Maleic Anhydride1

[108-31-6]  · C4H2O3  · Maleic Anhydride  · (MW 98.06)

(reactive dienophile and dipolarophile; undergoes thermal and photochemical [2 + 2] cycloadditions; alkylating and acylating agent)

Alternate Name: MA.

Physical Data: mp 54-56 °C; bp 200 °C; d 1.314 g cm-3.

Solubility: sol ether, acetone, chloroform, ethyl acetate, benzene, toluene, carbon tetrachloride, petroleum ether, dioxane.

Form Supplied in: white solid; widely available. Drying: at 100 °C.

Purification: recrystallization from acetone/petroleum ether or from hot water. Alternatively sublimed.

Handling, Storage, and Precautions: toxic, an irritant, and corrosive. Avoid inhalation. Store in a tightly sealed brown bottle; avoid exposure to moisture.

Cycloadditions.

Maleic anhydride has served as an excellent dienophile in a variety of Diels-Alder cycloadditions.2 The use of purified maleic anhydride in the Diels-Alder reaction is recommended in order to remove trace amounts of maleic acid, which may lead to polymerization or diene isomerization. Of historical significance, the first [4 + 2] cycloaddition reported by Otto Diels and Kurt Alder employed maleic anhydride as a dienophile and butadiene as the diene component. Since the initial report, many variations on the cycloaddition process have been published. Reaction conditions vary from below rt to greater than 250 °C. As a representative example, the Diels-Alder reaction of Cyclopentadiene and MA proceeds at rt to provide the endo product in quantitative yield (eq 1).3 Heterosubstituted dienes typically undergo endo selective cycloaddition reactions with maleic anhydride (eqs 2-4).4 Maleic anhydride also reacts stereoselectively with ortho-quinodimethanes. For example, photoenolization of o-tolualdehyde stereoselectively generates an (E)-dienol, which is trapped by MA (eq 5).5

A number of maleic anhydride derivatives have been examined in the Diels-Alder reaction. For example, the conjugate addition of thiophenol to maleic anhydride followed by chlorination and finally dehydrochlorination affords 2-(phenylthio)maleic anhydride in good overall yield (eq 6). 2-(Phenylthio)maleic anhydride reacts with cyclopentadiene at rt to provide the corresponding Diels-Alder adduct in 83% yield.6 Maleic anhydride readily undergoes Diels-Alder reactions with furan. However, the Diels-Alder reaction of furan with dimethylmaleic anhydride fails due to the rapid reversion of the Diels-Alder adduct to starting material. On the other hand, the dihydrothiophene derivative of maleic anhydride reacts with furan at high pressure to produce a 20:80 mixture of endo and exo Diels-Alder adducts in good yield (eq 7).7 Subsequent Raney Nickel desulfurization produces the dihydro version of the Diels-Alder adduct corresponding to the dimethylmaleic anhydride product.

Maleic anhydride undergoes [2 + 2] photocycloadditions with a variety of substrates. Aromatic species (eq 8),8 isolated alkenes (eq 9),9 and alkynes (eq 10)10 readily undergo sensitized photochemical cycloadditions with maleic anhydride. Photochemical [2 + 2] cycloadditions usually employ benzophenone as a sensitizer; however, other sensitizers such as acetophenone, propiophenone, benzaldehyde, and diacetylbenzene have also been utilized. For example, irradiation of a solution of benzene and maleic anhydride in the presence of benzophenone produces a 2:1 maleic anhydride/benzene adduct, which presumably arises from a photochemical [2 + 2] photocycloaddition followed by a Diels-Alder reaction of the resulting diene with a second equivalent of maleic anhydride (eq 8). Irradiation of a solution of maleic anhydride in acetone produces the Paterno-Büchi product in good yield (eq 11).11 Maleic anhydride can also undergo thermal [2 + 2] cycloadditions. For example, thermolysis of a mixture of allene and maleic anhydride produces the corresponding cyclobutane in 22-26% yield (eq 12) (also see Dimethyl Maleate).12

Maleic anhydride reacts with a variety of dipoles to produce the corresponding cycloadducts in good to excellent chemical yield. For example, cycloadditions with nitrones,13 diazo compounds,14 nitrile oxide,15 and azomethine ylides16 have been reported (eqs 13-16).

Acylations and Alkylations.

Maleic anhydride acylates aromatic ring systems under Friedel-Crafts acylation conditions.17 A typical example is the acylation of benzene (eq 17) to provide b-benzoylacrylic acid in 80-85% yield.18 The useful quinone naphthazarin can be prepared from dihydroxybenzene and MA under rigorous reaction conditions (eq 18).19 Substituted aryl-1,3-dioxocarboxylic acids have been prepared by the generation of enolates from aryl ketones followed by acylation with MA (eq 19).20

Maleic anhydride can also partake in Michael-type reactions. As previously described, thiophenol adds in a conjugate fashion to maleic anhydride (eq 6).6 On the other hand, amines undergo acylation with maleic anhydride to afford the corresponding amides (eqs 20 and 21).21 It should be mentioned that maleic anhydride is a poor radical acceptor relative to other commonly used radical traps (see Dimethyl Fumarate and Dimethyl Maleate) due to competing polymerization. For example, benzyl radicals generated by heating a mixture of dibenzylmercury and MA at 100 °C produce only 22% of benzylsuccinic anhydride (eq 22).22

Miscellaneous.

