[7440-23-5]  · Na  · Sodium-Ammonia  · (MW 22.99) (NH3)

[7664-41-7]  · H3N  · Sodium-Ammonia  · (MW 17.04)

(strong reducing agent; reduces polyunsaturated hydrocarbons, carbonyl compounds, and other electron acceptors by electron transfer; strongly basic medium)

Physical Data: sodium: mp 97.8 °C; d 0.968 g cm-3. Ammonia: mp -77.7 °C; bp -33.4 °C.

Solubility: sodium is soluble to the extent of 25 g in 100 g ammonia at -33 °C.

Form Supplied in: sodium: flammable, metallic solid. Ammonia: compressed gas.

Purification: sodium: by melting and removal of oxide shell.2 Ammonia: by distillation from alkali metal solutions or passage through a drying tube containing barium oxide.1o

Handling, Storage, and Precautions: Sodium reacts violently with water (frequently explosively) and many other protic or halogenated solvents. While it is best handled under an inert atmosphere, it is usually stored under oil and common practice is to rinse the metal with hydrocarbon solvent and weigh it in air. Ammonia is a corrosive gas with a pungent odor, and must be handled in a good fume hood.

Sodium-Ammonia Solutions.

Sodium dissolves in liquid, anhydrous ammonia to form a deep-blue solution.3 At high concentrations, the solution separates into two liquid phases: the more dilute lower phase retains the deep-blue color while the upper phase has a metallic bronze appearance. Sodium reacts slowly with ammonia to produce sodium amide and hydrogen (eq 1), and this reaction is catalyzed by metals such as iron, cobalt, and nickel. The addition of trace amounts of iron salts to sodium-ammonia solutions is a convenient method for the preparation of Sodium Amide. Sodium-ammonia solution serves as an excellent reducing agent, with a half-wave potential of -2.59 V at -50 °C.1f

Birch Reduction of Aromatic Rings.

A major use of the sodium-ammonia reagent is the Birch reduction of aromatic rings to cyclohexadienes or sometimes higher levels of unsaturation.1,4,5 With benzene and less reactive aromatics (electron donor substituents), a proton donor is necessary and alcohols such as ethanol and t-butyl alcohol are commonly used. With more reactive aromatics (electron-withdrawing substituents and polynuclear aromatics), alcohols are generally unnecessary and are often deleterious.1n The kinetically controlled regiochemistry6 affords 1,4-dihydroaromatics (1,4-cyclohexadienes), with preference for the regioisomer with the maximum number of alkyl and/or alkoxy groups located on the remaining double bonds (i.e. the Birch rule).1h,7 Due to the limited solubility of many aromatic compounds in ammonia, cosolvents are often included in amounts of 25-35% relative to the volume of ammonia. While the most common cosolvents are ethers, such as diethyl ether and THF, protic solvents are sometimes used as both cosolvent and proton source. The range of metal concentrations is usually 0.1-0.5 g metal per 100 mL of ammonia, and highly concentrated solutions producing so-called metallic or bronze phases are generally avoided for Birch reductions.

Benzenes containing alkyl or ether substituents, especially where these substituents may be attached to vinyl positions in the product, are reduced in high yields by sodium-ammonia solution in the presence of ethanol or t-butyl alcohol (eq 2).8 The reduced ethers are useful in synthesis since subsequent acid hydrolysis leads to either nonconjugated or conjugated ketones; alternatively, products may be used directly in Diels-Alder reactions without hydrolysis (eq 3).9

In cases where this substitution pattern does not apply, however, reduction may be more difficult. For example, while 6-methoxytetralin is reduced smoothly by sodium-ammonia (eq 4), 5-methoxytetralin requires the use of Lithium with the alcohol added last (eq 5).5a,10,11 This latter procedure is known as the Wilds and Nelson modification,11 and is useful for less reactive substrates.

