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

Area of Science:

• Solid-state chemistry
• Crystallography
• Computational chemistry

Background:

• Crystal structure determination is crucial for understanding material properties.
• X-ray diffraction (XRD) is a primary method, but computational methods and NMR spectroscopy offer complementary validation.
• Paracetamol and its derivatives are important pharmaceutical compounds with diverse solid-state forms.

Purpose of the Study:

• To refine and validate crystal structures of monoclinic paracetamol, its cocrystal with oxalic acid (ParaOA), and its HCl monohydrate salt (ParaHCl).
• To compare the accuracy of density functional theory (DFT) calculations and NMR crystallography against initial X-ray diffraction (XRD) data.
• To present the first 1H and 13C magic-angle spinning (MAS) NMR peak assignments for ParaHCl and ParaOA.

Main Methods:

• Refinement of crystal structures using density functional theory (DFT) calculations.
• Comparison of experimental 1H and 13C chemical shifts (magic-angle spinning nuclear magnetic resonance - MAS NMR) with DFT-predicted values.
• Application of a 2D 1H-1H double-quantum-single-quantum (2Q-1Q) NMR correlation experiment for direct interatomic distance evaluation.
• Validation of structures using NMR crystallography by assessing 1H-1H distances.

Main Results:

• Geometry-optimized ParaHCl structure showed significantly better agreement with NMR chemical shift and distance data than the initial XRD structure.
• The XRD structure of paracetamol agreed excellently with NMR data, with only marginal improvement from DFT optimization.
• The XRD structure of ParaOA showed good agreement with NMR constraints, though minor discrepancies were noted for 1H chemical shifts and 1H-1H distances.
• First 1H and 13C MAS NMR peak assignments for ParaHCl and ParaOA were successfully made.

Conclusions:

• DFT calculations and NMR crystallography provide robust validation for crystal structure determination.
• Geometry optimization in DFT can significantly improve structural accuracy, especially for salts like ParaHCl.
• NMR spectroscopy, particularly NMR crystallography, is a powerful tool for assessing interatomic distances and chemical shifts, complementing XRD and DFT methods.