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 cyclization from enediynes are investigated with unrestricted DFT using B3LYP/6‐31G(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‐top 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 due to lowering of antibonding orbitals, shortening of ring bonds by anomeric effect, and increased overlap between the interacting orbitals. Strong through‐bond interactions lead to a stabilization of the S state and an increase 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 for the use of N‐containing enediynes and their biradicals in connection with the design of new antitumor drugs. The S para‐didehydropyridine biradical 2 is strongly stabilized and, therefore, has only reduced biradical character. However, the latter can be enhanced by protonation, because this always leads to a lengthening of ring bonds and a reduction of the overlap between interacting orbitals. In the weakly acidic medium of a tumor cell, S biradicals containing an amidine group can be protonated to yield S biradicals with high biradical character (low S‐T splittings, small changes in bond alternation relative to the T state), which will abstract H atoms from the DNA of a tumor cell. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 216–229, 2001