Sodium Ethoxide1

NaOEt

[141-52-6]  · C2H5NaO  · Sodium Ethoxide  · (MW 68.06)

(used as a base for the a-deprotonation of carbonyl-containing compounds for subsequent intermolecular2 or intramolecular1f condensations, displacements,3 or skeletal rearrangements,1d,4 arylacetonitriles,5 nitro-containing aliphatic compounds,6 sulfonium salts,3j,7 for the dehydration of carbinolamines8 and for dehydrohalogenation,1b,9 for the N-deprotonation of amides,10a-d tosylamines,10e amine hydrochlorides1c or toluenesulfonates,10f cyanamide,10g and the S-deprotonations of sulfides,1c,11 often followed by cyclizations;1c,10b,10g,11 can be used as a nucleophile in ipso substitution reactions of vinyl sulfides,12a aromatic halides,12b-i sometimes catalyzed by copper12c or palladium,12h,i aryl sulfones,12j and aromatic nitro compounds,12k in the Williamson ether synthesis,13a-c in displacements of halo,13d-h nitro,13e thiooxy,13g,h and phenoxy13g groups from dichloromethane and chloroform analogs, in a novel transesterification-conjugate addition protocol of acrylic esters,14 with a-nitro epoxides to form a-ethoxy ketones,15 in the nucleophilic attack on nitriles1e,16 and polyhaloalkenes,17 in reaction with chlorodiphenylphosphine to form Arbuzov precursors,18 and with Grignard reagents to form organomagnesium ethoxides19)

Physical Data: mp >300 °C.

Solubility: sol ethanol, diethyl ether.

Form Supplied in: white or yellowish powder or as 21 wt % solution in ethanol; widely available.

Preparative Methods: it is often necessary to prepare sodium ethoxide immediately prior to its use. Preparation of a 6-10% solution in ethanol: to commercial absolute ethanol is added the required amount of Sodium in lumps or slices with or without stirring and with or without a nitrogen atmosphere and the solution is cooled or heated as required until the metal is dissolved. The evolved hydrogen should be vented into a hood. Addition of ethanol to sodium is also reported. Alcohol-free reagent can also be prepared.1a

Handling, Storage, and Precautions: is a hygroscopic, flammable, corrosive, and toxic solid which will decompose upon exposure to air. The solid or solution reagent should be tightly sealed under an inert atmosphere in a dark bottle.

General Discussion.

Kinetic studies of the proton transfer reaction between bis(4-nitrophenyl)methane and alkoxide base systems reveal that sodium ethoxide is a kinetically faster (kH = 2.16 M-1 s-1) base than either sodium isopropoxide (kH = 0.280 M-1 s-1) or sodium t-butoxide (kH = 1.05 M-1 s-1) (eq 1).20a Reaction between alkali alkoxides and p-nitrophenyl methanesulfonate have revealed the following order of reactivity: LiOEt< NaOEt < CsOEt &AApprox; KOEt &AApprox; KOEt + 18-crown-6 < KOEt + [2.2.2]cryptand.20b

Condensations of esters with the enolate of acetone can be effected using sodium ethoxide as a base to yield products such as acetylacetone2a and the precursor to chelidonic acid depicted in eq 2.2b The corresponding enolates of methyl aryl ketones can similarly be utilized.2c,1f

Condensation of the sodium ethoxide-generated enolate of cyclohexanone with ethyl formate yields 2-hydroxymethylenecyclohexanone which, upon treatment with hydrazine monohydrate, forms indazole in excellent yield (eq 3).2d

Sodium ethoxide is often the base of choice in the a-acylation2e-i and alkylation3h of esters. Interesting intramolecular cyclizations sometimes follow in good yield (eq 4).

