| License: Publishing license for publications including print on demand PDF - Accepted Version (39MB) |
- URN to cite this document:
- urn:nbn:de:bvb:355-epub-337422
- DOI to cite this document:
- 10.5283/epub.33742
| Item type: | Thesis of the University of Regensburg (PhD) |
|---|---|
| Number of Pages: | 190 |
| Date: | 10 May 2017 |
| Referee: | Prof. Dr. Robert Wolf and Prof. Dr. Burkhard König |
| Date of exam: | 2 May 2016 |
| Institutions: | Chemistry and Pharmacy > Institut für Anorganische Chemie Chemistry and Pharmacy > Institut für Anorganische Chemie > Arbeitskreis Prof. Dr. Robert Wolf |
| Keywords: | flavin, oxygenation, oxidation, alkylbenzenes, non-heme iron complexes, scandium, photocatalysis, aerobic oxidations |
| Dewey Decimal Classification: | 500 Science > 540 Chemistry & allied sciences |
| Status: | Published |
| Refereed: | Yes, this version has been refereed |
| Created at the University of Regensburg: | Yes |
| Item ID: | 33742 |
Abstract (English)
Chapter 1. Photocatalytic C−H Bond Oxygenation In the first chapter of this thesis, recent developments in photocatalytic C−H bond oxy-genation reactions are reviewed. Inspired by Nature, metal porphyrin and porphyrinoid catalysts have been designed to achieve the elusive goal of selective oxygenation reactions with dioxygen as oxidant. The visible-light-driven generation of distinct high-valent ...
Abstract (English)
Chapter 1. Photocatalytic C−H Bond Oxygenation
In the first chapter of this thesis, recent developments in photocatalytic C−H bond oxy-genation reactions are reviewed. Inspired by Nature, metal porphyrin and porphyrinoid catalysts have been designed to achieve the elusive goal of selective oxygenation reactions with dioxygen as oxidant. The visible-light-driven generation of distinct high-valent oxo-species is believed to be the key to trigger selective oxygenation reactions. Furthermore, [Ru(bpy)3]2+ and organic dyes such as methylene blue, eosin Y, and riboflavin tetraacetate were also applied in selected reactions. Over the last years, the development of acridinium-derived catalysts significantly improved the scope of oxygenation reactions. Interestingly, the combination of [Ru(bpy)3]2+ photocatalysis with transition metal porphyrins gave new insights into the oxygenation of substrates with water as oxygen source inspired by photosystem II. This oxidative activation of water led to the de-velopment of covalently linked dyads consisting of a light-harvesting chromophore and an oxygenation catalyst.
Chapter 2: Photocatalytic Benzylic C−H Bond Oxidation with a Flavin Scandium Com-plex[1]
One aim of this thesis was to expand the scope of visible-light-driven C−H bond oxy-genation reactions with the purely organic, cheap and non-toxic chromophore riboflavin tetraacetate (RFT). This dye effectively catalyzes the aerobic photooxidation of benzyl alcohols, benzyl amines, and sulfoxides,[i] but has severe limits for the challenging oxy-genation of alkylbenzenes to the corresponding aldehydes. The oxidation of only very few selected electron-rich substrates was achieved purely with RFT, because the reduction potential of photoexcited, 3RFT*, is too low to trigger an electron transfer from substrates with higher oxidation potentials to 3RFT*. An efficient electron transfer from the substrate to 3RFT* is the key prerequisite for photocatalytic activity.
Building on pioneering work by Fukuzumi,[ii] who found that the reduction potential of RFT can be increased by metal ion coordination, we developed a photocatalytic Sc(OTf)3/RFT system (RFTH+-2Sc3+, Scheme 1) which effectively catalyzes the aerobic oxidation of alkylbenzenes and electron-deficient benzyl alcohols under acidic conditions. The coordination of the Lewis-acidic scandium(III) ions enables an efficient electron transfer from the substrate to a photoexcited RFTH+-2Sc3+ complex (step i), which is not feasible in the absence of Sc3+ ions. The formed benzyl radical cation is trapped by dioxygen and subsequently yields the desired oxygenated product (step ii). The catalyst
is regenerated in air under concomitant formation of H2O2 as the sole by-product
(step iii). For example, toluene is converted to benzaldehyde in 71% yield. Benzyl ethers do not give the corresponding esters, but form benzaldehydes. Diarylmethylene deriva-tives and benzyl alcohols are oxidized with good to excellent yields as well. An explora-tion of the effect of redox-active metal ions on the catalytic performance of RFT is the subject of the next chapter.
