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Reactant Destabilization in the Bergman Cyclization and Rational Design of Light-and pH-Activated Enediynes

Summary: Reactant Destabilization in the Bergman Cyclization and Rational Design of Light- and
pH-Activated Enediynes
Igor V. Alabugin* and Mariappan Manoharan
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida 32306-4390
ReceiVed: August 13, 2002; In Final Form: October 22, 2002
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 -orbitals along the IRC path was gained using natural bond orbital (NBO) dissection. In the vicinity
of the Nicolaou's threshold (3.20 ) where the -orbitals become parallel and their interaction pattern resembles
that in the TS of the symmetry-forbidden thermal [2s + 2s] cycloaddition, the four-electron repulsive interaction
of filled in-plane -orbitals (i-i) becomes a dominant destabilizing factor without any compensation from
the bond-forming, attractive two-electron interaction of the in-plane -orbitals (i f i*). The dominant role
of the interplay between attractive and repulsive interactions in the in-plane -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 -* orbitals becomes larger than that of the repulsive - 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.


Source: Alabugin, Igor - Department of Chemistry and Biochemistry, Florida State University


Collections: Chemistry; Biology and Medicine