1 H and 13 C chemical shift-structure effects in anhydrous β-caffeine and four caffeine-diacid cocrystals probed by solid-state NMR experiments and DFT calculations.

By using density functional theory (DFT) calculations, we refined the H atom positions in the structures of β-caffeine (C), α-oxalic acid (OA; (COOH) 2 ), α-(COOH) 2 ·2H 2 O, β-malonic acid (MA), β-glutaric acid (GA), and I-maleic acid (ME), along with their corresponding cocrystals of 2 : 1 (2C-OA, 2C-MA) or 1 : 1 (C-GA, C-ME) stoichiometry. The corresponding 13 C/ 1 H chemical shifts obtained by gauge including projector augmented wave (GIPAW) calculations agreed overall very well with results from magic-angle-spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy experiments. Chemical-shift/structure trends of the precursors and cocrystals were examined, where good linear correlations resulted for all COO 1 H sites against the H⋯O and/or H⋯N H-bond distance, whereas a general correlation was neither found for the aliphatic/caffeine-stemming 1 H sites nor any 13 C chemical shift against either the intermolecular hydrogen- or tetrel-bond distance, except for the 13 C OOH sites of the 2C-OA, 2C-MA, and C-GA cocrystals, which are involved in a strong COO H ⋯ N bond with caffeine that is responsible for the main supramolecular stabilization of the cocrystal. We provide the first complete 13 C NMR spectral assignment of the structurally disordered anhydrous β-caffeine polymorph. The results are discussed in relation to previous literature on the disordered α-caffeine polymorph and the ordered hydrated counterpart, along with recommendations for NMR experimentation that will secure sufficient 13 C signal-resolution for reliable resonance/site assignments.