Chapter 3: C–H Photooxygenation of Alkylbenzenes Catalyzed by Riboflavin Tetraacetate and a Non-Heme Iron Catalyst[2]
As shown in chapter 2, the additive Sc(OTf)3 enables the oxygenation of alkylbenzenes with electron-withdrawing substituents, but this Sc(OTf)3/RFT system still performs poorly for various other benzylic substrates. We became aware that the formation of hydrogen peroxide as a by-product is a major drawback of RFT-catalyzed oxygenations of benzylic substrates. This is exemplified by the oxygenation of 4-ethylanisole
(1, Scheme 2, step i) established by König and co-workers which produces one equivalent of H2O2 per substrate molecule consumed. Unfortunately, H2O2 degrades RFT under irradiation quite rapidly. As a result, 4-acetylanisole (2) and 4-methoxy-α-methylbenzyl alcohol (3) are obtained as a product mixture in poor yields due to rapid photocatalyst bleaching. Feringa reported that bioinspired iron complexes with tetra- and pentadentate nitrogen ligands catalyze the oxidation of 1 using H2O2 as an oxidant (step ii), albeit with low yields and selectivities.[iii] Moreover, the ability of such iron complexes to catalyze H2O2 disproportionation (step iii) is well-known. Lower H2O2 concentrations could enable a higher photostability of RFT, allowing the flavin-mediated oxidation of the benzyl alcohol 3 to the ketone 2 (step iv) to proceed.
We discovered that the combination of the RFT with the bioinspired complex [Fe(TPA)(MeCN)2](ClO4)2 (4, TPA = tris(2-pyridylmethyl)amine, Scheme 2) affords a
readily accessible, cheap, and efficient catalyst for the visible-light-driven aerobic C‒H bond oxidation of various alkylbenzenes. Contrary to the Sc(OTf)3/RFT system, the re-duction potential of RFT is not altered by the iron complex. Instead, the reactivity of the iron complex with photocatalytically generated H2O2 is key to ensure high conversions and selectivities. Co-catalyst 4 acts as a H2O2 disproportionation catalyst and an oxygen-ation catalyst at the same time. Different to the complementary enzyme-based photobio-catalytic tandem catalyst reported by Hollmann et al.,[iv] the present system uses a transi-tion metal co-catalyst; a sacrificial electron donor is not required.
Chapter 4: Aerobic Photooxidation of Cycloalkenes Catalyzed by Riboflavin Tetraacetate and a Non-Heme Iron Complex[3]
In chapters 2 and 3, we reported the photooxygenation of a variety of benzylic substrates. In pursuit of our aim of expanding the scope of the flavin-mediated oxygenation reac-tions, we investigated the oxygenation of cycloalkenes. In this case, we exploited the ability of RFT to mediate energy transfer reactions and sensitize singlet oxygen. This in contrast to the Sc(OTf)3/RFT- and non-heme iron/RFT-systems described in chapters 2 and 3, where the initial step is an electron transfer from the substrate to the catalyst and singlet oxygen is a negligible pathway.
The excitation of RFT leads to the formation of singlet oxygen (1O2), which readily reacts with cycloalkenes to allylic hydroperoxides in the well-known Schenck-ene reaction (Scheme 3, step i). A non-heme iron catalyst [Fe(bpmen)(OTf)2] (5, bpmen = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1,2-diaminoethane, Scheme 3) utilizes the in situ generated allylic hydroperoxide as an oxidant for the selective epoxidation of cycloal-kenes with concomitant formation of the allylic alcohol (step ii). In the case of cy-clooctene, the main product is cyclooctene oxide (31% yield) with a turnover number (TON) of 28, which is significantly higher than those reported reported in the literature for iron catalyst/H2O2 systems. Two equivalents of cycloalkene are needed to generate one equivalent of oxygenated substrate. Additionally, only traces of allylic alcohol are observed, which is presumably due to its polymerization. In the case of cyclohexene, the product distribution is significantly shifted from the epoxide (TON = 14) towards allylic oxygenation products.
Chapter 5: Aerobic Photooxidation of Aldehydes to Esters Catalyzed by Riboflavin Tetraacetate[4]
Esters are an important class of compounds widely utilized as fine chemicals, pharma-ceuticals, and food additives. Classical methods for their preparation include the Brønsted or Lewis acid-catalyzed condensation of benzoic acids with alcohols at elevated temperatures. The direct formation of esters from aldehydes has attracted much attention as an alternative protocol to traditional methods, because it utilizes easily available starting materials, and an isolation of the corresponding carboxylic acid is not required.
We report a convenient photocatalytic protocol for the aerobic esterification of aldehydes to the corresponding methyl esters under visible light irradiation in the presence of meth-anol and acidic conditions (Scheme 4, Route A). Mechanistic studies revealed an electron transfer from the in situ formed acetal (Scheme 4, step i) to the photoexcited chromophore RFT as the key step (step ii). Other alkyl benzoates only gave unsatisfactory yields, which is mainly caused by the impaired formation of the acetal in the case of sterically more demanding alcohols. Therefore, another photocatalytic approach to alkyl benzoates was needed.
