What new things are there to say about sodium borohydride? Very little, really. I have to say that I was generally unaware that NaBH4 had utility in the reduction of esters. The Gray Beast or Lucifer’s Hydride- LiAlH4- has always been the reagent of choice for carboxylates. But while enroute to other applications of NaBH4, I stumbled upon a few recent references. This is why I like to browse.
A 2006 article by de Souza in ARKIVOC, reports that aliphatic and aromatic esters are cleanly and rapidly reduced by NaBH4 in methanol/THF. OK, that’s nice (yawn). Other references to ester reduction can be found dating back at least to Persterfield in 1965 and references therein to 1961. It’s obviously not new, but I do think that it is relatively obscure.
Reduction of benzylic ketones and alcohols as well as assorted amides in acidc media to form the corresponding -CH2- or N-alkylation product was reviewed by Gribble at Dartmouth in 1998.
Well, here is the reason for my excitement. I did some pricing and found that the $/hydride cost of NaBH4 is approximately 25 % that of LiAlH4 at the bulk scale. That’s a big deal. What is a bigger deal is that NaBH4 is arguably safer to use than LAH and you can run reactions in water, MeOH, and various combinations of other solvents. Kill the excess hydride with aq NH4Cl and you’re off to the races. Though I dearly love and respect LAH, handling bulk material as the solid or as an Et2O or THF soln brings unfortunate hazards to the plant. And, LAH quench can lead to large volumes of pasty aluminate solids that present serious filtration issues.
I’m sure that a lot of hot shots out there knew this, but it was new to me. The great breadth of reactivity of NaBH4 as well as its stability to protic solvents provides many useful possibilities for the process chemist. The ability to run a reaction in methanol as opposed to anhydrous ether or THF can provide cost, safety, and competitive advantages for a manufacturer.
1/25/09. Update. US patent 2,765,346 teaches a process wherein Na or K BH4 in THF is treated with LiCl to form a composition that reportedly reduces a variety of esters to the corresponding alcohols. Examples of selective ester reduction are ethyl benzoate, butyl stearate, and ethyl p-nitrobenzoate. While I have not personally tested this process, it seems plausible enought to try.
Lamentations on Chemistry 
I like NaBH4. Nice and mellow. Haven’t yet had occasion to use LiAlH4. I’ll avoid it for as long as I can, since I’m not really a fan of accidental fires.
I have had an LAH reaction blow up in my face. I could feel the hydrides tingly effervescence as it reacted with the water on my lips. I was able to hose off my face quickly and wasn’t injured. After I quit shaking I dried off my face and cleaned up the mess.
Ah – the cleansing effect of LAH. I can’t wait to offer it along with some AlCl3 as a underarm drying agent. Can’t you just imagine the packaging?
On the other hand – I am shocked! SHOCKED! at your revealing such an important point on NaBH4. It really does sound like it has great potential for those who dread weighing LAH by the kilo. I nominate this as post of the year.
Pfizer left a plant in Holland, Mi – did you you ever visit it? Well it is yours (mine) for a song and dance. The state of Mi will practically pay you to take it over and start making stuff there again. All we need is a few good NaBH4 reductions at the ton scale and we are in business. Is it a deal?
Happy Easter man.
Yeah, I visited that plant back in 2000 when it was owned by someone else. If it is the same facility that I am thinking of, they manufactured Benedryl there. We sold ’em a bit of Grignard back then. Nothing big. Pharma companies can be very fickle customers. I really don’t care for the pharma business- too brutal for my taste. Gigabuck business really brings out the savage in people.
You mean Warner-Lambert, I believe. They had a plant, I believe, for making Lipitor – it was first scaled up in Holland, MI I beleive and moved to Europe in 2000 or so.
Oh well. I don’t see you biting on the
I have used NaBH4 to reduce methyl and ethyl esters with great yields and much less pain than LAH… the prep was the heat the ester and borohydride in dioxane at reflux, then add MeOH dropwise to get the reaction going. i think i got that from the SI of the first symbionine tot syn, but not exactly sure…
aa,
That general protocol sounds familiar. There seems to be something special about the combination of THF and MeOH. Generally, aqueous solutions of NaBH4 are rendered alkaline to increase the stability to MeOH. In my experience, there is considerable gas evolution when NaBH4 is dissolved in MeOH/THF.
wrw, I seem to recall that when I was on my buisiness trip to Holland, MI, it was before Warner-Lambert had the facility. I seem to recall it was Parke-Davis. Could I be crazy??
