Sciencemadness Discussion Board

Reduction of carboxylic acid to alcohol!

zbde00 - 15-9-2008 at 16:47

Can anyone tell me a pactical and economical method to reduction of carboxylic acid to alcohol!
NaBH4+I2,LiAlH4,LiBH4 +TMSCl are expensive methods.
I have done NaBH4+H2SO4 method,but the yield is low(10%).

This is a problem worthy of heavy discussion.

Thanks in advance!

not_important - 15-9-2008 at 17:53

see https://sciencemadness.org/talk/viewthread.php?tid=2726&...

as well as electrolytic methods.

Swany - 15-9-2008 at 19:34

NaBH4 will reduce some methyl esters cleanly to an alcohol, at least in the case of methyl 2,6-dibromoisonicotinate (80% yields, in abs. EtOH).

solo - 15-9-2008 at 20:04

.................or in 50% ethanol and water with 80+ yields and NaBH4.....which one can save the absolute alcohol for somethng else...........solo

zbde00 - 15-9-2008 at 21:36

Thank you!

To not_important
I have read this article.It use diethyl ether as the solvent.DME is dangerous in factory.

To Swany
My substrate is a carboxylic acid,not methyl ester.So your method should need two steps.This will cost much in factory due to much solvent and purification.

To solo
I don't understand what you have said.Your meaning is that the solvent is 50% aqueous ethanol ?

Klute - 15-9-2008 at 21:36

Here is a fairly complete document on modifying borohydrides:
http://www.rohmhaas.com/assets/attachments/business/process_...

Thanks to Nicodem for sharing this.

You might want to try forming tdiborane with BF3.Et2O: it isn't too expensive, and is routinely used with apparently great yields in various diborane reductions.

Nicodem - 16-9-2008 at 03:01

Refluxing carboxylic acids or their esters in diglyme with NaBH4 is said to work well. This way you don't need any additional reagent to form borane in situ while diglyme is not a particularly expensive solvent. I'm quite sure the paper describing the method was already uploaded on this forum somewhere, so search for it.

Barium - 16-9-2008 at 03:21

1. It would help if you provided the proper information about the trials using diborane generated from sodium borohydride and sulfuric acid in order to understand why it gave such low yields.

2. What is your substrate? How can you expect help if you can't tell us what you need help with? I assume the acid isn't the only functional group in the molecule.

3. You mentioned factory in your replies to not_important and Swany. Are we to understand that a commercial entity wants free help from a bunch of chem enthusiasts?

ziqquratu - 16-9-2008 at 03:41

NaBH4 with I2 might do the job for you.

Attachment: NaBH4.I2 reduction and hydroboration.pdf (390kB)
This file has been downloaded 8045 times

ScienceSquirrel - 16-9-2008 at 03:44

There was a bloke a while back that had thousands of gallons of water contaminated with hydrogen sulphide which he had to neutralise with potassium permanganate.
Some of them have access to the Internet and that is about it, no books or journals of any consequence.
Others are distinctly cagey as they are do not want to give much away for commercial reasons.

zbde00 - 16-9-2008 at 05:11

To ziqquratu
I2 is expensive .

To ScienceSquirrel
Thank you.

I think dibrane may not be scaled up to 300L reactor.
Now I'm working on ZrCl4 +NaBH4 method.It is unfortunate that ZrCl4 is dangerous! When I weighed it, ZrCl4 fired due to the presence of some other unkown impurities in the container.Anyone can tell me the reason?Some paper report TiCl4 +NaBH4 method.But TiCl4 is more dangerous!
I will tell the results using this method.

Nicodem - 16-9-2008 at 05:33

ZrCl4 can not "fire". It does not burn. All it does is fume a bit since it is a strong acid that hydrolyses in the presence of atmospheric moisture. What you saw was probably just fog from the evolved HCl. Just keep it away from water. You can always use dry nitrogen atmosphere if the fog annoys you. I take it that you are aware that you need to use dried THF (or whatever other solvent you will be using) or else you will get no conversion (if you get anything at all since I don't remember if ZrCl4/NaBH4 even works on plain carboxylic acids).

PS: If you consider ZrCl4 and TiCl4 dangerous then perhaps you should consider changing profession. It is less acidic and less dangerous than AlCl3 which is regularly used in the industry in tons amounts without much problems. Also, using a forum dedicated to amateur chemists for your job&profit related problems is… well, I don’t even know how to express myself…

Barium - 16-9-2008 at 06:28

Diborane can be made in situ and then safely be used for reaction volumes of several thousands of gallons, if you know what you are doing. Diborane will also give high to very high yields in the reduction of carboxylic acids to alcohols, if you know what you are doing.

