Cs2CO3-mediated synthesis of 2-alkoxy-3-cyanopyridines: integrated crystallographic, photophysical, and DFT analyses

Abstract

We report a Cs₂CO₃-promoted O-alkylation of 4-(4-chlorophenyl)-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile 1 with alkyl bromides 2a–c, affording 2-alkoxy-3-cyanopyridines 3a–c in high yields (87–95%) and excellent O : N selectivity ranging from 91 : 9 to 100 : 0. The structures of the 2-alkoxy-3-cyanopyridines were confirmed by FT-IR, NMR, and HRMS analyses. Thermal analyses revealed that TGA confirmed the overall thermal stability of compounds 3a–c, DSC identified their phase transition temperatures and associated enthalpies, and DTG provided precise decomposition temperatures, unequivocally establishing 3c as the most thermally stable. A comparative photophysical analysis revealed a marked enhancement in fluorescence quantum yields following O-alkylation at position 2 of the 3-cyano-2(1H)-pyridone core. Specifically, the 2-alkoxy-3-cyanopyridines 3a–c exhibited Φ_F values of up to 0.263, more than twice that of the unmodified 4-(4-chlorophenyl)-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile 1 (Φ_F up to 0.112), underscoring the pivotal role of electronic modulation in fine tuning emissive properties. DFT calculations at the B3LYP/def2TZVP level accurately reproduced the experimentally resolved crystal structures as well as the absorption and emission spectra, showing excellent agreement with the measured data. These results offer a solid theoretical framework for understanding photophysical behavior and provide complementary insights into frontier molecular orbitals and global reactivity descriptors. Moreover, single-crystal X-ray diffraction unambiguously confirmed the structures of 3a–c, revealing distinct packing arrangements governed by directional non-classical hydrogen bonding and the electronic effects of nitrile and chloro groups. Notably, compound 3c crystallizes in the chiral Sohncke space group P2₁2₁2₁, despite its achiral nature, suggesting the presence of subtle asymmetric intermolecular forces influencing crystal packing.