Metalloenediynes: Ligand Field Control of Thermal Bergman Cyclization Reactions

Abstract

We report the preparation and thermal reactivities of unique Cu(I) and Cu(II) metalloenediyne complexes of the flexible 1,8-bis(pyridine-3-oxy)oct-4-ene-2,6-diyne ligand (bpod, 1). The thermal reactivities of these metalloenediynes are intimately modulated by metal oxidation state. Using differential scanning calorimetry (DSC), we demonstrate that the [Cu(bpod)2]+ complex (2) undergoes Bergman cyclization at 203 °C, whereas the Cu(II) analogue (3) is substantially more reactive and cyclizes at 121 °C. Similar results are also observed for mixed ligand [Cu(bpod)(pyridine)2]+/2+ analogues 4 (194 °C) and 5 (116 °C), suggesting that both complexes of a given oxidation state have comparable structures. The Cu(bpod)Cl2 compound (6) exhibits a cyclization temperature (152 °C) midway between the those of Cu(I) and Cu(II) complexes, which can be explained by the propensity for cis-CuN2Cl2 structures to exhibit dihedral angle distortion. The oxidation-state-dependent thermal reactivity is unprecedented and reflects the influence of the ligand field geometry on the barrier to enediyne cyclization. On the basis of X-ray structures of Cu(pyridine)4+ complexes, 2 and 4 are proposed to be tetrahedral. In contrast, the electronic absorption spectra of 3 and 5 each show a broad envelope that can be Gaussian resolved into three ligand field transitions characteristic of a Cu(II) center in a tetragonal-octahedral environment. This structural assignment is confirmed by the EPR spin Hamiltonian parameters (g∥/A∥ (cm) = 134 (3), 138 (5)) and is consistent with crystallographically characterized Cu(pyridine)4X2 structures. Molecular mechanics calculations have independently derived comparable tetrahedral and tetragonal structures for 2 and 3, respectively, and determined the average alkyne termini separation to be 〈a〉 = 4.0 Å for 2 and 3.6 Å for 3. Thus, the tetrahedral geometries of the copper centers in 2 and 4 increase the distance between alkyne termini relative to the tetragonal Cu(II) geometries of 3 and 5, and are therefore responsible for the increase in the thermal cyclization temperatures. The DSC and spectroscopic data for 6 support these conclusions, as the latter suggests a distorted four-coordinate structure in the solid state, and a six-coordinate geometry in solution, which gives rise to an intermediate Bergman cyclization temperature. Overall, our results emphasize the utility of newly emerging metalloenediyne complexes for controlling thermal Bergman cyclization reactions and provide insights into designing novel, pharmacologically useful metalloenediyne compounds.