AM1 calculations of bond dissociation energies. Allylic and benzylic C-H bonds

Хурсан, С. Л.; Михайлов, Д. А.; Yanborisov, V. M.; Борисов, Д. И.

doi:10.1007/bf02477518

Cited by 24 publications

(28 citation statements)

References 6 publications

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“…The bond dissociation energy, which is a good indicator of the radical energy (31), is estimated to be approximately 86.2 kcal/ mol for a benzyl radical with a p-methyl group (35), although the value would be affected slightly depending on the relative location of the alkyloxy group on the aromatic group of GEM-1-O-gluc (m-alkyloxy group relative to the benzyl radical would decrease the energy, but the effects of a o-alkyloxy group are less predictable). This estimated value is near the lower limit (88 ( 1 kcal/mol) that Worjciechowski and Ortiz de Montellano have identified as the minimal energy needed to react with a meso-carbon on compound II of horseradish peroxidase (31).…”

Section: Discussionmentioning

confidence: 99%

Benzylic Oxidation of Gemfibrozil-1-O-β-Glucuronide by P450 2C8 Leads to Heme Alkylation and Irreversible Inhibition

Baer

DeLisle

Allen

2009

Chem. Res. Toxicol.

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Gemfibrozil-1-O-beta-glucuronide (GEM-1-O-gluc), a major metabolite of the antihyperlipidemic drug gemfibrozil, is a mechanism-based inhibitor of P450 2C8 in vitro, and this irreversible inactivation may lead to clinical drug-drug interactions between gemfibrozil and other P450 2C8 substrates. In light of this in vitro finding and the observation that the glucuronide conjugate does not contain any obvious structural alerts, the current study was conducted to determine the potential site of GEM-1-O-gluc bioactivation and the subsequent mechanism of P450 2C8 inhibition (i.e., modification of apoprotein or heme). LC/MS analysis of a reaction mixture containing recombinant P450 2C8 and GEM-1-O-gluc revealed that the substrate was covalently linked to the heme prosthetic heme group during catalysis. A combination of mass spectrometry and deuterium isotope effects revealed that a benzylic carbon on the 2',5'-dimethylphenoxy group of GEM-1-O-gluc was covalently bound to the heme of P450 2C8. The regiospecificity of substrate addition to the heme group was not confirmed experimentally, but computational modeling experiments indicated that the gamma-meso position was the most likely site of modification. The metabolite profile, which consisted of two benzyl alcohol metabolites and a 4'-hydroxy-GEM-1-O-gluc metabolite, indicated that oxidation of GEM-1-O-gluc was limited to the 2',5'-dimethylphenoxy group. These results are consistent with an inactivation mechanism wherein GEM-1-O-gluc is oxidized to a benzyl radical intermediate, which evades oxygen rebound, and adds to the gamma-meso position of heme. Mechanism-based inhibition of P450 2C8 can be rationalized by the formation of the GEM-1-O-gluc-heme adduct and the consequential restriction of additional substrate access to the catalytic iron center.

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Section: Discussionmentioning

confidence: 99%

Benzylic Oxidation of Gemfibrozil-1-O-β-Glucuronide by P450 2C8 Leads to Heme Alkylation and Irreversible Inhibition

Baer

DeLisle

Allen

2009

Chem. Res. Toxicol.

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“…disclosed two additional examples of photoredox sulfur multicatalysis, in which both simple alkenes and alcohols were used as substrates for radical cross‐coupling with electron‐deficient (hetero)arenes 2 and 16 , respectively (Scheme ) . In the first of these investigations, the low BDE of allylic C(sp 3 )−H bonds (81–83 kcal mol −1 ) was harnessed for the allylic arylation of mono‐, di‐, and trisubstituted olefins 13 and compounds with similarly labile C−H bonds (Scheme A) . The conversion of these substrates was facilitated by 1 mol % of iridium catalyst 6 and 5 mol % of triisopropylsilanethiol (S‐cat.…”

