Two conformational polymorphs of 4‐methylhippuric acid. Issue 6 (7th December 2020)

• Record Type: Journal Article
• Authors: Guillén, Marilia; Mora, Asiloé J.; Belandria, Lusbely M.; Seijas, Luis E.; Ramírez, Jeans W.; Burgos, José L.; Rincón, Luis; Delgado, Gerzon E.
• Is Part Of: Acta crystallographica. Volume 76:Issue 6(2020:Dec.)
• Page Start: 1077
• Page End: 1091
• Publication Date: 2020-12-07
• Subjects: conformational polymorphism -- noncovalent interactions -- hydrogen bonding -- Hirshfeld surface analysis -- DFT calculations -- QTAIM and NCI topological analysis -- single‐crystal X‐ray diffraction
• DOI: 10.1107/S2052520620013773
• Languages: English
• ISSNs: 2052-5206

Abstract

Abstract : A combination of resources – FT–IR, X‐ray diffraction, PES, RMSD, Hirshfeld surface analysis and the Quantum Theory of Atoms in Molecules (QTAIM), and electron localization theories implemented in QTAIM, ELF and NCI – were used to study two conformational polymorphs of 4‐methylhippuric acid obtained by solvent evaporation and mechanical grinding. Abstract : 4‐Methylhippuric acid {systematic name: 2‐[(4‐methylbenzoyl)amino]ethanoic acid}, a p ‐xylene excreted metabolite with a backbone containing three rotatable bonds (R‐bonds), is likely to produce more than one stable molecular structure in the solid state. In this work, we prepared polymorph I by slow solvent evaporation (plates with Z ′ = 1) and polymorph II by mechanical grinding (plates with Z ′ = 2). Potential energy surface (PES) analysis, rotating the molecule about the C—C—N—C torsion angle, shows four conformational energy basins. The second basin, with torsion angles near −73°, agree with the conformations adopted by polymorph I and molecules A of polymorph II, and the third basin at 57° matched molecules B of polymorph II . The energy barrier between these basins is 27.5 kJ mol −1 . Superposition of the molecules of polymorphs I and II rendered a maximum r.m.s. deviation of 0.398 Å. Polymorphs I and II are therefore true conformational polymorphs. The crystal packing of polymorph I consists of C (5) chains linked by N—H…O interactions along the a axis and C (7) chains linked by O—H…O interactions along the b axis. In polymorph II, two molecules ( A with A or B with B ) are connected by two acid–amide O—H…O interactions rendering R 2 2 (14) centrosymmetric dimers. These dimers alternate to pile up along the b axis linked by N—H…O interactions. A Hirshfeld surface analysis localized weaker noncovalent interactions, C—H…O and C—H…π, with contact distances close to the sum of the van der Waals radii. Electron density at a local level using the Quantum Theory of Atoms in Molecules (QTAIM) and the Electron Localization Function (ELF), or a semi‐local level using noncovalent interactions, was used to rank interactions. Strong closed shell interactions in classical O—H…O and N—H…O hydrogen bonds have electron density highly localized on bond critical points. Weaker delocalized electron density is seen around the p ‐methylphenyl rings associated with dispersive C—H…π and H…H interactions.