Considering that you doesn't even know the properties of your reagents or seem to be unable to get that information, I highly doubt that you will be able to scale up this reaction from lab scale to production scale without killing, at least, yourself. Do you even have a clue how the reaction parameters change when you change reaction volume from 250 ml to 10 L to 300 L?

not_important - 16-9-2008 at 06:43

Barium and others have made the important points that if you do not describe the starting substrate at least in terms of the functional groups present, and all other constraints (no ether, one step, intended scale of reaction, can't cost much money), then you are not going to get good answers.

Given what you have said, I agree with Barium that diborane based methods are likely the best choice for fine chemicals. On a very large scale with simple substrates, catalytic hydrogenation is an alternative.

You state
Quote:

I have read this article.It use diethyl ether as the solvent.DME is dangerous in factory.
My reference said di-ethyl, you say di-methyl ether - a gas at STP and a bit more difficult to work with. But both are used industrially.

As for what Nicodem ended with
Quote:
... Also, using a forum dedicated to amateur chemists for your job&profit related problems is… well, I don’t even know how to express myself…
I do know what to say - asking amateur experimenters for free advice on manufacturing problems is a very good way to get yourself and maybe your factory in the news as the latest industrial disaster.

Do yourself and your company a favour, hire industrial chemists/chemical engineers.

Barium - 16-9-2008 at 08:57

Quote:
Given what you have said, I agree with Barium that diborane based methods are likely the best choice for fine chemicals. On a very large scale with simple substrates, catalytic hydrogenation is an alternative.


If using diborane is out of the question then I would make the methyl ester and reduce it to the alcohol with Ca(BH4)2. Methanol and some tosic acid isn't exactly expensive. Neither are calcium chloride and sodium borohydride.
The equipment needed to handle the pressure requirements for the catalytic hydrogenation of -COOH --> -C-OH is expensive to say the least. But you are correct in that it is the most economic route on a very large scale.
Quote:
Quote:
I have read this article.It use diethyl ether as the solvent.DME is dangerous in factory.
My reference said di-ethyl, you say di-methyl ether - a gas at STP and a bit more difficult to work with. But both are used industrially.


DME is generally the short name for dimethoxyethane or glyme, not dimethyl ether.

Swany - 16-9-2008 at 10:09

As far as the methyl ester goes, why not just toss in some methanol and H2SO4, heat, then add NaBH4? Extremely crude, but....

EDIT: And what compound are you trying to reduce? That would help a bit. If you are using an amateur forum for professional work I would say we are at least entitled to know the compound in question.

[Edited on 16-9-2008 by Swany]

zbde00 - 16-9-2008 at 20:03

To Barium
sorry.It's diethyl ether.I use wrong word.

To Nicodem
It is not the ZrCl4 burns,but is the impurities burn when contact with ZrCl4.
NaBH4+BF3.Et2O can product BH3 in situ.I will consider this method if I fail.

To others
I'm sorry.I have a feeling of crime because I use free resources for commercial use.

I come to this forum for some general idea(not for a detailed solution) like I go to a library or search internet by google.Companies can give individual charities,but can individual give help to companies ?Companies's tax go to where?And I only a individual.I must finish my work.If I cann't finish,I will be fired.I don't know whether you help me or help our company.
If someone can give me a perfect solution to my problem,I can give him money.Please contact me with U2U message.Thank you!

solo - 16-9-2008 at 21:47

Reference Information



Studies on Optically Active Amino Acids. V. Synthesis of Optically Active #945;-Aminoalcohols by the Reduction of #945;-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

http://www.4shared.com/file/27987730/72b2dc70/Studies.html

Abstract
A facile reduction of optically active alpha-amino acid esters and their hydrochlorides took place with sodium borohydride in ethanol or aqueous ethanol to give the corresponding optically active alpha-aminoalcohols in fair yields. The reaction conditions were investigated.



