Time resolved spectroscopic studies on the substituent effect induced high reactivity of benzophenone derivatives and dehalogenation reaction of the antifungal drug itraconazole

Abstract

Photochemical reactions of selected benzophenone derivatives with two methoxy groups substituted at para, meta and ortho positions on the benzene rings and the photoinduced dehalogenation reaction of the antifungal drug Itraconazole (ITR) have been studied in detail using time resolved transient absorption from femtosecond (fs-TA) to nanosecond (ns-TA) time domains and nanosecond time resolved resonance Raman (ns-TR3) spectroscopy. Density functional theory (DFT) calculations were employed to further characterize the absorption and vibrational frequencies of major intermediates observed in the photoreaction processes and to elucidate the corresponding mechanisms. Direct observation of two excited triplet states n, π* and π, π* by time-resolved spectroscopy experiments for 4, 4’-Dimethoxybenzophenone (4, 4'-DMBP) and 3, 3’- Dimethoxybenzophenone (3, 3’-DMBP) in various solvents found that 4, 4'-DMBP has a typical n, π* configuration in nonpolar solvents while π, π* triplet can only be observed in strong polar solvents. Comparison of the transient absorption spectra of 3, 3’-DMBP and 4, 4’-DMBP found that the position of the substituent is a key factor affecting the characteristics of a π, π* triplet state. The study here found that adding an electron-donating methoxy group onto the benzene ring can accelerate the photoreduction and photohydroxylation reactions significantly. High efficiency cross coupling reaction via n, π* triplets could be directly derived from the photoreaction of the 4, 4’-DMBP molecule in an ACN/isopropanol (IPA) mixed solution. The TR3 experiments showed that the long lived light absorbing transient (LAT) intermediate of 4, 4'-DMBP in mixed solvents of ACN/IPA can only be generated in the presence of the n, π* triplet and a hydrogen donor reagent. Para effect of the electron donating substituent can strongly promote the radical-radical cross coupling reaction so that no diphenyl ketyl radical (DPK) of 4, 4’-DMBP was observed in the ns-TR3 experiments. The ortho-substituents effect appear to activate the benzene ring of 2, 2’-Dimethoxybenzophenone (2, 2’-DMBP), which can dramatically stabilize the π, π* character to be the lowest triplet state. Further studies on 2, 2’-DMBP in ACN aqueous solutions give convincing evidence that efficient photohydroxylation reaction can take place via the π, π* triplet state in this case to generate a solvent-water adduct product. The study on photoinduced dehalogenation reaction of Itraconazole revealed that the reaction rate of the triplet state intermediate in the dehalogenation reaction would tend to be faster than that of the singlet excited state. In ACN, the C-Cl cleavage most likely accomplished via a singlet excited state route with the leaving of the ortho-position chlorine radical followed by a cyclization reaction to give rise to its final product. The addition of a strong polar solvent (e.g. water) can lower the energy gap between the singlet and triplet states so the ISC process is much more probable, so that the corresponding dehalogenation process mainly takes place via triplet states which leads to different final products. The fs-TA spectra showed the dehalogenation reaction may be blocked under a strongly acidic condition (pH<1) since the oxygen atom of the carbonyl group and the nitrogen atom of the triazole group were likely protonated. This acid protection effect offers a method to reduce the phototoxicity of ITR due to the release of aryl or halogen radicals.