C3-symmetric metacyclophane-based anion receptors with three thiourea groups as linkers between aromatic groups

Article abstract of DOI:10.1016/S0040-4039(00)00966-7

Neutral anion receptors based on the C₃-symmetric metacyclophane structure with three thiourea groups as linkers between aromatic groups have been prepared and examined for their anion-binding ability. The association constants of 1 and 2 with various anions were measured by the ¹H NMR titration method. Compound 2, with three convergent thiourea groups pointing toward the binding cavity, showed increased binding affinities to anions and selective binding to AcO^- compared to conformationally more flexible 1, which exhibited selective binding to H₂PO₄^- in DMSO-d₆. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00966-7

Tetrahedron Letters 41 (2000) 6083±6087
C3-Symmetric metacyclophane-based anion receptors with
three thiourea groups as linkers between aromatic groups
Kwan Hee Lee and Jong-In Hong*
School of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, South Korea
Received 27 April 2000; revised 5 June 2000; accepted 9 June 2000
Abstract
Neutral anion receptors based on the C3-symmetric metacyclophane structure with three thiourea groups
as linkers between aromatic groups have been prepared and examined for their anion-binding ability. The
1
association constants of 1 and 2 with various anions were measured by the H NMR titration method.
Compound 2, with three convergent thiourea groups pointing toward the binding cavity, showed increased
binding anities to anions and selective binding to AcO^ compared to conformationally more ¯exible 1,
which exhibited selective binding to H2PO^4 in DMSO-d6. # 2000 Elsevier Science Ltd. All rights reserved.
1
Keywords: anion recognition; metacyclophane; thiourea; H NMR titration.
In spite of recent advances and the variety of anion receptors developed so far, the problem of
achieving strong and selective anion recognition has not yet been solved, in contrast to the far
more developed classical cation receptors.1 So far, the basic strategy for the construction of
anion-binding receptors has been to exploit electrostatic interactions2 and/or hydrogen bonds,3 or
Lewis acidic metal±ligand interactions.4 Among these noncovalent interactions, we have been
interested in developing hydrogen bond-based neutral anion receptors. Owing to the relatively
strong hydrogen bonding ability of urea and thiourea groups, a number of molecules possessing
urea or thiourea groups have been designed as neutral receptors for various anions.3 For strong
and selective binding, these groups should be preorganized to complement the target anion and
minimize intramolecular hydrogen bonding. One way to achieve this is to make cyclic receptors
with urea or thiourea groups connected to rigid spacers.3e,f This paper describes the synthesis of
C3-symmetric metacyclophane-based anion receptors with three thiourea groups and their
binding properties toward various anions in polar organic media.
We chose 15 as a novel framework for anion receptors. Compound 1 can be envisioned as a
hexahomooxacalix[3]arene6 analog: six oxygens used for metal ion complexation6b are replaced
* Corresponding author. Tel: +82-2-880-6682; fax: +82-2-889-1568; e-mail: jihong@plaza.snu.ac.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00966-7

6084
with three thiourea groups as hydrogen bond donors for anion binding; their conformational
¯exibility is similar.
The judicious molecular design of arti®cial receptors starting from the basic skeleton of 1 is
expected to lead to a very active area of anion recognition. We wanted to orient thiourea NH
protons toward the macrocyclic cavity for e€ective anion binding. However, MM2 calculations
on 1 indicate that low energy conformations within the 3 kcal/mol window are not preorganized
for binding to anionic guests inside the macrocyclic cavity.7 One way to reduce the reorganization
costs of complexation and thus enhance the binding eciency is to exploit nonbonded, con-
formational locking interactions.8 The design principle comes from the conformation of hexa-
ethylbenzene; avoidance of nonbonded interactions of the adjacent methylene hydrogens assures
that the b groups alternate above (a) and below (b) the ring in a trigonally symmetric conforma-
tion (ababab).2f,9 We thought that placing three ethyl groups on the 2, 4 and 6 positions of the
aromatic spacer of 1 would give rise to conformationally less ¯exible 2. This design would result
in orienting the six thiourea NH groups of 2 preferentially toward the inner side of the bowl-
shaped macrocycle. Indeed, conformational searching of 2 con®rms the expected cone con-
formation of all conformers within the 3 kcal/mol window of the lowest energy conformer in
which a cavity is formed by six inwardly predisposed NH groups for anion binding (Fig. 1).7
Modeling also suggests that intramolecular hydrogen bonding between these groups is clearly
Figure 1. The energy-minimized structure of 2 (left: top view, right: side view). Hydrogens except NHs have been
omitted for clarity.