Alkylation of malonate esters through the intermediacy of enolates generated using sodium ethoxide is quite common.3 Subsequent decarboxylation to the carboxylic acid can then be induced, as depicted in eq 5.3d

Sodium ethoxide and Sodium Hydroxide have both proven effective in the cyclopropanation of various g,d-epoxy ketones, as illustrated in eq 6. Adducts are generated in good to excellent yields.4

Deprotonation a to nitriles has been found to be strongly influenced by the purity of the sodium ethoxide used5a and can be done selectively over a-deprotonation of an ester.5b Reactions with aromatic aldehydes lead to condensation adducts (eq 7).5c

Deprotonations a to nitro functionalities have been found to proceed with greater ease using sodium ethoxide rather than Sodium Methoxide.6 The in situ generated anion of 2-nitropropane transforms a benzylic bromide to its aromatic aldehyde derivative in good yield (eq 8).7a

Sodium ethoxide serves as a multipurpose base to generate both the ylide of dimethyl-2-propynylsulfonium bromide and the anion of acetylacetone in the synthesis of 3-acetyl-2,4-dimethylfuran illustrated in eq 9.3j The intermediacy of an allene has been suggested.7b

Sodium ethoxide both dehydrates and nucleophilically assists in the deacylation of the carbinolamine intermediate depicted in eq 10.8 Furthermore, sodium ethoxide-mediated dehydrohalogenation in DMSO solvent has been achieved in excellent yield (eq 11).1b,9

Heteroatom deprotonations using sodium ethoxide as the base are also quite common. Sodium ethoxide serves as an effective base when the nitrogen of cyanoacetamide must be condensed on an ester. Subsequent intramolecular cyclization proceeding via a-deprotonation to the nitrile leads to excellent yield of the dicyanoglutarimide shown in eq 12.10a

Other N-deprotonations include that of urea,10b thiourea,10c succinimide,10d tosylamines,10e cysteamine hydrochloride (eq 13),1c ribofuranosylamine toluenesulfonate,10f and cyanamide (eq 14).10g Similarly, S-deprotonations of sulfides (eq 13)1c,11 have been reported. Often, adducts can be used in subsequent cyclizations.1c,10b,g,11

The synthesis of 6,6-dialkoxyfulvenes from 6,6-bis(methylthio)fulvene has been reported in good yield via treatment with sodium ethoxide or related nucleophiles, followed by thermolysis (eq 15).12a

Addition of a large excess of sodium ethoxide or methoxide to 11-chloro[5]metacyclophanes leads to good yields of ipso alkoxy-substituted adducts.12b Sodium ethoxide proves to be the fastest of a series of nucleophiles in ipso substitution reactions of aromatic bromides employing a Copper(I) Bromide catalyst (eq 16). Once again, purity of alkoxide seems to be important.12c Substitution of aryl iodides is also known.12d

Ipso ethoxy substitutions of halo-pyrimidines,10g -purines (eq 17),12e -thiophenes,12c,f -furans,12c and -triazines12g using sodium ethoxide have also been reported in good yield.

Aryl iodides, vinyl bromides, and tricarbonyl(chloroarene)chromium complexes have been found to react under mild conditions with sodium alkoxides in the presence of catalytic dichlorobis(triphenylphosphine)palladium(II) (see Palladium(II) Chloride) to afford the corresponding benzoate esters as the major products (eq 18).12h,i It has been rationalized that the higher base strength of sodium ethoxide compared to that of sodium methoxide allows the former to successfully decarbonylate ethyl formate, whereas the latter proves more sluggish, yielding poorer results.

Ipso substitution of 2- and 4-pyridyl sulfones is also possible using a variety of nucleophiles, including sodium ethoxide. The sulfone moiety is preferentially displaced over a chlorine substituent also present on the aromatic ring (eq 19). The same reaction utilizing sulfoxides gives mixed results, while sulfides fail to react.12j

It has been suggested that displacement of the nitro group of the radical anion of p-nitrobenzophenone by sodium ethoxide is followed by chain transfer from the resulting p-ethoxybenzophenone radical, resulting in the adduct pictured in eq 20.12k

Sodium ethoxide is frequently employed as the nucleophile in the Williamson ether synthesis,13a-c as illustrated in eq 21. Furthermore, polydisplacements of halo,13d-h nitro,13e thiooxy,13g,h and phenoxy13g groups of dichloromethane and chloroform analogs have been realized by the use of sodium ethoxide as the nucleophile. This methodology has been used in the syntheses of ethyl orthocarbonate (eq 22) and ethyl diethoxyacetate (eq 23) in moderate to good yields.

