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Photooxygenations and SCHENCK-En-Reactions

Photosensitizers can be used to introduce oxygen into organic compounds. One of the best investigated reactions of this type is the synthesis of ascaridole starting from α-terpinene and singlet oxygen (see fig.1a). The synthesis was described first by SCHENCK ET AL..[1;2] One of the first production sites for ascaridole is shown in figure 1b. Eosin was added to an alcoholic solution of α-terpinene and irradiated in the presence of oxygen. After work up ascaridole could be isolated and characterized. SCHENCK ET AL. generalized the results and pointed out, that 1,3-dienes react with oxygen to yield an endoperoxide when a photosensitizer is used. This could be proven by transfering the reaction concept to other diene-systems, e.g. α-phellandrene and 1,3-cyclohexadiene, which also resulted in the formation of endoperoxides.[3]

 

SchenkEn1

 Schenck_Ascaridol

                                             (a)                                                                                                      (b)

Figure 1: (a) Reaction scheme for the synthesis of ascaridole from α-terpinene and 1O2. (b) Production site for ascaridole by solar irradiation.[2]

 

By irradiating the sensitizer with light of appropriate wavelength, excitation from the electronic ground state to the first excited electronic state S1 occurs. In the following, the sensitizer undergoes intersystem crossing and transitions to the first triplet state. Due to the relatively long lifetime of this electronic state, it is possible that the sensitizer in the triplet state interacts with a molecule of dissolved oxygen, which is in the triplet state as well. The sensitizer molecule returns to the electronic ground state, while the oxygen molecule changes into the first excited electronic state. For a oxygen molecule this is the first singlet state. The singlet oxygen (1O2) is able to react with suitable organic reactants.[48] The lifetime of 1O2 in the liquid phase is a crucial parameter for the efficiency of the photooxygenation because this excited state will fall back to the more stable 3O2. The lifetime of 1O2 is influenced significantly by the solvent. In aprotic solvents such as tetrachloromethane the lifetime can reach values of up to 30ms, while the lifetime in polar and/or protic solvents is much shorter. For example, the lifetime in methanol is just 10 µs.

 SchenkEn2

Figure 2: Possible reaction pathways of 1O2 with organic substances. (a) Formation of 1,2Dioxetanes, (b) SCHENCK-En-Reaction, (c) [4+2] DIELS-ALDER-Reaction.

When the reactivity of the organic substrate is low, a short lifetime of 1O2 will additionally slow down the overall reaction rate because the probability of collisions between the organic substrate and activated oxygen decreases. Hence, the choice of the solvent is crucial for photooxygenations. Many 1,3-dienes are known, which undergo photooxygenation to forms the corresponding endoperoxide via the [4+2] DIELS-ALDER-reaction. Besides forming endoperoxides, singlet oxygen can also react differently. Alkenes with α-hydrogen atom form hydroperoxides via the SCHENK-En-reaction.[9] Simple alkenes without an α-hydrogen atom can react with 1O2 to form 1,2-dioxetanes through a 2+2 cycloaddition. These three reaction types are shown in Figure 2.

Different dyes can be used as sensitizers. Popular examples are methylene blue, rose bengal and tetraphenylporphyrin (see Figure 3).[10] The choice of the sensitizer is mainly influenced by the available light source and the chosen solvent. Singlet oxygen can be generated through thermal reactions as well. In most cases, hydrogen peroxide is used with several additives such as molybdates or hypochlorite.

 SchenkEneq1

Because only the path of generation changes, but not the reactants, the product spectrum, which can be accessed, is similar to that of the photosensitized reactions.[1113] Although the design of the reactors for the thermal generation of singlet oxygen is easier, these methods have issues with the high oxidation potential of e.g. hypochlorite or hydrogen peroxide.[14] The presence of such oxidative reactants can lead to unwanted side reactions.                                                SchenkEn3

         Bengalrosa                                                Methylen Blau

SchenkEn4 

Tetraphenylporphyrin

Figure 3: Chemical structures of selected photosensitizers.

