Intramolecular Interactions versus Hydration Effects on p‑Guanidinoethyl-phenol Structure and pK_a Values

We analyze the structure, hydration, and pK_a values of p-guanidinoethyl-phenol through a combined experimental and theoretical study. These issues are relevant to understand the mechanism of action of the tetrameric form, the antibacterial compound tetra-p-guanidinoethyl-calix­[4]­arene (Cx1). The investigated system can also be useful to model other pharmaceutical drugs bearing a guanidine function in the vicinity of an ionizable group and the effect of arginine on the pK_a of vicinal ionizable residues (in particular tyrosine) in peptides. The p-guanidinoethyl-phenol monomer (mCx1) has two ionizable groups. One important particularity of this system is that it exhibits high molecular flexibility that potentially leads to enhanced stabilization in folded structures by direct, strong Coulombic interactions between the ionizable groups. The first pK_a corresponding to ionization of the −OH group has experimentally been shown to be only slightly different from usual values in substituted phenols. However, because of short-range Coulombic interactions, the role of intramolecular interactions and solvation effects on the acidities of this compound is expected to be important and it has been analyzed here on the basis of theoretical calculations. We use a discrete-continuum solvation model together with quantum-mechanical calculations at the B3LYP level of theory and the extended 6-311+G­(2df,2p) basis set. Both intra- and intermolecular effects are very large (∼70 kcal/mol) but exhibit an almost perfect compensation, thus explaining that the actual pK_a of mCx1 is close to free phenol. The same compensation of environmental effects applies to the second pK_a that concerns the guanidinium group. Such a pK_a could not be determined experimentally with standard titration techniques and in fact the theoretical study predicts a value of 14.2, that is, one unit above the pK_a of the parent ethyl-guanidinium molecule.