Alkyl chain length as a molecular switch: from supramolecular reprogramming to biointerface modulation in α-aminophosphonate assemblies

Abstract

Alkyl chain length is commonly regarded as a passive determinant of lipophilicity in bioactive molecules. Here, we demonstrate that it functions instead as a molecular switch that reprograms supramolecular organization and transport-related behavior in dialkyl 2-(((4-acetamidophenyl)amino)propan-2-yl)phosphonates. A combined experimental–theoretical investigation was performed on the diethyl derivative (compound I) and the dibutyl derivative (compound II) using single-crystal and powder X-ray diffraction, DFT (ωB97X-D/6-31G*), DLS, NMR, IR/ATR spectroscopy, UV–vis absorption, fluorescence spectroscopy, HRMS, thermal analysis, QSAR, ADMET, and in vitro cytotoxicity studies. Structural analyses revealed that compound I forms hydrogen-bonded dimers, whereas compound II assembles into cooperative tetramers through complementary PO⋯H–N (amine) and CO⋯H–N (amide) interactions. Excellent agreement between experimental and calculated structural parameters validated the proposed supramolecular models. DLS, QSAR, and frontier orbital analyses showed that tetramer formation substantially increases molecular size, anisotropy, accessible surface area, and polarizability. Although compound II exhibits a slightly smaller HOMO–LUMO gap, both compounds remain electronically stable, with the reduced gap reflecting enhanced electronic delocalization rather than increased chemical reactivity. Thermal and ATR studies demonstrated that alkyl chain elongation decreases crystal packing efficiency and promotes hydrogen-bond reorganization without compromising the stability of the phosphonate core. Both compounds exhibited low cytotoxicity (IC₅₀ > 100 μM), indicating good biological tolerance. While monomer-based ADMET predictions suggest a shift from absorption-favored behavior in compound I to permeability-limited characteristics in compound II, these models do not fully capture the persistence of the experimentally verified tetrameric assembly. Collectively, the results establish alkyl chain length as a supramolecular design parameter governing assembly state, intermolecular interactions, and potential delivery pathways in phosphonate-based systems.