Sodium Hydroxide1

NaOH

[1310-73-2]  · HNaO  · Sodium Hydroxide  · (MW 40.00)

(inorganic source of hydroxide ion for the saponification of carboxylic acid derivatives;3,4 alkylation of phenols,7 alcohols,13 aldehydes,18 and ketones;19 transformation of amides to amines,11 generation of dichlorocarbenes;22 also useful for removing water from amines27)

Physical Data: mp 318.4 °C; d 2.13 g cm-3.

Solubility: in water: 0.42 g mL-1 at 0 °C; 3.47 g mL-1 at 100 °C.

Form Supplied in: pellets or standard aqueous solutions of variable concentrations.

Purification: dissolve in dry ethanol, 100 g L-1, filter solution through a fine frit. Concentrate the solution under vacuum until a thick slurry is formed. Place slurry on a coarse sintered-glass disk, remove mother liquor and wash several times with dry ethanol. Vacuum dry crystals with mild heating for 30 h to give fine white powder.

Handling, Storage, and Precautions: hygroscopic; keep in a sealed container in a dry environment. Keep away from flame. Avoid contact and ingestion.

Hydrolysis of Carboxylic Acid Derivatives.

The hydrolysis of esters, amides, nitriles, and ureas to the corresponding carboxylic acid can be accomplished with NaOH as hydroxide source, although milder methodology is available.2 Ester hydrolysis is typically carried out in combinations of 1 N NaOH and either ethanol or methanol.3 The hydrolysis of amides, nitriles and ureas is usually accomplished using excess NaOH in refluxing ethylene glycol with trace amounts of water.4

Dehydration of Sulfoxides and Selenoxides.

Thiophenes and selenophenes can be generated by the dehydration of the corresponding sulfoxides5 and selenoxides6 using 40% and 50% NaOH (aq), respectively.

Alkylation Reactions.

The NaOH-promoted conversion of phenols and carboxylic acids to their corresponding ethers7 and esters8 is accomplished in almost quantitative yield when excess Hexamethylphosphoric Triamide (HMPA) is added. The procedure calls for substrate, alkylating agent, 25% NaOH (aq), and HMPA to be combined at room temperature (eq 1).

Phenols can be methylated with dimethyl sulfate,9 and epoxides can be derived from halohydrins10 using NaOH to generate the phenolate and alcoholate anions.

Conversion of Amides to Amines.

The conversion of amides to amines containing one less carbon, the Hoffman reaction, is accomplished by the combination of bromine (or chlorine) with NaOH followed by heating (eq 2).11 The reaction works well with aliphatic, aryl, and heterocyclic amides. The reaction can also be carried out in alcohol solutions, and the resulting urethane hydrolyzed in a subsequent step.

Phase-Transfer-Catalyzed Alkylation Reactions.

The use of phase-transfer-catalyzed two-phase reactions introduces hydroxide ion into organic solvent.12 Under these conditions, hydroxide acts as a powerful base that efficiently promotes many transformations. Phase-transfer methodology is superior to the traditional Williamson synthesis of ethers (eq 3).13

Reaction conditions consist of a fivefold excess of 50% NaOH (aq), alcohol, excess alkyl chloride, and 3-5 mol % tetrabutylammonium bisulfate (TBAB). This method does not work with secondary alkyl halides but was successful with secondary alcohols. Alcohols can also be methylated under phase-transfer conditions using Dimethyl Sulfate, 50% NaOH (aq), alcohol, and Tetra-n-butylammonium Iodide (TBAI) with methylene chloride or petroleum ether as the second phase.14 This method works well for primary alcohols, is sluggish for secondary alcohols, and works not at all for tertiary alcohols. The use of a chiral phase-transfer catalyst gave alkylation of racemic alcohols15 and ring closure of racemic chlorohydrins16 with only moderate enantiomeric excess. Diphenylphosphinic hydrazide was alkylated in high yield using a mixture of solid K2CO3, NaOH, and tetra-n-butylammonium sulfate in boiling benzene.17

The combination of TBAI and 50% NaOH (aq) promotes aldehyde alkylation in modest yield.18 The use of N-benzylcinchonine salts as phase-transfer catalysts results in excellent yield and good enantioselectivity in the alkylation of indonanes (eq 4).19

Phase-Transfer-Catalyzed Ylide Chemistry.

