Palladium(II) Chloride-Copper(I) Chloride1

PdCl2-CuCl
(PdCl2)

[7647-10-1]  · Cl2Pd  · Palladium(II) Chloride-Copper(I) Chloride  · (MW 177.31) (CuCl)

[7758-89-6]  · ClCu  · Palladium(II) Chloride-Copper(I) Chloride  · (MW 99.00)

(oxidation of alkenes2)

Physical Data: PdCl2, mp 680 °C; CuCl, mp 430 °C.

Solubility: PdCl2 sol water, acetone, alcohol; CuCl insol most solvents.

Form Supplied in: PdCl2, red-brown crystals; CuCl white/pale green powder; both widely available.

Handling, Storage, and Precautions: CuCl is oxygen, moisture, and light sensitive and should be stored in the dark under an inert atmosphere.

Oxidation of Alkenes to Ketones and Aldehydes.

The combination of Palladium(II) Chloride and Copper(I) Chloride to oxidize alkenes to ketones and aldehydes is a variant of the well-known Wacker reaction, first used to make acetaldehyde from ethylene.3 The catalytic reaction comprises three individual steps (eq 1).

The first step is the PdII-induced oxidation of the alkene to give aldehyde/ketone and Pd0. The reduced palladium is reoxidized by Copper(II) Chloride which in turn is reduced to CuCl. Finally, CuCl is oxidized by O2 in the presence of HCl to regenerate CuCl2. A variety of other oxidants have been used to reoxidize the palladium, including CuCl/O2 (discussed herein), benzoquinone, FeCl3, H2O2, t-BuOOH, and heteropoly acids (reactions using CuCl2 or other Pd salts will be referenced occasionally in this article, given the similarity of various systems). CuCl2 is problematic because it produces chlorinated byproducts or otherwise lowers the yields. For this reason, CuCl in combination with O2 is favored.4

The solvent of the original Wacker reaction is water, which causes solubility problems and correspondingly lower rates with higher alkenes. This has been partially resolved by adding surfactants, both ionic and non-ionic,5 or by using solvents that dissolve both water and the organic substrate to a certain extent such as DMF.6 Alcohols, however, give acetals. Another problem is double bond isomerization, which is particularly severe in alcohols or acetic acid, but minor in DMF. For these reasons, DMF has become the solvent of choice for the oxidation of alkenes with PdCl2/CuCl.

Terminal alkenes are more reactive than disubstituted alkenes (eq 2),7 and are generally oxidized with good selectivity to methyl ketones. Aldehydes can also be formed in certain cases as discussed below. Indeed, terminal alkenes, which are easy to synthesize and relatively inert under a variety of conditions, may be considered masked methyl ketones because they are readily oxidized by the existing procedures.8 They can generally be oxidized selectively in the presence of various functional groups such as internal alkenes, alcohols, ketones, aldehydes, carboxylic acids and esters, ethers, acetals, chlorides, bromides, and sulfones among others, although cyclization reactions can sometimes occur. Alcohols can be oxidized if the reaction conditions become severe, and acetals are somewhat prone to hydrolysis due to the acidic nature of the reaction. Amine-containing substrates can be oxidized provided that the amine is protonated by acid.9

The reagents can distinguish among several terminal alkenes, with the least sterically hindered being more readily oxidized. For instance, in eq 3 the least hindered double bond required 3 h whereas the more hindered double bond required 36 h (71% overall yield).2 There are numerous applications of this procedure in natural product synthesis,10 with some of the more important being the preparation of 1,4-dicarbonyl compounds, cyclopentenones (eq 4), 1,5-dicarbonyl compounds, cyclohexenones (eq 5),11 and steroids.

Aldehydes can sometimes be obtained instead of methyl ketones, if the alkene is conjugated with an electron withdrawing group or if certain remote functionalities are present.12 The reaction conditions can also influence the ketone/aldehyde selectivity. For instance, the use of t-BuOH as solvent,13 or anhydrous 1,2-dichloroethane and HMPA,14 can significantly enhance the selectivity toward aldehyde formation.

