Bergman cyclization substituent effects

An illustrative example of how rehybridization can be used to control the Bergman cyclization is provided by substituent effects at the alkyne termini of enediynes. This effect in cycloaromatization chemistry was first studied by Schreiner and coworkers, who found dramatic acceleration of the Bergman cyclization upon... 

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. 

The Bergman cyclization is quite sensitive to substituent effects, and substituents at the alkyne termini are generally the most effective. It has been demonstrated that electron acceptor substituents, and more in particular cr-acceptors and/or Tr-donors. can facilitate the thermal cyclization, but apart from the work reported by Sander for the tetrafluoro-substituted enediyne 110 (which undergoes an exothermic Bergman cyclization), so far this approach has not produced particularly promising results (Scheme 19.30). 

Prall, M. Wittkopp, A. Fokin, A.A. Schreiner, P.R. Substituent effects on the Bergman cyclization of (Z)-l,5-hexadiyne-3-enes A systematic computational study. J. Comput. Chem. 2001, 22, 1605-1614. 

Kinetic and DFT studies have found that the rapid cycloaromatization of 2,3-diethynyl-l-methoxybenzene compared with 1,2-diethynylbenzene can be attributed to intramolecular hydrogen abstraction by the p-bcnzyne diradical intermediate from the OMe substituent. This has been shown to render the cyclization effectively irreversible by leading to a more stable diradical, and may have significant implications for the action of therapeutic enediynes.57 In general, the Bergman cycloaromatizations of 1-substituted 2,3-diethynylbenzenes have been found to be highly sensitive to the nature of the ortho-substituent, but the measurements and even the relative trends... 

Klein and Kdnig," for example, have reported the synthesis of a sulfonamide substituted 1,2-aryldiyne 111, where the sulfonamide group, being a cr-acceptor, should facilitate the Bergman cycloaromatization. However, as reported by Zaleski for a series of l,S-bis substituted oct-4-ene-2,6-diyne derivatives 113, steric hindrance and hydrogen bond formation between the terminal substituents can influence the temperature of the cyclization, and therefore the reactivity of the sulfonamide compound 111 is comparable with the one of the unsubstituted analog 112, since the electron withdrawing effect of the substituent is compensated by its steric hindrance (Scheme 19.30). 

The effect on the Bergman cycloaromatization of sulfur-containing substituents in the acetylene branch was studied for simple models, such as butyl-2-(triisopropylsilylethynyl)phenylethynylsulfide 3.922 (Scheme 3.133) [411]. The starting sulfide 3.922 was synthesized by treatment of the mono-trisopropylsilyl-protected orf o-diethynylbenzene 3.921 with butyllithium excess followed by the addition of sulfur dichloride [411]. Cyclization of compound 3.922 (benzene, 200°C, 6 M of 1,4-cyclohexadiene) gave butyl-2-naphthylsulfide 3.923 in 53% yield. Comparison of the parameters of this reaction with the cyclization of ortho-diethynylbenzene showed that the presence of the sulfur atom increases the cyclization barrier although the yield from compound 3.922 is much less than that from ort/ o-diethynylbenzene. These studies are consistent... 

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