Nicotinamide, donor-acceptor interaction

Aakeroy and co-workers and Nangia and co-workers were successful in the exploitation of Etter s hydrogen bonding hierarchy rule to design binary and ternary complexes of nicotinamide (2) and iso-nicotinamide (3) with carboxylic acids and phenols [14]. Synthon I was retained in iso-nicotinamide co-crystals with succinic acid and 3-hydroxybenzoic acid (Figure 7.6) [14d]. In these structures the carboxylic acid interacts, as a strong proton donor, with a strong proton acceptor such as pyridine. 

The carboxylic acid is well known to form stronger hydrogen bonds than the -NH2 moiety on the amide, and the best donor clearly displays a strong preference for the pyridine moiety, the best acceptor site. Once these functionalities have found each other via an acid py synthon, it is left to the amide to interact with itself (typically across an inversion center) via a classic homomeric amide amide dimer. In order to determine whether these structures are representative of cocrystals of acids and nicotinamide, we performed an additional analysis of all relevant data found in the Cambridge Stmctural Database [47]. The search, which included all nicotinamide and iso-nicotinamide co-crystals with carboxylic acids, but excluded other potentially competing moieties such as -OH, yielded 32 hits. In every single case, the pyridine - carboxylic acid synthon was present, which emphasizes that these intermolecular interactimis are very selective, remarkably reliable, and robust, despite the fact that we are dealing with readily reversible non-covalent interactions. The consistency of the motifs can be explained in the context of best donor-best acceptor scenario underpinned by electrostatic considerations. 

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