Resorcin[4]arene-based anion receptors with four phenylurea substituents

Article abstract of DOI:10.1016/j.tetlet.2011.07.119

Cavitand-based anion receptors were developed by the introduction of four phenylurea moieties on the upper rim of a resorcin[4]arene. Their binding properties for various anions were investigated in DMSO-d₆ using ¹H NMR spectroscopic

Full text of DOI:10.1016/j.tetlet.2011.07.119

Tetrahedron Letters 52 (2011) 5176–5179
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Resorcin[4]arene-based anion receptors with four phenylurea substituents
⇑
Yeon Sil Park, Sungjong Seo, Kyungsoo Paek
Department of Chemistry and Molecular Engineering Research Lab., Soongsil University, Seoul 156-743, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Cavitand-based anion receptors were developed by the introduction of four phenylurea moieties on the
upper rim of a resorcin[4]arene. Their binding properties for various anions were investigated in DMSO-
d6 using 1H NMR spectroscopic methods, and the high 1:1 binding affinity for carboxylates was observed
due to hydrophobic as well as charge-dipole interactions between host and guest.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 20 June 2011
Revised 25 July 2011
Accepted 27 July 2011
Available online 4 August 2011
Keywords:
Anion binding
Resorcin[4]arene
Urea
Carboxylate anion
Anions play important roles in biological, medical, environmen-
tal, and chemical sciences.1 Due to these facts, there have been
intensive efforts on exploring efficient artificial receptors for tar-
geted anion recognition in supramolecular chemistry.2,3 Urea,4
amide,5 and amidourea6 groups have been used as useful structural
moieties for calix[4]arene-based anion receptors because they func-
tion as good hydrogen-bonding donors as well as acceptors with the
proper directionality important for binding-site organization. A
variety of functional groups have been attached on the upper rim
of resorcin[4]arene-based cavitands having concave molecular
structure, which enables resorcin[4]arene-based cavitands to be
attractive supramolecular building blocks for various organic recep-
tors.7 However, there are only a few resorcin[4]arene-based anion
receptors capable of selective anion recognition.8 Herein, we have
developed new anion receptors with four phenylurea moieties that
can recognize anions through hydrogen-bonding.
The syntheses of tetraphenylurea-cavitands 4 started with the
Pd(0)-catalyzed Suzuki coupling reaction between cavitand 1 and
3-nitrobenzeneboronic acid using Pd(PPh3)4 as a catalyst which
gave tetra(3-nitrophenyl)cavitand 2 in 64% yield (Scheme 1).9 Sub-
sequent transformation of cavitand 2 into tetra(3-aminophe-
nyl)cavitand 3 was accomplished under catalytic hydrogenation
using H2/Raney Ni in toluene.10 The target cavitands 4 were syn-
thesized in 78–82% yield from the reaction of tetra(3-aminophe-
nyl)cavitand 3 with the corresponding isocyanate (Y = H or NO2)
in triethylamine/THF (Scheme 1).11 Pure cavitands 4 were obtained
by recrystallization from a 4:1 mixture of CH2Cl2 and MeOH, and
were fully characterized with 1H and 13C NMR, high-resolution
MALDI-TOF mass spectrometry, and elemental analyses.
The recognition properties of tetrakis(phenylurea)cavitands 4
toward anions of various geometries were investigated using 1H
NMR spectroscopic methods with tetra-n-butylammonium salts
(Bu4N+Xꢀ). Cavitands 4 are hardly soluble in common organic sol-
vents such as CH2Cl2 or CHCl3, but soluble in highly polar solvents
such as DMSO. Due to their limited solubility, titration experi-
ments were carried out in DMSO-d6.
Despite of the high hydrogen-bonding acceptor property of
DMSO-d6, the addition of various anions such as CH3COꢀ, H2POꢀ,
2
4
BFꢀ4 , PF6ꢀ, NOꢀ3 , and Iꢀ to the DMSO-d6 solution of receptor 4a or
4b exhibited the peak broadening and a significant down-field shift
of the urea ꢀNH protons. No noticeable shifts of other signals of
receptor could be observed. This imply that the anions were bound
by urea NHꢁ ꢁ ꢁXꢀ hydrogen bonding. The 1H NMR titration curves of
cavitand 4a with various anionic guests are shown in Figure 1.
