Author Topic: A really wet reductive alkylation  (Read 26756 times)

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Rhodium

  • Guest
How to isolate the byproduct MDP2Pol for re-use
« Reply #40 on: January 09, 2004, 08:01:00 PM »
The crude MDP2Pol will be a mess of other byproducts, so it is imperative that you purify it by distillation before carrying on to the oxidation step. Naturally, the MDP2P gotten after the oxidation step also needs to be distilled before use.

How to isolate MDP2Pol, the major byproduct of reductive amination of MDP2P

If you are using the procedure in

Post 328680

(Barium: "A really wet reductive alkylation", Novel Discourse)
then the MDP2Pol will remain in the toluene phase after the acidification and extraction of it with the 5% HCl.

If you are using

Post 458857

(Barium: "Improved "wet" reductive alkylation", Novel Discourse)
then acidify as usual and evaporate the isopropanol, then extract the MDP2Pol into the non-polar solvent of your choice.

Regardless of method used above, the MDMA will be in the aqueous phase and the MDP2Pol in the non-polar one. Now wash the non-polar solution with dilute aqueous sodium bicarbonate to remove any remaining acid (which could hurt the MDP2Pol), distill off the solvent, and vacuum distill the residue (preferably with a fractionation column) to isolate the MDP2Pol, bp 125°C/25mmHg (Ref:

Post 399715

(Rhodium: "Piperonal -> MDP2NP -> MDP2P -> MDP2Pol", Novel Discourse)
).


The MDP2Pol is now ready to be oxidized to MDP2P again, using any known method.


Some suggestions on how to do it:

Post 432203

(Rhodium: "Jones Oxidation of P2Pols to P2Ps", Methods Discourse)

Post 392005 (missing)

(Aurelius: "Oxidation of alcohols with (NH4)2Cr4O7 in solution", Methods Discourse)

Post 392008 (missing)

(Aurelius: "P2Pol to P2P", Methods Discourse)

Post 434379

(Megatherium: "To generate P2P from the P2Pol, one could use...", Chemistry Discourse)

Post 367709

(Rhodium: "Phenyl-2-propanol", Chemistry Discourse)

Post 367667

(ChemisTris: "Oxidation of P2Pol - a literature search", Chemistry Discourse)

Post 236500

(Acme: "Ref's for Propylene oxid method", Methods Discourse)

Post 272729

(Rhodium: "Re: Grignard P2Pol In Situ Oxidation", Novel Discourse)

Post 290388

(foxy2: "Here it is", Novel Discourse)



ClearLight

  • Guest
Need some help with this..
« Reply #41 on: January 17, 2004, 04:45:00 AM »
By unfortunate circumstances, the NaOH was added BEFORE the MeAM solution, then the MeAm solution was added....

  Am I doomed???  or do I still have potential product at the end..  the solution went brownish w/ the NaOH and is now a yellowish orange, w/ MeAm smell present.. please advise ASAP!


terbium

  • Guest
Methylamine in situ.
« Reply #42 on: January 17, 2004, 07:06:00 AM »
Should work the same no matter which of these was added first. I always used methylamine freebase prepared by dissolving methylamine gas in methanol; the solution would turn slighlty yellow as the imine was formed.


zero_nrg

  • Guest
first attempt
« Reply #43 on: February 29, 2004, 08:18:00 PM »
Decided to give this a try using the Aliquat 336 method instead of the IPA as the Aliquat was readily available and Barium had such high yields with it.

 33,54 gr. (250 mmol) phenyl-2-propanone (note 1)
25,3 gr. (375 mmol) methylamine HCl (note 2)
11 gr. (290 mmol) sodium borohydride
4,8 gr. Aliquat 336

In a 1000 ml 3 neck RBF fitted with overhead stainless steel stirrer the ketone in 100 ml toluene was added followed by the additon of the MeNH2 mixed with 30 ml water in one portion.  While stirring violently 15 gr. NaOH in 40 ml water was added dropwise over a period of 19 minutes (some ammonia scent escaping from flask at this point).