In polynuclear aromatics, regiochemistry generally follows protonation at the positions bearing the highest coefficients in the HOMO of the anionic intermediates, with sometimes little influence from substituents.1g,m Both anthracene (eq 6) and naphthalene (see below) are reduced in nearly quantitative yields by sodium-ammonia solution, provided that highly acidic quenching agents such as water or ammonium chloride are used rather than alcohols. However, some reductions of polynuclear aromatics are hard to control even under these conditions, and iron salts have been used to keep the reaction to a single stage. Such is the case with chrysene (eq 7) and phenanthrene.1o

Sodium vs. Lithium.

While sodium and lithium are the most commonly employed metals in Birch reduction (and Potassium to a lesser extent), the choice between these two metals is not always obvious due to the relative lack of comparison data. Although lithium is the most reactive due to its greater heat of solvation of the cation, its reactivity relative to sodium has probably been overestimated. Early experiments with sodium-ammonia solutions containing impurities in either the metal or ammonia probably showed diminished reactivity due to the greater sensitivity of sodium to amide formation catalyzed by trace contaminants.1f Thus metal selection may be based on expense, reactivity, or demonstrated superiority with a particular substrate. With very small scale reactions, the higher atomic weight of sodium may make it more practical due to accuracy in weighing. Lithium is the metal of choice when greater reactivity is required, but greater reactivity can sometimes lead to overreduction, whereupon sodium becomes the reagent of choice.

In many cases (eq 8)12,13 the results are comparable with either metal. However, a comparison of the two metals in the reduction of naphthalene14 shows best results with sodium at low temperatures (eq 9). At higher temperatures, and especially with lithium, protonation of the intermediates and subsequent isomerization of the 1,4-dihydro product to the 1,2-dihydro isomer leads to appreciable overreduction. The reductive methylation of naphthalene shows even greater differences between the metals, with lithium affording monoalkylation (95%) and sodium dialkylation (93%).14,15 This is due to a second alkylation via proton abstraction by amide ion during the alkylation step, a process that does not occur with lithium due to the relative lack of solubility of lithium amide in ammonia as compared to sodium amide. Similar results are observed for biphenyl, where lithium provides 99% monomethylation and sodium leads to 40% dimethylation with 10% trimethylation.16

Regioselectivity and Stereoselectivity.

The regiochemistry of Birch reduction is generally driven by electron densities in the radical anions, dianions, and monoanions that serve as intermediates in the reaction. An attempt has been made to control regiochemistry by use of trimethylsilyl substituents.17 For example, while 1-methylnaphthalene reduces exclusively in the unsubstituted ring, 1-methyl-4-trimethylsilylnaphthalene reduces in the silylated ring, and subsequent removal of the silyl group affords a misoriented Birch product (eq 10).

Excellent diastereoselectivities have been accomplished in the reductive methylation of benzoic acids where L-proline has been introduced as a chiral auxiliary (eq 11).18 Results with a variety of derivatives appear to give comparable results with sodium, lithium, or potassium.

Reduction of Carbonyl Functions.

The sodium-ammonia reduction of cyclic aliphatic ketones has some utility for the preparation of the more stable epimeric alcohols (such as 11a-hydroxy steroids) derived from sterically hindered ketones.11,m In other cases, product mixtures resemble those obtained with reagents such as borohydride. Similarly, esters may be reduced (Bouveault-Blanc reduction), but there is little advantage except with monoesters of diacids where the acid carbonyl remains unreduced (eq 12).19 Carboxamides are reduced by sodium-ammonia, often affording rather good results, as illustrated with the L-asparagine derivative (eq 13).

The most common use of sodium-ammonia reagent for the reduction of carbonyl compounds is the reduction of a,b-unsaturated ketones, and an extensive list of examples has been provided by Caine.1k Of special interest are bicycloalkenones, where the a,b-double bond is exocyclic to the second ring (eq 14).20 In these cases, stereochemistry is dictated by the protonation at the b-position, and the most favored transition states are those involving protonation of an axial anionic center; this most often results in the formation of trans products, although the stereochemistry can be reversed by 6b- and 7a-substituents. a,b-Unsaturated acids and esters can also be reduced, and reductive alkylation can be achieved by adding alkylating agents before the protic quench. However, Li and K have more often been used for the latter process.

