the recognition of anions by artificial
receptors became another goal of supramolecular
chemistry.2 As anions display wide range of geometries,
a host–guest complementarity is required for the design
of anion receptor. Therefore, hydrogen bonds are fre-
quently used by many researchers as recognition ele-
ments due to their directionality. Correct orientation of
hydrogen bonds can differentiate among anionic guests
with different geometries. Nature also utilizes neutral
amide N–H groupto achieve anion binding by pro-
teins.3 For synthetic receptor with amide group, the
amide groups are arranged through a space in a
rigid and convergent manner. This has been achieved
by incorporating amide group inside macrocycle4
or utilizing molecular scaffold to arrange amide
groups. Benzene ring,5 pyrrole,6 cyclohexane,7 cholic
acid,8 tris(aminoethylamine),9 and calixarenes10 have
been utilized as molecular scaffolds to arrange amide
bonds. Recently, we have introduced glycoluril as a new
molecular scaffold to arrange four amides at the corner
of glycoluril. This anion receptor 1 utilizes four amide
hydrogen bonds cooperatively to bind spherically-
shaped halide ion with 1:1 stoichiometry and has a high
affinity for fluoride ion.11 We also synthesized glycoluril
based tweezer-type receptor 2, which has only two
amide hydrogen bonds. Anion binding studies carried
out using 1H NMR and UV–vis revealed that this
compound displays good affinities for Y-shaped anions
such as acetate and benzoate, while binding spherical-
shaped anions and tetrahedral-shaped anions only
weakly.
O
O
O
NHR
RHN
O
NHR
O
O
N
N
N
N
N
Ph
N
N
Ph
N
Ph
Ph
NHR
O
O
RHN
NHR
O
O
1
2
The synthesis of the receptor 2 was achieved as depicted
in Scheme 1. The synthesis stared from the reaction
between 10 equiv of excess diphenyl glycoluril and a,a0-
dibromo-o-xylene in the presence of potassium tert-
butoxide. This reaction gave the one side protected
glycoluril 3 in 40% yield. Then the compound 3 treated
with potassium tert-butoxide was reacted with methyl-
bromoacetate in DMSO to give the compound 4 in 46%
yield. Hydrolysis of the compound 4 with 10 equiv of
lithium hydroxide in methanol afforded the compound 5
in 84% yield. Treatment of the compound 5 with oxalyl
chloride gave diacyl chloride 6 in quantitative yield.
Finally the reaction with 4-nitroaniline, 4-fluoroaniline
or butylamine with diacyl chloride 6 gave the desired
Keywords: Carboxylate selective receptor.
q Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tetlet.2004.05.040
* Corresponding author. Tel.: +82-234083213; fax: +82-24629954;
e-mail: kangjm@sejong.ac.kr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.040

5226
J. Kang et al. / Tetrahedron Letters 45 (2004) 5225–5228
O
O
O
O
Br
( 2eq.)
Br
( 0.1 eq.)
Br
OCH
3
HN
Ph
HN
NH
Ph
NH
N
N
NH
Ph
NH
Ph
t-BuOK ( 2eq.)
t-BuOK (2eq.)
DMSO
DMSO 6hr 46%
O
1hr 40%
3
O
O
O
O
OCH
OCH
O
OH
OH
3
1) LiOH ( 10eq.)
Cl
Cl
MeOH
overnight
N
N
N
N
N
N
N
O
Ph
Ph
O
Ph
Ph
O
2) 12% HCl pH2
5% DMF-M.C. M.C. 1hr
N
H O
2
84 %
O
O
3
4
5
O
O
O
O
Cl
Cl
O
NHR
N
N
N
N
RNH (6eq.)
N
2
2a R = 4-nitrobenzene 83%
2b R = 4-fluorobenzene 99%
2c R = n-butyl 88%
Ph
Ph
Ph
Ph
N
CHCl
1hr
N
N
3
NHR
O
O
O
6
2
Scheme 1. The synthetic procedure for the anion receptor 2.
compounds 2a,b and 2c in 83%, 99% and 88% yield,
respectively (Scheme 1).
induced chemical shifts versus anion concentration gave
typical titration curves corresponding to the formation
of a 1:1 complex (Fig. 1A). The association constants
calculated from NMR titration gave 8.9 · 104 Mꢀ1 for
acetate and 3.5 · 104 Mꢀ1 for benzoate. However, these
The complexation abilities of compounds 2a,b and 2c
1
were measured by standard H NMR titration experi-
1
ments in CD3CN using a constant host concentration
(1.5–2 mM) and increasing concentrations of anions
(0.1–10 equiv). The chemical shift data were analyzed by
EQNMR.12 The addition of tetrabutylammonium anion
salts to the solution of 2 in CD3CN resulted in downfield
shifts in both the amide N–H hydrogen and CH2
hydrogens next to amides. Therefore, the signals of
amide NH2 or the signals of CH2 protons located next
to amide groups were used to determine the association
constants for complex 2 and anions. Whichever peaks
we chose, binding constants between the receptor 2 and
anions showed similar values.
values are too large to accept from H NMR titration
experiments.13 Therefore, the binding properties of 2a
with acetate or benzoate were further assessed by UV–
vis spectroscopy. Figure 1B shows the dependence of
UV–vis spectra of 2a on the concentration of acetate in
CH3CN. Increasing the concentration of acetate pro-
duced a bathochromic shift in the kmax from 317 to
329 nm and clear isosbestic point appears at 321 nm.
