Oxidations of Amines. II. Substituent Effects in Chlorine Dioxide Oxidations

Rosenblatt, David H.; Hull, Larry A.; Luca, D. C. De; Davis, George T.; Weglein, R. C.; Williams, Howell

doi:10.1021/ja00981a022

Cited by 105 publications

(45 citation statements)

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“…These relationships are very similar to those reported for accepted 1-electron oxidation processes, e.g. oxidation of aromatic amines by diphenylpicrylhydrazyl (51) and the oxidation of benzyldimethylamines by ClO 2 (52).…”

Section: Kinetic Deuterium Isotope Effects In Nadph-supported P450supporting

confidence: 86%

Evidence for a 1-Electron Oxidation Mechanism in N-Dealkylation of N,N-Dialkylanilines by Cytochrome P450 2B1

Guengerich

Yun

Macdonald

1996

Journal of Biological Chemistry

158

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Many enzymes catalyze N-dealkylations of alkylamines, including cytochrome P450 (P450) and peroxidase enzymes. Peroxidases, exemplified by horseradish peroxidase (HRP), are generally accepted to catalyze N-dealkylations via 1-electron transfer processes. Several lines of evidence also support a 1-electron mechanism for many P450 reactions, although this view has been questioned in light of reported trends for kinetic hydrogen isotope effects for N-demethylation with a series of 4-substituted N,N-dimethylanilines. No continuous trend for an increase of isotope effects with the electronic parameters of para-substitution was seen for the P450 2B1-catalyzed reactions in this study. The larger value seen with the 4-nitro derivative is consistent with a shift in mechanism due to either a reversible electron transfer step preceding deprotonation or to a hydrogen atom abstraction mechanism. With HRP, the trend is to lower isotope effects with para electronwithdrawing substituents, due to an apparent shift in rate-limiting steps. Biomimetic model high-valent porphyrins showed reduction rates with variously 4-substituted N,N-dialkylanilines that were consistent with a positively charged intermediate; such relationships were not seen for anisole O-demethylation with P450 2B1. In contrast to the case with the NADPH-supported P450 reactions, high deuterium isotope effects (ϳ7) were seen in the N-dealkylations supported by the oxygen surrogate iodosylbenzene. With iodosylbenzene, colored aminium radicals were observed in the oxidations of aminopyrine, N,N-dimethyl-4-aminothioanisole, and 4-methoxy-N,N-dimethylaniline. With the latter compound, a substantial intermolecular deuterium isotope effect was observed for N-demethylation. In the N-dealkylation of N-ethyl,N-methylaniline by P450 2B1 (NADPH-supported), the ratio of N-demethylation to Ndeethylation was 16. Although it is probably possible for P450s to catalyze amine N-dealkylations via hydrogen atom abstraction when such a course is electronically or sterically favored, we interpret the evidence to favor a 1-electron pathway with N,N-dialkylamines with P450 2B1 as well as HRP and several biomimetic models.

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Section: Kinetic Deuterium Isotope Effects In Nadph-supported P450supporting

confidence: 86%

Evidence for a 1-Electron Oxidation Mechanism in N-Dealkylation of N,N-Dialkylanilines by Cytochrome P450 2B1

Guengerich

Yun

Macdonald

1996

Journal of Biological Chemistry

158

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“…Had the substituent interactions on the protonation and oxidation reactions been identical a Brsnsted slope of a = 1.CO would have been expected. It is possible that the deviation from unity may be a solvent effect; however it should also be noted that an a of the magnitude observed in this work has been reported for other reactions where iminium ions have been proposed as intermediates (25).…”

Section: Discussionsupporting

confidence: 68%

“…The former is a trisubstituted carbon- The same reasoning also explains why the oxidation of benzyldimethylamine, which is described in this paper, gave benzaldehyde as the primary product, and it is significant to note that the yield of benzaldehyde increased from 52 to 70-80% on going from benzyldipropylamine to benzyldimethylamine. ' These observations also point out a difference between this reaction and the oxidation of the corresponding compounds by chlorine dioxide (25). The latter reaction, which is apparently initiated by a free radical abstraction results in 'It should be noted that the small primary isotope effect observed for this reaction may also be partially as a consequence of the fact that benzyldimethylamine can undergo cleavage of either the N-benzyl or the N-methyl bonds.…”

Section: Discussionmentioning

confidence: 87%

The Oxidation of Benzyldimethylamine by Bromine

Lee¹,

Srinivasan²

1973

Can. J. Chem.

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The rates of oxidation of several substituted benzyldimethylamines by bromine in 50% aqueous acetic acid have been determined spectrophotometrically. Electron-withdrawing substituents decrease the rate of reaction with the Hammett p value being -0.95. The reaction is subject to general base catalysis and substitution of deuterium in the a-position decreases the rate of reaction by approximately 30%, thus indicating that the a-C-H bond is cleaved in the slow step of the reaction. All results are consistent with a mechanism which involves, in the rate determining step, loss of an a-hydrogen atom as a proton with concomitant transfer of electrons from nitrogen to the oxidant.

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“…11 and 12) is based on hydrogen abstraction Petryaev et al, 1984). Electron abstraction has been proved but only for tertiary amines (Dennis et al, 1967;Hull et al, 1967Hull et al, , 1969Rosenblatt et al, 1967). Fig.…”

Section: Oxidative Degradationmentioning

confidence: 99%