Carboxylic Acid Derivatives
Di-isobutyl Aluminum Hydride (DIBAL) For The Partial Reduction of Esters and Nitriles
Last updated: November 2nd, 2022 |
DIBAL (Di-isobutyl Aluminum Hydride) – A Bulky Reducing Agent For The Partial Reduction Of Esters and Nitriles
- DIBAL (also known as DIBAL-H or DIBAH) is a strong, bulky reducing agent.
- It’s most useful for the reduction of esters to aldehydes.
- Unlike lithium aluminum hydride, it will not reduce the aldehyde further provided that only one equivalent is added and the reaction mixture is kept cold.
- It will also reduce other carbonyl compounds such as amides, aldehydes, ketones, and nitriles.
Table of Contents
- Di-isobutyl Aluminum Hydride (DIBAL)
- Reduction of Esters to Aldehydes with DIBAL
- DIBAL Reduction of Esters to Aldehydes – The Mechanism
- Reduction of Nitriles with DIBAL
- Reduction of Nitriles with DIBAL – The Mechanism
- Reduction of Aldehydes and Ketones with DIBAL-H
- Quiz Yourself!
- (Advanced) References and Further Reading
1. Structure of Di-isobutyl Aluminum Hydride (DIBAL)
DIBAL is a strong, bulky reducing agent. Reactivity-wise, it bears a lot of similarity to lithium aluminum hydride.
Unlike LiAlH4 which can (in theory) deliver four equivalents of hydride, DIBAL bears only a single Al-H bond.
This makes the stoichiometry of its reactions much easier to control.
2. Reduction Of Esters To Aldehydes With DIBAL
The most notable reaction of DIBAL is the reduction of esters to aldehydes. Unlike lithium aluminum hydride (LiAlH4), which reduces esters to primary alcohols, reductions with DIBAL can stop at the aldehyde stage if the temperature is kept very low.
The advantage of DIBAL here is that it is more efficient. If we use LiAlH4, we obtain a primary alcohol, which we would then have to oxidize up to the aldehyde using a reagent such as PCC, Dess-Martin periodinane, or the Swern oxidation. (See post: Alcohol Oxidation)
3. Reduction Of Esters To Aldehydes By Di-Isobutyl Aluminum Hydride: Mechanism
The mechanism for reduction of esters to aldehydes with DIBAL is roughly similar to the familiar addition-elimination mechanism of nucleophilic acyl substitution, with a slightly modified first step. (See post: Nucleophilic Acyl Substitution)
DIBAL-H is neutral, and aluminum, being in the same column of the periodic table as boron, has an empty p-orbital. This makes it a Lewis acid.
The carbonyl oxygen of esters is a Lewis base. So the first step is coordination of the Lewis basic carbonyl oxygen to the Lewis acidic aluminum, to give a species with a negative formal charge on aluminum.
Then comes nucleophilic addition of a hydride (H-) to the carbonyl carbon alongside breakage of the C-O pi bond (form C-H, break C-O pi). (See post: Nucleophilic Addition to Carbonyls)
This forms a new tetrahedral intermediate which is essentially a hemiacetal coordinated to aluminum. (See post: Acetals and Hemiacetals)
If the temperature is kept low (the convenient dry ice-acetone bath of –78°C is often quoted) , a reaction quenched with acid at this stage will give a neutral hemiacetal which quickly loses ROH to give an aldehyde.
(Note: getting the reaction to stop at the aldehyde stage looks great on paper but can sometimes be difficult to achieve in practice)
4. Reduction Of Nitriles To Imines With DIBAL (And Subsequent Hydrolysis To Aldehydes)
DIBAL will also do partial reductions of nitriles to imines. The imines are then hydrolyzed to aldehydes upon addition of water. (See post: Imines – Properties, Formation and Mechanisms) In this respect DIBAL again differs from LiAlH4, which will reduce nitriles all the way to primary amines.
5. Reduction Of Nitriles To Imines: Mechanism
Reduction of nitriles follows a similar mechanism to that for the reduction of esters. Coordination of the Lewis-basic nitrile nitrogen to aluminum is followed by delivery of hydride to the nitrile carbon (form C-H, break C-N (pi) ). This is another example of an addition mechanism.
From this point, quenching the reaction with water results in protonation of the nitrogen and then hydrolysis of the imine to give an aldehyde.
6. Reduction Of Ketones And Aldehydes To Alcohols With Di-IsobutylAluminum Hydride (DIBAL)
Although not often used this way, it’s worth noting that DIBAL can do all the reductions that NaBH4 does, so ketones and aldehydes are reduced to secondary and primary alcohols, respectively.