Under thermal conditions, alkenes bearing an allylic hydrogen will undergo an ene reaction with maleic anhydride. Historically, the first reported ene reaction employed maleic anhydride as the enophile component. This reaction has proven to be quite general and typically requires elevated temperatures to occur (eqs 23 and 24). As an alternative to harsh thermal conditions, high pressure has been reported to induce the ene reaction. For example, maleic anhydride reacts with b-pinene at elevated temperatures to afford the corresponding ene adduct (eq 23), while the same reaction occurs at ambient temperature utilizing 4000 MPa pressure to afford the same adduct in 74% yield.23

Maleic anhydride has been utilized as a ligand in a coupling reaction between an alkenylzirconium(IV) complex and a (h3-allylic)palladium chloride dimer to produce a 1,4-diene (eq 25).24 In contrast, the overall rate of the coupling reaction was retarded by the addition of a phosphine ligand.

Related Reagents.

Diethyl Malonate; Methylthiomaleic Anhydride; N-Phenylmaleimide.


1. (a) Trivedi, B. C.; Culbertson, B. M. Maleic Anhydride; Plenum: New York, 1982.
2. Kloetzel, M. C. OR 1948, 4, 1.
3. Alder, K.; In Neuere Methoden der Praparativen Organischen Chemie; Foerst, W., Ed.; Verlag Chemie: Berlin, 1943; Part I, p 251. (b) Alder, K.; In Neuere Methoden der Praparativen Organischen Chemie; Foerst, W., Ed.; Verlag Chemie: Berlin, 1953; Part II, p 125.
4. (a) Danishefsky, S.; Kitahara, T.; Schuda, P. F.; Golob, D.; Dynak, J.; Stevens, R. V. OS 1983, 61, 147 (b) Oppolzer, W.; Bieber, L.; Francotte, E. TL 1979, 4537. (c) Kozikowski, A. P.; Huie, E.; Springer, J. P. JACS 1982, 104, 2059.
5. Sammes, P. G. T 1976, 32, 405.
6. Kaydos, J. A.; Smith, D. L. JOC 1983, 48, 1096.
7. (a) Dauben, W. G.; Kessel, C. R.; Takemura, K. H. JACS 1980, 102, 6893. (b) Dauben, W. G.; Gerdes, J. M.; Smith, D. B. JOC 1985, 50, 2576.
8. Grovenstein, Jr., E.; Rao, D. V.; Taylor, J. W. JACS 1961, 83, 1705.
9. Owsley, D. C.; Bloomfield, J. J. JOC 1971, 36, 3768.
10. Smith, III, A. B.; Boscelli, D. JOC 1983, 48, 1217.
11. Turro, N. J.; Wreide, P. A. JOC 1969, 34, 3562.
12. Stevenson, H. B.; Cripps, H. N.; Williams, J. K. OS 1963, 43, 27.
13. (a) Hendrickson, J. B.; Pearson, D. A. TL 1983, 24, 4657. (b) Huisgen, R.; Grashey, R.; Seidl, H. CB 1969, 102, 736. (c) Joucla, M.; Hamelin, D. G. J. T 1973, 29, 2315.
14. Hampel, W. ZC 1970, 10, 225.
15. Quilico, Q.; D'Aleontres, G. S.; Grunanger, P. G 1950, 80, 479.
16. Heine, H. W.; Peavy, R. TL 1965, 3123.
17. (a) Berliner, E. OR 1949, 5, 229. (b) Pets, A. G. In Friedel-Crafts and Related Reactions; Olah, G., Ed.; Wiley: New York, 1964; Vol. 3.
18. Grummitt, O.; Becker, E. I.; Miesse, C. OSC 1955, 3, 109.
19. (a) Zahn, K. v.; Ochwat, P. LA 1928, 462, 72. (b) FF 1967, 1, 1027.
20. Murray, W. V.; Wachter, M. P. JOC 1990, 55, 3424.
21. (a) Anshutz, R. LA 1891, 259, 137. (b) Takaya, T.; Ono, T.; Okuda, Y. CA 1974, 81, 119 908. (c) Jacobi, P.; Blum C. A.; DeSimone, R. W.; Udodong, U. E. S. JACS 1991, 113, 5384.
22. Bass, K.; Nababsingh, P. CI(L) 1965, 1599.
23. (a) Arnold, R. T.; Showell, J. S. JACS 1957, 79, 419. (b) Gladysz, J. A.; Yu, N. CC 1978, 599.
24. Temple, J. S.; Riediker, M.; Schwartz, J. JACS 1982, 104, 1310.

Gary A. Sulikowski & Michelle M. Sulikowski

Texas A&M University, College Station, TX, USA



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