Thomas C. Lewis

The observed and energetically feasible crystal structures of 5-substituted uracils

A search of the Cambridge Structural Database for crystal structures of 5-substituted uracils shows that, although there is a recurrent motif with symmetric hydrogen bonding and interdigitation of the 5-substituent R, a range of other hydrogen bonded ribbons, sheets and three-dimensional motifs are possible. In order to try and rationalize this, we have performed a combination of experimental studies and computational searches for low energy structures for the 12 simple 5-substituted uracils with R = H, CH3, CH2CH3, CHCH2, CN, OH, NH2, NO2, F, Cl, Br and I. Crystallization experiments on these compounds yielded the first single crystal X-ray determinations of 5-ethyluracil and 5-cyanouracil, as well as low temperature redeterminations of the disordered structures of 5-chlorouracil and 5-bromouracil. The lattice energies were calculated for the known crystal structures and compared with the computed lattice energy landscape for each molecule (except R = Br and I). Although the symmetric ribbon motif often dominates the computed crystal energy landscape, all of the molecules show a variety of different hydrogen bonding structures within a small energy range (5 kJ mol−1) of the global minimum and exhibit quite a diverse range of energetically competitive motifs. Thus, the range of crystallization outcomes, from polymorphism and other multiple forms, to the difficulty in growing single crystals (R = CHCH2 and NH2) probably reflects the sensitivity of the various hydrogen bonding motifs to the substituent and limited range of crystallization conditions that can be applied.

Which organic crystal structures are predictable by lattice energy minimisation?Electronic supplementary information (ESI) available: downloadable version of Table 2. See http://www.rsc.org/suppdata/ce/b1/b108135g/

A survey of the molecules which have been used in crystal structure prediction studies is presented. The results of these studies have been analysed in terms of whether the experimentally observed crystal structures are found at or near the global minimum in the lattice energy. The results suggest that whilst some crystal structures can be predicted just on the basis of lattice energy searches, there is yet insufficient experience to judge for which molecules this energetic criterion is sufficient, within the limitations of current force-field accuracy. The molecules chosen to test crystal structure prediction methods appear to be biased away from the types that would be expected to be readily predictable and suitable for crystal engineering. The survey highlights the need for more theoretical and experimental collaboration to understand what determines whether a molecules crystal structure will be so favourable that other polymorphs are unlikely.

Computational prediction and X-ray determination of the crystal structures of 3-oxauracil and 5-hydroxyuracil—an informal blind test

A manual crystallization screen was performed on 3-oxauracil and 5-hydroxyuracil (isobarbituric acid), culminating in the first determination of their crystal structures. Concurrently but independently, the low energy crystal structures of these molecules were computed by a search for minima in the lattice energy. The crystal structure of 3-oxauracil corresponded to the global minimum in the lattice energy, with an unusually large energy gap of 4 kJ mol−1 between the observed and other hypothetical crystal structures. Therefore, this structure was easily predicted despite some inadequacies in the computational model. The combination of the experimental and computational search suggests that this is the most thermodynamically stable anhydrous crystal structure of 3-oxauracil and it seems unlikely that it will have any readily produced polymorphs. The experimental crystal structure of 5-hydroxyuracil was also found as a low energy crystal structure in the search but a few other hypothetical structures with different hydrogen bonding motifs were predicted to be thermodynamically competitive. It is therefore possible that other polymorphs might be found for 5-hydroxyuracil, although they were not found in this crystallization screen. These successful crystal structure predictions illustrate that the confidence with which crystal structures and polymorphism can be predicted varies between structurally similar molecules.

A low-temperature determination of butyramide

The low-temperature structure determination of butyramide, C4H9NO, obtained as part of a experimental polymorph screen on adenine, is reported here. Each molecule takes part in four hydrogen bonds to form a three-dimensional ribbon structure.

Redetermination of guaninium chloride dihydrate

The low-temperature redetermination of guaninium chloride dihydrate, C5H6N5O+·Cl−·2H2O, obtained as part of an experimental polymorph screen on guanine, is reported here.

Redetermination of adeninium di­chloride: the question of centrosymmetry

The low-temperature redetermination of adeninium(2+) dichloride, C5H7N52+·2Cl−, obtained as part of an experimental polymorph screen on adenine, is reported here. The crystal structure is shown to be centrosymmetric. Cations and anions are connected through N—H⋯N and N—H⋯Cl hydrogen bonds [N⋯N = 2.899 (2) A and N⋯Cl = 3.0274 (14)–3.5155 (16) A] to form sheets perpendicular to the b axis.