Mapping out the Relative Influence of Hydrogen and Halogen Bonds in Crystal Structures of a Family of Amide-Substituted Pyridines

The simultaneous use of hydrogen bonds and halogen bonds in crystal engineering strategies has previously been employed in order to generate new solid forms with applications in e.g. pharmaceutical and agrochemical industries. Unfortunately, it is not easy to predict how these will coexist or compete in systems where multiple structural outcomes are possible. To address this challenge, we have investigated the solid-state landscape of a family of amide-substituted pyridines, belonging to four series, N-(pyridin-2-yl)benzamides (Bz), N-(pyridin-2-yl)picolinamides (2Pyr), N-(pyridin-2-yl)nicotinamides (3Pyr) and N-(pyridin-2yl)isonicotinamides (4Pyr), functionalized with three different halogen atoms (chlorine, bromine, and iodine). We analyzed crystal structures of 16 compounds and identified their primary intermolecular interactions. Within each series, the chlorinated and brominated compounds present the same primary hydrogen-bond interactions as shown by the nonhalogenated parent. The N-(pyridin-2-yl)benzamides assembled via N-H center dot center dot center dot N(Py) synthons to form dimers, N-(pyridin-2-yl)picolinamides showed intramolecular N-H center dot center dot center dot N(Py) hydrogen bonding, and both N-(pyridin-2-yl)nicotinamides (3Pyr) and N-(pyridin-2-yl) isonicotinamides (4Pyr) assembled via N-H center dot center dot center dot N(Py) synthons leading to the formation of chains or four-membered rings. In three out of the four series (Bz, 2Pyr, and 4Pyr) the chloro and bromo compounds were isostructural. Three out of the four iodinated compounds exhibited halogen bonds to a neighboring molecule. In two of these compounds, Bz-I and 2Pyr-1, the primary hydrogen bonding resembled that of the other members of the family, indicating that the interactions mediated via the iodine atom were complementary to rather than competitive with the hydrogen bonds. Two polymorphs of 4Pyr-I were found, and in both forms, a halogen bond was formed with the N(py) acceptor which was engaged in N-H center dot center dot center dot N hydrogen bonds in the other members of this family. Since iodine acted as a halogen-bond donor in four-fifths of the crystal structures of iodinated compounds, these results show that the solid-state assembly of analogues compounds capable of hydrogen bonding have a high likelihood of being altered even in the presence of a nonactivated iodine atom.