ZINC AMALGAM 1
retained, but dehalogenation may occur rarely as a side reaction7c).
Zinc Amalgam1
The Ä…-thioether linkage of (2) is retained,8a but the S atom of
(3) is excised8b before reduction of the carbonyls.
Zn/Hg
O O
O
S
(Zn)
R1
S
R2
[7440-66-6] Zn (MW 65.39)
OH
InChI = 1/Zn O
(CH2)10
InChIKey = HCHKCACWOHOZIP-UHFFFAOYAS
(1) (2)(3)
(Hg)
[7439-97-6] Hg (MW 200.59)
Some benzophenones may react as expected,1a but dimeriza-
InChI = 1/Hg
tion to pinacols has also been recorded in certain cases.9 Rarely,
InChIKey = QSHDDOUJBYECFT-UHFFFAOYAU
the alcohol may be formed,10 possibly intramolecularly trapped.6b
(reducing agent in the Clemmensen reduction,1 principally of
Ä…,²-Unsaturated ketones may reduce normally (but with compet-
aryl ketones to alkanes)
ing dimerization)11a or cyclize1,11b (eq 2).11b On occasion, dike-
tones may react by intramolecular pinacol coupling,12 but further
Solubility: insol organic solvents.
reactions are common.1b
Preparative Methods: various forms of zinc (zinc turnings, wool,
or powder, or mossy or granulated zinc) have been successfully
O OAc
Zn/Hg, HCl, Et2O, Ac2O
employed, with preliminary activation of the metal by washing  35 °C, 20 min
(2)
with hot HCl reportedly being of advantage. Amalgam forma-
65%
tion is then accomplished by treatment of the zinc metal with
an aqueous, possibly very slightly acidic, solution of HgCl2.
Compounds not suitable for reduction under these acidic
After an appropriate length of time, the aq solution is decanted,
replaced by fresh HCl, and the amalgam is used immediately.1a Clemmensen conditions may still be reduced by the Wolff
Handling, Storage, and Precautions: as well as the corrosive na- Kishner13a reduction (or, better, its Huang Minlon modi-
fication13b), which, being performed under basic conditions,
ture of the (usually conc) HCl often employed, requiring normal
serves as a complementary procedure.
chemical precautions, the mercury-containing wastes must be
disposed of with due attention.
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
Clemmensen Reduction.1 The reagent as prepared above has
alcohols16a or alcohol derivatives (e.g. a lactone16b) are cleaved
been successfully used to reduce a wide variety of substances.
to the alkane. Allylic alcohols17a or acetates17b are reduced with
If the substrate is not adequately soluble in the aqueous acidic
migration of the double bond. Sulfonyl chlorides may be reduced
solution, a miscible organic cosolvent may, on occasion, be use-
to the thiol.18
fully added. An immiscible solvent such as toluene, however, is
commonly employed, but efficient stirring, and extended reaction
Ring Contractions. 3-Oxopiperidine (4) undergoes ring
times at reflux, are often required.
contraction19a,b under Clemmensen conditions (eq 3). The
A more modern variant uses Zn/Hg (or Zn alone1) with HCl
corresponding (3-oxo)azepine19c and their thia analogs19d react
in anhydrous solvents. Reaction can often proceed much more
similarly, although the latter do so in lower yields.
rapidly, even at the lower temperatures sometimes used  a clear
advantage if the substrate is not fully stable to acidic conditions.
Zn/Hg, conc HCl
O
Phenolic acetate esters, for example, are typically cleaved under
reflux, 12 h
(3)
the classical reaction conditions.2
65 71%
N
N
A great number of ketones, and some aldehydes, have been
H
H
reduced by this method to the corresponding alkanes (eq 1), often
(4)
in excellent yields.1 The reaction can tolerate a wide variety of
aryl substituents.
3-Arylindoles20a and azaindoles20b can be formed by reduction
of, for example, (5) in AcOH (eq 4) (see also Zinc Acetic Acid
O
Zn/Hg
for similar reactions).
