Polymorphism, Crystal Packing, Twinning, and Molecular Conformations in 5′-Halo-5′-deoxyguanosines and a Hydrate of the Pseudohalide Analogue, 5′-Azido-5′-deoxyguanosine

Crystalline 5′-iodo-5′-deoxyguanosine (I) exists as a pair of solvent-free polymorphs (Ia, Ib) and as a mixed water/methanol solvate (Ic). The solvent-free polymorphs are capable of epitaxial intergrowth to give hybrid crystals that by visual inspection appear to be single crystals (Parkin et al. Cryst. Growth Des. 2016, 16, 6343-6352; hereafter PTGB). To investigate the generality and origin of the unusual polymorphism of the solvent-free forms, we have prepared and characterized the 5′-bromo- and 5′-chloro-5′-deoxyguanosine analogues (II and III, respectively), as well as the pseudohalide derivative 5′-azido-5′-deoxyguanosine (IV). Monoclinic and orthorhombic polymorphs of II (IIa and IIb, respectively) and an orthorhombic form of III all grow from water as small nonsolvated, tightly packed needles or laths. Although IIa is isostructural with the dominant polymorph of I (i.e., Ia in PTGB), all of these crystals (IIa, IIb, III) have similar molecular conformations and packing characteristics to Ia, in which the halogen adopts a gauche conformation relative to the deoxyribose ring oxygen. In spite of having different space group symmetries (P2₁ for Ia and IIa vs P2₁2₁2₁ for IIb and III), the crystal structures of IIb and III are also clearly related to Ia. Unlike I, however, no experimental evidence for conformational polymorphism, or of solvated forms was found for either II or III. Similar to PTGB work on I, density functional theory calculations show that the experimental gauche halide-atom conformations in II and III are ∼2.0 kcal/mol higher in energy than the energy-minimized anti-conformation (which occurs in the minor polymorph of I, i.e., Ib). The 5′-azido analogue (IV) in contrast, crystallized solely as a hydrate, initially forming minuscule irregular shards that were far too small for conventional X-ray analysis. By a process of Ostwald ripening, these shards could be enlarged sufficiently to allow structure determination by X-ray crystallography. The hydrate of IV shares many structural characteristics with Ic, but is much more complicated. It contains four independent molecules of IV (i.e., Z′ = 4, vs Z′ = 2 in Ic), which exhibit a range of distinctly different molecular conformations, as well as five full occupancy water molecules.