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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Org Lett. Author manuscript; available in PMC 2010 October 15.
Published in final edited form as:
PMCID: PMC2762122
NIHMSID: NIHMS147809

A new peroxide fragmentation: efficient chemical generation of 1O2 in organic media

Abstract

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Monoactivated derivatives of 1,1-dihydroperoxides undergo an unprecedented base-promoted fragmentation to efficiently generate singlet oxygen (1O2) in anhydrous organic solvents.

Singlet molecular oxygen (1O2), an important oxidant in chemistry, biology, and medicine,1a,b is most commonly generated via photosensitized excitation of ground state (3O2) dioxygen.1b,2 The discovery that 1O2 is also produced from reaction of H2O2 and HOCl led to the discovery of a number of additional methods for chemical generation.1a,3,4 However, many of these “dark” oxygenations have significant limitations. Due to the short half-life of 1O2 in aqueous media,5 methods based upon reaction of H2O2 with hypohalites,3 alkaline earth metals,6 transition metals,7 lanthanides,8 or metalloenzymes9 must typically employ biphasic or emulsion conditions for preparative oxidations.10 Thermal generation of 1O2 from phosphite ozonides,11 silyl hydrotrioxides,12 or arene endoperoxides13 can be conducted in organic solvents but requires preparation of unstable precursors. We report an efficient and convenient generation of 1O2 in organic solvents via an unprecedented fragmentation of derivatives of 1,1-dihydroperoxides (Scheme 1).

Scheme 1
Fragmentation of peroxyacetals

Our discovery stemmed from earlier research on “reductive” ozonolysis, in which the presence of amine N-oxides was found to promote direct ozonolytic conversion of alkenes to aldehydes and ketones.14 The proposed mechanism, involving formation and fragmentation of a zwitterionic peroxy/oxyammonium acetal, also predicted stoichometric generation of 1O2 (Scheme 1). However, this prediction could not be easily tested within an ozonolysis reaction. In search of more accessible precursors for the putative fragmentation, we discovered that readily available derivatives of 1,1-dihydroperoxides will generate 1O2 under preparatively useful conditions.

The precursor 1,1-dihydroperoxides are readily available and possess surprising kinetic stability.15,16 The dihydroperoxides of 4-t-butylcyclohexanone and 4-phenyl-2-butanone, 1b and 2b respectively, were prepared in high yield by Re2O7-catalyzed reaction of the ketones with aq. H2O2 (Scheme 2).17 Monoperesters (1c, 1e, 2c) and a monopercarbonate (1d) were prepared by acylation or carboxylation of the dihydroperoxides.18 The monoesters were stable for several days at room temperature or weeks at −20 °C.19 In contrast, monopercarbonate 1d could be isolated and purified but undergoes slow ring-exansion to 4-t-butylcaprolactone even at room temperature.20

Scheme 2
Preparation of peroxide substratesa

Addtion of KOtBu to a THF solution of 1c resulted in immediate bubbling, accompanied by disappearance of starting material and formation (TLC) of 4-t-butylcyclohexanone. Encouraged by this observation, we repeated the reaction in the presence of 1O2 trapping reagents (Table 1 and Figure 1).1a Addition of KOtBu to a THF solution of 1c and terpinene (3) resulted in formation of ketone 1a (TLC) and endoperoxide 3-O2.21 A similar result was obtained with percarbonate 1d. An increased yield of 1O2 from 1c was observed at lower temperature, in acetonitrile (MeCN), or in the presence of diphenylisobenzofuran (DPBF, 4), a more reactive trap which was completely consumed whether present in 0.5 or 0.75 equivalents relative to the monoperester.22 Efficient 1O2 generation was also observed from reaction of monoperester 1c with Cs2CO3, but not K2CO3 or KOAc. This disparity drew our attention to the potential importance of ion pairing, and we turned to nBu4NF (TBAF) as a convenient base which would afford a highly dissociated peroxyanion. Gratifyingly, treatment of 1c with TBAF led to extremely rapid reaction and a 39% yield of 1O2 (as 3-O2).

