Molecular interactions and binding mechanisms of hydrophobic hofmeister cations to macromolecules

It’s been known for over a century that ions specifically affect the bulk properties of solutions, behavior of macromolecules and a myriad of interfacial phenomena occurring in solution. Yet, the molecular mechanisms underlying these so-called Hofmeister effects are only recently being realized within the last few decades. In the resurgence in specific ion effects studies, the role attributed to cations has been relatively understated in comparison to the effects of anions. Whereas various molecular mechanisms have been elucidated for a diverse spectrum of anions, cationic effects have largely remained limited to common metal ions. Within the cationic Hofmeister series for cations, strongly-hydrated cations exhibit very weak binding to polar, electronegative groups, but weakly-hydrated cations in particular are classified as non-interacting. This thesis brings a much-needed expansion to specific cation effects by investigating the interactions between the weakly-hydrated tetraalkylammonium cations and model neutral thermoresponsive polymers, principally poly(N-isopropylacrylamide) (PNIPAM). The hydrophobicity of the cations is incrementally tuned by increasing the length of their alkyl chains, thus forming the series of salts investigated herein: NR4Cl where R = H, Me, Et, n-Pr, n-Bu, and the anion is kept constant as Cl-. By using a multi-instrumental approach, it is demonstrated that the largest of these cations exhibit a significant binding to the polymers and that the resulting salting-in effects are comparable in magnitude to those observed for sodium salts of weakly-hydrated anions. Thermodynamic phase transition measurements of the polymers are complemented by ATR-FTIR and quantitative 1H-NMR spectroscopic studies to systematically investigate the nature and molecular-level mechanism of the interaction. In stark contrast to the known behavior of the strongly-hydrated cations, through the temperature-controlled ATR-FTIR investigations it is found that carbonyl moieties are not the primary sites of interaction. Instead, it is found that these weakly-hydrated, ‘greasy’ cations preferentially interact with the most hydrophobic groups on the polymer: the isopropyl group on the PNIPAM side-chain, as revealed by a quantitative externally-referenced 1H-NMR methodology developed to elucidate ion-macromolecule interactions. The binding generally follows a Langmuir-type saturation behavior and exhibits site-specific dissociation constants as low as KD ≈ 0.2 M. This unprecedented, hydrophobically-mediated interaction between weakly-hydrated tetraalkylammonium cations and neutral macromolecules is then demonstrated to be a general mechanism and is shown to extend to polymers of vastly different molecular architectures. The results presented, thus, signify a new, more expansive view of cationic Hofmeister effects, where the far weakly-hydrated region of the series interacts with a novel mechanism entirely unlike that of other cations.