Sodium Borohydride - an overview (2023)

Sodium borohydride (NaBH4) is a reagent that transforms aldehydes and ketones to the corresponding alcohol, primary or secondary, respectively.

From: Experimental Organic Chemistry, 2016

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Tsuneo Imamoto, in Comprehensive Organic Synthesis, 1991 Sodium Borohydride

Sodium borohydride, a representative borohydride reagent, behaves as an effective source of nucleophilic hydride in an aprotic polar solvent, such as DMSO, sulfolane, HMPA, DMF or diglyme, and is used for the reduction of alkyl halides.93,94 As shown in Table 3, primary and secondary iodides, bromides and chlorides are converted to hydrocarbons at temperatures between 25 and 100°C using sodium borohydride. Vicinal dihalides, such as 1,2-dibromooctane, are smoothly converted to the corresponding saturated hydrocarbons, in contrast to the reductions using LiAlH4 or low-valent metal salts, which predominantly afford alkenes.

Table 3. Reduction of Alkyl Halides with NaBH4 in Polar Aprotic Solvents93

Alkyl halideMolar ratiSolventTemperatureTimeProductYield
1 -Bromododecane1HMPA250.022Docecane73
1 -Bromododecane2DMSO851.5Dodecane95
ω-Bromoundecanoic acid2DMSO252.5Undecanoic acid98
1 -Chlorododecane2DMSO854Dodecane91
1 -Chlorododecane2Sulfolane1006Dodecane85
Ethyl 5-bromovalerate4HMPA250.5Ethyl valerate85
Styrene dibromide4DMSO851.5Ethylbenzene65
Styrene dibromide4Sulfolane1001.5Ethylbenzene64

Sodium borohydride reduction offers a significant advantage in synthetic applications. The method allows the reductive removal of halides selectively without affecting other functional groups, such as ester, carboxylic acid, nitrile and sulfone. A typical chemoselective dehalogenation is illustrated in Scheme 19.95

Sodium Borohydride - an overview (1)

Scheme 19.

Some alkyl halides (primary I, Br, Cl and secondary Br) are reduced by NaBH4 under phase-transfer conditions, as shown in equation (4).96 This reaction is carried out by the addition of a concentrated aqueous solution of NaBH4 to a stirred solution of substrate and catalyst in a suitable solvent, such as toluene. Yields are nearly quantitative in most cases, although an excess of sodium borohydride is required.

(4)Sodium Borohydride - an overview (2)

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Robert J. Ouellette, J. David Rawn, in Organic Chemistry, 2014

Stereoselectivity of Metal Hydride Reduction

Sodium borohydride and lithium aluminum hydride have only moderate stereoselectivity. The anions tend to attack sterically hindered compounds from the least sterically hindered side. For example, reduction of bicyclo[2.2.1]heptan-2-one yields a mixture of two alcohols in which the endo compound predominates. The exo face of the carbonyl group is more open to attack by the nucleophilic hydride reagent, and as a result the endo alcohol is the major product.

Sodium Borohydride - an overview (3)


Write the structure of the product of each of the following reactions, assuming an excess of each metal hydride.

Sodium Borohydride - an overview (4)


Reduction of 7,7-dimethylbicyclo[2.2.1]heptan-2-one with sodium borohydride yields two isomeric alcohols in a 6:1 ratio. Considering the effect of the methyl groups, write the structures of the products.

Sodium Borohydride - an overview (5)

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(Video) Introduction to Reductions & Sodium Borohydride (Theory & Problems)

Synthesis: Carbon with Two Heteroatoms, Each Attached by a Single Bond

David T. Macpherson, Harshad K. Rami, in Comprehensive Organic Functional Group Transformations, 1995 By reduction of dicarbonyl derivatives

Sodium borohydride, a common reagent for this purpose, was used to reduce the symmetrical dicarbonyl compound (21) to afford the hemiacetal in a high yield (Equation (11)) <64T2181>. In a similar manner the hemiacetals (22) and (23) were prepared by reduction of dicarbonyl precursors with sodium borohydride <89JOC91> and aluminum triisopropoxide <51JA1668>, respectively. An attempt to use LAH for this type of reduction resulted in the formation of diols rather than hemiacetals <74H(2)177>. Enzymatic reduction of dicarbonyl compounds was used to prepare a hemiacetal from the dialdehyde (Equation (12)). Besides selective reduction of the enal carbonyl, stereospecific hydroxylation also occurred in the saturated ring <80JCS(P1)2535, 83JCS(P1)1579>.