Section: Functionalization Of Element–hydrogen Bondsmentioning

confidence: 99%

Light‐Driven Single‐Electron Transfer Processes as an Enabling Principle in Sulfur and Selenium Multicatalysis

Breder

Depken²

2019

Angew Chem Int Ed

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Cooperativity has become a mainstay in the context of multicatalytic reaction design. The combination of two or more catalysts that possess mechanistically distinct activation principles within a single chemical setting can enable bond constructions that would be impossible for any of the catalysts alone. An emerging subdomain within the field of multicatalysis is characterized by single‐electron transfer processes that are sustained by the synergistic merger of sulfur or selenium organocatalysis with photoredox catalysis. From a synthetic viewpoint, such processes have tremendous value, as they can offer new and economic pathways for the concise assembly of complex molecular architectures. Thus, the aim of this Review is to highlight recent methodological progress made in this area and to contextualize representative transformations with the mechanistic underpinnings that enable these reactions.

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“…16 (Schema 4) fungieren kçnnen. [27] In der ersten der beiden Studien nutzten die Autoren die niedrige BDE allylischer C(sp 3 ) À H-Bindungen (81-83 kcal mol À1 ) [28] fürdie allylische Arylierung von mono-, di-und trisubstituierten Olefinen 13 und Verbindungen mit ähnlich labilen CÀH-Bindungen (Schema 4a). [27a] Der Umsatz der Reaktionspartner konnte mithilfe von einem Mol-% des Iridium-Katalysators 6 und 5Mol-% an Tr iisopropylsilanthiol (S-Kat.…”

Section: Funktionalisierungen Von Element-wasserstoff-bindungenunclassified

Lichtgetriebene Ein‐Elektronen‐Transferprozesse als Funktionsprinzip in der Schwefel‐ und Selen‐Multikatalyse

Breder

Depken²

2019

Angewandte Chemie

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Das Prinzip der Kooperativität stellt inzwischen einen Grundpfeiler im Bereich der Multikatalyse dar. Durch die Kombination zweier oder mehrerer Katalysatoren mit mechanistisch unterschiedlichen Aktivierungsmodi, die gemeinsam chemische Prozesse vorantreiben, werden zuweilen Bindungsknüpfungen ermöglicht, zu denen keiner der beteiligten Katalysatoren einzeln imstande wäre. Ein stetig wachsender Teilbereich der Multikatalyse befasst sich mit lichtgetriebenen Ein‐Elektronen‐Transferprozessen, die durch die synergistische Verzahnung von Schwefel‐ oder Selenkatalysatoren mit Photoredoxkatalysatoren aufrechterhalten werden. Reaktionen, die auf diesem Funktionsprinzip beruhen, bergen ein enormes synthetisches Potential, da sie rasche und hoch ökonomische Zugangswege zu komplexen molekularen Strukturen ermöglichen können. Vor diesem Hintergrund ist das Ziel dieses Aufsatzes, jüngste methodische Entwicklungen auf diesem Gebiet näher zu beleuchten und anhand ausgewählter Beispielreaktionen einen allgemeinen Einblick in ihre mechanistischen Grundlagen zu vermitteln.

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AM1 calculations of bond dissociation energies. Allylic and benzylic C-H bonds

Abstract: AM1 method and correlation dependence between electronic relaxation energy and valence change on the C atom of the breaking bond were used to calculate the bond dissociation energies in 50 compounds with allylic or benzylic C-H bonds. The average calculation error is 0.8 keal/mol.

Cited by 24 publications

References 6 publications

Benzylic Oxidation of Gemfibrozil-1-O-β-Glucuronide by P450 2C8 Leads to Heme Alkylation and Irreversible Inhibition

Benzylic Oxidation of Gemfibrozil-1-O-β-Glucuronide by P450 2C8 Leads to Heme Alkylation and Irreversible Inhibition

Light‐Driven Single‐Electron Transfer Processes as an Enabling Principle in Sulfur and Selenium Multicatalysis

Lichtgetriebene Ein‐Elektronen‐Transferprozesse als Funktionsprinzip in der Schwefel‐ und Selen‐Multikatalyse

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