What this means is that DIBAL will not selectively reduce an ester in the presence of an unprotected aldehyde or ketone – those groups will get reduced too.
7. Summary: DIBAL
DIBAL is a useful reagent for the partial reduction of carboxylic acid derivatives. A successful DIBAL reduction of an ester to an aldehyde will save an extra step relative to LiAlH4 followed by oxidation.
Likewise, DIBAL reduction of nitriles gives us a route to aldehydes (after hydrolysis) that is not available through reduction with LiAlH4, which completely reduces nitriles to amines.
Note 1. What about other functional groups?
From this article (abstract is freely available):
- Alcohols and thiols react with the hydride to give H2 and their corresponding conjugate bases
- Conjugated aldehydes and ketones reduce at C=O to give the allylic alcohols
- Carboxylic acids liberate H2 to give the carboxylates
- Alkyl halides are inert.
- Epoxides are reduced primarily at the less hindered position to give alcohols
- Tertiary amides are reduced to amines, but primary amides only reduce slowly.
Note 2. You can read about the chemistry of DIBAL and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF.
(Advanced) References and Further Reading
- Metallorganische Verbindungen, XXVII Aluminiumtrialkyle und Dialkyl‐Aluminiumhydride Aus Aluminiumisobutyl‐Verbindungen
Ziegler, K.; Martin, H.; Krupp, F. Liebig. Ann. Chem 1960 629 (1), 14-19
Diisobutyl aluminum hydride (DIBAL or DIBAL-H) was originally investigated by the Nobel Laureate Prof. K. Ziegler as a co-catalyst for the polymerization of alkenes.Two early publications on DIBAL-H reduction of esters:
- Reduction of esters of carboxylic acids into aldehydes with diisobutylaluminium hydride
Zakharkin, L. I.; Khorlina, I. M. Lett. 1962, 3 (14), 619-620
- Reductions with Dialkylaluminum Hydrides
ALFRED E. G. MILLER, JEAN W. BISS, and LOUIS H. SCHWARTZMAN
The Journal of Organic Chemistry 1959 24 (5), 627-630
- Reaction of diisobutylaluminum hydride with selected organic compounds containing representative functional groups
Nung Min Yoon and Young Soo Gyoung
The Journal of Organic Chemistry 1985 50 (14), 2443-2450
This paper exhaustively covers the reductions of basically every type of functional group in organic chemistry with DIBAL-H.
- Applications of Diisobutylaluminium Hydride (DIBAH) and Triisobutylaluminium (TIBA) as Reducing Agents in Organic Synthesis
Ekkehard WINTERFELDT. Synthesis 1975; 1975(10): 617-630
A classic review on the use of DIBAL-H and triisobutylaluminum in organic synthesis. Even though this might be dated today, it is still a valuable resource.
- SYNTHESIS AND UTILIZATION OF INDIUM (I) IODIDE FOR IN SITU FORMATION OF ENANTIOENRICHED ALLENYLINDIUM REAGENTS AND THEIR ADDITION TO ALDEHYDES: (2R,3S,4S)-1-(tert-BUTYLDIPHENYLSILYLOXY)-2,4-DIMETHYL-5-HEXYN-3-OL
Brian A. Johns, Charsetta M. Grant, and James A. Marshall
Org. Synth. 2002, 79, 59
Step C in this procedure is a silyl protection of an alcohol followed by a DIBAL-H reduction of the ester. Note the special workup conditions with Rochelle’s salt (potassium sodium tartrate) required for the DIBAL-H reduction.
42 thoughts on “Di-isobutyl Aluminum Hydride (DIBAL) For The Partial Reduction of Esters and Nitriles”
re: real life disclaimer. And man those hydrolized aluminum salts are some of the nastiest emulsions I’ve ever experienced!
According to my dissertation, my largest DIBAL-H reduction ran on 10.1 g (17.9 mmol) in 175 mL CH2Cl2. The good news about this reaction for me are twofold. 1) The starting material is bright crayon yellow and the product was colorless. 2) The reaction was instantaneous. It was like titrating in DIBAL-H. Curiously, it always took 2 eq of DIBAL (still not quite sure why, only one equiv of H- is incorporated), but as soon as the yellow disappeared, I was sure the reaction was at 100% conversion. Sure, I’d take a TLC just to be sure, and it was always complete.