(11)Sodium Borohydride - an overview (6)

Sodium Borohydride - an overview (7)

(12)Sodium Borohydride - an overview (8)

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G.E. Arnott, in Comprehensive Organic Synthesis (Second Edition), 2014 Boron hydrides

Sodium borohydride is very efficient at reducing an acid chloride to the primary alcohol and has been used quite extensively. The advantages over the aluminum hydrides are that NaBH4 is readily available, easy to handle, and has a good degree of functional group tolerance (esters, lactones, amides, nitriles, etc.; see Scheme 5 for some examples). A plethora of variations including NaBH4–TiCl4,34 NaBH4–alumina,35 Zn(BH4)2·TMEDA,36 and Bu4NBH437 have also been reported, though these are infrequently applied in the literature. The advantage of these modifications stems more from their solubility in other nonalcoholic solvents, for example, the more popular of these, Bu4NBH4, can be used in dichloromethane. Nevertheless sodium borohydride has itself been used in THF (Scheme 5). Lastly, it should be mentioned that borane and its derivatives react very slowly with acid chlorides and are therefore not generally used to achieve this transformation.

Sodium Borohydride - an overview (9)

Scheme 5.

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George W. Kabalka, Rajender S. Varma, in Comprehensive Organic Synthesis, 1991 Borohydride and Borane Reductions

Sodium borohydride is an effective and widely used reducing agent. The relatively low cost and the ease with which it can be handled contribute to its popularity. However, borohydride does not generally reduce aromatic nitro compounds to the corresponding aniline derivatives in the absence of a catalyst74 such as cobalt(II) chloride,75 palladium,76 titanium(IV) chloride77 or tin(II) chloride.78 Relatively inexpensive systems such as NaBH4–iron(II) chloride79 and NaBH4–copper(I) chloride80 also reduce nitroarenes containing electron-donating groups in the ortho or para positions.

Sodium borohydride reduces disulfides to thiols, which can then be used to reduce nitro groups. Based on the redox properties of 1,2-dithiolane, lipoamide (17) was used for the selective reduction of monosubstituted nitrobenzenes to the corresponding anilines.81 Lipoamide (17) can also be immobilized on hydrophilic polymers such as polyvinylamine, polyethyleneimine and chitosan.82 These polymeric reducing catalysts can be recycled and are easy to separate from the reaction mixture. The system has been used to reduce nitroarenes to anilines.83

(15)Sodium Borohydride - an overview (10)

Sodium borohydride can also be used to couple dinitrobenzenes.84 1,3-Dinitrobenzene (19) and 1,3,5-trinitrobenzene (21) produce diphenylamine derivatives in reactions that are of preparative value when the nitro compound is present in excess (Scheme 3). The method involves the addition of a suspension of sodium borohydride in methanolic sodium hydroxide to a solution of the nitro compound in refluxing methanol. Under these conditions, no reduction to dinitrocyclohexenes is observed.85,86 Coupling products are not obtained from 1,2,4-trinitrobenzene, even though two of the nitro groups have a meta relationship. 1,4-Dinitrobenzene (23) undergoes reductive coupling to yield 4,4′-dinitroazobenzene (24).

Sodium Borohydride - an overview (11)

Scheme 3.

(Video) Sodium Borohydride NaBH4 Reduction Reaction Mechanism

Curiously, 1,2-dinitrobenzene (25) couples with the loss of one nitro group; however, the product is a diphenylhydroxylamine derivative (26) rather than a diphenylamine (equation 16). Nitroso compounds can also be reduced to amines in good yields using diborane (equation 17).87

(16)Sodium Borohydride - an overview (12)

(17)Sodium Borohydride - an overview (13)

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Functional Group Exchange Reactions

Michael B. Smith, in Organic Synthesis (Fourth Edition), 2017

7.4 Sodium Borohydride

Sodium borohydride (NaBH4) was first prepared by Schlesinger and Brown in 1943,27,28 but experimental details were not reported until the 1950s.29 Sodium borohydride was first prepared by reaction of sodium hydride (NaH) with trimethylborate, B(OMe)3.30