I want to reduce 4 hydroxyphenyl acetate toalcohol . will this borohydride+ methanol ork ?
Sounds like a science experiment to me. \;-)
anybody knows a good process to reduce methyl ester in the presence of an amide group using a borohydride?
in Germany and then in the United States
sodium borohydride is a my favorite reducing agent, because handling in piolt or plant level is very very easiely compare to other reagnt. Fir accidents are very rare compare to LAH
regards
cheluva
It there any mechanistic reason to use SBH over LAH?
Well, I’m not sure how to answer that question. LAH is far more reactive to acidic protons, so -OH groups will lose a proton and the -O: can coordinate the AlH3. This has the effect of limiting the reach of hydride attack on the molecule. That may or may not be desirable- just depnds on what you want to do.
Some people will distill certain non-protic solvents off of LAH to dry them. Works fairly well, but eventually you have to quench the LAH. This can be exciting.
methyl or ethyl esters of an amino acid will reduce to the amino alcohol in NaBH4 and ethanol %50 and H2O in 4.5 hours reflux with an 80% yield……..java
Java, Thanks for the tip.
I’ve been having some problems with the MeOH/THF procedure in reducing esters. No detectable reduction. The NaBH4 seems to react in the MeOH, venting hydrogen.
Studies on Optically Active Amino Acids. V. Synthesis of Optically Active α-Aminoalcohols by the Reduction of α-Amino Acid Esters with Sodium Borohydride
Seki Hedeo 1 Koga Kenji 2 Matsuo Hisayuki 3 Ohki Sadao 4 Matsuo Ichiro 5 Yamada Shun-ichi 6
Chemical & pharmaceutical bulletin Vol.13, No.8, pp. 995-1000,1965
Abstract
A facile reduction of optically active α-amino acid esters and their hydrochlorides took place with sodium borohydride in ethanol or aqueous ethanol to give the corresponding optically active α-aminoalcohols in fair yields. The reaction conditions were investigated.
Hey, thanks for the reference. I’ll look it up!
In grad school I used to reduce valine to valinol routinely with NaBH4/Iodine in THF. Great rxn, especially since it avoids the aluminate solids I used to get with LAH. I never used the NaOH workup. Used to add solid Na2SO4 decahydrate to the THF reaction mixture and stir until the gray color went away. Nice quench, but lots of solids to filter.
Anyone knows how to reduce a primary amino alcohol with NaBH4 …..but no AlCl3 please ! or any other way…..java
I don’t know if this thread is still active but I had a question about NaBH4 reactivity. NaBH4CN is less reactive b/c the EWG CN “steals away” electron density. So to increase the reactivity of NaBH4, you could just add a EDG correct? Ifso, what kind of EDG would work?
sorr that was NaBH3CN not NaBH4CN
Hi Deegs,
But we need to take care that we understand the mechanism of the reaction. Off-hand, I’m not sure what the CN does to the reagent. This particular reducing agent is prized for its ability to participate in reductive amination. The liberation of HCN in an acidic workup causes much fear and loathing.
Treatment of naBH4 with an oxidizer or a hydride acceptor will produce BH3. This isn’t going to be a naked BH3, it will be coordinated by whatever donor is around (i.e., a solvent like THF) or it will dimerize to afford B2H6, diborane. Oxidation of NaBH4 in THF with iodine will produce THF-BH3 complex. NaBH4 and BF3 in THF does this as well.
If you want to increase the reactivity of BH4, try LiBH4, or try BH3-THF or BH3-SMe2. NaBH3OAc is used as an alternative to the cyano analog. OtBu is a good donor as well. NaB(OtBu)3H is useful if you need selectivity and sterics will help. BH3 will coordinate at B with lone-pairs (C=O) to add H-B across a double bond.
Maybe others have a better idea. What you do depends on your substrate. If you’re trying to reduce an unsaturated carbonyl compound, BH3 may hydroborate your olefin group. That’d be a bummer. CeCl3 affords some selectivity in alpha, beta-unsaturated ketones, favoring the carbonyl.
