Pentaammineruthenium moves on ambidentate nitrogen heterocycles by both rotation and linkage isomerization, which may affect the biological activity of potential ruthenium metallopharmaceuticals. The rapid rotation rates of [(NH3)(5)sRu(III)] coordinated to the exocyclic nitrogens of isocytosine (ICyt) and 6-methylisocytosine (6MeICyt) have been determined by LH NMR. Since these rotamers can be stabilized by hydrogen bonding between the coordinated ammines acid the N1 and N3 endocyclic nitrogens,rotamerization is under pH control. Spectrophotometrically (UV-vis) measured pK(a) values for the two endocyclic sites for the ICyt complex are 2.78 and 9.98, and for 6MeICyt are 3.06 and 10.21, which are probably weighted averages for ionization from N3 and N1, respectively. Activation parameters for the rotamerizations were determined by variable-temperature NMR at pK(al) < pH < pK(a2) for the complexes with (ICyt(kappa)(-)(N2))-, (6MeICyt kappa (N2))-, and 2AmPyrm kappac(N2): For [(6MeICyt kappa (N2))-(NH3)(5)RUIII](2+), DeltaH* = 1.6 kcal/mol, DeltaS* = -37 cal/mol K, and E-a = 2.2 kcal/mol. Due to strong Ru-III-N pi -bonding, the activation enthalpies are approximately 10 kcal lower than the expected values for the free ligands. Rotameric structure is correlated with pK(a) values, pH-dependent reduction potentials, and H-1 NMR parameters. Linkage isomers of [(2AmPym)(NH3)(5)Ru](n+) are reported in which Ru-II is coordinated to the endocyclic nitrogen (NZ) and Ru-III to the exocyclic nitrogen (N2). The rate constant for the kappa (N2) --> kappa (N1) isomerization as part of an ECE mechanism is 3.9 s(-1) at pH 3. The pH dependence of the acid-catalyzed hydrolysis of [(2AmPym kappa (N1))(NH3)(5)RU](2+) is determined.