Modeling liquid properties, solvation, and hydrophobicity: A molecular size-based perspective

Abstract

A recently introduced molecular size-based model that allows a unified description of enthalpies of vaporization, boiling points, gas–liquid solubilities, and vapor pressures for simple organic liquids using a free energy expression obtained from molecular-level assumptions is summarized. By changing the interaction-related constant ω used by the model when water is the solvent, the model can be extended to describe alkane–water partition,octanol–water partition, and water solubility of solutes that have no hydrogen-bonding or strongly polar substituents. Here, it is shown that thisΔω change, which is most likely related to the changes that the solute produces in the hydrogen-bonded structure of water, agrees very well with the value that can be derived from the modified hydration-shell hydrogen-bond model of Muller. By combining the present molecular size-based model with this hydrogen-bonding model, a simplified but consistent description is obtained for the properties of water and for the hydrophobic effect. This indicates that many unusual properties of water may be accounted for by a proper combination of the nonspecific interactions as extrapolated from other liquids, the unusually small size of its molecules, and an adequate model of hydrogen-bonding. A fully computerized method (QLogP) that can estimate octanol–water log P for a large variety of organic solutes also fits within this unified approach. Despite using only two parameters (molecular volume and a novel, quantified parameter that is probably hydrogen-bonding-related), the predictive power of this method is similar to that of the considerably more complex fragment-contribution methods often used by medicinal chemists (ACD/LogP, AFC, CLOGP, KLogP, MLogP, Rekker), as illustrated by a comparison based on various structures.

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Buchwald, P. Modeling liquid properties, solvation, and hydrophobicity: A molecular size-based perspective. Perspectives in Drug Discovery and Design 19, 19–45 (2000). https://doi.org/10.1023/A:1008711420953

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  • aqueous solubility
  • hydration
  • hydrogen-bonding
  • hydrophobicity
  • lipophilicity
  • molecular size
  • octanol–water partitioning