Aldehydes and Ketones
Sodium Borohydride (NaBH4) Reduction of Aldehydes and Ketones
Last updated: February 16th, 2023 |
Sodium borohydride (NaBH4) For the Reduction of Aldehydes and Ketones
- Sodium borohydride (NaBH4) is a convenient source of hydride ion (H-) for the reduction of aldehydes and ketones.
- Aldehydes are reduced to primary alcohols and ketones are reduced to secondary alcohols.
- Esters (including lactones) and amides are not reduced.
- As a source of hydride ion, NaBH4 will also act as a strong base, deprotonating water, alcohols, and carboxylic acids.
- NaBH4 also sees use in the reduction of organomercury bonds after oxymercuration reactions.
Table of Contents
- Sodium Borohydride, NaBH4
- NaBH4 For The Reduction of Aldehydes and Ketones
- Mechanism For the Reduction of Aldehydes and Ketones by Sodium Borohydride
- NaBH4 Will Not Reduce Esters or Amides
- Reduction of Hemiacetals
- Reduction of Organomercury Compounds with NaBH4
- Quiz Yourself!
- (Advanced) References and Further Reading
Sodium borohydride (NaBH4) can be made through the addition of sodium hydride (NaH) to our old friend borane (BH3 – See post: Hydroboration-Oxidation of Alkenes) in an appropriately chosen solvent [Note 1]. We generally don’t think of the hydride ion (NaH) as being a very good nucleophile, but the empty p-orbital of BH3 makes this addition much easier.
In contrast to BH3, which is a highly air-sensitive liquid requiring special inert-atmosphere (Schlenk line) techniques, sodium borohydride NaBH4 is a white crystalline solid generally dispensed in the form of pellets, very easily handled and weighed on the benchtop.
It’s worth a reminder about the properties of the B-H bond because this can be a common source of confusion.
That negative charge on boron does not represent a lone pair on boron, however!
Because hydrogen is more electronegative (2.20) than boron (2.04) the electrons in the B–H bond are polarized towards the hydrogen.
So where are the electrons, if they’re not on the boron?
They’re on the hydrogens!
True to its name, sodium borohydride acts as a source of hydride ion, H(-).
You may recall that hydride is the conjugate base of hydrogen (H2) (pKa about 36), making it a very strong base. NaBH4 reacts with water and other weak acids (such as methanol) to generate hydrogen gas (H2).
See if you can draw an arrow-pushing mechanism for the formation of H2 :
(It’s actually quite common to use methanol (CH3OH) as the solvent for sodium borohydride reductions. As long as the temperature is kept low (a dry ice / acetone cold bath at –78°C is common) the bubbling can be kept under control. It’s nowhere near as reactive towards water as lithium aluminum hydride (LiAlH4), which requires rigorously dry solvents to be used).
The most important reaction of NaBH4 is its use in the reduction of aldehydes and ketones to give alcohols.
(You may recall that in organic chemistry, reduction generally refers to a process whereby a C-H bond is formed at the expense of a C-O bond. This results in a decrease in the oxidation state of the carbon – see article: Oxidation and Reduction in Organic Chemistry)
The reduction of aldehydes with sodium borohydride gives primary alcohols. Note the bonds that form and break here – a new C-H bond is formed, and a C-O (pi) is broken. An additional O-H bond forms during during a workup step with mild acid.
The reduction of ketones follows a similar pattern, and results in the formation of secondary alcohols. A C-H bond is formed and a C–O (pi) bond is broken.
Note that if the two R groups flanking the C=O bond are different, a new chiral center will be created. In the case of a simple ketone such as acetophenone (phenyl methyl ketone) this will result in a racemic mixture. (See article: What’s A Racemic Mixture?)
If the molecule already contains one or more stereogenic centers, a mixture of diastereomers will form. One notable example is the reduction of the bicyclic ketone [2.2.1]bicycloheptanone (above). Addition of the hydride ion occurs preferentially from the least hindered face (where there is only one bridging carbon) to give an 86:14 ratio of diastereomers.
Chiral reducing agents similar in reactivity to NaBH4 have been developed that are capable of performing enantioselective reductions of ketones. One prominent example is the CBS (Corey-Bakshi-Shibata) family of reagents.
The mechanism for these reductions follows the very common two-step addition-protonation pattern often found in reactions of aldehydes and ketones (See article: The Common Two-Step Pattern for Addition to Aldehydes and Ketones)
The addition is followed by protonation of the oxygen with a mild acid (leading to the formation of O–H).
In practice, this reaction is usually performed in an alcoholic solvent like CH3OH and the reaction is quenched with a mild acid such as a saturated solution of ammonium chloride (NH4Cl)
(This reaction can be done by LiAlH4 , however. See article – Lithium Aluminum Hydride LiAlH4)
Why are esters and amides so unreactive? After all, shouldn’t these functional groups be more reactive than aldehydes and ketones since the carbonyl is attached to the electronegative oxygen and nitrogen atoms?
It’s actually the opposite! The lone pairs from oxygen and nitrogen are capable of donating electron density to the carbonyl carbon through forming a pi bond. This makes the carbonyl carbon less electrophilic and less reactive with nucleophiles.
(You might recall that this is the exact same reason why OH and NH2 are activating groups in electrophilic aromatic substitution reactions – See Article: Understanding Ortho, Para and Meta Directors)
What about anhydrides and acid halides?
Aldehydes and ketones, check. Esters and amides, no go. So what else can be reduced by sodium borohydride.
The molecule below might look familiar. It’s glucose!
