Intramolecular Kinetic Isotope Effects Research Articles

Highly Selective Benzylic CH Bond Activation of Toluene 1 by ‘Bare’ FeO+ in the Gas Phase. Short communication

AbstractThe reaction of FeO+ with toluene in the gas phase occurs at collision rate (kr = 1.36 × 10−9 cm3 molecule−1 s−1), and labeling experiments demonstrate that the total products due to CH bond activation involve to > 92% the benzylic position. In the ‘hydride’ abstraction process (formation of FeOH and C7H), the H‐atom originates elusively from the benzylic position to generate a benzyl cation, and an intramolecular kinetic isotope effect kH/kD = 1.75 has been obtained. There is no evidence for the existence of isotopically sensitive branching (‘metabolic switching’) in the system studied.

The microsomal demethylation of N, N-dimethylbenzamides : Substituent and kinetic deuterium isotope effects

The metabolism of N, N-dimethylbenzamides by phenobarbital-induced rat liver microsomes results in the formation of N-methylbenzamides and formaldehyde. The reaction proceeds via the formation of an intermediate N-hydroxymethyl- N-methylbenzamide, which, for the microsomal oxidation of N, N-dimethylbenzamide, was isolated and characterized. Confirmation of the N-hydroxymethyl- N-methylbenzamide was obtained by its independent synthesis from N-methylbenzamide and formaldehyde. The intermolecular kinetic deuterium isotope effects for the reaction are 0.9 (±0.1) for V max and 1.4 (±0.1) for V max/ K m . The intramolecular kinetic deuterium isotope effect, determined from the relative amounts of N-methylbenzamide and N-trideuteriomethylbenzamide formed in the microsomal demethylation of N-trideuteriomethyl- N-methylbenzamide, is 6.0 ± 0.3. There is no correlation of V max or V max/ K m with the substituent in the aromatic ring, nor with the calculated ionization potentials of the benzamides. The results are interpreted in terms of a mechanism in which the benzamide undergoes direct hydrogen atom abstraction to form a carbon centred radical. This carbon centred radical subsequently forms an N-hydroxymethyl- N-methylbenzamide that decomposes to formaldehyde and an N-methylbenzamide. Semi-empirical AMI self consistent field molecular orbital calculations identify that loss of a hydrogen atom from the E-methyl group is thermodynamically more favourable than from the Z-methyl group by ca. 5 kJ/mol.

On the mechanism of Fe +-mediated CH/CC bond activation as studied by intramolecular kinetic isotope effects

A detailed insight into the mechanistic aspects of the Fe +-mediated formation of molecular hydrogen and ethylene from 4-heptanone ( 1a) and its isomer 3-ethyl-2-pentanone ( 2a) is provided by determining the intramolecular kinetic isotope effects associated with several stages of these multi-step processes. The subtle differences observed in the metastable ion dissociation of the two complexes 1a-Fe + and 2a-Fe + point to changes in (i) the energy contents and (ii) the CH clouds seen by the (anchored) Fe +.

A combined theoretical and experimental approach to the unimolecular loss of molecular hydrogen from protonated formaldehyde: Determination of the average internal energy of metastable [CH2OH]+ ions

AbstractAb initio quantum chemical calculations (MP2/4–31G**) were performed for the dihydrogen elimination reaction from protonated formaldehyde. The energy difference between reactants and products and the activation energies were found to be in good agreement with the corresponding experimental quantities. Theoretical rate vs. energy curves were computed for a series of isotopic variants of the reaction using the Rice–Ramsperger–Kassel–Marcus (RRKM) method. The vibrational frequencies used in these calculations were taken from the 4–31G** geometry‐optimized transition state and reactant structures. Quantum mechanical tunnelling was introduced to explain the existence of metastable CH2OH ions, and a negative kinetic shift of about 0.1 eV was found. The intramolecular kinetic isotope effect for loss of HH/HD and DH/DD was calculated and compared with the experimental data. The result is consistent with the assumption that the average internal energy of metastable [CH2OH]+ ions is very close to the critical energy for H2 loss.