6085
impossible. A binding cavity formed by meta-substituted aromatics may function as a hydro-
phobic pocket for the nonpolar part of a substrate. From these structural features, the designed
C3 host 2 could act as an e€ective binder for various shapes of anions and polyatomic substrates.
The known compound 1 was prepared according to a published procedure.5 Compound 210
was obtained from 1,3-bis(aminomethyl)-2,4,6-triethylbenzene (3) in four steps, as shown in
Scheme 1.
Scheme 1.
The bridging methylene protons (±CH2±NHCSNH±) appearing as a broad singlet at 4.66 ppm
at 30ꢀC were split into two signals at 4.99 and 4.21 ppm at 0ꢀC, exhibiting a large geminal
coupling of 13.4 Hz at ^25ꢀC, which indicates a cone-shaped conformer as expected from con-
formational searching.
Addition of the tetrabutylammonium salts of anions to 1 or 2 in CDCl3 and DMSO-d6 caused
1
substantial down®eld shifts of the NH resonances in the H NMR spectra, indicating the forma-
tion of hydrogen-bonded complexes. Aromatic proton signals of 2 experienced up®eld shifts upon
complexation with anions, indicating that anions should be surrounded by aromatic rings.
Additionally, the bridging benzylic protons became diastereotopic (AcO^, Áꢀ=0.14 ppm;
^
^
H2PO4 , Áꢀ=0.33 ppm; Br^, Áꢀ=0.45 ppm: N3 , Áꢀ=0.37 ppm) after addition of 1 equiv.
anions in CDCl3, suggesting the formation of a conformationally rigid 1:1 complex with a cone
conformation.
A Job titration11 between 1 and H2PO4 conducted in DMSO-d6 showed that the maximum
^
signal change was observed at 0.5 mol fraction of 1, indicative of 1:1 complex formation. Analysis
of the 1H NMR titration data gave the binding constants listed in Table 1. Compound 1 showed
^
binding selectivities in the order H2PO4 >AcO^>Cl^ in DMSO-d6. In spite of the less basic
character of H2PO4 ^ compared to AcO^, H2PO4 ^ showed stronger binding to 1 than did acetate.
The binding tendency of 1 for anions is similar to that of acyclic3c or cyclic thioureas.3e,f This
means that although 1 has a macrocyclic structure, it seems to have a similar local conformation
to acyclic 1,3-bis(thioureido)methylbenzene.3c Thus, we believe that the favorable binding of 1
^
toward H2PO4 can be rationalized based on the complex geometry3c and di€erent solvation
e€ects of anions by DMSO.3f In contrast, compound 2 showed binding selectivities in the order
^
^
AcO^>H2PO4 >Cl^>N3>Br^ in DMSO-d6. Compound 2 exhibited good selectivity for AcO^
^
compared with H2PO4 , which bound to 1 with a higher anity. We assume the main reason is
the di€erent basicity between AcO^ and H2PO4 : pKa (AcOH)=4.76, pKa (H3PO4)=2.16 (H2O
^

6086
Table 1
Association constants (Ka, M^1) of 1 and 2 with anions in DMSO-d6 at 25ꢀCa
at 25ꢀC, I=0).12 Compared to 1, compound 2 shows a twofold increase in binding anity for
^
H2PO4 and Cl^, and a notable 17-fold increase for AcO^ in DMSO-d6. The higher binding
anities of 2 to anions would result from the preorganized NH groups of 2 for anion binding.
Interactions of 2 with AcO^ or H2PO4 ^ were examined using the MacroModel/Batchmin V5.5
package.7 The global minimum structures clearly demonstrate the hydrogen bonding between
^
thiourea NHs and AcO^ oxygens or H2PO4 oxygens.
In summary, we have developed novel anion-binding agents (1, 2) based on the C3-symmetric
metacyclophane structure with three thiourea groups as linkers between aromatic groups. The
cooperative action of thiourea NHs as hydrogen bond donors toward guest anions was achieved
by placing three ethyl groups on the 2, 4 and 6 positions of the aromatic spacer of 1. Compound
2, with three convergent thiourea groups pointing toward the binding cavity, showed increased
binding anities to anions and selective binding to AcO^ compared to conformationally more
^
¯exible 1, which exhibited selective binding to H2PO4 in DMSO-d6. Introducing other binding
elements to the aromatic spacer would facilitate the rational design of more e€ective and selective
anionophores.
Acknowledgements
This study was supported by a grant (No. HMP-97-D-4-0014) of the `97 Good Health R&D
Project, Ministry of Health & Welfare and CMDS (KOSEF). K.H.L. thanks the Ministry of
Education for the BK 21 postdoctoral fellowship.
References
1. (a) Izatt, R. M.; Bradshaw, J. S.; Nielsen, S. A.; Lamv, J. D.; Christensen, J. J.; Sen, D. Chem. Rev. 1985. 85, 271.
(b) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L. Chem. Rev. 1991, 91, 1721. (c) Pedersen, C. J.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1021. (d) Cram, D. J.; Cram, J. M. Science 1974, 183, 803±809.
2. (a) Tabushi, I.; Kobuke, Y.; Imuta, J. J. Am. Chem. Soc. 1981, 103, 6152±6157. (b) Kuroda, Y.; Hatakeyama, H.;
Seshimo, H.; Ogoshi, H. Supramol. Chem. 1994, 3, 267±271. (c) Schneider, H.-J.; Blatter, T.; Palm, B.; P®ngstag,
U.; Rudiger, V.; Theis, L. J. Am. Chem. Soc. 1992, 114, 7704±7708. (d) Kral, V.; Furuta, H.; Shreder, K.; Lynch,
V.; Sessler, J. L. J. Am. Chem. Soc. 1996, 118, 1595±1607. (e) Jubian, V.; Veronese, A.; Dixon, R. P.; Hamilton,

