Novel Classes of Porphyrazine Macrocycles: Effect of -Delocalization, Exocyclic Coordination and Quaternization Processes

The pyrazinoporphyrazine macrocycles having formula [Py8TPyzPzH2], (Figure 1B) and its metal complexes [Py8TPyzPzM], with M = bivalent first transition series and non transition series metal ions, were extensively investigated by our group [1]. Structural and electronic features were studied by single crystal X-ray work, spectral (IR, UV-visible, NMR) and electrochemical investigations, and contributed by detailed theoretical DFT and TDDFT studies. The important role of the external pyridine rings has been examined by considering their capability of electronic contact with the central pyrazinoporphyrazine core. Their ability to coordinate metal centers [2] or to undergo quaternization processes at the N atoms [1b,c] has also been studied. The attention for applicative aspects has been particularly devoted to learn about their behavior as photosensitizers in PDT and their potentialities as multimodal anticancer agents [3, 2b-d]. The present thesis work has selected as the main subject the synthesis of two novel types of porphyrazine macrocycles, strictly related to the above considered “pyrazinoporphyrazines”, but showing a narrower (“restricted” macrocycle) or more extended porphyrazine core (“expanded” macrocycle”). The two compounds, in the form of unmetalated species are schematically shown in Figures 1A and 1C respectively. The targets of the present project were to explain: a) how the change in the expansion or contraction of the central planar or quasi-planar -conjugated skeleton, with respect to that of the pyrazinoporphyrazine core, will modify stability, solubility, tendency to aggregation, general physicochemical and redox behaviour of the new species and their applicative potentialities, with attention centered on their photoactivity properties; b) how the presence of the external pyridine rings, directly attached to the porphyrazine core (“restricted” macrocycle; Figure 1A) or more far away than in the already studied “pyrazinoporphyrazine” macrocycle (“expanded” macrocycle; Figure 1C) added of local metal coordination or quaternization processes, can produce consistent effects on the structural and electronic features of the new macrocyclic skeletons; c) how do the data concerning the response of the new species as photosensitizers compare with those already known for the original “pyrazinoporphyrazine” macrocycles. UV-visible spectral data in the low-donor nonaqueous solvents indicate that there is a progressive highly remarkable bathochromic shift of the barycentre of the overall spectrum in the direction pyridylporphyrazines  pyrazinoporphyrazines  quinoxalinoporphyrazines, in line with the parallel enhanced extension of the -conjugated system of the macrocycles in the order given. The eight external pyridines allow the accomplishment of exocyclic coordination and formation of pentanuclear species carrying externally PdCl2 and PtCl2. Figure 2 shows the pentametallic species for the pyridyl- (A) and quinoxalinoporphyrazines (B). Data at hand indicate that coordination of the PdII or PtII units takes place in all cases at the pyridine N atoms, and sites of the type N2(pyr)MCl2 (M = PdII, PtII; “py-py” coordination) are generated, displaying a square planar geometry and directed nearly perpendicularly to the plane of the central -conjugated macrocyclic system. External ligation modifies the UV-visible spectrum of the initial mononuclear species, the effect evidencing a bathochromic shift of the original main Q band by an average value of 15-20 nm. This remarkable shift is surprising if account is taken that exocyclic coordination of PdII and PtII, particularly for the pyrazino- and even more for the quinoxalinoporphyrazine compounds, takes place at the extreme periphery of the macrocycle and progressively more far away from the central metal. Further