Sciencemadness Discussion Board

Amide reduction: LiAlH4 vs BH3

Klute - 19-7-2009 at 09:41

I'm planning on reducing a secondary amide to the amine soon. The original procedure calls for 2eq of LiAlH4, but it's quite old (1961), and I wondering if BH3.THF wouldn't be more suited here. I think I have some fresh BH3.THF at work so I won't even need to make it in-situ. I have a ref where a compound very similar to the one I want to reduce (one CH2 more) is reduced with NaBH4-BF3.Et2O in good yields, after hydrolysis of the formed amine-borane complexe. Now this is what makes we unconfortable. i have never done a BH3 workup, and although I think it should be similar to NaBH4 reductions, I don't want to loose my product during difficulties in the workup.

So I'm still unsure. What would your advice be? Anyone have some experience with BH3.THF he would like to share?

JohnWW - 19-7-2009 at 11:30

BH3-ether complexes, such as with THF and diethyl ether, are formed when B2H6 gas (spontaneously flammable in air, obtained by the acid hydrolysis of an alkali or alkaline earth metal boride) is dissolved in the liquid ether, which also serves as the solvent. They are used primarily for reaction with alkenes to obtain hydroborated compounds by addition of B and H across the double bond, i.e. borocarbons. However, they do not seem to be able to reduce, on their own, amines or alcohols, or related compounds such as amides, carboxylic acids, esters, or ketones or aldehydes, under ordinary conditions.

NaBH4, due to the negative charge on BH4-, will however reduce C=O double bonds to -OH in aldehydes and ketones and acyl chlorides by nucleophilic attack, and can be used in aqueous or alcoholic solution. LiAlH4 is an even stronger reducing agent, reacting violently with water, and can additionally reduce (preferably in ethereal solution) esters and carboxylic acids (water being added cautiously afterwards to hydrolyze the aluminate complex), and should also reduce substituted amides to aminoalcohols, -CH(OH)-NR2. Alternatives, preferable on an industrial scale, are catalytic hydrogenation with H2 and use of a sodium alkoxide in alcoholic solution.

But to further reduce an -OH group, as on an aminoalcohol -CH(OH)-NR2, to a secondary or tertiary amine would require even more rigorous conditions, in the light of the textbooks. On the face of the above reactions, achieving it with a mixture of NaBH4 and BF3.Et2O complex (or is that an error for BH3.Et2O complex?) in ethereal solution would seem unlikely, except possibly under conditions of elevated temperatures and pressures. NaH in an ether would form an alkoxide and H2 with such a compound. So are you sure that the reference that asserts this further reduction is correct? Otherwise, the only other method would be catalytic hydrogenation, probably under high pressure.

PS: I have come across one textbook instance, according to which an aromatic primary amide can be reduced by LiAlH4 in ethereal solution, followed by water hydrolysis, all the way to benzylamine (or a derivative thereof) with 93% yield, although the other reaction conditions such as temperature and pressure are not stated, or what would be the success with aliphatic amides. It states that this LiAlH4 reduction ALL THE WAY to an amine is specific for amides and with this reagent and type of solvent only, and does not occur for other carboxylic acid derivatives such as esters, acids, or acyl chlorides. It effectively converts the -C=O group to a -CH2- group.

[Edited on 20-7-09 by JohnWW]

Eclectic - 19-7-2009 at 11:44

http://www.erowid.org/archive/rhodium/pdf/zinc.borohydride.p...

solo - 19-7-2009 at 11:56

...how about using some 10% NaOH and regular bleach cold and stir in your amide ....Hoffman rearrangement....although I;m not sure about using this method with a secondary amide.....it's worth a try.....solo

[Edited on 19-7-2009 by solo]

Klute - 19-7-2009 at 12:26

No, I can't do an hoffamn on this amide, it the kind R2N-CH(Me)-CO-NH-Ph, and I want to keep the N-phenyl.

JohnWW, borane is definatively able to reduce amides, such as mentionned inthis document:
http://www.d-orland.com/pdf/Bthf.pdf

In this document, they reduce a amide very close to my product:
http://www.alsnotebook.com/amidebh3.html

NaBH4 and BF3.Et2O simply genrates BH3.THF in-situ, which is the actuall reducting agent. NABH4 alone will not reduce the amide, unless one eq of acetic acid or similar is added...

LiAlH4 will reduce the amide to the amine directly, without stopping at the amino-alcohol stage: the amino-alkoxide formed by reduction of the C=O is rearranged to an iminium ion which is then reduced:

http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch22/ch22-2...

I will find the origianl litt that use NaBH4 and BF3.Et2O, which is for nitrile reduction origianlly.

