What are the limits of applicability for graph theoretic descriptors in QSPR/QSAR? Modeling dipole moments of aromatic compounds with TOPS-MODE descriptors.

The numerous possibilities of using graph theoretic descriptors in QSPR/QSAR are analyzed, and some misunderstandings on the role of this theoretical approach in chemistry are clarified. Principal component analysis is used to obtain a property space for several physicochemical properties of aromatic compounds. It is proved that most of the QSPR applications of the graph-theoretic structure descriptors are concentrated to the description of properties in a very limited region of this property space. Here, we show that graph-theoretic approaches are also applicable to the modeling of physicochemical properties that are far away from this region traditionally studied. The molecular dipole moments of benzene derivatives, mono-, ortho-, meta-, and para-susbtituted, are modeled by using the Topological Sub-Structural Molecular Design (TOPS-MODE) approach. The TOPS-MODE approach used permits to calculate group dipole moments that are given for several substituents. The differences between these group dipoles and those obtained by simple difference between experimental values are analyzed. Some difficulties arising from this traditional way of deriving substituent constants are identified and analyzed.