problems and solution reducing nitropropene

[starlight]

edit: solution found further down the thread

I hope that by discussing the following we can help both myself and others who have experienced similar issues:

I've been having some problems getting decent yields when reducing nitropropenes to nitropropanes with borohydride. Until now I've had no clue as to why. Now I have a good clue, but it does not fit with the experimental writeups that I have read.

To cite an example of the problem:

The method followed was taken from the foot of the following page:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/nitrostyrene.nabh4.reduction.html

where the reduction of the 2,4,5 substrate is detailed. The same method was followed as described here (using the same substrate), with all reactants and solvents scaled down to 63% (16g of substrate). Slightly greater proportion of borohydride (1.1x) was used than in the writeup as that that was available was from a previously opened canister.

The reduction proceeded as described, with the orange color fading completely to white. The reaction mixture became a white paste (still completely stirrable). Stirring was continued for another 60min after the reaction finished as I had to go and do something else.

The excess borohydride was destroyed with acetic acid until effervescence on further addition ceased. The reaction mixture by this point was a yellow liquid with white solid in it.

Brine and toluene were used to separate organic and inorganic components as described. On evaporation of the organic layer only 6g of yellow liquid were obtained (starting to crystallize but still some toluene in there so probably needs further evaporation).

So I got to wondering where all the product was? As a test I poured some 5% HCl into the aqueous layer that I had separated earlier. The clear solution turned immediately light green and cloudy and became progressively darker green and cloudier over the next minute or two. Extracting this solution with toluene and subsequent evaporation produced a brown oil (~8.5g).

What I deduce from this is that much of my product was still in solution as a nitronate and that the addition of mineral acid cased a nef reaction (with accompanying green by-products due to the fact that the temperature was room as opposed to 0C.

My questions are as follows:

1. Was the white paste during the reaction due to nitronate coming out that was insoluble in the ethyl acetate/alcohol solvent mixture? Does this matter at all?

2. The experimental writeup cited above says to add acetic acid until gas evolution ceases. Whem I do this it seems that much of my product is still in a nitronate salt form. Why would I have the discrepancy from other experimenters?

3. Do I just have to add more acetic acid (say until pH4 or something)?

4. Has anyone else experienced similar problems with this reaction? - If not why do you think this has happened to me and not you?

Hope I have included enough detail - if not please ask!

thanks.....

[Bandil]

1. Was the white paste during the reaction due to nitronate coming out that was insoluble in the ethyl acetate/alcohol solvent mixture? Does this matter at all?
With the exact same reaction i have noticed the same. Added a bit more ethanol(not ethylacetetate), to clear it up. I don't think it matters, as long as the finished reaction is not a big foamy mess.

2. The experimental writeup cited above says to add acetic acid until gas evolution ceases. Whem I do this it seems that much of my product is still in a nitronate salt form. Why would I have the discrepancy from other experimenters?
? Just don't add to much GAA, it can seriously fuck up the phases and make a lot of your product go over in the water phase.

3. Do I just have to add more acetic acid (say until pH4 or something)?
No, only till gas evolution ceases and then stop.

4. Has anyone else experienced similar problems with this reaction? - If not why do you think this has happened to me and not you?
Well with 2,4,5-trimethoxynitropropene, the reaction went like a beauty. However subsequent trials with phenyl-2-nitropropene, has shown a lot of the problems you adress. Untill now, these are the things i have noticed that are important in the reaction:

1:
Cool the reaction and do not let i exceed 30 degrees. It seems to drive of to much solvent and lower the yields a great deal.

2:
Use a reflux condensor, do not just perform this reaction in a beaker, although it seems tempting due to the low temperature. During several trials, the EtOAc layer has been almost halved due to some of the solvent coming of with the hydrogen evolution. So condense those vapours; very important point!! This has lowered the yield of phenyl-2-nitropropane to less than 50% on several occasions.

3:
If to much foam forms during reaction, use a bit of ethanol to clear it up. Ethylacetate doesn't do much good!

4:
Try to use 80% of the ethylacetate in the borohydride mixture and 20% for dissolving the nitropropene, which you are adding. It is MUCH easier to control the reaction with the solvated substrate, rather than throwing in chunks. It almost never causes boil overs that way.

5:
This reaction takes a little practice, as it seems to be a little sensitive to how you do it(more than LAH reductions for instance), so a good idea is to get a bunch of dirt cheap phenylnitropropene to practice on to get the feel of the reaction, before using those really nice nitropropenes.

Hope you can use some of the advice!

Regards
Bandil

[starlight]

Bandil, thanks for taking the time to comment.

The temperature was kept between 18-24C during the course of the reaction.

The reaction never became a foamy mess.

The borohydride was neutralized with dil. AA as in the writeup, rather than GAA.

Vapors were condensed.

I think that the my product is there as a nitronate. Otherwise I would not get a Nef type reaction on adding dil. HCl would I?

I will do the reaction again and measure the pH of the aqueous layer after neutralizing the borohydride and report back.

