Molecular Descriptor of Electronic Transition for Regulating Polarity-Responsive Behavior of Heterocycle-Containing Probes

Heterocycle-containing luminescent probes exhibit intricate polarity responses, notably due to the presence of lone pair(s), which increases the complexity of the excited state and brings additional challenges for their rational design. In this work, we present three classes of fluorescent probes with "on-off", "insensitive", and "off-on" polarity responses by attaching different substituents to the same fluorophore core. Class I probes with nonaromatic six- and five-membered bulky heterocycle moieties exhibit an "on-off" response due to the transition from a local excited state to a twisted intramolecular charge transfer state with increasing polarity. Class II probes with more compact nonaromatic four- and three-membered heterocyclic moieties display an "insensitive" response originating from an excited-state electronic structure that is insensitive to environmental polarity. Class III probes with bulky aromatic six-membered moieties show an "off-on" response due to the transition from a dark (π, σ*)/(n, π*) state to a bright (π, π*) state as the polarity increases. This design strategy is shown to be applicable to a wide variety of electron-accepting fluorophores. Additionally, a simple metric, Δα, is proposed to predict polarity-response behaviors: Δα < 0 suggests Class I; Δα ≈ 0 indicates Class II; Δα > 0 hints at Class III. Our theoretical predictions are experimentally corroborated, and the wash-free lipid droplet imaging of one of the predicted dyes exhibits relatively high contrast. In a nutshell, this work provides theoretical guidance for designing polarity-responsive probes for both bioimaging and disease diagnosis.