In ‘J. Chem.Sci.’ vol.118, no.5, september 2006, pp.419-423 (Indian Academy of Sciences) Saeed A and Ashraf Z. described sodium borohydride reduction of methyl esters into corresponding primary alcohols using a NaBH4-THF-methanol system with 70-92% yields. This method also allows selective reduction of esters in presence of acids, amides, nitriles or nitro functions. [www.ias.ac.in/chemsci/Pdf-Sep2006/419.pdf]
Btw in my hands aliphatic methyl ester was reduced into primary alcohol in the presence of NaBH4/EtOH in 0C/1 hour.
From Wikipedia, the free encyclopedia: ‘Oxidation of NaBH4 with iodine in tetrahydrofuran creates the BH3-THF complex, which can reduce esters.’
‘What is the best method of quenching the reaction of LAH and amide in THF?’
[http://chem.chem.rochester.edu/nvdcgi/qandatopic.cgi?topic=94]
Journal of Organometallic Chemistry 609 (2000) 137–151
‘Methods of enhancement of reactivity and selectivity of sodium
borohydride for applications in organic synthesis’
Mariappan Periasamy *, Muniappan Thirumalaikumar
Abstract
NaBH4 does not reduce carboxylic acids, esters, amides and nitriles under ambient conditions. However, the reactivity of
NaBH4 can be enhanced by the addition of certain additives. For example, addition of iodine to NaBH4 in THF provides
H3B–THF that is useful for hydroborations and reductions of various functional groups. The aldehydes and ketones are reduced in a fast manner by the NaBH4 reagent. Even so, the selectivities realised in such reductions can be enhanced using NaBH4 along with another additive. In this article, various methods used for the enhancement of reactivity and selectivity of NaBH4 in organic synthesis are described. © 2000 Elsevier Science S.A. All rights reserved.
My favorite quench method is not necessarily the one you want to scale-up. But here it is- Powderize sone excess Na2SO4 decahydrate in a mortar and carefully add it portionwise to the stirring LAH reaction mixture. As the active hydrides are quenched, the slurry will exotherm evolve H2 rapidly. Be cautious. An ice bath is useful here. If you add at least 2 equivalents in hydride of water of hydration, the slurry will eventually turn white, indicating the consumption of hydride. It is then safe to filter the THF supernatant followed by wash THF. I have done this many, many thime with amino acids to produce amino alcohols. It seems easier than the “Fieser method” which calls for careful addition of aq NaOH.
Does it prefrable to use NaBH4/MeOH for diester to dialcohol conversion. Dot you think it affects the yield of synthesis?
reduction of α,β-unsaturated ester to allylic alcohol in presence of an acid group at ortho position.selectively reduce the ester not the acid group. is it possible?which reagent i will use? can anybody there to answer these ?
Hi Mahesh,
Methanol seems to be important in this reaction. The reduction of esters in THF is slow. The addition of methanol leads to a more prompt reaction.
Hello Subhendu,
Have you done a literature search on this one? I can’t think of a good answer for you off the top of my head. It’s hard to believe that someone hasn’t already solved this kind of problem without a lot of gymnastics.
Could anyone tell me the elaborate mechanism of reduction of keto ester by Sodium borohydride using methanol-THF system?
Please email me
Can you tell me Which amide reduce to amine by using Sodium borohydride complex?
What is a good eay to chemoselectively reduce an acid to alcohol in the presence of amide?
Thanks
HNJ
ps…Please email me
Do any body have idea for best quenching method for DIABL-H reactions.
is it possible to reduce hetero cyclic esters. when i tried it forms acid and alcohol mixture.how i will reduce the formation of acid because we need alcohol only.
i tred with all solvents meoh-thf,meoh-ipa,etoh-water.
Is it possible to reduce carboxylic ester to alcohol in presence of nitro group selectively?
I need it urgent. Please………..
sai.
did you get the answer for your question
sir how can i qunch LAH reaction. i was used NaoH followd bY Hcl but i got some Inorganic solid.
Is it possible to reduce carboxylic ester to alcohol in presence of nitro group selectively in the aromatic compunds?
Dear saikumar, when u get the answer for your question just tell me yeah….again am repeating the question ..Is it possible to reduce carboxylic ester to alcohol in presence of nitro group selectively in the aromatic compunds?
Sorry. I don’t know offhand. Maybe somebody else knows. Seems sketchy.
is there any one who can please tell how to reduce carboxilic acid and ester to alcohol. i am been trying by using NaBH4/I2, NaBH4/MeOH etc in THF but it does,t work.
use borane DMS in THF for acid to alcohol, NaBH4 for ester to alcohol in methanol at rt.
