· Dibenzoyl Peroxide
· (MW 242.23)
(initiator for radical reactions such as allylic and benzylic halogenation,5 radical addition to carbon-carbon multiple bonds to form C-heteroatom (halogen, S, Si, Ge, P, and N) bonds,2 C-H additions across multiple bonds4 in an intermolecular1 and intramolecular6 fashion, homolytic aromatic substitution in electron-deficient heteroaromatics;7 reagent for benzoyloxylation of enolates, enamines, and other electron-rich systems;8 oxidizing agent for N, P, Si, S, and Se compounds; oxidizing agent in redox chain reactions with transition metals9)
Alternate Name: DBP.
Physical Data: mp 103-106 °C (dec).
Solubility: sparingly sol water or alcohol; sol benzene, chloroform, and ethers.
Form Supplied in: white crystalline powder.
Analysis of Reagent Purity: the peroxide content can be established by iodometric titration.10
Handling, Storage, and Precautions: explosive; harmful if exposed by ingestion or skin contact; strong oxidizer; susceptible to explosion by shock, friction or heat; autoignition temperature 79 °C. Caution: all experiments involving peroxy compounds should be carried out behind a safety shield. Excess peroxide should be destroyed before working up the reaction.11
Dibenzoyl peroxide is a widely used initiator for radical reactions. It undergoes thermal homolytic cleavage of the O-O bond with a half-life of about 1 h at 95 °C (eq 1).12 This homolysis may also be effected by light as well as transition metal catalysts.9
Initiator for Halogenation Reactions.
Even though DBP has been used as an initiator for functionalization of unactivated hydrocarbons (eq 2), more common are the applications for halogenations of allylic (eqs 3 and 4)5,13 and benzylic (eq 5)14 positions. DBP also serves as an initiator for halogenation of silanes by replacement of a Si-H bond.15
Initiator for Radical Additions to Unsaturated Compounds.
The primary steps in the radical addition of X-Y to unsaturated compounds are shown in eqs 6-10. By far the largest application of this reagent16 is in radical chain polymerization of vinyl compounds such as vinyl chloride, vinyl acetate, butadiene derivatives, styrene, and various acrylic monomers. The topic of polymerization is beyond the scope of this article. Excellent monographs and reviews dealing with this subject are available.17
Formation of a 1:1 adduct (eq 9) will be favored when X-Y is an efficient chain transfer agent. For reactions of short chain lengths, an excess of X-Y and a steady concentration of the initiator should be present in the reaction medium.2 Since the original discoveries of the anti-Markovnikov addition of HBr (eq 11),18 and of carbon tetrachloride to alkenes (eq 12),1 a large number of related reactions have been reported. DBP catalyzes the addition of a wide variety of X-Y type compounds to carbon-carbon multiple bonds. These include H-Br, thiols, mercapto acids, thiophosphoric acids, hydrogen sulfide, silanes, germanes,
phosphorus halides, phosphorus acids and esters, and various oxides of nitrogen.2 The important C-C bond-forming reactions are described below.
Intermolecular Carbon-Carbon Bond Forming Reactions.
When the compound X-Y contains an activated C-H bond, initiators such as DBP and di-t-butyl peroxide initiate the radical reactions by abstraction of this hydrogen (eq 10) from the substrate, and the resultant radical enters the radical chain cycle. Substrates of this kind are poor chain transfer agents and typically a higher concentration of the substrate and a steady supply of the initiator are needed for a viable reaction. Representative examples of carbon-carbon bond forming reactions initiated by DBP are listed in Table 111,41-45 (see also 1,1-Di-t-butyl Peroxide). A more complete list is available in two excellent reviews.1,4
The intermolecular additions may be coupled to an intramolecular cyclization (eq 13)19 or an SH2 reaction.20 The SH2 reactions are useful for the synthesis of epoxy compounds (Scheme 1) or lactones (eq 14). Radicals from nitriles, ketones, ethers, and polyhaloalkanes also undergo similar addition-substitution reactions.
Addition of various a-carboxyl radicals to alkenes is best carried out with a high temperature initiator such as di-t-butyl peroxide, although reports of using DBP are known. This subject has been extensively reviewed.21
The intramolecular versions of the C-H additions mentioned above have been extensively studied by Julia and co-workers (eqs 15 and 16).6 These reactions, while not very practical from a synthetic standpoint, nonetheless have played a key role in the development of radical synthetic methodology.22,23 A related cyclization (eq 17) was used by Barton and co-workers for the synthesis of a tetracycline intermediate.24 An interesting variant of this reaction is the cyclization of geranyl acetate to a benzoyloxyfarnesyl acetate (eq 18).25 The radical reaction is initiated by DBP and the Cu salt serves as an oxidant for the final cyclized radical.
