Dibal-h Workup

[Ermelindo Klatt]

It is an electrophilic reducing agent, usually employed in selective reductions of esters or nitriles to aldehydes; lactones to lactols; α,β-unsaturated carbonyl compounds to allylic alcohols, at low temperatures (-78oC).

* But it undergoes rapid oxidation in air and reacts vigorously with hydroxylic compounds such as water, alcohol etc. Hence the reductions with DIBAL should be carried out in the absence of air and moisture.

* DIBAL is said to be an electrophilic reducing agent because of its coordination to the carbonyl oxygen prior to the transfer of hydride onto carbonyl carbon. Hence it reacts fast with electron rich carbonyl groups.

* At low temperatures (-78oC), the reduction of esters, nitriles and lactones can be stopped after the transfer of one hydride to the carbonyl carbon. It is because the tetrahedral intermediate formed is stable at low temperatures. This tetrahedral intermediate will furnish the corresponding aldehyde only upon hydrolytic workup.

1) Aldehydes, Ketones, Carboxylic acids & Esters to Alcohols: At ordinary temperatures, DIBAL-H reduces variety of carbonyl compounds, like aldehydes, ketones, carboxylic acids and esters, to corresponding alcohols. These reductions are chemoselective as well as stereospecific.

E.g. i) Cinnamaldehyde can be reduced to cinnamyl alcohol. It is observed that only one-third of an equivalent of DIBAL-H is required and isobutylene is formed as a byproduct. This indicates, not only the hydrogen on aluminium but also the β-hydrogen on isobutyl groups participates in the reduction. But the double bond is intact during the reduction. A case of chemoselectivity.

Carboxylic acids require 3 moles of DIBAL-H for their conversion into alcohols at higher temperatures. One equivalent is consumed for the formation of salt of carboxylic acid. The rest for the conversion into alcohol.

Sometimes it only take a coffee to allow the Rochelle's salt to do it's thing - other times it can take overnight. I stick with the semi-aqueous workup most times - and I've done some pretty huge LAH reduction. The real bastard was a reduction of butyne-1,4-diol to the alkene. I'd normally go through an entire 1L bottle of LAH solution.

I just wanted to let you know that your posts are greatly appreciated. They may be necessarily infrequent, but I have learned several quite useful things from Curly Arrow and look forward eagerly to each one.

Your dry column vacuum chromatography technique alone has saved me many hours of tedium!

Couple of comments about your set-up, as shown in the pic.

You need a lab jack and a cork ring.

Dunno if the comment is helpful or irritating: trying to be the former; apologies if I'm being the latter.

@Daniel

German? - No.

Why lab jack? To be able to quickly apply either coolant and hence hold exotherm, or empty bowl to stop the the liquors spilling onto the f/c. Standard practice wherever I've worked.

Gyges, I was also taught to do chemistry like that. I do tend to have a crystallisation dish under my flask to collect my compound in case of breakage. However, with the possible exception of removing a heating source I generally haven't found lab jacks particularly useful under my stirrer. I don't think there is anything fast about a lab jack. The models I have encountered tend to be rather slow and involve a fair bit of twisting. I find readjusting the clamp to be a much faster process. Anyway, enough of this. I am a firm believer in "whatever works for you" as long as it doesn't pose any danger to your surroundings. D!

krest17, yes this is one of the alternative methods that I referred to that works really well too. I also can't remember the exact conditions but I know that this work-up procedure can be found in the following paper: Skouroumounis, G.; Winter, B. Helv. Chim. Acta 1996,

79, 1095.

I'll look it up when I'm back at work on Monday, if someone doesn't beat me to it. Have a nice weekend chemists. D!

hm... that's new to me with Rochelle's salt. i did some low valent titanium reduction (TiCl4 with Zn dust) which give during work up also a mess of black/grey stuff. i broke this suspension with a mixture of citric acid/ammonium acetate which worked very well too.

currently i have some problems with braking up a hydrolised ZnI2 suspension... tried it with citric acid too but it didn't work... maybe you have some ideas?

I've done a few LAH reductions and always use the Fieiser workup.

And for DiBAl, quench with EtOAc, then add saturated tartaric acid solution, works better than Rochelle's.

Can also use citric acid to solubilise aluminium salts.

I did DIBALH reaction on few analogues and I had problems with it too:

-troubleshooting.html

On the other hand, I reduced ester and amide on the same compound with classic rx with DIBALH, but only all amide was reduced to amine and very little ester reduced to alcohol.