A few minutes after after the addition of the NaOH a slight pinkish hue was noticed which
seemed to get slightly darker in color as the mixture was stirred for 1 hour at room temp.

After stirring, the mixture was seperated and the aqueous layer discharged.  The organic layer was a tranparent purple color.  Very pretty, but not expected.  Worried at this point.

The purple imine was tranferred to a 1000 ml, 3 neck RBF fitted with the mechanical stirrer used in previous procedure.  Added the Aliquat 336 in approx. 4 minutes (had weighed amount in test tube- very viscous).  Prepared the borohydride by placing it along with 25 mg NaOH in  a beaker and added 35 ml water and swiled by hand for 3 seconds.  Added this in one portion to the imine/Aliquat mix and started violent stirring.  At this point an exothermic reaction ensued (noticed condensation in the flask).  This was confusing as Barium used slight heating to 35 degrees.  Stirring was slowed (still very fast though-enough to create emusion) and a cold water bath was applied until temp came down to 40C where it stayed fairly stable until it started to drop after about 20 minutes of stirring.  Also, the purple color dissappeared after the addition of the borohydride and the mix was a somewhat cloudy white color which changed to a somewhat golden yellow color as stirring progressed.
After the reaction the residual borohydride was destroyed by adding dropwise a 20% acetic acid soln. until no gas evolved.  The aqueous layer was seperated and discharged.  The organic layer was extracted with 3x100ml 10% HCl, which was washed with toluene and saturated with NaCl.  The soln. was then basified until pH 14.  Noticed at this point that there was very little oil present.  Perhaps 3-5 ml.  Extracted anyway with 2x50 ml toluene which was washed with water and dilute NaCl soln.  About 80 ml of the solvent was stripped off before exhaustion set in and called it a night.   Suspect wise bees will say to fractionally distill ketone.  Please advise and I will give this one another go.    -zero







Note 1- made using store bought phenylacetic acid using xtaldocs PbO method [

https://www.thevespiary.org/rhodium/Rhodium/chemistry/p2p.paa-pb.html

] Post reaction workup consisted of:

Seperating the orgaincs in sep funnel, washing the organic layer with 20% NaOH soln. until washing were alkaline to pH paper and then washing organics with water which created a serious emulsion.  The emulsion was effectively broken up by adding NaCl to the sep funnel and swirling.  The aqueous portion of the post reaction mix was extracted with 2x50 ml portions of diethyl ether, and treated as per organic layer procedure above.  The ether extracts were then added to main product, dried over MgSO4, and the ether stripped off.  The resulting ketone was vacuum distilled but not fractionationally distilled. 

Note 2-made using Vogel procedure. Recrsyallized in methanol.  Clear crytals that look snow white when all together in a flask.

Bond_DoubleBond

  • Guest
Re: In a 1000 ml 3 neck RBF fitted with ...
« Reply #44 on: March 02, 2004, 06:22:00 AM »

In a 1000 ml 3 neck RBF fitted with overhead stainless steel stirrer the ketone in 100 ml toluene was added followed by the additon of the MeNH2 mixed with 30 ml water in one portion.  While stirring violently 15 gr. NaOH in 40 ml water was added dropwise over a period of 19 minutes (some ammonia scent escaping from flask at this point).




swim is unfamiliar with meth synths (they're illegal  :o ) but isn't the intermediate imine unstable in the presense of water?  water azeotropes with toluene, true.  but that's about two mols h2o per mol toluene.

from swim's understanding, meth reductions must be anhydrous.


fanofshulgin

  • Guest
Uh oh Zero_nrg
« Reply #45 on: March 02, 2004, 06:31:00 AM »
Upon completion of your addition of the acetic acid....did you measure the pH of the aqueous layer?  From the sounds of things, you have over-acidified and the majority of your freebase has gone into aqueous solution and you have discarded it!

I hope not!  First rule of the lab....never discard ANYTHING until you have identified all your expected product.

