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The amide group (R-C(=O)-NH-R) is crucial in the functionality of biologically relevant compounds, such as peptides, proteins, and active pharmaceutical ingredients. Its significance in drug design and development is underlined by its presence in several top-selling drugs, where it contributes to the formation of hydrogen bonds. This research examines how heteroatoms in a six- or five-membered pyridine, thiophene or furan ring spacer between two carboxamide groups influence the hydrogen-bonding for advancements in supramolecular chemistry and drug development. The solvent-free crystal structures of 3,5-pyridinedicarboxamide (PDC), 2,5-thiophenedicarboxamide (TDC) and 2,5-furandicarboxamide (FDC-subl, crystallized by sublimation) and the monohydrate structure of FDC-solv (crystallized from methanol) were described by the Etter graph-set notation in level 1 units with the shortest rings and chains as calculated by Mercury. The nearly planar dicarboxamide molecules all have an angular or V-shaped orientation of the two amide groups. The carbon atoms of the amide groups form an angle of 124° in PDC, 129° in TDC and 117° in FDC with the ring centroid. The orientations of the two amide groups with respect to each other are C=O anti NH2 in PDC, syn-CO and syn-NH2 in TDC and FDC. In TDC the CO groups are on the side of the sulfur heteroatom. In FDC the NH2 groups lie on the side of the furan O atom which enables a chelating-type R21(10) ring H-bonding interaction with with the O=C group of a nearby symmetry-related molecule. Only in the structure of PDC the heteroatom acts as an H-bond acceptor as part of a C11(6) chain. In TDC and FDC the heteroatoms do not interact with the amide -NH2 groups. In all structures except for FDC-subl complementary head-to-tail R22(8) rings are formed together with C11(6) and C11(8) chains in PDC, with three different C11(4) chains in TDC with two of them straight and one 21-helical, and with C11(8), C22(10) and C22(16) chains, two finite D11(2) patterns and R21(10) rings in FDC-solv. From sublimation the FDC-subl crystals contain two symmetry independent molecules in the asymmetric unit combining through two C11(4), two C11(8) chains, four different finite D11(2) patterns and two R21(10) rings.
Mohabbat et al. (Tue,) studied this question.