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I for the inactivation of MCAD by 19 or 20 based on a similar approach shown in Figure 3 proved to be problematic. The inactivation follows first-order kinetics only at high inhibitor concentration but deviates from the first-order kinetics at low inhibitor concentration. The amount of inhibitor (260 mM) used in the incubations shown in Figure 4 was at the saturation conditions.
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20 It should be noted that the apparently greater ring strain associated with the spiropentyl system is misleading since it contains one more cyclopropyl ring than the methylenecyclopropane case. Interestingly, recent calculations showed that the major source of the "strain" resulting from the introduction of a trigonal center into cyclopropane is not the increase in angle strain but the loss of a very strong cyclopropane C-H bond (Johnson, W. T. G.; Borden, W. T. J. Am. Chem. Soc. 1997, 119, 5930).
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Cyclopropylcarbinyl radicals (such as 34) readily undergo β-scission because the SOMO can assume an eclipsed conformation with respect to a β,γ bond. On the contrary, cyclopropyl radicals (such as 35) cannot attain such a conformation without the development of great strain, and therefore, β-scission is hampered due to a much higher activation energy (Kennedy, A. J.; Walton, J. C.; Ingold, K. U. J. Chem. Soc., Perkin Trans. 2 1982, 751).
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The structures listed in Scheme 7 for the inhibitor-enzyme adducts are by no means a complete set of all possible variations. For example, a fully oxidized C-6-substituted flavin has also been proposed as the structure of a minor component isolated from the incubation of MCPA-CoA (5) with MCAD (Zeller, H. D.; Ghisla, S. In Flavins and Flavoproteins; Edmondson, D. E., McCormick, D. B., Eds.; Walter de Gruyter: Berlin, 1987; p 161).
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2642639532
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Personal communication
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Ab initio calculations were carried out to compute the energies of primary cyclopropylcarbinyl and tertiary cyclopropyl radicals using an unrestricted Hartree-Fock level of theory with 6-31G* basis set (UHF/6-3/G*). The results suggested that the energy difference is about 5 kcal/mol, favoring the primary cyclopropylcarbinyl radical. These energy differences reflect the bond dissociation energies (BDEs) of primary alkyl C-H versus the tertiary cyclopropyl C-H bonds (Borden, W. T. Personal communication).
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