Kinetics and Equilibrium Constants for Reactions of α-Phenyl-Substituted Cyclopropylcarbinyl Radicals

Halgren, Thomas A.; Roberts, John D.; Horner, John H.; Martinez, Felix N.; Tronche, Christopher; Newcomb, Martin

doi:10.1021/ja991114h

Cited by 76 publications

(72 citation statements)

References 39 publications

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“…This is an agreement with what Newcomb et al [32,33] reported that cyclopropylcarbinyl phenyl radical rearranges much slower than cyclopropylcarbinyl radical that has been utilized as radical clock [34] (Scheme 6). Thus, it is reasonable that ketyl radical 7 decays by reacting with solvent rather than undergoing ring opening rearrangement of its cyclopropyl moiety.…”

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confidence: 90%

Photolysis of acetophenone derivatives with α‐cyclopropyl substituents

Ranaweera

Weragoda

Bain

et al. 2014

J of Physical Organic Chem

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Laser flash photolysis of cyclopropyl(phenyl)methanone 6 in argon-saturated methanol yields the triplet ketone (T 1K ) of 6 that is formed with a rate constant of~1.7 × 10 7 s À1 (λ max = 360 nm) and has a lifetime of~1.4 μs. T 1K of 6 decays to form ketyl radical 7 (λ max~3 00 nm), which dimerizes to form photoproducts, pinacol derivatives 8 and 9. In comparison, photolysis of trans-phenyl(2-phenylcyclopropyl)methanone 1 in argon-saturated chloroform-d results in cis-phenyl (2-phenylcyclopropyl)methanone 2 and a smaller amount of 3, presumably through 1,3-biradical 11. Nanosecond laser flash photolysis of 1 does not reveal significant transient absorption, although the T 1K of 1 is detected with phosphorescence at 77 K. Density functional theory calculations were used to elucidate the triplet reactivity of 1, 2 and 6 by comparing the feasibility of H atom abstraction, cyclopropyl cleavage and β-quenching of their triplet ketones.

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supporting

confidence: 90%

Photolysis of acetophenone derivatives with α‐cyclopropyl substituents

Ranaweera

Weragoda

Bain

et al. 2014

J of Physical Organic Chem

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“…Assuming that log A = 13.1 (Δ S ‡ = 0), we calculated the activation energy E a for each reaction. Bond dissociation energies (BDEs) are from a compendium of values52 and approximations for the C–H BDEs of the methyl group in methylcyclopropane,53 of the methyl groups in trimethylamine,54 and of the benzylic bonds in benzyl alcohol 38. Note that benzphetamine contains various C–H bonds, but the product of the P450 Compound I reaction is from hydroxylation of a methyl group adjacent to a tertiary amine 27.…”

Section: Resultsmentioning

confidence: 99%

Quantitative Production of Compound I from a Cytochrome P450 Enzyme at Low Temperatures. Kinetics, Activation Parameters, and Kinetic Isotope Effects for Oxidation of Benzyl Alcohol

et al. 2009

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Cytochrome P450 enzymes are commonly thought to oxidize substrates via an iron(IV)-oxo porphyrin radical cation transient termed Compound I, but kinetic studies of P450 Compounds I are essentially non-existent. We report production of Compound I from cytochrome P450 119 (CYP119) in high conversion from the corresponding Compound II species at low temperatures in buffer mixtures containing 50% glycerol by photolysis with 365 nm light from a pulsed lamp. Compound I was studied as a reagent in oxidations of benzyl alcohol and its benzylic mono-and dideuterio isotopomers. Pseudo-first-order rate constants obtained at −50 °C with concentrations of substrates between 1.0 and 6.0 mM displayed saturation kinetics that gave binding constants for the substrate in the Compound I species (K bind ) and first-order rate constants for the oxidation reactions (k ox ). Representative results are K bind = 214 M −1 and k ox = 0.48 s −1 for oxidation of benzyl alcohol. For the dideuterated substrate C 6 H 5 CD 2 OH, kinetics were studied between −50 °C and −25 °C, and a van't Hoff plot for complexation and an Arrhenius plot for the oxidation reaction were constructed. The H/D kinetic isotope effects (KIEs) at −50 °C were resolved into a large primary KIE (P = 11.9) and a small, inverse secondary KIE (S = 0.96). Comparison of values extrapolated to 22 °C of both the rate constant for oxidation of C 6 H 5 CD 2 OH and the KIE for the non-deuterated and dideuterated substrates to values obtained previously in laser flash photolysis experiments suggested that tunneling could be a significant component of the total rate constant at −50 °C. Cytochrome P450 enzymes (P450s or CYPs) are heme-containing enzymes that are widely distributed in nature and catalyze a wide range of reactions including numerous oxidations. 1,2 In humans, P450s are the major oxidants of drugs, pro-drugs, and xenobiotics, [3][4][5] generating great interest from the pharmaceutical perspective in regard to toxicology and drug dosing. P450s also are of medicinal interest due to the relationships of P450 over-expression with cancer and other disease states. [6][7][8] The active oxidizing forms of P450 enzymes have not been detected under turnover conditions, but they are widely believed to be iron(IV)-oxo species with the porphyrin oxidized to a radical cation. 1,9 Such species, termed Compounds I, are analogous to known intermediates formed in other heme-containing enzymes, such as peroxidases and catalases, upon reaction of the enzymes with hydrogen peroxide. 10 Unlike peroxidases and catalases, P450s typically are activated by a sequence of reactions comprised of reduction of the enzyme to the ferrous state, oxygen binding, a second-reduction step, and protonation steps. Nonetheless, activations of men@uic.edu. a Current address: School of Pharmacy, Luzhou Medical College, Luzhou, Sichuan, China, 646000 Supporting Information Available: Detailed kinetic results, NMR spectra of BA-d 1 and BA-d 2 , mass spectra for BA isotopomers. This material is available fre...