extension of the work focused on the synthesis of supercharged macrocycles for the pyridyl- and quinoxalinoporphyrazines. The new octacationic compounds which are moderately water soluble, were prepared from the mononuclear species upon reaction with CH3I, a process which results in the full N-methylation of the pyridine rings (Figure 3). The UV-visible spectra in water solution and in the low-donor solvents pyridine, DMSO and DMF show interesting effects which parallel those determined by the external metalation. The spectra evidence in the process from neutral to octacationic species a bathochromic shift of the Q bands about of the same order observed for the change mononuclear  pentanuclear species. This means that the charged macrocycles enhance their electron deficiency; a fact that should be confirmed by the electrochemical behaviour in terms of the expected less negative half-wave potentials with respect to those pertinent to the neutral mononuclear species. The final challenge of some of the pyridyl- and quinoxalinoporphyrazines, especially those carrying centrally ZnII and MgII (closed shell metal ions) is their measured photoactivity for the generation in DMF of singlet oxygen, 1O2, the cytotoxic agent in the photodynamic therapy of cancer (PDT). The quantum yields of 1O2 measured, particularly for the two pyridylporphyazines having centrally ZnII and MgII, qualify these compounds as excellent photosensitizers. A combination of purity of the samples, water solubility, stability under the appropriate irradiation (600-750 nm), absence of aggregation in solution may be profitable for application in the PDT curative modality. The species carrying outside PtCl2 units may open perspectives for applications as bimodal PDT/cis-platin anticancer agents. Concomitant work was conducted on “pyrazinoporphyrazine” macrocycles carrying externally thienyl rings (Figure 4). The work on the thienyl pyrazinoporphyrazines involved modifications of the peripheral part of the macrocycle, focusing on the coordination properties of the S atoms inserted in the external 2-thienyl rings, in an interesting comparison with those seen for the pyridine rings in the pyridinated “pyrazinoporphyrazines” [4]. On the other hand the singlet oxygen and fluorescence response of the mono- and pentametallic complexes open perspectives for their potential use in PDT of cancer and for medical imaging and diagnosis. References: [1] a) Donzello, M. P.; Ou, Z.; Monacelli, F.; Ricciardi, G.; Rizzoli, C.; Ercolani, C.; Kadish, K. M. Inorg. Chem. 2004, 43, 8626; b) Donzello, M. P.; Ou, Z.; Dini, D.; Meneghetti, M.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2004, 43, 8637; c) Bergami, C.; Donzello, M. P.; Ercolani, C.; Monacelli, F.; Kadish, K. M.; Rizzoli, C. Inorg. Chem., 2005, 44, 9852; d) Bergami, C.; Donzello M. P.; Monacelli, F.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2005, 44, 9862. [2] a) Donzello, M. P.; Viola, E.; Cai, X.; Mannina, L.; Rizzoli, C.; Ricciardi, G.; Ercolani, C.; Kadish, K. M.; Rosa, A. Inorg. Chem., 2008, 47, 3903; b) Donzello, M. P.; Viola, E.; Cai, X.; Mannina, L.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2010, 49, 2447; c) Donzello, M. P.; Viola, E.; Mannina, L.; Barteri, M.; Fu, Z.; Ercolani, C. J. Porphyrins Phthalocyanines, 2011, 15, 984; d) Donzello, M. P.; Vittori, D.; Viola, E.; Manet, I.; Mannina , L.; Cellai, L.; Monti, S.; Ercolani, C. Inorg. Chem., 2011, 50, 7391. [3] Donzello, M. P.; Viola, E.; Bergami, C.; Dini, D.; Ercolani, C.; Giustini, M.; Kadish, K. M.; Meneghetti, M.; Monacelli, F.; Rosa, A.; Ricciardi, G. Inorg. Chem., 2008, 47, 8757. [4] a) De Mori, G.; Fu, Z.; Viola, E.; Cai, X.; Ercolani, C.; Donzello, M. P.; Kadish, K. M. Inorg. Chem., 2011, 50, 8225; b) Donzello, M.P.; De Mori, G.; Viola, E.; Ercolani, C.; Bodo, E.; Mannina, L.; Capitani, D.; Rizzoli, C.; Gontrani, L.; Aquilanti, G.; Kadish, K. M.; D’Angelo, P. Inorg. Chem., 2011, 50, 12116