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.