The para-didehydropyridine, para-didehydropyridinium, and related biradicals - A contribution to the chemistry of enediyne antitumor drugs

Structure and stability of seven singlet (S) biradicals formed by Bergman c yclization from enediynes are investigated with unrestricted DET using B3LY P/G-31G(d,p) and B3LYP/6-311+G(3df,3pd). The corresponding triplets (T) are also calculated and compared with their S states utilizing the on-toy pair density and the S-T difference on-top pair density. A relationship between the geometry of a S biradical, its stability, and its biradical character is established using the on-top pair density and calculated S-T splittings. Through-bond coupling between the single electrons of the S biradical can be enhanced by the incorporation of a N atom into para-didehydrobenzene 1 d ue to lowering of antibonding orbitals, shortening of ring bonds by anomeri c effect, and increased overlap between the interacting orbitals. Strong th rough-bond interactions lead to a stabilization of the S state and an incre ase of the S-T splitting. Because through-bond interactions also determine the degree of coupling between the single electrons, stabilization of the S biradical, and an increase of the S-T splitting always means a lowering of the biradical character and the H abstraction ability, which is relevant f or the use of N-containing enediynes and their biradicals in connection wit h the design of new antitumor drugs. The S para-didehydropyridine biradical 2 is strongly stabilized and, therefore, has only reduced biradical charac ter. However, the latter can be enhanced by protonation, because this alway s leads to a lengthening of ring bonds and a reduction of the overlap betwe en interacting orbitals. In the weakly acidic medium of a tumor cell, S bir adicals containing an amidine group can be protonated to yield S biradicals with high biradical character (low S-T splittings, small changes in bond a lternation relative to the T state), which will abstract H atoms from the D NA of a tumor cell. (C) 2000 John Wiley & Sons, Inc.