Wittig reactions can be done by combining 50% NaOH (aq), TBAI, a phosphonium salt, and a ketone in CH2Cl2. Benzylic phosphonium salts are converted to alkenes in good yields, but no stereoselectivity is observed (eq 5).20

Similarly, trimethylsulfonium iodide (eq 6) and trimethyloxosulfonium iodide (eq 7) are converted to the corresponding sulfur ylides.21

Phase-Transfer-Catalyzed Carbene Chemistry.

Dichlorocarbene can be generated from chloroform using 50% NaOH (aq) with 1-5% phase-transfer catalyst. This methodology can be used for dichlorocyclopropanation (eq 8),22 C-H insertion (eq 9)23 and the conversion of primary amines into isocyanides.24

Micelles have been shown to give increased yields compared to tetraalkylammonium salt phase-transfer catalysts.25 Similiar reactions can be done using bromoform, but the ease with which dibromocarbene undergoes hydrolysis makes this methodology less useful than the generation of dichlorocarbene.26

Related Reagents.

Potassium Carbonate; Potassium Hydroxide; Sodium Carbonate.


1. Fyfe, C. A. The Chemistry of the Hydroxy Group, Part 1; Wiley: New York, 1971.
2. Haslam, E. T 1980, 36, 2409.
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4. (a) Newman, M. S.; Wise R. M. JACS 1956, 78, 450. (b) Tsai, L.; Miwa, T.; Newman, M. S. JACS 1957, 79, 450. (c) Pearson, D. E.; Baxter, J. F.; Carter, K. N. OSC 1955, 3, 154.
5. Horner, C. J.; Saris, L. E.; Lakshmikantham, M. V.; Cava, M. P. TL 1976, 2581.
6. Saris, L. E.; Cava, M. P. JACS 1976, 98, 867.
7. Shaw, J. E.; Kunerth, D. C.; Sherry, J. J. TL 1973, 689.
8. Shaw, J. E.; Kunerth, D. C. JOC 1974, 39, 1968.
9. Hiers, G. S.; Hager, F. D. OSC 1941, 1, 58.
10. Elderfield, R. C. Heterocyclic Compounds; Wiley: New York, 1950; Vol. 1, Chapter 1.
11. Wallis, E. S.; Lane, J. F. OR 1946, 3, 267.
12. Weber, W. P.; Gokel, G. W. Phase Transfer Catalysis in Organic Synthesis; Springer: Berlin, 1977.
13. Freedman, H. H.; Dubois, R. A. TL 1975, 3251.
14. Merz, A. AG(E) 1973, 12, 846.
15. Verbicky, J. W. Jr.; O'Neil E. A. JOC 1985, 50, 1787.
16. Hummelen, J. C.; Wynberg, H.; TL 1978, 1089.
17. Mlotkowska, B.; Zwierzak, A. TL 1978, 4731.
18. Dietl, H. K.; Brannock, K. C. TL 1973, 1273.
19. Bhattacharya, A.; Dolling, U-H.; Grabowski, E. J. J.; Karady, S.; Ryan K. M.; Weinstock, L. M. AG(E) 1986, 25, 476.
20. Märkl, G.; Merz, A. S 1973, 295.
21. Merz, A.; Märkl, G. AG(E) 1973, 12, 815.
22. (a) Starks, C. M. JACS 1971, 93, 195. (b) Moss, R. A.; Smudlin, D. J. JOC 1976, 41, 611.
23. Tabushi, I.; Yoshida, Z-I.; Takahashi, N. JACS 1970, 92, 6670.
24. Weber, W. P.; Gokel, G. W.; Ugi, I. K. AG(E) 1972, 11, 530.
25. Joshi, G. C.; Singh, N.; Pande, L. M. TL 1972, 1461.
26. Skattebøl, L.; Abiskaroun, G.; Greibrokk, T. TL 1973, 1367.
27. Gordon, A. J.; Ford, R. A. The Chemist's Companion: A Handbook of Practical Data, Techniques, and References; Wiley: New York, 1972; 446.

Kurt D. Deshayes

Bowling Green State University, OH, USA



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