Tetra-n-butylammonium Borohydride


[33725-74-5]  · C16H40BN  · Tetra-n-butylammonium Borohydride  · (MW 257.38)

(selective reducing agent for aldehydes and ketones;1 soluble in nonaqueous media)

Physical Data: mp 123-128 °C.

Solubility: readily sol CH2Cl2, CHCl3; moderately sol benzene; relatively insol ether solvents, H2O.

Form Supplied in: colorless crystalline solid; commercially available.

Preparative Methods: can be prepared by the reaction between Sodium Borohydride and tetrabutylammonium chloride.2 The reagent can also be prepared from the less expensive Tetra-n-butylammonium Iodide by ion exchange.1

Purification: recrystallization from ethyl acetate followed by careful drying under vacuum at 50-60 °C.

Handling, Storage, and Precautions: crystalline samples showed no loss of active hydrogen after storage at rt for more than 1 year.1 As with other borohydrides, the material reacts rapidly with aqueous acids to produce hydrogen (and, potentially, borane).2 Use in a fume hood.

General Considerations.

Tetrabutylammonium borohydride, by virtue of its high solubility in organic solvents such as CH2Cl2, permits the reduction of aldehydes and ketones to be carried out in high yields in aprotic solvents. The general reactivity of the reagent is analogous to that of sodium borohydride in aqueous or alcoholic media, and reductions are highly selective for the carbonyl groups of aldehydes and ketones relative to unconjugated carbon-carbon multiple bonds. At rt, acid chlorides are reduced very rapidly, aldehydes and ketones are reduced at convenient rates (with half-times of a few hours), and esters are reduced quite slowly. The solubility properties1,4 of this compound relative to that of other quaternary ammonium borohydrides make it an excellent reagent for reductions of aldehydes and ketones, which sometimes exhibit poor solubility in the protic solvents needed for sodium borohydride reductions.

The tetrabutylammonium reagent is considerably easier to handle and purify2 than the tetraethylammonium salt, because it is less hygroscopic and is more soluble in organic solvents (although the greater water solubility of most tetraethylammonium salts can facilitate workup of reductions with the latter derivatives). Tetrabutylammonium borohydride was first used to prepare solutions of Diborane in CH2Cl22 and was then found to be a mild and selective reagent for the reduction of dioxolenium ions.5 Subsequently, the reductions were extended to carbonyl reductions in aprotic solvents. Related reductions were reported using Tetra-n-butylammonium Cyanoborohydride in Hexamethylphosphoric Triamide.6

The reactivity of tetrabutylammonium borohydride decreases along the sequence acid chlorides > aldehydes > ketones > esters. The extremes are illustrated by Benzoyl Chloride (1), which is reduced rapidly, even at -78 °C (eq 1),1 and ethyl laurate (2), which undergoes only 25% reduction after 4 d at 25 °C (eq 2).1

Aldehydes and ketones undergo reduction at 25 °C at convenient rates, which vary with respect to the steric bulk of the substituents. While the reduction of unhindered aldehydes proceeds readily and nearly to completion with only 1 equiv of tetrabutylammonium borohydride, it was found preferable to use 4 equiv of the reducing agent as a general procedure for ketones, where the reaction is otherwise inconveniently slow or does not proceed to completion. The typical reaction time of 2 d for ketone reduction (rt, CH2Cl2) can be decreased to several hours if the reduction is carried out at the higher temperature of refluxing CHCl3.1

A typical reduction is accomplished by allowing a CH2Cl2 solution of the carbonyl derivative (1 M) and tetrabutylammonium borohydride (0.4-1 M) to stand in a stoppered vessel at rt for 0.25-48 h. The reaction mixture is then quenched by stirring for 2 h with alkaline, aqueous Hydrogen Peroxide (2 vol of 3% hydrogen peroxide and 1 vol of 10% NaOH). After drying the organic layer and evaporating the solvent at reduced pressure, insoluble ammonium salts can be removed by dissolving the crude product in Et2O and filtering the solution through a short column of alumina. The use of aqueous hydrogen peroxide in the workup not only serves to destroy any unreacted hydride, but also facilitates the hydrolysis of the borate esters formed in the reduction.7 If this step is omitted, much lower yields result. In order to destroy any peroxides that may have formed during workup, a CH2Cl2 solution of the product is washed with aqueous sodium sulfite prior to distillation.

Selective Reductions.