[Edited on 19-7-2009 by Klute]

DJF90 - 19-7-2009 at 12:33

JohnWW: BH3.THF is perfectly capable of reducing many functionalities. It is "the reagent of choice" for reducing carboxylic acids to alcohols.

"The reduction of amides to amines is another major synthetic application of the reagent. The reactivity order is tertiary> secondary >> primary. All types of amides and lactams are reduced rapidly and quantitatively by excess of borane in refluxing THF"

The following references are given (for amide reduction):
Brown, H. C.; Heim, P. JOC 1973, 38, 912
Danishefsky, S. J.; Hamson, P. J.; Webb, R. R.; O’Neill, B. T. JACS 1985, 107, 1421
Sammes, P. G.; Smith, S. Chem. Commun. (J. Chem. Soc.) 1982, 1143
Northrop, Jr., R. C.; Russ, P. L. JOC 1977, 42, 4148
Treadgill, M. D.; Webb, P. Synth. Commun. 1990, 20, 2319
Denmark, S. E.; Marlin, J. E. JOC 1987, 52, 5742
Nagarajan, S.; Ganem, B. JOC 1986, 51, 4856

Klute made no mention of reducing alcohols or amines, so I am not sure what your point is here. But you obviously didn't search for the capabilities of the reagent in question.

Klute: I hope these references prove useful for you. I also expect they will provide experimental details concering work up and reaction conditions. Good luck in your work.

Nitro groups, amines, organohalides, organosulfurs (thiols, sulfides, sulfones and sulfonic acids), and alcohols are not reduced by the reagent. Phenols are stable too, but apparently there is hydrogen evolution.

Klute - 19-7-2009 at 12:37

Thanks alot DJF90, I look into them tomorow at work.

Finally I think I will try both, starting by LiAlH4 as this is the origianl ref, then BH3.THF to simplify the procedure if possible...

Here is th eref for the NaBH4/BF3.Et2O reduction of nitriles: Org Syn Vol 6 p.223

I checked out, fresh BF3.Et2O needs to be used, so I will have to distill it under vacuum over CaH2 in presence of a little exces ether (Purification of Lab. Chemicals)

[Edited on 19-7-2009 by Klute]

Klute - 21-7-2009 at 08:00

I decided on using LiAlH4 to start with, as I realized i have 100mmol of amide to reduce, so this would use a whole bottle of BH3.THF... Pretty pricey...

In an oven-dried 500mL 3-neck RBF equipped with a stir bar was charged 8.10g (213.4mmol, ~2eq) of fresh light grey LiAlH4. 200mL of benzophenone-ketyl-dried THF is then added, which causes vigorous bubbling (even with a perfectly dried solvant!). The flask is fitted with a condenser and a addition funnel, both oven-dried, and placed under argon atmospher. The flask is immersed in a ice bath, and stirred.
99.84mmol of the amide are placed in a sclenk, degassed and dissolved in 100mL of dry THF, and transfered to the addition funnel via canula. The amide solution is added dropwise to the stirred hdyride, each drop causing vigorous fizzing. Half way through the addition, the hydride suspension takes a light green tint.
Once the addition is finished, the ice bath is replaced by an oil bath, and the flask heated to reflux (90°C oil bath temp). The reaction mixture is left to reflux overnight.

Work up using H2O and 15% NaOH will be done tomorow morning.

Eclectic - 21-7-2009 at 08:24

Zinc Borohydride did not look promising?

Klute - 21-7-2009 at 08:32

I simply don't have any! And I prefered sticking to the ref for the first try.. Did it by the book! Hopefully i will get the yields stated (80%)

[Edited on 21-7-2009 by Klute]

Methyl.Magic - 21-7-2009 at 10:59

Zinc borohydride can be prepared from ZnCl2 and NaBH4.


LINK HERE

Klute - 21-7-2009 at 11:16

Hum, stirring for 72h seems pretty long to me... Better throw in some LiAlH4 and reflux overnight IMHO.

Zinc borohydride seems like a pretty exotic reagent, used in particuliar cases. If I have to use NaBH4 + coreagent, I would use BF3.Et2O..

Foss_Jeane - 21-7-2009 at 22:04

Quote: Originally posted by Klute  
I'm planning on reducing a secondary amide to the amine soon.


This just might be a good candidate for an electrolytic reduction. Amides are, more or less, easily reduced electrolytically. It generally goes easiest if the amide is attached to benzene as a side chain. For the aliphatics, it all depends regarding ease of reduction.

The general procedure is to use a partitioned cell, sulphuric acid solvent, and a lead cathode.

