Photoreaction of indazole metastable-state photoacid

Indazole metastable-state photoacids have been recently applied to modulating local pH of tumor and brain in animal studies. The mechanism of this type of photoacid was previously assumed to be the same as that of the extensively studied merocyanine photoacids. However, this work showed that the photo reaction of indazole photoacid is significantly different from merocyanine photoacid in water. An indazole photoacid with high water solubility up to 70 mM was designed and synthesized. Photoirradiation generates a quinoidal cis-conformer in water instead of the spiro conformer generally expected for a metastable-state photoacid. Although the twisted conformation reduced conjugation between the electron-withdrawing moiety and the acidic moiety, the cis -conformer possesses a higher acidity than that of the trans-conformer due to the unusual quinoidal structure. In organic solvents, the cis-isomer possesses a Kekule structure, which has lower acidity than that of the trans -conformer. In the presence of a weak base, photoirradiation reversibly converted the trans-conformer to the spiroconformer. Experiments showed that deprotonated cis-conformer is the intermediate for both the spiro formation and the reverse cis-to -trans reaction. Addition of an acid stops both reactions and locks the photo -product to the protonated cis-conformer.