Surprising lipophilicity observations identify unexpected conformational effects

Contrary to expectation N-aryl pyrrolidinones (and isosteric imidazolinones and oxazolinones) are more lipophilic and less soluble than the corresponding piper-idinones (tetrahydropyrimidinones and oxazinones). Exploration of the basis for these results uncovered a subtle interplay of steric and electronic effects that result in different conformations for the two classes of compounds which drive the observed effects.

Automated summary

Contrary to expectations, N-aryl pyrrolidinones (and isosteric imidazolinones and oxazolinones) have higher lipophilicity and lower solubility than corresponding piper-idinones (tetrahydropyrimidinones and oxazinones). The observed effects are driven by a subtle interplay of steric and electronic effects, resulting in different conformations for the two classes of compounds.