One of the long-standing challenges in working with organic hydrates in general, and channel hydrates in particular, is their propensity to lose water over time and convert (either partially or fully) to anhydrous solid forms. In this work, we demonstrate the ability to rationally increase the thermal stability of a model channel hydrate, the DNA nucleobase thymine hydrate (TH), through the systematic creation of lattice substitutions with 5-aminouracil (AUr). Mixed crystals of TH−AUr with up to 17 mol % AUr were isomorphous with the pure hydrate, confirming our molecular-level design strategy which places 5-amino groups at the one-dimensional channel surfaces. The enhanced stabilization of the water molecules afforded by the proximal 5-amino substitutions resulted in mixed crystals with significantly higher thermal stability. The magnitude of the thermal stability enhancement scaled linearly with the included AUr concentration, yielding TH−AUr dehydration temperatures nearly double that of the pure hydrate. Kinetic analyses and time-resolved synchrotron structural studies of process-induced dehydration of the mixed composition hydrate indicated changes in both the solid-state mechanism and the resultant anhydrous products compared to those generated from the pure hydrate. The strategy adopted herein should be applicable to other hydrate systems to rationally tune their thermal stabilities.

Thymine hydrate (TH) is a classic hydrate system in which water molecules are highly confined in linear one-dimensional channels. Here, we describe our efforts to tune the channel volume by preparing isomorphous mixed crystals with increasing concentrations of uracil (Ur) and 5-ethyluracil (EUr), molecular analogues with slightly smaller and larger volumes, respectively. Solutions with up to 20 mol % Ur successfully yielded isomorphous mixed crystals of TH-Ur x in phase-pure form, though analysis of the mixed crystal compositions indicated that only ∼46% of the Ur available in the initial growth solution was proportionately included in the host lattice. The thermal stability of the mixed TH-Ur x material was significantly altered, with a greater fraction of water loss occurring at low temperature compared to the pure hydrate phase. Isomorphous mixed crystals with EUr substitutions, TH-EUr x , were successfully prepared from solutions with 5–10 mol % EUr, although the fraction of EUr included was much lower (∼13–36%) than Ur. As the concentration of EUr in the growth solution increased to 15–20 mol %, an unexpected mixed composition anhydrate emerged as the dominant crystallization product. Although packing fraction estimates suggested that higher EUr substitution levels in the hydrate were theoretically possible, the formation of the mixed anhydrate presented a more favorable route to a dense material phase.

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The nucleobase derivative 5-aminouracil (AUr, C 4 H 5 N 3 O 2 ) is of interest for its biological activity, yet the solid state structure of this compound has remained elusive owing to its propensity to crystallize as aggregates of microcrystalline particles. Here we report the first single-crystal structure of AUr determined from synchrotron x-ray diffraction data. An early crystal structure prediction effort, which assumed that AUr was rigid in the isolated molecule optimized conformation, provided several poor matches to the simu-lated PXRD pattern. Revisiting these crystal structures, by periodic electronic level modelling (PBE-TS optimization) gave more realistic relative lattice energies, but a good match to the experimental powder pattern required using the experimental cell parameters. PXRD and Raman spectroscopy suggest that phase impurities may be present in the bulk crystallization product, though the identity of alternative polymorphs could not be confirmed on the basis of the data available.