Mechanochemical Conversions Between Crystalline Polymorphs of a Complex Organic Solid

We report the conversion between
three crystalline polymorphs of
a capped amino acid, N-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 Z′,
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.