Mechanism of the microsomal demethylation of 1-aryl-3,3-dimethyltriazenes

The metabolism of 1-aryl-3,3-dimethyltriazenes by phenobarbital-induced rat liver microsomes results in the formation of 1-aryl-3-methyltriazenes and formaldehyde. Intermolecular kinetic deuterium isotope effects for the reaction are found to be 1.0 (±0.03) in both V max and V max/ K m respectively. The intramolecular kinetic deuterium isotope effects in V max and V max/ K m are found to be 4.8 (±0.05). There is no correlation of V max or V max/ K m with calculated ionization potentials of the triazenes. For 3-ethyl-3-methyltriazene comparison of values of V max and V max/ K m for ethyl VS methyl loss give rise to values of 3.68 in V max and 2.02 in V max/ K m . Thus, loss of an ethyl group is favoured. The results are discussed in terms of a mechanism in which the triazene undergoes direct hydrogen atom abstraction to form a carbon centred radical. This radical subsequently forms a hydroxymethyltriazene that collapses to formaldehyde and a monomethyltriazene.

Kinetic deuterium isotope effects on the N-demethylation of tertiary amides by cytochrome P-450.

Liver microsomal cytochrome P-450 readily N-dealkylates N,N-dimethylamides. N-Methyl-N-hydroxymethyl amides were isolated as intermediates and characterized by gas chromatography-mass spectrometry as their trimethylsilyl ethers. Intramolecular kinetic deuterium isotope effects measured for the enzymic N-demethylation of a series of 12 aromatic and aliphatic N-methyl-N-trideuteriomethyl amides, RCON(CH3)CD3, varied from 3.6 to 6.9 but were independent of both amide bond rotation rate and substrate oxidation potential. These values, which represent a lower limit to the intrinsic isotope effect (Dkintrinsic), are significantly larger than those observed for anodic N-demethylation and are consistent with a mechanism involving hydrogen atom abstraction. On the other hand, with N,N-dimethylbenzamide the intermolecular kinetic deuterium isotope effects on Vmax and Vmax/Km were found to be much smaller (1.23 and 1.75, respectively) indicating substantial suppression of the intrinsic isotope effect. Such suppression indicates the occurrence of a rate-limiting step other than the isotopically sensitive step together with a strong commitment to catalysis.

The intramolecular kinetic isotope effect for the reaction O(3P)+HD

The branching ratio for the reaction O(3P)+HD to produce OH and OD was measured over the temperature range 339–500 K using a discharge-flow reactor. The OH and OD products were detected using laser-induced fluorescence under steady-state conditions. In order to determine the relative concentrations of OH and OD produced in this reaction, calibration runs were performed using the reactions of O(3P)+H2 and D2 to produce known relative amounts of the same species. Kinetic modeling showed that secondary reactions and the production of vibrationally excited OD did not affect the measured branching ratio. We found that the OH/OD ratio increased rapidly with decreasing temperature, in qualitative agreement with theory, showing that the reaction is dominated by tunneling below 400 K. At the lowest temperatures, the observed branching ratio is larger than predicted. The reason for this discrepancy is not known.

Semiclassical and Quantum Mechanical Calculations of Isotopic Kinetic Branching Ratios for the Reactionof O(3P) with HD

Tunneling probabilities for the reactions O + HD → OH + D and O + DH → OD + H have been calculated by semiclassical dynamical methods and compared to accurate quantal calculations for the same potential energy surface. The results are used to test the reliability of variational transition state theory with the least-action semiclassical method for tunneling probabilities for the prediction of intramolecular kinetic isotope effects.

