Substituent-controlled charge transfer in donor–π–acceptor thieno[2,3-d]pyrimidines: A computational study of electronic structure, nonlinear optical response, and EGFR binding

A series of four thieno[2,3-d]pyrimidin-4(3H)-one derivatives (TP-1 to TP-4) was investigated by density functional theory (DFT) and time-dependent DFT (TD-DFT) at the B3LYP-D3BJ/def2-TZVP level to establish how substituent electron demand at positions 2 and 6 tunes their electronic, nonlinear optical, and target-binding behavior. The series spans an unsubstituted parent to a donor–π–acceptor system bearing an amino donor and a para-nitro acceptor. Optimized geometries reveal a planar fused core and a phenyl twist that decreases from TP-2 to TP-4 as donor–acceptor coupling strengthens. The HOMO–LUMO gap narrows monotonically from 4.97 eV (TP-1) to 3.38 eV (TP-4), driven first by HOMO destabilization on amino substitution (TP-1→TP-3) and then by LUMO stabilization on nitro substitution (TP-3→TP-4); natural bond orbital analysis confirms that amino lone-pair donation into the ring is strongest in TP-4. Consistent with this, the lowest-energy absorption red-shifts to 364 nm for TP-4 in DMSO; hole–electron analysis shows that the donors extend the delocalization of the excitation, whereas genuine charge separation emerges only in TP-4, in line with its strong positive solvatochromism. The static first hyperpolarizability rises steeply along the series, reaching 1.9 times that of p-nitroaniline (117 times that of urea) for TP-4, an ordering preserved with CAM-B3LYP. Topological analyses (QTAIM, NCI-RDG, ELF, LOL) characterize the covalent framework and intramolecular weak interactions, while molecular electrostatic potential maps and Fukui functions locate the nucleophilic carbonyl and ring-nitrogen sites and the electrophilic nitro group. Molecular docking against the EGFR kinase domain (PDB: 1M17) indicates that TP-2 to TP-4 bind comparably to the reference inhibitor erlotinib, with score differences within the scoring-function uncertainty, so the ranking is treated as indicative. Taken together, the results define a clear substituent-based strategy for tuning charge transfer in this scaffold and identify TP-3 and TP-4 as the most promising candidates for nonlinear optical and EGFR-targeted applications.