Tetrakis(40-nitrophenylurea)cavitand 4a showed the large
down-field shifts of the urea ꢀNHb peak from 9.35 ppm to
11.53 ppm (
d = 2.06 ppm) upon the complexation with acetate anion. And
small down-field shifts ( d = 0.14–0.25 ppm) for the ortho- protons
Dd = 2.18 ppm) and –NHc from 8.85 ppm to 10.91 ppm
(D
D
of the phenyl rings (Ha, Hd, and He) were observed in the same con-
ditions. Cavitand 4a also shows a moderate down-field shifts of the
urea ꢀNH signal (
D
d = 1.02 ppm) with H2POꢀ. But only small com-
4
plexation-induced chemical shifts were observed in the case of
BFꢀ4 , PFꢀ6 , NOꢀ3 , and Iꢀ. The strong affinity of acetate anion may be
attributed to its geometry. Due to Y-shaped geometry of acetate,
the hydrogen bonding interactions between the carboxylate group
and the two across urea –NH groups become more feasible. Together
with the cavity filling effect of methyl group acetate anion was
proved to be a favorable guest.
The same trends can be seen for tetrakis(phenylurea)cavitand
4b. For cavitand 4b, the signal of urea –NH is unresolved and
⇑
Corresponding author. Tel.: +82 2 820 0435; fax: +82 2 826 1785.
E-mail address: kpaek@ssu.ac.kr (K. Paek).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.119

Y. S. Park et al. / Tetrahedron Letters 52 (2011) 5176–5179
5177
NO2
(HO)2B
Br
Br
Br
O
Br
O
O
O
O
O
O
O
Pd(PPh3)4, K2CO3
toluene/EtOH/H2O
reflux
Y
Y
Y
Y
C7H15
C7H15
C7H15
C7H15
1
Ha
NHb
Ha
NH
NH
HN
HN
HN
HN
O
He
O
O
O
NHc
X
X
X
X
OCN
Y
Hd
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
C7H15
C7H15
C7H15
C7H15
C7H15
C7H15
C7H15
C7H15
2 : X = NO2
3 : X = NH2
H2 / Raney Ni
toluene, 45 oC
4a : Y = NO2
4b : Y = H
Scheme 1. Synthesis of tetrakis(phenylurea)cavitands 4.
0.4
0.3
0.2
0.1
0.0
0.0
0.2
0.4
0.6
0.8
1.0
[G]/[H+G]
Figure 2. Job plot of cavitand 4a with Bu4NþCH3COꢀ in DMSO-d6.
2
Figure 1. 1H NMR titration curve of cavitand 4a with tetrabutylammonium salts of
anionic guests in DMSO-d6. (Dd: complexation-induced chemical shifts of the urea –
NHb protons).
Table 1
Binding constants (K, Mꢀ1) of cavitand 4 with tetrabutylammonium salts in DMSO-d6
at 25 °C
Host
C3H7COꢀ2
CH3COꢀ2
H2POꢀ4
BFꢀ4
PFꢀ6
NOꢀ3
Iꢀ
gradually moved to down-field from 8.62 ppm to 10.58 ppm
4a
4b
433
352
421
343
213
200
21
19
23
23
17
25
13
12
(
D
d = 1.96 ppm) upon the addition of up to 8 equiv of acetate anion.
To determine the binding stoichiometry of cavitands 4 with an-
ions, Job plot experiments12 were used. Figure 2 shows the Job plot
of cavitand 4a with CH3COꢀ. The concentration of caviplex CH3COꢀ
2
2
@4a approaches a maximum when the molar fraction of anion is
the other hand, the complexation of other anions (BFꢀ4 , PF6ꢀ, NO3ꢀ,
and Iꢀ) exhibited weak binding affinities (K <30 Mꢀ1).
about 0.5, which indicates that CH3COꢀ forms a 1:1 complex with
2
cavitand 4a.
The binding affinity of cavitand 4a is stronger than cavitand 4b.