Carbon-hydrogen oxidative addition and reductive elimination reactions in a dinuclear iridium complex

Thermolysis of the hydridoallyliridium complex ({eta}{sup 5}-C{sub 5}Me{sub 5})({eta}{sup 3}-C{sub 3}H{sub 5})(H)Ir at relatively high concentrations of starting material in benzene leads to the dinuclear benzene C-H oxidative addition product ({eta}{sup 5}-C{sub 5}Me{sub 5})(C{sub 6}H{sub 5})Ir({eta}{sup 1},{eta}{sup 3}-C{sub 3}H{sub 4})({mu}-H)-Ir({eta}{sup 5}-C{sub 5}Me{sub 5}) (1). Heating this material causes reductive elimination of benzene from the dinuclear complex 1 in a clean first-order process. The lack of dependence of the rate of this process on the concentration of entering ligand demonstrates than an intermediate is formed in the reductive elimination; this species is proposed to be the coordinatively unsaturated dinuclear complex ({eta}{sup 5}-C{sub 5}Me{sub 5})Ir({eta}{sup 1},{eta}{sup 3}-C{sub 3}H{sub 4})Ir({eta}{sup 5}-C{sub 5}Me{sub 5}) (13). Transient intermediate 13 reacts with dative ligands such as phosphines, ethylene, and tert-butyl isocyanide to give direct trapping products ({eta}{sup 5}-C{sub 5}Me{sub 5})(L)Ir({eta}{sup 1},{eta}{sup 3}-C{sub 3}H{sub 4})Ir({eta}{sup 5}-C{sub 5}Me{sub 5}) (2-6), formed by coordination of the ligand to one of the iridium centers. Reaction of 13 with reagents having activated X-H bonds, such as benzene-d{sub 6}, H{sub 2}, and acetonitrile, leads to intermolecular oxidative addition products having structures analogous to that of 1. Comparative inter- and intramolecular kinetic isotope effect studies have provided evidence that in the reversible reactionmore » of 13 with benzene, an additional {eta}{sup 2}-arene intermediate is not required to explain the results. Thermolysis of 2 and 4, the PMe{sub 3{sup {minus}}} and ethylene-trapped products of 13, leads to three new dinuclear complexes (7, 8, and 9). These materials are formed by intramolecular insertion into the dative ligand C-H bonds, followed by rearrangement. 30 refs., 6 figs., 2 tabs.« less

Laser measurements of the unimolecular kinetics of energy-selected molecular ions: Isotope effects in benzene

Metastable ion decay rates for isotope decay channels differing only by one mass unit have been measured in a reflectron mass spectrometer with high mass resolution. Several decay channels with H, H2, C2H2, and C3H3 (and their isotopic analogs) elimination from C6H+6, C6D+6, and C6D5H+ are investigated. We present examples of intermolecular and for the first time of intramolecular kinetic isotope effects for internal energy selected reactants. The reaction coordinate for the decay channels can be characterized as C–H or alternatively as C–C stretching vibrations and the total looseness of the activated complex with respect to the remaining 3N−7 vibrations can be attributed to the subsets of the C–H and C–C vibrations. Furthermore, from the good agreement of RRKM calculations and all inter- and intramolecular isotopic results for a given decay channel it is concluded that C–H vibration participate in the random energy flow before dissociation.

Intramolecular deuterium isotope effect and enantiotopic differentiation in oxidative demethylation of chiral [monomethyl- D 3]methoxychlor in rat liver microsomes

Intramolecular deuterium kinetic isotope effects on the O-demethylation of methoxychlor [2,2-bis-(4-methoxyphenyl)-1,1,1-trichloroethane] were measured in liver microsomes taken from rats treated with phenobarbital or β-naphthoflavone and from untreated rats. The substrates were ( R)-, ( S)- and racemic [monomethyl-d 3]methoxychlor, and the ratio of [d 3]- to [d 0]-mono-O-demethylated metabolites was measured by GC-MS selected-ion monitoring. The magnitude of the observed ratio of [d 3]- to [d 0]-metabolites in each microsomal preparation was largest on the reaction of the ( S)- substrate, followed by racemic substrate, and then ( R). Each value is a composite of the intramolecular kinetic isotope effect and enantiotopic differentiation during the reaction. Each intramolecular isotope effect value estimated from these values was smaller than the reported intrinsic value. A relatively slow intramolecular interchange of two methoxyl groups in the methoxychlor molecule in the enzyme-substrate complex was indicated during the reaction. There also was evidence of high enantiotopic differentiation.

