Aldehydes and Ketones

By James Ashenhurst

Sodium Borohydride (NaBH4) Reduction of Aldehydes and Ketones

Last updated: May 22nd, 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.

summary of nabh4 as a reducing agent in organic chemistry

Table of Contents

    1. Sodium Borohydride, NaBH4
    2. NaBH4 For The Reduction of Aldehydes and Ketones
    3. Mechanism For the Reduction of Aldehydes and Ketones by Sodium Borohydride
    4. NaBH4 Will Not Reduce Esters or Amides
    5. Reduction of Hemiacetals
    6. Reduction of Organomercury Compounds with NaBH4
    7. Summary
    8. Notes
    9. Quiz Yourself!
    10. (Advanced) References and Further Reading

1. Sodium Borohydride (NaBH)

Sodium borohydride (NaBH4) can be made through the addition of sodium hydride (NaH) to our old friend borane (BHSee 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.

-structure of sodium borohydride nabh4 and its formation from bh3 2

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.

NaBH4 has a tetrahedral arrangement of hydrogen atoms about the central boron atom, and a formal charge of -1 on the boron.

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!

in nabh4 and borane the electrons are polarized towards the hydrogen atom

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 :

Click to Flip

(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). 

2. NaBH4 For The Reduction of Aldehydes and Ketones

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.

sodium borohydride nabh4 can be used for the reduction of aldehydes to primray alcohols

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?)

reduction of ketones with sodium borohydride with examples

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. 

3. Mechanism for the Reduction of Aldehydes and Ketones With NaBH4

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 first step in this reaction is nucleophilic addition to the carbonyl carbon. (See article: Nucleophilic Addition to Carbonyls), forming a C-H bond and breaking a C–O (pi) bond.

mechanism for the reduction of aldehydes and ketones by sodium borohydride

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)

4. NaBH4 Will Not Reduce Esters or Amides

NaBH4 will not generally reduce esters or amides. (Note 2).

(This reaction can be done by LiAlH4 , however. See article – Lithium Aluminum Hydride LiAlH4)

nabh4 will not reduce esters and amides

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.

why no reduction of esters by nabh4

(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?

NaBH4 will reduce anhydrides and acid halides, but in practice, these functional groups will react with the solvent (CH3OH) before they have a chance to react with NaBH4.

5. Reduction of Hemiacetals

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!

When treated with NaBH4, glucose is reduced to the alcohol sorbitol. 

Reduction of glucose by nabh4 to give sorbitol

Hold on for a second. What happened here? There’s no aldehyde or ketone.  Or is there? 

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:

Click to Flip

(Sodium borohydride can also be used in the reductive amination of iminium ions to give amines. For more on that, see this article on Reductive Amination. )

6. Reduction of Organomercury Compounds

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.

oxymercuration demercuration reaction using nabh4

The resulting organomercury compound can then be treated with NaBH4 to give an alcohol.

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.

reduction of alkylmercury compound to alkane with nabh4 mechanism

7. Summary

  • 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.

Notes

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).

structure of sodium borohydride nabh4 and its formation from bh3

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)

Note 3. If protic solvents are rigorously excluded and the reaction is run in a polar aprotic solvent like DMF, the resulting product of sodium borohydride reduction will be a boronic ester.

reduction of ketones without alcoholic solvent

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.

Rates for reduction of cyclic ketones with NaBH4


Quiz Yourself!

Click to Flip

(Advanced) References and Further Reading

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].

  1. Forty Years of Hydride Reductions
    Herbert C. Brown and S. Krishnamurthy
    Tetrahedron197935, 567-607
    DOI: 10.1016/0040-4020(79)87003-9
    A very accessible review on the history and development of hydride reducing agents, including NaBH4 and its many relatives.
  2. 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

    Journal of the American Chemical Society 1953 75 (1), 205-209
    DOI: 10.1021/ja01097a054
    NaBH4 was discovered in 1942 but this work was not declassified until 1953. The prepration of NaBH4 through the method described in this paper is still in use today.
  3. Reaction of Sodium Borohydride With Carbonyl Groups
    Brown, H.C.; Wheeler, O.H.; Ichikawa, K.
    Tetrahedron 1:214 (1957)
    DOI: 10.1016/0040-4020(57)88041-7
    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.
  4. Mechanistic studies
    Brown, H. C.; Ichikawa, K.
    Tetrahedron 1:221 (1957)
    DOI: 10.1016/0040-4020(57)88042-9
    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.).
  5. Reference To An Experimental Procedure
    Antonio Bermejo Gómez, Nanna Ahlsten, Ana E. Platero-Prats and Belén Martín-Matute
    Org. Synth. 2014, 91, 185
    DOI: 10.15227/orgsyn.091.0185
    The first step in this procedure uses NaBH4 to reduce a cinnamyl ketone to the alcohol.
  6. Reduction of ketones by sodium borohydride in the absence of protic solvents. Inter versus intramolecular mechanism.
    Kayser, M., Eliev, S., & Eisenstein, O.
    Tetrahedron Letters1983 24(10), 1015–1018.
    DOI: 10.1016/S0040-4039(00)81590-7
  7. 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
    DOI: 10.1021/ja00475a040
    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.