6087
A. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 1237±1239. (f) Metzger, A.; Lynch, V. M.; Anslyn, E. V. Angew.
Chem., Int. Ed. Engl. 1997, 36, 862±865. (g) Yeo, W.-S.; Hong, J.-I. Tetrahedron Lett. 1998, 39, 8137±8140. (h)
Jung, Y.-G.; Yeo, W.-S.; Lee, S. B.; Hong, J.-I. Chem. Commun. 1997, 1061±1062. (i) Ahn, D.-R.; Kim, T. W.;
Hong, J.-I. Tetrahedron Lett. 1999, 40, 6045±6048.
3. (a) Fan, E.; Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 369±370. (b) Kelly,
T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072±7080. (c) Nishizawa, S.; Buhlmann, P.; Iwao, M.; Umezawa,
Y. Tetrahedron Lett. 1995, 36, 6483±6486. (d) Buhlmann, P.; Nishizawa, S.; Xiao, K. P.; Umezawa, Y.
Tetrahedron 1997, 53, 1647±1654. (e) Tobe, Y.; Sasaki, S.; Mizuno, M.; Naemura, K. Chem. Lett. 1998, 8, 835.
(f) Sasaki, S.-I.; Mizuno, M.; Naemura, K.; Tobe, Y. J. Org. Chem. 2000, 65, 275±283. (g) Scheerder, J.;
Engbersen, J. F. J.; Casnati, A.; Ungaro, R.; Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6448±6454. (h) Xie, H.;
Yi, S.; Wu, S. J. Chem. Soc., Perkin Trans. 2 1999, 2751±2754.
4. (a) Rudkevich, D. M.; Verboom, W.; Brzozka, Z.; Palys, M. J.; Stauthamer, W. P. R. V.; van Hummel, G. J.;
Franken, S. M.; Harkema, S.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Am. Chem. Soc. 1994, 116, 4341±4351. (b)
Eliseev, A. V.; Schneider, H.-J. J. Chem. Soc., Chem. Commun. 1993, 1834±1836.
5. Gross, R.; Durner, G.; Gobel, M. W. Liebigs Ann. Chem. 1994, 49.
6. (a) Dhawan, B.; Gutsche, C. D. J. Org. Chem. 1983, 48, 1536. (b) Daitch, C. E.; Hampton, P. D.; Duesler, E. N.;
Alam, T. M. J. Am. Chem. Soc. 1996, 118, 7769±7773. (c) Tsubaki, K.; Otsubo, T.; Tanaka, K.; Fuji, K. J. Org.
Chem. 1998, 63, 3260±3265.
7. MacroModel/Batchmin V5.5, employing Amber* and MM2* force-®elds with GB/SA chloroform solvation
model. See: Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Cau®eld, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
8. Iimori, T.; Still, W. C.; Rheingold, A. L.; Staley, D. L. J. Am. Chem. Soc. 1989, 111, 3439±3440.
9. (a) Iverson, D. J.; Hunter, G.; Blount, J. F.; Damewood, J. R.; Mislow, K. J. Am. Chem. Soc. 1981, 103, 6073±
6083. (b) Stack, T. D. P.; Weigel, J. A.; Holm, R. H. Inorg. Chem. Soc. 1990, 29, 3745±3760. (c) Stack, T. D. P.;
Hou, Z.; Raymond, K. N. J. Am. Chem. Soc. 1993, 115, 6466±6467.
10. Compound 2: mp 260±261ꢀC; IR (KBr) 3742, 3434, 3225, 3051, 2965, 1691, 1645, 1531, 1337, 1262 cm^1; 1H NMR
1
(300 MHz, CDCl3) ꢀ 6.89 (s, 3H), 4.98 (s, 6H), 4.67 (s, 12H), 2.65±2.60 (m, 18H), 1.20±1.16 (m, 27H); H NMR
