Author Topic: Wet NaBH4 reductive amination  (Read 997 times)

letters

  • Subordinate Wasp
  • ***
  • Posts: 138
Re: Wet NaBH4 reductive amination
« Reply #80 on: May 25, 2011, 05:01:40 PM »
For your consideration, revised in BOLD

1.  To a 2-neck 2000 mL RB flask set in an ice bath and containing a stirbar is added 45.5g of methylamine hydrochloride which is then carefully dissolved in the minimum amount of water needed. Stirring is begun, and the amount of water used is recorded.

2.  Add an amount of dry toluene that is 10X the volume of water just used in the above step.  

3.  Slowly add 27g of NaOH using a powder funnel. (1 mol eq compared to the methylamine.hcl used)

4.  Then add additional NaOH in the amount of 8g for every milliliter of water used in Step 1. So for example if it took 50mL water to dissolve the methylamine, 400g dry NaOH would be added.

5.  Then add 27g more NaOH to account for the water formed by the reaction between OH(-) and MeNH3(+) (1 mol eq compared to methylamine.hcl used)

6.  Unclamp the reaction flask, remove the stirbar, stopper the necks, and swirl/shake the contents well to mix thoroughly. Immediately check for and release any pressure buildups. Replace flask in the ice bath, clamp it again, and allow all solids to settle. This must be done several times over the course of 30 minutes.

7.  After the mix has settled, unclamp the flask and decant the (upper) toluene phase into a separatory funnel, taking care not to let any of the lower aqueous phase contaminate it.  If you're like me you will fastidiously finalize the separation using the separatory funnel, avoiding all traces of the aqueous phase with extreme prejudice (this kind of hypervigilant separation is a personal quirk of mine; others may want to simply decant once and/or pour through a fluted filter). Cover or cap the vessel used to temporarily hold the toluene/amine phase to protect it from atmospheric moisture. Pour the aqueous phase into a beaker and set aside, out of the way.

8.  Clean out and dry !!!! the original reaction flask, place the stirbar back into it, and return the toluene/amine phase to it.

9.  Then add 500 ml dry MeOH and 100g ketone, and return it to the ice bath. Reclamp the flask, affix the thermometer, stopper the other neck, and begin medium stirring. Stir for 30 minutes. at least

10.  After 30 minutes, increase the stirring speed so that it's quite vigorous and add, via a number of small portions, 10.4g NaBH4 (or up to [?]g depending on the freshness/staleness of the NaBH4 this is up to you, cant tell you how degraded your borohydride is ). Some frothing will be visible upon the additions (between additions, loosely restopper the neck H2 production does occur due to decomposition of the borohydride without reduction, this HAS to be vented or will shatter your glass!)

NOTE: Judge the amount of the portions and the time between additions by monitoring the temperature. Add the borohydride at a rate which is slow enough to keep the temperature below 10°C. So start by adding say 0.5g once and then watching the temperature. It will rise on addition of the borohydride and will drop back when most of it has reacted or has gone into solution. Adjust the amounts until the sweet spot is found---the rate at which the temperature stays low, but doesn't take all day to add the borohydride. the first few additions may not generate so much heat, but heat is stored in the liquid phase (heat exchange rates and all that, to the physics inclined) and will build up upon subsequent additions, so dont let it fool you.

Whatever color had formed in the imine formation step gradually disappears during the NaBH4 additions to give a white/yellow opaque mixture. Very good stirring continues to be needed here. If you have an overhead stirrer, this is a must for good yields in the larger batches. Otherwise (smaller to medium scale), increase stirring as much as is possible without stirbar instability.


11.  After the addition of the NaBH4 is complete, allow the mix to stir rapidly for two hours at room temperature.  

12.  When the reaction mixture has been stirred for the two hours, an addition funnel is filled with [?] (*see note at end) mL of ~50% W/V acetic acid and attached to the flask. The residual borohydride is then destroyed by cautious dropwise addition of the acid until the gas evolution stops and pH 3 is reached (in other words, when gas evolution begins to visibly diminish, start testing pH). This is done with fume hood and mask, or outdoors with a breeze, as the gases evolved are highly toxic diborane and highly flammable H2. ive never worn a mask when doing this, but i do carry all my reactions in the hood. besides, diborane isnt all that bad. H2 is bad though, since it ignites super easily

NOTE:  When quenching with the acid, a type of goo (borax or something similar) forms which gradually goes mostly back into solution. With larger batches an overhead stirrer is an absolute must, since this goo can be hard on magnetic stirrers.

13.  A distillation apparatus is set up, and the alcohol is then removed by vacuum distillation. When the alcohol has finished coming over, the heat to the setup is turned off and the setup allowed to cool to room temperature. When cooled, the vacuum to the glass is released and the setup is dismantled. I use a rotary evaporator. if you dont own one yet, get one. they can be had on ebay. do not distill the toluene away.