Initiator for Radical Additions to Electron-Deficient Heteroaromatic Compounds.
Minisci and co-workers have developed radical-mediated homolytic substitution reactions for various electron-deficient aromatic nuclei.7 Radicals derived from alkyl halides, dioxane,26 dimethylformamide,27 and even cyclohexane26 can be added to protonated heteroaromatic compounds. The addition of a cyclohexyl radical (eq 19) proceeds in good yields even when the reaction medium contains a large excess of chloroform and acetonitrile. The highly electrophilic nature of the &bdot;CCl3 and &bdot;CH2CN completely inhibits the reaction towards the protonated heterocycle. Under these conditions, ethyl acetate gives the electrophilic radical &bdot;CH2CO2Et and the nucleophilic radical MeCO2&bdot;CHMe, but only the latter adds.
As an Oxidant.
Benzoyl peroxide oxidizes ethers to a-benzoyloxy ethers, and alkyl sulfides to a-benzyloxy sulfides (eq 20).28 Tertiary amines are oxidized to amine oxides, while secondary amines give N-benzoyloxy amines (eq 21).29 In the presence of a mild base, DBP acts as a very selective oxidizing agent for hydroquinones.30 Aldehydes and benzylic positions are not affected. Two key steps in the Eschenmoser synthesis of the corrin nucleus make use of DBP (eqs 22 and 23).31 Secondary alcohols are oxidized to ketones with dibenzoyl peroxide and Nickel(II) Bromide (eq 24).32 A benzoyl peroxide-mediated annulation used by Kishi in the synthesis
of sporidesmin B (eq 25)33 is likely to be an ionic (vis-á-vis radical) reaction. A 1:1 mixture of DBP and Hexamethyldisilazane has been used as an epoxidizing agent for acid-sensitive alkenic substrates.34
As a Benzoyloxylation Agent.8
Under catalysis by Iodine, benzoyloxylation of aromatic and heteroaromatic compounds takes place. Nucleophilic compounds such as malonates,35 phenols,36 enamines, and indoles37 also react with DBP to give benzoyloxylation products. Secondary amines are converted into N-benzyloxy amines (eq 20).29 An improved protocol38 for this reaction and an application for synthesis of N5-hydroxy-L-ornithine39 have appeared in the literature.
Benzoyl peroxide has been used for a-benzoyloxylation of an enolate (eq 26).40
- 1. Walling, C.; Huyser, E. S. OR 1963, 13, 91. This article also gives an excellent account of the early history of the developments in radical chemistry.
- 2. Stacey, F. W.; Harris, J. F., Jr. OR 1963, 13, 150.
- 3. Kropf, H. MOC 1988, E13.
- 4. Ghosez, A.; Giese, B.; Zipse, H. MOC 1989, E19a, 533.
- 5. Greenwood, F. L.; Kellert, M. D.; Sedlak, J. OSC 1963, 4, 108.
- 6. Julia, M. ACR 1971, 4, 386. See also: Julia, M. PAC 1974, 40, 553.
- 7. Minisci, F. S 1973, 1.
- 8. Bouillon, G.; Lock, C.; Schank, K. In The Chemistry of Functional Groups, Peroxides; Patai, S.; Ed.; Wiley: New York, 1983; p 279.
- 9. Sheldon, R. A.; Kochi, J. K. Metal Catalyzed Oxidations of Organic Compounds; Academic: New York, 1981.
- 10. Kropf, H.; Munke, S. MOC 1988, E13, 1386.
- 11. La Zerte, J. D.; Koshar, R. J. JACS 1955, 77, 910.
- 12. Walling, C. T 1985, 41, 3887.
- 13. Grob, C. A.; Gagneux, A. HCA 1957, 40, 130.
- 14. Swenton, J. S.; Madigan, D. M. T 1972, 28, 2703. See also: Campaigne, E.; Tullar, B. F. OSC 1963, 4, 921.
- 15. Nagai, Y.; Yamazaki, K.; Shiojima, I.; Kobori, N.; Hayashi, M. JOM 1967, 9, 21.
- 16. Bevington, J. C. Angew. Makromol. Chem. 1991, 185-186, 1.
