Thepara-didehydropyridine,para-didehydropyridinium, and related biradicals?a contribution to the chemistry of enediyne antitumor drugs

Abstract

Structure and stability of seven singlet (S) biradicals formed byBergman 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.

Problematic p-benzyne: Orbital instabilities, biradical character, and broken symmetry

“…24,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] Clearly, energy and geometry are not directly affected by orbital near-instabilities within the reference wave function and, therefore, useful energetics may be obtained with a restricted reference function provided threeelectron correlation effects are included in the calculation. However, the stationary points calculated along the reaction path have to be characterized with the help of the vibrational frequencies and, of similar importance, the calculated energy differences must be converted to enthalpy differences at 298 K in order to be directly compared with the experimental thermochemical data.…”

“…1,2,[13][14][15][16][17][18][19]25,26 Since singlet biradicals are difficult to detect and analyze by experimental means, 1,2,[20][21][22][23]25,26 most of their properties have been determined by quantum chemical calculations, which have become an indispensable tool in this connection. 1,24,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] Highlevel theoretical investigations of p-benzyne have been carried out with wave-function-based theories such as coupled cluster ͑CC͒, [47][48][49][50][51][52][53] while work on the larger, derivative enediyne systems is increasingly carried out with density functio...…”

100 Jahre Didehydroaromaten

“… Die auf UB3LYP/6‐31G(d,p)‐Niveau berechneten Strukturen von para ‐Didehydrobenzol ( 4 ), 2,5‐Didehydropyridin ( 81 ) und 81 ‐H + 81c. (Bindungslängen in pm.)…”

“…Interessant ist auch ein Vergleich von 4 mit 2,5‐Didehydropyridin ( 81 ) und der protonierten Form 81 ‐H + 38. 39, 80d, 81c, 84 Die auf UB3LYP/6‐31G(d,p)‐Niveau berechneten Singulett‐Triplett‐Abstände betragen hierin 2.5, 8.2 und 2.8 kcal mol −1 (mit anderen Methoden werden zumindest ähnliche Tendenzen erhalten)38, 39, 80c,d, 84. Eine detaillierte Interpretation dieser Energiedifferenzen wurde von Kraka und Cremer gegeben 81c.…”

“…39, 80d, 81c, 84 Die auf UB3LYP/6‐31G(d,p)‐Niveau berechneten Singulett‐Triplett‐Abstände betragen hierin 2.5, 8.2 und 2.8 kcal mol −1 (mit anderen Methoden werden zumindest ähnliche Tendenzen erhalten)38, 39, 80c,d, 84. Eine detaillierte Interpretation dieser Energiedifferenzen wurde von Kraka und Cremer gegeben 81c. Durch anomere Delokalisation des einsamen Elektronenpaars am Stickstoffatom in die vicinalen C‐C‐Bindungen kommt es zur Verkürzung der N‐C2‐ und N‐C6‐Bindungen (Abbildung 11); die Verkürzung der C2‐N‐Bindung verstärkt die Through‐Bond‐Kopplung durch eine Erhöhung der Überlappung der wechselwirkenden Orbitale.…”