Argox
(Hive Bee)
01-30-02 23:33
No 263099
      Whew! 93.7% yield from ketone
(Rated as: excellent)
 Bookmark   

Whew!

SWIA is breathing a huge sigh of relief.  He panicked too soon.   This story has a happy ending.

Final results:  1.0x  of ketone yielded 1.0166x  of distilled  base, a 93.7% yield.

The reason SWIA was worried was because the freebase didnt look right.  Turns out it was super clean.   Yield of base was high and very nice appearance of hydrochloride.  And no brown tar after base distillation.  One rinse with hot water and the RB flask was clean.  That, in and of itself, was fucking amazing. 

Oh, and the aliquot that did not crystallize and which made him come to me in a panic and ask Hive for help?--it was SWIAs mistake, not enough acid addition (he used quick salt and sulfuric method to make direct addition acid and save time on glassware setting up--his mistake--lots of bubbles, but little acid--he vows only to use my tried and true method, as posted on Rhodiums page.   Anyway, after adding more acid, left overnight in freezer, and voila-- aliquot of 1x  grams of base yielded 1.145x grams hydrochloride, a 96.5% conversion.  The remainder can be recovered from acetone/IPA as base (there is always residual product that can be recovered from acetone). 

Since neither SWIA nor I do anything harder these days than a cup of tea, a sample given to a buddy was confirmed to be the desired compound, yes sir! 

Why was base different this time?  Why so clean?

Two main things were done differently from LaBTops writeup of reductive amination.

1.  No dessicant was added to remove water before, during, or after imine formation.   -15C ketone was slowly dripped into equally cold MeOH/ MeNH2 solution and allowed to stir without cooling for 3 hours,  temp never went beyond 5C.  (Literature suggests that keeping the solution below the boiling point of primary amine increases formation of imine-- who knows?, maybe theres something to it.) Cooling was applied to the reactor and NaBH4 was added every time temp came down to 9C and temp never increased beyond 15C.   This took 4 hours.  Contents allowed to react for 35 hours at 15C with stirring after last borohydride addition.  Contents remained greenish, yellow lemonade color, not brown.  Molar ratio ketone : MeNH2 : NaBH4 was 1: 1.2: 0.47.  MeOH was three times weight of ketone.

2.  MeOH was distilled off prior to water addition.  I believe this to be an important factor in high yield of base, because base is soluble in MeOH and IMHO some base will always stay in solution no matter how much water is added.  Besides--distilling MeOH while playing poker on the computer is a hell of lot easier than manipulating lots of stinking water/MeNH2/MeOH/NaOH/base solution and separating the desired product from the rest of the solution.  A whole lot easier.  Plus it is my opinion that valuable product is thrown away as long as MeOH is present in the wash water.   And the amount of NaOH that must be added when flooding the reaction contents with MeOH present may affect the product and cause some of the polymerization that seems to cause the residual tar upon distillation.  SWIA has always flooded the reaction contents, then last time he partially distilled MeOH and found that yield improved.  This time, removing absolutely all MeOH, yield is approaching quantitative.   After MeOH is removed, then base is washed with a reasonable amount of water, then NaOH, DCM added.  The volume of water is reduced by a tenth and NaOH becomes almost insignificant compared to how much must be used when MeOH is present.  I have read the debate as to which is easier: removing MeOH first, or flooding reaction contents with a large volume of water.  I vote for removing MeOH first.  Besides being easier, the yield is higher.

Remaining contents washed with water twice and separated.  Wash water treated with very little NaOH and normal amount of DCM for the volume of water.  The DCM/base was distilled apart from main batch.  The main batch of base was distilled, and you should have seen SWIA sweating bullets, because it came over crystal clear, like water, not yellowish, as has been his experience when doing A/B workup, a la LaBTop.  Base came over at 103C at stillhead.  (Decent vacuum.)  He thought something was wrong, but what a surprise when sample crystallized.  Beautiful white crystals.  Almost stoichiometric conversion of base to hydrochloride, with the difference to be recovered, as usual, from mother and wash liquors. 

Thanks go PolySam and terbium for calming posts.  terbium is right, as always--this is a reaction thats hard to screw up.  And this ketone is one tough molecule--still good after 9 months and room temp storage.

