Isoprene

[78-79-5]  · C5H8  · Isoprene  · (MW 68.13)

(Diels-Alder diene and dienophile; natural product subunit)

Physical Data: mp -145.9 °C; bp 34.1 °C; d 0.6809 g cm-3 (20 °C).1

Solubility: sol most common hydrocarbons; practically insol water; forms binary and ternary azeotropes.1

Form Supplied in: liquid; widely available.

Preparative Methods: because of its industrial importance, many sequences have been developed suitable for the large scale synthesis of isoprene.1 Eq 1 shows a typical example.3

Handling, Storage, and Precautions: highly flammable; forms explosive peroxides; forms dangerous ozonide; low narcotic effect but does cause bronchial irritation at high concentrations.2

Diels-Alder Chemistry.

Isoprene (1) has been employed as a substrate in numerous Diels-Alder reactions. Several publications have considered the equilibrium (eq 2) between the cisoid isomer (s-cis-1) and the transoid isomer (s-trans-1).4 While the difference in energy between the two isomers is insufficient to affect the Diels-Alder reactions, this equilibrium may play a role in certain polymerizations.5 The facile Diels-Alder reaction between Maleic Anhydride and isoprene has received considerable mechanistic scrutiny.6 Similarly, combination of (1) and Cyclopentadiene yields the expected 2-isopropenylbicyclo[2.2.1]hept-5-ene.7 Reaction of isoprene (1) and Acrylic Acid (5) affords the carboxylic acid (6) (eq 3), a useful synthetic intermediate as is shown by its conversion into terpinolene (7) (eq 4).8 Reaction of isoprene and 2-bromoacrylic acid gives a reasonable yield (eq 5) of the a-bromo acid (8).9

Lewis acid catalyzed reaction of (1) and Methyl Vinyl Ketone (9) exhibits a significant variation in isomer distribution of (10) and (11) (eq 6) versus the same reaction run without catalysis.10 This effect also extends to the reaction of (1) and Acrolein.10 Tin(IV) Chloride mediated reaction of isoprene with isopropenyl methyl ketone (12) gives 1,4-dimethylcyclohex-3-enyl ketone (13) in good yield (eq 7).11 This methodology can be extended to the synthesis of unusual spirocycles. Tin(IV) chloride mediated reaction of isoprene with 2-methylenecyclopentanone (eq 8) provides (14) and (15) in a ratio of 24:1. In the absence of the catalyst, the ratio of (14) to (15) fell to 2:1.12 Applied to sesquiterpene synthesis, this approach has led to successful production of a-alaskene (16) and d-acoradiene (17) using 3-methyl-2-methylenecyclopentanone as the common precursor.13

For Diels-Alder reactions that combine isoprene with a simple dienophile (18) in a reaction that is able to produce two regioisomers (19) and (20), the so-called 1,4-isomer (19) will generally predominate (eq 9).14

Like cyclopentadiene, isoprene may function as both a diene and a dienophile. With careful exclusion of peroxides and air, dimerization of isoprene affords four substituted cyclohexene Diels-Alder adducts (21), (22), (23), and (24) as well as two dimethylcyclooctadienes (25) and (26).15

An interesting Diels-Alder variant consists of the reaction of isoprene with the vinylchromium complex (27) to give (28) and (29) with 92:8 regioselectivity (eq 10). Adduct (28) is easily transformed into (30).16

Reaction of isoprene with 2-(morpholino)acrylonitrile (31) gives the adducts (32) and (33) (eq 11).17 Each of these adducts can be hydrolyzed with water in ether/THF in the presence of Silver(I) Nitrate to yield the corresponding unconjugated cyclohexenone. Combination of isoprene, the anthracene analog (34) of juglone, and boron triacetate provides (35) (eq 12) exclusively in 60% yield.18

Dimerization, Oligomerization, and Polymerization.

