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Author: Subject: Sodium triacetoxyborohydride
Tsjerk
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Sodium triacetoxyborohydride

I want to do a reductive amination with sodium triacetoxyborohydride between aniline and a ketone with DCM as solvent.

In this review posted before on this forum in scheme 3 they show a second ethylation after the first reaction when using straight NaBH4 and GAA at elevated temperatures, and this I want to avoid. So what I'm after is what they show in scheme 5; a single addition of aniline and no ethylation by GAA. The reaction between solid NaBH4 and GAA seems to be not too fast, so in situ formation of the triacetoxy compound without complete dissolution seems not to be the way to go.

Therefor I want to make some sodium triacetoxyborohydride; I have sodium borohydride, glacial acetic acid (GAA), various solvents and a rotavap. No high vacuum possible though, maximum around 100 mbar.

Does anyone have experience doing this?

I did some research and found DMF as solvent (18 gram /100gram DMF). Simply adding GAA and evaporating the DMF under vacuum sounds simple, but I'm afraid for the high boiling point of DMF and the needed temperature to remove it. Does anyone know what temperature triacetoxyborohydride is stable at? Or would DMF react in this case?

I also found somewhere on this forum, but without reference, that ethyl acetate could be used as solvent, does anyone know if this works and what the solubility of NaBH4/Na(OAc)3BH is in ethyl acetate? Ethyl acetate would be easy to remove with a rotavap.

Maybe another solvent? Does anyone know what NaBH4 does in DCM? For some reason 1,2-dichloroethane is a preferred solvent for the reductive amination (see scheme 5 of the first source, I also saw this elsewhere).

And if everything else fails... would a bit of DMF hurt a reductive amination?

[Edited on 1-3-2017 by Tsjerk]
Dr.Bob
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Sodium triacetoxyborohydride is not very soluble, so that may be why people use DCE. I have used methanol as well, might react slowly. THF is another good choice, but few will dissolve it much, it is often reacted as a slurry. But even it can do double alkylations in many cases, getting monoalkylation is tough, often you need a large excess of one reagent to get the monoadduct. Sometimes minor solvent effects can change the reactivity, I just follow the empirical data and use DCE often, as it works.

Some DMF might be fine, and might help dissolve it, it often contains traces of dimethylamine, which is not much help. You might be able to just mix the NaBH4 and GAA ahead of time in whatever solvent you plan to do the reaction and let them sit a few days. Sodium triacetoxyborohydride is pretty stable, so mild temps should be OK.
Tsjerk
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Ok, I will try reacting borohydride and GAA in DCM and see what happens. I will post about the results.
CuReUS
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 Quote: Originally posted by Tsjerk I want to do a reductive amination with sodium triacetoxyborohydride between aniline and a ketone with DCM as solvent. Therefor I want to make some sodium triacetoxyborohydride; I have sodium borohydride, glacial acetic acid (GAA), various solvents and a rotavap. No high vacuum possible though, maximum around 100 mbar. Does anyone have experience doing this?

if you can tell what you want to synthesize exactly,maybe an alternative reagent and/or reaction condition could be suggested ?
 Quote: Originally posted by Dr.Bob I have used methanol as well

but according to wiki-https://en.wikipedia.org/wiki/Sodium_triacetoxyborohydride
 Quote: triacetoxyborohydride is water-sensitive, and water cannot be used as a solvent with this reagent, nor is it compatible with methanol.

 Quote: Sodium triacetoxyborohydride is pretty stable, so mild temps should be OK.

But I remember reading somewhere that STAB has explosive tendencies
Dr.Bob
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I agree that ethanol may be better for STAB, especially at RT or higher, but I have used methanol for both STAB and NaBH4, there are some cases where they work OK, especially in the presence of base. For example, I'm running a NaBH4 reaction overnight in methanol right now, and it goes great. But for starting out, it is best to follow the general guidelines, just be aware that there are exceptions.

As for hazards, I am not aware of any explosion hazard of STAB, other than the production of hydrogen around water or other protic solvents.

If you want to do reductive aminations, I often prefer cyanoborohydride, it is more stable to water and alcohols, more soluble in almost every solvent (I have run reactions at very high concentrations with it, well over 1 Molar), and I often have better luck than with STAB. Every chemist seems to have their preference between the two, but I almost always start with cyanoborohydride and only use STAB if cyano does not work well. Sometimes, I will just set up a combinatorial array of those two reducing agents, a few solvents, and sometimes other additives. For cyanoborohydride, a drop or two of acetic acid can often improve the reaction, maybe due to a trace of STAB forming, but the pH can be critical for imine formation as well.