 

Comments

Comment section

87 thoughts on “Sodium Borohydride (NaBH4) Reduction of Aldehydes and Ketones

  1. Can the reduction reaction take place in basic conditions? For example for the reduction of sugars to their respective polyols, sodium borohydride is used with ammonium hydroxide or ammonium acetate but it is suggested to wait for at least 12 hours. Is it because the reaction is slow under basic conditions without the presence of H+?

    1. Reaction should be very fast, in particular in basic conditions since base will catalyze conversion of the anomeric center to the ring-opened aldehyde form (which is reduced). I’m not sure what procedure you’re referencing, but it’s generally very quick.

  2. Hi. i am looking for a reaction mechanism to reduce an oil sample ( aldehyde to alcohol). I found that NaBH4 can be used to reduce it to the desired form. Could anyone please guide me the entire procedure to do it? I am not sure about the amount of NaBH4 to be added and the solvent to be used for the same. Also the temperature conditions during the reaction.

    1. NaBH4 in the presence of even weak acids such as water will form hydrogen gas and may result in fires if a source of ignition is present. I am very reluctant to act as a guide for those planning on carrying out this reaction without adequate background and training.

  3. Hi
    Can Sodium Borohydride reduce Acid anhydrides? I have seen some sources saying that.can you explain it?
    Thank you

    1. It actually can reduce cyclic anhydrides to esters. When reducing anhydrides however you have to be careful about the choice of solvent, as solvents under basic conditions (e.g. MeOH with NaBH4) will just undergo nucleophilic acyl substitution.

  4. Hi all!

    I have a fun project I am working on right now but I think I am running into some issues.

    I am trying to make a di-ol derivative of caffeine. Initially, I would like to reduce both ketones to secondary alcohols. So far, I have tried NaBH4 (2 molar excess) + caffeine in MeOH (dry-ish / used some 3A dessicant beads) and stirred at 0C for 8 hours.

    I do not seem to have made the product. Any suggestions?

    Thanks in advance!!

    1. Hi, there’s a fundamental problem with trying to do that. The functional groups are not actually ketones, they are flanked by nitrogens with lone pairs and this affects their reactivity significantly. Furthermore even if reduction were achieved the resulting product would not be particularly stable; it would likely dehydrate (lose water) to give the aromatic heterocycle known as “purine”. In fact if you look up the structure of purine you will note the similarity to caffeine (and DNA bases adenine and guanine).
      In short it’s *possible* to make the reduced form(s) of caffeine but you would need some way of protecting the resulting OH groups, and furthermore you would need to prevent the molecule from dehydrating to purine.

  5. Hi, thank you for the post, I did found it very interesting but I have one question:
    I did myself one reduction with NaBH4 in the laboratory of organic chemistry, but the weird thing its that I was using MeOH as solvent for the ethylphenilketone to reduce it to 1-phenylpropan-1-ol, but the NaBH4 was prepared in water and was aded to the reaction mixture dropwise. How its posible that the NaBH4 don’t decomposes in protic solvents?

    1. It does decompose in protic solvents (there are 4 equiv of hydride per mole of NaBH4) but the decomposition is relatively slow compared to, say, LiAlH4.
      [edited your comment to say, “dropwise”]

  6. We’ve learnt so far that NaBH4 cannot reduce ester but can reduce a cyclic ester such as lactone, I’m confused 🤔

  7. Why BH3 forms as a side product and NOT B(OH)3?
    In a similar reaction by LiAlH4, what will be the side products?

  8. Two more questions:
    I saw H2 evolving after I added NaBH4 to MeOH?. Is this because of residual moisture in the solvent?
    Can I run the NaBH4 reaction in Ammonium-MeOH?

    Thank you!