Sodium borohydride is considered to be a selective reagent,31 which means that it is a weaker reducing agent when compared to LiAlH4 (e.g., see Section 7.6). Sodium borohydride is useful for the reduction of aldehydes, ketones, or acid chlorides in the presence of other easily reducible functional groups.32 The relatively poor reactivity of sodium borohydride is reflected in the solvents used for the reduction. Water and alcohol solvents are preferred due to the excellent solubility of sodium.27 Sodium borohydride reacts with water to form hydroxyborohydride intermediates, and these products are also mild reducing agents. Similar reaction with an alcohol is relatively slow, so the most common reaction solvents for reduction or organic substrates are ethanol and propan-2-ol, although methanol is also used. Sodium borohydride is relatively insoluble in ether solvents, so these are rarely used for borohydride reductions. As will be seen in the following discussions, a hydrolysis step is required to decompose an initially formed borate when sodium borohydride is used as a reducing agent. In most cases, aqueous ammonium chloride, aqueous acetic acid, or dilute mineral acids are used for hydrolysis.

Sodium borohydride is a relatively selective reducing agent. Ethanolic solutions of sodium borohydride reduce aldehydes and ketones in the presence of epoxides, esters, lactones, acids, nitriles, or nitro groups.27,33 Reduction of aldehydes is straightforward. In Shao and coworker's34 synthesis of limaspermidine, reduction of the aldehyde moiety in 5 gave alcohol 6 in 95% yield. In general, sodium borohydride is an excellent reagent for the reduction of ketones or aldehydes in the presence of esters,35 hydroxyl groups that are α to the carbonyl,36 a carbohydrate residue,37 or halogens in the α-position.38 Aryl ketones39 or aryl aldehydes40 are also easily reduced.

Sodium Borohydride - an overview (14)

Sodium borohydride often yields the 1,2-reduction product (an alcohol) from conjugated carbonyl derivatives, particularly when the terminal carbon of the conjugated system is sterically hindered. However, unconjugated ketones and aldehydes are usually reduced in preference to a conjugated carbonyl elsewhere in the molecule. Paquette and coworkers41 treated 7 with NaBH4 and obtained 8 in good yield, without reduction of the conjugated ketone unit, as part of a synthesis of magellanine.

Sodium borohydride reduces ozonides (Section 6.7.2) to an alcohol.42 An example is the ozonolysis of 9 where borohydride reduction gave alcohol 10 in 94% yield in a synthesis of (−)-cytoxazone by Jung and coworkers.43

Sodium Borohydride - an overview (15)

Sodium borohydride can be used for the reduction of enamines, imines, or iminium salts, and such reductions are particularly useful in alkaloid and amino acid syntheses. In a synthesis of amphorogynine C, Mann and coworkers44 reduced the imine unit in 11 to the amine (12) by reaction with NaBH4, and immediate protection with Boc anhydride gave 13 in 85% overall yield. Enamines can also be reduced to give the corresponding amine.45

Sodium Borohydride - an overview (16)

An important variation is called reductive amination, in which an aldehyde or ketone is mixed with an amine in the presence of sodium borohydride, generating the corresponding N-alkyl amine. Miranda and Gómez-Prado46 employed reductive amination in a synthesis of hericerin, where the reaction of aldehyde 14 and benzylamine, followed by in situ treatment with sodium borohydride, yielded 15 in >82%. In a related reaction, sodium borohydride reduces iminium salts to the amine,47 and pyridinium salts can also be reduced.48

Sodium Borohydride - an overview (17)

Amides are not reduced directly by NaBH4, but if they are first converted to an iminium derivative reduction to the amine is rapid. Reaction of 16 with phosphorus oxychloride (POCl3) gave the so-called Vilsmeier-Haack complex49 (17), which was reduced to the piperidine derivative 18.50 Primary amides are converted to nitriles by this procedure. Vilsmeier complex 17 is related to an intermediate generated in what is known as the Vilsmeier reaction,49 which converts aromatic derivatives to aryl aldehydes. In a Vilsmeier reaction, POCl3, and DMF react to form Me2NSodium Borohydride - an overview (18)CHCl+, and this intermediate reacts with an aromatic compound to form an aldehyde after hydrolysis. Note that imides react with sodium borohydride under mild conditions to yield a 2-hydroxylactam.51

Anhydrides are related to lactones as imides are related to lactams. Partial reduction of an anhydride to a hydroxy-lactone is difficult, but reduction (with ring opening) to a hydroxy acid is facile. Subsequent ring closure can generate a lactone when NaBH4 is used to reduce cyclic anhydrides that have less than six carbon atoms in the ring. An example is the reduction of anhydride 19 in DMF, to give lactone 21 in 55% yield.52 Norbornyl systems usually react via the exo-face, as discussed in Section 7.9.6, which accounts for the selectivity of this reduction. In this particular example, reduction of the exo-carbonyl gave alcohol 20, which spontaneously closed to the lactone (21) in the presence of the carboxyl group.

