ZINC AMALGAM

1

Zinc Amalgam

1

Zn/Hg

(Zn)
[7440-66-6]

Zn

(MW 65.39)

InChI = 1/Zn
InChIKey = HCHKCACWOHOZIP-UHFFFAOYAS
(Hg)
[7439-97-6]

Hg

(MW 200.59)

InChI = 1/Hg
InChIKey = QSHDDOUJBYECFT-UHFFFAOYAU

(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 forma-
tion is then accomplished by treatment of the zinc metal with
an aqueous, possibly very slightly acidic, solution of HgCl

2

.

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 na-

ture 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 use-
fully 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 alone

1

) 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.

R

1

R

2

O

R

1

R

2

R

1

usually aryl

Zn/Hg

(1)

Polyfunctional substrates, however, may exhibit some differ-

ences of reactivity. Thus, for example, α-, but not β- or longer,
keto acids

1a

are reduced to α-hydroxy acids. Acyloins (1) may

be completely reduced,

3

or reduced only to the ketone

4

or

alkene (stilbene).

5

ArCOCCl

3

is reduced near-quantitatively to

ArCH

2

CH

3

6

(aromatic Cl

7a

or Br

7b

substitutents are usually

retained, but dehalogenation may occur rarely as a side reaction

7c

).

The α-thioether linkage of (2) is retained,

8a

but the S atom of

(3) is excised

8b

before reduction of the carbonyls.

R

2

O

R

1

OH

S

O

O

S

O

(CH

2

)

10

(1)

(2)

(3)

Some benzophenones may react as expected,

1a

but dimeriza-

tion to pinacols has also been recorded in certain cases.

9

Rarely,

the alcohol may be formed,

10

possibly intramolecularly trapped.

6b

α

,β-Unsaturated ketones may reduce normally (but with compet-

ing dimerization)

11a

or cyclize

1,11b

(eq 2).

11b

On occasion, dike-

tones may react by intramolecular pinacol coupling,

12

but further

reactions are common.

1b

(2)

O

OAc

Zn/Hg, HCl, Et

2

O, Ac

2

O

–35 °C, 20 min

65%

Compounds not suitable for reduction under these acidic

Clemmensen conditions may still be reduced by the Wolff–
Kishner

13a

reduction (or, better, its Huang–Minlon modi-

fication

13b

), which, being performed under basic conditions,

serves as a complementary procedure.

Other Reductions. The dithioesters RCS

2

Me may be reduced

to the thioethers RCH

2

SMe,

14

but with unspectacular yields.

Nitro groups may also be reduced to amines.

15

Certain benzylic

alcohols

16a

or alcohol derivatives (e.g. a lactone

16b

) are cleaved

to the alkane. Allylic alcohols

17a

or acetates

17b

are reduced with

migration of the double bond. Sulfonyl chlorides may be reduced
to the thiol.

18

Ring Contractions.

3-Oxopiperidine (4) undergoes ring

contraction

19a,b

under Clemmensen conditions (eq 3). The

corresponding (3-oxo)azepine

19c

and their thia analogs

19d

react

similarly, although the latter do so in lower yields.

(3)

N
H

O

N
H

Zn/Hg, conc HCl

reflux, 12 h

(4)

65–71%

3-Arylindoles

20a

and azaindoles

20b

can be formed by reduction

of, for example, (5) in AcOH (eq 4) (see also Zinc–Acetic Acid
for similar reactions).

(4)

N

N

Ph

N
H

Ph

Zn/Hg, aq. AcOH

reflux, 2 h

(5)

88%

Reformatsky-type Reactions.

Zn/Hg has been noted to

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

formed), and γ-addition of a crotyl group (from the bromide) to a
ketone.

22

(5)

Zn/Hg, CH

2

O, THF

0–40 °C, 3.5 h

Br

OH

57%

1.

(a) Martin, E. L., Org. React. 1942, 1, 155. (b) Vedejs, E., Org. React.
1975, 22, 401.

2.

Bramwell, P. S.; Fitton, A. O., J. Chem. Soc. 1965, 3882.

3.

Horner, L.; Weber, K. H., Chem. Ber. 1962, 95, 1227 (Chem. Abstr. 1962,
57

, 7199).

4.

Smith, W. T., Jr., J. Am. Chem. Soc. 1951, 73, 1883.

5.

Shriner, R. L.; Berger, A., Org. Synth., Coll. Vol. 1955, 3, 786.

6.

Whalley, W. B., J. Chem. Soc. 1951, 665.

7.

(a) Witiak, D. T.; Stratford, E. S.; Nazareth, R.; Wagner, G.; Feller, D.
R., J. Med. Chem. 1971, 14, 758. (b) Bergmann, E. D.; Loewenthal,
E., Bull. Soc. Chem Fr. Part 2 1952, 66 (Chem. Abstr. 1953, 47, 3832).
(c) Fieser, L. F.; Seligman, A. M., J. Am. Chem. Soc. 1938, 60, 170.

8.

(a) Cagniant, P.; Cagniant, D., Bull. Soc. Chem Fr. Part 2 1959, 1998
(Chem. Abstr. 1961, 55, 27 364). (b) Bacchetti, T.; Canonica, L., Gazz.
Chim. Ital. 1952

, 82, 243 (Chem. Abstr. 1953, 47, 8718).

9.

Bradlow, H. L.; Vander Werf, C. A., J. Am. Chem. Soc. 1947, 69, 1254.

10.

Ferles, M.; Attia, A., Collect. Czech. Chem. Commun. 1973, 38, 611.

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.

Chim. Acta 1976

, 59, 962.

12.

Greenhouse, R.; Borden, W. T., J. Am. Chem. Soc. 1977, 99, 1664.

13.

(a) Todd, D., Org. React. 1948, 4, 378. (b) Huang-Minlon J. Am. Chem.
Soc. 1946

, 68, 2487.

14.

Mayer, R.; Scheithauer, S.; Kunz, D., Chem. Ber. 1966, 99, 1393 (Chem.
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.
(b) Phillips, D. D.; Chatterjee, D. N., J. Am. Chem. Soc. 1958, 80, 4364.

17.

(a) Elphimoff-Felkin, I.; Sarda, P., Org. Synth., Coll. Vol. 1988, 6, 769.
(b) Honda, T.; Imai, M.; Keino, K.; Tsubuki, M., J. Chem. Soc., Perkin
Trans. 1 1990

, 2677.

18.

Caesar, P. D., Org. Synth., Coll. Vol. 1963, 4, 695.

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.
(c) Leonard, N. J.; Barthel, E., Jr., J. Am. Chem. Soc. 1950, 72, 3632.
(d) Leonard, N. J.; Figueras, J., Jr., J. Am. Chem. Soc. 1952, 74, 917.

20.

(a) Bruce, J. M., J. Chem. Soc. 1959, 2366. (b) Atkinson, C. M.; Biddle,
B. N., J. Chem. Soc. (C) 1966, 2053.

21.

Hanack, M.; Wächtler, A. E. F., Chem. Ber. 1987, 120, 727 (Chem. Abstr.
1987, 107, 6809).

22.

Cook, J. W.; Schoental, R., J. Chem. Soc. 1945, 288.

Peter Ham

SmithKline Beecham Pharmaceuticals, Harlow, UK

A list of General Abbreviations appears on the front Endpapers