A DFT study on the mechanism of a novel, regioselective, intramolecular N-π rearrangement of cis and trans-η1-N-Cp* Rh-hydroxytamoxifen complexes to their η6 derivatives; potential breast cancer pharmaceuticals, and fluorescent probes

The previously reported reactions of cis and trans-hydroxytamoxifen drug derivatives, 1 and 2, with [Cp* Rh(L)(3)](2+) complexes (L = H2O, CH3OH), initially provided the kinetically controled eta(1)-N complexes, 4(OTf, CH3OH) and 5(OTf, CH3OH), which underwent a novel, intramolecular, regioselective N-pi rearrangement to provide the eta(6) complexes, 6 and 7. A dramatic solvent effect was also observed on the rate of this N-pi rearrangement in CH3OH or CH2Cl2. Therefore, a DFT study was conducted that provided further mechanistic and thermodynamic data on this N-pi rearrangement. The preferred structures of both the eta(1)-N and cis eta(6) complexes in the two solvents were determined, and a thorough analysis of their geometries and electronic structures has been provided. The influence of the solvent on the N-pi rearrangement was studied by including the solvent both implicitly using a PCM model, and explicitly by introducing the counterion and/or the solvent molecules into the inner and outer coordination spheres of the complexes. It was shown that the triflate (OTf-) counterion was strongly bound in the inner coordination sphere of the eta(1)-N complexes, 4(OTf) and 5(OTf), and in the outer sphere of the coordinatively saturated eta(6) complexes, 6 and 7, especially in non-polar media. The cleavage of the ionic Cp* Rh-OTf bond was found to be the rate-limiting step in the N-pi rearrangement. The thermodynamic results suggested that the eta(6) complexes were more stable than the eta(1)-N complexes in CH2Cl2 and in CH3OH at elevated temperatures. The opposite relationship for the stabilities of the eta(1)-N complexes was found in CH3OH at room temperature, thus corroborating the experimental results that the N-pi rearrangement did not occur, under these conditions. A plausible mechanistic pathway for the N-pi rearrangement was proposed from our extensive DFT studies, that included several important intermediates and transition states, and provided a unique view of this novel transformation.