Sciencemadness Discussion Board

reductive am. why inert atmosphere?

chemrox - 2-4-2007 at 18:02

I'm doing a reductive amination of an aldehyde with Na(OAc)3BH, the procedure calls for N2 atmosphere (I'm using Ar) for the immine part which is in the first half hour before the hydride is added. Then the hydride goes in and no more mention of N2. The general procedure is in another paper on this reducing agent and all the examples use N2 at least for the immine part (if two step) and many of them use it for the whole reaction sequence. Why? Why during the immine development with aldehydes and why with the whole sequence in other cases?

This specific aldehyde has a phenyl group but it is a couple of carbons away from the carbonyl and I'm not considering it as an aromatic aldehyde per se but maybe I should. Would that make a difference?

Some of you were most helpful in the inert gas setup and my heartfelt thanks go to you. This balloon trick is trick indeed!

Nicodem - 3-4-2007 at 00:07

Whether the inert atmosphere is truly necessary or not can not be answered without knowing what the reactants and conditions are. Often the inert atmosphere is obsolete, but just as often it is crucial for the yields or even the nature of the product. However, after the addition of STAB you probably do not need to vent with inert gas anymore since the air has been purged from the solution. But I would keep a balloon up to prevent air from coming inside the flask.

stoichiometric_steve - 3-4-2007 at 01:27

the N2/Ar is used to minimize the oxidation of imines by O2. i just read somewhere that certain imines are quite unstable in the presence of H2O (yeeeaah, we knew that) but also oxygen is an imine killer!

STAB insertion under Ar or n2 or is this enough evacuation?

chemrox - 9-4-2007 at 21:39

So how does one get the STAB (or any other powedered reagent) into the mixture with the imine or enamine depending? I'm finding this may be necessary. Air coming in with the STAB may be killing the Schiff base before it can be reduced. I thought of filling a hemple column with gas, adding the STAB to it, stuffing some glass wool in one end and running some more gas in .. stoppering the thing and rigging a plug on a wire in the end of it .. might work.. might hang up .. could try it with chalk and an empty flask I guess.

Maybe I'm not doing enough to get the air out of the reaction flask. I used a volatile solvent .. pumped until it boiled and let gas in to replace the air.. did it again and kept positive pressure on with a balloon .. a trick I learned in this thread.

stoichiometric_steve - 10-4-2007 at 03:28

why don't you use a solution of the reagent to be added? all you need is a pressure equalized addition funnel.

chemrox - 10-4-2007 at 12:10

I'm hip but STAB doesn't dissolve in the solvent we're using. I shall see if there's a non-protic solvent for it. I'm sort of curious this issue wasn't covered in the paper and wondering if this isn't overkill. Maybe the problem is elsewhere.

stoichiometric_steve - 10-4-2007 at 14:00

STAB is soluble in toluene...

chemrox - 15-4-2007 at 18:06

and toluene is miscibile with DCE and DCM ... I'm wondering why the primary JOC paper on STAB red ams doesn't use this solvent and focus is on DCE and EtCN instead .. alcohols were also mentioned as I recall..

chemrox - 15-4-2007 at 18:08

also STAB is made in benzene and remains dissolved in it 'til you pull it out

could there be a problem with conjugated systems?

chemrox - 15-4-2007 at 22:24

and why should I have to?

the general procedure is in: J. Org. Chem. 1996, 61, 3849-3862

they just mix in the STAB and stir under N2 for the ones that need it

is there a problem with welding gasses?

reductive am under Ar or N2

chemrox - 9-2-2008 at 22:15

I'm getting ready to follow the general procedure for reductive ams in STAB with cyclopentanecarbaldehyde and 4-piperidone. I plan to assemble the following apparatus:

5 neck, 3L rb. flask, condenser, liq addition funnel, powder addition funnel, stir bar, stirrer, gas line, vacuum line.

I was going to assemble the above and evacuate to around 1mm and replace with gas and do this twice before loading the acetic in the addition funnel and the STAB in the powder funnel. The piperidone should be in the flask and the aldehyde should be in a syringe. Or a bent necked flask ...(?)

Actually, I'm stuck here as to whats the best way to load the apparatus with reagents and get rid of all the air before starting the reaction. The aldehyde and combining it with the amine is where the most air sensitivity becomes most critical and hence the most likely failure point.

Post script : also planned the same thing using hexanal

[Edited on 9-2-2008 by chemrox]

Klute - 10-2-2008 at 04:58

Are you following the procedure out of J. Org. Chem., Vol. 61, No. 11, 1996?

If I've got this right:
-The piperidone is in the flask
-The STAB in the powder funnel
-You add the aldehdye to the piperidone
Then add dropwise the acetic acid while adding the STAB in small portions.