Evidence for tunneling in the reaction O( 3P)+HD

The intramolecular kinetic isotope effect was determined for the title reaction by measuring laser-induced fluorescence from OH and OD in a discharge-flow apparatus. The OH/OD branching ratio was found to have a strong negative temperature dependence, showing that tunneling dominates the reaction at low temperatures. An apparent deviation from tunneling-corrected transition state theory calculations at low temperatures remains to be explained.

ChemInform Abstract: Ene Reaction Mechanisms. Part 3. Intermolecular and Intramolecular Kinetic Isotope Effects (KIE) for Some Ene Reactions of Hetero Enophiles.

Chemischer InformationsdienstVolume 17, Issue 25 Preparative Organic Chemistry ChemInform Abstract: Ene Reaction Mechanisms. Part 3. Intermolecular and Intramolecular Kinetic Isotope Effects (KIE) for Some Ene Reactions of Hetero Enophiles. W. STARFLINGER, W. STARFLINGERSearch for more papers by this authorG. KRESZE, G. KRESZESearch for more papers by this authorK. HUSS, K. HUSSSearch for more papers by this author W. STARFLINGER, W. STARFLINGERSearch for more papers by this authorG. KRESZE, G. KRESZESearch for more papers by this authorK. HUSS, K. HUSSSearch for more papers by this author First published: June 24, 1986 https://doi.org/10.1002/chin.198625093AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume17, Issue25June 24, 1986 RelatedInformation

ChemInform Abstract: The Mechanism of Lewis Acid Catalyzed Ene Reactions.

AbstractIntermo1ecular[with (V) and (VI)] and intramolecular kinetic isotope effects [with (I), (VII), and (VIII)] establish that the Lewis acid catalyzed ene reactions of formaldehyde (II) [e.g.

Ene reaction mechanisms. 3. Intermolecular and intramolecular kinetic isotope effects (KIE) for some ene reactions of hetero enophiles

Ene reaction mechanisms. 3. Intermolecular and intramolecular kinetic isotope effects (KIE) for some ene reactions of hetero enophiles

Variational transition state theory calculations of the reaction rates of F with H2, D2, and HD and the intermolecular and intramolecular kinetic isotope effects

We use variational transition state theory to calculate rate constants and kinetic isotope effects for the reactions F+H2→HF+H (with rate constant k1), F+D2→DF+D(k2), and two other isotopic analogs as functions of temperature. The calculations are performed using a recently proposed partly empirical, partly ab initio potential energy surface, called surface No. 5, and also using a new surface, called surface No. 5A, introduced here to test the effect of a higher classical saddle point on the reaction rates, kinetic isotope effects, and reaction thresholds. The various theoretical results are compared to the available experiments to test the validity of these potential energy surfaces. For those rate constants and kinetic isotope effects for which there is more than one experimental value at a given temperature, the theoretical results for reactions on surface No. 5 agree with experiment about as well as the individual experiments agree with each other. At T>373 K where there is only one experimental measurement for k1 and k2, the theoretical rate constants for surface No. 5 are up to 44% lower than experiment, and at T<190 K where there is only one experimental measurement of k1/k2, the theoretical rate constant ratio is as much as 43% low. These discrepancies could be due to experimental error or they could indicate that the theoretical activation energy is low, but by no more than 0.5 kcal/mol, which is considerably less than the 2.5 kcal/mol discrepancy from the most recently published large-scale calculation. If, however, the potential energy surface were adjusted to raise the activation energy by even 0.5 kcal/mol above the value for surface No. 5, the threshold energies would no longer be in such good agreement with experiment, and several other aspects of the results presented here would be in much worse agreement with experiment. Taken as a whole then, we interpret the present calculations as providing further confirmation of the methods used to obtain surface No. 5. With this interpretation, the most important implication about the experiments is that Persky’s low-temperature measurements of k1/k2, especially those for T≤200 K, are systematically high.

