An Experimental and Theoretical Search for Polymorphs of Barbituric Acid:  The Challenges of Even Limited Conformational Flexibility

Abstract

An experimental study of barbituric acid found a new P 2 1 / c polymorph with two conformations of barbituric acid in the asymmetric unit, one molecule adopting an envelope conformation and the other refining as planar. The new Form ii involves different hydrogen bond acceptors to Form i. An ab initio conformational analysis study found that barbituric acid can change its envelope conformation by over 20° from planar with a small energy change that can be compensated for by packing forces, so that the new Form ii is predicted to have a lower lattice energy than Form i. A computational search for minima in the lattice energy found many hypothetical structures of barbituric acid within the energy range of possible polymorphism, with a variety of hydrogen bonding acceptors and motifs. The search was found to be very sensitive to the assumed molecular structure of barbituric acid, so further plausible low energy variations in the molecular conformation would produce even more low energy crystal structures. Thus, the combined experimental and theoretical studies show that barbituric acid can pack in such a variety of low energy structures that further polymorphs seem possible.