The Bergman cyclization of (Z)-hexa-3-ene-1,5-diyne to the <i>p</i>-benzyne diradical has recently garnered interest as a potential anti-tumor therapeutic target by leveraging the DNA degradation activity of triplet diradicals to induce cell death. Here, we present a theoretical investigation of several extensions of the Bergman theme for the first time: the electrocyclizations of the penta-1,5-diyne anion, hepta-1,6-diyne cation, and octa-1,7-diyne dication. We apply both single- and multiconfigurational approaches, as well as recently introduced spin-flip formulations of time-dependent density functional theory (SF-TDDFT) and equation-of-motion coupled cluster theory with single and double substitutions (SF-EOM-CCSD) to determine the thermodynamics and kinetics of these cyclizations, as well as to accurately quantify the contributions of static and dynamic electron correlation to their electronic structure. We find that the cyclization barrier is inversely related to chain length, with the penta-1,4-diyne anion being significantly disfavorable in both thermodynamic and kinetic quantities, while the cyclization of the hepta-1,6-diyne cation is thermally accessible and thermodynamically favorable, making it a promising therapeutic target. Finally, we find that in the case of the cyclization of the octa-1,7-diyne dication, ring flexibility of the diradical product encourages the subsequent formation of a closed-shell bicyclic species as a result of radical ring closure, nullifying its antitumor activity.

Variations on the Bergman cyclization theme: Electrocyclizations of penta-, hepta, and cctadiynes

ACS Spring Meeting 2021

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