14.  The remaining aqueous/toluene solution is transferred to a separatory funnel, then extracted once with 50 mL DCM to recover any unreacted ketone. The DCM/ketone is appropriately labeled and set aside for future recovery. never tried this trick, dont know how it will work with the toluene that is also left... anyway DCM is known to cause emulsions for newbies, so advocating its use in a writeup is wrong. a better bet would be to use additional toluene in dcm's stead

15.  The aqueous solution is then taken to pH 12 to 13 with 25% NaOH and extracted twice with 50 mL toluene and then once with 75 mL toluene. i would do either 4x50-100ml or the like. the smaller the volume the cleaner is the extraction, and the more times you extract, the more product you get

16.  The toluene extractions are combined and then washed twice with a small portion of distilled water to remove trace NaOH. and then once with brine (this raises the ionic strength of the water, giving better final separation of the water

17.  The toluene/product is then dried with MgSO4 (MgSO4 is slightly acidic. Other drying agents such as Calcium Sulfate, Na Sulfate and the likes are adequate as well. few hours are required for "thorough" drying, however if youve used toluene and choose to distill you oil, during the evaporation of toluene you will dry it as well due to the toluene/water azeotrope filtered, and gassed with dry HCl to form the crude salt (or optionally, salted by one's technique of choice).
I never gas. i always rotovap the solvent away, then distill the oil, dissolve in a dry solvent of choice, and add dry acid of choice to make the salt. Alternatively, I add concentrated hcl  to a methanol solution of the oil, then rotovap all the methanol away and spread the aq./solid salt in a shallow pan to fully evaporate.

18.  The crude salt is collected by filtration, dried of residual toluene, weighed, and then recrystallized with isopropyl and acetone (or by one's preferred solvent pair or method). Ive found water to be a very good recrystallization solvent. also ipa/hexanes works well for me.

19.  Have a cold beer and a fat joint. You've earned it.

Acetic Acid Note : a safe amount would be 1mol eq. with respect to the borohydride added, so at least 17-18g (predilution) of glacial acetic acid as a ball park measure. Depending on the amount of goo you get (amount of borohydride, purity of borohydride) you might need alot more or alot less.

Hope this helps. Report back with results!

Methyl Man

  • Subordinate Wasp
  • ***
  • Posts: 143
Re: Wet NaBH4 reductive amination
« Reply #81 on: May 26, 2011, 11:57:05 PM »
Thank you letters for returning and adding all that. Very helpful stuff.

What sort of threw me for a loop though is your insistence on using a rotovap.  I don't know if cheap ones can be used just as well, but usually good ones are thousands of dollars. Problem for me right now is that even a cheap one would be something I can't really afford for the time being. If you really think it's indispensable to this process, then I may have to shelf my propensity for this process for a while. Not forever, but just on the back burner until a rotovap can be afforded.

No matter what the deal ends up being, I sure appreciate all your input.
There's a methyl to my madness...
==+==+==+==+==+==+==+==+==+==

RoidRage

  • Dominant Queen
  • ****
  • Posts: 386
Re: Wet NaBH4 reductive amination
« Reply #82 on: May 27, 2011, 12:02:44 AM »
Just vacuum distill if you don't have a rotovap ;)

Methyl Man

  • Subordinate Wasp
  • ***
  • Posts: 143
Re: Wet NaBH4 reductive amination
« Reply #83 on: May 27, 2011, 02:50:43 AM »
Well that would sure be the easier way to go for now, RR.

Letters, with regard to your comment on step 10, problem is I don't know either how degraded the NaBH4 is! It's still white in color, is 10 years old, but is clumped hard in the jar from soaking up some moisture I assume sometime during its storage. But it passed the "burn test" (ignited by flame, a knifepoint of it burns with a fierce little white flame as it's supposed to) so that should indicate it's still NaBH4.

To your comment on step 14, you know what, if that might cause problems I'm perfectly willing to skip it. I think it's just something I got from the Strike book anyway. I agree it could be weird extracting a solution that already has toluene in it, with DCM. Also it does even seem strange to extract a solution that already has some toluene in it, with more toluene. In fact, the more I think about it, I'd be afraid I might also extract end product in addition to any ketone. I'm all for reclaiming unreacted ketone, but not if it could cause problems. Moreover, if you never felt compelled to do it doing this same kind of reaction, then hell with it. The whole idea is starting to sound retarded and I don't recall where it even came from.

Regarding the comment on step 17:  HCl gassing is all I've ever done, so that's probably why I wrote it in... it also seems the most direct path to the salt once you have the product f/b in toluene. In the past it always worked great for me, no purity issues whatsoever after a recrystallization. I wasn't back then (nor am I now) willing to go through vac distilling the f/b oil. For me that's a bridge too far.