The introduction of electron-withdrawing para-substituents,
ꢀNO2, to the urea phenyl ring of cavitand 4a increase the acidity
of the urea –NH and accordingly strengthen the hydrogen bonding
interaction between the urea –NH and anions.13
The binding constant, K was determined through the monitor-
ing of the complexation induced shifts of the urea ꢀNHb protons
using the WinEQNMR,13 a nonlinear least squares regression com-
puter program. The binding constant values for cavitands 4a and
4b with various anions in DMSO-d6 are summarized in Table 1.
Tetrakis(4-nitrophenylurea)cavitand 4a showed a significant
binding affinity toward carboxylate anions (Kacetate = 421 Mꢀ1 and
Kpropionate = 433 Mꢀ1). Also, the binding of the tetrahedral H2POꢀ4
is moderate (Kdihydrogen phosphate = 213 Mꢀ1). These affinities may
To estimate the orientation of anion in the cavity of cavitand 4a,
1H NMR titration experiments were performed with the larger
C3H7COꢀ (Fig. 3). As C3H7COꢀ was added to the solution of cavit-
2
2
and 4a, 1H NMR spectra showed the up-field shift of the methyl
protons of the complexed anion from 0.93 to 0.72 ppm
be due to the basicity of carboxylate anions and H2POꢀ, allowing
(D
d = ꢀ0.21 ppm). The relatively small upfield chemical shift and
4
it to form stronger hydrogen-bonding with the urea –NH.14 On
binding constant of complexed C3H7COꢀ seem to be due to the fast
2

5178
Y. S. Park et al. / Tetrahedron Letters 52 (2011) 5176–5179
Figure 5. The energy-minimized structures of tetrakis(4-nitrophenylurea)-cavit-
and 4a (left) and caviplex C3H7COꢀ2 @4a (right) using Spartan’04 V1.03 (Molecular
Mechanics MMFF).
showed the high affinities for 1:1 binding with carboxylate anions
due to the dual hydrophobic as well as hydrogen bonding interac-
tions. Currently various modifications to increase their solubility
are on going.
Figure 3. 1H NMR spectra showing the chemical shift changes of cavitand 4a
(4 mM) by the addition of Bu4N+C3H7CO2ꢀ in DMSO-d6 at 25 °C.
Acknowledgments
This work was supported by CBMH (Yonsei University) and the
Korea Research Foundation Grant funded by the Korean Govern-
ment (KRF- 2009-0072919).
References and notes
1. (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor Chemistry; The Royal
Society of Chemistry: Cambridge, 2006. pp. 171–226; (b) Wallace, K. J.; Steed, J.
W. Advances in Supramolecular Chemistry In Gokel, G., Ed.; Cerberus: New
York, 2004; pp 221–262. Vol. 9; (c) Steed, J. W.; Atwood, J. L. Supramolecular
Chemistry; John Wiley & Sons Ltd., 2000.
2. (a) Gale, P. A.; García-Garrido, S. E.; Garric, J. Chem. Soc. Rev. 2008, 37, 151; (b)
Vickers, M. S.; Beer, P. D. Chem. Soc. Rev. 2007, 36, 211; (c) Gale, P. A. Acc. Chem.
Res. 2006, 39, 465; (d) Yoon, J.; Kim, S. K.; Singh, N. J.; Kim, K. S. Chem. Soc. Rev.
2006, 35, 355.
3. (a) Cho, E. J.; Moon, J. W.; Ko, S. W.; Lee, J. Y.; Kim, S. K.; Yoon, J.; Nam, K. C. J.
Am. Chem. Soc. 2003, 125(41), 12376; (b) Yeo, H. M.; Ryu, B. J.; Nam, K. C. Org.
Lett. 2008, 10(14), 2931; (c) Jeon, N. J.; Ryu, B. J.; Lee, B. H.; Nam, K. C. Bull.
Korean Chem. Soc. 2009, 30, 1675; (d) Dydio, P.; Zielin´ ski, T.; Jurczak, J. Org. Lett.