Only the keto group of methyl 3-benzoylpropionate (3) was reduced, and the corresponding lactone (formed spontaneously during distillation of the product) was obtained (eq 3).1

On the other hand, the reactivity differences of aldehyde and ketone carbonyl groups do not appear to be sufficient to allow selective reduction. Although the aldehyde is reduced preferentially, the product distribution in the following example is only 80:20 at best (eq 4).3

Although diborane is probably formed during the reduction of ketones, hydroboration of the carbon-carbon double bond in 6-methyl-5-hepten-2-one was not observed, and the unsaturated alcohol was isolated in good yield.1 As with other borohydride reductions,8,9 there is evidence that the reaction can be assisted by electrophilic catalysis. While not a prerequisite for reduction, the addition of an equivalent amount of ethanol results in an approximate twofold increase in the rate of reduction of cyclohexanone by tetrabutylammonium borohydride in CH2Cl2.1 The identity of the actual reducing agent in reductions performed with Bu4NBH4 in CH2Cl2 is uncertain. The ability of Bu4NBH4 to reduce certain functional groups, such as the cyano group of nitriles,10 might be due to the presence of diborane in CH2Cl2 solutions of this reagent. However, the exact nature of the species present in CH2Cl2 solutions of Bu4NBH4 is unknown. These solutions are probably complex since it is known11 that heptahydrodiborate ion (B2H7-) is produced in solutions which contain borohydride ion (from Bu4NBH4) and diborane.

Tetrabutylammonium borohydride has also been used effectively in aprotic solvents for the reduction of indoles to idolines12 and for the selective 1,4-reduction of a,b-unsaturated cyclic ketones.13 Other reports of the use of this reagent that may be of relevance for organic synthesis include deoxy sugar synthesis (in an SN2 reduction),14 reduction of thiol esters,15 stereoselective synthesis of indanols from 2-methyl-2-aryl-1-indanones,16 preparation of methylboronic acid and trimethylboroxin,17 the use of borohydrides on solid supports,18 and synthesis of organic selenides and tellurides.19

Related Reagents.

Diborane; Sodium Borohydride; Tetra-n-butylammonium Cyanoborohydride.

1. Raber, D. J.; Guida, W. C. JOC 1976, 41, 690.
2. Brändström, A.; Junggren, U.; Lamm, B. TL 1972, 3173.
3. Raber, D. J.; Guida, W. C.; Shoenberger, D. C. TL 1981, 5107.
4. Sullivan, E. A.; Hinckley, A. A. JOC 1962, 27, 3731.
5. Raber, D. J.; Guida, W. C. S 1974, 808.
6. Hutchins, R. O.; Kandasamy, D. JACS 1973, 95, 6131.
7. Brown, H. C.; Dickason, W. C. JACS 1970, 92, 709.
8. (a) Brown, H. C.; Mead, E. J.; Subba Rao, B. C. JACS 1955, 77, 6209. (b) Kollonitsch, J.; Fuchs, O.; Gabor, V. Nature (London) 1954, 173, 125.
9. Brown, H. C.; Ichikawa, K. JACS 1961, 83, 4372.
10. Wakamatsu, T.; Inaki, H.; Ogawa, A.; Watanabe, M.; Ban, Y. H 1980, 14, 1437.
11. (a) Hertz, R. K.; Johnson, H. D.; Shore, S. G. IC 1973, 12, 1875. (b) Hertz, R. K.; Johnson, H. D.; Shore, S. G. Inorg. Synth. 1977, 17, 21.
12. Wakamatsu, T.; Inaki, H.; Ogawa, A.; Wantanabe, M.; Ban, Y. H 1980, 14, 1441.
13. D'Incan, E.; Loupy, A. T 1981, 37, 1171.
14. Sato, K.; Hoshi, T.; Kajihara, Y. CL 1992, 1469.
15. Liu, H.-J.; Luo, W. SC 1989, 19, 387.
16. Berlan, J.; Sztajnbok, P.; Besace, Y.; Cresson, P. CR(2) 1985, 301, 693.
17. Brown, H. C.; Cole, T. E. OM 1985, 4, 816.
18. Bram, G.; d'Incan, E.; Loupy, A. NJC 1982, 6, 573.
19. Bergman, J.; Engman, L. S 1980, 569.

Douglas J. Raber

National Research Council, Washington, DC, USA

Wayne C. Guida

Ciba-Geigy Corporation, Summit, NJ, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.