Stable isotopes kinetic isotope effects

The cases of pentamethylbenzene and anthracene reacting with nitronium tetrafluoroborate in sulpholan were mentioned above. Each compound forms a stable intermediate very rapidly, and the intermediate then decomposes slowly. It seems that here we have cases where the first stage of the two-step process is very rapid (reaction may even be occurring upon encounter), but the second stages are slow either because of steric factors or because of the feeble basicity of the solvent. The course of the subsequent slow decomposition of the intermediate from pentamethylbenzene is not yet fully understood, but it gives only a poor yield of pentamethylnitrobenzene. The intermediate from anthracene decomposes at a measurable speed to 9-nitroanthracene and the observations are compatible with a two-step mechanism in which k i k E and i[N02" ] > / i. There is a kinetic isotope effect (table 6.1), its value for the reaction in acetonitrile being near to the... 

What concerns us here are three topics addressing the fates of bromonium ions in solution and details of the mechanism for the addition reaction. In what follows, we will discuss the x-ray structure of the world s only known stable bromonium ion, that of adamantylideneadamantane, (Ad-Ad, 1) and show that it is capable of an extremely rapid degenerate transfer of Br+ in solution to an acceptor olefin. Second, we will discuss the use of secondary a-deuterium kinetic isotope effects (DKie) in mechanistic studies of the addition of Br2 to various deuterated cyclohexenes 2,2. Finally, we will explore the possibility of whether a bromonium ion, generated in solution from the solvolysis of traAU -2-bromo-l-[(trifluoromethanesulfonyl)oxy]cyclohexane 4, can be captured by Br on the Br+ of the bromonium ion, thereby generating olefin and Br2. This process would be... 

Fig. 2 Schematic representation of the so-called semiclassical treatment of kinetic isotope effects for hydrogen transfer. All vibrational motions of the reactant state are quantized and all vibrational motions of the transition state except for the reaction coordinate are quantized the reaction coordinate is taken as classical. In the simplest version, only the zero-point levels are considered as occupied and the isotope effect and temperature dependence shown at the bottom are expected. Because the quantization of all stable degrees of freedom is taken into account (thus the zero-point energies and the isotope effects) but the reaction-coordinate degree of freedom for the transition state is considered as classical (thus omitting tunneling), the model is ealled semielassieal.

The tropylium cation (274) first observed 1891 and rediscovered in 1957 is perfectly stable and isolable. Cyclopropenyl cations have been observed in solution a long time ago, but 273 remained elusive until very recently. Benzocyclo-propene (1) reacts with triphenylfluoroborate via hydride transfer some 5 times less rapidly than cycloheptatriene. The reaction of deuterated 1 exhibits a kinetic isotope effect of 7.0. However, only a low yield of benzaldehyde (277), the expected hydrolysis product of 273, could be isolated from the reaction mixture. ... 

For oxidation of G in duplex DNA, Steenken concluded that the proton on N-1 of G shifts spontaneously to N-3 of the cytosine in the normal Watson-Crick base pair to generate [C+(H)/G ]. Consistent with this proposal, calculations indicate that charge transfer in oxidized DNA is coupled with proton transfer from G to Experiments carried out in D2O also reveal a kinetic isotope effect for G oxidation, implicating a concerted proton-coupled electron transfer mechanism. However, density functional theory (DFT) calculations in the gas phase predict that the structure with a proton on G N-1 [C/HG ] is more stable than [C (H)/G ] by 1.4kcal/mol. " ... 

Quantum chemical calculations need not be limited to the description of the structures and properties of stable molecules, that is, molecules which can actually be observed and characterized experimentally. They may as easily be applied to molecules which are highly reactive ( reactive intermediates ) and, even more interesting, to molecules which are not minima on the overall potential energy surface, but rather correspond to species which connect energy minima ( transition states or transition structures ). In the latter case, there are (and there can be) no experimental structure data. Transition states do not exist in the sense that they can be observed let alone characterized. However, the energies of transition states, relative to energies of reactants, may be inferred from experimental reaction rates, and qualitative information about transition-state geometries may be inferred from such quantities as activation entropies and activation volumes as well as kinetic isotope effects. 

Experiments cannot tell us what transition states look like. The fact is that transition states cannot even be detected experimentally let alone characterized, at least not directly. While measured activation energies relate to the energies of transition states above reactants, and while activation entropies and activation volumes, as well as kinetic isotope effects, may be invoked to imply some aspects of transition-state structure, no experiment can actually provide direct information about the detailed geometries and/or other physical properties of transition states. Quite simply, transition states do not exist in terms of a stable population of molecules on which experimental measurements may be made. Experimental activation parameters provide some guide, but tell us little detail about what actually transpires in going from reactants to products. 