Reductive Cleavage.

The sodium-ammonia reagent is effective in cleaving a variety of bonds including carbon-carbon (especially when strained), carbon-sulfur, carbon-nitrogen (especially positively charged nitrogen), and carbon-halogen; also allylic and benzylic alcohols, ethers and esters, epoxides, and many phenol ethers. While most halides are cleaved, vinyl halides are cleaved stereospecifically (eqs 15 and 16).21,22

Cleavage of the hydrazine derivative in eq 17 represents an especially useful application since Zinc-Acetic Acid, Aluminum Amalgam, and Raney Nickel all give no reduction.23 An interesting example of carbon-carbon bond cleavage is provided by an important step in the synthesis of (C2)-dioxa-C20-octaquinane (eq 18),24 and sulfur-sulfur bond cleavage is illustrated with the mercaptosulfinate synthon shown in eq 19.25 In the latter example, both sodium hydride and Sodium Borohydride gave poor results.

Reduction of Alkenes and Alkynes.

Conjugated polyenes are reduced by sodium-ammonia, although complications such as dimerization generally limit good results to cyclic systems and styrenes.1f The reduction of alkynes to trans-alkenes is well-known,1f,h the stereochemistry presumably resulting from the trans nature of the intermediate radical anion. Terminal alkynes can be protected by removal of the acidic proton by sodium amide, allowing synthetically useful strategies (eq 20).26