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“…Substrate relative reactivities can be anticipated from homolytic bond dissociation energies (BDEs). The BDE of a C-H bond in an N -methyl group is smaller than that of a C-H bond in a cyclopropylmethyl group, which is smaller than the BDE of an alkyl C-H bond (39,40). Thus, the rate constants for CYP119 Compound I oxidations are consistent with BDEs.…”

Section: Discussionmentioning

confidence: 95%

Kinetic Isotope Effects in Hydroxylation Reactions Effected by Cytochrome P450 Compounds I Implicate Multiple Electrophilic Oxidants for P450-Catalyzed Oxidations

et al. 2009

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Kinetic isotope effects were measured for oxidations of (S,S)-2-(p-trifluoromethylphenyl) cyclopropylmethane containing zero, two, and three deuterium atoms on the methyl group by Compounds I from the cytochrome P450 enzymes CYP119 and CYP2B4 at 22 °C. The oxidations displayed saturation kinetics, which permitted solution of both binding constants (K bind ) and firstorder oxidation rate constants (k ox ) for both enzymes with the three substrates. The binding constant for CYP2B4 Compound I was about one order of magnitude greater than that for CYP119 Compound I, but the oxidation rate constants were similar for the two. In oxidations of 1-d 0 , k ox = 10.4 s −1 for CYP119 Compound I, and k ox = 12.4 s −1 for CYP2B4 Compound I. Primary kinetic isotope effects (P) and secondary kinetic isotope effects (S) were obtained from the results with the three isotopomers. The primary KIEs were large, P = 9.8 and P = 8.9 for CYP119 and CYP2B4 Compounds I, respectively, and the secondary KIEs were small and normal, S = 1.07 and S = 1.05, respectively. Large intermolecular KIEs for 1-d 0 and 1-d 3 of k H /k D = 11.2 and 9.8 found for the two Compounds I contrast with small intermolecular KIEs obtained previously for the same substrate in P450-catalyzed oxidations; these differences suggest that a second electrophilic oxidant, presumably ironcomplexed hydrogen peroxide, is important in cytochromes P450 oxidations under turnover conditions. The ubiquitous cytochrome P450 enzymes (P450s or CYPs) 1 are heme-containing enzymes that catalyze a wide range of oxidation reactions in nature including hydroxylations of high energy C-H bonds to give alcohol products (1). In humans, P450s catalyze both highly specific oxidation reactions such as oxidations of androgens to estrogens, and broad spectrum oxidations of drugs, pro-drugs, and other xenobiotics in the liver (2). In addition, overexpression of P450s is related to disease states in humans including cancer and liver disease. Thus, the details of the reactions of P450s are of considerable interest from pharmacological and medical perspectives.Detection and study of the active oxidants in P450 enzymes have been the objectives of much research in the four decades since the first reports of P450s. In heme-containing enzymes †

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Kinetics and Equilibrium Constants for Reactions of α-Phenyl-Substituted Cyclopropylcarbinyl Radicals

Cited by 76 publications

References 39 publications

Photolysis of acetophenone derivatives with α‐cyclopropyl substituents

Photolysis of acetophenone derivatives with α‐cyclopropyl substituents

Quantitative Production of Compound I from a Cytochrome P450 Enzyme at Low Temperatures. Kinetics, Activation Parameters, and Kinetic Isotope Effects for Oxidation of Benzyl Alcohol

Kinetic Isotope Effects in Hydroxylation Reactions Effected by Cytochrome P450 Compounds I Implicate Multiple Electrophilic Oxidants for P450-Catalyzed Oxidations

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