Iodinated zinc phthalocyanine : the novel visible-light activated photosensitizer for efficient generation of singlet oxygen

Abstract Phthalocyanines are promising photosensitizers for photodynamic therapy (PDT). A novel zinc 1,8(11),15(18),22(25)-tetraiodo-3,10(9),17(16),24(23)-tetra- tert -butylphthalocyanine has been synthesized and characterized. The synthesis of iodinated phthalocyanine was achieved through templated cyclotetramerization of 6- tert -butyl-4-iodo-1,3-diiminoisoindoline around zinc ions (Zn 2+ ). A six step route leading to 6- tert -butyl-4-iodo-1,3-diiminoisoindoline was proposed. The synthesis started with a regiospecific iodination of 4- tert -butyl- o -xylene to 5- tert -butyl-2,3-dimethyl-iodobenzene, followed by oxidation of the methyl groups to phthalic acid, conversion of phthalic acid to phthalimide, hydrolysis of phthalimide to phthalamide, conversion of phthalamide to phthalonitrile, followed by conversion of phthalonitrile to a more reactive 6- tert -butyl-4-iodo-1,3-diiminoisoindoline. Highly desirable photophysical and photochemical properties were induced in zinc phthalocyanine by iodination of the aromatic rings, while the presence of tert -butyl groups rendered the compound non-aggregating in solution. The photosensitizer studied exhibits absorption band within the so-called “therapeutic window”, with λ max at 689 nm and very high molar absorption coefficient of 295 000 [M −1  cm −1 ] in DMF. Transient absorption experiment revealed T 1  → T n absorption spanning from ca. 400 nm to ca. 600 nm and allowed determination of the excited triplet state lifetime ( τ T ). The estimated τ T in THF equaled 3.3 μs. The phosphorescence maximum was found to be located at λ P 1103 nm and the excited triplet state energy ( E T ) equaled 1.12 eV in 2-methyltetrahydrofuran at 77 K. The photosensitizer studied is characterized by a high value of singlet oxygen quantum yield (Φ Δ ) of ca. 0.76 and the photooxygenation process proceeds via Type II mechanism under the experimental conditions applied. The photodegradation studies revealed that the iodinated phthalocyanine was moderately stable in the presence of oxygen with quantum yield of photodegradation (Φ d ) equaled 4.01 × 10 −4 . Moderate photostability of photosensitizer is advantageous from a PDT point of view where rapid breakdown and fast clearance from the patient’s system is necessary to avoid prolonged skin photosensitivity following treatment.