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 this Δω 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.
Original language | English (US) |
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Pages (from-to) | 19-45 |
Number of pages | 27 |
Journal | Perspectives in Drug Discovery and Design |
Volume | 19 |
DOIs | |
State | Published - Jan 1 2000 |
Externally published | Yes |
Keywords
- Aqueous solubility
- Hydration
- Hydrogen-bonding
- Hydrophobicity
- Lipophilicity
- Molecular size
- Octanol-water partitioning
ASJC Scopus subject areas
- Organic Chemistry
- Drug Discovery
- Pharmacology