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

ST Reddy and D Sivaramakrishna and K Mamatha and M Sharma and MJ Swamy, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 23, 25264-25277 (2021).

DOI: 10.1039/d1cp03704h

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 (Nn-O16s) and N-acyl (n = 8-14), O-pentadecanoylethanolamines (Nn-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 Nn-O16s and Nn-O15s. Differential scanning calorimetric studies revealed that dry Nn-O16s exhibit odd-even alternation in their calorimetric properties, which is absent in Nn-O15s. The 3-dimensional structures of three Nn-O16s (n = 12-14) and two Nn-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 (alpha and beta) in the crystal lattice of Nn-O16s, whereas only the beta polymorph was observed in the Nn-O15s. Further, intermolecular hydrogen bonding interactions (N-HMIDLINE HORIZONTAL ELLIPSISO and C-HMIDLINE HORIZONTAL ELLIPSISO) 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 beta polymorph is slightly energetically preferred over the alpha 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.

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