- 17. See for example: Hodge, P. In Comprehensive Organic Chemistry; Barton, D. H. R. Ed.; Pergamon: Oxford, 1991; Vol. 5, p 833 and references therein.
- 18. Tedder, J. M.; Walton, J. C. ACR 1976, 9, 183.
- 19. Dowbenko, R. OSC 1973, 5, 93.
- 20. Maillard, B.; Kharrat, A.; Rakotomanana, F.; Montaudon, E.; Gardrat, C. T 1985, 41, 4047.
- 21. Vogel, H.-H. S 1970, 99. For an attractive organometallic variation of several of the reactions described in this article, see: Heiba, E. I.; Dessau, R. M.; Rodewald, P. G. JACS 1974, 96, 7977. See also: Fristard, W. F.; Peterson, J. R. JOC 1985, 50, 10.
- 22. Beckwith, A. L. J. T 1981, 37, 3073.
- 23. Curran, D. P. S 1988, 417 and 489.
- 24. Barton, D. H. R.; Clive, D. L. J.; Magnus, P. D.; Smith, G. JCS(C) 1971, 2193.
- 25. Breslow, R.; Olin, S. S.; Groves, J. T. TL 1968, 1837. For possible mechanisms, see: Kochi, J. K. Science 1967, 155, 415. See also: Lellemand, J. Y.; Julia, M.; Mansuy, D. TL 1973, 4461.
- 26. Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M.; Giordano, C. JOC 1986, 51, 4411.
- 27. Gardini, G. P.; Minisci, F.; Palla, G.; Arnone, A.; Galli, R. TL 1971, 59.
- 28. Baldwin, J. E.; Christie, M. A.; Haber, S. B.; Kruse, L. I. JACS 1976, 98, 3045. See also: Henbest, H. B.; Reid, J. A. W.; Stirling, C. J. M. JCS 1964, 1220.
- 29. Buchi, G.; Fliri, H.; Shapiro, R. JOC 1977, 42, 2192. See also: Huisgen, R.; Bayerlein, F. LA 1960, 630, 138; Zinner, G. AP 1970, 303, 488 and Refs. 38 and 39.
- 30. McCay, P. G.; Mitchell, A. S. AJC 1989, 42, 2295.
- 31. Eschenmoser, A. QR 1970, 24, 366.
- 32. Doyle, M. P.; Patrie, W. J.; Williams, S. B. JOC 1979, 44, 2955. See also: Doyle, M. P.; Dow, R. L.; Bagheri, V.; Patrie, W. J. TL 1980, 21, 2795.
- 33. Nakatsuka, S.; Fukuyama, T.; Kishi, Y. TL 1974, 1549.
- 34. Baruah, R. N.; Sharma, R. P.; Baruah, J. N. C1(L) 1983, 825.
- 35. Larsen, E. H.; Lawesson, S.-O. OS 1973, 5, 379.
- 36. Walling, C.; Hodgdon, R. B., Jr. JACS 1958, 80, 228.
- 37. Kanaoka, Y.; Aiura, M.; Hariya, S. JOC 1971, 36, 458. See also: Nishio, T.; Yuyama, M.; Omote, Y. CL 1975, 480.
- 38. Biloski, A. J.; Ganem, B. S 1983, 537. See also: White, E. H.; Ribi, M.; Cho, L. K.; Egget, N.; Dzadzic, P. M.; Todd, M. J. JOC 1984, 49, 4886.
- 39. Milewska, M. J.; Chimiak, A. S 1990, 233. See also: Milewska, M. J.; Chimiak, A. AJC 1987, 40, 1919.
- 40. Greene, A. E.; Muller, J. C.; Ourisson, G. TL 1972, 3375. See also: Huffman, J. W.; Desai, R. C.; Hillenbrand, G. F. JOC 1984, 49, 982.
- 41. Jacobs, R. L.; Ecke, G. G. JOC 1963, 28, 3036.
- 42. Patrick, T. M., Jr.; Erickson, F. B. OSC 1963, 4, 430.
- 43. Wiberg, K. B.; Waddell., S. T.; Laidig, K. TL 1986, 27, 1553.
- 44. Bentrude, W. G.; Darnall, K. R. JACS 1968, 90, 3588.
- 45. Sanderson, J. R.; Lin, J. J.; Duranleau, R. G.; Yeakey, E. L.; Marquis, E. T. JOC 1988, 53, 2859.
T. V. (Babu) RajanBabu
The Ohio State University, Columbus, OH, USA
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