05-14-01 22:43
No 194369
There seems to be a considerable amount of controversy regarding the reaction time and conditions for the Sodium cyanoborohydride (SCBH) + ammonium acetate (AA) reaction.
First regarding pH control. When using SCBH in reductive amination, the pH must be maintained in the range of 6-8. When one adds the not-ketone and AA and silica gel (7-10x molar excess) the pH of the system is around 8-8.5 even before addition of SCBH. This is already too high.
The solution for this is to use Glacial acetic acid (GAA) in sufficient amounts to bring the pH down to approx. 7. This has two advantages: firstly the acid helps to catalyse immine formation and of course it maintains the pH in a range that is favourable only for immine reduction. And since the AA and GAA form a weak buffer, the pH will remain somewhat stable even after addition of the SCBH (which usually causes the pH to rise as the reaction progresses).
I also believe that one should allow the AA + ketone + Silica + GAA to pre-stir for at least 3 hours, preferrably 4-5. This allows enough imine formation and water uptake to reduce the amount of ketone in the mix (thus reducing the amount of ketone that could be reduced).
As to the overall reaction time, I believe that some people on the hive have suggested that anything in excess of 30 hours will lead to reduction of the amine to an alcohol. This is not true (nor really possible with SCBH). I think the source of this confusion arrises from the fact that most of these people do not use pH control and in the absence of this some of the starting ketone will be reduced to alcohol (and consequently the longer the reaction is allowed to progress, the higher the apparent amount of reduced alcohol by-product). It is not the formed amine that is reduced as SCBH is not capable of this reduction.
Since the MDA immine is not as stable and fast forming as the MDMA immine, this reaction does require longer reduction time. with proper pH control and enough silica gel to adsorb all the formed water, I believe that higher that 80+ % yields can be achieved.
Any thoughts on this?
(Hive Bee)
05-18-01 06:45
No 195287
My grandmother has pumped out quite a few of these with not more than 50-60% yield, which she's sure is fairly average for anyone who has attempted this reaction.
Most of these ideas are def worth trying, but my grandma was wondering why none of the more experienced bee's commented on these ideas? Some feedback on this would be great reading.
peace.
If some of us were not so far ahead, the rest of you would not be so far behind!
(Hive Bee)
05-18-01 08:00
No 195302
I agree DEE man! Strikes method in TSII reports around 90% yeild but there is no mention of pH control or the addition of silica, and now I wonder if there are more appropriate reaction times- Experienced bees please give us some input!
(Newbee)
05-18-01 19:54
No 195428
pH control in the cyano reaction is neccessary because the pH of the system affects the reduction properties of the cyano. too low or too high and the rate of ketone reducton increases dramatically (unfavourable.) I'm not sure that this would apply to Al-Hg.
(Hive Bee)
05-30-02 23:10
No 316053
So is the ph control with GAA done only at the begining (before the cyano is added)? Or should the ph be checked periodically too? (at what intervals)
Does any bee know for a fact (from experience) that ph control between 6 and 8 will improve yield?
(Hive Bee)
05-31-02 02:29
No 316126
Since SWIM is such a nice person, theyll do it as you ask tomorrow. And report the findings in 3 to 4 days. SWIM has been wanting to tr the improvements anyway. Befor never checked ph at all and always had good yields. Just tell swim what PH? 7 right? And SWIM always lets sit 48-72 hours.
So SWIM will add silica gel and adjust PH with gaa. any thing else? SWIM aint got shit to do anyway.
I think i like it!
(Hive Bee)
05-31-02 21:42
No 316383
Sorry guy SWIM ran out of stock of NaCNBH. So itll have to wait until early next week. But SWIM will do it and do a write up.
I think i like it!
(Hive Bee)
06-03-02 20:48
No 317219
hsark - thats great. The only other thing swim can think of it to know what pressure the rxn spins under.
Swim assumes that keeping it under more pressure (5-10 psi has been mentioned)would be better to keep the ammonia gas in the solution.
oh and hsark, please also put the amounts of methanol, cyano, etc used (for ratio comparison to swims) and apparatus used when you get around to it
. thanks.
(Hive Bee)
06-04-02 07:02
No 317388
In a 6L flask is placed 1.5L methanol, 200g MD-P2P,920g ammonium acetate and pre stirred 1 hour. 500ml more methanol and 73g NaCNBH mixed together are then added to first mix. Then stirred rappidly for 72 hours. As you might have read in SWIMs other post the acid wasnt extracted in the A/B. But it will be for this run. SWIM isnt sure about the pressure yet. But if SWIM can find a suitable fitting for the flask it will be attempted also. Thanks for the input on pressure. SWIM when done will try to do a write-up worth the hives space.
I think i like it!
(Hive Bee)
06-04-02 07:56
No 317407
hsark, what yield would that get on a good day? For a baseline b4 the pressure and GAA?
72 hours - swim may try longer - he's never done more than 40
Swim has shiny new 1/2 hp overhead stirrer (lab-grade not converted drill etc)- and hopes super extra stirring will bring down rxn time needed? What do you think? (it will create a 6 inch wide vortex at the bottom into 20 liters easy)
you wrote: (hsark)
"As you might have read in SWIMs other post the acid wasnt extracted in the A/B."
Which acid? Swim confused?
Hsark, ever done scale up of this one? did yields go way down like swims?
On this scale(73 cyano, 200 md) swim got plus %50, with bigger (200 cyano, 600 md) never more than 30-35% (someday maybe with help he will get better)
(Hive Bee)
06-04-02 10:39
No 317442
After 72 hours and distillation of methanol it was recommended to acid wash the MDA/MDP2P product to destroy the CN and then seperate the MDP2P with DCM. SWIM was not collecting the MDP2P. Just going straight to basification then removing the MDA freebase with DCM. On 3 setups with a total yield of 380g,chemputer says its a 52.03% yield. these were done in seperate 6L flasks. After SWIM will try a bigger scale up. but this seems to work real well. maybe when you scale up the ph is more of a concern. Might be worth checking. Maybe SWIMs next project.
I think i like it!