Singlet Oxygen


[7782-44-7]  · O2  · Singlet Oxygen  · (MW 32.00)

(electrophilic oxidizing agent for oxygenation of cisoid 1,3-dienes, many types of heterocyclic systems, enamines, alkenes containing allylic hydrogen atoms, sulfides, carbon-phosphorus double bonds, and other electron-rich unsaturated organic compounds)

Physical Data: singlet oxygen (1O2) is the first excited electronic state of molecular oxygen (1Dg), lying 22.4 kcal mol-1 above the ground state triplet. The second singlet state (1&SSigma;+g), 37 kcal mol-1 above the ground state, is relatively short-lived in solution (10-12 s) due to a rapid spin-allowed transition to the longer-lived (10-3-10-6 s) first excited state. Because of the short lifetime of the 1&SSigma;+g state, the more stable singlet oxygen species (1Dg) is considered to be the reactive intermediate in the oxygenation of organic compounds in solution.1

Solubility: sol aqueous and organic solvents.

Form Supplied in: singlet oxygen is an unstable, short-lived species and must be prepared in situ or immediately prior to use.

Preparative Methods: among the methods for generating singlet oxygen in solution are: (a) the dye-sensitized photooxidation of triplet oxygen;2 (b) the decomposition of phosphite ozonides;3 (c) the decomposition of transannular peroxides such as 9,10-diphenylanthracene peroxide;4 (d) the reaction of Hydrogen Peroxide with Sodium Hypochlorite;5,6 and (e) subjecting gaseous oxygen to electrodeless discharge.7 In the following section, the procedures for generating singlet oxygen by the methods (a)-(d) above are discussed, and some typical reactions of singlet oxygen with organic compounds are reviewed.

Handling, Storage, and Precautions: the initial peroxidic products formed in 1O2 reactions usually undergo decomposition or rearrangement under the conditions of workup, but in some cases (certain transannular peroxides or dioxetanes) they may remain in the reaction mixture as potentially explosive materials. Unless the peroxides are sought as reaction products, they may be deoxygenated by the action of Dimethyl Sulfide, diphenyl sulfide, or Triphenylphosphine.

Preparative Methods.

Generation by Dye-Sensitized Photooxygenation.2

The most common method for generating 1O2 in solution is the dye-sensitized photochemical excitation of triplet oxygen. The mechanism for generating 1O2 in this way involves the excitation of an appropriate dye with visible light to form the corresponding excited singlet state. Rapid intersystem crossing generates the excited triplet state of the sensitizer (ET > 22.4 kcal mol-1) which undergoes energy transfer with triplet oxygen to form singlet oxygen, regenerating the ground state of the sensitizer (eq 1). Among the sensitizers which can be utilized in solution are methylene blue, Rose Bengal, eosin yellow, chlorophyll, riboflavin, zinc tetraphenylporphyrin, bis-naphthalenothiophene, erythrosin B, and hematoporphyrin. In addition to the soluble, homogeneous sensitizers, polymer-bound dyes such as Rose Bengal have been used for the photochemical generation of 1O2.8

Singlet oxygen may be generated in a wide range of solvents, the choice of solvent being dictated by the solubility of substrate and sensitizer and by solvent properties that influence ease of workup. The lifetime of 1O2 varies from 2 ms in H2O to approximately 700 ms in CCl4 (Table 1) and is considerably longer when the solvent is deuterated (the lifetime of 1O2 is almost always increased by a factor of ten when the solvent is perdeuterated).9

The light sources used are generally high intensity lamps which emit light in the visible range. Sun lamps have been employed in certain instances but they may bring about competing UV-promoted reactions and rearrangements. Among the lamps used as light sources are Sylvania 500 W tungsten halogen,10 Osram-Vialox 250 W,11 500 W Halogen-Argaphoto,12 500 W Toshiba JD,13 200 W halogen,14 650 W tungsten halogen,15 100 W tungsten halogen,16 and 500 W high pressure sodium.17

Generation from Phosphite Ozonides.3

Triphenyl Phosphite is treated with Ozone at -78 °C (dry ice-acetone) in methylene chloride until the blue color of excess ozone is observed. Ozonization is then discontinued and the solution is purged with dry nitrogen to remove the excess oxidant. A cold solution of the acceptor in methylene chloride is then added, and mixing is effected by the nitrogen stream. The -78 °C bath is then removed and replaced with a -25 °C bath (ice-methanol). Alternatively, the reaction mixture is permitted to warm to rt and then worked up by concentration and chromatography.

