Solvation-Enhanced\nSalt Bridges

Salt bridges formed by amidines and carboxylic acids\nrepresent\nan important class of noncovalent interaction in biomolecular and\nsupramolecular systems. Isothermal titration calorimetry was used\nto study the relationships between the strength of the interaction,\nthe chemical structures of the components, and the nature of the solvent.\nThe stability of the 1:1 complex formed in chloroform changed by 2\norders of magnitude depending on the basicity of the amidine and the\nacidity of the acid, which is consistent with proton transfer in the\ncomplex. Polar solvents reduce the stabilities of salt bridges formed\nwith <i>N,N’</i>-dialkylamidines by up to 3 orders\nof magnitude, but this dependence on solvent polarity can be eliminated\nif the alkyl groups are replaced by protons in the parent amidine.\nThe enhanced stability of the complex formed by benzamidine is due\nto solvation of the NH sites not directly involved in salt bridge\nformation, which become significantly more polar when proton transfer\ntakes place, leading to more favorable interactions with polar solvents\nin the bound state. Calculation of H-bond parameters using density\nfunctional theory was used to predict solvent effects on the stabilities\nof salt bridges to within 1 kJ mol<sup>–1</sup>. While H-bonding\ninteractions are strong in nonpolar solvents, and solvophobic interactions\nare strong in polar protic solvents, these interactions are weak in\npolar aprotic solvents. In contrast, amidinium–carboxylate\nsalt bridges are stable in both polar and nonpolar aprotic solvents,\nwhich is attractive for the design of supramolecular systems that\noperate in different solvent environments.