Green synthesis of α-aminophosphonates: from hydrogen-bonded Janus dimers to pharmaceutical potential

Abstract

A family of α-aminophosphonates, dimethyl (A), dipropyl (B), and diisopropyl (C), was synthesized through a green, catalyst-free Kabachnik–Fields reaction and characterized using FT-IR, NMR, and UV–Vis spectroscopy, single-crystal X-ray diffraction, DFT calculations, and multiscale physicochemical analyses. All compounds crystallize as asymmetric Janus-type dimers stabilized by strong intermolecular N–H⋯OP hydrogen bonds, with alkyl substituents tuning their packing efficiency, directional interactions, and supramolecular organization. SC-XRD and ωB97X-D calculations show excellent agreement with their bond lengths, angles, and overall geometry, validating their dimeric structural model. Vibrational and NMR data corroborate the donor–acceptor polarity of the amide N–H and phosphoryl groups, while XRPD and DLS measurements confirm their structural robustness and concentration-dependent aggregation. Photophysical analyses reveal consistent π → π* transitions on the aromatic amide core with substituent-dependent relaxation. Thermal analysis shows that A possesses the most ordered hydrogen-bonded lattice yet decomposes first due to internal strain, B melts earlier but decomposes slightly later owing to its reduced packing efficiency, and C exhibits the highest melting point via compact dispersive stabilization. DFT and QSAR results further indicate distinct electronic behaviors, where compound A exhibits stronger hydrogen-bonding propensity toward biological targets, B shows steric stabilization, and C balances polarity and hydrophobicity to achieve the most favorable drug-like profile. Overall, this study demonstrates that substituent-driven modulation of hydrogen bonding, steric effects, and dispersive forces enables precise control over the supramolecular and physicochemical properties of α-aminophosphonate dimers, positioning them as versatile scaffolds for pharmaceutical and materials applications.