Triazolyl Scaffolded Enediyne‐Amino Acid Hybrids: Modulation of Thermal Reactivity Toward Bergman Cyclization via Through‐Bond Charge‐Transfer‐Delocalization

ABSTRACT A series of triazole‐scaffolded enediyne‐amino acid hybrids featuring donor‐acceptor substituted aromatics at the two acetylenic termini has been rationally designed and synthesized. Their solid‐state thermal reactivity toward Bergman cyclization was investigated using differential scanning calorimetry (DSC), revealing the following reactivity trend: neutral–neutral > donor–acceptor (D–A) > donor–donor (D–D) > acceptor–acceptor (A–A). To rationalize this trend, both electronic perturbations and geometric distortions were considered and analyzed at the B3LYP/6‐31G(d,p) level of theory. Natural Bond Orbital (NBO) calculations highlight the critical role of through‐bond charge‐transfer‐delocalization in stabilizing the diradical transition state, particularly in D–A substituted enediynes. In contrast, A–A substituted enediynes exhibited destabilization due to increased dihedral distortion prohibiting through‐bond charge‐transfer‐delocalization, leading to coulombic repulsion at the C‐C bond‐forming termini in the TS, thereby hindering effective cyclization. Furthermore, the steric influence of the amino acid moiety linked to the triazole‐N of the hybrid was found to induce out‐of‐plane distortion in one of the enediyne arms, thereby playing a vital role in modulating thermal reactivity. UV–Vis spectroscopy, in conjunction with TD‐DFT calculations, further supports the influence of through‐bond charge‐transfer‐delocalization in tuning thermal reactivity. Overall, a notable enhancement in thermal Bergman cyclization reactivity via through‐bond charge‐transfer‐delocalization‐mediated stabilization of diradical TS is observed for donor–acceptor substituted enediynes.