Sorry for the panic.  I thank the Hive mavens (LaBTop, terbium, PolySam, etc) for responding to my post.  Im sure most of you have gone through the same thing when something doesnt look right.  Especially when stakes are high.  I guess its human nature to doubt, thinking something must have gone wrong, when if we would just wait, have patience and confidence in ourselves, take it step by step, and reserve judgment until the job is over, we might be surprised at the positive results.

What a shame to have recently sworn off booze and coke:  now would be a perfect time to pop a magnum of Dom Perignon and celebrate.  Oh well, somebody, somewhere, have a drink in my name.


Regards
Argox

Disclaimer:  No quantities are given or implied by anything here.  I am relating a story told to me by SWIA about how he experimented with synthesizing a small amount of a commonly available substance for personal use.   In this country, minimal amounts for personal use are tolerated.     

 
 
 
 
    Rhodium
(Chief Bee)
01-31-02 00:16
No 263107
      Re: Whew! 93.7% yield from ketone  Bookmark   

Wow. Cool. I really should get that NaBH4 reductive amination document going soon...
 
 
 
 
    LaBTop
(Daddy)
02-01-02 13:10
No 263926
      Re: Whew! 93.7% yield from ketone  Bookmark   

That's all the fuckin replies he gets? ? ?

Ok, lemme try to imagine :
Here we stand at nightfall, at the beach of a small tropical island, kneedeep in a wirlpool filled with ketone, boro, methylamine and methanol, and trying to imagine how to distillate off all that fuckin MeOH.
AHH, forget it, dump in that water, tap or suck off that raw freebase and also forget all that A/B washing stuff, because we are going to distillate off that raw stuff, and get the same beautifull clear pure freebase as when you should have tried to boil off all that methanol first.

Much easier because now we can use the wirlpool this evening under the full moon again, after the butler has cleaned it thoroughly with 10 boxes of washing powder. smile

It's ofcourse much better to distillate off that methanol first in small to medium batches. You got your methanol back, and don't have those amounts of wastewater to care about.

Don't even think about it at real scale, there, time which can be won, can be the difference between time spend in jail, or not.

We've seen here a born researcher, who reads and reads until he understands what he read and definitely loves his job. Someone who's not only in it for the money, what a relief.
WELL DONE ! LT/laugh

WISDOMwillWIN
 
 
 
 
    Vibrating_Lights
(Hive Bee)
02-01-02 19:14
No 264072
      Re: Whew! 93.7% yield from ketone  Bookmark   

If swim only had some boro.
 
 
 
 
    psychokitty
(Her Majesty, Stoni's Kitty)
02-01-02 23:36
No 264141
      Re: Whew! 93.7% yield from ketone  Bookmark   

You distilled off the methanol at atmospheric or reduced pressure distillation?  Seems to me either way a stinky process.  Also, did you need to neutralize the excess boro once the reaction was complete or was it simply a matter of going straight to the distillation once the 36 hours or so ended?

More information please for the hopeful but naturally skeptical.
 
 
 
 
    mushhead
(Stranger)
02-01-02 23:46
No 264142
      Re: Whew! 93.7% yield from ketone  Bookmark   

I know this probably belongs in the Acquisition forum, but I've seen NaBH4 being sold (in small amounts) for use in hydrogen fuel cells.  I'm sure one could fairly easily social engineer larger amounts if necessary.
 
 
 
 
    sYnThOmAtIc
(Hive Bee)
02-02-02 00:26
No 264147
      Re: Whew! 93.7% yield from ketone  Bookmark   

Yea I hear you on that one, I keep pointing that out lately too but nobody cares to comment about it. Guess you'll just have to set up enough phony addresses to get enogh those lil 10g bottles that you'll need!
 
 
 
 
    sunlight
(Pioneer Researcher)
02-02-02 06:54
No 264192
      Re: Whew! 93.7% yield from ketone  Bookmark   

We use to distill the methanol with the aspirator, mixing it with the water that will use in the extration (it seems that evaporation is less violent). We've never got a 93.7 %, but 87-91 % is a very consistent yield in our experience, just like Sir LabTop told us...
 