Klute - 22-7-2009 at 02:49

Hum, not too much in electrochemistry. I wait to see real results before considering it as a preparative methode. It more "it can work" than a good option IMHO.

DJF90 - 22-7-2009 at 05:20

I think the best options are LiAlH4 and BH3.THF. I have not heard of ZnBH4 being able to reduce amides; only in the article attached by Methyl.Magic. However I have just read this:
Quote:

The alkali borohydrides in an ether medium do not reduce amides at room
temperature, but under reflux of THF secondary and tertiary amides are
reduced to amines.


and these following references are cited:
H. C. Brown, S. Krishnamurthy, Tetrahedron 35, 567, (1979)
A. Pelter, K. Smith, Comprehensive organic chemistry vol. 3, p695 (Pergamon press, Oxford, 1979)

Also, this was said:
Quote:

In the presence of an organic acid and under reflux, NaBH4 reduces all amides to amines.


And again here are the supporting references:
G. W Gribble and C. F. Nutaitis, Org. Prep. Proc. Int. 17, 317 (1985).
N. Umino, T. Iwakuma, and N. Itoh, Tetrahedron Lett., 2875 (1976).

Klute - 22-7-2009 at 09:54

Workup:

The flask was cooled in a ice bath, then 8,1mL of dH2O added very slowly, causing vigorous gas evolution and prcipitation of a white solide. Then 24mL of 15% NaOh were added, followed by 24mL H2O. This gave a white solid very easy to filter. The salts were filtered on a glass frit with a plug of celite, and the solids re-extracted with 2x100mL THF. The filtrate was dried and evaporated. The residu was dissolved in 200mL 10% HCl, washed with 3x100mL DCM, basified with conc. KOH which released a light yellow strongly smelling oil. The oil was extracted with DCM, organics washed, dried and evaporated to offer the amine in 83,13% yield. An impurity, comming from the starting material, is present, so the freebase is currently being purified by colum chromatography (eluant: 60:40 chloroform:pentane + 1% Et3N)

Definatively the right choice, the reduction was a breeze, easy workup, and great yields. The product is very pur execpt for the other amine present, but no other side product du to the reduction are seen.

I don't even think I'll bother with BH3.THF now! I love LiAlH4! :)

[Edited on 22-7-2009 by Klute]

grind - 28-7-2009 at 04:33

Why not use such methods like NaBH4 and I2 or CuSO4? There are a lot of references where they use NaBH4 + a simple (!) modification agent for reducing amides. If I remember correctly they even use aqueous CuSO4 and get good results with amides. If you need a reference, I will take a look in my files...

Klute - 28-7-2009 at 08:43

Yes, please post the ref! I prefered using a method published for my amine or its derivatives at first, and I am totally satisfied by the LiAlH4, I don't think I will change even if I have to do the reaction again.

grind - 3-9-2009 at 01:59

Ok sorry for waiting. References I´ve found are:
Tetrahedron Letters 10, 763-766 (1976)
Synlett 419 (1990)
Angewandte Chemie Int. Ed. 28 (1989)
Tetrahedron 48, No. 22, 4623 (1992)
I have only hard copies of them...

Concerning the CuSO4 I was wrong. The CuSO4-modified NaBH4 reduces a lot of functional groups, but not amides.

Luderlasse - 13-5-2015 at 01:45

Sorry for the bump, but I am interested in amide reduction and I did not find any other suitable thread.

I heard somewhere that amides can be reduced with Al/Hg, but I can not find any references for this at all.
Does anyone here know if it is possible? Or maybe have a reference for this?

Thanks
Luderlasse


[Edited on 13-5-2015 by Luderlasse]

karlos³ - 13-5-2015 at 11:43

Amides can be Reduced with Red-Al/Vitride, it isnt cheap, but its easier to handle than, say, LiAlH4.
Its IUPAC name is Sodium-bis(2-methoxyethoxy)-aluminiumhydride.
I would prefer it all the time over LiAlH4, much easier to work with and the work-up is a charm.

The price is ok for all its advantages over LiAlH4.
Well, maybe hard to get for some people, but if you can acquire it, do so.

Al/Hg doesnt reduce Amides. Zinc Borohydride does.
But not much else.

CuReUS - 14-5-2015 at 08:36

Quote: Originally posted by karlos³  

Al/Hg doesnt reduce Amides.

Al/Hg with HCl alone will not reduce amides.you have to pass H2 gas too.

byko3y - 14-5-2015 at 09:16

CuReUS, are you serious? Do you want to say it's actually possible to reduce amine by using aluminium metal?

