Intramolecular deuterium isotope effect

A methodology that has turned out to be a very powerful tool in trying to unravel the intricacies of the mechanism of cytochrome P450-catalyzed oxidation reactions has been the use of deuterium isotope effects. The use of intramolecular deuterium isotope effects have been particularly important in this regard as will be described in chapter 4 where a number of such studies are presented. But, before describing the specific technique that intramolecular isotope effect studies entail, a quick mini review on the nature of deuterium isotope effects is probably in order. 

FIGURE 3.7 Selectively deuterated o-xylenes for an intramolecular deuterium isotope effect experiment. 

In a more recent study (105), the intramolecular deuterium isotope effect and the relative rates of benzylic hydroxylation for six para-substituted (OCH3, CH2D, H, Cl, Br,... 

TABLE 4.2 Intramolecular deuterium isotope effects for benzylic hydroxylation of substituted toluenes catalyzed by CYP1A2, CYP1B1, CYP2C9, CYP2E1, and CYP101... 

Hales,D. B., Ho, B. Thompson,J. A. (1987). Inter-and intramolecular deuterium isotope effects on the cytochrome P-450-catalyzed oxidative dehalogenation of 1,1,2,2-tetrachloroethane. Biochemical and Biophysical Research Communications, 149, 319—25. 

GT Miwa, WA Garland, BJ Hodshon, AYH Lu, DB Northrop. Kinetic isotope effects in cytochrome P-450 catalysed oxidation reactions. Intermolecular and intramolecular deuterium isotope effects on N-demethylation of N,N-dimethylphentermine. J Biol Chem 255 6049—6054, 1980. 

The principal reason for the adoption of structure 20 as an irreversibly formed intermediate in the reaction under consideration comes from fascinating intramolecular deuterium isotope effects observed by Stephenson and coworkers [123, 125, 131]. The key finding was that the deuteriated derivatives, 21 and 22, of 2,3-dimethyl-2-butene exhibited the intramolecular isotope effects shown. It was therefore concluded that C-H and C-D bonds had to be cis to one another to compete, demanding an intermediate with a geometry operationally equivalent to a perepoxide. In addition, that intermediate had to be formed irreversibly and inversion of the oxonium oxygen had to be slow on the reaction timescale. 

The lack of a large intramolecular deuterium isotope effect in the reaction of hot tritium with partially deuteriated methanes has been explained by Rowland and coworkers by postulating the existence of a very large secondary deuterium isotope effect which counterbalances the normal primary replacement isotope effect. 

In terms of nonequilibrium interaction conditions the lack of the intramolecular deuterium isotope effect in the hot tritium atoms reaction with partial deuteriated methane, implies that the greater chance of encounter between fast moving... 

A true intramolecular proton transfer in the second step of an azo coupling reaction was found by Snyckers and Zollinger (1970a, 1970b) in the reaction of the 8-(2 -pyridyl)-2-naphthoxide ion (with the transition state 12.151). This compound shows neither a kinetic deuterium isotope effect nor general base catalysis, in contrast to the sterically similar 8-phenyl-2-naphthoxide ion. Obviously the heterocyclic nitrogen atom is the proton acceptor. 

Measurements of the deuterium isotope effect for unsymmetrical di-Schiff bases fully confirmed the interrelation between proton transfer equilibria in both intramolecular hydrogen bonds.46... 

The intramolecular and intermolecular deuterium isotope effects in the cycloaddition of acrylonitrile to allene (equation 98) have been studied by Dolbier and Dai231,232. The intramolecular KIEs in the allene-acrylonitrile system were found to be 1.21 0.02 at 206°C and 1.14 0.02 at 225°C. A negligible intermolecular SKIE was found in the reaction of the mixture of tetradeuteriated and undeuteriated allene using a limited amount of acrylonitrile (ku/ku) = 1.04 0.05 at 190-210 °C for D0/D4 allene. An equilibrium deuterium IE of 0.92 0.01 was found at 280-287 5°C (15-45 h reaction time). 