Figure 1
Trapping substrates and products
Table 1
Generation of 1O2 from 1c and 1da

Further exploring the TBAF-promoted reaction (Table 2), we found that the use of excess TBAF and 1c allowed consumption of furan 4 but failed to oxidize the less reactive 7. Concerned that overly rapid generation of 1O2 might allow escape from a saturated solution, we investigated the decomposition of excess (1.5 – 8 equiv) monoperester in the presence of CsF and Me4NOAc (TMA). Reactions were allowed to run for 30 min, but were typically complete (TLC) within 10 min. Complete consumption of all substrates was now observed. Citronellol (7) reacted to furnish a 91% yield of a 58:28:14 mixture of 7-O2, 9-O2, and ketone 8. The formation of the isomeric hydroperoxides is characteristic for reactions of 1O2 with 7;6,7 ketone 8 derives from base-promoted fragmentation of 7-O2.23 The CsF protocol was also successfully applied to monoperesters 1e and 2c.

Table 2
Protocols for preparative oxidation

Finally, 1O2 can be generated via in situ formation and decomposition of monoperoxysulfonates. Although we were unable to isolate a monoperoxysulfonate, reaction of 1b and terpinene (3) with toluenesulfonyl chloride (1.0 equiv) and KOtBu resulted in the rapid disappearance (TLC) of the dihydroperoxide and the formation of 3-O2 (Scheme 3).

Scheme 3
Generation of 1O2 from 1,1-dihydroperoxide

The unprecedented fragmentation described above could involve a Grob-like fragmentation,24 or, alternatively, decomposition of an unstable peroxetane derived from 4-exo tet attack of the peroxyanion on the activated peroxide (Scheme 4).25 Regardless of pathway, the fragmentation clearly requires both a highly dissociated peroxyanion and a peroxide activated towards heterolytic O-O scission. For example, the monoperesters do not generate oxygen in the absence of base, while we found the 1,1-dihydroperoxides to be unaffected by the bases employed in these studies.26 The efficiency of 1O2 production from the new fragmentation compares very favorably with known oxygen-generating systems.4,6,7,8

Scheme 4
Potential mechanisms

In conclusion, we have developed a new heterolytic fragmentation that allows efficient and rapid generation of 1O2 in nondeuterated organic solvents from readily available precursors. The clean regeneration of the parent ketone suggests an avenue for possible development of solid-supported or phase-separable reagents while the efficiency and rate of 1O2 production points to potential application as a power source for chemical oxygen/iodine lasers.30

Supplementary Material

1_si_001

2_si_002

Acknowledgments

Research was conducted with NSF funding (CH-0749916) in facilities remodeled with NIH support (RR016544). NMR spectra were acquired, in part, on instruments purchased with NSF support (MRI 0079750 and CHE 0091975).

Footnotes

Supporting Information Available: Experimental procedures and spectral characterization for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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5. The half-life of 1O2 ranges from 1–2 usec in H2O to 60 usec in CH3CN to nearly msec in perhalogenated solvents. See ref. 1a, and Wilkinson F, Helman WP, Ross AB. J Phys Chem Ref Data. 1995;24:663.
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16. Dihydroperoxide 1b is not detonated by a hammer blow and melts without decomposition at 78–80 °C. However, even though no hazards were experienced in the course of this work, any preparative work with peroxides should be conducted with an awareness of the potential for spontaneous and exothermic decomposition reactions. See Supporting Information for references related to safe handling of peroxides.
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19. Monoester 1c is not detonated by a hammer blow and melts without decomposition at 37 °C. It is stable for less than a day at 60 °C.
20. Percarbonates of tertiary hydroperoxides and monoperesters of 1,1-dihydroperoxides are both known to undergo Criegee rearrangement: Villenave JJ, Filliatre C, Maillard B, Jaouhari R. Bull Soc Chim Belg. 1982;91:301.Velluz L, Amiard G, Martel J, Warnant J. Compt Rend. 1957;244:1937. We are uncertain as to the basis for the increased stability of 1c vs. 1d.
21. Reported yields are based upon either isolation or quantitative GC/MS of oxidation products relative to an internal standard; see Supporting Information for details. In general, the ketone byproduct (1a or 2a) was recovered in good yield from the decomposition reactions.
22. Due to the facility of self-sensitized oxidation, the use of DPBF for quantitative experiments should include control reactions or take care to exclude light and oxygen. See: Owakowsa M. J Chem Soc, Faraday Trans 1. 1984;80:2119.
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26. 1,1-Dihydroperoxides have been successfully bisalkylated in the presence of Cs2CO3: Kim HS, Nagai Y, Ono K, Begum K, Wataya Y, Hamada Y, Tsuchiya K, Masuyama A, Nojima M, McCullough KJ. J Med Chem. 2001;44:2357–61. [PubMed]
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