In some cases making the imine first can help favor monoalkylation, as well as accelerate the reaction. See the imine formation thread for more info, and a nice example.

[Edited on 3-3-2017 by Dr.Bob]
Tsjerk
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The papers I read about this reaction are saying STAB is the way to go and is better than cyanoborohydride and NaBH4, but if the STAB thing doesn't work I can settle for a lower yield and use NaBH4 at 80 degrees instead of STAB at room temperature.
Tsjerk
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It was easier than expected.

My NaBH4 is quite granular and after seeing the first attempt stopped giving off hydrogen before everything was homogeneous I decided to crush a bit in aluminium foil, which worked wonderfully.

In both cases (not-crushed and crushed) 0,57 gram (15mmol) was added to 20-30 ml DCM and to this was 45 mmol GAA added. Vigorous evolution of hydrogen was observed for a short amount of time, hydrogen evolution completely ceased after 1 hour and half an hour respectively. This reaction formed a thick gel of which I was afraid it would start puking in the rotavap, which it didn't (yeah!). By the time the second reaction was done, the first was also almost a homogeneous white thick slurry.

DCM was rotavapped off, and a white, dry, crunchy powder was left. It was quite hard to scrape it out of the round bottoms, but in the end I was left with 6,2 grams (95% yield) of presumably STAB.

It could be that I have a mixture of tetra, tri and di acetoxyborohydride, but I don't think this is the case as STAB is quite stable in the presence of the acetate salt of protonated secondary amines (this protonation actually gives a higher yield in reductive aminations). Steric hindrance?

Easiest compound to wash out of round bottoms ever, it dissolves in water almost before it touches it.

[Edited on 6-3-2017 by Tsjerk]
cubalibre
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Did you test your STAB-H yet?
Tsjerk
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Yes Cereus, that is what I mean, but if you overfill a rotavap they quickly "puke", also when there is only liquid in the flask. It especially happens fast if you have a really low boiling liquid with a bit to warm waterbath.

I didn't test yet, I'm already waiting for weeks for a delivery.

edit: strange.... now Cereus' message I was replying to is gone... or am I crazy

He was referring to this phenomenon .

https://en.wikipedia.org/wiki/Syneresis_(chemistry)

[Edited on 11-3-2017 by Tsjerk]
Dope Amine
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Hello Tsjerk. I tried to send you a u2u but it wasn't working for some reason...

I know about the Lawrence Livermore paper you were referring to for your STAB reduction. I have some helpful information for you- the first product can be crystallized from petroleum ether, the second product can be crystallized from isopropanol (requires a fairly large amount), and the final HCl product can be crystallized from acetone. This way no column chromatography is required to get very pure materials.

Did you get a similarly high yield using STAB? I tried making STAB insitu by adding NaBH4 to a cold DCM solution containing the first product, aniline, and an appropriate amount of acetic acid but the yield was more similar to the normal yield with NaBH4.

By the way, the idea of doing the NaBH4 reduction at 80 deg. C doesn't make any sense because DCM boils at a much lower temperature.

It's nice to know someone else appreciated that article as much as I did!

