Singlet versus Triplet Excited State Mediated Photoinduced Dehalogenation Reactions of Itraconazole in Acetonitrile and Aqueous Solutions

Abstract

Photoinduced dehalogenation of the antifungal drug itraconazole (ITR) in acetonitrile (ACN) and ACN/water mixed solutions was investigated using femtosecond and nanosecond time-resolved transient absorption (fs-TA and ns-TA, respectively) and nanosecond time-resolved resonance Raman spectroscopy (ns-TR) experiments. An excited resonance energy transfer is found to take place from the 4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one part of the molecule to the 1,3-dichlorobenzene part of the molecule when ITR is excited by ultraviolet light. This photoexcitation is followed by a fast carbon-halogen bond cleavage that leads to the generation of radical intermediates via either triplet and/or singlet excited states. It is found that the singlet excited state-mediated carbon-halogen cleavage is the predominant dehalogenation process in ACN solvent, whereas a triplet state-mediated carbon-halogen cleavage prefers to occur in the ACN/water mixed solutions. The singlet-to-triplet energy gap is decreased in the ACN/water mixed solvents and this helps facilitate an intersystem crossing process, and thus, the carbon-halogen bond cleavage happens mostly through an excited triplet state in the aqueous solutions examined. The ns-TA and ns-TR results also provide some evidence that radical intermediates are generated through a homolytic carbon-halogen bond cleavage via predominantly the singlet excited state pathway in ACN but via mainly the triplet state pathway in the aqueous solutions. In strong acidic solutions, protonation at the oxygen and/or nitrogen atoms of the 1,2,4-triazole-3-one group appears to hinder the dehalogenation reactions. This may offer the possibility that the phototoxicity of ITR due to the generation of aryl or halogen radicals can be reduced by protonation of certain moieties in suitably designed ITR halogen-containing derivatives.