Negative cooperativity in the formation of two H-bonds with an oxygen H-bond acceptor

Cooperative effects in H-bond networks can be quantified by measuring the effect of an intramolecular H-bond on the association constant for formation of a second intermolecular H-bond with the same functional group. This approach has been used to quantify the cooperativity associated with the interaction of a phosphoryl oxygen with two H-bond donors. A series of compounds that have an intramolecular H-bond between a phosphinamide oxygen and a phenol hydroxyl group were prepared, using substituents on the phenol to vary the strength of the intramolecular H-bond. The presence of the intramolecular interaction was confirmed by NMR spectroscopy in n-octane solution, and titrations were used to measure the association constants for formation of an intermolecular H-bond with perfluoro-t-butanol in n-octane. Electron-withdrawing substituents on the phenol, which increase the strength of the intramolecular H-bond, were found to decrease the strength of the intermolecular H-bond between the phosphoryl oxygen and perfluoro-t-butanol. The results were used to determine the H-bond acceptor parameters for the phosphinamides, β, and there is a linear relationship between the values of β and the H-bond donor parameter of the phenol involved in the intramolecular H-bond, α. The slope of this relationship was used to determine the cooperativity parameter (κ = -0.82), which quantifies the negative allosteric cooperativity between the two H-bonding interactions. Polarisation models for cooperativity in H-bond networks would predict positive cooperativity for this system, due to an increase in the polarity of the phosphorus-oxygen bond. The observation of substantial negative cooperativity suggests that the effects observed are due to secondary electrostatic interactions between the two H-bond donors that make through-space repulsive interactions with one another.