Sodium Amalgam

Na(Hg)

[11110-52-4]  · Na  · Sodium Amalgam  · (MW 22.99)

(used in the preparation of alkenes and alkynes; to reductively cleave C-S and N-O bonds; for the reductive cleavage of quaternary phosphonium and arsonium salts; selective dehalogenation of aryl halides; also for the reduction of a variety of other functional groups)

Physical Data: the consistency and mp vary with the sodium content; 1.2% sodium is a semisolid at room temperature and melts completely at 50 °C; 5.4% sodium melts above 360 °C.

Solubility: sodium amalgams are decomposed by water but more slowly than sodium.

Form Supplied in: crushed solid; limited commercial availability.

Analysis of Reagent Purity: the amalgam can be analyzed for sodium by titration with 0.1 N sulfuric or hydrochloric acid.

Preparative Methods: several procedures for the preparation of sodium amalgam have been reported.1-4 Amalgams containing 2-6% sodium are the most commonly employed for synthetic work. The safest and most convenient procedure for the preparation of 2% sodium amalgam is the addition of Mercury(0) to ribbons of Sodium metal.5,6 No external heating is required with this protocol. The resulting solid can be crushed and stored indefinitely in a tightly stoppered container.

Handling, Storage, and Precautions: moisture sensitive; keep tightly closed.

Alkyne Synthesis.

Reductive cleavage of the triflate salts of vinyl phosphonium triflates with 2% sodium amalgam affords pure alkynes in good to excellent yield (eqs 1 and 2).7 This represents a significant improvement in yield and purity over the method involving thermal cleavage of acyl ylides. The highest yields are obtained when one group is aryl (eq 2). Alkynes are also obtained in respectable yields by the reductive elimination of enol phosphates of b-oxo sulfones with the reagent (6%) in DMSO-THF (eq 3).8

Longer reaction times are required for nonconjugated enol phosphates. Aromatic cis- and trans-enediol diesters are reported to give the corresponding diaryl alkynes in modest yield by reductive elimination with the reagent (eq 4).9 This procedure has been modified to provide for a one-pot operation in which 4 equiv of an aromatic acyl chloride is treated with an excess of the reagent in ether.9

Alkene Synthesis.

The preparation of trans-alkenes from the reaction of b-alkoxy or acyloxy sulfones with sodium amalgam has been reported (eq 5).10 Trisubstituted and tetrasubstituted precursors generally give disappointing results. Stereoselective introduction of the double bond in a total synthesis of diumycinol was accomplished with this method (eq 6).11 This protocol is effective when other standard conditions fail.

Desulfurization.12-17

This reaction has perhaps found the widest use of the reagent. The value of sulfides, sulfoxides, and sulfones in organic synthesis is increased by the ease with which their removal is accomplished. For example, sulfones are conveniently hydrogenolyzed with 6% reagent in boiling ethanol (eq 7).12 The use of disodium hydrogen phosphate is recommended as a buffer with the reagent in some applications with allylic sulfones and b-keto sulfides (eqs 8 and 9).15

Desulfonylation of unsaturated a,b-unsaturated acetals with the reagent in buffered methanolic medium gives the reduced products as a mixture of isomers (eq 10).17 Hydrolysis of the mixture affords the desired a,b-unsaturated ketone as the major product. b-Hydroxynitriles have been prepared in good yield and with retention of stereochemistry by the action of the 2% reagent in wet THF on sulfonylisoxazolines (eqs 11 and 12).18 The addition of aqueous phosphate buffer is sometimes required to prevent further hydrogenolysis (eq 12).

Enantiomerically pure 4,5-dihydroisoxazoles are available by selective desulfurization of 3-p-tolylsulfinylmethyl-4,5-dihydroisoxazoles with the reagent in a buffered medium (eq 13).19 Further treatment of the products with Raney Nickel affords the corresponding amino alcohols. Selective desulfurization of methyl 3,4,6-tri-O-benzyl-2-O-(methylsulfonyl)-a-D-mannopyranoside derivatives was accomplished with 6-7% reagent in 2-propanol and ether (eq 14).20 Treatment with Nickel in ethanol, Sodium Naphthalenide in THF, or Sodium-Ammonia resulted in removal of the benzyl groups as well.

N-O Bond Hydrogenolysis.

Reductive cleavage of N-O bonds is easily accomplished with the reagent (eqs 15 and 16). Keck reported the facile hydrogenolysis of the intramolecular Diels-Alder acyl-nitroso cycloadduct with excess reagent in a buffered alcoholic medium to yield a hydroxy lactam (eq 15).21 Similarly, Jager subjected dihydroisoxazoles to hydrogenolysis with 6% sodium amalgam to afford the corresponding 1,3-amino alcohols (eq 16).22 The syn and anti stereoselectivity is reported to be lower with this reagent than with Lithium Aluminum Hydride. This method of N-O bond reduction is less common than those using either Aluminum Amalgam or LAH.

Reductive Cleavage of Quaternary Phosphonium and Arsonium Salts.

