Macrocyclic Metalloenediynes of Cu(II) and Zn(II):  A Thermal Reactivity Comparison

Abstract

The syntheses of tetradentate enediyne macrocycles with 24 (tact1:1)-, 26 (tact1:2)-, and 28 (tact2:2)-membered rings are described, along with their thermal reactivities and those of the corresponding Cu(II) (Cu(tact1:1), Cu(tact1:2)) and Zn(II) (Zn(tact1:1), Zn(tact1:2)) complexes. These enediyne macrocyclic ligands are not benzannulated and thus exhibit thermal Bergman cyclization temperatures near 200 degrees C by differential scanning calorimetry (DSC). Moreover, the synthetic route allows incorporation of additional carbon atoms into the macrocycles which increases their conformational flexibilities and lowers their Bergman cyclization temperatures. Specifically, as the size of the macrocycle increases, the temperatures at which these compounds undergo Bergman cyclization decrease by approximately 5 degrees C per additional carbon atom, leading to an overall decrease across the series of 19 degrees C. Incorporation of Cu(II) and Zn(II) into these macrocycles further reduces their cyclization temperatures relative to those of the free ligands. More uniquely, for Cu(tact1:1) and Zn(tact1:1), the observed cyclization temperatures vary by 27 degrees C with the Zn(II) complex lying to higher temperature (Cu(tact1:1) = 121 degrees C, (Zn(tact1:1) = 148 degrees C). As the macrocycle size is increased, the decrease in the Bergman cyclization temperatures observed for the free ligands does not systematically hold for the Cu(II) and Zn(II) derivatives. Rather, the Cu(II) complex exhibits the expected 9 degrees C decrease in the cyclization temperature (Cu(tact1:2) = 112 degrees C), whereas the temperature for the Zn(II) analogue increases by 15 degrees C (Zn(tact1:2) = 163 degrees C). From the X-ray crystal structure of the free ligand and the geometric structural preferences of the electronic configurations of Cu(II) and Zn(II), the higher cyclization temperatures for the Zn(II) complex with the larger ring size can be explained by a distortion of the macrocycle toward a more tetrahedral metal center geometry.

Unique Metal‐Diyne, ‐Enyne, and ‐Enediyne Complexes: Part of the Remarkably Diverse World of Metal‐Alkyne Chemistry

“…For the more flexible bis(pyridyl-oxy) enediynes (Scheme 89), the response to changes in metal geometry [tetrahedral Cu(I) vs. tetragonal Cu(II)] is $90 C, whereas their smaller, rigid analogous reflect the same differences in thermal reactivity ($170 C) that the 1,2-bis(diphenylphosphinoethynyl)benzene ligand exhibits when complexed to d 10 versus d 8 metals. This same geometry-ligand flexibility trend is also observed in macrocyclic and tetradentate metalloenediynes (Scheme 90) (554,555). These enediyne ligands are prepared by sequential coupling of alkyne fragments to the desired enyne precursor allowing systematic variation of the size of the macrocycle-ligand and the nature-steric bulk of two of the metal-binding R groups (554).…”

The role of ligand covalency in the selective activation of metalloenediynes for Bergman cyclization

“…Within this theme, the Bergman cyclization reactivity of Zn( QuiED )·2Cl mirrors that demonstrated by Mg( QuiED )·2Cl (Table 3), even though the structural origin of this observation may or may not be the same. The Zn( QuiED )·2Cl can maintain a 6-coordinate structure similar to the Mg(II) –quinoline metalloenediyne, or possibly adopt a 4-coordinate tetrahedral structure that would be expected to exhibit similarly high Bergman cyclization temperatures [23,24,70–72]. However, since addition of free pyridine–enediyne to preformed Zn(II) –Aβ fibrils at 43 °C leads to significant radical-induced fibril disaggregation within 2 h [19], and we would predict the binding motifs of the pyridine and quinoline ligands to be parallel, this indicates that the solution structure preference for Zn–metalloenediynes cannot be 4-coordinate.…”

“…Our experience with enediyne activation via metal coordination and photochemical diradical formation has taught us that slight changes in the enediyne molecular framework can have a large impact on the activation parameters [20–24]. The ligand (Z)-N,N ′-bis[quinolin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine ( QuiED ) [25] seemingly engenders only a small change to the structure of the PyED framework through addition of a fused aromatic ring on each pyridine functionality.…”

Recent Developments in Enediyne Chemistry

“…The 24-, 26-, and 28-membered macrocyclic enediynes 219, 223, and 220, respectively, and their metal complexes 221, 222, 224, and 225 have also been reported [126]. Again, the macrocyclic enediyneÀmetal complexes exhibited lower BC temperatures than the corresponding macrocyclic enediynes.…”