Isomers of 2,2′;6′,2′′-terpyridine and 2,6-dipyrazin-2-ylpyridine with aliphatic substituents: synthesis, coordination chemistry, catalytic and anticancer activities

Abstract

While the synthesis of 4′-aryl substituted 2,2′;6′,2′′-terpyridine and its common isomer 4,2′;6′,4′′-terpyridine is trivial using the one-pot Krönke condensation procedure, their 4′-alkyl substituted ligands have been sparsely approached. 2,2′;4′,2′′-Terpyridine and 4,2′;4′,4′′-terpyridine as their rare isomers have only been reported in a few examples as unexpected byproducts during the synthesis of their 4′-aryl derivatives. Likewise, a closely related ligand of 2,2′;6′,2′′-terpyridine, 2,6-dipyrazin-2-ylpyridine containing an aliphatic substituent, is unknown to our knowledge, and its isomer 4,6-dipyrazin-2-ylpyridine is yet to be discovered. In this work, we employed the simple one-pot reactions between an aliphatic aldehyde and 4-acetylpyridine or 2acetylpyrazine and reported for the first time the synthesis and structural characterization of several aliphatically substituted 4,2′;4′,4′′-terpyridine and 2,6-dipyrazin-2-ylpyridine isomers as major products (3-5). Two possible intermediates featuring dearomatized structures (6 and 7) from similar reactions at lower temperature were uncovered based on X-ray structural analysis. We assumed that reaction temperature was critical in determing the major products in each of the reactions. We further investigated their coordination chemistry with various zinc and cobalt salts by isolating crystals of three complexes (8-10) of these new ligands and clarifying their solid-state structures by X-ray crystallography. Both a one-dimensional (1-D) polymeric chain of Zn II (8) and a 2-D network of Co II (9) with the divergent ligand, 4′-t Bu-4,2′;4′,4′′-terpyridine (3), were characterized, along with a mononuclear Co II complex (10) of 4-t Bu-2,6-dipyrazin-2-ylpyridine (4). The new metal complexes have been examined for preliminary catalytic performance on the hydroboration and hydrosilylation reactions of styrene, highlighting the potential of complex 10 as an active catalyst for both reactions, even though the regioselectivity remains to be improved through further ligand modification and/or condition optimization. Finally, the biopharmaceutical application of these new compounds as potent anticancer agents has been explored, and the in-vitro toxicity studies suggest that among all new compounds tested, metal complexes (8 and 9) based on isomer 3 are promisng drug candidates against breast cancer cells MCF-7 and MDA-MB 468, while they showed lower toxicity levels towards the non-tumorigenic epithelial cell, MCF-10, compared to cisplatin.