Why is that?

At the end of the day, I collected the esters and did transesterification with methoxide to get desired alcohol as the side product.

Never owned a lab jack, but could see how it'd help. I tend to do a lot of heating using tin foil tipi's as opposed to oil baths. That way, if things get over excited, I can flick the plate off and whip the foil away and it'll cool in a controllable manner (particularly if I'm not roasting the plate to full in the first place). Also, no spills, no fires, no slippery glass, doesn't smell like an old chippy that's failed all of it's last health inspections etc.

I use a ball and socket if I need to support heavy flasks or stretches of glass, so the run can be 'bent' to be clamped (without fiddling for ages for a semi-decent results) or rest in the right place (minus a jack). Even with the clamp tight, there is still enough flexibility to save the glass in some accidental knocks, as it can move a little.

I would certainly have a cork ring under that though. But then, I bet that rail behind the glass is bolted to the hood and not going anywhere fast.

My most annoying glassware problems as of late was watching all the keck clips disintegrate and then ping off my glass when porting reactive gases around (despite them being QuickFit and lined with Krytox).

PTFE.

Quenching with EtOAc can be risky. If your alcohol is unhindered enough, you can transesterify the EtOAc to get some acyl protected alcohol. I quenched with EtOAc for the reduction of undecanoic acid and ended up with 44% acyl protected alcohol.

Hello everyone. I am currently working on a reduction using LiAlH4 and AlCl3. Does anyone have experience which workup works best for this combo? So far I've tried: 1. quenching with HCl, then extraction.

2. Fieser workup.

I feel like both aren't perfect. Thanks a lot in advance!

Hello,

I will be doing my first LiAlH4 reduction pretty soon, fingers crossed this week. I have been trying to do some reading to prep and have in my head the procedures so I don't fumble in the midst of it all. Do you happen to know of any good videos or readings I can look up? I will be using a manifold. Any help would be Appreciated!! THANK YOU! :)

Hello,

I will be doing my first Lithumiun Al. Hydride Reduction this week, Fingers Crossed!! I have been trying to do some prep work to figure out what exactly I will be doing procedure wise so I don't fumble in the midst of it all. I came across this blog with my online adventure of LiAlH4 Reduction. If you happen to know of any good youtube videos or papers I could read it would be much appreciated!! I am planning on using a manifold as my setup. THANK YOU!! ps: I am not sure if this comment will be posted twice, I did not see if the first time I posted it so I tried again....

Hello all,

I used LiAlH4 to reduce an epoxide. Has any one done this ? and did it work? If it worked, can you please give me some details , like the amount that you used, the time it had taken to form the products... etc

Thanks

Thank you for this post, Curly, I found some nice advice reading it !

I am struggling with one specific LAH reduction.

N-Boc tyramine is reduced by LAH in 1,4-dioxane. Work in a real pain.

N-methyl tyramine combine high solubility in water, basic center (NHMe) and a phenol... I've tried almost every work-up I could find and none give me the desired product, pure enough. (I can't run a chromatography on it, it's way to polar... )

Any advice from you or any reader please ?

So, I will argue that quenching the hydride with EtOAc is a rather bad idea when reducing molecules containing an amine functional group. It is better to use H2O or if you dont want H2, then another non-protic solvent that will not react with the amine.

In my case I wanted to methylate a primary amine. So I did the formylation and then the reduction with LiAlH4. I then quench the reaction with EtOAc which was reduced to ethanal and before going to ethanol reacted with my amine to give the imine which was then reduced to a nice byproduct. So I got a methyl, ethyl amine...quite the byproduct I say.

Just like any other reduction reaction, an acidic or aqueous workup is needed to get rid of the ionic intermediates. If the final product of the reaction is an amine, then usually it is treated with a hydroxide to deprotonate and isolate it in a neutral amine form.

The reaction starts with q nucleophilic addition of hydride ion. This forms an imine salt which undergoes another nucleophilic addition by AlH3 producing a highly reactive derivative of an amine:

Notice that the arrow starting from the N-Li bond indicates the electrons forming an N-H bond and not Li-H. The lithium is almost ionic (positively charged) and reacts with the -OH forming LiOH. Likewise, in the second step of the workup, the arrow starting from the N-Al bond forms a new N-H bond and Al(OH)H2.

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