Electronic control of the Bergman cyclization: the remarkable role of vinyl substitution

We report an ab initio study of the effect of vinyl substitution on the cycloaromatization of 3-ene-1,5-diynes (the Bergman cyclization). The majority of the calculations were conducted by using the BLYP version of Density Functional Theory, and higher level Brueckner orbital calculations were used for a few key compounds. In all, 46 enediynes, 44 cyclization transition states, 39 singlet p-benzynes, and 28 related triplet p-benzynes were studied, including simple vinyl-substituted and annulated examples. The data indicate that strongly electron-withdrawing groups increase the cyclization barrier, while sigma-donating groups decrease it; pi conjugation, especially donation, has little effect. Most annulations, including those involving heteroaromatic rings, lower the barrier slightly (6 MR) or raise it slightly (5 MR). Larger effects are seen for smaller rings or charged rings. Some previously observed apparent rate inhibitions are seen to be due to reversibility or forward reactivity of the intermediate p-benzynes, which are thereby inhibited from the H abstraction step that completes cycloaromatization. H abstraction reactivity, as judged from the p-benzyne singlet-triplet energy gap and from isodesmic equations, is also examined. Unexpected behavior is predicted for some heteroaromatic systems. Finally, we anticipate how these results may be applied to the design of prodrug candidates for subsequent biological application.