High-throughput UV-vis titrations in combination with chemical double-mutant cycles (DMCs) have been used to study the competition of a polar solvent for formation of intramolecular H-bonds. Twenty-four different zinc porphyrin-pyridine complexes were investigated in mixtures of toluene and phenol. DMCs were used to determine effective molarities (EM) for the formation of intramolecular phenol-amide H-bonds as a function of solvent composition. The values of EM increase by an order of magnitude with increasing concentrations of the more polar solvent, phenol. Phenol solvates the amide groups on the ligands strongly, increasing the steric bulk and destabilizing the complexes. These adverse steric interactions are removed when intramolecular H-bonds are formed and therefore provide an increased driving force for formation of cooperative interactions. The result is that the effects of competitive interactions with polar solvents that reduce binding affinity are attenuated to a significant extent by a corresponding increase in EM in multivalent complexes.