Zinc Amalgam1


[7440-66-6]  · Zn  · Zinc Amalgam  · (MW 65.39) (Hg)

[7439-97-6]  · Hg  · Zinc Amalgam  · (MW 200.59)

(reducing agent in the Clemmensen reduction,1 principally of aryl ketones to alkanes)

Solubility: insol organic solvents.

Preparative Methods: various forms of zinc (zinc turnings, wool, or powder, or mossy or granulated zinc) have been successfully employed, with preliminary activation of the metal by washing with hot HCl reportedly being of advantage. Amalgam formation is then accomplished by treatment of the zinc metal with an aqueous, possibly very slightly acidic, solution of HgCl2. After an appropriate length of time, the aq solution is decanted, replaced by fresh HCl, and the amalgam is used immediately.1a

Handling, Storage, and Precautions: as well as the corrosive nature of the (usually conc) HCl often employed, requiring normal chemical precautions, the mercury-containing wastes must be disposed of with due attention.

Clemmensen Reduction.1

The reagent as prepared above has been successfully used to reduce a wide variety of substances. If the substrate is not adequately soluble in the aqueous acidic solution, a miscible organic cosolvent may, on occasion, be usefully added. An immiscible solvent such as toluene, however, is commonly employed, but efficient stirring, and extended reaction times at reflux, are often required.

A more modern variant uses Zn/Hg (or Zn alone1) with HCl in anhydrous solvents. Reaction can often proceed much more rapidly, even at the lower temperatures sometimes used - a clear advantage if the substrate is not fully stable to acidic conditions. Phenolic acetate esters, for example, are typically cleaved under the classical reaction conditions.2

A great number of ketones, and some aldehydes, have been reduced by this method to the corresponding alkanes (eq 1), often in excellent yields.1 The reaction can tolerate a wide variety of aryl substituents.

Polyfunctional substrates, however, may exhibit some differences of reactivity. Thus, for example, a-, but not b- or longer, keto acids1a are reduced to a-hydroxy acids. Acyloins (1) may be completely reduced,3 or reduced only to the ketone4 or alkene (stilbene).5 ArCOCCl3 is reduced near-quantitatively to ArCH2CH36 (aromatic Cl7a or Br7b substitutents are usually retained, but dehalogenation may occur rarely as a side reaction7c). The a-thioether linkage of (2) is retained,8a but the S atom of (3) is excised8b before reduction of the carbonyls.

Some benzophenones may react as expected,1a but dimerization to pinacols has also been recorded in certain cases.9 Rarely, the alcohol may be formed,10 possibly intramolecularly trapped.6b a,b-Unsaturated ketones may reduce normally (but with competing dimerization)11a or cyclize1,11b (eq 2).11b On occasion, diketones may react by intramolecular pinacol coupling,12 but further reactions are common.1b

Compounds not suitable for reduction under these acidic Clemmensen conditions may still be reduced by the Wolff-Kishner13a reduction (or, better, its Huang-Minlon modification13b), which, being performed under basic conditions, serves as a complementary procedure.

Other Reductions.

The dithioesters RCS2Me may be reduced to the thioethers RCH2SMe,14 but with unspectacular yields. Nitro groups may also be reduced to amines.15 Certain benzylic alcohols16a or alcohol derivatives (e.g. a lactone16b) are cleaved to the alkane. Allylic alcohols17a or acetates17b are reduced with migration of the double bond. Sulfonyl chlorides may be reduced to the thiol.18

Ring Contractions.

3-Oxopiperidine (4) undergoes ring contraction19a,b under Clemmensen conditions (eq 3). The corresponding (3-oxo)azepine19c and their thia analogs19d react similarly, although the latter do so in lower yields.

3-Arylindoles20a and azaindoles20b can be formed by reduction of, for example, (5) in AcOH (eq 4) (see also Zinc-Acetic Acid for similar reactions).

Reformatsky-Type Reactions.

Zn/Hg has been noted to effect this reaction in a few cases, such as the propargyl bromide hydroxymethylation with Formaldehyde (eq 5)21 (note: no allene formed), and g-addition of a crotyl group (from the bromide) to a ketone.22

1. (a) Martin, E. L. OR 1942, 1, 155. (b) Vedejs, E. OR 1975, 22, 401.
2. Bramwell, P. S.; Fitton, A. O. JCS 1965, 3882.
3. Horner, L.; Weber, K. H. CB 1962, 95, 1227 (CA 1962, 57, 7199).
4. Smith, W. T., Jr. JACS 1951, 73, 1883.
5. Shriner, R. L.; Berger, A. OSC 1955, 3, 786.
6. Whalley, W. B. JCS 1951, 665.
7. (a) Witiak, D. T.; Stratford, E. S.; Nazareth, R.; Wagner, G.; Feller, D. R. JMC 1971, 14, 758. (b) Bergmann, E. D.; Loewenthal, E. BSF(2) 1952, 66 (CA 1953, 47, 3832). (c) Fieser, L. F.; Seligman, A. M. JACS 1938, 60, 170.
8. (a) Cagniant, P.; Cagniant, D. BSF(2) 1959, 1998 (CA 1961, 55, 27 364). (b) Bacchetti, T.; Canonica, L. G 1952, 82, 243 (CA 1953, 47, 8718).
9. Bradlow, H. L.; Vander Werf, C. A. JACS 1947, 69, 1254.
10. Ferles, M.; Attia, A. CCC 1973, 38, 611.
11. (a) Banerjee, A. K.; Alvárez, J. G.; Santana, M.; Carrasco, M. C. T 1986, 42, 6615. (b) Jefford, C. W.; Boschung, A. F. HCA 1976, 59, 962.
12. Greenhouse, R.; Borden, W. T. JACS 1977, 99, 1664.
13. (a) Todd, D. OR 1948, 4, 378. (b) Huang-Minlon JACS 1946, 68, 2487.
14. Mayer, R.; Scheithauer, S.; Kunz, D. CB 1966, 99, 1393 (CA 1966, 64, 19 477).
15. Yamada, F.; Makita, Y.; Suzuki, T.; Somei, M. CPB 1985, 33, 2162.
16. (a) Campbell, N.; Marks, A.; McHattie, G. V. JCS 1955, 1190. (b) Phillips, D. D.; Chatterjee, D. N. JACS 1958, 80, 4364.
17. (a) Elphimoff-Felkin, I.; Sarda, P. OSC 1988, 6, 769. (b) Honda, T.; Imai, M.; Keino, K.; Tsubuki, M. JCS(P1) 1990, 2677.
18. Caesar, P. D. OSC 1963, 4, 695.
19. (a) Leonard, N. J.; Ruyle, W. V. JACS 1949, 71, 3094. (b) Leonard, N. J.; Barthel, E., Jr. JACS 1949, 71, 3098. (c) Leonard, N. J.; Barthel, E., Jr. JACS 1950, 72, 3632. (d) Leonard, N. J.; Figueras, J., Jr. JACS 1952, 74, 917.
20. (a) Bruce, J. M. JCS 1959, 2366. (b) Atkinson, C. M.; Biddle, B. N. JCS(C) 1966, 2053.
21. Hanack, M.; Wächtler, A. E. F. CB 1987, 120, 727 (CA 1987, 107, 6809).
22. Cook, J. W.; Schoental, R. JCS 1945, 288.

Peter Ham

SmithKline Beecham Pharmaceuticals, Harlow, UK

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