Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3).

Accurate structure determinations by X-ray crystal analysis and computation using semi-empirical self-consistent field molecular orbital calculations are described and compared for five monofluorinated analogues of 4-chlorobiphenyl, i.e. 2-fluoro-4-chlorobiphenyl, 2'-fluoro-4-chlorobiphenyl, 3-fluoro-4-chlorobiphenyl, 3'-fluoro-4-chlorobiphenyl and 4'-fluoro-4-chlorobiphenyl. Intermolecular interactions for all monofluorinated isomers are dominated by phenyl-phenyl stacking and C-H-phenyl interactions. C-F bond lengths varied between 1.341 and 1.374 A, C-Cl between 1.733 and 1.765 A, and both correlate with electron-density differences as determined by (13)C NMR shifts. The interior ring angles at ipso-fluoro substitution increase up to 122.2-124.2 degrees due to hyperconjugation by 2p-pi-orbital overlapping, a phenomenon that was also reflected in the computer calculation. The angles of C-F and C-Cl relative to the aromatic ring for vicinal fluoro- and chloro substituents show an attraction, not a repulsion, between the adjacent F and Cl substituents. This finding is explained on the basis of electron donor and acceptor properties. The dihedral angles of ortho-substituted biphenyls show that monofluoro substitution results in slightly smaller increases compared with chlorine, while additional ortho-fluorination results in little further change in the dihedral angle. In contrast, ortho-chlorination strongly decreases the co-planarity. This is likely to be due to interior ring-angle distortion and the size of the halogen substituent. Fluoro substitution does indeed affect the planarity of the PCB3 analogues, but these effects are minor compared with chloro substitution. Fluorine tagging offers promise for use in in vitro and in vivo studies. Differences in computational versus measured data emphasize the need to use a variety of methods to ascertain the true nature of the physical properties of a compound.