Many organic compounds can exist in hydrated and anhydrous crystalline forms, each of which exhibits its own different set of physical properties. This makes dehydration–rehydration processes an important class of solid-state reactions; yet, the molecular-level mechanisms and cooperative motions which govern such transformation in molecular solids have been notoriously difficult to establish. Here using time-resolved synchrotron X-ray powder diffraction (sPXRD) and other methods, we identify a number of early subtle changes in thymine hydrate (TH) which set its trajectory for the formation of anhydrous products. An early cooperative “morning stretch” motion, characterized by a coordinated increase in the interlayer separation and angular rotation, was observed prior to the appearance of the first major anhydrous phase, Td1. Kinetic analyses indicated the overall solid-state reaction proceeds via a one-dimensional diffusion mechanism with an E a = 115–122 kJ/mol. At temperatures ≥45 °C, solid state dehydration yielded mixtures of Td1 and a second major anhydrous phase, Td2. Multiphase refinement of sPXRD data proved that Td2 is formed via two distinct routeseither directly due to water loss from TH or via the polymorphic transformation of Td1. Heating above ∼180 °C yielded Td2 as the major product. A limited number of weak diffraction peaks evidence the presence of a third transient form, Td*, which also converts to Td2. The time-resolved methods used here illustrate that solid-state dehydration even in a seemingly simple molecular hydrate system involves a significantly more complex set of coordinated molecular motions and solid–solid transformations than originally thought. The ability to glean a more complete picture of the cooperative motions that occur during water loss from soft crystalline hydrates is an important step in the development of a deeper understanding of this important class of materials.

Uric acid crystallization in humans is associated with undesirable medical conditions including the formation of gout deposits and kidney stones. A major contributing factor to uric acid biomineralization, most often as either monosodium urate (MSU) or anhydrous uric acid (UA), is its relatively low solubility in physiologic solutions. Using bidentate and tridentate binding patterns designed to disrupt the binding motifs observed in the major physiologic forms, several heterocycles were identified which (1) significantly delay the time required for visible uric acid crystals to appear and/or (2) yield new 1:1 uric acid cocrystal phases. All five of the new phases obtained exhibited a multidentate hydrogen bonding motif between components. Fluorescence assays showed that three of the cocrystals were 3–6× more soluble than the natural forms. The same competitive-binding approach was then extended to trimethoprim, an FDA-approved drug with the same substructure as the most effective binding agents. Addition of trimethoprim to uric acid solutions significantly delayed the crystallization times and also yielded a new cocrystal form with a solubility greater than MSU. These results serve to illustrate the potential benefits of repurposing existing pharmaceuticals to treat uric acid diseases.

Monohydrate and anhydrate crystalline forms of the DNA nucleobase cytosine interconvert via a topotactic solid-state mechanism where water functions as a molecular switch. The solid-state dehydration mechanism and kinetics were elucidated using complementary time-resolved synchrotron powder X-ray diffraction and thermogravimetric methods. Results indicate the reaction initiates from the crystal surface, involves no other crystalline intermediates, and proceeds at rates that depend on the monohydrate processing. A molecular-level model, based on least-motion arguments and consistent with the totality of the experimental data, is proposed to account for the high degree of structure transfer associated with the transformation. Water loss on the monohydrate crystal surface activates the rotation of one-dimensional cytosine ribbons, which in turn alters the local environment of the neighboring unit cell, facilitating the release of additional water molecules and ribbon rotation. As the dehydration front progresses into the solid, this cooperative mechanism effectively converts two-dimensional layers of antiparallel π-offset stacked ribbons into orthogonal two-dimensional layers of parallel π-face–face stacked ribbons. Moisture sorption experiments performed under high-humidity conditions confirm the anhydrate product can be reversibly rehydrated back to the monohydrate and that repeated dehydration–rehydration cycles proceed at consistent rates. The ability to track both the structural and compositional changes in the sample throughout the course of the reaction makes this a powerful combination of techniques for characterizing cooperative rotational motions triggered by water loss and/or uptake from crystalline materials.