The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides

Strategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramolecular challenge, we attempted to co-crystallize ten aliphatic dicarboxylic acids (co-formers) with three groups of target molecules; N-(pyridin-2-yl)picolinamides (2Pyr-X), N-(pyridin-2-yl)nicotinamides (3Pyr-X), N-(pyridin-2-yl)isonicotinamides (4Pyr-X); X=Cl/ Br/ I. The structural outcomes were compared with co-crystals prepared from the non-halogenated targets. As expected, none of the reactions with 2Pyr-X produced co-crystals due to the presence of a very stable intramolecular N-H center dot center dot center dot N hydrogen bond. In the 3Pyr series, all six structures obtained showed the same synthons, -COOH center dot center dot center dot N(py) and -COOH center dot center dot center dot N(py)-NH, that were found in the non-halogenated parent 3Pyr and were additionally accompanied by structure directing X center dot center dot center dot O(OH) interactions (X=Br/I). The co-crystals of the unhalogenated parent 4Pyr co-crystals assembled via intermolecular -COOH center dot center dot center dot N(py) and -COOH center dot center dot center dot N(py)-NH synthons. Three of the analogues 4Pyr-X co-crystals displayed only COOH center dot center dot center dot N(py) and -COOH center dot center dot center dot N(py)-NH interactions. The three co-crystals of 4Pyr-X with fumaric acid (for which no analogues structures with 4Pyr are known) formed -COOH center dot center dot center dot N(py)-NH and -NH center dot center dot center dot O=C hydrogen bonds and showed no structure-directing halogen bonds. In three co-crystals of 4Pyr-I in which -COOH center dot center dot center dot N(py)-NH hydrogen bond was present, a halogen-bond based -I center dot center dot center dot N(py) synthon replaced the -COOH center dot center dot center dot N(py) motif observed in the parent structures. The structural influence of the halogen atoms increased in the order of Cl < Br < I, as the size of sigma-holes increased. Finally, it is noteworthy that isostructurality among structures of the homomeric targets was not translated to structural similarities between their respective co-crystals.