Factors Impacting sigma- and pi-Hole Regions as Revealed by the Electrostatic Potential and Its Source Function Reconstruction: The Case of 4,4 '-Bipyridine Derivatives

Positive electrostatic potential (V) values are often associated with sigma- and pi-holes, regions of lower electron density which can interact with electron-rich sites to form noncovalent interactions. Factors impacting sigma- and pi-holes may thus be monitored in terms of the shape and values of the resulting V. Further precious insights into such factors are obtained through a rigorous decomposition of the V values in atomic or atomic group contributions, a task here achieved by extending the Bader-Gatti source function (SF) for the electron density to V. In this article, this general methodology is applied to a series of 4,4 '-bipyridine derivatives containing atoms from Groups VI (S, Se) and VII (Cl, Br), and the pentafluorophenyl group acting as a pi-hole. As these molecules are characterized by a certain degree of conformational freedom due to the possibility of rotation around the two C-Ch bonds, from two to four conformational motifs could be identified for each structure through conformational search. On this basis, the impact of chemical and conformational features on sigma- and pi-hole regions could be systematically evaluated by computing the V values on electron density isosurfaces (V-S) and by comparing and dissecting in atomic/atomic group contributions the V-S maxima (V-S,V-max) values calculated for different molecular patterns. The results of this study confirm that both chemical and conformational features may seriously impact sigma- and pi-hole regions and provide a clear analysis and a rationale of why and how this influence is realized. Hence, the proposed methodology might offer precious clues for designing changes in the sigma- and pi-hole regions, aimed at affecting their potential involvement in noncovalent interactions in a desired way.