Can you not use add the aldehyde in a solvant? IIRC DCE is mentionned in the article. Thsi could be more practical when transfering the aldehyde, especially if it's viscous.
And can the STAB be added as a solution in GAA?
WIll you be using any way of removing the water formed during imine formation? AT the same time, considering the substartes, I guess the condensation would proceed well enough without.

If strict inert conditions are required, here is how I would proceed:

-Distill DCE or THF over NaH or benzophenone ketyl under argon into a large schlenk after a few hours reflux. Maintain under slight pressure of argon. WHen distillation is finished, introduce a flow or argon from the receiver, disconnect from the distn apparatus, and cap with a glass stopper, maintained with a clip because of the slight argon pressure.
Ideally, distill your GAA under argon too. Under P2O5 maybe? Might be an overkill.

-Add the piperidone to the mounted setup, and the STAB into the powder addtion funnel, purge the system a few times, while stirring to avoid bumping when ebullition starts. (Be carefull to cut vacuum as soon as very small bubbles appear; this can be tricky at first especially when using solvants, that can suddenly bubble violently depending on your vacuum source).

-Add the aldehyde to a suitably sized schlenk, purge 3 times. Under a flow of argon, replace the stopper with a punctured septum. Use a oven-dried glass syringe to draw out a suitable amount of DCE out of the distn schlenk: Under a flow of argon, quickly replace the glass stopper with a rubber septum, pre-punctured to faciliate the introduction of the needle. When the needle will be underneath the surface of the solvant, the argon over-pressure will "push" the solvant into the syringe. Do not fill the syrnge more 2/3. Firmly maintain the plunger with your right hand (it can be tricky to hold the syringe AND block the plunger with the same hand: use your index while the rest of the hand is holding the syringe) and direct the needle into the peirced septum of the schlenk containing the aldehdye. Very slowly let the solvant dribble into the schlenk, don't push on the plunger to much as this will force solvant out from the sides of the plunger (these syringes ar enever hermetic). You ahve your aldehdye in DCE.

On the setup, under a flow of argon, replace the stopper of the addtion funnel with a pierced septum. Introduce a canula, or a double-tip needle into the septum of the schlenk containg the aldehdye, letting a constant flow of argon coming out that will chase the air out of it. Then introduce the other end into the septum of the addition funnel. Use a small needle to pierce the addition funnel's septum next to the canula: the argon will flow out from there. Insure yourself that the addtion funnel tap is closed, and place the tip of the canula under the surface of the DCE/Aldehyde solution: the solution will be pushed through, into the addition funnel.
Remove the small needle, then the canula from the additon funnel, then from the schlenk. Wash it thoroughly by passing acetone a few times through it (apply vacuum to the schlenk's inlet, and tunr the tap very quickly to only briefly evacuate while the other tip of the canula is in a beaker of acetone. The replace canula in the oven.
Drip your aldehdye solution into the piperidone. Introducing some solvant before the aldehdye into the piperidone could be prefered, as too obtain a solution of the amine. Just use the syringe to transfer some solvant via the addition funnel before adding the aldehyde.


-Repeat this procedure with the acetic acid, although the GAA could just be purged a couple of time instead of distilled. Although the amout of water should be kept to minimal, totally anhydrous conditions aren't needed as water si formed during the imine formation. The absence of oxgen is more critical I guess. Then proceed to your additions.



Having a argon/vacuum ramp is very practical as you don't ahev to disconnect the schlenk to swap to either vacuum or argon. Unfortuanly, these are very expensive, and require the use of different equippement (vacuum gauge, safetly pressure releif, liq N2 trap, etc.) At home, I place the vacuum and argon inlet in different points of the setup.



The tube hanging nowhere on the right in normally connected to the safetly pressure releif valve. The trap on the right is normally immersed into a Dewar full of liq. N2.


Once you ahev finsihed using your distilled solvant, replace a glass stopper, and evacuate a few times to be sure no oxygen came in. If you haven't got a manifold, place a vacuum inlet tap in place of the stopper, purge a few times, and quickly replace the vacuum inlet with a glass stopper under a generous flow of argon. Such solvants, if handled correctly, can be considered totally air/water free for at least a month (that what we do at work), but that is for very sensible reactions, they can be kept for a LONG time. The distilled THF I use for grignards or LAH reductions has been distilled nearly 6 months ago and has no problem whatsoever.

Next time I perform such a reaction, I might take a few photos to illustrate the differents steps of inert atmospher use. IIRC Aldrich published a bulletin on handling sensible reagents, you will find most of the technics mentionned with some drawings.


Good luck with your reaction!

