Perturbation of the NH2 pKa Value of Adenine in Platinum(II) Complexes: Distinct Stereochemical Internucleobase Effects

The degree of acidification of the exocyclic N6 amino group of the model nucleobase 9‐methyladenine (9MeA) in relation to the number and site(s) of PtII binding has been studied in detail. It is found that twofold PtII binding to N1 and N7 lowers the pKa value from 16.7 in the free base to 12–8. The lowest pKa values are observed when the resulting N6H− amide group is intramolecularly stabilized by an H‐bond donor such as the N6H2 group of a suitably positioned second 9MeA ligand. Deprotonation of the N6 amino group facilitates Pt migration from N1 to N6, and subsequent reprotonation of the N1 position yields a twofold N7,N6‐metalated form of the rare imino tautomer of 9MeA, which has a pKa value of 5.03. These findings demonstrate a principle that is of potential relevance to the topic of “shifted pKa” values of adenine nucleobases, which is believed to be important with regard to acid–base catalysis of RNAs at physiological pH values. The principle states that a nucleobase pKa value can be sufficiently lowered to reach near‐neutral values and that the pKa value of the protonated base does not necessarily have to be increased to accomplish this effect. Surprisingly large shifts in the pKa values of weakly acidic adenine nucleobase protons into the near‐neutral pH range can be brought about by metal coordination. The finding may be relevant to acid–base catalysis involving RNAs (see schematic representation).