Sodium ethoxide has been employed for a transesterification-conjugate addition protocol, which takes advantage of the syn-selective addition of sodium alkoxides to acrylic esters such as the one depicted in eq 24.14

An interesting synthesis of a-ethoxy ketones employs nucleophilic reaction of sodium ethoxide with a-nitro epoxides. The reaction appears to be quite general and a variety of nucleophiles may be employed (eq 25).15

Nucleophilic attack of sodium ethoxide on 3,4- or 2,3-cyanomethyl cyanopyridines followed by cyclization provides access to amino alkoxy naphthyridines (eq 26).1e,16 The reaction is believed to proceed through an imidate intermediate.16a Unfortunately, treatment of the analogous carbocyclic 2-cyanobenzyl cyanides under similar conditions leads to dimerization of starting material, and cyclization must be achieved under acidic conditions.16b

Sodium ethoxide is also known to nucleophilically add to polyhaloalkenes with preferential attack on the methylene with the highest degree of fluorine substitution (eqs 27 and 28).17 Excess nucleophile unveils an ethyl ester (eq 28).

Reaction of sodium ethoxide with chlorodiphenylphosphine provides access to Arbuzov precursors, which can be further reacted with suitable electrophiles to form phosphine oxides (eq 29).18

Treatment of Grignard reagents (RMgBr) with sodium ethoxide offers a synthetic route to organomagnesium ethoxides (RMgOEt).19 No yields are reported for this reaction.

Related Reagents.

Potassium t-Butoxide; Potassium 2-Methyl-2-butoxide; Sodium Hydroxide; Sodium Methoxide.


