A comprehensive analysis of crystal packing and energetic features of the selected uracil derivatives (i.e., 1-methyluracil, 1,5dimethyluracil, 5-fluorouracil, 2-thiouracil, 4-thiouracil, 2,4-dithiouracil, and 6-methyl-2-thiouracil) is reported. High-quality X-ray diffraction data sets of the studied compounds were subjected to the TAAM procedure (Transferable Aspherical Atom Model based on the Hansen−Coppens formalism), which gave results comparable both with the optimized and neutron-diffraction-derived geometries. Crystal packing motifs were investigated with the aid of Hirshfeld surface fingerprint plots. Most of the structures form hydrogen-bonded layers kept together by π-stacking interactions. The only exception is 2,4-dithiouracil, which exhibits a rather complex 3D network based on N−H•••S and C−H•••S contacts. The TAAM procedure allows also for a quite reliable reconstruction of the electron density distribution in a crystal structure. It was therefore possible to rationalize the existence of some F•••F interactions in 5-fluorouracil on the basis of the derived deformation density map. Additional insight into the nature of crystal architectures was obtained through theoretical computations, concerning cohesive energy, dimer interaction energy, and molecule deformation energy evaluation. The balance between molecular layer stabilization and their mutual interactions is essential for crystal growth, and thus it is reflected in crystal morphology and quality. Cohesive energy ranges from −100 kJ•mol −1 for 2,4-thiouracil to about −140 kJ•mol −1 for uracil and 5-fluorouracil, and there is no significant correlation with the melting point temperature observed. Hydrogen-bonded layers are more strongly stabilized one with another, when methyl substituents or sulfur atoms are present. Remarkable differences between 2-thio and 4-thio derivatives were found and supported by the corresponding values of aromaticitity indices. Furthermore, the energy calculations revealed the particular importance of properly determined positions of hydrogen atoms.
