Mechanochemical Conversions Between Crystalline Polymorphs of a Complex Organic Solid

We report the conversion between three crystalline polymorphs of a capped amino acid, <i>N</i>-acetyl-l-phenylalanyl-NH₂, using mechanochemistry, with conversion between the α and γ polymorphs being reversible, depending on the milling conditions used. Solvent drop grinding of the α and β polymorphs with water yields the γ polymorph, whereas dry grinding of the β or γ polymorph yields the α polymorph. The α and β polymorphs are also accessible from solution (from methanol and water, respectively), and their structures were solved from single crystal diffraction data. The γ polymorph, so far only accessible mechanochemically, was solved and refined from powder X-ray diffraction data. The polymorphs show various degrees of crystallographic disorder, and the numbers of crystallographically independent molecules vary. These observations are supported by ¹³C and ¹⁵N magic angle spinning solid-state NMR data. Possible reasons for the formation of multiple polymorphs and their respective stability as a function of <i>Z</i>′, degree of disorder, and molecular shape and conformation are discussed. The results have implications for understanding the accessibility of new polymorphs of complex, low-symmetry organic solids with multiple dihedral degrees of freedom