Abstract
The Cp (x) C-H protons in certain organometallic Rh(III) half-sandwich anticancer complexes [(η(5)-Cp (x) )Rh(N,N')Cl](+), where Cp (x) = Cp*, phenyl or biphenyl-Me(4)Cp, and N,N' = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involving abstraction of a Cp* proton by the Rh-hydroxido complex, followed by sequential H/D exchange, with the Cp* rings behaving like dynamic molecular 'twisters'. The calculations reveal the crucial role of p(π) orbitals of N,N'-chelated ligands in stabilizing deprotonated Cp (x) ligands, and also the accessibility of Rh(I)-fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp*)Rh(III)(en)Cl](+) and [(Cp*)Ir(III)(bpy)Cl](+) do not have activated Cp* rings. The thiol tripeptide glutathione (γ-l-Glu-l-Cys-Gly, GSH) and the activated dienophile N-methylmaleimide, (NMM) did not undergo addition reactions with the proposed Rh(I)-fulvene, although they were able to control the extent of Cp* deuteration. We readily trapped and characterized Rh(I)-fulvene intermediates by Diels-Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9Z,11E)-linoleic acid in aqueous media, including cell culture medium, the first report of a Diels-Alder reaction of a metal-bound fulvene in aqueous solution. These findings will introduce new concepts into the design of organometallic Cp* anticancer complexes with novel mechanisms of action.