Trifluoromethyl Engineered 9-Amino-Si-Xanthene with Distinct p K a and Emission Shift for Imaging Ethanol-Induced Gastric Ulcer

High-fidelity visualization of dynamic pH fluctuations in acidic and ultra-acidic microenvironments is imperative for elucidating pH-regulated pathophysiological processes. A critical challenge is the scarcity of robust near-infrared (NIR, >650 nm) fluorescent tools with tailored acidic p K a, large Stokes shifts, and exceptional stability under harshly acidic conditions for high-contrast imaging. To address this, we proposed trifluoromethyl molecular engineering on 9-alkylamino-Si-xanthene by adding a trifluoromethyl tail at the terminal of the 9-alkyl chain. This subtle structural modification induced surprising photophysical transformations: significant bathochromic shifts of 35–105 nm to ∼700 nm and dramatic p K a reduction from ∼8 to ∼4. The observed performance was rationalized through theoretical calculations, including HOMO–LUMO gaps, molecular electrostatic potential, natural population analysis, configuration changes, and Gibbs free energy difference. Utilizing the optimal probe SiNF2, we successfully observed enhanced lysosome-mitochondria communication during ferroptosis and achieved a striking 21.3-fold fluorescence contrast between cancer cells and normal cells. Notably, we demonstrate the first detection of diminished gastric acidity in an ethanol-induced gastric ulcer mouse model, highlighting the probe’s potential for imaging-guided diagnosis and therapeutic monitoring of gastric disorders.