Radical Bergman cyclization

In these reactions, a er-bond is formed at the expense of two re-bonds and, thus, the process leads to a net loss of one chemical bond that is intrinsically unfavorable thermodynamically. Formation of the new er-bond leads to ring closure, whereas the net loss of a bond leads to the formation of two radical centers, which can be either inside (the endo pattern in Scheme 1) or outside of the newly formed cycle (the exo pattern). Note that er-radicals are formed through the endo path, while exo-closures may produce either a er-radical when a triple bond is involved or a conjugated re-radical when the new bond is formed at the central carbon of an allene. The parent version of this process is the transformation of enediyne 1 into p-benzyne diradical2 (the Bergman cyclization), shown in Scheme 2. 

Fig. 18 Crossings of in-plane and out-of-plane frontier MOs in radical-anionic Bergman and C1C5 cyclizations (crossings for photochemical, dianionic and radical-cationic cyclizations involve the same MOs but differ in the number of electrons).

In this analysis, the activation barrier for both C1-C6 and C1-C5 cyclizations of enediyne radical-anions can be described as the avoided crossing between the out-of-plane and in-plane MOs (configurations). One-electron reduction populates the out-of-plane LUMO of the enediyne moiety. At the TS (the crossing), the electron is transferred between the orthogonal re-systems to the new (in-plane) LUMO. This effect leads to the accelerated cyclization of radical-anions of benzannelated enediynes, a large sensitivity of this reaction to re-conjugative effects of remote substituents and the fact that this selectivity is inverse compared to that of the Bergman cyclization. Similar electronic effects should apply to the other reductive cyclization reactions that were mentioned in the introduction. 

Enediynes tend to undergo Bergman cyclizations, and the C4-C9 bond can be made in this way. The C5 and C8 radicals produced thereby can each abstract H from Cl and C12, respectively. Fragmentation of the C10-C11 bond, then radical-radical combination gives the product. 

CH4, and H2 while minor products such as HCCCN, H2C=CHCN, C2H4 and C4H2 were also detected. Ab initio chemical calculations revealed that the pyrolysis of acetonitrile is initiated by CH bond fission, forming a cyanomethyl radical. Products such as HCCN and H2C=CHCN have been shown to arise from the decomposition of succinonitrile, that forms by the recombination of two cyanomethyl radicals. The kinetics of thermocyclization of 2,3-diethynylquinoxaline (109) (Bergman cyclization) have been studied in various solvents. Non-polar solvents give shorter half-lives and better yields. The cyclization rates observed were found to be solvent dependent. ... 

For synthetic purposes, organometallic reagents can be used to generate a precursor to the Bergman Cyclization in which the metal centre forms a part of the cumulated unsaturated system these cyclizations occur at relatively low temperatures. Here the cyclization can be viewed as a Myers-Saito Cyclization that gives rise to a metal-centreed radical ... 

The real reactive, DNA-cleaving, toxophore is a phenylene-1,4-diyl radical that is formed via a Bergman cyclization. 

The ene-diyne reaction (Bergman cyclization) chemistry described below is not part of the biologically related radical reactions. However, after the successive discovery of... 

Bergman cyclization 35 PTOC Esters 36 Chlorination 37 Radical clocks 37... 

The diyne ene (84) undergoes photochemical cyclization on irradiation at 350 nm. The product obtained was identified as the phenanthrene derivative (85). " A variant of the photo-Bergman cyclization has been reported following the irradiation of the enediynes (86). The reactions are brought about using electron transfer from cyclohexa-1,4-diene in acetonitrile. This affords the products (87) in the yields reported under the structure. The products are formed by cyclization via the fulvene radical anion intermediate (88). " ... 

Bergman proposed that the reaction mechanism of the cyclization under thermal conditions (200 °C) involved the initial generation of a 1,4-benzenediyl diradical species known as para-benzyne (2). Bergman reported that when the reaction was carried out in a hydrocarbon solvent, such as 2,6,10,14-tetramethylpentadecane, benzene was formed as the final product. This suggests that the hydrocarbon solvent (RH) acts as a hydrogen atom donor to quench the diradical intermediate 2. This result hints at the radical nature of the mechanism operative in the Bergman cyclization. 

Extensive mechanistic studies of this cyclization reaction were carried out by Myers et al. and extended with theoretical work by Squire s et al. It is known that, in contrast to the Bergman cyclization of the ene-diyne (Chapter 4.2), this transformation proceeds as an exothermic process determined by the increased stability of a benzyl radical versus a phenyl radical. The barrier for cyclization from substrate to a diradical product is low and can further be reduced by an appropriate substitution at the allenic terminus of the substrate. The dichotomous (polar and free radical) reactivity is observed on pyrolysis in the presence of polar reactants. Both radical and polar products arise from a common intermediate, which is described as a polar diradical, a linear combination of limiting structure 7 and zwitterion 11. According to Squires, polar diradical singlet species are involved. Based on computational studies supported by experimental product distribution studies, it has been proposed that both the diradical 7 and... 

In addition to the aforementioned transformations, the photo-induced Bergman cyclization was utilized by Zhu and coworkers to form intramolecular polymeric nanoparticles.The appropriate reactive diyne unit was incorporated into the polymer using both direct controlled radical polymerization and aHqme protection strategies. The resulting linear polymers were subjected to photochemical Bergman cyclization conditions using a continuous addition strategy, similar to the case previously discussed. ... 

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