1. (a) Birch, A. J. QR 1950, 4, 69. (b) Birch, A. J.; Smith, H. QR 1958, 12, 17. (c) Smith. H. Organic Reactions in Liquid Ammonia, Chemistry in Nonaqueous Ionizing Solvents; Wiley: New York, 1963; Vol. 1, Part 2. (d) Zimmerman, H. E. In Molecular Rearrangements; de Mayo, P., Ed.; Wiley: New York, 1963. (e) Hückel, W. Fortschr. Chem. Forsch. 1966, 6, 197. (f) Smith, M. In Reduction: Techniques and Applications in Organic Synthesis; Augustine, R. L., Ed.; Dekker: New York, 1968. (g) Harvey, R. G. S 1970, 161. (h) Birch, A. J.; Subba Rao, G. S. R. In Advances in Organic Chemistry, Methods and Results; Taylor, E. C., Ed.; Wiley: New York, 1972. (i) Akhrem, A. A.; Reshetova, I. G.; Titov, Y. A. Birch Reduction of Aromatic Compounds; Plenum: New York, 1972. (j) Pradhan, S. K. T 1986, 42, 6351. (k) Caine, D. OR 1976, 23, 1. (l) Huffman, J. W. ACR 1983, 16, 399. (m) Hook, J. M.; Mander, L. N. Natural Prod. Rep. 1986, 3, 35. (n) Rabideau, P. W. T 1989, 45, 1579. (o) Rabideau, P. W. OR 1992, 42, 1.
2. Fieser, M.; Fieser, L. F. FF 1967, 1, 1022.
3. For a more detailed description of metal-ammonia solutions, see, for example: The Chemistry of Nonaqueous Solvents; Lagowski, J. J., Ed.; Academic: New York, 1967; Vol. 2, pp 265-317.
4. Wooster, C. B.; Godfrey, K. L. JACS 1937, 59, 596.
5. (a) Birch, A. J. JCS 1944, 430. (b) For a complete list of Birch's contributions, see: T 1988, 44 (10), v.
6. Birch, A. J.; Hinde, A. L.; Radom, L. JACS 1980, 102, 3370; 1980, 102, 4074; 1980, 102, 6430; 1981, 103, 284.
7. For recent discussions about mechanistic aspects of the Birch reduction, see Ref. 1n; also Zimmerman, H. E.; Wang, P. A. JACS 1990, 112, 1280; 1993, 115, 2205.
8. (a) Pearson, A. J.; Ham, P.; Ong, C. W.; Perrior, T. R.; Rees, D. C. JCS(P1) 1982, 1527. (b) Pearson, A. J. TL 1981, 22, 4033.
9. Evans, D. A.; Scott, W. L.; Truesdale, L. K. TL 1972, 121.
10. (a) House, H. O.; Blankley, C. J. JOC 1968, 33, 53. (b) Burkinshaw, G. F.; Davis, B. R.; Hutchinson, E. G.; Woodgate, P. D.; Hodges, R. JCS(C) 1971, 3002.
11. Wilds, A. L.; Nelson, N. A. JACS 1953, 75, 5360.
12. Pillai, K. M. R.; Murray, W. V.; Shooshani, I.; Williams, D. L.; Gordon, D.; Wang, S. Y.; Johnson, F. JMC 1984, 27, 1131.
13. Dryden, H. L.; Webber, G. M.; Burtner, R. R.; Cella, J. A. JOC 1961, 26, 3237.
14. Rabideau, P. W.; Burkholder, E. G. JOC 1978, 43, 4283.
15. Rabideau, P. W.; Harvey, R. G. TL 1970, 4139.
16. Lindow, D. F.; Cortez, C. N.; Harvey, R. G. JACS 1972, 94, 5406.
17. Marcinow, Z.; Clawson, D. K.; Rabideau, P. W. T 1989, 45, 5441.
18. Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A.; Welch, M. JACS 1988, 110, 7828. See also: (a) Schultz, A. G.; Sundararaman, P. TL 1984, 25, 4591. (b) Schultz, A. G.; Sundararaman, P.; Macielag, M.; Lavieri, F. P.; Welch, M. TL 1985, 26, 4575. (c) Schultz, A. G.; McCloskey, P. J.; Sundararaman, P.; Springer, J. P. TL 1985, 26, 1619. (d) McCloskey, P. J.; Schultz, A. G. H 1987, 25, 437. (e) Schultz, A. G.; McCloskey, P. J.; Court, J. J. JACS 1987, 109, 6493. (f) McCloskey, P. J.; Schultz, A. G. JOC 1988, 53, 1380. (g) Schultz, A. G.; Macielag, M.; Podhorez, D. E.; Suhadolnik, J. C.; Kullnig, R. K. JOC 1988, 53, 2456. (h) Schultz, A. G. ACR 1990, 23, 207. (i) Schultz, A. G.; Harrington, R. E. JACS 1991, 113, 4926. (j) Schultz, A. G.; Green, N. J. JACS 1991, 113, 4931. (k) Schultz, A. G.; Harrington, R. E.; Holoboski, M. A. JOC 1992, 57, 2973. (l) Schultz, A. G.; Taylor, R. E. JACS 1992, 114, 3937. (m) Schultz, A. G.; Taylor, R. E. JACS 1992, 114, 8341.
19. Paquette, L. A.; Nelson, N. A. JOC 1962, 27, 2272.
20. Granger, F.; Chapat, J. P.; Crassous, J.; Simon, F. BSF 1968, 4265.
21. Vogel, E.; Roth, H. D. AG(E) 1964, 3, 228.
22. Hoff, M. C.; Greenlee, K. W.; Boord, C. E. JACS 1951, 73, 3329.
23. Mellor, J. M.; Smith, N. M. JCS(P1) 1984, 2927.
24. Balogh, D.; Begley, W. J.; Bremner, J.; Wyvratt, M. J.; Paquette, L. A. JACS 1979, 101, 749.
25. Field, L.; Eswarakrishnan, V. JOC 1981, 46, 2025.
26. Dobson, N. A.; Raphael, R. A. JCS 1955, 3558.

Peter W. Rabideau

Louisiana State University, Baton Rouge, LA, USA

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