Magnus et al. conducted kinetic studies on enediynes to correlate between strain energy and its reactivity.24 They concluded that the cyclization rates of enediynes are influenced by strain-energy modulation in the pseudocyclic transition state. From their experimental observation it has been concluded that the rate of cyclization is governed much more strongly by strain energy rather than the proximity of the acetylenic carbon (cd distances). Other studies reinforce this conclusion, including an elegant comparison between computer modeled cd, rates and strain energy, and those determined by experiment, which found excellent correlation between theoretical and experimental values.23,25




Another factor involved in determining the activity of enediynes to cyclization is the electronic effect. Several aspects of this category have been studied to date, including heteroatomic effects, solvent dependence, aryl ring substitutions, and acetylenic substitutions. In order to investigate how electronic factors influence the rate of cyclization, Kim et al. synthesized some aromatic heteroatomic enediynes (29 - 32) and did some kinetics experiments.26





It has been reported that non-aromatic enediynes have shorter half-lives than arenediynes, however, the influence of the double bond has yet to be clarified.25 Kim et al. concluded in their report that electron-withdrawing substituents associated with the double bond tend to increase the Bergman cyclization. The synthesized enediynes (18 -21) were used to measure their respective activation energy utilizing an Arrhenius relationship (rate of disappearance of enediyne versus time). The measured activation energy was compared to analogous nonheteroatomic enediynes (21). Compounds 19 and 20 were found to have decreased activation energies compared to 21. Enediyne 20 was found to be the most reactive acyclic arenediyne studied to date. It was determined that the activation energy of the enediyne increased due to the addition of the aromatic ring in compound 18 relative to 21.26 If electron-withdrawing groups are attached to a proximal position to the propargylic carbon 22, there appears to be a rate accelerating effect.27 Vinyl substitution has also been studied and the results appear to indicate that electron-withdrawing groups lower the rate of reaction by increasing activation energy (22, 23, 24).22,28 Numerous studies25,29-31 have been employed on benzannulated enediynes (25) and they found that the nature of double bond has little to no effect on reaction rate , although it may cause a change to rate limiting step.25,32 During the observation of these experiments, cyclized products were formed in better yields with less polar solvents, and the half-lives were found to correlate linearly with dielectric constants and ET(30) values.21,26 This observation is intriguing because it has been reported that cyclization of similar enediynes is solvent independent. More study is necessary to examine whether this phenomenon is general for cyclizations.



In 1994 Turro et al. reported the Bergman photochemical cyclization of 26.33 They irradiated this compound in a number of solvents and the product (27) formed was the expected Bergman cyclization product (Scheme 3). This was further evidence of the formation of a biradical intermediate.
Scheme 3



References
(23) Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630.
(24) Magnus, P.; Fortt, S.; Petterna, T.; Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 4986.
(25) Semmelhack, M. F.; Neu, T.; Foubelo, F. Tetrahedron 1992, 33, 3277.
(26) Kim, C. S.; Russell, K. C. J. Org. Chem. 1998, 63, 8229.
(27) Boger, D. L.; Zhou, J. J. Org. Chem. 1993, 58, 3018.
(28) Jones, G. B.; Warner, P. M. J. Am. Chem. Soc. 2001, 123, 2134.
(29) Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang, Y. J. Org. Chem. 1994, 59, 5833.
(30) Singh, R.; Just, G. Tetrahedron Lett. 1990, 31, 185.
(31) Nicolaou, K. C.; Liu, A.; Zheng, Z.; McComb, S. J. Am. Chem. Soc. 1992, 114, 9279.
(32) Kaneko, T.; Takahashi, M.; Hirama, M. Tetrahedron Lett. 1999, 40, 2015.
(33) Turro, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35, 8089.
(34) Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.