Development of a Non-Polarizable Force Field for N-Methylacetamide: Non-Bonding Interactions and Dielectric Properties in Aqueous and Organic Mixtures

In this study, a new non-polarizable force field for N-methylacetamide (NMA), termed UAMI-FF, was developed using the 3SSPP procedure by combining cluster-derived Hirshfeld charges with systematic optimization of Lennard-Jones parameters to achieve an improved description of condensed-phase electrostatics and hydrogen-bond cooperativity. Hirshfeld cluster-derived atomic charges combined with charge scaling were important for reproducing the experimental dielectric constant and improving the description of the Kirkwood correlation factor ( g K ), demonstrating the importance of incorporating local intermolecular environments and collective dipolar correlations into force-field parameterization. UAMI-FF reproduces the dielectric constant, liquid density, and surface tension of pure NMA over a temperature range of 303.15-363.15 K. Structural analysis further shows that the model reproduces intermolecular N-H···O=C hydrogen-bonded associations and provides insight into the relationship between molecular organization, collective dipolar correlations, and the unusually high dielectric response of liquid NMA. Beyond the pure liquid phase, UAMI-FF shows improved performance in the binary mixtures examined in this work with water, dimethylacetamide, methanol, and ethanol, describing density, dielectric constant, and composition-dependent g K trends across solvents with different polarities and hydrogen-bonding capabilities. The model also reproduces the experimentally observed non-monotonic density behavior of aqueous NMA mixtures and provides an overall improved description of pure-liquid and mixture properties compared with the conventional transferable force fields evaluated in this work. Collectively, these results demonstrate the potential of UAMI-FF for describing the structural, dielectric, and physicochemical properties of liquid NMA and its aqueous and organic mixtures.