A Peptoid-like Approach Led to Lactam-Lactam Dimer Formation in 2-Hydroxy- N -alkyl- N -phenyl-nicotinamides and Their Polymorphism and Solvatomorphism.

Four 2-hydroxy- N -alkyl- N -phenyl-nicotinamides ( 1 - 4 ) were synthesized, and their crystal structures were analyzed to investigate the effect of substitution on their crystal packing of N -phenyl-2-hydroxynicotinanilides. In these compounds, substituents were introduced on the amide N, leading to a peptoid-like structure. One solvent-free form and two hydrates were harvested for compound 1 , and one anhydrous form and one hydrate were obtained for compound 2 . Polymorphism was observed in compounds 3 and 4 . The molecules were found to be in the keto form rather than the enol tautomer. Because of steric effects, the molecules took on an E configuration, leading to a hairpin-like geometry. A lactam-lactam dimer synthon was formed in all solvent-free structures, and a tetramer motif was observed for the first time. Dehydration of the two hydrates of 1 and the hydrate of 2 led to their respective solvent-free form. Phase transition between the polymorphs was revealed in compound 3 . Theoretical calculations, including conformational energy evaluation, hydrate forming propensity assessment, and lattice energy appraisal, were performed to provide a reasonable explanation for the keto tautomer and the formation of the hydrates of compound 1 .