Lithium pyrollidino boraneDMS can be used for reduction of ester to alcohol in presence of cyano or nitro.
6 out of 10 People in the US, Canada and Europe are Over weight, so losign weight has become the most important goal for many around the globe. If someone is a lazy slob who wants a ‘magic pill’ to give him a fabulous bpdy, that will always remain as a dream.
One should be willing and determined to in efforts over a period of time and only then they can get lasting results. I find a few programs quite interesting and effective, you can also check some programs here and rate them based on your experience. Find the programs here [url=http://www.weightlosskarma.com]WeightLossKarma.Com, lose weight easily[/url]
– by Melinda
i want to reduce 1,1-cyclopropanediester to 1,1-cyclopropanedimethanol usingn NaBH4.
what is the procedure?
Well, have you done a literature search? Using NaBH4 to reduce esters requires that the borohydride be activated in some way. Oxidation to give BH3-THF in situ or the use of ZnCl2 all increase the reactiity of the hydrides, but may do so at the expense of other functional groups. Without having done this rxn, I do not know how well the cyclopropyl group on the diester will tolerate the hydride. Conjugate-type addition of a hydride would give a ring-opened malonate ion for instance. I think you’ll have to do some experiments.
literature says reduction using NaBH4 /THF and adding MeOH at reflux
no progress
What if the NaBH4 reduction goes fine but the product alcohol is water soluble…How to remove the B salts yet not lose the product?
Have you tried to steam distill the product out then extraction? Will your product partition into hexane or toluene?
The product is completely water soluble and will not extract out. will think about steam distilation. any other ideas. If the B salts are not removed the material will decomp on distillation.
saturate with brine and than extract with suiatable solvent
The product is completely water soluble and will not extract out
does anyone know anything about running NaBH4 reactions without using an aqueous work up
I have done reduction with SBH without aqueous work up. Instead HCl gas in methanol was added in reaction mixture. NaCl is filtered, methanol is removed under vacuum, residue is dissolved in ethanol. Additional NaCl is removed by filtration. Filtrate was evaporated. For 0.11 mol of methyl ester I took 85 ml appr. 3N solution of HCl in methanol. Original methodology: Patent EP 0 220 409 B1 p.9
mfedor thanks!!!
I’m having trouble reducing an aliphatic ester with the NaBH4/THF/MeOH/reflux system. TLC shows evidence of product but very little relative to SM. It’s been going for 4 days!!! I see that some people observe success with Dioxane as the non-protic solvent…does this substitution lead to a better rate of reaction? I’d prefer to not use dioxane for obvious reasons but will if I have to. Any advice would be appreciated 🙂
Hi Sean,
I’ve had mixed results as well. Doesn’t sound like your system is going to go any further. Esters with electron withdrawing goups reduce best. You might try starting over with ZnCl2 as an additive, though I’d be a little careful. This makes for a hotter reagent. I have also seen Zn plate out on the inside of my flask doing this. You can also try using iodine/THF to make BH3 in situ (don’t use MeOH with the iodine or BF3 method). BF3 works for this as well. This will take carboxylic acids to the alcohol. I have done this many tiimes reducing valine to valinol.
This Rohm and Haas online resource is very nice- http://www.dow.com/assets/attachments/industry/pharma_medical/chemical_reagents/reducing_agents/sodium_borohydride_digest.pdf
Good luck. There is always LAH \;-)
Thanks! I had some unexpected success yesterday with reducing the acid chloride with NaBH4! My ultimate goal is the aldehyde and I found this neat procedure that converts RCOCl -> RCHO, however, it involves CdCl2. (Rosenmund has proven to be problematic) I tried reducing the RCOCl with NaBH4/CdCl2 but only observed a trace of RCHO with mostly CH2OH!!! Currently I have the same reaction on but without Cadmium Chloride so we’ll see how it goes, then I’m going to TEMPO it back up to the RCHO (hopefully)
Ok, sure, but LiBH4 is much faster and just as selective as lithium aluminum hydride
What if you add LiCl to the reaction mixture with NaBH4?
See: Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry, Oxford University Press, Oxford , 2001, pp. 618
ive been using NaBH4 to reduce esters the whole yr of my honours degree…got the idea from a paper…simple…use an excess of reagent in a 1:1 mixx of water/dioxane at room temp…good yields, easy work up…nice