Then quench the reaction with saturated aq. Rochelle’s salt (hm… TIL Rochelle was the city in which it was discovered, not the name of the guy) to help break the Al emulsion. Our lab also found empirically that diluting the CH2Cl2 reaction with a LOT of Et2O helped break the emulsion. The bad news is you had to let this biphasic mixture stir vigorously for at least 90 min-2hr before separating the layers. As long as enough Et2O was added, the emulsion broke down and separation became very manageable if stirred long enough.
(In case you were wondering, 92% yield of the aldehyde with 93% recovery of the ‘other side’ of the ester (it was a precious chiral auxiliary, and we wanted to reuse it!)
I’ve done a few DIBAL reductions this year and often had trouble with them – in particular, if your product is water soluble and loves the aqueous phase in a work-up (one can never quite tell), then it’s an absolutely horrible to job to try and recover it from a saturated aqueous phase full of Rochelle salts.
Somebody recommended to me that the Fieser work up followed by a filtration over Celite should remove the Al salts emulsion just as well. I am probably going to use this method as a first choice from now on, because trying to extract my product from Rochelle salts solution caused me a lot of grief!
Also, having re-read this site properly, I will now always use H2O to quench my DIBAL reductions of nitriles. I mistakenly used methanol earlier on and looking at the mechanism of imine hydrolysis above, that might explain why I got a nasty mixture of crap when I quenched the imine with Methanol! Guess I can just pour the reaction on to water at 0 Celsius, rather than quenching direct at -70.
I personally was not able to obtain an aldehyde on the one occasion I tried DIBAL. Part of the problem was likely the scale (<25 mg) and titre of the (old) DIBAL, as well as not choosing the solvent well (should have used CH2Cl2 instead of ether). So I just re-oxidized the alcohol with DMP and was done with it.
Aluminum salts are notorious for their bitching emulsions. For DIBAL I made sure to stir with Rochelle's salt for a good long while. For LiAlH4 I always use the Fieser workup and filter off the solid… no extraction required, thank goodness.
To be complete, I wasn’t reducing an ester, it was a thioimide. It was an (OH-protected) aldol adduct utilizing a thiazolidinethione as a chiral auxiliary. We developed the conditions for the aldol addition in our laboratory. Suffice it to say we did the diastereoselective aldol addition a lot. Partial reduction of the thioimide to the aldehyde was a common next transformation, so we always had a fresh bottle of DIBAL in the fridge. I reduced 5 different thioimides this way who knows how many times as I ran through the synthetic scheme who knows how many times.
The one time I did reduce an actual ester, it was on 0.7 g scale (2.4 mmol). 68% yield of aldehyde, 30% yield of alcohol. Also reoxidized the alcohol with DMP back to the aldehyde in 63% (or 87% total from ester -> aldehdye) That reduction was following a Frater-Seebach alkylation (which was a pain to run (-40 degC, 3 days), but a great reaction to have experienced.
Is it not DIBAH instead of DIBAL?
It can be referred to as DIBAH, DIBAL, or DIBAL-H. Usually when discussing it amongst themselves, organic chemists call it DIBAL because it rolls more easily off the tongue than either of the other two.
Can we obtain alcohol from ketone, by DIBAH at –70°C? I know we can at room temperature, but I don’t know if we can at –70°C. Any reference you have?
can you demonstrate how hydrolysis occurs? im a little stuck
Under the acidic conditions, convert the aluminum salt to the hemiacetal. Don’t worry, students have this problem all the time because, well, they just do. When we grade quizzes, students freak out when they see the hemiacetal under acid conditions and they are unable to figure out what to do next. Then the students proceed to use OH- because remember in student parlance, OH- is always available in acidic solution.
I use 2,5-3,5 eq to reduce my esters to alcohols. So no, it doesn’t stop at aldehyde, it’s actually more difficult to stop the reduction at aldehyde than to continue to alcohol.
thats because you use more then ONE eq.
Does your DIBAL acquire an extra carbon atom when it coordinates the oxygen?
Shoot. Yes, it does. Fixed
i used 6 year old DIBAL for opening up my isopropyldene ring itwas working fantastic but when i used new Dibal it producing unusual reports does anyone feel any prb like this
what can be degraded product of DIBAL-H ?
Does this also reduce carboxylic acids?
No, DIBAL-H does not react with carboxylic acids. You have two options: perform an esterification of your -COOH to -COOMe for example and then use DIBAL-H, or you can use the -COOH directly with another reagent like LiAlH4 or NaBH4.
Yes. Thanks Chris!
You usually use a couple of eqivs of dibal to reduce ester to aldehyde not 1 eq as stated above. The important thing is to keep the temp low [<-50] and quench at low temps (Ihave al3ways used MeOH to quenchrather than water – water will freeze at this temp!)