-----------------------------------------------------------

...and a better method posted by chi from the WD forum/////

i fail to see how conversion to the ester and reduction of that is "better" than reduction of the free acid with 4-6 times less borohydride.

from Aldrichimica Acta 31(1), 19 (1998):

"Preparation of Zn(BH4)2
In a typical procedure, a 500-mL roundbottom flask, equipped with a magnetic pellet and fitted with a reflux condenser carrying a take-off adapter, is flame-dried while a stream of nitrogen is passed through the system. The assembly is allowed to cool to room temperature while the flow of nitrogen is maintained. Freshly fused ZnCl2 (18g; 125mmol) is added followed by NaBH4 (11g; 291mmol). 250 mL of dry THF is then added through a double-ended needle and the contents are stirred at room temperature for 72 hours. The clear supernatant layer is used as such for reactions after estimating its hydride strength (4.4 M in H–)...The reagent is stable over a period of 6 months when stored under nitrogen at room temperature."

from Synth Comm 26(4), 703 (1996) and one of the same authors as the above:

"A solution of zinc borohydride in THF was prepared by the metathesis reaction of sodium borohydride and zinc chloride as reported earlier. (Ind. J. Chem., 1991, 30B, 1150.) After the completion of the reaction, the solution was allowed to settle and the clear supernatant liquid (0.28M in borohydride) was used as such.

Initially, we reduced the amino acids with two equivalents of borohydride and quenched the reaction after 5 hours. The hydrolysis of the excess reagent was very fast, unlike in the case of borane reductions, which require drastic conditions indicating that the excess reagent may not form a strong complex similar to amine boranes which are well known to be quite unreactive. Therefore, we inferred that just one equivalent of borohydride would be sufficient for the conversion of amino acids to alcohols. Indeed, we found that under stoichiometric conditions phenyl alanine was reduced to phenylalanol in 87% yield.

In a typical procedure, phenyl alanine (5 mmol) was added to zinc borohydride (18 mL, 0.28M of borohydride in THF, 20 mmol of hydride). The reaction mixture was refluxed for 5h and then quenched with MeOH. The residue was dissolved in water (10 mL) and NaOH (2g) was added and was stirred at room temperature for 0.5 hours. The solution was then saturated with potassium carbonate and the layers were separated. The aqueous layer was extracted with THF and the combined organic extracts were dried over anhydrous potassium carbonate. The solvent was removed under vacuum to yield 0.7g (87%) of phenylalanol melting at 89°C (90-91)."

Nicodem - 17-9-2008 at 00:02

Quote:
Originally posted by zbde00
To others
I'm sorry.I have a feeling of crime because I use free resources for commercial use.

I come to this forum for some general idea(not for a detailed solution) like I go to a library or search internet by google.Companies can give individual charities,but can individual give help to companies ?Companies's tax go to where?And I only a individual.I must finish my work.If I cann't finish,I will be fired.I don't know whether you help me or help our company.
If someone can give me a perfect solution to my problem,I can give him money.Please contact me with U2U message.Thank you!

Corporations give money for charity to get tax reduction and they pay taxes because they have to. This is all profit related behavior and there is no move a corporation does without it being profit motivated. Have you ever heard of a company paying any of its damage to the society without a court order or law threat? I hope you understand why most of us feel uncomfortable helping professionals who are paid for their work by companies most likely part of some corporation that makes the life of amateur chemists and people in general more miserable that it should be. But if you want to play this kind of game you can always make a donation to the forum. However, you don’t understand a very simple thing. There is no way anybody can give you proper advice without knowing what kind of carboxylic acid you are trying to reduce. There is no method that is cheap, easy and general at the same time. The process needs to be adapted to the specific substrate and the economic requirements. You did not bother even telling if it an aromatic or aliphatic acid, what functional groups it contains and where…

zed - 17-9-2008 at 01:31

Thank you solo! Nice reference.

Zebedee, I personally have no objection to your using this forum to garner information that you are going to use for commercial purposes. Money makes the world go around.

As for I2 being expensive......I'm not sure it really is. Initially, it costs quite a bit, but It recycles pretty well. Oxidize your effluent, recover the I2 crystals that form, and reuse them. They do it all over the world, but here in the US, it has become a must. I2 consumption, especially excessive I2 consumption, may bring irritating government inspectors around.

For ease of running, with water as the solvent, NaBH4-NiCl2 is reported to do a good job on amino acids. Uses a lot of Borohydride though.

http://journals.tubitak.gov.tr/chem/issues/kim-99-23-2/kim-2...

Other than that, you are being awfully vague. O. Chem being what it is, there are so many special cases that general rules often don't apply. Pick the right carboxylic acid, and you could reduce it to an alcohol via a catalyst, sunlight, and a very mild reducing agent, like water.

[Edited on 17-9-2008 by zed]

[Edited on 17-9-2008 by zed]