Sodium Methoxide

NaOMe

[124-41-4]  · CH3NaO  · Sodium Methoxide  · (MW 54.03)

(highly basic solid capable of catalyzing numerous reactions, including condensations, dehydrohalogenations, and other base-catalyzed mechanisms; also acts as a nucleophile in SN2 and SNAr reactions)

Physical Data: mp >300 °C.

Solubility: sol methanol, ethanol, pentane, and DMSO, as well as a wide variety of other solvents; insol hydrocarbon solvents.

Form Supplied in: widely available commercially as a free flowing white powder of 95% purity.

Handling, Storage, and Precautions: flammable solid which spontaneously combusts at 70-80 °C; corrosive; sensitive to and may decompose upon contact with air and moisture; harmful if swallowed, inhaled, or absorbed through the skin; store in a cool, dry place. Capable of creating a dust explosion; keep away from heat, sparks, and flame; incompatible with chlorinated solvents; reacts violently with water and acids.

Basicity of Sodium Methoxide.

The basicity of sodium methoxide is highly dependent on the solvent medium. Solvation and separation of the sodium cation from the methoxide anion affects base strength,1 as does the degree of hydrogen bonding between the solvent and methoxide ion. Base strength and rates of base-catalyzed reactions may increase by several orders of magnitude in going from a polar protic solvent like methanol to a polar aprotic solvent like DMSO1,2 (see Potassium Methoxide-Dimethyl Sulfoxide). In comparison to other metalmethoxides, the basicity of sodium methoxide in methanol is greater than that of lithium methoxide but less than that of potassium methoxide.3 The same basicity order has also been found for solutions of the metal methoxides in DMSO.1

Uses as a Base.

Sodium methoxide is the preferred base in the Kolbe electrolytic coupling reaction in methanol.4 Methoxide ion is generated at the cathode, so only catalytic amounts of NaOMe are required.5 Sodium methoxide is the preferred base here because of its low cost and the low cost of methanol from which the methoxide is regenerated. Tashiro and co-workers6 have used the Kolbe electrolysis to synthesize 4-phenylbutyric acid (eq 1). Sodium methoxide has also found use as the preferred base for forming dichlorocarbene from Ethyl Trichloroacetate.4 An example is the reaction with dihydropyran (eq 2).7

As a base, sodium methoxide may also perform dehydrohalogenation reactions. Benzalacetophenone dibromide may be treated in this way with sodium methoxide (eq 3).8 The mechanism of this reaction involves first the nucleophilic displacement of bromide,4 followed by E2 elimination.4 Acid hydrolysis then gives dibenzoylmethane.8 Sodium methoxide also catalyzes the Favorskii rearrangement (eq 4). The first step of the reaction is dehydrochlorination, followed by SN2 attack of methoxide on the bicyclic intermediate.9 These examples illustrate one drawback of using sodium methoxide as a base for dehydrohalogenation, namely that NaOMe may also act as a nucleophile, often causing a competition between E2 and SN2 reactions. Sodium methoxide is not as efficient for E2 reactions as a sterically bulky base might be (see Potassium t-Butoxide).

Sodium methoxide is a basic condensation catalyst typically employed in the aldol condensation reaction as a means of generating the enolate (eq 5).10 Metal hydroxides do not have sufficient base strength to convert a substantial fraction of the aldehyde or ketone to the enolate, so the equilibrium lies far to the left.10 For condensation reactions that are difficult to drive forward, as in the condensation of ketones, a stronger base must be used, such as Lithium Diisopropylamide. Although NaOMe is not as strong as LDA in generating the enolate, it has the advantages of lower cost, longer shelf life, and ease of handling, storage, and preparation.10 It is also used in the Robinson annulation reaction (eq 6).10 Sodium methoxide has been used to catalyze the condensation of g-butyrolactone as the first step in the synthesis of dicyclopropyl ketone (eq 7).11

Seus and Wilson have used sodium methoxide as the basic catalyst for synthesis of stilbene, 2-stilbazole, 2-styrylfuran, and 2-styrylthiophene (eq 8).12 This method of synthesis provides good yields (75-85%) of the trans-alkenes, and is a more convenient procedure than the Wittig alkene synthesis.12 Sodium methoxide has also been used to condense methyl N,N-dimethylsebacamate to give N,N,N,N-tetramethyl-9-methoxycarbonyl-10-oxononadecanediamide, which, after further processing, yields nonadecanoic acid (eq 9).13

Sodium methoxide has found use as a condensation catalyst for a particularly interesting category of reactions, namely the synthesis of various heterocycles.4 For example, 2-amino-4-anilino-6-chloromethyltriazine may be synthesized from phenylbiguanide hydrochloride and ethyl chloroacetate in one step (eq 10).14 Also, 2-thio-6-methyluracil may be synthesized in a similar reaction from Ethyl Acetoacetate and Thiourea (eq 11).15 A final example is the condensation of Urea and Diethyl Oxalate to generate parabanic acid (eq 12).16

Carbanion Formation.

Sodium methoxide is also useful for generating carbanions. The synthesis of anthraquinones provides an example (eq 13).17 Sodium methoxide in HMPA is also capable of cleaving carbon-silicon bonds, resulting in a carbanion (eq 14) that is useful in the synthesis of alkenes.18 When the carbanion is reacted with a carbonyl compound, the alkene results (eq 15).

