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 |
|---|---|
| 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 |
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Keywords
- Aqueous solubility
- Hydration
- Hydrogen-bonding
- Hydrophobicity
- Lipophilicity
- Molecular size
- Octanol-water partitioning
ASJC Scopus subject areas
- Organic Chemistry
- Drug Discovery
- Pharmacology
Cite this
Modeling liquid properties, solvation, and hydrophobicity : A molecular size-based perspective. / Buchwald, Peter.
In: Perspectives in Drug Discovery and Design, Vol. 19, 01.01.2000, p. 19-45.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modeling liquid properties, solvation, and hydrophobicity
T2 - A molecular size-based perspective
AU - Buchwald, Peter
PY - 2000/1/1
Y1 - 2000/1/1
N2 - 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.
AB - 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.
KW - Aqueous solubility
KW - Hydration
KW - Hydrogen-bonding
KW - Hydrophobicity
KW - Lipophilicity
KW - Molecular size
KW - Octanol-water partitioning
UR - http://www.scopus.com/inward/record.url?scp=0033820397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033820397&partnerID=8YFLogxK
U2 - 10.1023/A:1008711420953
DO - 10.1023/A:1008711420953
M3 - Article
AN - SCOPUS:0033820397
VL - 19
SP - 19
EP - 45
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
SN - 0920-654X
ER -