Kinetic isotope effect profile

Tresadern G, H Wang, PF Faulder, NA Burton, IH Hillier (2003) Extreme tunnelling in methylamine dehydrogenase revealed by hybrid QM/MM calculations potential energy surface profile for methylamine and ethanolamine substrates and kinetic isotope effect values. Mol. Phys. 101 (17) 2775-2784... 

Recent studies by Baciocchi et al. on kinetic deuterium isotope effect profiles and substituent effects in the oxidizing N-demethylation of iV,JV-dimethylanilines catalyzed by tetrakis (pentafluorophenyl)porphyrin also supports the electron-transfer mechanism and exclude the hydrogen-atom transfer mechanism in such processes [218]. 

The rate of initial electron transfer from A,7V-dimethylaniline to [Fe(phen)3] + is diffusion-limited. This is followed by the rate-determining proton transfer from the radical cation to pyridine to give the deprotonated a-amino radical which is rapidly oxidized by a second equivalent of [Fe(phen)3] + to yield the product iminium ion. Kinetic isotope effects [kii/kjf) for the proton transfer were determined from the J3/tfo ratios of the products derived from p-substituted A-methyl-A-trideuteromethylanilines. The k /kx) value first increases and then decreases with increasing pAa of p-substituted A,A-dimethylaniline. Such a bell-shaped isotope effect profile is typical of proton-transfer reactions [82, 85]. The maximum kn/fco value is determined as 8.8 which is much larger than the corresponding value for the demethylation of the same substrate by cytochrome P-450 (2.6) [79]. 

Evidence for the dual proton and electron tunneling process required for simultaneous electron and proton transfer has been obtained from both enzymatic and model systems. In biomolecular systems, the strongest evidence for proton tunneling processes is obtained from kinetic isotope effects, where both anomolously high protium-tritium kinetic isotope effects and distinct temperature profiles for these isotope effects can be used as diagnostic tools for proton tunneling events [57]. 

Figure 6.10 Schematic one-dimensional energy profile of degenerate single-barrier hydron (H, D, T) transfers in coupled networks of 1 to 4 cyclic hydrogen bonds. The hydron transfer can be an over-barrier process or a tunneling process, as indicated by the double arrows in the energy profile. The overbarrier process leads to kinetic isotope effects...

Fig, 4. Variation of the primary kinetic isotope effect in the elimination reaction of 2-phenylethyl-dimethylsulphonium bromide with hydroxide ion as the solvent composition is changed from water to 84% dimethyl sulphoxide. (A similar profile has recently been obtained for the elimination reaction of 2-phenylethyltrimethylammonium ion under the above reaction conditions " ). (Reproduced with permission from Cockerin ".)... 

In view of the complications imposed on interpretation of kinetic isotope effects by quantum mechanical tunnelling and a variable profile of isotope effect with proton transfer to different bases, a more certain prediction would seem most probable if comparisons are restricted to reactions of a series of similar substrates within a given reaction medium. Within this framework it is possible to make reasonable predictions of the effect of substrate structure on the nature of the transition state for elimination using only primary kinetic hydrogen isotope effects. 

Baciocchi E, Lanzalunga O, Lapi A, Manduchi L (1998) Kinetic deuterium isotope effect profiles and substituent effects in the oxidative N-demeth-ylation of N, N-dimethylanilines catalyzed by tetrakis(pentafluorophenyl)porphyrin iron(III) chloride. J Am Chem Soc 120 5783-5787... 

FIGURE 3.10 A general energy profile that illustrates the origin of the kinetic isotope effect in terms of the zero-point energies in both the initial and transition states. The ZPE for the heavy isotope (subscript h) and for the light isotope (subscript 1) arise from summation over the various vibrational modes (i). Source Buncel and Dust (2003) with permission from the American Chemical Society. 

Finally, the involvement of deoxy-Breslow species as intermediates and related to the reactivity profile of acrylates under NHC catalysis has been reported twice. The first report dealt with detailed mechanistic studies of the well-known tail-to-tail dimerization of methyl acrylate. By means of complementary and robust experiments (including kinetic isotope effects, deuterium-labelling studies and competitive reactions), the formation of the dimer (148) has been unambiguously rationalized. The second report has described/or the first time the NHC-catalysed cyclotetramerization of acrylates. Using imidazolium chloride (135) as NHC source, various trisubstituted cyclopen-tenones (149), thus resulting from the cyclotetramerization of acrylates, have been obtained in moderate yields. 

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