Even in the typical Diels-Alder reaction, two byproduct cyclooctadienes, (25) and (26), are produced.15 A variety of conditions and reagents (e.g. UV radiation,19 sulfuric acid,20 and Ziegler-Natta catalysts21) have been explored for dimerization of isoprene. The ratio of products, especially with regards to the presence of higher homologs, often varies greatly from one system to another. An efficient head-to-tail dimerization of isoprene can be achieved with certain organophosphine-ligated palladium catalysts.22 One known reaction (eq 13) affords a reasonable yield of the trans,trans,cis-cyclododecatriene (36) as well as the linear dimer (37).23 Numerous radical-mediated dimerizations of isoprene have been examined.24 Polymerization of isoprene is also a vast topic, but the fundamental references have been reviewed.1 Isoprene undergoes reaction with alkali metals, tritylsodium, and other organometallic reagents to produce a variety of products.25 Thus reaction of isoprene, Sodium Naphthalenide, and diethylamine gives (38) and (39) (eq 14).26

Building Block Chemistry.

Novel means exist whereby isoprene units (or their equivalents) can be attached to preexisting substrates in order to create the skeletal backbone of complex natural products. That these isoprenylation reactions27 are often quite efficient is illustrated (eq 15) by the reaction of (1) with substituted phenols (40) to afford 2,2-dimethylchromans (41).28 Epoxidation of isoprene produces a monoepoxide that has proven a useful synthetic intermediate.29

Miscellaneous Chemistry.

Isoprene reacts with dichlorophenylphosphine to afford, after hydrolysis, 3-methyl-1-phenyl-2-phospholene 1-oxide.30 Isoprene undergoes an interesting cycloaddition with a,a-dihalo ketones in the presence of Zinc/Copper Couple on alumina to yield cycloheptenones.31 Halogenation of (1) and carbene addition to (1) have been reviewed.1

Related Reagents.

1,3-Butadiene; Cyclopentadiene; 1-Methoxy-3-trimethylsilyloxy-1,3-butadiene; 1-Trimethylsilyloxy-1,3-butadiene; 2-Trimethylsilyloxy-1,3-butadiene.