Nucleophile.

Sodium methoxide solvates to produce a relatively small nucleophile. As previously shown, it may displace halogens from an sp3 carbon in a typical SN2 reaction. A wide variety of such methoxylations are possible.19 One interesting use of sodium methoxide as a nucleophile is in the synthesis of secondary amines from aminosilanes.20 Typical methods of secondary amine synthesis involve reaction of ammonia or a primary amine with an alkyl halide. This method, however, is not highly selective since the alkylation of the ammonia or amine will not stop at the secondary amine stage and will proceed to yield tertiary amines. Ando and Tsumaki have reported a simple and selective synthesis of secondary amines20 in which nucleophilic attack of methoxide on the silicon atom of the aminosilane is the first step (eq 16), followed by nucleophilic attack of the amide anion on the alkyl halide of choice (eq 17).

Sodium methoxide is also used as a nucleophile in the simple and efficient synthesis of phloroglucinol from 1,3,5-tribromobenzene (eq 18).21 Nucleophilic attack of methoxide proceeds by an SNAr mechanism, and the trimethoxybenzene is then hydrolyzed to give a high yield (~80%) of phloroglucinol.21 This method has the advantage over the old synthesis in that only two steps are required and no toxic wastes are produced. Sodium methoxide may also be employed in nucleophilic aromatic substitution reactions to synthesize phenols, anisoles, and methoxyphenols from unactivated aryl halides (eq 19)22 or 3,5-dinitroanisole from 1,3,5-trinitrobenzene (eq 20).23

Other Reactions.

Sodium methoxide may be used to perform selective dealkylation of bis(alkylthio)benzenes.24,25 Depending on whether sodium methoxide or sodium methanethiolate is used, removal of either the more branched or the less branched alkyl group is possible. If sodium methanethiolate is used, then the less highly substituted alkyl group is eliminated (eq 21). The postulated mechanism24 for this involves the methanethiolate anion (which is a much better nucleophile than the methoxide anion) attacking the less highly substituted alkyl group in an SN2 reaction to displace the substituted phenyl group.24 If sodium methoxide is used, however, then the more highly substituted alkyl group is removed in an elimination reaction, which produces propene and the thiolate with the less substituted alkyl group (eq 22).24 The reaction may be performed in HMPA24 or DMF.25

Another interesting reaction performed by sodium methoxide is the methylation of fluorene. Heating a mixture of fluorene, methanol, and sodium methoxide together in a bomb results in the formation of 9-methylfluorene (eq 23).26


1. Exner, J. H.; Steiner, E. C. JACS 1974, 96, 1782.
2. Cram, D. J.; Rickborn, B.; Kingsbury, C. A.; Haberfield, P. JACS 1961, 83, 3678.
3. Bagno, A.; Scorrano, G.; Terrier, F. JCS(P2) 1990, 1017.
4. (a) FF 1967, 1, 1091. (b) Drayton, C. J. In Comprehensive Organic Chemistry; Barton, D.; Ollis, W. D., Eds.; Pergamon: New York, 1979; Vol. 6, pp 1515-1516.
5. Swann, S., Jr.; Garrison, W. E., Jr. OSC 1973, 5, 463.
6. Tashiro, M.; Tsuzuki, H.; Goto, H.; Ogasahara, S.; Mataka, S. J. Labelled Compd. Radiopharm. 1991, 29, 475.
7. Parham, W. E.; Schweizer, E. E.; Mierzwa, S. A., Jr. OSC 1973, 5, 874.
8. Allen, C. F. H.; Abell, R. D.; Normington, J. B. OSC 1941, 1, 205.
9. Goheen, D. W.; Vaughan, W. R. OSC 1963, 4, 594.
10. March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 937-945.
11. Curtis, O. E., Jr.; Sandri, J. M.; Crocker, R. E.; Hart, H. OSC 1963, 4, 278.
12. Seus, E. J.; Wilson, C. V. JOC 1961, 26, 5243.
13. Cohen, H.; Shubart, R. JOC 1973, 38, 1424.
14. Overberger, C. G.; Michelotti, F. W. OSC 1963, 4, 29.
15. Foster, H. M.; Snyder, H. R. OSC 1963, 4, 638.
16. Murray, J. I. OSC 1963, 4, 744.
17. Davies, J. S.; Davies, V. H.; Hassall, C. H. CC 1968, 1555.
18. Sakurai, H.; Nishiwaki, K.; Kira, M. TL 1973, 4193.
19. Bretzinger, D.; Josten, W. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.; Grayson, M., Ed.; Wiley: New York, 1978; Vol. 2, pp 1-17.
20. Ando, W.; Tsumaki, H. CL 1981, 693.
21. McKillop, A.; Howarth, B. D.; Kobylecki, R. J. SC 1974, 4, 35.
22. Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M. T 1983, 39, 193.
23. Reverdin, F. OSC 1941, 1, 219.
24. Tiecco, M.; Tingoli, M.; Testaferri, L.; Chianelli, D.; Maiolo, F. S 1982, 478.
25. Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M. S 1983, 751.
26. Schoen, K. L.; Becker, E. I. JACS 1955, 77, 6030.

Yahya El-Kattan & Jeff McAtee

Emory University, Atlanta, GA, USA



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