The Origin of Selectivity in the Complexation of N‑Methyl Amino Acids by Tetraphosphonate Cavitands

We report on the eligibility of tetraphosphonate resorcinarene cavitands for the molecular recognition of amino acids. We determined the crystal structure of 13 complexes of the tetraphosphonate cavitand Tiiii­[H, CH₃, CH₃] with amino acids. ¹H NMR and ³¹P NMR experiments and ITC analysis were performed to probe the binding between cavitand Tiiii­[C₃H₇, CH₃, C₂H₅] or the water-soluble counterpart Tiiii­[C₃H₆Py⁺Cl^‑, CH₃, C₂H₅] and a selection of representative amino acids. The reported studies and results allowed us (i) to highlight the noncovalent interactions involved in the binding event in each case; (ii) to investigate the ability of tetraphosphonate cavitand receptors to discriminate between the different amino acids; (iii) to calculate the K_a values of the different complexes formed and evaluate the thermodynamic parameters of the complexation process, dissecting the entropic and enthalpic contributions; and (iv) to determine the solvent influence on the complexation selectivity. By moving from methanol to water, the complexation changed from entropy driven to entropy opposed, leading to a drop of almost three orders in the magnitude of the K_a. However, this reduction in binding affinity is associated with a dramatic increase in selectivity, since in aqueous solutions only N-methylated amino acids are effectively recognized. The thermodynamic profile of the binding does not change in PBS solution. The pivotal role played by cation−π interactions is demonstrated by the linear correlation found between the log K_a in methanol solution and the depth of ⁺N–CH₃ cavity inclusion in the molecular structures. These findings are relevant for the potential use of phosphonate cavitands as synthetic receptors for the detection of epigenetic modifications of histones in physiological media.