FanofShulgin


zero_nrg

  • Guest
Bond_doublebond : not sure if the imine is...
« Reply #46 on: March 02, 2004, 08:57:00 PM »
Bond_doublebond : not sure if the imine is stable. Questioning the necessity to do this under anhydrous conditions is what this thread is all about.  Barium laid the groundwork but other ketones are the big questions in my mind. 

Fanofshulgin :   No I saved it all.  Will check this out and report. Thanks for the reply btw.  Doesn´t seem to be much support for those in the trenches.  -zero

fanofshulgin

  • Guest
Bond_DoubleBond: its true that schiff-bases...
« Reply #47 on: March 03, 2004, 08:08:00 AM »
Bond_DoubleBond: its true that schiff-bases are not very stable in the presence of water (thus why their formation is often carried out under Dean-Stark conditions), but you would be surprised.....the main point is the imine formation is reversible - there is an equilibrium between imine and ketone.  The reductive amination is possible due to the  basically irreversible reduction of imine to amine.  Le Chatillier's principle would suggest that as the imine was consumed (even if slowly) then more imine would be formed.

zero:  Let me know how things go. I would try rebasifying the aqueous layer then extracting with organic solvent (DCM or ethyl acetate perhaps).

Fanofshulgin


RepVip

  • Guest
Constructive Criticism Needed
« Reply #48 on: March 17, 2004, 10:30:00 AM »

Post 458857

(Barium: "Improved "wet" reductive alkylation", Novel Discourse)

Swim followed this post exactly using P2P and methylamine.hcl made from ammonium chloride + paraformaldehyde, and had a problem.


The residual borohydride was destroyed by addition of diluted hydrochloric acid (1:5 conc hydrochloric acid:water) until gas evolution ceased and pH 3 was reached. The alcohol was removed by distillation in a rotovap and the aqueous solution diluted with 100 ml water




After destroying the remaining borohydride swim attempted to distill out the alcohol from the aqueous mixture. However, swim noticed that he had two layers at this point--a bottom aqueous layer and a top layer that is...? Is it unreacted P2P?

It's a possibility that swims methylamine synth was a failure. However, the recrystalized methylamine appears ok, even though it is slightly blue from the otc paraformaldehyde. This is the only thing he can think of that might have caused this?

The reductive amination went perfectly, from what swim could tell, but obviously there was a problem because he didn't get any yield at all.

Swim would appreciate any constructive criticism.


Bandil

  • Guest
Are you talking about the post reaction ...
« Reply #49 on: March 17, 2004, 10:44:00 AM »
Are you talking about the post reaction mixture, that is made up by two layers?

IPA sometimes separates from water if too much sals is present in the aquous solution. You used methylammoniumchloride + HCl + borohydride, which indeed would give you a very "salty" mixture of this and that. Perhaps it's simply the alcoholic layer floating on top?

Regards
Bandil


RepVip

  • Guest
Ahh.. I didn't know that!
« Reply #50 on: March 17, 2004, 11:21:00 AM »
Ahh.. I didn't know that! That would make sense. I was thinking that was the case at first, but after I looked up the solubility of IPA in H2O I disregarded that thought.

Swim separated the two layers and proceeded to work up the aqueous phase, with no product at all. Swim saved the other phase and will maybe try to work it up later. In order to work it up, if it is IPA after all, you would have to add some water and distill of the IPA first, correct? Damn! That's exactly what Barium described, swim just got confused  ::) .

Thanks for the reply!

zero_nrg

  • Guest
The "improved procedure" was tried...
« Reply #51 on: March 17, 2004, 06:58:00 PM »
The "improved procedure" was tried with p2p (250 mmol,fractionally distilled under reduced pressure,very pale yellow,light scent) and recrystallized MeNH2 (absolutely clear crystals).
Upon addition of the NaOH in H2O to liberate the freebase a salt precipitated out of the liquid which stuck to the sides of the flask accompanied by the strong scent of MeNH2 freebase.  Guessing that the salt is NaCl.  The alcohol was stripped via vac distillation and at this point a pale violet color was noticed in reaction mix.  Violet colored substance seperated to top in sep funnel and was extracted into the toluene wash.  The reaction mix was basified, extracted with toluene, the toluene removed via vac distillation and the clear oil (19 grams) was acidified with aqueous HCL, the water boiled off, and the liquid was poured into freezing cold dry acetone.  Crystals precipitated immediately.  However there was also a strange looking wax like substance which stuck to the sides of the glass in small globs.  There was alot of the waxy substance.  Yield of good substance not yet determined.  The procedure works but most likely needs fine tuning by a chem badass.  Unsubbed ketone may require a special procedure.    -zero

