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

Abstract 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.