Generation by the Decomposition of 9,10-Diphenylanthracene Endoperoxide. Oxidation of an Oxazole to a Triamide.

In contrast to dialkyl peroxides, which usually undergo oxygen-oxygen bond cleavage on pyrolysis, many aromatic endoperoxides break down on heating with release of oxygen in the singlet state.18 Among the available endoperoxides, 9,10-diphenylanthracene peroxide (1) has been found to be a particularly efficient donor of 1O2 in this type of decomposition. It can easily be prepared as a stable product (dec 180-181 °C, mp 254 °C) by irradiation of a cold solution of 9,10-diphenylanthracene in carbon disulfide for 48 h in a stream of oxygen using a 275 W Sylvania RS lamp.19

A typical singlet oxygen reaction using this peroxide is illustrated in the conversion of 2,5-diphenyl-4-methyloxazole to N-acetyldibenzamide (eq 2).18 In this oxidation, an anhydrous benzene solution containing the peroxide and the oxazole is stirred at reflux temperature in the dark for 94 h under a positive pressure of nitrogen. Removal of benzene and chromatography on silica gel yields the triamide (92%), as well as some diamide formed during chromatography, in addition to 9,10-diphenylanthracene.4

Generation of 1O2 by Hypochlorite-Hydrogen Peroxide Oxygenation.5

In this procedure, illustrated by the conversion of 2,3-dimethylbutene to the allylic hydroperoxide (eq 3), a methanolic solution of the substrate is treated with 3 equiv of 30% Hydrogen Peroxide and stirred at 10 °C. To this mixture, aqueous Sodium Hypochlorite is slowly added (2.5 equiv). The solution is then diluted with water, extracted with ether, and worked up.

Oxygenations with 1O2.

Singlet oxygen undergoes three classes of reaction with alkenes: an ene type of reaction forming allylic hydroperoxides; 1,4-cycloaddition with cisoid 1,3-dienes; and 1,2-cycloaddition with electron-rich or strained alkenes. In addition, 1O2 reactions take place with many types of heterocyclic compounds including furans, pyrroles, oxazoles, indoles, imidazoles, and thiophenes.20,21 Other types of 1O2 reaction take place with sulfides, carbon-phosphorus double bonds, and electron-rich aromatic systems. In many cases, competition exists between different modes of oxidation, as in the reaction of dihydropyran with 1O2 (eq 4), which takes place either by 1,2-dioxetane formation and subsequent cleavage, or by an ene reaction forming a hydroperoxide which undergoes O-O bond fission by a b-elimination. In this case, it is found that the ratio of products (2) to (3) varies over a 58-fold range depending on the solvent used (Table 2), with polar solvents favoring 1,2-dioxetane formation over the ene reaction.22

The Singlet Oxygen Ene Reaction.

The reaction of alkenes containing at least one allylic hydrogen with singlet oxygen, yielding a hydroperoxide with accompanying shift of the double bond, bears a close resemblance to the Alder ene reaction (eq 5). This ene type of oxidation has been extensively used in synthesis. Reduction of the allylic hydroperoxide yields the corresponding allylic alcohol. An analogous reaction of enol silyl ethers yielding silylperoxy esters is assumed to take place by the same mechanism (eq 6).23 Formation of allylic hydroperoxides is not stereoselective, as is shown by the intermediates in the garrya and atisine alkaloid syntheses (eqs 7 and 8).24

