title: A DFT study on the mechanism of a novel, regioselective, intramolecular N-pi rearrangement of cis and trans-eta1-N-Cp*Rh-hydroxytamoxifen complexes to their eta6 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 = H(2)O, CH(3)OH), initially provided the kinetically controled eta(1)-N complexes, 4(OTf, CH(3)OH) and 5(OTf, CH(3)OH), 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 CH(3)OH or CH(2)Cl(2). 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 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 CH(2)Cl(2) and in CH(3)OH at elevated temperatures. The opposite relationship for the stabilities of the eta(1)-N complexes was found in CH(3)OH 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.
authors: Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel. irena.efremenko@weizmann.ac.il
authors: Irena
authors: I
authors: Efremenko
authors: Siden
authors: S
authors: Top
authors: Jan M L
authors: JM
authors: Martin
authors: Richard H
authors: RH
authors: Fish
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003198:Computer Simulation; D005260:Female; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011789:Quantum Theory; D012238:Rhodium / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D008024:Ligands; D012997:Solvents; D013629:Tamoxifen; C016601:afimoxifene; D012238:Rhodium