Modern Strategies in Electroorganic Synthesis

Yoshida, Junichi; Kataoka, K.; Horcajada, Roberto; Nagaki, Aiichiro

doi:10.1021/cr0680843

Cited by 1,284 publications

(510 citation statements)

References 418 publications

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“…While electrosynthesis has been extensively performed in batch mode, 8,9 continuous-flow technology provides increased electrode surface ratios by design. 9 Additionally, at the microfluidic scale the distance between the working electrode and the counter electrode is shortened. This can help overcome conversion limitations linked to solution resistivity, and even enable electrolyte-free reactions.…”

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confidence: 99%

Preparative Microfluidic Electrosynthesis of Drug Metabolites

Stalder

Roth

2013

ACS Med. Chem. Lett.

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In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. Electrochemistry can be used to simulate CYP450 oxidation, yet it is often confined to the analytical scale, hampering product isolation and full characterization. In an effort to replicate hepatic oxidations, while retaining high throughput at the preparative scale, microfluidic technology and electrochemistry are combined in this study by using a microfluidic electrochemical cell. Several commercial drugs were subjected to continuous-flow electrolysis. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. It is demonstrated that such metabolites can be synthesized by flow electrolysis at the 10 to 100 mg scale, and the purified products are fully characterized. KEYWORDS: Drug metabolites, electrochemistry, microfluidic synthesis, continuous-flow oxidation T he first step toward elimination of xenobiotic compounds in vivo occurs predominantly through first pass hepatic oxidation. In the liver, the oxidation takes place at the iron center of the porphyrin that constitutes the catalytic site of the CYP450 family of enzymes. 1,2 The oxidized metabolites (Phase I) may undergo subsequent transformations (Phase II) including, among others, conjugation with glutathione (GSH). This is of particular importance in the design of new drug candidates since their toxicity levels are regulated by such metabolic processes. 3,4 Significant research effort has been devoted to develop synthetic methodologies to simulate the metabolism of drugs. These methodologies fall into four distinct categories: microsomal incubation, porphyrin-catalyzed chemical oxidation, Fenton-type reactions, and electrochemical oxidations. 5,6 Electrosynthetic transformations offer the advantage of atom economy since the oxidation takes place at the surface of an electrode, which provides the electron from a current source. 7 These transformations are thus heterogeneous reactions by definition. To achieve high conversion, the substrate solution must be conductive, and the ratio of electrode surface-tosolution volume ought to be as high as possible. While electrosynthesis has been extensively performed in batch mode, 8,9 continuous-flow technology provides increased electrode surface ratios by design. 9 Additionally, at the microfluidic scale the distance between the working electrode and the counter electrode is shortened. This can help overcome conversion limitations linked to solution resistivity, and even enable electrolyte-free reactions. 10 In the past few years, the study of drug metabolites has benefited from the emergence of in-line electrochemical/mass spectrometry (EC-MS) systems used to generate phase I and phase II metabolites. 13,14 Unfortunately, full structure elucidation is limi...

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confidence: 99%

Preparative Microfluidic Electrosynthesis of Drug Metabolites

Stalder

Roth

2013

ACS Med. Chem. Lett.

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“…[63][64] The feasibility of a paired electrosynthesis of anthraquinone in a microband electrodes reactor, from the oxidation of anthracene and reduction of dioxygen ( Figure 4) has also been attained not long time ago, 65 opening new avenues in the area of electrolysis in microreactors. 17 …”

Section: Anthraquinonementioning

confidence: 99%

“…17,[210][211][212] The chloroalkali industry entered the 1960's somewhat content with relatively "low-tech" diaphragm cell improvements such as inert moulded plastic cell tops (instead of concrete), somewhat longer duration graphite anodes (about 6 months), and more energy efficient cells. By 1970, the industry awoke to noble metal catalysed titanium electrodes, so-called "dimensionally stable anodes", which could last for several years, could generate chlorine uncontaminated by halocarbons, and could provide impressive energy savings because they could operate at very low overpotential (i.e.…”

Section: A Summary Of Technological Advancesmentioning

confidence: 99%

“…Product quality is also important, and typically an electrochemical process originates products more pure than those synthesised by the chemical route. 17 Although, as strange as it may seem, in very special cases failure of an electrochemical process can occur precisely because the product is too pure when compared to the one obtained chemically. For example, certain anthraquinone dyes produced by chemical means contain coloured by-products in addition to the major product, and the mixture of a particular colour may have been accepted for decades by a very conservative industry.…”

Section: Introductionmentioning

confidence: 99%

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Electrochemical routes for industrial synthesis

Sequeira¹,

Santos²

2009

J. Braz. Chem. Soc.

118

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Esta revisão examina as razões que justificam um interesse crescente da indústria química pelos processos eletrolíticos. Reveem-se as indústrias químicas, nas quais compostos orgânicos e inorgânicos são processados e descrevem-se os avanços tecnológicos mais relevantes. Inicialmente, abordam-se processos bem estabelecidos, como as indústrias cloroalcalinas de produção de alumínio, p-aminofenol, adiponitrila, etileno glicol, antraquinona, produtos perfluorados, ácido glioxílico e L-cisteína. Face à grande quantidade de informação disponível, o assunto é tratado com base científica, mas de modo bastante simplificado. Posteriormente, descrevem-se processos orgânicos e inorgânicos emergentes, nomeadamente processos eletroquímicos mediados e síntese em líquidos iónicos. Estabelecem-se paralelos entre síntese química e síntese eletroquímica. Estimula-se o interesse nos processos de eletrossíntese, particularmente em líquidos iónicos, não desmerecendo a importância das vias puramente químicas de síntese orgânica e inorgânica.This review examines the reasons for increasing interest towards electrolyses by the chemical industry, reviews the electrochemical industries as most of them now exist, and provides a status report on the key technological advances which are occurring to meet present and future needs. Classical industries like those of chloroalkali, aluminium, p-aminophenol, adiponitrile, ethylene glycol, anthraquinone, perfluorinated products, glyoxylic acid and L-cysteine are initially covered. Considering the large amount of available publications in these topics of electrochemical engineering, the covered relevant information is treated at a scientific level, although in a simplified way. Then the paper deals with emerging inorganic and organic processes, e.g. electrosynthesis in ionic liquids and mediated electrochemical processes, and finishes by assessing what the future development trend might be given the electrochemical and non electrochemical competing influences. With this approach it is hoped to stimulate the interest of chemical engineers and scientists non-specialised in electrochemical routes, and to review some cutting edge research, particularly as far as electrosynthesis in ionic liquids is concerned.

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“…In contemporary electrochemical publications, such C-C couplings are still a minor subject 1 . Herein we reported an application of a new electrochemical cell which uses graphite powder in the cathode cavity combined with an aqueous anolyte [2][3][4] to promote the dimerization of benzyl halides in good yield.…”

Section: Introductionmentioning

confidence: 99%