The photooxygenation of D9-octalin followed by reduction with hydrazine yields D1(9)-10-octalol, a key intermediate in the synthesis of trans-cyclodecenone (eq 9).25 The ene reaction has also been used for the contrathermodynamic isomerization of an alkene (eq 10)26 and in the formation of allylic alcohols for later conversion to a,b-unsaturated ketones (eq 11).27

An interesting use of the ene 1O2 reaction in conjunction with the Diels-Alder type of 1O2 addition is found in the dye-sensitized photooxidation of neoabietic acid.28 The first step involves an ene reaction at the more highly substituted double bond, generating a hydroperoxide along with the shift of the double bond to form a cis-1,3-diene. The second-stage [2 + 4] addition yields a transannular peroxide which undergoes a b-elimination and reduction to form the product (eq 12).

In the final steps of a total synthesis of tetracycline, the anhydro derivative is converted to a hydroperoxide in high yield by a singlet oxygen addition in the ene mode (eq 13). The reaction is very sensitive to overoxidation and succeeds only when the dye-sensitized photooxidation is terminated after a few minutes.29


The reaction of singlet oxygen with cisoid 1,3-dienes takes place in both carbocyclic and heterocyclic systems. In general, the formation of 1,4-cycloaddition products from 1,3-dienes is the hallmark of singlet oxygen reactivity, in contrast to other less well-defined oxidation processes effected by oxygen in the ground state. The early synthesis of (±)-ascaridol by the dye-sensitized photooxygenation of a-terpinene is a classic case of 1,4-addition by singlet oxygen (eq 14).30 The Schenck synthesis of cantharidine31 also makes use of an endoperoxide formed by a Diels-Alder type cycloaddition of singlet oxygen (eq 15). In another application, the formation of bis-epoxides by thermolysis of 1,4-endoperoxides generated in a singlet oxygen addition is employed in the synthesis of (±)-crotepoxide (eq 16).32

Furan photooxidation by 1,4-cycloaddition of 1O2 has been widely used as a means of generating carbonyl compounds from transannular peroxide intermediates. In an early example, 2-furfural was converted by 1O2 to the unsaturated lactone intermediate (eq 17) in a synthesis of camptothecin.33 Likewise, oxidation of 3-methyl-2-furoic acid yields the corresponding methyl derivative used as a key component in a synthesis of (±)-strigol (eq 18).34 These transformations most probably take place by solvolysis of the intermediate endoperoxide followed by fragmentation, as shown in eq 19. Examples have been reported of singlet oxygen reactions with styrene derivatives where a benzene ring acts as part of a 1,3-diene system (eq 20).35,36

A recent example of 1,4-addition of singlet oxygen to a pyrrole involves the dye-sensitized photooxidation of 2-carboxy-4-methoxy-5-(methoxycarbonyl)-1-methylpyrrole (eq 21). The intermediate endoperoxide undergoes fragmentation by decarboxylation and cleavage of the O-O bond to give 5-hydroxy-4-methoxy-5-(methoxycarbonyl)-1-methyl-3-pyrrolin-2-one).37

Addition of Singlet Oxygen to Alkenes Activated by Electron-Releasing Groups.

The addition of singlet oxygen to alkenes occurs in the presence of amino or alkoxyl groups in the absence of active allylic hydrogens in the same molecule. The addition takes place stereospecifically by cis addition to form dioxetanes as isolable products. These, in turn, undergo thermolysis to form electronically excited carbonyl compounds with accompanying chemiluminescence. Thus photooxidation of 1,1,2,2-tetramethyoxyethylene sensitized by either zinc tetraphenylporphyrin or dinaphthalenothiophene proceeds smoothly to give an isolable clear, pale-yellow liquid shown to be the tetramethoxydioxetane (eq 22).38 On the other hand, the crystalline cis-dioxetane, formed on dye-sensitized photooxidation of cis-diethoxyethylene in fluorotrichloromethane at -78 °C under irradiation with a 500 W lamp for 25 min, explodes on warming to rt (eq 23).39

Reactions of Enamines with Singlet Oxygen.