1. Saltman, W. M. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.; Wiley: New York, 1981; vol. 13, pp 819-837.
2. Isoprene Technical Data Bulletin No. 1; Goodrich-Gulf Chemicals: Cleveland, OH, 1968.
3. (a) Hydrocarbon Process 1971, 50, 170. (b) DeMalde, M. Chim. Ind. (Milan) 1963, 45, 665.
4. (a) Compton, D. A. C.; George, W. O.; Maddams, W. F. JCS(P2) 1976, 1666. (b) Gresser, J.; Rajbenbach, A.; Szwarc, M. JACS 1960, 82, 5820. (c) Dodziuk, H. J. Mol. Struct. 1974, 20, 317. (d) LeFeure, R. J. W.; Sundaran, K. M. S. JCS 1963, 3547. (e) LeFeure, R. J. W.; Sundaran, K. M. S. JCS 1964, 3518.
5. (a) Orr, R. J. J. Polym. Sci. 1962, 58, 843. (b) Szwarc, M. J. Polym. Sci. 1959, 40, 583. (c) Stearns, R. S.; Forman, L. E. J. Polym. Sci. 1959, 41, 381. (d) Kuntz, I.; Gerber, A. J. Polym. Sci. 1960, 42, 299.
6. (a) Craig, D.; Shipman, J. J.; Fowler, R. B. JACS 1961, 83, 2885. (b) Gil-Av, E.; Herzberg-Minzly, Y. Proc. Chem. Soc. 1961, 316. (c) Bergman, F.; Eschinazi, H. E. JACS 1943, 65, 1405.
7. Plate, A. F.; Belikova, N. A. ZOB 1960, 30, 3953.
8. Krapcho, A. P.; Jahngen, E. G. E. JOC 1974, 39, 1322.
9. Kuehne, M. E.; Horne, D. A. JOC 1975, 40, 1287.
10. Lutz, E. F.; Bailey, G. M. JACS 1964, 86, 3899.
11. Kreiser, W.; Haumesser, W.; Thomas, A. F. HCA 1974, 57, 164.
12. Williamson, K. L.; Hsu, Y. F. L. JACS 1970, 92, 7385.
13. Marx, J. N.; Norman, L. R. TL 1973, 4375.
14. (a) Holmes, H. L. OR 1948, 4, 60. (b) Hennis, H. E. JOC 1963, 28, 2570. (c) Titov, Y. A.; Kuznetsova, A. I. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1960, 1297. (d) Nazarov, I. N.; Titov, Y. A.; Kuznetsova, A. I. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1959, 1412. (e) Volkov, A. N.; Bogdanova, A. V.; Shostakovskii, M. F. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1962, 1280. (f) Shostakovskii, M. F.; Bogdanova, A. V.; Volkov, A. N. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1962, 1284.
15. Onishchenko, A. S. Diene Synthesis; Davey: New York, 1964; pp 592-596.
16. Wulff, W. D.; Bauta, W. E.; Kaesler, R. W.; Lankford, P. J.; Miller, R. A.; Murray, C. K.; Yang, D. C. JACS 1990, 112, 3642.
17. Boucher, J.-L.; Stella, L. T 1985, 41, 875.
18. Russell, R. A.; Collin, G. J.; Sterns, M.; Warrener, R. N. TL 1979, 4229.
19. (a) Hammond, G. S., Turro, N. J.; Liu, R. S. H. JOC 1963, 28, 3297. (b) Liu, R. S. H.; Turro, N. J.; Hammond, G. S. JACS 1965, 87, 3406.
20. Greensfelder, B. S.; Voge, H. H. Ind. Eng. Chem. 1945, 37, 983.
21. (a) Heck, R. F. Organotransition Metal Chemistry; Academic: New York, 1974; p 162. (b) Misono, A.; Uchida, Y.; Hidai, M.; Ohsawa, Y. BCJ 1966, 39, 3425. (c) Candlin, J. P.; Janes, W. H. JCS(C) 1968, 1856.
22. Neilan, J. P.; Laine, R. M.; Cortese, N.; Heck, R. F. JOC 1976, 41, 3455.
23. (a) U.S. Patent 3 429 940. (b) Fr. Patent 1 393 071.
24. (a) Srinivasan, R. JACS 1962, 84, 4141. (b) Crowley, K. J. T 1965, 21, 1001. (c) Crowley, K. J. Proc. Chem. Soc. 1962, 334. (d) Pearson, J. M.; Szwarc, M. Trans. Faraday Soc. 1964, 60, 553. (e) Rajbenbach, A.; Szwarc M. Proc. Roy. Soc. (London) 1959, A251, 394. (f) Trecker, D. J.; Brandon, R. L.; Henry, J. P. CI(L) 1963, 652. (g) Conant, J. B.; Scherp, H. W. JACS 1931, 53, 1941.
25. (a) Shiihara, I.; Hoskyns, W. F.; Post, H. W. JOC 1961, 26, 4000. (b) Wittig, G.; Schloeder, H. LA 1955, 592, 38. (c) Wittig, G.; Wittenberg, D. LA 1957, 606, 1. (d) Akutagawa, S.; Otsuka, S. JACS 1975, 97, 6870. (e) Suga, K.; Watanabe, S. S 1971, 91. (f) Fujita, T.; Suga, K.; Watanabe, S. CI(L) 1973, 231.
26. Fujita, T.; Suga, K.; Watanabe, S. AJC 1974, 27, 531.
27. (a) Sakurai, H.; Hosomi, A.; Saito, M.; Sasaki, K.; Iguchi, H.; Sasaki, J.; Araki, Y. T 1983, 39, 883. (b) Mehta, G.; Reddy, A. V. TL 1979, 2625. (c) Hosomi, A.; Saito, M.; Sakurai, H. TL 1979, 429.
28. Bolzoni, L.; Casiraghi, G.; Casnati, G.; Sartori, G. AG(E) 1978, 17, 684.
29. (a) Pummerer, R.; Reindel, W. CB 1933, 66, 335. (b) Aithie, G. C. M.; Miller, J. A. TL 1975, 4419. (c) Fujimura, O.; Takai, K.; Utimoto, K. JOC 1990, 55, 1705. (d) Eletti-Bianchi, G.; Centini, F.; Re, L. JOC 1976, 41, 1648. (e) Tamura, M.; Suzukamo, G. TL 1981, 22, 577.
30. (a) Quin, L. D.; Barket, T. P. CC 1967, 914. (b) Hunger, K.; Hasserodt, U.; Korte, F. T 1964, 20, 1593. (c) McCormack, W. B. OS 1963, 43, 73.
31. (a) Chidgey, R.; Hoffmann, H. M. R. TL 1977, 2633. (b) Vinter, J. G.; Hoffmann, H. M. R. JACS 1974, 96, 5466.

John L. Belletire & R. Jeffery Rauh

University of Cincinnati, OH, USA



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