Irradiation of a mixture of RFT and aldehydes in the presence of DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) and alkyl bromides as coupling reagents turned out to be another suitable method for ester synthesis. The flavin-mediated oxidation of the sacrificial electron donor DBU leads to the in situ generation of the hydroperoxide anion, HOO─, which subsequently oxidizes aldehydes to their corresponding benzoic acids or carboxylates (step iii). These nucleophilic species react to the corresponding esters in the presence of alkybromides via an SN2-type reaction (step iv). This visible-light-driven esterification is limited to benzaldehydes bearing electron-withdrawing substituents due to the competing formation of phenol derivatives for electron-donating substituents. Nevertheless, this RFT/DBU system gives access to the highly nucleophilic species HOO─ directly from atmospheric dioxygen, which might be an easily accessible and useful oxidant for other oxygenation reactions.
Chapter 6: Halogenase-Inspired Oxidative Chlorination Using Flavin Photocatalysis[5]
Chlorinated aromatic compounds are ubiquitous in organic chemistry, which are classi-cally synthesized by using hazardous and toxic chlorine gas or synthetic equivalents such as NCS and tBuOCl. Nature has developed a more elegant strategy based on flavin-dependent halogenase (FAD) enzymes, which elegantly oxidizes chloride to an
active species that functions as a “Cl+” source in the presence of the co-factor NADH2 and air (Scheme 5, top). Enzymes are substrate specific, thus, the scope of accessible products is limited. Moreover, the isolation and handling of the enzymes is difficult. Therefore, we sought to develop an artificial photocatalytic system based on our experience with RFT. We replaced the biomolecules FAD by RFT and NADH2 by
4-methoxybenzyl alcohol, which serves as a cheap reducing agent (Scheme 5, bottom). It is noteworthy that no chlorination of the test substrate anisole was observed when the reaction was irradiated under these conditions. We assume that in situ photogenerated H2O2 and RFT do not form the same hydroperoxy species as in the FAD-dependent hal-ogenase in the absence of the complex environment of the enzyme. Therefore, acetic acid was added, forming peracetic acid in situ which acts as a mediator for chloride oxidation (Scheme 6). Compared to the specific binding pocket of an enzyme, the activation by peracetic acid is a more general strategy and thus allows a broader substrate scope. The developed system allows the chlorination of electron rich arenes, e.g. anisole, methylani-lines, diphenyl ether and amides, as well as the -chlorination of acetophenones.
Translation of the abstract (German)
Diese Doktorarbeit berichtet über photokatalytische Oxidationsreaktionen mit Hilfe des Vitamin B2-Derivats Riboflavin Tetraacetate (RFT). Diese Dissertation erweitert das Feld an Oxidationsreaktionen, welche durch RFT katalysiert werden. Sie legt dabei speziell den Fokus auf die anspruchsvolle Oxygenierung von C−H Bindungen mit Hilfe von sichtbarem Licht und Luft als terminalen Oxidationsmittel. ...
Translation of the abstract (German)
Diese Doktorarbeit berichtet über photokatalytische Oxidationsreaktionen mit Hilfe des Vitamin B2-Derivats Riboflavin Tetraacetate (RFT). Diese Dissertation erweitert das Feld an Oxidationsreaktionen, welche durch RFT katalysiert werden. Sie legt dabei speziell den Fokus auf die anspruchsvolle Oxygenierung von C−H Bindungen mit Hilfe von sichtbarem Licht und Luft als terminalen Oxidationsmittel. Kapitel 1 gibt einen Überblick über die neuesten Entwicklungen auf dem Feld der photokatalytischen C−H Oxygenierung. In Kapitel 2 zeigen wir, dass die Photooxidation von elektronenarmen benzylischen Substraten durch die Modifikation des Reduktionspotentials mit Hilfe von Lewissäuren möglich ist. In Kapitel 3 wird erläutert, wie die Zugabe eines nicht-häm Eisenkomplexes als Kokatalysator die photokatalytische Aktivität von RFT verbessert. In Kapitel 4 wird dieses Katalysatorsystem auf die Epoxidierung von Cycloalkenen angewendet. Ein weiteres Ziel neben der flavinvermittellten C−H Oxygenierung, war die Nutzung von RFT als Oxidationskatalysator für anspruchsvolle Reaktionen. Diesbezüglich berichten wir in Kapitel 5, basierend auf der Flavinphotokataylse, über zwei Synthesewege für die direkte Veresterung von Aldehyden. Kapitel 6 beschreibt ein von Enzymen inspiriertes, künstliches Photosystem für die schwierige oxidative Chlorierung von Arenen ausgehend von Chlorid-Anionen als Cl-Quelle. Die Ergebnisse dieser Dissertation werden abschließend in Kapitel 7 zusammengefasst.
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