Will try again today I think. Last bit of substrate :-(

If anybody else has experienced this problem and solved it, please help me wasting my last bit of substrate!

[Bandil]

You wrote: "Slightly greater proportion of borohydride (1.1x) was used than in the writeup as that that was available was from a previously opened canister."

Have you considered that the borohydride was destroyed by exsposure to air? How has it been stored?

Did you get a lot of fizzing while adding the acid to quench the remaining borohydride?

Regards
Bandil

[starlight]

because there was a whole lot of fizzing when adding the AA indicating incomplete consumption. It was stored in a sealed plastic bag inside a relatively airtight container.

[starlight]

Well the reaction was run again, using 16g of substrate. This time the mixture became unstirrable by mag. stirrer, so 60ml of additional ethanol were added and the thick paste was stirred using a mechanical stirrer until the mixture was completely white and back down to ambient temperature (9C).

The borohydride was then neutralized with 50% Acetic Acid (thanks Bandil). Acid addition was continued after effervescence ceased whilst measuring the pH with a digital meter (of course the reading is not accurate in an ethyl acetate/ethanol/water mixture but it serves as a guide). In all 80ml of 50% AA were added and the pH meter was reading 5.2 at the end of acid addition (pH reading after effervescence stopped was 6.. When adding the acid, it was if the pH was being buffered (probably the nitronate salt being protonated?).

Workup was perfomed in the usual way to yield 15g of yellow/orange oil solidifying to dirty white crystals. Hooray!!

The aqueous phase of the reaction mix was pH 4 after separation and addition of 5% HCl created only a marginal amount of cloudiness and hardly any green color.

Seems like it is necessary to get the post reaction mixture acidic to get a decent yield, so for any of you out there that are achieving lousy yields with this reaction, maybe this is your problem.

Last time I used a 10% acetic acid solution and added enough to stop the effervescence (about 70ml I think). I therefore suggest that you use a 50% AA solution and add acid until the reaction mixture is moderately acidic.

I can't believe it worked - hopefully no more problems with the yield using this method (for nitropropanes).

[Rhodium]

Seems like it is necessary to get the post reaction mixture acidic to get a decent yield

Yes, that is essential - if you do not acidify, the borate decomposition products of the NaBH₄ will chemically "hold on" to the product nitroalkane, similar to this:

[starlight]

Thanks Rhodium, this is such a simple solution to something that has been causing me and others problems for ages.

It is not explained in the writeups (not a criticism, just the reason why those with limited knowledge such as myself have had problems), and it seems that the cessation of effervescence is not always acidic enough.

However, some methods even achieve results without any acidification:

Post 426052

(Barium: "Novel high-yielding C=C reduction of nitrostyrenes", Novel Discourse) - only washes the toluene layer with GAA whereas I would have thought that a good part of the product would end up held in the water layer by the borate decomposition products. What is it that I am overlooking here?

Post 462409

(Barium: "Fuck!!", Novel Discourse)- points out that acidification is sometimes not necessary. Is this nitroalkane-borate decomposition salt going to end up in the IPA layer in preference to the water layer (I would have expected it to prefer being in the water layer)?

[Barium]

I saw this thread yesterday and was just about to write a answer to you when I decided not to. This because I wanted to see if any other bee have been able to, not only use my methods but also understand the mechanisms behind them and start making their own variants of them to solve any problems encountered. Both Bandil and you made me very proud. This is exactly what I want to see.

Now the problem. The nitronate forming is rarely seen when 1-1,2 eq sodium borohydride is used. Thus no acidification is needed. But when 3-5 eq sodium borohydride is used at least 50% of the nitroalkane will be trapped as the nitronate and acidification must be used to liberate it. The acidification will trigger the nef-reaction even if one is very careful, and using a mineral acid or another strong acid will waste a lot of nitroalkane. This is particulary true if the EtOAc/EtOH-system is used.

The new "wet-IPA" system takes care of this problem. Since a lot of water is present the nitronate is decomposed and the nitroalkane is liberated at once.

With the EtOAc/EtOH or other anhydrous system

* When the reduction is over add only water first. This will decompose the nitronate and also the  various ethoxyborohydrides formed. Be careful since a lot of hydrogen will be liberated. Then add diluted acetic acid to decompose residual sodium borohydride.

* Use weak acids to avoid the nef reaction. Acidic salts can be used too. Ammonium chloride is very useful to decompose excess borohydrides.

[starlight]

now I understand, thanks.

BTW although I reckon you are right that a nef reaction will be triggered to some extent by adding acetic acid to anhydrous reaction systems, I think this pathway is not favoured for the substrate used in this thread (no ketone smell, no blue/green color).

With other substrates it may be a different story. I have found before that what works fine for one substrate does not for another.

For instance in your method:

Post 439553

(Barium: "Ketone formation by nef reaction", Novel Discourse) you keep the temperature at 60C during the nitroalkane addition. When this is done with P2NP you get a very dark green organic layer that is heavily contaminated with by-products. Keeping the temperature below 0C during addition results in much cleaner product.