Reactions of enamines with 1O2 take place readily to form the carbonyl products expected from the cleavage of dioxetane intermediates. In the case of the piperidine enamine of methyl isopropyl ketone, the reaction is carried out in benzene using zinc tetraphenylporphyrin as sensitizer (eq 24).40 In related work, photooxygenation of the 22-morpholine enamine of 3-oxobisnor-4-cholen-22-al in DMF at 15 °C using Rose Bengal as sensitizer yields a quantitative yield of progesterone (eq 25).41 Likewise, 1O2 cleavage of the highly electron-rich enamines formed from the silyl enol ethers of azetidinecarboxylic esters provides a route to b-lactams (eq 26).42

Reactions of Enols with 1O2.

As electron-rich alkenes, enols react with singlet oxygen along the lines of the ene reaction to give unstable intermediate hydroperoxides which undergo further transformations. The reactions are enhanced by the presence of fluoride ion, presumably by the formation of a strong hydrogen bond between the enol-OH and the fluoride.43 Thus 1,3-cyclohexanedione reacts with 1O2 in the presence of fluoride ion to give pyrogallol (eq 27). 4-Hydroxycoumarin, which is normally relatively inert toward 1O2, readily undergoes oxygen uptake with 1O2 in the presence of fluoride ion (eq 28).

While it has generally been assumed that alkenes with electron-withdrawing groups are inert to 1O2, it has recently been shown that a,b-unsaturated ketones which are constrained in the s-cis conformation are rapidly oxidized by 1O2. Systems which prefer the s-trans conformation react slowly or not at all.44,45 For example, compound (4) yields 88% of the hydroperoxide (eq 29) while compound (5) shows no reaction toward 1O2. The difference is accounted for in terms of an initial [4 + 2] cycloaddition of 1O2 to form a 1,2,3-trioxine (eq 30),44 which then undergoes further transformations.

Oxidation of Sulfides.

Sulfides react with singlet oxygen to form sulfoxides and sulfones.46-49 The reaction takes place through intermediate persulfoxides. The rate of uptake of 1O2 appears to be relatively independent of solvent and temperature. Other reaction paths have been observed. Thus although the 1O2 oxidation of the linear sulfide yields the expected mixture of sulfoxide and sulfone (eq 31), oxidation of the thiazolidine with singlet oxygen, followed by deoxygenation with Me2S or Ph3P, gives a quantitative yield of the product of a-hydroxylation (eq 32). Formation of this alcohol is considered to take place by a Pummerer-type of rearrangement of an intermediate persulfoxide.50

Cleavage of Carbon-Phosphorus Double Bonds by Singlet Oxygen.

Singlet oxygen cleaves phosphorus ylides to form carbonyl compounds and the corresponding phosphine oxide (eq 33).51 The reported procedure involves dye-sensitized photooxidation of the phosphorane in a solvent such as chloroform, benzene, or methanol using meso-tetraphenylporphyrin or Rose Bengal as sensitizer with irradiation from a 500 W tungsten filament lamp while oxygen is bubbled through the solution. This method has recently been employed in one of the procedures for oxidizing phosphoranes to tricarbonyl compounds (eq 34).52

Trapping Dioxetanes and Other Peroxidic Singlet Oxygen Oxidation Products.

In certain cases, dioxetane intermediates and other peroxidic species may be deoxygenated by reaction with diphenyl sulfide, a species which is unreactive toward 1O2.48 As an example,53 the dye-sensitized photooxygenation of tetraphenylimidazole normally yields the dibenzoyl derivative in nearly quantitative yield, presumably through the dioxetane (eq 35). In the presence of diphenyl sulfide, a product of rearrangement is also formed along with diphenyl sulfoxide. Other studies on trapping agents for peroxidic intermediates have included the use of pinacolone for perepoxides54 and dimethyl sulfide or triphenylphosphine for persulfoxides.55

Sensitivity of 1O2 Reactions to the Environment.

