Spiro‐Conjugated π–σ–π Architectures Enable Single‐Molecule Insulators via Destructive Quantum Interference

Controlling molecular conductance beyond highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO-LUMO) interference is essential for advancing single-molecule electronics. Here we employ π-σ-π frameworks-linear diphenylmethane and orthogonal 9,9'-spirobifluorene-to investigate destructive quantum interference (DQI) governed by orbitals on the same side. Four model molecules (DM22-MT, DM44-MT, SF33-MT, SF44-MT) were designed with site-specific -SMe anchoring groups and examined by scanning tunneling microscope-break junction (STM-BJ) measurements and theoretical simulations. All exhibit intrinsically low conductance, consistent with destructive quantum interference (DQI) effect. Importantly, site-dependent effects in spiro systems disrupt spiro-conjugation and alter anchor-electrode coupling, leading to counterintuitive conductance trends. This study provides the first experimental evidence for bilateral DQI in π-σ-π systems and establishes a molecular design strategy for insulating and functionalized single-molecule devices.