There actually is an aldehyde present here, but it is in equilibrium with a cyclic hemiacetal. (In cyclic molecules such as sugars, this equilibrium process is known as ring-chain tautomerism – See Ring Chain Tautomerism in Sugars)
Although the open-chain aldehyde form only comprises 0.02% of an aqueous mixture of glucose at equilibrium, NaBH4 will quickly reduce any aldehyde that is present to give sorbitol. Via Le Chatelier’s principle, equilibrium between the cyclic hemiacetal and the aldehyde will eventually result in all of the cyclic hemiacetal being reduced to the alcohol.
See if you can draw the mechanism:
There’s one more use of NaBH4 worth noting.
You may recall that alkenes can undergo oxymercuration when treated with water (or alcohols) in the presence of mercuric acetate Hg(OAc)2 or similar (See article – Oxymercuration of Alkenes) which results in net Markovnikov addition of water to an alkene.
The precise details of this “demercuration” step are often skipped over, but for completeness we’ll briefly go through it here.
The first step is addition of hydride to mercury, giving NaOAc and a new Hg-H bond. Carbon-mercury bonds are extremely weak (this is part of the reason why organomercury compounds are extremely toxic) and upon homolytic cleavage of Hg-C, the resulting carbon radical is then reduced with Hg-H to give C-H and metallic mercury (Hg0). On large enough scale, this results in a little puddle of mercury forming at the bottom of the reaction flask.
- Sodium borohydride will reduce aldehydes to primary alcohols and ketones to secondary alcohols.
- This proceeds via a two-step mechanism consisting of 1) nucleophilic addition, followed by 2) protonation.
- Esters and amides are not reduced by NaBH4 under normal conditions. (They can be reduced by lithium aluminum hydride (LiAlH4) however).
- NaBH4 is also used in the demercuration step of oxymercuration-demercuration.
Note 1. In practice NaBH4 is made on industrial scale by the treatment of trimethyl borate [B(OCH3)3] with sodium hydride at high temperatures (250°C).
The reaction with LiH and BH3 in ether works well to make lithium borohydride, LiBH4. However the same reaction between NaH and BH3 requires using either THF or diglyme (ethylene glycol dimethyl ether) as the solvent, not diethyl ether.
Prior to the development of NaBH4, aldehydes and ketones were reduced either with sodium amalgam , sodium in alcohol solvent [Ref] , or through reductions such as the Meerwein-Pondorff-Verley reduction, all of which have various drawbacks. [Ref] Having a convenient crystalline solid as a bench-stable reducing agent has made reductions of aldehydes and ketones much more efficient.
Note 2. The reaction of esters with NaBH4 is extremely slow. However, lithium borohydride (LiBH4) will successfully reduce esters, owing to the greater Lewis acidity of the lithium ion that helps to activate the carbonyl oxygen towards attack. (See article – Acid Catalysis In Addition-Elimination Reactions)
This article has more detail.
Note 4. The rate of reduction of cyclobutanone is about 3300 times faster than the reduction of cyclooctanone. This is due to the relief of ring strain upon going from sp2-hybridization (bond angle 120 °) to sp3 hybridization (109 .5 °) . Reduction of cyclo-octanone is considerably slower due to the presence of transannular strain in eight-membered rings.
A useful (graduate-level) PDF handout on reducing agents can be found in these course notes from Prof Andrew G. Myers’ Chemistry 115 class at Harvard
Sodium borohydride was discovered in 1942 as part of a wartime research program toward finding volatile compounds of uranium that would enable isotopic enrichment through centrifugation. [Uranium (IV) borohydride, a volatile green solid, was synthesized in pound-scale quantities for this purpose].
- Forty Years of Hydride Reductions
Herbert C. Brown and S. Krishnamurthy
Tetrahedron, 1979, 35, 567-607
A very accessible review on the history and development of hydride reducing agents, including NaBH4 and its many relatives.
- The Preparation of Sodium Borohydride by the High Temperature Reaction of Sodium Hydride with Borate Esters
H. I. Schlesinger, Herbert C. brown, and A. E. Finholt
- Reaction of Sodium Borohydride With Carbonyl Groups
Brown, H.C.; Wheeler, O.H.; Ichikawa, K.
Tetrahedron 1:214 (1957)
Early paper by Nobel Laureate H. C. Brown describing the reactivities of simple aldehydes and ketones to reduction by NaBH4, in which it is shown that aldehydes are more reactive than ketones to nucleophilic reactions.
- Mechanistic studies
Brown, H. C.; Ichikawa, K.
Tetrahedron 1:221 (1957)
This paper and the above are both mechanistic studies on the reduction of carbonyls – this paper investigates the effect of ring size on the reduction of cyclic ketones (e.g. reduction of cyclobutanone vs. cyclopentanone, cyclohexanone, etc.).
- Reference To An Experimental Procedure
Antonio Bermejo Gómez, Nanna Ahlsten, Ana E. Platero-Prats and Belén Martín-Matute
Org. Synth. 2014, 91, 185
The first step in this procedure uses NaBH4 to reduce a cinnamyl ketone to the alcohol.
- Reduction of ketones by sodium borohydride in the absence of protic solvents. Inter versus intramolecular mechanism.
Kayser, M., Eliev, S., & Eisenstein, O.
Tetrahedron Letters, 1983 24(10), 1015–1018.
- Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated ketones
Jean Louis Luche
Journal of the American Chemical Society 1978 100 (7), 2226-2227
Using sodium borohydride for the reduction of unsaturated ketones sometimes results in the side reaction of conjugate reduction, i.e. the reduction of the double bond instead of the carbonyl. This paper shows that selectivity for 1,2-addition (to the carbonyl) can be greatly increased by treating the alpha,beta unsaturated ketone with 1.1 equivalent of the Lewis acid cerium chloride. This makes the carbonyl carbon more electrophilic and allows for a “chemoselective” reduction of the carbonyl. This procedure has become known as the Luche reduction.