~Dope Amine
spankyetal
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toluene is another solvent, see US Pat. US 20060100438
wherein STAB is used outright \$ or created in situ in the toluene reaction. There are newer reactions but 95% therein is hard to beat. The PEMB cat. is really expensive. Nano silicasulfuric acid reactions (NSSA) get things off to a fast pace. (95+% yields of certain alky- 4-piperidone
spankyetal
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 Quote: Originally posted by Tsjerk I want to do a reductive amination with sodium triacetoxyborohydride between aniline and a ketone with DCM as solvent. In this review posted before on this forum in scheme 3 they show a second ethylation after the first reaction when using straight NaBH4 and GAA at elevated temperatures, and this I want to avoid. So what I'm after is what they show in scheme 5; a single addition of aniline and no ethylation by GAA. The reaction between solid NaBH4 and GAA seems to be not too fast, so in situ formation of the triacetoxy compound without complete dissolution seems not to be the way to go. Therefor I want to make some sodium triacetoxyborohydride; I have sodium borohydride, glacial acetic acid (GAA), various solvents and a rotavap. No high vacuum possible though, maximum around 100 mbar. Does anyone have experience doing this? I did some research and found DMF as solvent (18 gram /100gram DMF). Simply adding GAA and evaporating the DMF under vacuum sounds simple, but I'm afraid for the high boiling point of DMF and the needed temperature to remove it. Does anyone know what temperature triacetoxyborohydride is stable at? Or would DMF react in this case? I also found somewhere on this forum, but without reference, that ethyl acetate could be used as solvent, does anyone know if this works and what the solubility of NaBH4/Na(OAc)3BH is in ethyl acetate? Ethyl acetate would be easy to remove with a rotavap. Maybe another solvent? Does anyone know what NaBH4 does in DCM? For some reason 1,2-dichloroethane is a preferred solvent for the reductive amination (see scheme 5 of the first source, I also saw this elsewhere). And if everything else fails... would a bit of DMF hurt a reductive amination? [Edited on 1-3-2017 by Tsjerk]

you won't have any problems with DCM. Very inert solvent for that Rx. You want to avoid the higher temps used in the early literature. best and easiest is to make it in situ. Just follow the stoichiometery. Start with a molar ratio 1.5:1
Doc B
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For the next idiot who attempts their first synthesis of Sodium Triacetoxyborohydride as a 1M solution in a 100ml Schott reagent jar, with 80ml of dry THF already in there. Please note the following...

1. Accept that you really are quite a dick at times and try to correct this.
3. Note that your reaction volume will be 80ml of THF *PLUS* 15.85g of GAA so the use of a 100ml jar is retarted.
4. I haven't read this anywhere but the reaction is not only exothermic but its froths and foams in addition to the solvent boiling under the heat of the reaction.
5. So maybe, I don't know, use one of your many bloody addition funnels to add the GAA dropwise and put a condensers on the flask because the neighbours already have had a spit about THF vapours permeating the building.

100ml 1M NaBH(OAc)3 a.k.a STAB in THF.

To a chilled 2 necked 1L flask, in an ice bath over a magnetic stirrer/hotplate, charged with 80ml dry THF add; 3.02g NaBH4, a stir bar, a cold water condenser fitted with a CaCl2 drying tube atop to one neck and finally an addition funnel with 15.85g of glacial acetic acid (GAA) to the remaining neck:
Begin stirring and addition of the GAA, at a rate of one drop per second. A vigorous exothermic reaction commences and is controlled by the rate of addition and the cooling of the ice bath. Once the addition is complete and H2 gas ceases to be evolved, the ice bath is removed. The flask is wiped dry and returned to the hotplate stirrer where it is slowly heated to reflux and held there for 15min or until H2 gas and effervescence ceases, indicating the end of the reaction.
Tsjerk
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I forgot to post the results, but the reductive amination worked as published with the STAB produced as described above.
Doc B
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Glad to hear that, Tsjerk. I hope things work out as well for me.

I'm curious to see if it's more convenient and without negative consequences to simply make up a stock solution of STAB, where the solvent it's formed in is the same as for the reaction it's used in. Any reason to expect otherwise?
Tsjerk
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I don't see why that wouldn't work, but the solubility of at least STAB in DCM is poor, so it would form a suspension, and after forming STAB as I did it forms a thick gel. But if you can pipette or otherwise measure the gel it should work.
Doc B
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It doesn't seem very soluble in THF at all. It hasn't been isolated yet but given the mishaps, it wouldn't be accurate to determine the yield. I will filter off the precipitate and compare it's mass to the starting materials and theoretical on the next occasion, when I prepare it with my above method.
Tsjerk
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I don't think knowing the precise yield is necessary here, as the reaction will go to completion, and because STAB is used in excess anyway.

 Sciencemadness Discussion Board » Fundamentals » Organic Chemistry » Sodium triacetoxyborohydride Select A Forum Fundamentals   » Chemistry in General   » Organic Chemistry   » Reagents and Apparatus Acquisition   » Beginnings   » Responsible Practices   » Miscellaneous   » The Wiki Special topics   » Technochemistry   » Energetic Materials   » Biochemistry   » Radiochemistry   » Computational Models and Techniques   » Prepublication Non-chemistry   » Forum Matters   » Legal and Societal Issues