In Guo, after the very fast protonation of the electron adduct by water at the heteroatom [k > 107 s 1, von Sonntag 1991 Candeias et al. 1992 at 0(6), N(3) or N(7), cf. reaction (180)], a rapid transformation occurs [reaction (181) k in H20) = 1.2 x 106 s k(in D20) = 1.5 x 10s s 1] which is also catalyzed by phosphate buffer (k = 5.9 x 107 dm3 mol-1 s 1) which has been attributed to a protonation at C(8) (Candeias et al. 1992). This assignment is based upon solid-state EPR data, where C(8)-H--adduct is the thermodynamically most stable H -adducl radical (Rakvin et al. 1987 for DFT calculations see Naumov and von Sonntag, unpubl. results). The high solvent kinetic isotope effect of ku/ko = 8 is a strong indication that a proton is transferred in the rate-determining step. The magnitude of the rate of phosphate buffer catalysis points to a protonation at carbon (for a similar reaction observed with the Thy radical anion see Table 10.20). The C(8)-H -ad-duct has a pKa value of 5.4 [equilibrium (182)]. 

Initially, it was thought that the glycosylation proceeded through the episulfonium intermediate 35. However, the measured kinetic isotope effect (KIE) of 1.17-1.20 suggests an oxocarbenium ion intermediate rather than an episulfonium ion [27], Furthermore, computational studies also indicated that the 3E oxocarbenium ion 36 is considerably more stable than the strained episulfonium ion 35. The observed stereoselectivity was explained by an inside attack on the 3E oxocarbenium ion. 

The early experiments of Goldschmidt clearly indicated that phenols are sensitive to radical attack. Not only were fairly stable radicals found in oxidation processes of phenols (Goldschmidt and Schmidt, 1922 Goldschmidt and Stiegerwald, 1924), but the oxidation of hydroquinone to quinone could also be brought about by the stable free radical 2,2-diphenyl-l-picrylhydrazyl (DPPH, Goldschmidt and Renn, 1922). The mechanism of the radical attaok remained unknown for a long time. The kinetic isotope effect played a very important role in its elucidation. 

However, reaction with D+ in D2O reveals that this mechanism is incorrect. The product contains substantial amounts of deuterium at C4, not at C2 as predicted by the proposed mechanism. Protonation must occur at the end of the conjugated system to produce the more stable conjugated cation, which rotates about the same bond and loses H or D from C4 to give the product. More H than D will be lost, partly because there are two Hs and only one D, but also because of the kinetic isotope effect, of which more later. 

Another series of publications from Ken s group compared kinetic isotope effects, computed for different possible transition structures for a variety of reactions, with the experimental values, either obtained from the literature or measured by Singleton s group at Texas A M. These comparisons established the most important features of the transition states for several classic organic reactions — Diels-Alder cycloadditions, Cope and Claisen rearrangements, peracid epoxidations, carbene and triazolinedione cycloadditions and, most recently, osmium tetroxide bis-hydroxylations. Due to Ken s research, the three-dimensional structures of many transition states have become nearly as well-understood as the structures of stable molecules. 

There are also several experimental studies dedicated to the acetic acid + OH reaction [133-138]. According to the primary kinetic isotope effect (KIE) carried out by Singleton et al. [136], the preferential pathway in this case is also the H-atom abstraction from the carboxyl group. From the theoretical modeling on this reaction [137,138], it seems that the acidic H-abstraction, is greatly enhanced and largely controlled by the formation of very stable H-bonded reactant complexes. 

Perdenteration of the methylene hnker affords a relatively kinetically stable complex, which allows for the monitoring of exogenons snbstrate oxidations. When (7) is exposed to cold (-95 °C) acetone solntions of the lithium salts of para-substituted phenolates, clean conversion to the corresponding o-catechols is observed. Deuterium kinetic isotope effects (KIEs) for these hydroxylation reactions of 1.0 are observed, which is consistent with an electrophilic attack of the peroxo ligand on the arene ring. An electrophilic aromatic substitution is also consistent with the observation that lithium jo-methoxy-phenolate reacts substantially faster with (7) than lithium / -chloro-phenolate. Furthermore, a plot of observed reaction rates vs. / -chloro-phenolate concentration demonstrated that substrate coordination to the metal center is occurring prior to hydroxylation, and thus may be an important feature in these phenolate o-hydroxylation reactions. 

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