(300 MHz, DMSO-d6) ꢀ 7.00 (s, 6H), 6.92 (s, 3H), 4.68 (s, 12H), 2.61±2.53 (m, 18H), 1.15±1.03 (m, 27H); 13C
NMR (75 MHz, CDCl3) ꢀ 181.9, 143.6, 143.1, 131.5, 121.9, 41.8, 39.6, 26.3, 22.5, 16.2, 15.9; FAB-MS (m-NBA) m/
z 787 (M++H), FAB-HRMS (m-NBA) calcd for C45H67N6S3 [M+H]+ 787.4589, found 787.4589. Compound 3: IR
(KBr) 3283, 2965, 2094, 1571, 1458, 1374, 1297 cm^1; 1H NMR (300 MHz, CDCl3) ꢀ 6.96 (s, 1H), 3.88 (s, 4H), 2.85
(q, J=6 Hz, 2H), 2.72 (q, J=7.8 Hz, 4H), 1.25 (m, 9H); 13C NMR (75 MHz, CDCl3) ꢀ 141.7, 141.0, 136.5, 127.7,
39.3, 26.2, 22.4, 17.0, 16.2; EI-MS m/z 186, 203(M+^NH3); HRMS calcd for C14H21N1 [M^NH3]+ 203.1674, found
203.1681. Compound 4: mp: 42±44ꢀC; IR (KBr) 2968, 2160, 2076, 1459, 1332 cm^1; 1H NMR (300 MHz, CDCl3) ꢀ
7.04 (s, 1H), 4.72 (s, 4H), 2.81 (q, J=7.8Hz, 2H), 2.73 (q, J=7.5Hz, 4H), 1.26 (m, 9H); 13C NMR (75 MHz
CDCl3) ꢀ 144.6, 142.5, 131.3, 128.5, 128.2, 42.6, 26.5, 23.0, 16.3, 15.7; EI-MS m/z 304 (M+); HRMS calcd for
C16H20N2S2 [M]+ 304.1607, found 304.1061. Compound 5: mp 49±51ꢀC; IR (KBr) 3355, 3289, 3177, 2968, 1690,
1
1533, 1364, 1277, 1172 cm^1; H NMR (300 MHz, CDCl3) ꢀ 6.91 (s, 1H), 4.86 (broad, 1H), 4.30 (d, J=4.4 Hz,
2H), 3.81 (s, 2H), 2.77±2.58 (m, 6H), 1.40 (s, 9H), 1.22±1.13 (m, 9H); 13C NMR (75 MHz, CDCl3) ꢀ 155.5, 142.9,
142.7, 142.1, 136.2, 131.2, 127.6, 79.3, 50.1, 38.9, 38.3, 28.4, 26.1, 22.4, 16.8, 16.2, 16.0; EI-MS m/z 303 (M+^NH3);
HRMS calcd for C19H29N1O2 [M^NH3]+ 303.2198, found 303.2200. Compound 6: mp 172±173ꢀC; IR (KBr) 3660,
1
2969, 1686, 1516, 1361, 1250, 1168 cm^1; H NMR (300 MHz, CDCl3) ꢀ 6.93 (s, 2H), 5.96 (s, 2H), 4.64 (broad,
4H), 4.43 (s, 2H), 4.04 (s, broad, 4H), 2.68±2.54 (m, 18H), 1.27(s, 18H), 1.21±1.14 (m, 18H); 13C NMR (75 MHz
CDCl3) ꢀ 181.6, 155.5, 144.2, 143.6, 131.5, 130.4, 127.9, 42.9, 18.4, 28.4, 26.4, 26.2, 22.8, 16.8, 16.1, 16.0; FAB-MS
m/z 682 (M+); FAB-HRMS calcd for C39H62N4O4S [M]+ 682.4492, found 682.4492. Compound 7: mp 170±171ꢀC;
IR (KBr) 3583, 3960, 1675, 1200, 1137 cm^1; 1H NMR (300 MHz, DMSO-d6) ꢀ 8.19 (s, 6H), 7.18 (s, 2H), 7.03 (s,
2H), 4.63 (s, 4H), 4.03 (s, 4H), 2.74±2.58 (m, 6H), 1.17±1.06 (m, 9H); 13C NMR (75 MHz, CDCl3) ꢀ 181.7, 158.2,
144.7, 143.7, 143.1, 131.5, 127.5, 127.1, 41.8, 37.5, 25.7, 25.3, 22.3, 16.2, 15.8, 15.3; EI-MS m/z 482
[M^2CF3COO]+. HRMS calcd for C29H46N4S [M^2CF3COO]+ 482.3443, found 482.3440.
11. Conners, K. A. Binding Constants, 1st ed.; John Wiley: New York, 1987; pp. 24±28.
12. Lide, D. R. CRC Handbook of Chemistry and Physics; CRC Press: Cleveland, OH, 1994.