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 cyc loaromatization of 3-ene-1,5-diynes (the Bergman cyclization). The majority of the calculations were conducted by using the BLYP version of Density Fu nctional Theory, and higher level Brueckner orbital calculations were used for a few key compounds. In all, 46 enediynes, 44 cyclization transition st ates, 39 singlet p-benzynes, and 28 related triplet p-benzynes were studied , including simple vinyl-substituted and annulated examples. The data indic ate that strongly electron-withdrawing groups increase the cyclization barr ier, while a-donating groups decrease it; it conjugation, especially donati on, has little effect. Most annulations, including those involving heteroar omatic rings, Power the barrier slightly (6 MR) or raise it slightly (5 MR) . Larger effects are seen for smaller rings or charged rings. Some previous ly observed apparent rate inhibitions are seen to be due to reversibility o r forward reactivity of the intermediate p-benzynes, which are thereby inhi bited from the H abstraction step that completes cycloaromatization. H abst raction reactivity, as judged from the p-benzyne singlet-triplet energy gap and from isodesmic equations, is also examined. Unexpected behavior is pre dicted for some heteroaromatic systems. Finally, we anticipate how these re sults may be applied to the design of prodrug candidates for subsequent bio logical application.