Two Conformational Polymorphs Of 4-Methyl-Hippuric Acid

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 degrees, agree with the conformations adopted by polymorph I and molecules A of polymorph II, and the third basin at 57 degrees 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 angstrom. Polymorphs I and II are therefore true conformational polymorphs. The crystal packing of polymorph I consists of C(5) chains linked by N-H center dot center dot center dot O interactions along the a axis and C(7) chains linked by O-H center dot center dot center dot 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 center dot center dot center dot O interactions rendering R-2(2) (14) centrosymmetric dimers. These dimers alternate to pile up along the b axis linked by N-H center dot center dot center dot O interactions. A Hirshfeld surface analysis localized weaker noncovalent interactions, C-H center dot center dot center dot O and C-H center dot center dot center dot pi, 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 center dot center dot center dot O and N-H center dot center dot center dot 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 center dot center dot center dot pi and H center dot center dot center dot H interactions.