(1)
R1 R2
R1 R2
Ph
Ph
Zn/Hg, aq. AcOH
R1 usually aryl
reflux, 2 h
(4)
N 88%
N
N
Polyfunctional substrates, however, may exhibit some differ-
H
(5)
ences of reactivity. Thus, for example, Ä…-, but not ²- or longer,
keto acids1a are reduced to Ä…-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 Reformatsky-type Reactions. Zn/Hg has been noted to
ArCH2CH36 (aromatic Cl7a or Br7b substitutents are usually effect this reaction in a few cases, such as the propargyl bromide
Avoid Skin Contact with All Reagents
2 ZINC AMALGAM
hydroxymethylation with Formaldehyde (eq 5)21 (note: no allene 11. (a) Banerjee, A. K.; Alvárez, J. G.; Santana, M.; Carrasco, M. C.,
Tetrahedron 1986, 42, 6615. (b) Jefford, C. W.; Boschung, A. F., Helv.
formed), and Å‚-addition of a crotyl group (from the bromide) to a
Chim. Acta 1976, 59, 962.
ketone.22
12. Greenhouse, R.; Borden, W. T., J. Am. Chem. Soc. 1977, 99, 1664.
Br OH
13. (a) Todd, D., Org. React. 1948, 4, 378. (b) Huang-Minlon J. Am. Chem.
Zn/Hg, CH2O, THF
0 40 °C, 3.5 h Soc. 1946, 68, 2487.
(5)
14. Mayer, R.; Scheithauer, S.; Kunz, D., Chem. Ber. 1966, 99, 1393 (Chem.
57%
Abstr. 1966, 64, 19 477).
15. Yamada, F.; Makita, Y.; Suzuki, T.; Somei, M., Chem. Pharm. Bull. 1985,
33, 2162.
16. (a) Campbell, N.; Marks, A.; McHattie, G. V., J. Chem. Soc. 1955, 1190.
1. (a) Martin, E. L., Org. React. 1942, 1, 155. (b) Vedejs, E., Org. React. (b) Phillips, D. D.; Chatterjee, D. N., J. Am. Chem. Soc. 1958, 80, 4364.
1975, 22, 401.
17. (a) Elphimoff-Felkin, I.; Sarda, P., Org. Synth., Coll. Vol. 1988, 6, 769.
2. Bramwell, P. S.; Fitton, A. O., J. Chem. Soc. 1965, 3882. (b) Honda, T.; Imai, M.; Keino, K.; Tsubuki, M., J. Chem. Soc., Perkin
Trans. 1 1990, 2677.
3. Horner, L.; Weber, K. H., Chem. Ber. 1962, 95, 1227 (Chem. Abstr. 1962,
57, 7199). 18. Caesar, P. D., Org. Synth., Coll. Vol. 1963, 4, 695.
4. Smith, W. T., Jr., J. Am. Chem. Soc. 1951, 73, 1883. 19. (a) Leonard, N. J.; Ruyle, W. V., J. Am. Chem. Soc. 1949, 71, 3094.
(b) Leonard, N. J.; Barthel, E., Jr., J. Am. Chem. Soc. 1949, 71, 3098.
5. Shriner, R. L.; Berger, A., Org. Synth., Coll. Vol. 1955, 3, 786.
(c) Leonard, N. J.; Barthel, E., Jr., J. Am. Chem. Soc. 1950, 72, 3632.
6. Whalley, W. B., J. Chem. Soc. 1951, 665.
(d) Leonard, N. J.; Figueras, J., Jr., J. Am. Chem. Soc. 1952, 74, 917.
7. (a) Witiak, D. T.; Stratford, E. S.; Nazareth, R.; Wagner, G.; Feller, D.
20. (a) Bruce, J. M., J. Chem. Soc. 1959, 2366. (b) Atkinson, C. M.; Biddle,
R., J. Med. Chem. 1971, 14, 758. (b) Bergmann, E. D.; Loewenthal,
B. N., J. Chem. Soc. (C) 1966, 2053.
E., Bull. Soc. Chem Fr. Part 2 1952, 66 (Chem. Abstr. 1953, 47, 3832).
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(c) Fieser, L. F.; Seligman, A. M., J. Am. Chem. Soc. 1938, 60, 170.
1987, 107, 6809).
8. (a) Cagniant, P.; Cagniant, D., Bull. Soc. Chem Fr. Part 2 1959, 1998
22. Cook, J. W.; Schoental, R., J. Chem. Soc. 1945, 288.
(Chem. Abstr. 1961, 55, 27 364). (b) Bacchetti, T.; Canonica, L., Gazz.
Chim. Ital. 1952, 82, 243 (Chem. Abstr. 1953, 47, 8718).
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10. Ferles, M.; Attia, A., Collect. Czech. Chem. Commun. 1973, 38, 611. SmithKline Beecham Pharmaceuticals, Harlow, UK
A list of General Abbreviations appears on the front Endpapers