Computational and structural insights into the zwitterionic and neutral forms of N-substituted hydroxyformamidines in the solid state

Abstract

N-Hydroxyformamidines with the general formula [N-(Ar), N′(OH)-(Ar′)] were synthesized and characterized using NMR, IR and mass spectrometry. Analysis of single-crystal X-ray diffraction data of two of the compounds, along with previously reported structures of N-hydroxyformamidine derivatives, revealed that symmetrical hydroxyformamidines can exist as either zwitterionic or neutral species in the solid state. In contrast, unsymmetrical hydroxyformamidines are exclusively zwitterionic. The zwitterionic forms adopt Z_anti isomerism, while the neutral forms exhibit E_anti isomerism. Both symmetrical compounds and unsymmetrical compounds bearing relatively less bulky substituents, exhibit intermolecular interactions that result in the formation of dimeric molecular units characterized by R²₂(10) graph-set descriptor. In contrast, unsymmetrical compounds with bulkier substituents form extended chain-like structures. N–H⋯O, N–H⋯N, O–H⋯O and O–H⋯N classical hydrogen bonding patterns were observed to support the crystal lattices in dimeric units, while chains were formed by relatively weak C–H⋯O intermolecular interactions. Molecular pairwise interaction energy calculations indicated that electrostatic energy (E_ele) contributes more to the total energy of interaction of compounds forming dimeric units, whereas dispersion (E_dis) energy is the primary contributor in molecules adopting chain-like structures. Natural Bond order analysis indicate that electron-donating substituents enhance the basicity of the imine and the amine nitrogen atoms, facilitating cooperative resonance-driven proton transfer. Consequently, both zwitterionic and neutral hydroxy species are present in the solid state. This study offers insight into the role of substituents in modulating hydrogen-bonding patterns and charge distribution, providing valuable strategies for controlling crystal packing and polymorphism, which are critical factors in pharmaceutical and materials science.