Cooperative Control of Ion and Molecular Recognition by Molecular Assembling Tatsuya Nabeshima,* ,† Takayoshi Takahashi, ‡ Takeshi Hanami, † Akihiro Kikuchi, ‡ Tohru Kawabe, ‡ and Yumihiko Yano ‡ Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan, and Department of Chemistry, Gunma University, Kiryu, Gunma 376-8515, Japan Received March 4, 1998 Cooperative control of molecular and ion recognition is one of the most important regulatory processes in metabolism. 1 Thus, many studies of artificial binding systems have been carried out to clarify the cooperative mechanisms and their application. 2-4 We now report the synthesis of a novel host 1 which exhibits cooperative behavior in molecular and ion recognition. We also present a concept of changing genera- tions of artificial hosts to create a new molecular function different from the previous generation. 5 Upon complexation of 1 with 2 via multiple hydrogen bonding, 6 the generated new host, 1‚2 complex, was expected to show a binding ability toward alkali metal ions, if the three polyether chains are assembled and oriented in the same direction to make a new binding site for the metal ion (Figure 1). CPK model examination for 1‚2 complex sug- gests that the three polyether chains of 1 and 2 are assembled to wrap a metal ion well. The number of oxygen atoms in the polyether chain was determined to be three because a single nonassembled polyether chain containing more than four oxygen atoms shows binding ability toward alkali metal ions. 7 In this case the binding strength of 1 with respect to 2 should be increased in the presence of Na + due to the interaction between the ion and the polyether chains, as compared to the absence of any such interaction. In the new system, the first generation host 1 captures guest 2, and the 1‚2 complex thus formed is considered to be a second generation host, because the latter is an ionophore. The host 1 was prepared according to Scheme 1. The interaction between 1 and 2 was examined by 1 H NMR. The amide protons (H a ,H b ) of 1 were shifted downfield with the addition of the guest 2 in CDCl 3 (Figure 2). These changes are ascribed to formation of six hydrogen bonds between the host and guest, as shown in Figure 1. The association constants (K a ) with guests (2, 3) were determined from the shifts of H a (or H b ) using a nonlinear-least-squares method. The K a values for 2 and 3 are 1400 and 1600 M -1 , respectively (Table 1). The difference between the substit- uents of the guests does not influence the values signifi- cantly. In the presence of 1 equiv of Na + [B(3,5-(CF 3 ) 2 - C 6 H 3 ) 4 ] - (9), 1‚2 complexation due to the hydrogen bonding on the addition of 2 was more enhanced. The 1 H NMR spectra of 1:1 mixtures of 1 and 2 in the presence and absence of 9 show that the ratios of the host-guest com- plexes to free 1 are 5.8 and 0.97, respectively. The large enhancement of the ratio in the presence of Na + suggests that there is an effective cation-dipole interaction which makes the 1‚2 complexation favorable. In 3, however, an opposite effect of Na + on the ratio was observed. Hence, 9 decreased the hydrogen bonding strength between 1 and 3, probably because the polarity of the solution increased due to the addition of 9. This change also indicates that a cation-dipole interaction of the 1‚3 system is quite small. The results presented here suggest that (1) the oriented and assembled three polyether chains of the host and guest are in the same direction to form a much more effective recogni- tion site for metal ions, and that (2) the two chains are not sufficient to provide such a binding site in this system, although the two chains can approach each other more closely upon complexation compared to free 1. † University of Tsukuba. ‡ Gunma University. (1) (a) Cantor, C. R.; Schimmel, P. R. Biophysical Chemistry; Freeman: New York, 1980; Vol. I. (b) Perutz, M. F. Mechanism of Cooperativity and Allosteric Regulation in Proteins; Cambridge University Press: Cambridge, 1990. (2) (a) Rebek, J., Jr. Acc. Chem. Res. 1984, 17, 258-264. (b) Tabushi, I. Pure. Appl. Chem. 1988, 60, 581-586. (c) Nabeshima, T. Coord. Chem. Rev. 1996, 148, 151-169. (3) (a) Nabeshima, T.; Inaba, T.; Furukawa, N. Tetrahedron Lett. 1987, 28, 6211-6214. (b) Nabeshima, T.; Inaba, T.; Furukawa, N.; Hosoya, T.; Yano, Y. Inorg. Chem. 1993, 32, 1407-1416. (4) (a) Ebmeyer, F.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1990, 29, 1148-1150. (b) Schneider, H.-J.; Ruf, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1159-1160. (c) Schneider, H.-J.; Werner, F. J. Chem. Soc., Chem. Commun. 1992, 490-491. (d) Sijbesma, R. P.; Nolte, R. J. J. Am. Chem. Soc. 1991, 113, 6695-6696. (e) Toupance, T.; Ahsen, V.; Simon, J. J. Am. Chem. Soc. 1994, 116, 5352-5361. (5) Nabeshima, T.; Tamura, N.; Kawazu, T.; Sugawara, K.; Yano, Y. Heterocycles 1995, 41, 877-881. (6) (a) Hamilton, A. D.; Van Engen, D. J. Am. Chem. Soc. 1987, 109, 5035-5036. (b) Chang, S. K.; Hamilton, A. D. J. Am. Chem. Soc. 1988, 110, 1318-1319. (c) Tecilla, P.; Dixon, R. P.; Slobodkin, G.; Alavi, D. S.; Waldeck, D. H.; Hamilton, A. D. J. Am. Chem. Soc. 1990, 112, 9408-9410. (d) Tecilla, P.; Hamilton, A. D. J. Chem. Soc., Chem. Commun. 1990, 1232-1234. (e) Yano, Y.; Tamura, N.; Mitsui, K.; Nabeshima, T. Chem. Lett. 1989, 1655- 1658. (f) Tamura, N.; Mitsui, K.; Nabeshima, T.; Yano, Y. J. Chem. Soc., Perkin Trans. 2 1994, 2229-2237. (7) (a) Irie, M.; Kato, M. J. Am. Chem. Soc. 1985, 107, 1024-1028. (b) Schepartz, A.; McDevitt, J. P. J. Am. Chem. Soc. 1989, 111, 5976-5977. Scheme 1 a a Reagents and conditions: (a) thiourea, EtOH/H2O, reflux, 20 h; (b) KOH, H2O, reflux, 24 h; (c) H2SO4 (74% from 4); (d) ethyl 4-bromobutylate, NaH, THF, rt, 5 h (84%); (e) NaOH, EtOH/H2O; (f) HCl (89% from 6); (g) (COCl)2, CH2Cl2/DMF, 50 °C, 4 h; (h) 2,6- diaminopyridine, Et3N, THF, rt, 3 h (83% from 7); (i) glutaryl chloride, Et3N, THF, rt, 19 h (76%). Table 1. Binding Strength of 1 Determined by 1 H NMR (500 MHz) Titration in CDCl3 Ka (M -1 ) (R =[1‚guest complex]/ [free 1]) guest without Na + with Na + 2 1400 ( 100 a nd d R) 0.97 b R) 5.8 c 3 1600 ( 100 a nd d R) 1.0 b R) 0.69 c a [1] ) 1.25 × 10 -3 M. b [1] ) [2] ) 1.25 × 10 -3 M. c [1] ) [2] (or [3]) ) [9] ) 1.25 × 10 -3 M. d Not determined because accurate binding constants of a ternary complexes including Na + could not be obtained. 3802 J. Org. Chem. 1998, 63, 3802-3803 S0022-3263(98)00406-X CCC: $15.00 © 1998 American Chemical Society Published on Web 05/20/1998