2010, 12, 1076; (e) Hamon, M.; Ménand, M.; Gac, S. L.; Luhmer, M.; Dalla, V.;
Jabin, I. J. Org. Chem. 2008, 73, 7067; (f) Sun, X. H.; Li, W.; Xia, P. F.; Luo, H.-B.;
Wei, Y.; Wong, M. S.; Cheng, Y.-K.; Shuang, S. J. Org. Chem. 2007, 72, 2419; (g)
Amendola, V.; Boiocchi, M.; Colasson, B.; Fabbrizzi, L. Inorg. Chem. 2006, 45,
6138; (h) Turner, D. R.; Paterson, M. J.; Steed, J. W. J. Org. Chem. 2006, 71, 1598.
4. (a) Schazmann, B.; Alhashimy, N.; Diamond, D. J. Am. Chem. Soc. 2006, 128(26),
8607; (b) Nabeshima, T.; Saiki, T.; Iwabuchi, J.; Akine, S. J. Am. Chem. Soc. 2005,
127(15), 5507.
5. Tomapatanaget, B.; Tuntulani, T.; Chailapakul, O. Org. Lett. 2003, 5(9), 1539.
6. Quinlan, E.; Matthews, S. E.; Gunnlaugsson, T. J. Org. Chem. 2007, 72(20), 7497.
7. (a) Cram, D. J.; Cram, J. M. Container Molecules and Their Guests, Monographs in
Supramolecular chemistry; The Royal Society of Chemistry: Cambridge, UK,
1994; Vol. 4.; (b)Comprehensive Supramolecular Chemistry; Maverick, E. F.,
Cram, D. J., Vögtle, F., Eds.; Pergamon: Oxford, 1996. Vol. 2; (c) Warmuth, R.;
Yoon, J. Acc. Chem. Res. 2001, 34, 95.
8. (a) Jung, N. S.; Lee, J.; Choi, S. B.; Kim, J.; Paek, K. Tetrahedron Lett. 2010, 51,
1291; (b) Jung, N. S.; Lee, J.; Suh, S.; Paek, K. Bull. Korean Chem. Soc. 2009, 30,
2782; (c) Park, H. S.; Paek, K. Bull. Korean Chem. Soc. 2009, 30, 505; (d) Zhu, S. S.;
Staats, H.; Brandhorst, K.; Grunenberg, J.; Gruppi, F.; Dalcanale, E.; Lützen, A.;
Rissanen, K.; Schalley, C. A. Angew. Chem., Int. Ed. 2008, 47, 788; (e) Park, Y. S.;
Paek, K. Org. Lett. 2008, 10, 4867; (f) Gardner, J. S.; Conda-Sheridan, M.; Smith,
D. N.; Harrison, R. G.; Lamb, J. D. Inorg. Chem. 2005, 44, 4295; (g) Tancini, F.;
Gottschalk, T.; Schweizer, W. B.; Diederich, F.; Dalcanale, E. Chem. Eur. J. 2010,
16, 7813.
9. Cavitand 2: Tetrabromocavitand 1 (600 mg, 0.48 mmol), 3-nitrophenyl boronic
acid (448 mg, 2.69 mmol), Pd(PPh3)4 (111 mg, 0.10 mmol) and K2CO3 (398 mg,
2.88 mmol) were mixed in degassed toluene (30 ml), H2O (10 ml), and EtOH
(10 ml) and heated to reflux for 3 days under argon atmosphere.After cooling
the reaction mixture, the solvent was removed by distillation under reduce
pressure, and the residue was dissolved in CH2Cl2 (30 mL). The organic layer
was washed with water and brine, dried over MgSO4, filtered, and
Figure 4. Negative mode MALDI-TOF mass spectrum of C3H7COꢀ2 @4a.
complexation–decomplexation dynamic process of anion on the
NMR time scale in polar DMSO-d6 at 25 °C. However this implies
that the alkyl group in the C3H7COꢀ is heading to inner cavity
2
and Y-shaped –COꢀ2 binds with the urea –NH of cavitand 4a in
the upper part.15 The binding constant was calculated to be
433 Mꢀ1 by WinEQNMR.
In negative mode MALDI-TOF mass spectrum (Fig. 4) a peak at
m/z 2036.8261 corresponding to C3H7COꢀ@4a was clearly
2
observed.
