Pronounced electronic modulation of geometrically-regulated metalloenediyne cyclization

Abstract

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.

Scheme 1. Synthesis of phosphine enediynes (1a–1h) and phosphine oxide derivatives (2a–2h).

Fig. 1. X-ray crystallographic structures of phosphine enediynes (1d and 1e) and phosphine oxide analogues (2d and 2e). Thermal ellipsoids are illustrated at 50% probability and interalkynyl distances (d) are given below structures.

Scheme 2. (a) General synthesis of Pt(ii) phosphine enediyne dichloride complexes (3a–3g). (b) X-ray crystallographic structure of 3e with interalkynyl distance (d) shown below. Thermal ellipsoids are drawn at 50% probability.

Scheme 3. Synthesis and X-ray crystallographic structure of the Pt(ii) phosphine enediyne-bridged dimer 5d. Thermal ellipsoids are illustrated at 50% probability and the interalkynyl distance (d) is provided below.

Scheme 4. Ambient temperature Bergman cyclization of 3f to generate 4f. Thermal ellipsoids are illustrated at 50% probability and the interalkynyl distance (d) is given below.

Fig. 2. ³¹P NMR spectroscopy demonstrating the cyclization of 3a (δ = −17.44 ppm) in the presence of 1,4-CHD to afford 4a (δ = 39.42 ppm) in near quantitative yield at 25 °C. These data are representative of the cyclizations of 3b–3f which proceed cleanly to the cyclized products 4b–4f. The designated (*) signal corresponds to triphenylphosphine oxide, the internal standard.

Fig. 3. Summary of Bergman cyclization kinetics for complexes 3a–3g (a) at 25 °C and (b) at 15 °C. Sample Eyring plots of (c) 3f and (d) 3a used to calculate activation parameters.

Fig. 4. Key structural parameters of (U)BPW91/6-31G**/LANL2DZ optimized metalloenediynes 3a and 3e and their transition states 3a-TS and 3e-TS. These bond length (Å) and angle (°) changes are representative of those observed for all metalloenediynes 3a–3e and transition states 3a-TS–3e-TS.

Fig. 5. ¹³C NMR resonances of phosphine oxide analogues 2a–2e revealing the polar nature of the alkyne carbons, C_A (black) and C_B (red), the magnitude of which is enhanced in the presence of electron withdrawing substituents.

Fig. 6. Global distribution of charge throughout the enediyne framework can be approximated by considering (a) the net polarization of alkyne carbons C_A and C_B and (b) the magnitude of coulombic interactions between opposing acetylenic dipoles.

Fig. 7. Plots of ΔG^‡ as a function of alkyne dipole interaction energy, evaluated using (a) NBO charge analysis (representative example of 3a shown) for (b) enediyne ground states (3a–3e) and (c) calculated transition states (3a-TS–3e-TS) demonstrating the relationship between alkyne polarity (C_A–C_B) and experimental barrier height to thermal Bergman cyclization.

Fig. 8. Walsh diagram showing the in-plane alkyne π/π*-orbitals most stabilized and destabilized by the cyclization reaction of complexes 3b and 3e and their associated transition states 3b-TS and 3e-TS. The degree of stabilization or destabilization of these orbitals in the transition state varies significantly due to the presence of electron donating (3b: R = Ph-pOCH₃) or electron withdrawing (3e: R = Ph-m₂CF₃) groups at the alkyne termini.