Identification of Protonation State by XPS, Solid-State NMR, and DFT: Characterization of the Nature of a New Theophylline Complex by Experimental and Computational Methods

Recent studies suggested that X-ray photoelectron spectroscopy (XPS) sensitively determines the protonation state of nitrogen functional groups in the solid state, providing a means for distinguishing between co-crystals and salts of organic compounds. Here we describe how a new theophylline complex with 5-sulfosalicylic acid dihydrate was established as a salt by XPS prior to assignment with conventional methods. The presence of a CNH+ (N9) N1s peak in XPS allows assignment as a salt, while this peak is clearly absent for a theophylline co-crystal. The large low frequency shift for N9 observed by 15N solid-state nuclear magnetic resonance spectroscopy (ssNMR) and corresponding density functional theory (DFT) calculations confirm that protonation has occurred. The crystal structure and further analytical studies confirm the conclusions reached with XPS and ssNMR. This study demonstrates XPS as an alternative technique for determining whether proton transfer has occurred in acid−base complexes.