Various scientists had been gathering experimental data from which to extract descriptors that could be used to rationalise electronic (sigma values), size (molar refraction, MR and molecular weight, MW) and hydrophobic (pi values) effects caused by substituents, particularly on aromatic rings.  Hansch and co-workers aimed to bring all of these descriptors together in one place as a resource for those aiming to explore quantitative structure-activity relationships; an example of 4 groups that span the different types (polar vs hydrophobic, electron-donating vs withdrawing) is shown in the table.  Hansch et al.’s compilation of values remains a good starting point to understand the effects that various substituent types can exert, although Hansch and Leo went on to compile an even more comprehensive set: Some of our own work in matched molecular pairs has seen us effectively computing analogous values for the effect of aromatic substituents on solubility, plasma protein binding and other properties:


Group Pi Sigma(meta) Sigma(para) MR MW
Me +0.56 -0.07 -0.17 5.65 15.0
F +0.14 +0.34 +0.06 0.92 19.0
NH2 -1.23 -0.16 -0.66 5.42 16.0
NO2 -0.28 +0.71 +0.78 7.36 46


“Aromatic Substituent Constants for Structure-Activity Correlations” by Hansch, Leo, Unger, Kim, Nikaitani and Lien.

DOI: 10.1021/jm00269a003


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