1H–1H Interatomic Distances in Paracetamol-Based Structures Unveiled by Double-Quantum NMR and DFT Calculations

The crystal structures of monoclinic paracetamol, its cocrystal with oxalic acid (ParaOA), and its HCl monohydrate salt (ParaHCl) were refined by density functional theory (DFT) calculations and contrasted with the initial X-ray diffraction (XRD) structures. Two independent, but largely consistent, assessments were made: (i) comparisons between 1H and 13C chemical shifts obtained from magic-angle spinning (MAS) nuclear magnetic resonance (NMR) experiments and those predicted by plane-wave DFT calculations before and after geometry optimization; (ii) direct 1H–1H distance evaluations by a recently introduced NMR crystallography method that offers straightforward structure assessments due to interatomic-distance constraints from one double-quantum–single-quantum (2Q–1Q) 1H NMR correlation experiment. For both the 1H/13C chemical shift and 1H–1H distance assessments, the geometry-optimized ParaHCl structure offered a markedly better match than the initial XRD structure, while the XRD structure of paracetamol revealed excellent agreement with the NMR data, with only marginal improvements offered by the DFT optimization. The XRD-derived structure of ParaOA also agreed well with the NMR chemical shift/distance constraints: While the computed 13C chemical shifts showed better agreement with those from MAS NMR, slightly larger discrepancies were observed for the 1H chemical shifts and the 1H–1H distances. We also discuss the chemical shifts and present the first 1H and 13C MAS NMR-peak assignments for the ParaHCl and ParaOA structures.