Solid-State Structure of Xanthine Determined by a Combination of 3D Electron Diffraction, Powder X-ray Diffraction, and DFT-D Calculations

In the crystalline state, xanthine plays a significant role in several biological systems. For example, pathological crystallization of xanthine causes renal stones in humans and bladder stones in cats and dogs, while xanthine crystals can also serve as functional optical materials, including their role as reflective mirrors in the eye-like organs of certain insects. To understand the role of crystalline xanthine in such biological processes and functions, knowledge of the crystal structure is essential. However, crystal structure determination has so far proved elusive, as xanthine is recalcitrant to the formation of crystals suitable for single-crystal XRD, and severe preferred orientation in powder samples of xanthine has prevented structure determination from powder XRD data. Here we report the crystal structure of xanthine based on the analysis of 3D electron diffraction (3D-ED) data recorded for microcrystals in a powder sample, in conjunction with periodic DFT-D calculations and the analysis of powder XRD data. In common with certain other purines, the crystal structure of xanthine is a layered structure containing planar hydrogen-bonded sheets in which all hydrogen-bond donor and acceptor groups are engaged in intermolecular hydrogen bonds. Considering the tautomeric form of xanthine in the crystal structure, analysis of the 3D-ED data supports the presence of the N7H tautomer (the tautomer of lowest energy for an isolated xanthine molecule). However, the corresponding crystal structure containing the N9H tautomer is essentially isostructural, as it differs from the structure containing the N7H tautomer only in the position of the H atom within each intermolecular N–H···N hydrogen bond in the structure. Interestingly, the difference in energy (per molecule of xanthine) between the crystal structures containing the N7H and N9H tautomers is significantly lower than the difference in energy of an isolated xanthine molecule in the N7H and N9H tautomers.