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

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19 Citations (Scopus)

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 languageEnglish
Pages (from-to)19-45
Number of pages27
JournalPerspectives in Drug Discovery and Design
Volume19
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

Fingerprint

Solvation
Hydrophobicity
hydrophobicity
Hydrophobic and Hydrophilic Interactions
solvation
Water
Liquids
Hydrogen Bonding
liquids
Hydrogen bonds
water
hydrogen
Octanols
solutes
Solubility
Hydrogen
partitions
solubility
automatic frequency control
Vapor Pressure

Keywords

  • Aqueous solubility
  • Hydration
  • Hydrogen-bonding
  • Hydrophobicity
  • Lipophilicity
  • Molecular size
  • Octanol-water partitioning

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

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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.",
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