The reactions of singlet oxygen with organic substrates are very sensitive to the experimental environment. Temperature, reaction time, substituents, solvent, and dissolved solutes may all affect the oxidations, resulting in mixtures of products of varied composition. This phenomenon is well illustrated in the studies on the sensitized photooxidation of a 5,6-disubstituted 3,4-dihydro-2H-pyran, in which solvent effects lead to widely varying product distributions (eq 36).56 Table 3 illustrates these effects.

1. For reviews on the chemistry of singlet oxygen, see: (a) Gollnick, K.; Schenck, G. O. In 1,4-Cycloaddition Reactions, The Diels-Alder Reaction in Heterocyclic Synthesis; Hamer, J., Ed.; Academic: New York, 1967; pp 255-344. (b) Gollnick, K. Adv. Photochem. 1968, 6, 1. (c) Foote, C. S. Science 1968, 162, 963. (d) Foote, C. S. Acc. Chem. Res. 1968, 1, 104. (e) Wayne, R. P. Adv. Photochem. 1969, 7, 311. (f) Foote, C. S. PAC 1971, 27, 635. (g) Denny, R. W.; Nickon, A. OR 1973, 20, 133. (h) Adam, W. CZ 1975, 99, 142. (i) Singlet Molecular Oxygen; Schaap, A. P., Ed.; Halsted: New York, 1976. (j) Singlet Oxygen; Wasserman, H. H.; Murray, R. W., Eds.; Academic: New York, 1979. (k) Frimer, A. A. CRV 1979, 79, 359. (l) George, M. V.; Bhat, V. CRV 1979, 79, 447.
2. (a) Schenck, G. O. AG 1957, 69, 579. (b) Kautsky, H. Biochem. Z. 1937, 291, 271. (c) Adam, W.; Klug, P. JOC 1993, 58, 3416.
3. Murray, R. W.; Kaplan, M. L. JACS 1969, 91, 5358.
4. Wasserman, H. H.; Scheffer, J. R.; Cooper, J. L. JACS 1972, 94, 4991.
5. (a) Foote, C. S.; Wexler, S. JACS 1964, 86, 3879. (b) Foote, C. S.; Wexler, S.; Ando, W.; Higgins, R. JACS 1968, 90, 975.
6. McKeown, E.; Waters, W. A. JCS(B) 1966, 1040.
7. Corey, E. J.; Taylor, W. C. JACS 1964, 86, 3881.
8. Blossey, E. C.; Neckers, D. C.; Thayer, A. L.; Schaap, A. P. JACS 1973, 95, 5820.
9. (a) Merkel, P. B.; Kearns, D. R. JACS 1972, 94, 7244. (b) Long, C. A.; Kearns, D. R. JACS 1975, 97, 2018.
10. Hathaway, S. J.; Paquette, L. A. T 1985, 41, 2037.
11. Adam, W.; Klug, G.; Peters, E.-M.; Peters, K.; von Schnering, G. H. T 1985, 41, 2045.
12. Gollnick, K.; Griesbeck, A. T 1985, 41, 2057.
13. Matsumoto, M.; Dobashi, S.; Kuroda, K.; Kondo, K. T 1985, 41, 2147.
14. Ihara, M.; Noguchi, K.; Fukumoto, K.; Kametani, T. T 1985, 41, 2109.
15. Wasserman, H. H.; Pickett, J. E. T 1985, 41, 2155.
16. Utaka, M.; Nakatani, M.; Takeda, A. T 1985, 41, 2163.
17. Jefford, C. W.; Boukouvalas, J.; Kohmoto, S.; Bernardinelli, G. T 1985, 41, 2081.
18. Wasserman, H. H.; Scheffer, J. R. JACS 1967, 89, 3073.
19. Dufraise, C.; Etienne, A. CR 1935, 201, 280.
20. George, M. V.; Bhat, V. CRV 1979, 79, 447.
