New ways to control the reactivity of enediynes are suggested on the basis of computational analysis of reactant destabilization in cyclic enediynes. This analysis is based on monitoring electronic changes in the Bergman cyclization along the internal reaction coordinate (IRC) path. Insight into the relative importance and timing of a variety of bond-forming and bond-breaking processes involving both in-plane and out-of-plane pi-orbitals along the IRC path was gained using natural bond orbital (NBO) dissection. In the vicinity of the Nicolaou's threshold (3.20 Angstrom) where the pi-orbitals become parallel and their interaction pattern resembles that in the TS of the symmetry-forbidden thermal [2(s) + 2(s)] cycloaddition, the four-electron repulsive interaction of filled in-plane pi-orbitals (pi(i)-pi(i)) becomes a dominant destabilizing factor without any compensation from the bond-forming, attractive two-electron interaction of the in-plane pi-orbitals (pi(i)-->pi(i)*). The dominant role of the interplay between attractive and repulsive interactions in the in-plane g-system is further illustrated by the observation that the reaction becomes truly spontaneous (barrierless) when the magnitude of the attractive two-electron interaction of in-plane pi-pi* orbitals becomes larger than that of the repulsive pi-pi interaction. This theoretical analysis is applied toward a rational design of new highly reactive, pH-activated acyclic enediynes and toward increasing the efficiency of the photochemical Bergman cyclization.