Fine Tuning of the Cation Affinity of Artificial Receptors Based on Cyclic Peptides by Intramolecular Conformational Control

Abstract

A series of cyclic hexapeptides consisting of alternating 4-substituted 3-aminobenzoic acid units (R = CH3, Cl, CH2OCH3, OCH3, COOCH3) and residues of the natural amino acid proline has been prepared and their ion affinities have been investigated. Whereas the unsubstituted parent compound (R = H) is able to bind cations through cation−π interactions with the aromatic subunits, as well as anions through hydrogen bonding with the peptide NH groups, the introduction of substituents at the 4-positions of the aromatic rings results in complete loss of the anion affinity. The cation complex stabilities depend on the substituents and cover a wide range from Ka = 140 M−1 for R = CH3 to Ka = 10800 M−1 for R = COOCH3 (Ka = 1260 M−1 for R = H) with n-butyltrimethylammonium picrate. The conformations of the peptides in solution have been determined by one- and two-dimensional NMR techniques and FT-IR spectroscopy. It was found that all the substituents prevent the peptides from adopting the necessary conformation for anion binding. For one receptor (R = OCH3), the results have been corroborated by a crystal structure determination. AM1 calculations have been used to estimate the electrostatic potential surfaces of the substituted aromatic subunits. The variation in the cation complex stabilities can be mainly attributed to the effects of the substituents on the solution conformations of the peptides. The influence of the substituents on the electrostatic potentials of the aromatic peptide subunits appears to be less important.