CuReUS - 15-5-2015 at 04:21

Quote: Originally posted by byko3y  
CuReUS, are you serious? Do you want to say it's actually possible to reduce amine by using aluminium metal?

I saw it in a book,i am uploading that part in the word file


Attachment: reduction of amides.docx (98kB)
This file has been downloaded 507 times

karlos³ - 15-5-2015 at 05:03

Well thats not Al/Hg, thats Zn/Hg. Thats a whole different element? Where comes your conclusion from that this method is transferable to Al?

CuReUS - 15-5-2015 at 05:15

ok ok ,maybe Al cannot be used.but now you agree that the reaction is not impossible.
amides can be reduced by reagents other than hydrides .
actually I always had this doubt.Why can't Al be used in the place of Zn.If you see the electrochemical series,Al is below Zn.doesn't that mean Al is a better reducing agent than Zn ?
i found a good thread on Al/Hg
http://www.sciencemadness.org/talk/viewthread.php?tid=12514

[Edited on 15-5-2015 by CuReUS]

Luderlasse - 15-5-2015 at 06:42

Quote: Originally posted by CuReUS  
Quote: Originally posted by byko3y  
CuReUS, are you serious? Do you want to say it's actually possible to reduce amine by using aluminium metal?

I saw it in a book,i am uploading that part in the word file

Could you give more details about that book?
Are there an experimental section on that reduction?

Thanks

Chemosynthesis - 15-5-2015 at 15:33

Quote: Originally posted by karlos³  

Well, maybe hard to get for some people, but if you can acquire it, do so.

Shame how it seems inaccessible to many, and the synthesis per FR1515582A is rather unappealing from a hobbyist standpoint.
Quote: Originally posted by CuReUS  
ok ok ,maybe Al cannot be used.but now you agree that the reaction is not impossible.

You're being silly. If Al can't be used, the reaction using aluminum hasn't been shown to be possible in a lab. Sometimes using a transition metal with a lower reduction potential actually alters your reaction rather than yield, as I implicated in an indole ring closure discussion previously. Primary literature is invaluable, so I have to yet again recommend you use it when speculating. As far as the book goes, it's either Organic Reactions: Mechanisms with Problems by Tyagi, page 26 or Organic Name Reactions Reagents and Molecular Rearrangements by Raj page A-25. Neither appear to give citations for this transformation, though if I missed it, I would appreciate seeing it.

The source you quote appears to be using a Clemmenson reduction. Given I can't find a literature citation of this, the importance of which I have stressed to you in the past, I have to assume this is a textbook error. These things, sadly, happen. Helv. Chim Acta (1952), 35, pp1577 follows a similar scheme with LAH. Even assuming this Clemmenson is a valid scheme, not only is it useless without experimental conditions, but note how the example is a primary amide. Here is an example of what I can only presume to be similar conditions (without a methodology) leaving secondary and tertiary amides untouched in a molecule: J Antibiot (Tokyo) 1987 Jan;40(1):14–21. See pages 14 section "chemistry" near the bottom and the scheme on 15 for summary.
Find actual peer-reviewed experimentals of a secondary amide if you like.

CuReUS - 15-5-2015 at 23:50

Quote:
You're being silly. If Al can't be used, the reaction using aluminum hasn't been shown to be possible in a lab.

no no,I didn't mean that using Al was possible,I meant that amides could be reduced by other reagents,other than borohydrides.everyone seems to think that any other way is impossible
Quote:
As far as the book goes, it's either Organic Reactions: Mechanisms with Problems by Tyagi, page 26 or Organic Name Reactions Reagents and Molecular Rearrangements by Raj page A-25.

yes,you are correct,its from the organic name reactions,reagents and molecular rearrangements.I found it from google books
Quote:
Neither appear to give citations for this transformation

that's the exact problem I faced,even after searching so much,i couldn't find any reference.but why will someone make it up just like that ? If its an error,what do you think should be the correction.The scheme itself is dubious,do we have to pass H2 or is that [H] referring to nascent Hydrogen formed by the action of acid on metal ?

Chemosynthesis - 16-5-2015 at 01:48

I would expect that it was an editing error and that LAH would be the correct reagent.

karlos³ - 16-5-2015 at 18:38

Here look on page 166, it starts at the bottom of this page:
This will clear everything up you are saying CuReUS ;)
Kindest Regards

Attachment: reductions in o-chem.pdf (4MB)
This file has been downloaded 665 times

CuReUS - 16-5-2015 at 22:23

I quickly glanced over the pdf(which I already have) and the only thing I found was that sodium and sodium amalgam reduce amides but in very low yields