n00dle

  • Guest
Sorry for being noobish but can this be used...
« Reply #52 on: April 01, 2004, 10:34:00 AM »
Sorry for being noobish but can this be used re: dialkylamines?

Like, some synths requiring a low bp amine like dimethylamine might be easier to control (re:condensation of dimethylamine) when holding it in reflux with a high bp solvent.

Could this be achieved better using the wet alkylation method by say, holding the solvent containing the reactant + hydrochloride salt of dimethylamine and when reflux is reached, slowly add NaOH? Surely freebasing the amine in the solution should yeild better due to surface area, 'cuz more amine reacts with the other interesting chems before heating up to a point where it boils out of soln.

Any comments? Can this be done?

ephemeral

  • Guest
question on "wet" reduct. molar ratios
« Reply #53 on: April 16, 2004, 07:30:00 PM »
Looking at Bariums original post (458857), the molar ratios  were  .25: .375 : .375 : .14    but looking at the quantites he used there, the MeHCL was much greater and the Sod Bor a bit higher as well.
        What ratio did Andromeda use for the 350g (292.8 mL ?) ( 1.96 mol) batch?   And did 2000mL IPA suffice ?

     Would like to try the procedure, but could use some guidence on these points.  Thanks much

andromeda

  • Guest
Results
« Reply #54 on: June 06, 2004, 01:18:00 PM »
When I tried the wet alkylation method I kept ending up with 75% mdpdp-ol and 25% mdma. I have therefore been concentrating on labtop's anhydrous me.am method with great results. I concede that it is more work but it is simple.

I will have another go soon. Doesn't seem to be much discussion about this method considering the support that it is a breakthru?

XrLeap

  • Guest
noobee question....
« Reply #55 on: July 04, 2004, 12:11:00 AM »
was there a scale up for this route to be successful? any bee had any experience with scale up?


zero_nrg

  • Guest
post reaction acidification
« Reply #56 on: July 04, 2004, 07:07:00 AM »
Thought this might be relevant to this thread: From "Modern Synthetic Reactions" - Herbert O. House (pg. 53)

"it is customary in hydride reductions to employ a slight excess of the reducing reagent in the event that some of the metal hydride is unintentionally destroyed by reduction with  hydroxyl-containing materials present in the reaction medium...It should be noted that acidification of reaction solutions containing excess sodium borohydride can generate diborane which may cause further undesired reduction of groups in the initial reaction product." 

ref. J.A. Marshall and W.S. Johnson, J. Org. Chem., 28, 595 (1963).

XrLeap

  • Guest
Re: To a solution of the ketone in 300 ml IPA...
« Reply #57 on: August 11, 2004, 09:15:00 AM »

To a solution of the ketone in 300 ml IPA




What is the purity of the IPA? 91% or 99+%?
Can any experience bee tell us as it might make the mixture  containing more water for the 91% version. 9% of 300ml would be 27ml. That's about double of the NaBH4 solution.

Appreciate the answer.....




zero_nrg

  • Guest
amine in IPA
« Reply #58 on: August 12, 2004, 02:05:00 AM »
Perhaps you could just dissovle your methylamine in the 91% "wet" IPA and add a little extra water if necessary.

Bandil

  • Guest
Less is more!
« Reply #59 on: August 12, 2004, 08:46:00 AM »
How about just drying your IPA with some epsom salt or something akin, prior to its use? This will give you 99% IPA... The less water in the reaction the better.

Regards
Bandil