When H2O2  is used as oxygen source together with MoO42– , the generation of 1O2 only proceeds efficiently only in water and aqueous solutions of methanol or ethanol.[15] Hence, reactions with hydrophobic substrates are difficult. A possible solution is the use of biphasic systems, especially microemulsions.[16;17]

Endoperoxides are of high interest from a pharmaceutical point of view because several anticancer-and antimalaria-drugs are organic peroxides.[18;19] With this, efficient access to organic peroxides is very desirable. Several scientific publications deal with photooxygenations in microstructured photoreactors to develop efficient processes for the production of organic peroxides. First studies focused on the feasibility of gas-liquid for the reactions in this reactor type.WOOTTON ET AL. ; MEYER ET AL. More recent publications also addressed the reactor concepts for contacting a gas with a liquid phase and the required dimensions of the reactor.[22;23] It was also shown, that it is possible to set up photochemical processes of microstructured reactors, which shows an improved productivity compared to conventional photoreactors.[24] Such a setup can also be used to synthesize the antimalaria-drug artemisinin.[25]

 

  1. SCHENCK, G. O.; KINKEL, K. G.; MERTENS, H.-J.: Photochemische Reaktionen I. Über die Photosynthese des Askaridols und verwandter Endoperoxyde, Justus Liebigs Annalen der Chemie, 1953, 584 (1), 125–155, DOI: 1002/jlac.19535840110.
  2. SCHENCK, G. O.: Probleme präparativ Photochemie, Chem., 1952, 64 (1), 12–23, DOI: 10.1002/ange.19520640105.
  3. SCHENCK, G. O.: Photochemische Reaktionen II. Über die unsensibilisierte und photosensibilisierte Autoxydation von Furanen, Justus Liebigs Annalen der Chemie, 1953, 584 (1), 156–176, DOI: 1002/jlac.19535840111.
  4. KOCH, E.: Zur photosensibilisierten Sauerstoffübertragung: Untersuchung der Tterminationsschritte durch Belichtungen bei tiefen Temperaturen, Tetrahedron, 1968, 24 (21), 6295– 6318, DOI: 1016/S0040-4020(01)96823-1.
  5. BRAUN, A. M.; MAURETTE, M.-T.; OLIVEROS, E.: Photochemical technology, 1991, Wiley, ISBN 978–0–471–92652–8, DOI: 1002/ange.19921041147.
  6. BÖTTCHER, H.: Technical Applications of Photochemistry, 1991, Deutscher Verlag für Grundstoffindustrie, ISBN 978–3–3420–0627–5.
  7. WILKINSON, F.; HELMAN, W.; ROSS, A.: Rate Constants for the Decay and Reactions of the Lowest Electronically Excited Singlet State of Molecular Oxygen in Solution. An Expanded and Revised Compilation, Phys. Chem. Ref. Data, 1995, 24 (2), 663–1021, DOI: 10.1063/1.555965.
  8. ALBINI, A.; FAGNONI, M. (Eds.): Handbook of Synthetic Photochemistry, vol. koch, 1. edn., 2009, Wiley-VCH Verlag GmbH & Co. KGaA, ISBN 978–3–5273–2391–3.
  9. SCHENCK, G. O.: Zur Theorie der photosensibilisierten Reaktion mit molekularem Sauerstoff, Naturwissenschaften, 1948, 35 (1), 28–29, DOI: 1007/BF00626628.
  10. DEROSA, M. C.; CRUTCHLEY, R. J.: Photosensitized singlet oxygen and its applications, Chem. Rev., 2002, 233-234, 351–371, DOI: 10.1016/S0010-8545(02) 00034-6.
  11. OHTA, B. K.; FOOTE, C. S.: Characterization of Endoperoxide and Hydroperoxide Intermediates in the Reaction of Pyridoxine with Singlet Oxygen, Am. Chem. Soc., 2002, 124 (41), 12064–12065, DOI: 10.1021/ja0205481.