 
 
 
    RoundBottom
(Hive Bee)
02-02-02 12:10
No 264280
      Re: Whew! 93.7% yield from ketone  Bookmark   

SWIM has seen 500g NaBH4 for $200USD... but how to get it.

i learned a thing or two from charlie dontcha know.
 
 
 
 
    sYnThOmAtIc
(Hive Bee)
02-04-02 11:40
No 265123
      Chrysler rules!  Bookmark   

http://slashdot.org/articles/01/12/12/2227205.shtml
Boy I can't wait to see this day. I'll be consuming more fuel than the car..ehhehe
 
 
 
 
    Argox
(Hive Bee)
02-04-02 15:56
No 265211
      Re: Whew! 93.7% yield from ketone  Bookmark   

Hey LabTop, buddy,

Thx for recognition of a lot of research over last year.  You might remember the dumb questions that you had patience to answer. 'preciate it.  Experience is always the best teacher.

LT--I know you think big, but I assure you that boiling off MeOh can be done on REAL scale, just a matter of equipment, and results are better than just flooding initial product.  Like I said in post, no amounts are given or implied, just theoretical research, right?

As for smell, sure, do I sound stupid?  After condenser and receiver comes a hose attached to vacuum takeoff and immersed in a flask full of water.  MeNH2 smell is eliminated that way.  (SWIA thought he would be recovering/collecting MeNH2 this way, but that doesn't happen. Weight of water stays the same.  Just smell is eliminated.)  Now the MeOH that comes over in receiver has water and stinks to high heaven, but hey! nothing a little dessicant and a hermetically sealed container won't solve, and when you consider how many tragic cases can be found of guys getting their plans suddenly interrupted by WOD for MeOH purchase, recovery and reuse seems like good idea, of course not where SWIA lives where it's readily available, but for other places less amenable this seems like a must. 

Initial boiling is atmospheric.  MeOH starts to boil off at its normal bp of 65C and then slowly increases to 100C as water content increases.  MeOH forms azeotrope with H2O, the Merck has the bp of various concentrations MeOH/H2O, bees can look it up, but to give an idea: 20% boils at 88C, 10% MeOH boils at 93C.  Once it hits 100C, SWIA connects the aspirator and take off a little water vapor, not much, 'cause SWIA adds water/NaOH to it anyway later to wash out boro and more water to wash out NaOH, anyway this brief aspiration assures all MeOH is out.  Works like a charm and NO FUCKING EFFORT at all--not like dicking around with LOTS of stinking water/MeOH/MeNH2/boro.  SWIA sort of resents the sceptics, I know this guy pretty well and he doesn't make things up.  Results given are actual results--not one-tenth of a percent exaggeration--in fact, he has an idea on how to improve over 93.7%, will update if it works.  I write down what he tells me and pass it on to Hive, out of sense of obligation as repayment for advice/info Hive has provided.  If somebody can use SWIA's info and improve his/her yield, then great.  It's a big world, his little corner is unaffected by any knowledge that might be passed on and used to profit of other bees.

And LT, good to hear from you, buddy!  You are still the King. (Oh yeah, can't forget terbium.  OK, two Kings.)

Regards
Argox  
 
 
 
 
    Goodtimes
(Hive Addict)
02-05-02 21:20
No 265768
      Re: Whew! 93.7% yield from ketone  Bookmark   

Nice job Argox, but yea... hard substance to get compared to other methods.. 

Bee safe

"The gods are too fond of a joke."  (Aristotle)

 
 
 
 
    PolytheneSam
(Master Searcher)
03-09-02 13:00
No 279678
      Re: Whew! 93.7% yield from ketone
(Rated as: good read)
 Bookmark   

I didn't find this patent number when I did a search.
Patent US3689504
I posted a few like it before.

http://www.geocities.com/dritte123/PSPF.html
 
 
 
 
    LaBTop
(Daddy)
03-09-02 19:14
No 279897
      Re: Whew! 93.7% yield from ketone
(Rated as: good read)
 Bookmark   

Sam, that's fuckin HIGHLY interesting, it's a combination of my method and the method from that German researcher I posted in my first OnePot thread a few years ago, where he/she also refluxed to get MDEA, but got only 28% yield with it. It triggered my interest in the method, and lead to the cooling instead of refluxing.