Reductive cleavage of achiral and optically active quaternary and phosphonium salts with the reagent affords tertiary phosphines and arsines in high yields and with retention of configuration (eq 17).23

Selective reductive cleavage of the t-butyl group occurs in substrates containing both the t-butyl and benzyl substituents. The present method is reported to be superior to the conventional cathodic cleavage. Emde degradation of the quaternary ammonium chloride succeeds where the Hofmann method is unsuccessful (eq 18).24 In a similar fashion, hemimellitene was prepared by treating an aqueous suspension of the benzyltrimethylammonium iodide with a large excess of the reagent (eq 19).3

Dehalogenation of Aryl Halides.

Selective dehalogenation of aryl halides with the reagent in liquid ammonia has been found (eqs 20 and 21).25

Reduction of Miscellaneous Functional Groups.

Many additional functional groups react readily with the reagent to afford, in generally good yields, the corresponding reduced products. For example, phthalic acid reacts with the 3% reagent to yield trans-1,2-dihydrophthalic acid in good yield (eq 22).4 a,b-Unsaturated carboxylic acids are also readily reduced by the reagent. Thus cinnamic acid is reduced to hydrocinnamic acid with 2.5% reagent in aqueous base (eq 23).4

The product from the condensation of vanillin and creatinine is reduced by 3% reagent in water (eq 24).26 Xanthone was reduced to xanthydrol with the reagent in ethanol (eq 25).1 Triphenylchloromethane is converted to triphenylmethylsodium by action of the 1% reagent (eq 26).2 Oximes are reduced to primary amines with the 2.5% reagent with acetic acid in ethanol (eq 27).27 One of the oldest applications of sodium amalgam involves the reduction of aldonolactones to aldoses (eq 28).28

Other Applications.

Several recent useful miscellaneous applications have been reported. They include the use of the 3% reagent for the reduction of 1-ethyl-4-methoxycarbonylpyridinium iodide in acetonitrile to produce a stable radical (eq 29);29 the use of the reagent as a catalyst to initiate aromatic radical nucleophilic substitution reactions;30 and the use of the reagent for the preparation of novel titanium catalysts for the stereoselective cyclization of diynes to (E,E)-exocyclic dienes.31


1. Holleman, A. F. OSC 1941, 1, 554.
2. Renfrow, W. B., Jr.; Hauser, C. R. OSC 1943, 2, 607.
3. Brasen, W. R.; Hauser, C. R. OSC 1963, 4, 508.
4. McDonald, R. N.; Reineke, C. E. OS 1970, 50, 50.
5. Fieser, L. F.; Fieser, M. FF 1967, 1, 1030.
6. Blomquist, A. T.; Hiscock, B. F.; Harpp, D. N. JOC 1966, 31, 4121.
7. Bestmann, H. J.; Kumar, K.; Schaper W. AG(E) 1983, 22, 167.
8. (a) Lythgoe, B.; Waterhouse, I. TL 1978, 2625. (b) Lythgoe, B.; Waterhouse, I. JCS(P1) 1979, 2429.
9. Horner, L.; Dickerhof, K. CB 1983, 116, 1615.
10. Julia, M.; Paris, J.-M. TL 1973, 4832.
11. Kocienski, P.; Todd, M. CC 1982, 1078.
12. Posner, G. H.; Brunelle, D. J. TL 1973, 935.
13. Dabby, R. E.; Kenyon, J.; Mason, R. F. JCS 1952, 4881.
14. Julia, M.; Blasioli, C. BSF(2) 1976, 1941.
15. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R. TL 1976, 3477.
16. Chang, Y.-H.; Pinnick, H. W. JOC 1978, 43, 373.
17. Paquette, L. A.; Kinney, W. A. TL 1982, 23, 131.
18. Wade, P. A.; Bereznak, J. F. JOC 1987, 52, 2973.
19. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gilardi, A.; Restelli, A. JCS(P1) 1985, 2289. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Restelli, A. JCS(P1) 1985, 2293.
20. Webster, K. T.; Eby, R.; Schuerch, C. Carbohydr. Res. 1983, 123, 335.
21. (a) Keck, G. E.; Fleming, S. A. TL 1978, 4763. (b) Keck, G. E. TL 1978, 4767.
22. (a) Jager, V.; Buss, V. LA 1980, 101. (b) Jager, V.; Buss, V.; Schwab, W. LA 1980, 122.
23. Horner, L.; Dickerhof, K. PS 1983, 15, 213.
24. Emde, H.; Kull, H. AP 1936, 274, 173.
25. Austin, E.; Alonso, R. A.; Rossi, R. A. JCR(S) 1990, 190.
26. Deulofeu, V.; Guerrero, T. J. OSC 1955, 3, 586.
27. Hochstein, F. A.; Wright, G. F. JACS 1949, 71, 2257.
28. Sperber, N.; Zaugg, H. E.; Sandstrom, W. M. JACS 1947, 69, 915.
29. Kosower, E. M.; Waits, H. P. OPP 1971, 3, 261.
30. Austin, E.; Alonso, R. A.; Rossi, R. A. JOC 1991, 56, 4486.
31. Nugent, W. A.; Calabrese, J. C. JACS 1984, 106, 6423.

Keith R. Buszek

Kansas State University, Manhattan, KS, USA



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