Effect of Molecular Perturbation on Polymorphism: The Case of 8-Halotheophyllines (8-Cl-Tph and 8-Br-Tph)

The common alkaloid theophylline (Tph) is known to exist in five polymorphic forms. The structures of its 8-halo analogues were previously unreported. Here, we report three polymorphs for 8-chlorotheophylline (8-Cl-Tph) and an additional distinct one for 8-bromotheophylline (8-Br-Tph). While polymorphs for theophylline are dominated by NH---N inter-molecular hydrogen bonds, the halo compounds exclusively exhibit NH---O interactions. 8-Cl-Tph has two related structures with chains N(7)-H(7)---O(2); one is also the stable form for 8-Br-Tph. Polymorphs with a dimeric R22(10) ring structure using N(7)-H---O(6) H-bonds exist for all three compounds, though each with distinct 3D packing. DFT calculations indicate that the alkaloid ring nitrogen N(9) is a weaker base in 8-halo compounds, disfavoring NH---N interactions in their polymorphic forms.