    1. Yes, H2 is evolved. That’s because NaBH4 is basic (the hydride ion H-) , and will react with weak acids (like MeOH) to give H-H (hydrogen gas). The reaction of NaBH4 with MeOH is slower than the reaction of NaBH4 with aldehydes/ketones, especially at low temperatures. It’s common to run NaBH4 reductions at very low temperatures (e.g. -78) for this reason.

  9. Would you have some suggestions on how to clean up after nitrile reduction to amines? I thought to use acid to break down the NaBH4 first, then add base, and extract with solvent, then dry with NaSO4 (anh). Is this about right? Thanks!

    1. That sounds about right, but instead of trying to re-invent the wheel, I would look for a literature procedure and use that. Supporting information in papers is usually free to access.

  10. NaBH4 can be used in the imine reduction. So, I would like to know the by-products of this reaction and how to remove them.

  11. Hey,I have a doubt. Why can’t NaBH4 reduce nitriles when it can reduce imines? Shouldn’t triple bond be easier to reduce compared to double bond?

    1. Generally requires a stronger reducing group like LiAlH4. The problem is that addition of hydride to nitrile forms C=N(-) and the negatively charged nitrogen is quite basic. Can’t find a pKa number at the moment unfortunately.

  12. Hi, I have a question as to why NaBH4 is good for ketones/aldehydes but why it won’t work for esters?

  13. Hi, in the reduction with water, what becomes of the OH- ion. Does the solution just become more alkaline?

    PS thanks for your great website.

    1. Yes, NaBH4 plus H2O gives H2 , BH3, and NaOH. The solution does become basic. For that reason the reaction is often quenched with a very mild acid (saturated ammonium chloride) which protonates the conjugate base of the alcohol and sequesters any BH3.

  14. Hi, we did a reduction of ketone with NaBH4. We had ketone in n-hexanne, we added methanol and NaBH4, we stirred, left for couple minutes, than added 0.1M EDTA. What is the purpose of adding EDTA? Thank you for an answer.

    1. Haven’t heard of that workup before. The byproduct of the reaction is BH3 and the sodium salt of the alcohol (alkoxide). EDTA is a weak acid and also a metal complexing agent. When you add the aqueous solution of EDTA, you’ll protonate the alcohol and any Na+ ions will end up coordinated to it, as well as any residual BH3/borate salts

  15. Would NaBH4 reduce an alkene adjacent to an imine?

    For example:

    H2C=C—C=NH
    ………. |
    ………CH3

    1. Hi MIchael – in general NaBH4 will reduce the alkene in alpha,beta unsaturated ketones (“conjugate reduction”) unless a strong Lewis acid such as CeCl3 is used (“Luche reduction”).

      NaBH4 will also do conjugate reductions of alpha beta unsaturated nitriles.

      With conjugated imines I am not 100% sure. The imine you’ve drawn is a simple one with an N-H substituent. These types of imines are not very stable and easily lose water.

      My first guess is that NaBH4 in the absence of a Lewis acid would also perform conjugate reduction but I am not sure.

      Is this for laboratory work or is this exam question related?

      James

  16. Hi, I’ve got a question. I’m supposed to identify a carbonyl compoud with the formula c3h6o and one of the clues is that “reaction with NaBH4 in the presence of water produced a colourless liquid”. What does this mean, and what compound could it be? (I know it’s not an aldehyde and I already know that one of the possible structures is a ketone)

    1. The product is likely some kind of alcohol. The water was likely there to provide a proton source so that you get the neutral alcohol product (not the alkoxide, which would be a salt). Working backwards, you have a carbonyl compound of some kind. C3H6O only gives you two places to put it – on C-1 (which would be propanal) or C-2 (which would be acetone).

    1. Much milder reagent. Only reduces aldehydes and ketones, so you don’t have to worry about your esters getting reduced. Also, the workup is very simple. Usually just add saturated NH4Cl or similar, extract and dry. With LiAlH4, the aluminum salts are a pain, so you have to stir with Rochelle’s salt or do the Fieser workup protocol.

    1. Yes, it can. The way around that is to add anhydrous CeCl3, which will lead to a regioselective reduction of the carbonyl and it will leave the alkene alone. This is called the Luche reduction.

  17. Hi, I want to reduce ketone in the presence of primary alcohol is there any effect of free of alcohol with NaCNBH4 and ZnI2

    1. An ordinary alcohol should not interfere with the reduction of the ketone, but then you will have two alcohols and will have to differentiate them somehow. How do you plan to do that?

      1. One of them is from a ketone, so it’s bound to be secondary. You have another primary alcohol, so I suggest Lucas test(Dil.HCl + Zinc Chloride)

        Hope I helped!