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

Abstract

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 η¹-N complexes, 4(OTf, CH₃OH) and 5(OTf, CH₃OH), which underwent a novel, intramolecular, regioselective N–π rearrangement to provide the η⁶ complexes, 6 and 7. A dramatic solvent effect was also observed on the rate of this N–π rearrangement in CH₃OH or CH₂Cl₂. Therefore, a DFT study was conducted that provided further mechanistic and thermodynamic data on this N–π rearrangement. The preferred structures of both the η¹-N and η⁶ 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–π 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 η¹-N complexes, 4(OTf) and 5(OTf), and in the outer sphere of the coordinatively saturated η⁶ 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–π rearrangement. The thermodynamic results suggested that the η⁶ complexes were more stable than the η¹-N complexes in CH₂Cl₂ and in CH₃OH at elevated temperatures. The opposite relationship for the stabilities of the η¹-N complexes was found in CH₃OH at room temperature, thus corroborating the experimental results that the N–π rearrangement did not occur, under these conditions. A plausible mechanistic pathway for the N–π 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.