Theoretical Examination and Exploration of Intermolecular Interactions and Chemical Reactivity of Nitrofurantoin-4-Hydroxy Benzamide Co-Crystal

Abstract

This study explores the molecular, electronic, and chemical modifications of nitrofurantoin (NF) upon co-crystallization with 4-hydroxybenzamide (4HBAM), resulting in the formation of a NF–4HBAM (1:2) co-crystal. Molecular geometries were optimized using Density Functional Theory (DFT) at the B3LYP/6–31G(d,p) level via Gaussian09 to evaluate the impact of co-crystallization on NF's physicochemical properties. The co-crystal exhibited enhanced reactivity, characterized by increased polarizability, reduced kinetic stability, and greater chemical softness compared to the individual components, indicating stronger intermolecular interactions and a more compact molecular arrangement. Molecular Electrostatic Potential (MEP) surface mapping revealed distinct electrophilic and nucleophilic reactive sites. Natural Bond Orbital (NBO) analysis confirmed significant conjugative and hyperconjugative interactions, with second-order stabilization energies supporting the presence of strong hydrogen bonding. The co-crystal also demonstrated promising non-linear optical (NLO) behavior, evidenced by a high dipole moment (μ = 12.3556), polarizability (α = –30.1834 × 10⁻²⁴ e.s.u), and first-order hyperpolarizability (β₀ = 1.589 × 10⁻³⁰ e.s.u), suggesting potential optoelectronic applications. Additionally, the Fermi energy of NF-4HBAM is 2.8364 eV, observed through density of states (DOS) analysis, which highlights enhanced electronic performance. These findings underscore the role of co-crystallization in tuning NF's pharmaceutical and functional properties.