Pair distribution function “feat.” solid-state NMR in a combined approach for structure determination of organic molecules

Abstract Investigating the local structure of molecular solids is critical for establishing structure–property relationships and controlling material performance. Pair distribution function (PDF) analysis probes poorly crystalline, nanocrystalline and amorphous materials, yet its application to organic compounds remains limited. The recently developed Global-PDF-Fit method enables ab initio crystal structure determination of organic molecules, although intrinsic limitations can complicate unique structure identification. Here, we present a synergistic workflow integrating Global-PDF-Fit with solid-state NMR (SSNMR), demonstrating how restraints and intermolecular proximity constraints from 1D magic angle spinning (MAS) and 2D 1 H- 13 C double cross polarization and 1 H double quantum/ 1 H single quantum MAS SSNMR experiments reduce computational time, guide structure ranking, and increase reliability, enabling unambiguous structure determination. Demonstrated on 5-aminosalicylic acid and S-naproxen (crystallite sizes of 50–55 nm), the approach provides a robust strategy for structure determination and represents a significant advance in the field of local-structure elucidation of poorly crystalline and nanocrystalline organic solids, where conventional diffraction techniques fail.