EXAMPLE 1

p-Chloro-N-(cyclopropylmethyl)-.alpha.-methyl-phenethylamine

To 600 ml. of benzene is added 50.0 grams of p-chlorophenyl-acetone and 22.8 grams of cyclopropylmethylamine. The mixture is heated to reflux employing a Dean-Stark water separator and refluxed until no more water separates. The reaction mixture is then concentrated and the crude ketimine isolated.This is the imine forming, done totally different as me, but IT WORKS ALSO! The crude ketimine is dissolved in 600 ml. methanol and the solution is cooled in an ice bath. To this cooled solution is added 22.4 grams of sodium borohydride portionwise with stirring, Exactly the same as me! and the reaction mixture is refluxed for 4 hours. This is NEW and much faster then 36 hrs waiting! The solution is concentrated and 400 ml. of water is added.Same as me, except the concentrating, that's Sunlights and Argox way!

The mixture is rendered alkaline with 60 ml. of 45 percent aqueous potassium hydroxide and 60 grams potassium hydroxide pellets and the resulting oily mixture is extracted three times with ether. The combined ether solutions are washed once with water and dried over anhydrous magnesium sulfate. The solution is then filtered, concentrated and distilled yielding 47.3 grams of p-chloro-N-(cyclopropylmethyl)-.alpha.-methyl-phenethylamine having a boiling point of 107.5 DEG-109 DEG C, at 1.3 mm, nD@25 1.5233.

The acid-addition salts of these compounds are prepared by dissolving the base obtained in accordance with the procedure outlined above, in anhydrous ether and adding the acid corresponding to the salt desired. For example, the hydrochloride salt of the compound prepared according to Example 1 is prepared by dissolving the 47.3 grams of p-chloro-N-(cyclopropylmethyl)-.alpha.-methyl-phenethylamine in 700 ml. of anhydrous ether and the mixture is cooled in an ice bath. To this solution is added ethereal hydrochloric acid dropwise with stirring precipitating the hydrochloride salt out of solution. The acid is added until no more precipitate forms. In like manner, other acid-addition salts may be prepared such as the phosphate, sulfate, fumerate and oxalate, among others.

The procedure of Example 1 may be followed to prepare other phenethylamine derivatives by reacting the appropriately substituted phenylacetone with the desired amine derivative and reducing the product of this reaction to yield the desired compound. Following below in Table 1 is a list of compounds prepared in accordance with this invention showing the respective definitions of R, R1, R2, R3, R4 and X, with reference to Formula I, and the identifying physical constants. ##SPC2## ##SPC3## ##SPC4## ##SPC5##

The compounds of Examples 37 through 40 are prepared according to the method of Example 1 by substituting the correspondingly substituted phenylacetone as the starting material. For example, to prepare the compound of Example 37, the para-chlorophenylacetone is replaced with 3,4-methylene dioxy phenylacetone




[b]So Sam, can you, or anybody else, post the whole Example 37 procedure here, I'm VERY VERY curious about that one! Thanks for finding this.


I'm hoping that this could work for the MDA boro/ammonium acetate one pot, the only problem will be that the NH3 gas formed will be escaping the reflux column, but this could be mastered by a special reflux column with a fine screen in the bottom, and then filled up with chunks of dry ice !!! That way the NH3 can't escape. You could also slowly bubble small amounts of extra NH3 gas into the imine forming step, thus keeping NH3 gas, and ammonium ions as concentrated as can be. LT/


WISDOMwillWIN
 
 
 
 
    Rhodium
(Chief Bee)
03-09-02 19:52
No 279916
      Re: Whew! 93.7% yield from ketone  Bookmark   

There is no experimental procedure other than in example 1, the rest is just a list of different compounds and their mp/bp. Compound #37 is N-(cyclopropylmethyl)-MDA, and #40 is N-cyclopropyl-MDA.

However, a very interesting patent, Sam!
 
