Methyl-transfer reactions kinetic isotope effects

Three mechanisms have been proposed for this reaction (Scheme 21). The reaction is first order in each of the reactants. In another study, Reutov and coworkers159 found a large primary hydrogen-deuterium kinetic isotope effect of 3.8 for the reaction of tri-(para-methylphenyl)methyl carbocation with tetrabutyltin. This isotope effect clearly demonstrates that the hydride ion is transferred in the slow step of the reaction. This means that the first step must be rate-determining if the reaction proceeds by either of the stepwise mechanisms in Scheme 21. The primary hydrogen-deuterium kinetic isotope effect is, of course, consistent with the concerted mechanism shown in Scheme 21. 

An enantioselective imino-ene reaction was developed by Lectka to provide ct-amino acid derivatives.27 Aryl alkenes (cr-methyl styrene, tetralene), aliphatic alkenes (methylene cyclohexane), and heteroatom-containing enes, all gave high yields and high ee s of the homoallylic amides (Equation (17)). The mechanism of this reaction has been proposed to proceed through a concerted pathway. This mechanism is evidenced by a large kinetic isotope effect observed in the transfer of H(D). 

Recently, some attempts were nndertaken to uncover the intimate mechanism of cation-radical deprotonation. Thns, the reaction of the 9-methyl-lO-phenylanthracene cation-radical with 2,6-Intidine (a base) was stndied (Ln et al. 2001). The reaction proceeds through two steps that involve the intermediary formation of a cation-radical/base complex before unimolecular proton transfer and separation of prodncts. Based on the value of the kinetic isotope effect observed, it was concluded that extensive proton tnnneling is involved in the proton-transfer reaction. The assumed structure of the intermediate complex involves n bonding between the unshared electron pair on nitrogen of the Intidine base with the electron-deficient n system of the cation-radical. Nonclassical cation-radicals wonld also be interesting reactants for snch a reaction. The cation-radical of the nonclassical natnre are known see Ikeda et al. (2005) and references cited therein. 

We have examined the proton transfer reaction AH-B A -H+B in liquid methyl chloride, where the AH-B complex corresponds to phenol-amine. The intermolecular and the complex-solvent potentials have a Lennard-Jones and a Coulomb component as described in detail in the original papers. There have been other quantum studies of this system. Azzouz and Borgis performed two calculations one based on centroid theory and another on the Landau-Zener theory. The two methods gave similar results. Hammes-Schiffer and Tully used a mixed quantum-classical method and predicted a rate that is one order of magnitude larger and a kinetic isotope effect that is one order of magnitude smaller than the Azzouz-Borgis results. 

A number of other proton transfer reactions from carbon which have been studied using this approach are shown in Table 8. The results should be treated with reserve as it has not yet been established fully that the derived Bronsted exponents correspond exactly with those determined in the conventional way. One problem concerns the assumption that the activity coefficient ratios cancel, but doubts have also been raised by one of the originators of the method that, unless solvent effects on the transition state are intermediate between those on the reactants and products, anomalous Bronsted exponents will be obtained [172(c)]. The Bronsted exponents determined for menthone and the other ketones in Table 8 are roughly those expected by comparison with the values obtained for ketones using the conventional procedure (Table 2). For nitroethane the two values j3 = 0.72 and 0.65 which are shown in Table 8 result from the use of different H functions determined with amine and carbon acid indicators, respectively. Both values are roughly similar to the values (0.50 [103], 0.65 [104]), obtained by varying the base catalyst in aqueous solution. The result for 2-methyl-3-phenylpropionitrile fits in well with the exponents determined for malononitriles by general base catalysis but differs from the value j3 0.71 shown for l,4-dicyano-2-butene in Table 8. This latter result is also different from the values j3 = 0.94 and 0.98 determined for l,4-dicyano-2-butene in aqueous solution with phenolate ions and amines, respectively. However, the different results for l,4-dicyano-2-butene are to be expected, since hydroxide ion is the base catalyst used in the acidity function procedure and this does not fit the Bronsted plot observed for phenolate ions and amines. The primary kinetic isotope effects [114] also show that there are differences between the hydroxide ion catalysed reaction (feH/feD = 3.5) and the reaction catalysed by phenolate ions (kH /kP = 1.4). The result for chloroform, (3 = 0.98 shown in Table 8, fits in satisfactorily with the most recent results for amine catalysed detritiation [171(a)] from which a value 3 = 1.15 0.07 was obtained. 