Alkenes conjugated to carbonyl groups are poorly oxidized by PdCl2/CuCl and better results are obtained with peroxide reoxidants.15 Benzofurans can be hydrolytically and oxidatively cleaved.16 Internal alkenes are oxidized much more slowly than terminal alkenes,17 and are only poorly oxidized with the PdCl2 system unless certain functionality is present. For instance b,g-unsaturated esters or ketones can be oxidized to the respective ketones in 45-61% yield provided that the reaction is done in aqueous dioxane or THF (p-allyl Pd compounds are formed in DMF).18 In all cases, only the 1,4-dicarbonyl products were obtained (eq 6).

Similarly, allylic and homoallylic ethers and esters are regioselectively oxidized at the carbon more remote from the functional group (eq 7).19

Oxidation of Alkenes to Acetals.20

In alcohol solvents, acetals can be obtained from alkenes, but since an equivalent amount of water is generated under catalytic conditions, often the ketone is ultimately obtained.21 The yield of acetal is increased by using diol solvents. Electron withdrawing groups conjugated to a terminal double bond22 or the presence of certain remote functionalities23 favor oxidation at the terminal carbon. a,b-Unsaturated ketones require the use of Na2HPO4 to prevent simple Michael addition of the diol.22b The presence of a chiral auxiliary can lead to diastereomeric excesses as high as 95% (eq 8).24

Cyclization.

Intramolecular oxidative addition of an O-H or N-H bond to an alkene is a useful way to make heterocycles and can be accomplished with a number of Pd catalysts.20a,25 Specific examples with PdCl2/CuCl (or CuCl2) are given here. Diol alkenes can be cyclized to bicyclic acetals such as brevicomin;26 intramolecular optical induction can be observed, as in a similar synthesis of frontalin (eq 9).27

Aromatic heterocycles such as indoles can be synthesized by cyclizing b-amino alkenes and their toluenesulfonamide derivatives using PdII catalysts.28 Acetanilide derivatives, which cyclize poorly with other Pd catalysts,29 cyclize especially well with PdCl2/CuCl/O2 in 1,3-propanediol (eq 10).30 Styryl amides cyclize well under similar conditions (eq 11).31 Aliphatic amino alkenes, whose basicity interferes with catalytic cyclization, can be cyclized well in the presence of acid.32

Related Reagents.

Palladium(II) Acetate; Palladium(II) Chloride; Palladium(II) Chloride-Copper(II) Chloride.