Mechanisms of Enzymatic S-Oxygenation of Thioanisole Derivatives and O-Demethylation of Anisole Derivatives Promoted by Both Microsomes and a Reconstituted System with Purified Cytochrome P-450

Abstract Oxygenations of thioanisole derivatives have been shown to be promoted with phenobarbital induced rabbit liver microsomes. In order to understand the mechanistic details of the oxygenations, a kinetic study on the S-oxygenation promoted by a reconstituted system with purified cytochrome P-450 has been carried out. Log(Vmax) were correlated with the one electron oxidation potentials of the sulfides (Ep). The oxygenation is considered to proceed via one electron transfer from the sulfides to the iron-bound “oxenoid” intermediate of the enzyme. A similar O-demethylation of anisoles has been investigated. In the oxidative O-demethylation of p-methoxy-d3-anisole with rabbit liver microsomes, an intramolecular kinetic isotope effect of 3.4 was observed. Meanwhile, a large isotope effect of 5.1 was observed in the competitive O-demethylation of p-dimethoxybenzene and p-di(methoxy-d3) benzene. In order to clarify the oxidation pathway of O-demethylation with the enzymatic system of cytochrome P-450, the rates of the O-demethylation of p-substituted anisoles have been measured. Unlike the enzymatic oxygenation of sulfides, there was no correlation between the rates of O-demethylation reaction and one electron oxidation potentials of anisoles. These observations suggest that the O-demethylation of anisoles proceeds via the initial hydrogen abstraction with the iron-bound “oxenoid” intermediate of the cytochrome P-450.

Variational transition state theory and vibrationally adiabatic transmission coefficients for kinetic isotope effects in the Cl–H–H reaction system

Variational transition state theory and semiclassical adiabatic ground-state transmission coefficients are applied to calculate the kinetic isotope effects for D and T substitution in the reaction Cl+H2 at 245–445 K. The calculated isotope effects differ significantly from those calculated previously using conventional transition state theory and semiempirical potential energy surfaces. We use variational transition state theory and conventional transition state theory with the Wigner tunneling correction to adjust three new semiempirical surfaces to the experimental data. No one set of calculations is completely successful. The potential energy surfaces that are most successful at predicting the HD/DH intramolecular kinetic isotope effect have the earliest saddle points (the saddle points are collinear with R‡Cl–H=2.64–2.78a0, R‡H–H=1.88–1.72a0). For each surface studied except one, the canonical variational transition states are located past the saddle point for some of the isotopic reactions and earlier than the saddle point for others. The exceptional surface is the one of Valencich and co-workers; that surface has an early saddle point, but the variational transition states are always earlier than the saddle point.

Aromatic sulphonation. Part 75. Intramolecular kinetic isotope effects of hydrogen in the aprotic sulphonation of 1,2,4,5-tetramethylbenzene, naphthalene, and 1,6-methano[10]annulene. Implications for the mechanism of the sulphur trioxide sulphonation

The intramolecular substrate kinetic isotope effects of hydrogen for the sulphonation of 1,2,4,5-tetramethyl[3-2H]benzene and [1,4-2H2]naphthalene with sulphur trioxide in nitromethane as solvent at 0 °C have been determined as kH/kD= 5.6 ± 0.6 and 1.8 ± 0.1, respectively. With trichlorofluoromethane as solvent at –25 °C the intramolecular isotope effects for these two substrates are 3.1 ± 0.3 and 2.0 ± 0.1 respectively. For the sulphonation of 1,6-methano[2,7-2H2][10]annulene in dioxan at 12 °C kH/kD= 3.8 ± 0.3. The observed primary kinetic isotope effects are discussed in terms of the previously established σ,σ-mechanism for aromatic sulphonation with sulphur trioxide in aprotic solvents. They are ascribed to steric hindrance accompanying the intramolecular proton shift of the 1-arenium-1-pyrosulphonate σ-complex, yielding the arenepyrosulphonic acid. For trichlorofluoromethane as solvent the occurrence of an ‘encounter complex’ is discussed.

Intramolecular kinetic isotope effect in gas-phase proton-transfer reactions

The k/sub H//k/sub D/ isotope effects were determined by ICR for the reaction of substituted toluenes with several alkoxides. The results showed a definite trend for k/sub H//k/sub D/ starting as a normal isotope effect for appreciably exothermic reaction (> 3 kcal mol/sup -1/) and proceeding smoothly toward an inverse isotope effect as the reaction approached thermoneutrality or becomes endothermic. These observations were explained by a reaction which involved a double minima potential with a central energy barrier.