Group Contribution Approaches for Aqueous Solubility

Insertion of a methylene group into a molecule causes a decrease in aqueous solubility, however not with a universally applicable constant increment, as available GCMs might suggests. The odd-even effect (see Section 11.3) and the chain length have to be considered for accurate, quantitative estimations. In addition polar groups in the molecule affect the methylene contribution, as the following rule illustrates  

Insertion of a methylene group to an alkane, which is substituted 

This effect is particularly pronounced between low Nc members of homologous compounds. Generally, this effect is regarded as secondary to group additivity. 

The intramolecular group interaction in a solute molecule influences the aqueous solubility significantly. Henceforth, GCMs with a set of highly discriminative groups, 

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