Sodium Borohydride - an overview (19)

The functional group transforms for this section follows:

Sodium Borohydride - an overview (20)

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(Video) 07.06 Sodium Borohydride

Six-membered Rings with One Heteroatom, and their Fused Carbocyclic Derivatives

G.L. Edwards, ... R. Murugan, in Comprehensive Heterocyclic Chemistry III, 2008 Reactions at the Ring Carbons Reduction of ketone to alcohol

Sodium borohydride reduction of cyclic ketone 109 produced alcohol 110 <1997BMC1327> (Equation 19). Biheterocyclic 2-hydroxyphosphonates 111 were synthesized by reactions of phospha-bicyclodecanones 112 with dimethylphosphonates in the presence of NaOH/MeOH <1996RJC567> (Equation 20). 1-Cyclohexylphosphin-4-one 113 was reduced to the corresponding alcohol 114 by sodium borohydride <2004TL407> (Equation 21).

(19)Sodium Borohydride - an overview (21)

(20)Sodium Borohydride - an overview (22)

(21)Sodium Borohydride - an overview (23) Wolf–Kishner reduction

Reduction of the carbonyl groups of 115 and 116 was achieved by treatment with N2H4 under basic conditions <2006OL103> (Equation 22).

(22)Sodium Borohydride - an overview (24) Wittig reaction

The Wittig reaction of methylenetriphenylenephosphorane with ketones 117 gave 4-methyleneoxo-phosphorinane 118 in 66% yield <1996JA10168> (Equation 23). Reaction of the phenyl phosphonium bromide 73 with 3,4,5-trimethoxybenzaldehyde gave alkenes with greater trans selectivity <1998SL497>.

(23)Sodium Borohydride - an overview (25) Carboxylation (to COOH)

Carboxylation of 1-phenylphosphorinane was achieved via deprotonation (BuLi)–carboxylation (CO2) to give 1-phenylphosphorinan-2-carboxylic acid <2001TL7303>. Ketone protection

Condensation of derivatives of phosphabicyclodecanones 119 with ethylene glycol in the presence of PTS/ZnCl2 gave cyclic ketals 120 of the phosphabicyclodecane series <1996RJC564> (Equation 24). Oximes and semicarbazones were prepared from bicyclic ketones <1996RJC567>.

(24)Sodium Borohydride - an overview (26)

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Synthesis: Carbon With One Heteroatom Attached by a Single Bond

I. Shcherbakova, A.F. Pozharskii, in Comprehensive Organic Functional Group Transformations II, 2005 Sodium borohydride trisulfide (sulfurated sodium borohydride) and other borohydride trisulfides

Sodium borohydride trisulfide (NaBH2S3) converts aldehydes, ketones, or epoxides into symmetrical disulfides <1995COFGT(2)113>. The instability of the reagent, which decomposes rapidly in the presence of oxygen or atmospheric moisture, places limitations on its use. Firouzabadi and co-workers have reported the preparation of stable sulfurated calcium and barium borohydrides [Ca(BH2S3)2 and Ba(BH2S3)2] and investigated their reactivity as reducing reagents <2000PS(159)99, 2000PS(166)83>. With regard to disulfide formation from epoxides, the reactivity and regioselectivity of both reagents is higher than that of NaBH2S3. Substituted epoxides are opened from the less hindered side of the ring and in good yield (Scheme 120).

Sodium Borohydride - an overview (27)

Scheme 120.

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Synthesis: Carbon With No Attached Heteroatoms

J. Blanchet, ... Jieping Zhu, in Comprehensive Organic Functional Group Transformations II, 2005 Metal hydride demercuration

Sodium borohydride has been widely used to reduce organomercurials to produce the corresponding hydrocarbons. The mechanism involving the reduction of the organomercurials with sodium borohydride is believed to be a free radical process as shown in Scheme 17 <1976JA5973, 1984TL5239, B-1985MI006, 1991COS(8)850>.

Sodium Borohydride - an overview (28)

(Video) Sodium borohydride introduction and examples

Scheme 17.

