3,5-Bis(2-hexafluoro-isopropoxyl)phenyl: A Super-Fluorinated Moiety with Favorable Water-Solubility and Modifiability for ¹⁹ F Magnetic Resonance Imaging

Among molecular imaging techniques, 19 F magnetic resonance imaging ( 19 F MRI) is particularly attractive due to deep penetration and multiplexed molecular imaging. However, the further development of 19 F MRI remains constrained by its limited sensitivity, which largely depends on fluorinated probe design and more fundamentally on the availability of high-performance fluorinated moieties that define probe signal intensity. Here we systematically establish 3,5-bis(2-hexafluoro-isopropoxy)phenyl (BHFIP) as a structurally simple yet highly capable fluorinated moiety for 19 F MRI probe design. Starting from 1,3-bis(2-hexafluoro-isopropoxy)benzene, a simple two-step nitration-reduction procedure afforded 3,5-bis(2-hexafluoro-isopropoxy)aniline (BHFIP-NH 2 ), a modifiable BHFIP-based building block. Besides its high fluorine loading of 12 chemically equivalent fluorine atoms, BHFIP was found to possess an intrinsically short 19 F longitudinal relaxation time ( T 1 ), together enabling exceptionally high 19 F MRI sensitivity. Its 19 F chemical shift at approximately – 75 ppm is clearly distinguishable from those of established highly fluorinated moieties, supporting multiplexed 19 F MRI. The two hydroxyl groups of BHFIP contribute to water solubility and enable O -modification, while BHFIP-NH 2 further provides an additional amino handle for N -modification. Representative incorporation of BHFIP-NH 2 into 19 F MRI probes further verified that the advantages of BHFIP can be retained in functional probe molecules. This work establishes BHFIP as a promising fluorinated moiety for high-sensitive and multifunctional 19 F MRI probes.