PS: you are performing the reaction on a rather large scale, no? Wouldn't it be wiser to try the reaction out of a smaller scale until you have succes to familiarise yourself with the use of inert atmospher and the reaction itself?

chemrox - 11-2-2008 at 01:24

scale down? absolutely! Should I get a gas tight syringe? If I send you my email can you diagram the manifold for me? My setup my accomplish the same thing but it also may not. I've been waiting on a decent manometer for over a month! The monostat is trick .. built ala Vogels..

reductive am in inert atm

chemrox - 6-3-2008 at 21:07

To continue, I have a general procedure for reductive am of aldehyde with sec amine using STAB in acetic acid. In the writeup it says to stir under N2 for 24 hours after addition of the STAB. Question is, should the whole system by evacuated and charged with N2 (orAr) before combining the amine and aldehyde? If not, before adding the STAB? I'm coming back to these types of reax after a hiatus to practice technique and get better grounded in lab work. The general procedure is attached-

Aplologies to Nicodem and others for the redundancy. Still trying to understand the writeup in context.

[Edited on 7-3-2008 by chemrox]

Attachment: Reductive Amination of Aldehydes and Ketones with STAB.pdf (412kB)
This file has been downloaded 603 times

Drunkguy - 7-3-2008 at 05:55

Ive seen an interesting procedure which looks chemically related to the one you are attempting.

My advice is that disposable argon cylinders are available from welders for not much money. I have one myself and paid around £16 for it inclusive of delivery. On the bottle it says that it contains 60 litres of gas.

I have a brand new argon gauge that I spent £30 on in 2006 and havent used yet. I dont know if it will screw-in to this cylinder or not since I havent attempted it yet. You can buy used ones for less than this, but the flip-side is that you can also end up paying about quadruple what I did depending on where you buy it from.

The seller of the gas claimed to me that it is 99.9% pure. However, when it arrived I could see no proof to substantiate that claim. Upon consultation, he appoligised that he did not actually know the purity of the gas. He did however claim that he had spoken to somebody who said that it is at least 99% pure. And i'm thinking to myself "what the F**K?!"

Clearly, you are going to want to be using an inert gas on principle. It's common knowledge that both the reactant and the reagent in this procedure are moisture sensitive and possibly also oxidize in air. Therefore, it seems a logical consequence that measures are going to be taken to safe-guard against this.

At the absolute minimum, I would expect you to be using a CaCl2 filled drying tube.

JohnWW - 7-3-2008 at 12:59

It is a good idea to use argon. Even N2 gas can be "fixed" by certain transition metal complex cations, and alkali and alkaline earth metals can burn in it. In nature, it is a Mo compound that enables mostly legumes to fix atmospheric N2. By comparison, the only reaction of Ar is, just possibly, with F2 under the most extreme conditions of heat and pressure; and the only likely stable compound of it at ordinary temperatures is the theoretical ArF+ cation.

-jeffB - 7-3-2008 at 15:58

During a tour of a nearby lab's solvent-preparation facility, I heard of another reason to prefer argon: while nitrogen is very slightly less dense than air, argon is significantly MORE dense. Therefore, if you fill a vessel with argon, then add something through the top, very little argon will be displaced by air.

This lab actually had a sizeable argon dewar -- they used enough of the stuff that it was appropriate to use the bleed-off from a tank of liquid.

chemrox - 7-3-2008 at 16:29

I have Ar. I get it from a welding supply and will test it for CO2 to make sure but I think its 99%. This isn't the question. The question is, at what point is the inert gas mandatory?

Nicodem - 8-3-2008 at 00:42

Quote:
Originally posted by chemrox
The question is, at what point is the inert gas mandatory?

Quite a strange question I would say. You use inert atmosphere during the reaction so the inert gas is mandatory during the reaction. From the start to end, unless stated otherwise.

Drunkguy - 8-3-2008 at 06:19

Iv'e handled SmI2 though which is one of the strongest reducing agents u are ever likely to see. Inert gas is required there since the reagent reacts on contact and is oxidized in air, so its not just moisture which u need to watch out for.

Like I said, if you attempted the STAB reaction with nothing more than a CaCl2-filled drying tube and dry solvents, then the likelyhood is that the reaction would still yield viable quantites of product.

In PIHKAL, on preparing 2C-H a stream of N2 is used, whereas on preparing DMA-2 there is no mention of inert gases. That isnt saying that its mandatory in the former case but not in the latter. Ideally you want to use inert gases in all procedures of this nature wherever it is viable to do so.

Some undergrad texts describe performing a Grignard reaction with only a CaCl2 drying tube, whereas other texts instruct the chemist to use a stream of N2 at all times. It's not saying that N2 is mandatory in one of the procedures but not the other; it's simply a case of the materials that you have available to use.

Conversely, when handling compounds such as BuLi ive never seen N2 not being used to flush the atmosphere before introducing the reagents. The prcedure is further complicated by the fact that good syringe technique must be exercized and some of the time a canulla is used in the transfer of solutions under inert atmosphere.