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]. 

Experience with model calculations for equilibrium isotope effects and kinetic isotope effects, when using conventional TST, shows that the RGM is valid in the common circumstance in which the effects of coupled vibrational motions cancel between reactant and product states, or between reactant and transition states. The natural coupling expected between the various bends and stretches of the bonds in a methyl group is largely the same in the reactant state and transition state in the acetyl transfer example, so the free-energy effects of multiple isotopic substitutions are strictly additive. In the case of the glutamate dehydrogenase reaction of Fig. 

Large primary kinetic isotope effects have been measured for the H-atom transfer steps from substrate to dAdo and from dAdo to the product radical in a number of AdoCbl-dependent enzymes as indicated in Table 19.1. In methylmalonyl-CoA mutase, the steady-state deuterium isotope effect is 5-6 in the forward direction, and the intrinsic isotope effect of step (i) in Scheme 19.3 is masked by the kineti-cally coupled but slower later steps [37-39]. The steady-state tritium kinetic isotope effect kii/kj) in the forward direction has been reported to be 3.2 [38]. Note that the experiments with deuterium were performed with a fully deuterated methyl group, while those with tritium were carried out at the trace level and correspond to a single isotopic atom therefore these two isotope effects should not be directly compared. For the reverse reaction, the deuterium kinetic isotope effect is also par-... 

Kinetic Isotope Effects in Methyl-Transfer Reactions... 

However, Boozer and Hammond [7] have obtained additional support for the postulated chain termination via reaction (9) as opposed to reaction (5) on the basis of isotopic labelling experiments and from the inhibiting effect of amines not possessing a labile N—H function in their structure [8]. The use of deuterium-labelled methyl aniline and diphenyl-amine as inhibitors in the oxidation of tetralin and cumene did not show the isotope effect which would be expected if reaction (5) was important. Similarly, both AT-dimethylaniline and AT,AP-tetramethyl-p-phenylene-diamine have measurable inhibitory activity despite the fact that neither has a labile hydrogen [8]. However, it has been argued [12] that neither a kinetic isotope effect nor a labile hydrogen is necessary if inhibition results from an electron transfer reaction of the type... 

The final product ArCH ONO is formed in further oxidation of ArCH/ to ArCH/ by CAN and the subsequent reaction with NOj . For toluene derivatives with electron-donating substituents such as the methoxy group, the electron transfer reaction (Equation 4.73) was confirmed by the laser flash photolysis method [44]. For toluene, there is a probability for direct H-atom abstraction (Equation 4.72) with a highly polar transition state. Furthermore, for toluene derivatives with electron-withdrawing substituents, the addition ability of NO3 to phenyl 7t-bonds can be considered on the basis of data for reactions with phenols [41] and furan [45]. To clarify the interchanges in the reaction paths by the substituent in toluene, reaction rate constants for various toluene derivatives were evaluated by flash photolysis [44]. The substituent effect of the rate constants for toluene derivatives was correlated with ionisation energies (lEs) of these substances. The reaction rate for anisole is too fast to obtain accurate rate constants, and only lower limits of the rate constants are obtained (anisole) >310 M -s h For p-nitrotoluene, the rate constant is 2.3T0 M -s IE = 9.5 eV. A deuterium kinetic isotope effect of 1.6 was observed for the reaction of NO3 with toluene and toluene - dg. This indicates that NO3 predominantly abstracts the H atom from methyl groups. In the case of p-xylene, the deuterium isotope effect was not observed [43]. The rate constant forp-xylene (> 2 x 10 M/s) is close to the diffusion-controlled limit in acetonitrile, and consequently selectivity becomes low. 

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