Packing polymorphism, odd-even alternation and thermotropic phase transitions in -,-diacylethanolamines with varying -acyl chains. A combined experimental and computational study

N -, O -Diacylethanolamines (DAEs) are derived by simple esterification of bioactive N -acylethanolamines, which are present in plant and animal tissues. In this study, two homologous series of DAEs, namely N -acyl ( n = 8-15), O -palmitoylethanolamines (N n -O16s) and N -acyl ( n = 8-14), O -pentadecanoylethanolamines (N n -O15s) were synthesized and characterized with respect to thermotropic phase transitions, crystal structures and intermolecular interactions. In addition, computational studies were performed to get a molecular level insight into the role of different factors in selective polymorphism in N n -O16s and N n -O15s. Differential scanning calorimetric studies revealed that dry N n -O16s exhibit odd-even alternation in their calorimetric properties, which is absent in N n -O15s. The 3-dimensional structures of three N n -O16s ( n = 12-14) and two N n -O15s ( n = 12, 14) have been determined by single-crystal X-ray diffraction. Analysis of the molecular packing in these crystals showed the presence of two packing polymorphs (α and β) in the crystal lattice of N n -O16s, whereas only the β polymorph was observed in the N n -O15s. Further, intermolecular hydrogen bonding interactions (N-H O and C-H O) and dispersion interactions among acyl chains have been found to stabilize the molecular packing observed in the crystal lattice. Molecular dynamics simulations show that the β polymorph is slightly energetically preferred over the α polymorph in all the systems due to favorable packing of terminal methyl groups at the interlayers. These findings are relevant for understanding the interactions of the DAEs with membrane lipids and proteins. Odd-even alternation is observed in the calorimetric properties ( T t , Δ H t and Δ S t ) in N n -O16s, but not in N n -O15s. This is explained on the basis of differences in terminal methyl group packing.