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

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⋯OP 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 <i>via</i> 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.