The experimental design that can best meet the criterion of an observed deuterium isotope effect being equivalent to an intrinsic deuterium isotope effect is an intramolecular... 

To discern the ion-radical nature of reactions, the so-called intramolecular and intermolecular proton/deuterium isotope effects may be of use. Baciocchi et al. (2005) revealed ion-radical mechanism for A-demethylation of A,A-dimethylanilines, (CH3)2NAr, by phthalimide-A-oxyl radical (Scheme 4.14). In this reaction, ( e/ D)intra values were derived for reactivity of (CD3)(CH3)NAr, whereas ( H/ D)inter was referred for the reactivity of (CD3)2NAr. The values of (A e/ D)intra were found to be always different and higher than These results, although are incompat-... 

The kinetics of hydrolysis of N-salicylidene-2-aminothiazole (119 = HL) have been studied in aqueous 5% methanol in the presence and absence of Co11, Ni, Cu11 and Zn11.408 The solvent deuterium isotope effect on the rate of spontaneous and hydroxide-catalyzed hydrolysis of the Schiff-base anion (L ) is consistent with intramolecular catalysis by the phenoxide ion. Only... 

The overall mechanistic picture of these reactions is poorly understood, and it is conceivable that more than one pathway may be involved. It is generally considered that cycloheptatrienes are generated from an initially formed norcaradiene, as shown in Scheme 30. Equilibration between the cycloheptatriene and norcaradiene is quite facile and under acidic conditions the cycloheptatriene may readily rearrange to give a substitution product, presumably via a norcaradiene intermediate (Schemes 32 and 34). When alkylated products are directly formed from the intermolecular reaction of carbenoids with benzenes (Scheme 33 and equation 36) a norcaradiene considered as an intermediate alternatively, a mechanism may be related to an electrophilic substitution may be involved leading to a zwitterionic intermediate. A similar intermediate has been proposed143 in the intramolecular reactions of carbenoids with benzenes, which result in substitution products (equations 37-40). It has been reported,144 however, that a considerable kinetic deuterium isotope effect was observed in some of these systems. Unless the electrophilic attack is reversible, this would indicate that a C—H insertion mechanism is involved in the rate-determining step. 

Alpha- and beta-deuterium isotope effects in the MgX2 and methylaluminoxane promoted intramolecular olefin insertion of Cp2 TiCIR complexes... 

It must be remembered, furthermore, that the identification of the H-atom translocation mode is not equivalent to the identification of the reaction coordinate. We have attributed the absence of a deuterium isotope effect on the excited-state H-atom transfer (for the 10-ps component in hypericin and hypo-crellin A) to the zero-point energy in the proton coordinate lying above the barrier, with the H-atom being effectively delocalized between the two oxygen atoms. Consequently, the reaction coordinate for the excited-state H-atom transfer cannot be identified with the proton coordinate, and it must be concluded that other intramolecular motions are in fact responsible for the process. Temperature-dependent measurements indicate that these motions are extremely low amplitude, Ea 0.05 kcal/mol for hypericin [37]. Because the nature of this motion is not yet identified, we refer to it as the skeleton coordinate [48, 71, 82]. We propose that it is the time scale for this latter conformational change... 

Next reviews were dedicated to problems of hydrogen-bonded systems. Hydrogen/deuterium isotope effects on NMR parameters in liquids and solids have been reviewed by Limbach et al.11 Review covers period to 2004 and illustrates the correlation of intermolecular hydrogen-bonded systems geometry and H/D isotope shifts and coupling constants, particularly measured in the solid state and in liquids at low temperature. Several reviews concern the isotope effects on intramolecular hydrogen-bonded systems.12-17 Since that time several new papers dedicated to hydrogen-bonded systems were published, mostly on intramolecular systems.18-24... 

---