Enhanced binding of methyl alkylammonium cations through preorganization of a water-soluble calix[4]pyrrole†

We describe the synthesis of two tetra-α aryl-extended calix[4]pyrroles (C[4]Ps) 4a–b bearing four terminal carboxylic groups in their meso-propyl chains defining the lower rims. The synthesized C[4]Ps became soluble (1–3 mM) in water at pD = 10. We probed the interaction of 4a towards tetra-methylammonium (G1) chloride in water using ¹H NMR spectroscopy. The C[4]P 4a includes G1 in the shallow aromatic cavity defined by the pyrrole rings in cone conformation forming a 1 : 1 complex G1⊂4a. Pyridine-N-oxide (PNO) binding in the larger polar aromatic cavity of 4a results in the quantitative self-assembly of the supramolecular receptor PNO@4a featuring the pyrrole rings preorganized in cone conformation. The PNO@4a receptor displays improved binding properties towards G1 than the parent C[4]P 4a. We thermodynamically characterized (¹H NMR titrations and ITC experiments) the 1 : 1 complexes of PNO@4a with a series of tetra-alkylammonium salts, including biologically relevant examples. The PNO@4a supramolecular receptor displays significant affinity (log K = 3–4) but lacks selectivity in water binding of methyl trialkyl ammonium cations. Cation–π and coulombic interactions are the main intermolecular forces stabilizing the complexes. We also performed DFT calculations to gain some insights into the complexes’ structures.