21. Singlet Oxygen; Wasserman, H. H.; Murry, R. W., Eds.; Academic: New York, 1979; Chapter 9.
22. Bartlett, P. D.; Mendenhall, D.; Schaap, A. P. ANY 1970, 171, 79.
23. (a) Adam, W.; Fierro, J. d. JOC 1978, 43, 1159. (b) Adam, W.; Fierro, J. d.; Quiroz, F.; Yany, F. JACS 1980, 102, 2127.
24. Bell, R. A.; Ireland, R. E. TL 1963, 269.
25. Wharton, P. S.; Hiegel, G. A.; Coombs, R. V. JOC 1963, 28, 3217.
26. Büchi, G.; Hauser, A.; Limacher, J. JOC 1977, 42, 3323.
27. Ireland, R. E.; Baldwin, S. W.; Dawson, D. J.; Dawson, M. I.; Dolfini, J. E.; Newbould, J.; Johnson, W. S.; Brown, M.; Crawford, R. J.; Hudrlik, P. F.; Rasmussen, G. H.; Schmiegel, K. K. JACS 1970, 92, 5743.
28. Schuller, W. H.; Lawrence, R. V. JACS 1961, 83, 2563.
29. Wasserman, H. H.; Lu, T.-J.; Scott, A. I. JACS 1986, 108, 4237.
30. (a) Schenck, G. O.; Ziegler, K. N 1954, 32, 157. (b) Schenck, G. O. AG 1952, 64, 12.
31. Schenck, G. O. AG 1957, 69, 579.
32. Demuth, M. R.; Garrett, P. E.; White, J. D. JACS 1976, 98, 634.
33. Meyers, A. I.; Nolen, R. L.; Collington, E. W.; Narwid, T. A.; Strickland, R. C. JOC 1973, 38, 1974.
34. Heather, J. B.; Mittal, R. S. D.; Sih, C. J. JACS 1974, 96, 1976.
35. Foote, C. S.; Mazur, S.; Burns, P. A.; Lerdal, D. JACS 1973, 95, 586.
36. Rio, G.; Bricout, D.; Lacombe, L. T 1973, 29, 3553.
37. Boger, D. L.; Baldino, C. M. JOC 1991, 56, 6942.
38. Mazur, S.; Foote, C. S. JACS 1970, 92, 3225.
39. Bartlett, P. D.; Schaap, A. P. JACS 1970, 92, 3223.
40. Foote, C. S.; Lin, J. W.-P. TL 1968, 3267.
41. Huber, J. E. TL 1968, 3271.
42. Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.; Wu, J. S. JOC 1981, 46, 2991.
43. Wasserman, H. H.; Pickett, J. E. T 1985, 41, 2155.
44. Ensley, H. E.; Carr, R. V. C.; Martin, R. S.; Pierce, T. E. JACS 1980, 102, 2836.
45. Ensley, H. E.; Balakrishnan, P.; Ugarkar, B. TL 1983, 24, 5189.
46. Schenck, G. O.; Krauch, C. H. CB 1963, 96, 517.
47. Kacher, M. L.; Foote, C. S. Photochem. Photobiol. 1979, 29, 765.
48. Gu, C.; Foote, C. S.; Kacher, M. L. JACS 1981, 103, 5949.
49. Gu, C.; Foote, C. S. JACS 1982, 104, 6060.
50. Takata, G.; Tamura, Y.; Ando, W. T 1985, 41, 2133.
51. Jefford, C. W.; Barchietto, G. TL 1977, 4531.
52. Wasserman, H. H.; Ennis, D. S.; Blum, C. A.; Rotello, V. M. TL 1992, 33, 6003.
53. Wasserman, H. H.; Saito, I. JACS 1975, 97, 905.
54. Schaap, A. P.; Faler, G. R. JACS 1973, 95, 3381.
55. Foote, C. S.; Peters, J. W. JACS 1971, 93, 3795.
56. Chan, Y.-Y.; Li, X.; Zhu, C.; Liu, X.; Zhang, Y.; Leungg, H.-K. JOC 1990, 55, 5497.

Harry H. Wasserman

Yale University, New Haven, CT, USA

Robert W. DeSimone

Neurogen Corporation, Branford, CT, USA

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