Design and Synthesis of Tetrapyrrole Macrocycles for Studies in Photomedicine or Molecular Photonics

Abstract

This dissertation describes the synthesis of tetrapyrrolic molecules with distinct chemical and photophysical properties that are attractive for a wide range of applications in the field of photomedicine and molecular electronic and/or photonic devices. Palladium porphyrins are valuable photosensitizers and luminescent agents in biology and materials chemistry. In Chapter II of this dissertation, a novel methodology is described wherein a 1-acyldipyrromethane is directly converted into the palladium chelate of a trans-A2B2-porphyrin via a one-flask reaction. The reaction entails self-condensation of the 1-acyldipyrromethane in refluxing ethanol containing KOH (5-10 mol equiv) and Pd(CH3CN)2Cl2 (0.6 mol equiv) exposed to air. This direct route to palladium porphyrins is more expedient than the four steps of the traditional synthesis. This methodology readily affords palladium porphyrins directly from acyldipyrromethanes. A key challenge to the implementation of tetrapyrrolic molecules in photomedicine entails tailoring the molecules to exhibit appropriate solubility. In particular, synthetic motifs that impart water solubility are important for a number of biological studies. Tetrapyrrolic macrocycles (porphyrins, chlorins, and bacteriochlorins) present a particular challenge in this regard owing to the large size of the planar hydrocarbon macrocycle. For biological applications of tetrapyrrolic macrocycles, a typical requirement is to introduce substituents to achieve both water-solubility and facility for conjugation to biomolecules. The synthesis of three free base porphyrins, each of which bears a polar and facially encumbering 2,4,6-tris(carboxymethoxy)phenyl motif at one meso (5-) position is illustrated in Chapter III. The only other substituent (15-position) comprises phenyl, formyl, or p-aminophenyl. The porphyrins exhibit solubility in water (or aqueous buffer solutions) at pH ≥7 and concentrations >1 mM at room temperature. The concise syntheses, water-solubility, and bioconjugatable handle make these porphyrin constructs suitable for biological applications. One approach envisioned for achieving selectivity in photomedical applications of porphyrins is to employ a photosensitizer that is inactive until reaching the target tissue, where upon in vivo assemblage with a second agent, can give a photochemically active agent. Chapter IV presents preliminary studies to validate the in vivo activation concept. Synthesis of diverse porphyrinic molecules tailored with a 1,2-diketone quencher motif and the condensation of the 1,2-diketone-porphyrin conjugate with a diamine is presented therein. Insight into the electronic communication between the individual constituents of porphyrin arrays is essential for the rational design of molecular photonic devices. A strategy has been demonstrated for assessing the ground-state hole-transfer rate in cationic π-radical systems wherein the redox-active constituents lack substantial nuclear-hyperfine couplings. The strategy entails introduction of 13C labels at sites of substantial electron/spin density in the HOMO. A p-diphenylethyne-linked zinc-porphyrin dyad was prepared wherein one porphyrin bears two 13C-atoms and the other porphyrin is unlabeled and bearing pentafluorophenyl substituents at meso non-linking positions. The 13C-atoms are located at the 1- and 9-positions (α-carbons symmetrically disposed to the position of linker attachment), which are sites of electron/spin density in the a1u HOMO of the porphyrin. The 13C-labels were introduced by reaction of KS13CN with allyl bromide to give the allyl isothiocyanate, which upon pyrrole synthesis followed by methylation gave 2-(methylthio)pyrrole-2-13C. Reaction of the latter with paraformaldehyde followed by hydrodesulfurization gave dipyrromethane-1,9-13C, which upon condensation with a dipyrromethane-1,9-dicarbinol bearing three pentafluorophenyl groups gave the tris(pentafluorophenyl)porphyrin bearing 13C labels at the 1,9-positions. A sophisticated synthesis, culminating with Suzuki coupling of α-[1,9-13C]-labeled porphyrin monomer with an unlabeled porphyrin bearing a suitably functionalized diphenylethyne linker, gave the regiospecifically labeled porphyrin dyad. The new synthetic methodology for preparing α-[1,9-13C]-labeled porphyrins provides an entrée for examining hole transfer in electron-deficient porphyrin arrays.