We report the synthesis and properties of dipyrrins functionalized with ester and amide groups in the pyrrolic a,a'-positions. Upon complexation with Zn²⁺ the dipyrrins exhibit characteristic changes in their absorption spectra accompanied by increase in fluorescence, whereby the mechanism of the fluorogenicity is different from that traditionally employed in the design of Zn²⁺ sensors. Free-base tetraethyldipyrrin-diesters were found to undergo facile acid-catalyzed addition of water to the double bond at the meso-bridge, manifested by complete disappearance of visible absorption. The hydration reaction could be fully reversed in the presence of Zn²⁺, leading to chromogeneic regeneration of the dipyrrin p-system. The original free-base dipyrrin-diesters could be fully recovered upon de-metallation of the resulting Zn²⁺ complexes.
When modified with polyetheleneglycol residues (PEGs), the new dipyrrins become highly water-soluble and show no sign of aggregation in aqueous solutions. Their Zn²⁺ dissociation constants were found to be strongly dependent on the substituents in the a,a'-positions, displaying an unusual trend in Zn²⁺ binding affinity. In aqueous buffers, dipyrrins with more electron-rich a,a'-amide substituents exhibit nearly 10-fold lower affinity than the corresponding dipyrrin-esters, which is the opposite to the order of affinity in organic solvents (e.g. MeCN). By performing DFT calculations with explicit inclusion of water we were able to reproduce the observed trend and trace the low affinity of the dipyrrin-amides to the stabilization of the corresponding free-bases via hydrogen bonding with surrounding water molecules. Overall, our results provide important clues for the design of dipyrrin-based sensors for biological applications.

Dr. Mirna El Khatib

Research Associate, University of Pennsylvania

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