Tetrakis(phenylamidinium)-substituted resorcin[4]arene receptors for the complexation of dicarboxylates and phosphates in protic solvents

Three bowl-type cavitand receptors (1-3), consisting of a resorcin[4]arene core with four convergent phenylamidinium groups, were prepared in gram qua ntities by efficient synthetic routes (Schemes 1 and 2) for the recognition of organic anions in CD3OD and D2O. The key steps in the syntheses are the Suzuki cross-coupling reactions between the tetraiodo cavitands 12, 13, an d 23, respectively, with the m-cyanophenylboronic ester 14 and subsequent c onversion of the nitrile to amidinium groups by the Garigipati reaction. Co mpounds 1 and 2 displayed limited solubility in protic solvents, and eviden ce for stoichiometric host-guest association between 2 and AMP (28) could o nly be obtained by FAB-MS analysis of a complex precipitated from MeOH (Fig . 2). In contrast, receptor 3 with four triethyleneglycol monomethyl ether side chains was readily soluble in the protic environments, and complexatio n of isophthalates and nucleotides 25-37 was extensively studied by H-1-NMR titrations and Job's method of continuous variation. In CD3OD and pure D2O , isophthalates 25 and 26 formed stable 1:2 host-guest complexes (Table 1 a nd Fig. 3), whereas upon addition of berate (pH 9.2) or Tris/ HCl buffer (p H 8.3) to the D2O solution, the tendency for higher-order complexation vani shes. Stable 1:1 complexes formed in the buffered solutions (Fig. 4) with 5 -methoxyisophthalate being selectively bound over the 5-NO2 derivative. Com plexation-induced upfield shifts of specific isophthalate H-1-NMR resonance s (Fig. 5) suggest a preferred inclusion of the methoxyphenyl ring into the receptor cavity. Cavitand 3 forms stable 1:1 host-guest complexes with nuc leotides in Tris/HCl-buffered D2O. Association constants increase strongly with increasing guest charge in the series cAMP < AMP < ADP;ATP (Table 2). Association strength is strongly reduced in the presence of high salt (NaCl ) concentration (Table 3). Receptor 3 shows a slight preference for the com plexation of AMP (Fig. 7) and analogs dAMP or epsilon-AMP (Table 4) over nu cleotides containing G (guanine), C (cytosine), T (thymine), or U (uracil) as bases. According to the H-1-NMR analysis, only the nucleobase adenine an d derivatives thereof possess the necessary stereoelectronic complementarit y for inclusion into the bowl-type cavity. The major forces stabilizing the complexes of 3 with isophthalates and nucleotides result from ion pairing and ionic H-bonding between the charged groups of host and guest, and from the desolvation of these groups upon complexation. Apolar interactions and hydrophobic desolvation do not seem to make a large contribution to the mea sured binding free enthalpies.