  12. SELS, B. F.; DE VOS, D. E.; JACOBS, P. A.: Kinetics of the Oxygenation of Unsaturated Organics with Singlet Oxygen Generated from H2O2 by a Heterogeneous Molybdenum Catalyst, Am. Chem. Soc., 2007, 129 (21), 6916–6926, DOI: 10.1021/ja065849f.
  13. COLLINET-FRESSANCOURT, M.; AZAROUAL, N.; AUBRY, J.-M.; NARDELLO-RATAJ, V.: Dimethylsulfoxide as a kinetic booster for the chemical generation of singlet oxygen in methanol, Tetrahedron Lett., 2010, 51 (50), 6531–6534, DOI: 10.1016/j.tetlet.2010.10.022.
  14. AUBRY, J.-M.; BOUTTEMY, S.: Preparative Oxidation of Organic Compounds in Microemulsions with Singlet Oxygen Generated Chemically by the Sodium Molybdate/Hydrogen Peroxide System1, Am. Chem. Soc., 1997, 119 (23), 5286–5294, DOI: 10.1021/ ja9644079.
  15. MCKEOWN, E.; WATERS, W. A.: The oxidation of organic compounds by "singlet" oxygen, Journal of the Chemical Society B, 1966, 1040–1046, DOI: 1039/ J29660001040.
  16. NARDELLO, V.; HERVE, M.; ALSTERS, P. L.; AUBRY, J.-M.: "Dark" Singlet Oxygenation of Hydrophobic Substrates in Environmentally Friendly Microemulsions, Synth. Catal., 2002, 344 (2), 184–191, DOI: 10.1002/1615-4169(200202)344:2<184::AID-ADSC184>3.0.CO;2-Y.
  17. NARDELLO, V.; CARON, L.; AUBRY, J.-M.; BOUTTEMY, S.; WIRTH, T.; SAHAMÖLLER CHANTU, R.; ADAM, W.: Reactivity, Chemoselectivity, and Diastereoselectivity of the Oxyfunctionalization of Chiral Allylic Alcohols and Derivatives in Microemulsions: Comparison of the Chemical Oxidation by the Hydrogen Peroxide/Sodium Molybdate System with the Photooxygenation, Am. Chem. Soc., 2004, 126 (34), 10692–10700, DOI: 10.1021/ja048589f.
  18. DONG, Y.; CREEK, D.; CHOLLET, J.; MATILE, H.; CHARMAN, S. A.; WITTLIN, S.; WOOD, J. K.; VENNERSTROM, J. L.: Comparative Antimalarial Activities of Six Pairs of 1,2,4,5-Tetraoxanes (Peroxide Dimers) and 1,2,4,5,7,8-Hexaoxonanes (Peroxide Trimers), Antimicrob. Agents Chemother., 2007, 51 (8), 3033–3035, DOI: 10.1128/AAC.00264-07.
  19. RAMIREZ, A. P.; THOMAS, A. M.; WOERPEL, K. A.: Preparation of Bicyclic 1,2,4-Trioxanes from γ-Unsaturated Ketones, Lett., 2009, 11 (3), 507–510, DOI: 10.1021/ol8022853.
  20. WOOTTON, R. C. R.; FORTT, R.; DE MELLO, A. J.: A Microfabricated Nanoreactor for Safe, Continuous Generation and Use of Singlet Oxygen, Process. Res. Dev., 2002, 6 (2), 187–189, DOI: 10.1021/op0155155.
  21. MEYER, S.; TIETZE, D.; RAU, S.; SCHÄFER, B.; KREISEL, G.: Photosensitized oxidation of citronellol in microreactors, Photoch. Photobio. A., 2007, 186 (2-3), 248–253, DOI: 10.1016/j.jphotochem.2006.08.014.
  22. AURYA, R. A.; PARK, C. P.; KIM, D.-P.: Triple-channel microreactor for biphasic gasliquid reactions: Photosensitized oxygenations, Beilstein J. Org. Chem., 2011, 7, 1158–1163, DOI: 10.3762/bjoc.7.134.
  23. YAVORSKYY, A.; SHVYDKIV, O.; LIMBURG, C.; NOLAN, K.; DELAURE, Y. M. C.; OELGEMÖLLER, M.: Photooxygenations in a bubble column reactor, Green Chem., 2012, 14, 888–892, DOI: 1039/C2GC16439F.
  24. LEVESQUE, F.; SEEBERGER, P. H.: Highly Efficient Continuous Flow Reactions Using Singlet Oxygen as a "Green" Reagent, Org. Lett., 2011, 13 (19), 5008–5011, DOI: 10.1021/ol2017643.
  25. LEVESQUE, F.; SEEBERGER, P. H.: Kontinuierliche Synthese des Malariawirkstoffs Artemisinin, Chem., 2012, 124 (7), 1738–1741, DOI: 10.1002/ange. 201107446.


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