The energy-minimized structures of tetrais(4-nitrophenylurea)
cavitand 4a and tetrakis(4-nitrophenylurea)caviplex C3H7COꢀ@4a
2
using Spartan’04 V1.03 (Molecular Mechanics MMFF) showed that
four phenylurea groups of cavitand 4a are directing in-ward and a
well defined 1:1 caviplex C3H7COꢀ@4a (Fig. 5).
2
In summary, new anion receptors 4 with four phenylurea moi-
eties on the upper rim of a resorcin[4]arene cavitand were synthe-
sized and their anion binding properties were studied by 1H NMR
titration in DMSO-d6, negative mode MALDI-TOF mass spectrum,
and molecular mechanics calculations. These new receptors

Y. S. Park et al. / Tetrahedron Letters 52 (2011) 5176–5179
5179
concentrated. Purification of the crude product by flash column
chromatography on silica gel (Hexane:CH2Cl2 = 1:4) provided cavitand 2 as a
white solid (434 mg, 64%): 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 4H,
Ar-H), 7.89 (s, 4H, Ar-H), 7.52 (t, J = 8.0 Hz, 4H, Ar-H), 7.45 (d, J = 8.0 Hz, 4H, Ar-
H), 7.40 (s, 4H, Ar-H), 5.27 (d, J = 8.0 Hz, 4H, –OCHoutHinO–), 4.86 (t, J = 7.8 Hz,
4H, –CH–), 4.29 (d, J = 6.8 Hz, 4H, –OCHoutHinO–), 2.37 (m, 8H, –CH2–), 1.54–
1.31 (br m, 40H, –(CH2)5–), 0.92 (t, J = 6.8 Hz, 12H, –CH3).
(s, 4H, Ar-H), 7.59 (d, J = 9.2 Hz, 8H, Ar-H), 7.40 (s, 4H, Ar-H), 7.23 (t, J = 7.6 Hz,
4H, Ar-H), 7.17 (d, J = 7.6 Hz, 4H, Ar-H), 6.83 (d, J = 7.6 Hz, 4H, Ar-H), 5.24 (d,
J = 7.2 Hz, 4H, –OCHoutHinO–), 4.72 (t, J = 7.8 Hz, 4H, methine–CH–), 4.43 (d,
J = 7.2 Hz, 4H, –OCHoutHinO–), 2.48 (m, 8H, –CH2–), 1.48–1.28 (m, 40H,
–
d
(CH2)5–), 0.88 (t, J = 6.4 Hz, 12H, –CH3); 13C NMR (100 MHz, DMSO-d6)
151.80, 151.75, 146.2, 140.8, 138.3, 138.0, 134.0, 128.9, 128.1, 124.9, 124.2,
121.6, 120.1, 117.2, 99.8, 37.1 31.2, 29.5, 29.1, 28.8, 27.7, 22.0, 13.9; HRMS
10. Cavitand 3: Tetra(3-nitrophenyl)cavitand 2 (500 mg, 0.35 mmol) was dissolved
in toluene (50 mL) in an autoclave, and to this solution was added a catalytic
amount of Raney nickel, prewashed with ethanol (2 ꢂ 10 mL) and toluene
(2 ꢂ 10 mL). After the autoclave was flushed and then pressurized with
hydrogen (10 atm), the mixture was stirred at 45 °C for 24 h. After cooling to
room temperature, catalyst was filtered through a pad of celite and rinsed with
10% CH3OH/CH2Cl2 (2 ꢂ 30 mL). The filtrate was concentrated and dried under
high vacuum to give tetra(3-aminophenyl)cavitand 3 as a white solid (438 mg,
96%) that was taken directly to the next step: 1H NMR (400 MHz, DMSO-d6) d
7.72 (s, 4H, Ar-H), 6.94 (t, J = 8.0 Hz, 4H, Ar-H), 6.42 (d, J = 8.0 Hz, 4H, Ar-H),
6.21 (d, J = 8.0 Hz, 4H, Ar-H), 6.20 (s, 4H, Ar-H), 5.10 (d, J = 8.0 Hz, 4H,
ꢀOCHoutHinOꢀ), 4.96 (s, 8H, ꢀNH2), 4.64 (t, J = 8.0 Hz, 4H, methine–CH–), 4.26
(d, J = 8.0 Hz, 4H, –OCHoutHinO–), 2.44 (m, 8H, –CH2–), 1.47–1.28 (br m, 40H, –
(CH2)5–), 0.87 (t, J = 6.8 Hz, 12H, –CH3).