Just using 1eq would not help anyway as the aldehyde is more facile to reduce than the ester.
Love the site and have learnt a lot from it so far :)
Dibal has another trick up its sleeve. If you have an a,b-unsat. ester or ketone, it can cleanly reduce without affecting the double bond. Unlike NaBH4 or LAH.
Actualy, I have just used 2 eq. of DIBAL by accident in calculating and got 100% of alcohol and not a trace of aldehyde, so I wouldnt be so hasty with more than 1 eq.
In the last step of preperation of aldehydes from alkyl nitrile, how ammonia(NH3) is formed – I mean , where is an additional hydrogen proton (H+) available to form NH3? Thanks in advance.
It would come in the workup step when water is added. There’s excess water.
I want to reduce an ester to an aldehyde.
I’ll try DIBAL at -78°C in DCM.
If it doesn’t work, I’ll do the reduction to alcohol then oxidize with PCC.
My questions :
1) I thought non polar solvent would make the reaction slower. Then should I use toluene instead of DCM ?
2) If going to alcohol, why -78°C ? Can’t I do it at 0°C ?
And should I add the ester to the dibal or the opposite ?
3) Last question, if I go to aldehyde, can I quench with methanol ? Water will be frozen at -78°C.
Also, what do you think about the paper adding NaOtBu to Dibal to reduce to aldehyde at 0°C ?
Thanks a lot
I’d look for a prep online where someone successfully reduced an ester to an aldehyde. For example, if you go to the ACS Publications home page, search for “ester dibal reduction aldehyde total synthesis ” . You’ll come up with some reputable papers with supporting information. Use those conditions.
Follow this, for instance: http://pubs.acs.org/action/doSearch?text1=baran+ester+reduction+aldehyde+dibal&field1=AllField
If you want the aldehyde, you MUST keep it at -78. A non polar solvent is ideal. Avoid ethereal solvents (they tend to coordinate to the aluminum and this can affect reactivity), DCM should be fine. Toluene can present solubility problems, but might be OK for you at -78. If you are aiming for the alcohol, then warming is fine.
I haven’t come across the paper you mention at the end.
In the mechanism of Dibal reduction, from ester to aldehyde, we know that OCH3 is a bad leving group but it still goes out. Plz explain how?? I have to explain this dibal mechanism in my seminar
DIBAL reduction produces O(-) which itself is a strong base. The formation of the C-O double bond along with expulsion of CH3O(-) is therefore not accompanied by a huge energy barrier. CH3O(-) is not a great leaving group, but still a much better one than H(-) or most carbon-based leaving groups.
I was also wondering if DIBAL-H can be used to reduce carboxylic acids?! If it does, would the product be an aldehyde like it is when we reduce an ester with DIBAL-H?
You’d really have to crank on it. It’s possible, but you’d have to use over 3 equivalents and heat it up. It’s far superior to use LiAlH4 !
Did “dibal h ” reduce acid chlorides?
Yes, it should give an aldehyde.
Is it possible to reduce ethyl ester to aldehyde in presence of an aromatic nitro group?
In one of the comments its mentioned to use LiAlH4 for reduction of carboxylic acid and why is that? why not better with Dibal
It’s inefficient. LiAlH4 is considerably cheaper and you have to use fewer equivalents of it.
So.. using DIBAL-H on an ester, gives us an aldehyde. What about the other organic part of the ester? [RCOOR’] What about The R’ part? We get an Alcohol [OR’] I suppose?
Yes, that is correct.
You can break the aluminum complex by refluxing in methanol. DIBAL 2 eq. at zero deg reduces ester to alcohol. 1 Eq DIBAL at -78 reduces esters to aldehyde. those reactions are clean. yields are more than 90 %. after refluxing with methanol one can do celite filtration and concentrate the methanol extract..no need to even do a column. Of course there should be no other competing groups.
In my experience getting it to stop at the aldehyde can be capricious and quite solvent dependent. Refluxing in methanol seems extreme… why not just use Rochelle’s salt like everybody else?
U said in a comment that to reduce carboxylic acid, one can use NABH4… Is that correct?
Carboxylic acid is reduced easily by LIAlH4 and diborane only.
No, NaBH4 cannot reduce carboxylic acids. You are correct about LiAlH4 and BH3
I could not understand how the intermediate qualifies to be called a hemiacetal. I mean where is the -OH group of the general formula R1HC(OH)OR2
It’s essentially the conjugate base of a hemiacetal, where Al is coordinated to the oxygen instead of H.
Thanks James for your reply