Methyl group dynamics and conformational flexibility in methacetin revealed by neutron spectroscopy

• Neutron spectroscopy shows that the reorientational motions of the methyl groups in methacetin are highly sensitive to both temperature and pressure. • Analysis of the mean square displacement (MSD) reveals a clear deviation from the harmonic Debye model above 140-200 K. • DFT calculations demonstrate that in the crystalline state, methyl torsions are strongly coupled. • Quasi-elastic neutron scattering reveals that reorientational motion on the picosecond timescale is dominated by the O-CH₃ group. • Mixed C-CH₃ modes soften above 0.4 GPa, indicating reduced flexibility and increased rigidity under pressure. • Methacetin’s dynamic behaviour, influenced by subtle structural changes, highlights the importance of methyl group dynamics in pharmaceutical compounds. The dynamics of functional groups within drug molecules influences their medicinal or toxicological effects, with methyl groups’ conformational changes affecting binding to active sites. Here, we combine inelastic neutron scattering spectroscopy with density functional theory to investigate molecular dynamics and conformational flexibility of methacetin (C 9 H 11 NO 2 ), a member of the acetamide family that includes paracetamol (C 8 H 9 NO 2 ) and phenacetin (C 10 H 13 NO 2 ). Our results reveal that subtle variations in its crystal packing and hydrogen bonding lead to multiple conformations, with methyl group reorientations contributing significantly to the molecule’s dynamics. This study stresses the importance of integrating experimental and computational methods to understand the structural dynamics of pharmaceutical compounds and their implications for drug design.