The difference between the density of Ar and N2 dictates that Ar is to be preferred wherever possble. In a proper lab though N2 comes from giant reservoirs that are hooked up to literally 100 fumehoods gas taps. If using N2, then I typically turn on the tap and have quite a steady stream of gas blowing through the bubbler. If handling ar though, I would probably be more conservative in my use of this gas.

grind - 8-3-2008 at 12:23

Quote:
Originally posted by stoichiometric_steve
STAB is soluble in toluene...

But only very slightly!

You can do this:
Fill your flask with STAB and the solvent , add a mixture of the aldehyde/ketone, the amine and some GAA in the same solvent from the dropping funnel with good stirring and cooling with ice/NaCl. Let react the mixture for 1-2 days at RT. No need for N2 or Ar, only moisture protection is necessary. This procedure works fine.

using STAB

chemrox - 21-10-2010 at 23:58

I'm trying to optimize a process involving a reductive am . I've done it with NaBH4 a number of times but it takes about 4-5 days to collect the end point water volume. STAB appears to be quicker cutting out a step and affecting the reduction in 3 days or less. The issue is whether an inert atmosphere, adding expense, is required. The published procedures seem to favor N2 but I question is it necessary and why would it be? I live in a relatively dry climate and in the summer air conditioners are running keeping moisture down to ca 20%. I raised this question a few years back in a different context and a respected professional chemist member was of the opinion that N2 wasn't necessary as I recall but I couldn't find the discussion. I would dearly love to hear from (other cheap) chemists who use STAB in their labs.

Methyl.Magic - 22-10-2010 at 00:37

hi,

I used STAB a lot of times and multiple forms : solid STAB, solution in THF or AcOEt and toluene gel solution. I don't know why you want use STAB instead of NaBH4 in order to increase the reaction speed because STAB is less reactive than NaBH4. Therefore STAB is used to selectively reduce imines or iminium ions over ketone.

For the reductive amination with NaBH4 you have to previously form the imine BEFORE adding NaBH4. The imine formation can take a lot of time but it generally lasts 6-8h. With STAB, all the reaction is done in one batch.

What is your substrate ?

jon - 22-10-2010 at 07:00

NaH(CN)III has been used successfully without inert atmosphere for different substrates, geez you would think a functional group is a functional group but, not nessecarilly.
but if you want to go cheap just blanket it and seal it with a septum or a ballon.
one can use fluorcarbons and such as they are inert and quite heavy. freon and other things like that.
keyboard cleaner spray is basically flourocarbons and dimethyl ether for example.
or you can buy those disposable bottles of nitrogen for keeping wine fresh at the liquor store.


[Edited on 22-10-2010 by jon]

[Edited on 22-10-2010 by jon]

Methansaeuretier - 22-10-2010 at 07:31

Why not using methane, ethane, butane, propane etc.?

I used them (methane and butane) several times as inert atmosphere on reductive amination with benzylamines, MeOH as solvent. Worked everytime as well as with N2. Without inert atmosphere I had a sharp drop in yield (80%->5%).

Only drawback is that they dissolve good in nonpolar solvents.

chemrox - 24-10-2010 at 00:53

Yes that would be a problem with alkane gasses wouldn;t it. @nicodem thanks for the merge sorry for doubling. I see the experience has been reduced yields with aldehydes. I was working more recently with a ketone and got nearly theoretical yields in air with water removal. So if I can make the imine and reduce it with NaBH4 in atmosphere does it follow the STAB procedure would work well in air with the same ketone? Or is there something about taking the water out with acetic acid that makes the imine more labile to oxidation? This doesn't seem intuitively correct. ie if it works with NaBH4/-H2O in air so should it be with STAB/acetic but since costly reagents are involved I definitely want as much real-world advice on this as I can get.

Methansaeuretier - 24-10-2010 at 08:32

Btw. does STAB work also for dialkylation? Under which conditions?

jon - 25-10-2010 at 11:13

pretty much the same thing as reductive amination using primary amines.
only the double bond is on the carbon it's called an enamine.
it just occured to me STAB is'nt a way around azetropic distillation of the amine and the ketone because STAB is readily decomposed by water.
the only way around that is sodium cyano boro hydride.

Methansaeuretier - 25-10-2010 at 12:31

Quote: Originally posted by jon  
pretty much the same thing as reductive amination using primary amines.
only the double bond is on the carbon it's called an enamine.
it just occured to me STAB is'nt a way around azetropic distillation of the amine and the ketone because STAB is readily decomposed by water.
the only way around that is sodium cyano boro hydride.

STAB does defenitly work also without azeotropic destillation. I've done it myself.

jon - 25-10-2010 at 16:10

good to know