 
 
 
    LaBTop
(Daddy)
03-09-02 20:42
No 279934
      Re: Whew! 93.7% yield from ketone  Bookmark   

Especially the way they form the imine is worth testing for our ketones and amines, to see if they stand the heating at benzene reflux.
And the very short 4 hr reflux after cooled boro addition, what a gain in time! LT/

WISDOMwillWIN
 
 
 
 
    Argox
(Hive Bee)
03-09-02 21:02
No 279944
      Re: Whew! 93.7% yield from ketone  Bookmark   

L/T

Dean-Stark trap wouldn't work with straight MeOH to separate water.  Do we have practical knowledge of which other solvents are compatible with our ketone? (Ethanol + benzene would separate water)  Also, MeNH2(g) has to dissolve in the other solvent, right?  For clandestine chemists where conditions are not 100% methanol is bad enough to have to work with, but benzene?  My liver is already faxing me death threats.  Benzene would be the straw that breaks the camel's back.

And why is water removal so important during imine formation?  Nothing seems to happen to PMK-->mdma without removing water.

Results of lower limit test of boro and MeNH2 due in a few hours.

Edit--2 ideas

1.  I am convinced that slightly higher yield obtained from concentrating solution(the Sunlight--Argox way) as opposed to flooding it with water(the L/T way) is due to additional reduction activity during heating of solution.  This would tend to validate the idea of a 4 hour reflux for reduction phase.
wrong--on second thought, the reason yield is higher is that MeOH is removed before water wash, any MeOH present will draw some aminated base into solution with water, so best to remove it completely before washing.  Reduction is probably as efficient at 10C for 35 hours as b.p. solvent for 4 hours.

2.  I read somewhere that imine formation is increased when solution temperature is less than b.p. of primary amine, which would be minus 6 for methylamine, right?  So maybe we should try Lauda chiller/circulator or dry ice/solvent cooling bath instead of ice water.  A tweak here and a tweak there and pretty soon we'll be at 99+% yield in 8 hours instead of current 93% in 2.5 days.  (now if we could just get 90+% safrole to PMK in reduced time)   
 
 
 
 
    cheeseboy
(cheese head)
03-10-02 00:51
No 280018
      Re: Whew! 93.7% yield from ketone  Bookmark   

For a minute I thought that the futuristic car engine would be run on Nitromethane, NaBH4, crazy shit  sYnTho!!

Cheeseboy-a whiteboy with Soul Like a black guy without soul
May The Source Bee With You Always.
 
 
 
 
    TranceMe
(Hive Bee)
03-10-02 02:12
No 280038
      Re: Whew! 93.7% yield from ketone  Bookmark   


SWIM has seen 500g NaBH4 for $200USD... but how to get it.



Lucky you!! Here's $150/100g, BUT OTOH, it's 100% OTC :)


Chemically enhanced.
 
 
 
 
    PolytheneSam
(Master Searcher)
03-10-02 19:57
No 280396
      Re: Whew! 93.7% yield from ketone  Bookmark   

US patent 3689504 was listed here for a long time.
http://www.geocities.com/dritte123/phenpat.html
I just recently found something in my notes about the use of sodium borohydride in that patent.

http://www.geocities.com/dritte123/PSPF.html
 
 
 
 
    LaBTop
(Daddy)
03-10-02 22:32
No 280491
      Re: Whew! 93.7% yield from ketone  Bookmark   

Sam, that's related to the fact that when posts disappear over the Event Horizon of the first Forum main page, the chance that it will be found by us is very low, because we are so terribly overloaded with reading all the other more or less useless posts, that we lately miss a lot of the usefull ones.
All Administrators and Moderators have to deal lately with such an increase in posting that it's becoming physically impossible to read all posts anymore.
We deeply regret that, because curiosity is what drives us all, sadly there are only 24 hours per day available, minus the resting hours.
If you have a solution for this problem, please address it to me, or any other moderator. LT/

PS: don't try to feed us Meth, we don't want to become junkies.wink

WISDOMwillWIN
 
 
 
 
    PolytheneSam
(Master Searcher)
03-11-02 07:59
No 280670
      Re: Whew! 93.7% yield from ketone  Bookmark   

There is a link to that page on this page.
http://www.geocities.com/dritte123/PSPF.html


http://www.geocities.com/dritte123/PSPF.html
 
 
 
 
    alchemy_bee
(Hive Bee)
04-25-02 17:08
No 301407
      Amine vs water  Bookmark   

For applications like reductive amination of mdp2p with NaBH3, what effect does H2O have on the mdma amine?

Can a bee be visa vis its entity when half a bee philosophically must ipso facto half not be?