(MALDI-TOF) Calcd for C112H116N12NaO20 1972.8360, Found 1972.8156
[M+Na]+; Anal. Calcd for C112H116N12O20: C, 68.98; H, 6.00; N, 8.62. Found: C,
69.03; H, 5.80; N, 8.91. Cavitand 4b: white solid (78%): 1H NMR (400 MHz,
DMSO-d6) d 8.62 (s, 8H, –CONH), 7.82 (s, 4H, Ar-H), 7.41 (d, J = 7.6 Hz, 8H, Ar-
H), 7.38 (s, 4H, Ar-H), 7.24 (t, J = 7.6 Hz, 8H, Ar-H), 7.19 (t, J = 7.6 Hz, 4H, Ar-H),
7.14 (d, J = 7.2 Hz, 4H, Ar-H), 6.94 (t, J = 7.2 Hz, 4H, Ar-H), 6.77 (d, J = 7.2 Hz, 4H,
Ar-H), 5.23 (d, J = 7.6 Hz, 4H, –OCHoutHinO–), 4.72 (t, J = 8.0 Hz, 4H, methine–
CH–), 4.42 (d, J = 7.6 Hz, 4H, –OCHoutHinO–), 2.48 (m, 8H, –CH2–), 1.47–1.28 (m,
40H, –(CH2)5–), 0.87 (t, J = 6.8 Hz, 12H, –CH3); 13C NMR (100 MHz, DMSO-d6) d
152.3, 151.8, 139.6, 139.0, 138.0, 133.9, 129.1, 128.6, 128.5, 128.1, 123.5, 121.7,
121.5, 119.6, 118.1, 118.0, 116.7, 99.9, 37.1, 31.3, 29.6, 29.1, 28.9, 27.7, 22.0,
13.9; HRMS (MALDI-TOF) Calcd for
C112H120N8NaO12 1792.8957, Found
1792.8040 [M+Na]+; Anal. Calcd for C112H120N8O12: C, 75.99; H, 6.83; N, 6.33.
Found: C, 75.78; H, 6.96; N, 6.22.
11. Typical procedure: To a solution of tetra(3-aminophenyl)cavitand 3 (300 mg,
0.23 mmol) in dry THF (30 mL) was added triethylamine (0.1 mL, 1.0 mmol)
and the solution was stirred for 5 min at room temperature. 4-nitrophenyl
isocyanate (138 mg, 0.84 mmol) was added to the solution and the mixture
was stirred for 14 h. The reaction mixture was concentrated under reduced
pressure. The residue was recrystallized from CH2Cl2/MeOH (4:1) to give the
cavitand 4a as a yellow solid (362 mg, 82%). Cavitand 4a: 1H NMR (400 MHz,
DMSO-d6) d 9.35 (s, 4H, NH), 8.85 (s, 4H, NH), 8.12 (d, J = 9.2 Hz, 8H, Ar-H), 7.83
12. (a) Job, P. Ann. Chim. 1928, 9, 113; (b) K. A. Connors, Binding constants, The
Measurement of Molecular Complex Stability, Wiley, New York, 1987, p. 24.
13. Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311.
14. (a) Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62, 4492; (b) Bühlmann, P.;
Nishizawa, S.; Xioa, K. P.; Umezawa, Y. Tetrahedron 1997, 53, 1647.
15. (a) Sun, X. H.; Li, W.; Xia, P. F.; Luo, H.-B.; Wei, Y.; Wong, M. S.; Cheng, Y.-K.;
Shuang, S. J. Org. Chem. 2007, 72, 2419–2426; (b) Rudzevich, Y.; Rudzevich, V.;
Schollmeyer, D.; Böhmer, V. Org. Lett. 2007, 9(6), 957.