Thermal C¹−C⁵ Diradical Cyclization of Enediynes

Abstract

Computational studies at the BLYP/6-31G(d) level (supplemented by BCCD(T)/cc-pVDZ calculations) suggest that in aryl-substituted 1,2-diethynylbenzenes, steric effects disfavor the thermal C1-C6 diradical cyclization reaction (Bergman) and electronic effects favor the regiovariant C1-C5 cyclization to the extent that the C1-C5 process should become an important reaction pathway in the thermolyses of such compounds. Experimentally, thermolyses of 1,2-bis(2,4,6-trichlorophenylethynyl)benzene, a particularly favorable case, yields only products derived from C1-C5 cyclization [specifically, 1-(2,4,6-trichlorobenzylidene)-2-(2,4,6-trichlorophenyl)-1H-indene and its hydrogenation product 3-(2,4,6-trichlorobenzyl)-2-(2,4,6-trichlorophenyl)-1H-indene], and even for the parent hydrocarbon 1,2-bis(phenylethynyl)benzene, the formation of C1-C5 cyclization products is competitive with the major Bergman reaction. Although some C1-C5 cyclization products are probably formed by transfer hydrogenation from 1,4-cyclohexadiene (commonly included in such reactions), thermolyses in the absence of 1,4-CHD as well as deuterium labeling studies confirm the existence of direct C1-C5 diradical cyclizations for diaryl-substituted enediynes.

How to Lose a Bond in Two Ways ― The Diradical/Zwitterion Dichotomy in Cycloaromatization Reactions

“…In 1883, Richter reported the preparation of cinnolines31 by a process (“Richter cyclization”) that is topologically identical and electronically analogous to the zwitterionic Bergman cyclization (Figure 6). In a similar way, the ionic analogues of C 1 –C 5 cyclization (the “N 1 –C 5 ” cyclization of alkynyldiazonium salts) were reported by Vasilevsky and co‐workers32 long before the all‐carbon version of this process was discovered 33,34…”

Synthesis and reactivity of anthracenyl-substituted arenediynes

“…9,17 In order to predict the preferred cyclization pathways in 1-3, activation energies (DG à ) for the formation of both C 1 -C 5 and Bergman cyclized products in 1-3 were calculated at the B3LYP/6-31G(d) level of theory (Table 1). 16 The activation energy for both C 1 -C 5 and Bergman cyclization decreases as the size of the ortho substituents increases in 1-3.…”

“…The absence of exothermic peaks in 2 and 3 below their decomposition temperatures indicates that the cyclization reaction in these compounds in solid state is adversely affected by the geometrically constrained environment created by the bulky ortho (-CH 3 and -TMS in 2 and 3) and/or anthracenyl substituents. Since 1 showed an exothermic peak in DSC corresponding to a thermal induced reaction, a cyclization reaction of 1 was carried out in 1,4-cyclohexadiene 17,19 in a sealed tube at 250°C, which is the onset temperature determined from the DSC analysis. Thermal induced cyclization reaction of 1 resulted in a mixture of products.…”

“…For example, phenyl-substituted arenediyne generates both Bergman and C 1 -C 5 cyclized product whereas the bulky trichlorophenyl-susbstituted arenediyne yields only C 1 -C 5 cyclized products upon thermal induced cyclization (Scheme 1). 7,17 Electronic effects on the cyclization pathway are more apparent in the case of naphthalenylsubstituted arenediynes. 9 Photoreaction of electron rich naphthalenyl-substituted arenediyne (6-methoxy naphthalen-2-yl derivative) yields a Bergman cyclized product whereas the naphthalenyl-substituted arenediynes (naphthalen-1-yl and naphthalen-2-yl derivatives) do not generate the expected cyclized products.…”

Intracellular DNA Damage by Lysine‐Acetylene Conjugates

“…Because C1–C5 cyclization proceeds under photochemical conditions for thermal C1–C5 cyclization, see [10, 11], it takes advantage of the high degree of spatial and temporal controls over reactivity inherent to the photochemical activation. The use of tissue-penetrating light allows for efficient, and selective, spatial and temporal control over prodrug activation as light can be delivered directly to the tumor when it contains a high concentration of the prodrug.…”