1. (a) Maitlis, P. M. The Organic Chemistry of Palladium; Academic: New York, 1971; Vol. 2. (b) Tsuji, J. Organic Synthesis with Palladium Compounds; Springer: Berlin, 1980. (c) Henry, P. M. Palladium Catalyzed Oxidation of Hydrocarbons; Reidel: Dordrecht, 1980. (d) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic: New York, 1985.
2. (a) Tsuji, J. S 1984, 369. (b) Tsuji, J. COS 1991, 7, 449.
3. Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Rüttinger, R.; Kojer, H. AG 1959, 71, 176.
4. (a) McQuillin, F. J.; Parker, D. G. JCS(P1) 1974, 809. (b) Tsuji, J.; Shimizu, I.; Yamamoto, K. TL 1976, 2975.
5. (a) Alper, H.; Januszkiewicz, K.; Smith, D. J. H. TL 1985, 26, 2263. (b) Januszkiewicz, K.; Alper, H. TL 1983, 24, 5159.
6. Clement, W. H.; Selwitz, C. M. JOC 1964, 29, 241.
7. Dzhemileva, G. A.; Odinokov, V. N.; Dzhemilev, U. M. IZV 1987, 149.
8. General procedure given in: Tsuji, J.; Nagashima, H.; Nemoto, H.; Vedejs, E.; Gegner, J.; Mallman, T. K. OS 1984, 62, 9.
9. Dzhemileva, G. A.; Odinokov, V. N.; Dzhemilev, U. M. IZV 1988, 2148.
10. (a) Tsuji, J. ANY 1980, 333, 250. (b) Tsuji, J. Top. Curr. Chem. 1981, 91, 29. (c) Tsuji, J. PAC 1981, 53, 2371.
11. Hosomi, A.; Kobayashi, H.; Sakurai, H. TL 1980, 21, 955.
12. The following are some examples where various Pd-catalyzed oxidations have occurred at the terminal carbon: (a) Feringa, B. L. CC 1986, 909. (b) Nokami, J.; Ogawa, H.; Miyamoto, S.; Mandai, T.; Wakabayashi, S.; Tsuji, J. TL 1988, 29, 5181. (c) Bose, A. K.; Krishnan, L.; Wagle, D. R.; Manhas, M. S. TL 1986, 27, 5955. (d) Alyea, E. C.; Dias, S. A.; Ferguson, G.; McAlees, A. J.; McCrindle, R.; Roberts, P. J. JACS 1977, 99, 4985.
13. Wenzel, T. CC 1993, 862.
14. Hosokawa, T.; Aoki, S.; Takano, M.; Nakahira, T.; Yoshida, Y.; Murahashi, S.-I. CC 1991, 1559.
15. Tsuji, J.; Nagashima, H.; Hori, K. CL 1980, 257.
16. Gammill, R. B.; Nash, S. A. TL 1984, 25, 2953.
17. Kolb, M.; Bratz, E.; Dialer, K. J. Mol. Catal. 1977, 2, 399. Better results are obtained with heteropolyacids as reoxidants, especially with cyclic alkenes: Ogawa, H.; Fujinami, H.; Taya, K.; Teratani, S. BCJ 1984, 57, 1908.
18. Nagashima, H.; Sakai, K.; Tsuji, J. CL 1982, 859.
19. Tsuji, J.; Nagashima, H.; Hori, K. TL 1982, 23, 2679.
20. Reviews: (a) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic: New York, 1985, p 66. (b) Hosokawa, T.; Murahashi, S.-I. ACR 1990, 23, 49.
21. Lloyd, W. G.; Luberoff, B. J. JOC 1969, 34, 3949.
22. (a) Hosokawa, T.; Ohta, T.; Murahashi, S.-I. CC 1983, 848. (b) Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S.-I. JOC 1987, 52, 1758. (c) Hosokawa, T.; Ataka, Y.; Murahashi, S.-I. BCJ 1990, 63, 166.
23. Lai, J.-y.; Shi, X.-x.; Dai, L.-x. JOC 1992, 57, 3485.
24. Hosokawa, T.; Yamanaka, T.; Murahashi, S.-I. CC 1993, 117.
25. Review: Hosokawa, T.; Murahashi, S.-I. H 1992, 33, 1079.
26. (a) Byrom, N. T.; Grigg, R.; Kongkathip, B. CC 1976, 216. (b) Byrom, N. T.; Grigg, R.; Kongkathip, B.; Reimer, G.; Wade, A. R. JCS(P1) 1984, 1643.
27. Hosokawa, T.; Makabe, Y.; Shinohara, T.; Murahashi, S.-I. CL 1985, 1529. For similar syntheses, see: Hosokawa, T.; Nakajima, F.; Iwasa, S.; Murahashi, S.-I. CL 1990, 1387.
28. Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. JACS 1978, 100, 5800.
29. (a) Hegedus, L. S.; McKearin, J. M. JACS 1982, 104, 2444. (b) Harrington, P. J.; Hegedus, L. S. JOC 1984, 49, 2657.
30. Kasahara, A.; Izumi, T.; Murakami, S.; Miyamoto, K.; Hino, T. JHC 1989, 26, 1405.
31. Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara, A. JHC 1990, 27, 1419.
32. Pugin, B.; Venanzi, L. M. JACS 1983, 105, 6877.

Timothy T. Wenzel

Union Carbide Corporation, South Charleston, WV, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.