Synthesis of near-IR absorbing/emitting porphyrazine derivatives with tunable solubility

We report the synthesis of porphyrazines (pzs), or tetraazaporphyrins, of the form H₂[pz(A_n;B_4-n)], where A is [S(CH₂)₃COOR]₂ (R = n-Pr, H) and B is a fused β,β′-diisopropyloxybenzo group, including the compounds with n = 4 (6), n = 3 (7) and the trans compound with n = 2 (8) (Scheme 1). The synthesis employs Linstead crossover macrocyclization of dimethyl 6,7-dicyano-5,8-dithia-6(Z)-dodecenedioate, MNT(C₄O₂Me)₂ (2), with 1-imino-4,7-bis(1-methylethoxy)-1H-isoindole-3-amine (4). These pigments were characterized by ¹H NMR, ¹³C NMR, absorbance/fluorescence spectroscopy, mass spectrometry, and microanalysis. An X-ray crystal structure of 8 is presented. Of particular note, 6-8 display intense near-IR absorbance and dual UV-visible/near-IR emission which are very important in potential biomedical applications, both for cancer therapy (photodyanamic therapy, PDT) and cancer diagnosis (optical tumor imaging). For example, the trans-porphyrazine 8 has an intense long-wavelength absorption at ca. 800 nm (log ε = 4.18) and S1 fluorescence at ∼820 nm, where mammalian tissue is effectively penetrated by light. Transformation of the ester group permits a wide range of functionality and solubility to be generated without change in optical properties. As an example, hydrolysis of these compounds by LiOH in THF/H₂O gives the corresponding carboxylato-functionalized pigments 9-11, which are described. The last of these dissolves without aggregation in fetal calf serum.