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The para ‐didehydropyridine, para ‐didehydropyridinium, and related biradicals—a contribution to the chemistry of enediyne antitumor drugs
Author(s) -
Kraka Elfi,
Cremer Dieter
Publication year - 2000
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/1096-987x(20010130)22:2<216::aid-jcc9>3.0.co;2-x
Subject(s) - antibonding molecular orbital , chemistry , enediyne , computational chemistry , ring (chemistry) , singlet state , crystallography , molecular orbital , atomic orbital , protonation , density functional theory , atom (system on chip) , electron , stereochemistry , atomic physics , molecule , excited state , physics , organic chemistry , ion , quantum mechanics , computer science , embedded system
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