Reduction of exo- and endo-norbornylmercury(II) bromide with sodium borodeuteride provides exo-[2-D]norbornane as the major product (Equation (162)) <1970JA6611>. Other examples of this phenomenon can be found in the literature <1981JOC563>.

(162)Sodium Borohydride - an overview (29)

The diastereoselectivity in metal hydride demercuration of α-mercury(II) carbonyl compounds depends on the nature of the solvent, the amount of hydride used, the mode of addition, the nature of the hydride source, and the ligand on mercury (Equation (163)) <1986JOC2024>.

(163)Sodium Borohydride - an overview (30)

A frequent problem associated with the reductive demercuration of organomercurial compounds is deoxymercuration, which would result in the isolation of alkenes. This is often minimized by using alkaline borohydride (Equation (164)) <1984T2317, 1966JA993, 1983TL4923, 1997T2835, 2001T9915>. Alkaline borohydride in the demercuration of peroxymercurials has also been accomplished (Equation (165)) <1992CC428, 1992CC926, 1992T3835, 1993T2729>.

(164)Sodium Borohydride - an overview (31)

(165)Sodium Borohydride - an overview (32)

Phase-transfer reagents are sometimes used to avoid deoxymercuration and other side reactions (Equation (166)) <1986CC855, 1979S891, 1984JOC2838>.

(166)Sodium Borohydride - an overview (33)

Reductive demercurations using an excess of sodium borohydride in DMF without sodium hydroxide have been reported to give good results (Equation (167)) <1997JOC5267>. However, it seems that it is not a general method for the reduction of CSodium Borohydride - an overview (34)Hg bonds.

(167)Sodium Borohydride - an overview (35)

Zinc borohydride has been successfully used for reductive demercuration to give desired product as a milder reducing agent compared to alkaline borohydride, which resulted in the isolation of the starting alkenes used prior to mercury addition (Equation (168)) <1992SC3013>.

(168)Sodium Borohydride - an overview (36)

A number of demercurations also use tributyltin hydride (Equation (169)) <2002AG(E)2144, 2001TA597, 2001OL2567, 1996JOC2109, 1984T2317, 1983JA6882>, or triphenyltin hydride <1984JA8313, 1996CAR69>, but complete removal of tin residues can be difficult. As with sodium borohydride, there is also a problem with competitive deoxymercuration when tin hydrides are used <1984T2317>. The presence of sodium acetate prevents this problem if triphenyltin hydride is employed (Equation (170)) <1984JA8313, 1996CAR69>.

(169)Sodium Borohydride - an overview (37)

(170)Sodium Borohydride - an overview (38)

LAH has been used as the reducing agent in demercuration (Equation (171)) <1999JOC101, 1983JA6882, 1986JA2094, 1997JOC4653>. Methylmercurio derivatives RSodium Borohydride - an overview (39)HgMe are stable toward a number of hydrides (NaBH4, LiAl(OBut)3H, l-selectride, or superhydride) and the halomercurio functionality can be regenerated by treatment with HgCl2 or HgBr2. Alternatively, LAH gave the fully reduced product (Scheme 18) <1999JOC101>.

(171)Sodium Borohydride - an overview (40)

Sodium Borohydride - an overview (41)

Scheme 18.

The reduction of organomercury(II) halides with LAH has been investigated and the findings suggest an electron-transfer mechanism involving attack of the alkyl radical on the metal hydride (Scheme 19) <1983TL1411>.

Sodium Borohydride - an overview (42)

Scheme 19.

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Green Chemistry Experiments

Joaquín Isac-García, ... Henar Martínez-García, in Experimental Organic Chemistry, 2016

13.11.2 Background

Sodium borohydride (NaBH4) is a reagent that transforms aldehydes and ketones to the corresponding alcohol, primary or secondary, respectively. The conventional procedure is usually performed in MeOH or even with EtOH, but frequently the reaction with cyclohexanone as the starting product takes place with very poor yields. MeOH and EtOH react partially with NaBH4, producing hydrogen. NaBH4 is very soluble and relatively stable in aqueous alkali. For example, in a 0.2M aqueous solution of NaOH, less than 5% decomposition results in 2weeks. The main limitation of water as a solvent is aldehydes and ketones is that most are insoluble in water. Cyclohexanone can be reduced easily in an aqueous medium, using a stirred solution of aqueous NaBH4 stabilized with sodium hydroxide. This procedure is not necessarily a general one, but it can be applied to carbonylic compounds, partially water soluble.

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(Video) Burning sodium borohydride



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