Just some comments on your comments...
There's a methyl to my madness...
==+==+==+==+==+==+==+==+==+==

akcom

  • Dominant Queen
  • ****
  • Posts: 430
Re: Wet NaBH4 reductive amination
« Reply #84 on: May 27, 2011, 03:23:57 AM »
Thats a very poor way to recover your ketone.  What you should do is acidify the solution with 1M HCl, save the toluene (which now has the ketone).  Basify the aqueous phase and extract with toluene.  This second extraction now has your amine

Shake

  • Dominant Queen
  • ****
  • Posts: 276
Re: Wet NaBH4 reductive amination
« Reply #85 on: May 27, 2011, 04:36:22 PM »
letters can you please repost again but increment each step by 0.2 cheers

letters

  • Subordinate Wasp
  • ***
  • Posts: 138
Re: Wet NaBH4 reductive amination
« Reply #86 on: May 29, 2011, 08:04:32 AM »
@MethylMan : a rotovap is of course not necessary. it just makes lab life that much easier. Buchi rotovaps are super well made, and the old ones, if in good conditions work very well. last year buchi had a competition - whoever owns the oldest working buchi rotovap gets a brand new, top of the line rotovap. some1 with a rotovap from the 60's won iirc! my first rotovap was an old air driven unit, and it worked very well. cost me around 200USD to set it all up, not taking into account the air compressor. now i have a newer digital motorized one, cost me about 600USD to set it up, with a specialty extra long triple coil vertical condenser, but that was a while ago and prices may have gone up a bit. a decent rotovap today from germany can be had for around 400-1000euro, depending on model, and if you are willing to piece it together as opposed to buying a complete unit.
If you dont know how degraded your borohydride is, then do the first smallest batch as stated. record yield. you should yield at least 80%. lower then that, and it may signify that you need more borohydride the next batch (thats the beauty of doing small batches - you get to optimize the process for your reagents). a very good way to know how much borohydride to add is to follow your reaction with TLC (thin layer chromatography). you can easily follow with it the progress of reaction, judging when the imine is fully reduced! tlc plates are indispensable in a lab and help you know whats going on. they arent expensive (can be had on ebay for cheap, less then 100USD for a pack of 50 usually). I do have a few spare packs lying around which im selling for cheap, pm me if you are interested.
regarding the dcm/toluene thing - when you have acidified your reaction mixture, it is all in salt form. ionized amines will not dissolve in toluene (at least not the one you want) so you can feel safe washing your reaction mix with extra toluene.
you can also, before washing, first separate the left over toluene, then extract once or twice and combine all toluene phases to get the left over ketone.
regarding the gassing - like i said, ive never tried it without distilling first. im anal that way. i distill all my amines. this is a product of seeing the chromatograms of the usual drug products without distillation. the profile is usually much more dirty. if you are small time, shouldnt matter much, but if you do large scale, youd like to give the forensic analytical chemists as little info on your sources and route as possible! vacuum distillation is really easy, i dont know why people are refraining from it. just get a decent pump (doesnt even have to be an oil pump, there are diaphragm pumps today that can pull 3-5mbar), a vigreux if you still dont have one and a cow-type receiver. that is all thats really needed for simple distillations. you could ofcourse go all fancy and get yourself a variable reflux head. with those f/b purities of 95% and above are possible if done right.

@shake : what you mean? same procedure but 20% more on the quantities? thats asking too much. just do the math yourself, its not hard. you should read up on mol quantities, install chemdraw, and then youd be able to rescale reactions to your liking.

letters

  • Subordinate Wasp
  • ***
  • Posts: 138
Re: Wet NaBH4 reductive amination
« Reply #87 on: May 29, 2011, 02:34:23 PM »
lol, a sponge in the sahara will shrivel up into a powder and get blown with the winds.
im helping methylman out since i have respect to the early bees.
what you need help with?

letters

  • Subordinate Wasp
  • ***
  • Posts: 138
Re: Wet NaBH4 reductive amination
« Reply #88 on: May 29, 2011, 08:59:27 PM »
i need an ICP!

thescientist3000

  • Pupae
  • **
  • Posts: 50
Re: Wet NaBH4 reductive amination
« Reply #89 on: May 14, 2013, 06:25:14 AM »
Ferret it looking forward to how this turned out for MethylMan.

Ferret is also a al/hg girl, so going to something that scales easier and isnt as exothermic would be a nice present.

jon

  • Foundress Queen
  • *****
  • Posts: 1,883
Re: Wet NaBH4 reductive amination
« Reply #90 on: May 14, 2013, 02:49:01 PM »
yields are about 60 % you can get examples on sciencemadness