Molecular structure studies of novel bronchodilatory-active 4-azafluorenes

Two 5H-indeno[1,2-b]pyridines, 7a and 7b, were synthesized and characterized by X-ray crystallography. In the molecular packing, molecules of 7a are linked into chains by C-H center dot center dot center dot N hydrogen bond which, in turn, are connected by H center dot center dot center dot pi, N center dot center dot center dot pi, Cl center dot center dot center dot pi and pi center dot center dot center dot pi interactions. In the crystal structure of 7b, molecules are connected by C-H center dot center dot center dot N and C-H center dot center dot center dot Cl interactions as well as a set of N center dot center dot center dot pi and Cl center dot center dot center dot pi interactions. The molecular structures were studied by theory using AM1, PM3 and DFT. The basic difference between the theoretical and experimental structures was found in the relative orientation of dichlorophenyl ring attached to the indenopyridine residue, which was revealed to be aligned in nearly opposite orientations. This observation is attributed to the bulky chlorine atom(s) of the phenyl ring that prevent free rotation around the sigma bond attaching this ring with the heterocyclic system. DFT was used to determine the molecular electrostatic potential revealing the nitrile nitrogen to be the most nucleophilic site. A low HOMO-LUMO energy gap indicates high reactivity of 7a and 7b. The synthesized azafluorenes show more potent bronchodilation properties than the standard reference compound (theophylline).