Similar spectrum was observed for the titration of 2a
with benzoate. Association constants calculated using a
14
computer program ENZFITTER gave 9.1 · 104 Mꢀ1 for
acetate 2.4 · 104 Mꢀ1 for benzoate. The possible binding
mode and energy minimized structure of receptor 2a and
acetate were shown in Figure 2. Receptors 2b and 2c,
which have less acidic N–H than 2a, showed marked
decrease in association constants for the same anions,
which reflects the importance of hydrogen bond in the
binding event of the receptor 2 and anions. The associ-
ation constants are listed in Table 1. We also investi-
gated the associations of receptor 2a and spherical
anions such as halides, tetrahedral anions such as di-
hydrogenphosphate and hydrogen sulfate or linear an-
ion such as cyanide. Job plot experiments showed 1:1
binding stoichiometry (Fig. 3) for all kinds of anions
irrespective of anion shapes. The association constants
As the receptor 2a was expected to have the strongest
affinity for anions, the association constants of 2a for
different anions were determined first. From the exper-
iments, 2a showed the highest affinities for Y-shaped
anions such as acetate and benzoate. The addition of
tetrabutylammonium acetate or benzoate to the solution
of 2a leads downfield shifts of the CH2 peaks next to
amides. The amide N–H peaks disappeared upon addi-
tion of acetate or benzoate. The CH2 peaks next to
amides moved downfield about 0.17 ppm for 1 equiv
acetate ion and 0.27 ppm for 1 equiv benzoate ion. No
further shifts were observed for both anions. The plot of

J. Kang et al. / Tetrahedron Letters 45 (2004) 5225–5228
5227
0.8
4.4
4.35
4.3
Host
1eq.
3eq.
5eq.
7eq.
10eq.
20eq.
0.6
4.25
4.2
0.4
acetate
benzoate
0.2
4.15
4.1
0.0
4.05
250
300
350
400
450
0
2
4
6
8
10
(A)
(B)
Equivalents of anion
Wavelength
Figure 1. (A) Changes in the CH2 protons located next to amide groups in 2a with increasing acetate or benzoate concentration in acetonitrile-d3.
(B) Changes in UV–vis spectra of 2a titrated with acetate (as tetrabutylammonium salt).
0.7
0.6
0.5
0.4
Chloride
Dihydrogenphosphate
Cyanide
0.3
0.2
Figure 2. The energy minimized structure of 1:1 complex between
receptor 2a and acetate (Cache 3.2 MOPAC calculation); aromatic
rings are omitted for clarity.
0.1
0
0
0.2
0.4
0.6
0.8
1
[H] / ([H]+[G])
calculated from NMR titration are summarized in Table
1. For receptor 2a, the association constants were cal-
culated as 2770 for fluoride and 1645 for dihydrogen-
phosphate, which are much smaller values than acetate
or benzoate. The association constant for acetate is
about 30–50 times higher than those of fluoride or di-
hydrogenphosphate. Probably the binding site of
receptor 2 does not fit to the spherical halide ions, tet-
rahedral anions or linear cyanide anion. However, for
these anions the association constants still reflect bas-
icity of these anions.15 Fluoride and dihydrogenphos-
phate are stronger hydrogen acceptor than other halide
or hydrogen sulfate, respectively. Receptor 2b and 2c
also showed smaller association constants than 2a for
the same anions as expected. However, for these anions,
the differences in association constants among the
Figure 3. The Job plot of 2a with tetrabutylammonium chloride (d),
dihydrogenphosphate (m) and cyanide (j).
receptors 2a,b and 2c are much smaller than those of
carboxylate anions. The effect of amide N–H acidity
does not seem to play much role for the anions, which
does not fit to the binding site of receptor.
In conclusion, we have designed and synthesized new
anion receptor 2 with glycoluril molecular scaffold and
the receptor 2 displays selectivities for Y-shaped car-
boxylate anions over spherical-shaped halides, tetrahe-
dral anions or linear anions.
Table 1. Association constants (Mꢀ1) of 2 with tetrabutylammonium anions in CD3CN from 1H NMR titration
Anion
2a
2b
2c
ꢀ
ꢀ
CH3CO2
C6H5CO2
9.1 · 104a
2.4 · 104a
32b
2.7 · 103b
2.3 · 103c
2.2 · 102b
13c
5.3 · 102b
1.6 · 103c
1.1 · 102b
6.9 · 103b
5.0 · 103b
12c
2.1 · 102b
1.3 · 102b
6c
ꢀ
NO3
Fꢀ
Clꢀ
Brꢀ
Iꢀ
2.6 · 103b
1.7 · 103c
80b
2.5 · 102c
28b
13b
7c
11c
CNꢀ
2.3 · 102b
1.1 · 103c
1.1 · 102b
28b
ꢀ
H2POꢀ4
58c
HSO4
32b
a Association constants were calculated from UV–vis titration.
b Errors in Ka are estimated to be less than 10%.
c Errors in Ka are estimated to be less than 20%.

