Pronounced electronic modulation of geometrically-regulated metalloenediyne cyclization

Using a diverse array of thermally robust phosphine enediyne ligands (dxpeb, X = Ph, Ph-pOCH₃, Ph-pCF₃, Ph-m ₂CH₃, Ph-m ₂CF₃, ⁱPr, Cy, and ^t Bu) a novel suite of cisplatin-like Pt(ii) metalloenediynes (3, Pt(dxpeb)Cl₂) has been synthesized and represents unique electronic perturbations on thermal Bergman cyclization kinetics. Complexes 3e (Ph-m ₂CF₃) and 3f (ⁱPr) are the first of this structure type to be crystallographically characterized with inter alkyne termini distances (3e: 3.13 Å; 3f: 3.10 Å) at the lower end of the widely accepted critical distance range within which enediynes should demonstrate spontaneous ambient temperature cyclization. Despite different electronic profiles, these metalloenediynes adopt a rigid, uniform structure suggesting complexes of the form Pt(dxpeb)Cl₂ have orthogonalized geometric and electronic contributions to thermal Bergman cyclization. Kinetic activation parameters determined using ³¹P NMR spectroscopy highlight the dramatic reactivity and thermal tunability of these complexes. At room temperature, the half-life (t _1/2) of cyclization spans a range of ∼35 hours and for the aryl phosphine derivatives, cycloaromatization rates are 10-30 times faster for complexes with electron donating substituents (3b: Ph-pOCH₃; 3d: Ph-m ₂CH₃) compared to those with electron withdrawing substituents (3c: Ph-pCF₃; 3e: Ph-m ₂CF₃). Computational interrogation of the aryl phosphine metalloenediynes 3a-3e reveals that the origin of this precise electronic control derives from electronic withdrawing group-mediated alkyne carbon polarization that amplifies coulombic repulsion increasing the cyclization barrier height. Additionally, mixing between the in-plane π-orbitals and the phosphine aryl ring system is pronounced for complexes with electron donating substituents which stabilizes the developing C-C bond and lowers the activation barrier. This π-orbital mixing is negligible however, for complexes with electron withdrawing substituents due to an energetic mismatch of the orbital systems. Overall, this work demonstrates that for geometrically rigid frameworks, even remote enediyne functionalization can have pronounced effects on activation barrier.