Quinoline-Carbonitriles in Halogen Bonded Cocrystals: Does the Position Matter?

Quinolines are a class of organic bases of major biological and pharmaceutical importance. Being versatile electron donors, they are good coformer candidates for supramolecular association in crystal engineering based on π-stacking, hydrogen, or halogen bond (XB) interactions. In this work, the ability of two cyanoquinoline isomers, quinoline-6-carbonitrile (Q6CN) and quinoline-4-carbonitrile (Q4CN), to form XB cocrystals is explored. The selected ditopic XB donors are the often-used fluorine-activated 1,4-diiodo-3,4,5,6-tetrafluorobenzene (DITFB) and the weaker asymmetrical 1-bromo-4-iodobenzene (1B4IB). Three cocrystals with 2:1 ratios of Q6CN-DITFB, Q4CN-DITFB, and Q6CN-1B4IB were obtained by mechanochemical synthesis and characterized by vibrational, thermal analysis, and X-ray diffraction techniques. The structures of the new cocrystals were solved by single-crystal X-ray diffraction, revealing that the N pyridine (N_py) atom is the preferential site for XBs. Comparing the nature of their intermolecular interactions by several computational methods, the strength of the XB established with the N_py atom of both quinoline isomers were similar, while the strength of the N_py···H interaction is weaker than that of H···NC in both native precursors. However, the weaker nonfluorinated XB donor 1B4IB only produces a cocrystal with Q6CN, while DITFB achieves it with both isomers, suggesting that the position of the CN group could discriminate cocrystal formation with respect to the type of XB donors. DFT calculations confirmed that the strength of the N_py···H interactions in the native Q6CN and Q4CN isomers, to be replaced by the N_py···X XBs in the cocrystals, is dependent on the position of the CN group in the quinoline framework. The slightly weaker N_py electron donor ability in Q4CN contributes, together with packing effects, to explaining why a Q4CN-1B4IB cocrystal was not produced under the applied experimental conditions.