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J. Kang et al. / Tetrahedron Letters 45 (2004) 5225–5228
5. (a) Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J.
Acknowledgements
Org. Chem. 1999, 64, 1675; (b) Kavallieratos, K.; Gala, S.
R. D.; Austin, D. J.; Crabtree, R. H. J. Am. Chem. Soc.
1997, 119, 2325; (c) Beer, P. D.; Fletcher, N. C.; Grieve,
A.; Wheller, J. W.; Moore, C. P.; Wear, T. J. Chem. Soc.,
Perkin Trans. 2 1996, 1545.
This study was supported by a grant from the Korea
Association of Small Businesses Innovation Research
2004.
6. (a) Gale, P. A.; Camiolo, S.; Tizzard, G. J.; Chapman, C.
P.; Light, M. E.; Coles, S. J.; Hursthouse, M. B. J. Org.
Chem. 2001, 66, 7849; (b) Gale, P. A.; Camiolo, S.;
Chapman, C. P.; Light, M. E.; Hursthouse, M. B.
Tetrahedron Lett. 2001, 42, 5095; (c) Camiolo, S.; Gale,
P. A.; Light, M. E.; Hursthouse, M. B. Tetrahedron Lett.
2002, 43, 6995.
References and notes
1. (a) Pedersen, C. Angew. Chem., Int. Ed. 1998, 27, 1021;
(b) Lehn, J.-M. Angew. Chem., Int. Ed. Engl. 1988, 27,
90.
2. (a) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed. 2001,
40, 486; (b) Gale, P. A. Coord. Chem. Rev. 2000, 199, 181;
(c) Gale, P. A. Coord. Chem. Rev. 2001, 213, 79; (d) Gale,
P. A. Coord. Chem. Rev. 2003, 240, 191.
3. Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of
Biochemistry; Wiley: New York, 1999.
7. Raposo, C.; Perez, N.; Almaraz, M.; Mussons, M. L.;
Caballero, M. C.; Moran, J. R. Tetrahedron Lett. 1995, 36,
3255.
8. (a) Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem.
Soc. 1997, 119, 1793; (b) Ayling, A. J.; Perez-Payan, M.
N.; Davis, A. P. J. Am. Chem. Soc. 2001, 123, 12716.
9. Valiyaveetil, S.; Engbersen, J. F. J.; Verboom, W.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1993, 32,
900.
10. (a) Beer, P. D.; Timoshenko, V.; Maestri, M.; Passaiti, P.;
Balzani, V. Chem. Commun. 1999, 1755; (b) Cameron, B.
R.; Loeb, S. J. Chem. Commun. 1997, 573.
11. Kang, J.; Ju, H.-K.; Jo, J.-H. Supramol. Chem. 2004,
16(3), 175.
12. Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311.
13. Wilcox, C. S.; Schneider, H. Frontiers in Supramolecular
Chemistry; VCH: Weinheim, 1991; p123.
14. (a) This program is available from Elsevier-BIOSOFT, 68
Hills Road, Cambridge CB2 1LA, United Kingdom; (b)
Connors, K. A. Binding Constants; Wiley: New York,
1987.
4. (a) Szumna, A. Eur. J. Org. Chem. 2001, 4031; (b)
Hossain, M. A.; Liinares, J. M.; Powell, D.; Bowman-
James, K. Inorg. Chem. 2001, 40, 2936; (c) Choi, K.;
Hamilton, A. D. J. Am. Chem. Soc. 2001, 123, 2456; (d)
Hinzen, B.; Seiler, P. Helv. Chim. Acta 1996, 79, 942; (e)
Davis, A. P.; Gilmer, J. F.; Perry, J. J. Angew. Chem., Int.
Ed. 1996, 35, 1312; (f) Sansone, F.; Baldini, L.; Casnati,
A.; Lazzarotto, M.; Ugozzoli, F.; Ungaro, R. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 4842; (g) Beer, P. D.; Gale, P.
A.; Hesek, D. Tetrahedron Lett. 1995, 36, 767; (h)
Andrievsky, A.; Ahuis, F.; Sessler, J. L.; Vogtle, F.;
Gudat, D.; Moini, M. J. Am. Chem. Soc. 1998, 120, 9712;
(i) Pascal, R. A.; Spergel, J.; Engbersen, D. V. Tetrahedron
Lett. 1985, 27, 4099; (j) Fujita, T.; Lehn, J. M. Tetrahedron
Lett. 1988, 29, 1709; (k) Bisson, A. P.; Lynch, V. M.;
Monahan, M.-K. C.; Anslyn, E. V. Angew. Chem., Int. Ed.
1997, 36, 2340.
15. Nishizawa, S.; Buhlmann, P.; Iwao, M.; Umezawa, Y.
Tetrahedron Lett. 1995, 36(36), 6483.