1. (a) FF 1967, 1, 1065. (b) FF 1969, 2, 157. (c) FF 1972, 3, 265. (d) FF 1974, 4, 451. (e) FF 1977, 6, 540. (f) FF 1986, 12, 402.
2. (a) Denoon, Jr., C. E. OSC 1955, 3, 16. (b) Riegel, E. R.; Zwilgmeyer, F. OSC 1943, 2, 126. (c) Magnani, A.; McElvain, S. M. OSC 1955, 3, 251. (d) Tishler, M.; Gal, G.; Stein, G. A. OSC 1963, 4, 536. (e) Briese, R. R.; McElvain, S. M. JACS 1933, 55, 1697. (f) Hershberg, E. B.; Fieser, L. F. OSC 1943, 2, 194. (g) Floyd, D. E.; Miller, S. E. OSC 1963, 4, 141. (h) Holmes, H. L.; Trevoy, L. W. OSC 1955, 3, 301. (i) Friedman, L.; Kosower, E. OSC 1955, 3, 510.
3. (a) Allen, F.; Kalm, M. J. OSC 1963, 4, 616. (b) Adams, R.; Kamm, R. M. OSC 1941, 1, 245. (c) Cox, R. F. B.; McElvain, S. M. OSC 1943, 2, 279. (d) Callen, J. E.; Dornfield, C. A.; Coleman, G. H. OSC 1955, 3, 212. (e) Moffett, R. B. OSC 1963, 4, 291. (f) Mariella, R. P.; Raube, R. OSC 1963, 4, 288. (g) Andruzzi, F.; Hvilsted, S. Polymer 1991, 32, 2294. (h) Marvel, C. S.; King, W. B. OSC 1941, 1, 246. (i) Shriner, R. L.; Todd, H. R. OSC 1943, 2, 200. (j) Howes, P. D.; Stirling, C. J. M. OSC 1988, 6, 31.
4. (a) Gaoni, Y. T 1972, 28, 5525. (b) Gaoni, Y. T 1972, 28, 5533.
5. (a) Horning, E. C.; Finell, A. F. OSC 1963, 4, 461. (b) Coan, S. B.; Becker, E. I. OSC 1963, 4, 174. (c) Womack, E. B.; McWhirter, J. OSC 1955, 3, 714.
6. Dauben, Jr., H. J.; Ringold, H. J.; Wade, R. H.; Pearson, D. L.; Anderson, Jr.; A. G. OSC 1963, 4, 221.
7. (a) Hass, W. B.; Bender, M. L. OSC 1963, 4, 932. (b) Batty, J. W.; Howes, P. D.; Stirling, C. J. M. JCS(P1) 1973, 65.
8. McMurry, J. E. OSC 1988, 6, 781.
9. Norman, R. O. C.; Thomas, C. B. JCS(C) 1967, 1115.
10. (a) McElvain, S. M.; Clemens, D. H. OSC 1963, 4, 662. (b) Sherman, W. R.; Taylor, Jr., E. C. OSC 1963, 4, 247. (c) Ulbricht, T. L. V.; Okuda, T.; Price, C. C. OSC 1963, 4, 566. (d) Crockett, G. C.; Koch, T. D. OSC 1988, 6, 226. (e) Atkins, T. J.; Richman, J. E.; Oettle, W. F. OSC 1988, 6, 652. (f) Espie, J. C.; Lhomme, M. F.; Morat, C.; Lhomme, J. TL 1990, 31, 1423. (g) Schmidt, H.-W.; Koitz, G.; Junek, H. JHC 1987, 24, 1305.
11. Gillis, R. G.; Lacey, A. B. OSC 1963, 4, 396.
12. (a) Gupta, I.; Yates, P. SC 1982, 12, 1007. (b) Kraakman, P. A.; Valk, J.-M.; Niederländer, H. A. G.; Brouwer, D. B. E.; Bickelhaupt, F. M.; de Wolf, W. H.; Bickelhaupt, F.; Stam, C. H. JACS 1990, 112, 6638. (c) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. T 1992, 48, 3633. (d) Somei, M.; Yamada, F.; Kunimoto, M.; Kaneko, C. H 1984, 22, 797. (e) Carret, G.; Grouiller, A.; Chabannes, B.; Pacheco, H. Nucleosides Nucleotides 1986, 3, 331. (f) Puschmann, I.; Erker, T. H 1993, 36, 1323. (g) Konno, S.; Ohba, S.; Agata, M.; Aizawa, Y.; Sagi, M.; Yamanaka, H. H 1987, 26, 3259. (h) Carpentier, J.-F.; Castanet, Y.; Brocard, J.; Mortreux, A.; Petit, F. TL 1991, 32, 4705. (i) Carpentier, J.-F.; Castanet, Y.; Brocard, J.; Mortreux, A.; Petit, F. TL 1992, 33, 2001. (j) Furukawa, N.; Ogawa, S.; Kawai, T. JCS(P1) 1984, 1839. (k) Denney, D. B.; Denney, D. Z.; Perez, A. J. T 1993, 49, 4463.
13. (a) Slomkowski, S.; Winnik, M. A.; Furlong, P.; Reynolds, W. F. Macromolecules 1989, 22, 503. (b) Marei, M. G.; Mishrikey, M. M.; El-Kholy, I. El-S. Acta Chim. Hung. 1987, 124, 733. (c) Marei, M. G.; Mishrikey, M. M.; El-Kholy, I. El-S. IJC(B) 1987, 26B, 163. (d) Moffett, R. B. OSC 1963, 4, 427. (e) Roberts, J. D.; McMahon, R. E. OSC 1963, 4, 457. (f) Kaufmann, W. E.; Dreger, E. E. OSC 1941, 1, 253. (g) Connolly, J. M.; Dyson, G. M. JCS 1936, 827. (h) Tieckelmann, H.; Post, H. W. JOC 1948, 13, 265.
14. Mulzer, J.; Kappert, M.; Huttner, G.; Jibril, I. AG(E) 1984, 23, 704.
15. Vankar, Y. B.; Shah, K.; Bawa, A.; Singh, S. P. T 1991, 47, 8883.
16. (a) Alhaique, F.; Riccieri, F. M.; Santucci, E. TL 1975, 173. (b) Johnson, F.; Nasutavicus, W. W. JOC 1962, 27, 3953.
17. (a) Shainyan, B. A.; Rappoport, Z. JOC 1993, 58, 3421. (b) Englund, B. OSC 1963, 4, 184.
18. Yang, Z.; Geise, H. J.; Nouwen, J.; Adriaensens, P.; Franco, D.; Vanderzande, D.; Martens, H.; Gelan, J.; Mehbod, M. Synth. Met. 1992, 47, 111.
19. Gupta, S.; Sharma, S.; Narula, A. K. JOM 1993, 452, 1.
20. (a) Schroeder, G. React. Kinet. Catal. Lett. 1992, 46, 51. (b) Pregel, M. J.; Buncel, E. JACS 1993, 115, 10.

K. Sinclair Whitaker

Wayne State University, Detroit, MI, USA

D. Todd Whitaker

Detroit Country Day School, Beverly Hills, MI, USA



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