Mapping the influence of ligand electronics on the spectroscopic and 1O2 sensitization characteristics of Pd(II) biladiene complexes bearing phenyl-alkynyl groups at the 2- and 18-positions

Abstract

Photodynamic therapy (PDT) is a promising treatment for certain cancers that proceeds via sensitization of ground state ³O₂ to generate reactive ¹O₂. Classic macrocyclic tetrapyrrole ligand scaffolds, such as porphyrins and phthalocyanines, have been studied in detail for their ¹O₂ photosensitization capabilities. Despite their compelling photophysics, these systems have been limited in PDT applications because of adverse biological side effects. Conversely, the development of non-traditional oligotetrapyrrole ligands metalated with palladium (Pd[DMBil1]) have established new candidates for PDT that display excellent biocompatibility. Herein, the synthesis, electrochemical, and photophysical characterization of a new family of 2,18-bis(phenylalkynyl)-substituted Pd^II 10,10-dimethyl-5,15-bis(pentafluorophenyl)-biladiene (Pd[DMBil2-R]) complexes is presented. These second generation biladienes feature extended conjugation relative to previously characterized Pd^II biladiene scaffolds (Pd[DMBil1]). We show that these new derivatives can be prepared in good yield and, that the electronic nature of the phenylalkynyl appendages dramatically influence the Pd^II biladiene photophysics. Extending the conjugation of the Pd[DMBil1] core through installation of phenylacetylene resulted in a ∼75 nm red-shift of the biladiene absorption spectrum into the phototherapeutic window (600-900 nm), while maintaining the Pd^II biladiene's steady-state spectroscopic ¹O₂ sensitization characteristics. Varying the electronics of the phenylalkyne groups via installation of electron donating or withdrawing groups dramatically influences the steady-state spectroscopic and photophysical properties of the resulting Pd[DMBil2-R] family of complexes. The most electron rich variants (Pd[DMBil2-N(CH3)2]) can absorb light as far red as ∼700 nm but suffer from significantly reduced ability to sensitize formation of ¹O₂. By contrast, Pd[DMBil2-R] derivatives bearing electron withdrawing functionalities (Pd[DMBil2-CN] and Pd[DMBil2-CF3]) display ¹O₂ quantum yields above 90%. The collection of results we report suggest that excited state charge transfer from more electron-rich phenyl-alkyne appendages to the electron deficient biladiene core circumvents triplet sensitization. The spectral and redox properties, as well as the triplet sensitization efficiency of each Pd[DMBil2-R] derivative is considered in relation to the Hammett value (σ_p) for each biladiene's R-group. More broadly, the results reported in this study clearly demonstrate that biladiene redox properties, spectral properties, and photophysics can be perturbed greatly by relatively minor alterations to biladiene structure.

Figure 1:

Various tetrapyrrole-based photosensitizers.

Figure 2:

Ball and Stick representations of (a) Pd[DMBil2─H], (b) Pd[DMBil2─OCH₃], (c) Pd[DMBil2─CN], and (d) Pd[DMBil2─CF₃] as viewed from top and in profile. Hydrogen atoms and disordered solvent molecules have been omitted for clarity.

Figure 3:

UV-Vis absorption spectra recorded in methanol of (a) Pd[DMBil1] versus Pd[DMBil2─H], (b) electron-deficient Pd[DMBil2─R] derivatives (R = CN, CO₂Me, CF₃), and (c) electron-rich Pd[DMBil2─R] derivatives (OMe, NMe₂, t-Bu).

Figure 4:

Emission spectra recorded in methanol for Pd[DMBil2-H] under inert atmosphere of N₂ (black) and after exposure to air (red).

Figure 5:

Scatter plots showing the relationship between para-Hammett values (σ_p) and (a) absorption maximum (λ_max), (b) molar absorptivity (ε_max), (c) fluorescence quantum yield (Φ_fl), and (d) ¹O₂ quantum yield (Φ_Δ).

Figure 6:

Cyclic voltammograms recorded for (a) Pd[DMBil1] and Pd[DMBil2─H], (b) Pd[DMBil2─H] and Pd[DMBil2─R] derivatives bearing electron-withdrawing R-groups, (c) Pd[DMBil2─H] and Pd[DMBil2─R] derivatives bearing electron-donating R-groups, in anhydrous acetonitrile containing 0.1 M TBAPF₆ under Ar. Data were collected using a glassy carbon disk working electrode, platinum mesh counter electrode and Ag/AgCl reference electrode, at a scan rate of 100 mV s⁻¹. All data are referenced to Fc/Fc⁺.

Figure 7:

Scatter plots showing the relationship between the first oxidation potential of each Pd[DMBil2─R] derivative and (a) the corresponding para-Hammett values (σ_p), and (b) the corresponding ¹O₂ quantum yields (Φ_Δ).

Scheme 1:

Synthetic route employed to prepare Pd[DMBil2─R] derivatives.